Methods Of Treating Mixed Dyslipidemia

  *US09855237B2*
  US009855237B2                                 
(12)United States Patent(10)Patent No.: US 9,855,237 B2
  et al. (45) Date of Patent:*Jan.  2, 2018

(54)Methods of treating mixed dyslipidemia 
    
(75)Inventor: Amarin Pharmaceuticals Ireland Limited,  Dublin (IE) 
(73)Assignee:Amarin Pharmaceuticals Ireland Limited,  Dublin (IE), Type: Foreign Company 
(*)Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. 
  This patent is subject to a terminal disclaimer. 
(21)Appl. No.: 14/704,329 
(22)Filed: May  5, 2015 
(65)Prior Publication Data 
 US 2015/0231102 A1 Aug.  20, 2015 
 Related U.S. Patent Documents 
(63) .
Continuation of application No. 14/175,602, filed on Feb.  7, 2014, now Pat. No. 9,056,088 , which is a continuation of application No. 13/898,447, filed on May  20, 2013, now Pat. No. 8,691,871 , which is a continuation of application No. 13/540,319, filed on Jul.  2, 2012, now Pat. No. 8,618,166 , which is a continuation of application No. 13/417,899, filed on Mar.  12, 2012, now Pat. No. 8,563,608 , which is a continuation of application No. 13/266,085 .
 
(60)Provisional application No. 61/173,759, filed on Apr.  29, 2009.
 
Jan.  1, 2013 A 61 K 31 202 F I Jan.  2, 2018 US B H C Jan.  1, 2013 A 61 K 31 232 L I Jan.  2, 2018 US B H C Jan.  1, 2013 A 61 K 45 06 L I Jan.  2, 2018 US B H C Jan.  1, 2013 A 61 K 47 22 L I Jan.  2, 2018 US B H C Jan.  1, 2013 A 61 K 47 26 L I Jan.  2, 2018 US B H C Jan.  1, 2013 A 61 K 47 34 L I Jan.  2, 2018 US B H C Jan.  1, 2013 A 61 K 31 74 L A Jan.  2, 2018 US B H C
(51)Int. Cl. A61K 031/20 (20060101); A61K 031/202 (20060101); A61K 031/232 (20060101); A61K 045/06 (20060101); A61K 047/26 (20060101); A61K 047/34 (20170101); A61K 047/22 (20060101); A61K 031/74 (20060101)
(58)Field of Search  514/558, 559, 560

 
(56)References Cited
 
 U.S. PATENT DOCUMENTS
 4,377,526  A  3/1983    Fujita et al.     
 4,526,902  A  7/1985    Rubin     
 4,920,098  A  4/1990    Cotter et al.     
 4,935,243  A  6/1990    Borkan et al.     
 5,013,443  A  5/1991    Higashidate et al.     
 5,116,871  A  5/1992    Horrobin et al.     
 5,178,873  A  1/1993    Horrobin et al.     
 5,198,468  A  3/1993    Horrobin     
 5,215,630  A  6/1993    Hata et al.     
 5,252,333  A  10/1993    Horrobin     
 5,343,389  A  8/1994    Otvos     
 5,457,130  A  10/1995    Tisdale et al.     
 5,502,077  A  3/1996    Breivik et al.     
 5,567,730  A  10/1996    Miyashita et al.     
 5,589,508  A  12/1996    Schlotzer et al.     
 5,603,959  A  2/1997    Horrobin et al.     
 5,618,558  A  4/1997    Horrobin et al.     
 5,656,667  A  8/1997    Breivik et al.     
 5,698,594  A  12/1997    Breivik et al.     
 5,760,081  A  6/1998    Leaf et al.     
 5,776,978  A  7/1998    Bruzzese     
 5,792,795  A  8/1998    Buser et al.     
 5,837,731  A  11/1998    Vaddadi     
 5,840,944  A  11/1998    Furihata et al.     
 5,886,037  A  3/1999    Klor et al.     
 5,888,541  A  3/1999    Horrobin et al.     
 5,948,818  A  9/1999    Buser et al.     
 6,025,008  A  2/2000    Akahoshi     
 6,069,168  A  5/2000    Horrobin et al.     
 6,193,999  B1  2/2001    Gennadios     
 6,284,268  B1  9/2001    Mishra et al.     
 6,313,330  B1  11/2001    Kiyohara et al.     
 6,326,031  B1  12/2001    Hsia et al.     
 6,326,355  B1  12/2001    Abbruzzese et al.     
 6,331,568  B1  12/2001    Horrobin     
 6,368,621  B1  4/2002    Engel et al.     
 6,384,077  B1  5/2002    Peet     
 6,479,544  B1  11/2002    Horrobin     
 6,531,150  B1  3/2003    Sunohara et al.     
 6,555,700  B1  4/2003    Horrobin et al.     
 6,620,821  B2  9/2003    Robl     
 6,689,812  B2  2/2004    Peet     
 6,846,942  B2  1/2005    Rubin     
 7,022,713  B2  4/2006    Aoki et al.     
 7,112,609  B2  9/2006    Hermelin et al.     
 7,119,118  B2  10/2006    Peet     
 7,498,359  B2  3/2009    Yokoyama et al.     
 7,511,131  B2  3/2009    Crooke et al.     
 7,598,227  B2  10/2009    Crooke et al.     
 7,776,881  B2  8/2010    Aoki et al.     
 8,188,146  B2  5/2012    Peet et al.     
 8,293,727  B2  10/2012    Manku et al.     
 8,293,728  B2  10/2012    Manku et al.     
 8,298,554  B2  10/2012    Manku     
 8,314,086  B2  11/2012    Manku et al.     
 8,318,715  B2  11/2012    Manku et al.     
 8,324,195  B2  12/2012    Manku et al.     
 8,357,677  B1  1/2013    Manku et al.     
 8,367,652  B2  2/2013    Manku et al.     
 8,377,920  B2  2/2013    Manku et al.     
 8,431,560  B1  4/2013    Manku et al.     
 8,440,650  B1  5/2013    Manku et al.     
 8,518,929  B2  8/2013    Manku et al.     
 8,524,698  B2  9/2013    Manku et al.     
 8,546,372  B2  10/2013    Manku et al.     
 8,551,521  B2  10/2013    Manku et al.     
 8,563,608  B2  10/2013    Manku et al.     
 8,617,593  B2  12/2013    Manku et al.     
 8,617,594  B2  12/2013    Manku et al.     
 8,618,168  B2  12/2013    Fujii et al.     
 8,623,406  B2  1/2014    Manku et al.     
 8,642,077  B2  2/2014    Manku et al.     
 8,669,245  B2  3/2014    Osterloh et al.     
 8,680,144  B2  3/2014    Osterloh et al.     
 8,691,871  B2  4/2014    Osterloh et al.     
 8,703,185  B2  4/2014    Manku et al.     
 8,709,475  B2  4/2014    Manku et al.     
 8,906,964  B2  12/2014    Bobotas et al.     
 9,006,285  B2  4/2015    Ohnishi     
 9,056,088  B2*6/2015    Osterloh     
 9,060,981  B2  6/2015    Sato et al.     
 9,452,150  B2  9/2016    Ueshima et al.     
 2001//0035125  A1  11/2001    Talieh et al.     
 2002//0016312  A1  2/2002    Seed et al.     
 2002//0025983  A1  2/2002    Horrobin     
 2002//0035125  A1  3/2002    Shear     
 2002//0055529  A1  5/2002    Bisgaier et al.     
 2002//0055539  A1  5/2002    Bockow et al.     
 2002//0077361  A1  6/2002    Peet et al.     
 2002//0183389  A1  12/2002    Peet     
 2002//0193439  A1  12/2002    Peet et al.     
 2002//0198177  A1  12/2002    Horrobin et al.     
 2003//0100610  A1  5/2003    Shibuya     
 2003//0104048  A1  6/2003    Patel et al.     
 2003//0161918  A1  8/2003    Kendrick et al.     
 2003//0166614  A1  9/2003    Harrison     
 2003//0232385  A1  12/2003    Breit et al.     
 2004//0009208  A1  1/2004    Edson     
 2004//0048919  A1  3/2004    Dreon et al.     
 2004//0062847  A1  4/2004    Koiki et al.     
 2004//0077723  A1  4/2004    Granata     
 2004//0106591  A1  6/2004    Pacioretty et al.     
 2004//0121000  A1  6/2004    Bowe et al.     
 2004//0162348  A1  8/2004    Peet et al.     
 2004//0204356  A1  10/2004    Guenzler-Pukall     
 2005//0042214  A1  2/2005    Gershwin et al.     
 2005//0137253  A1  6/2005    Phinney et al.     
 2005//0147665  A1  7/2005    Horrobin et al.     
 2005//0187292  A1  8/2005    Aoki et al.     
 2005//0244367  A1  11/2005    Hui et al.     
 2005//0272095  A1  12/2005    Wang     
 2006//0034815  A1  2/2006    Guzman et al.     
 2006//0051418  A1  3/2006    Cowen et al.     
 2006//0088502  A1  4/2006    Sata et al.     
 2006//0111437  A1  5/2006    Aoki et al.     
 2006//0134178  A1  6/2006    Doisaki et al.     
 2006//0135607  A1  6/2006    Kobayashi et al.     
 2006//0135610  A1  6/2006    Bortz et al.     
 2006//0141022  A1  6/2006    Kawamura et al.     
 2006//0142390  A1  6/2006    Manku et al.     
 2006//0172012  A1  8/2006    Finley et al.     
 2006//0189682  A1  8/2006    Payne et al.     
 2006//0211749  A1  9/2006    Bobotas et al.     
 2006//0211761  A1  9/2006    Kumar et al.     
 2006//0211762  A1  9/2006    Rongen     
 2006//0211763  A1  9/2006    Fawzy et al.     
 2006//0217356  A1  9/2006    Wright et al.     
 2006//0252833  A1  11/2006    Peet et al.     
 2007//0021504  A1  1/2007    Yokoyama et al.     
 2007//0060532  A1  3/2007    Junien et al.     
 2007//0098787  A1  5/2007    Kakiuchi     
 2007//0104779  A1  5/2007    Rongen et al.     
 2007//0105954  A1  5/2007    Puri     
 2007//0141138  A1  6/2007    Feuerstein et al.     
 2007//0167520  A1  7/2007    Bruzzese     
 2007//0185198  A1  8/2007    Yokoyama et al.     
 2007//0191467  A1  8/2007    Rongen et al.     
 2007//0202159  A1  8/2007    Mathur et al.     
 2007//0219271  A1  9/2007    Mittmann et al.     
 2007//0265340  A1  11/2007    Shalwitz et al.     
 2007//0269507  A1  11/2007    Sachetto et al.     
 2008//0020018  A1  1/2008    Moodley et al.     
 2008//0085911  A1  4/2008    Rongen et al.     
 2008//0089876  A1  4/2008    Cavazza     
 2008//0113046  A1  5/2008    Gardette     
 2008//0125490  A1  5/2008    Svensson et al.     
 2008//0185198  A1  8/2008    Jones     
 2008//0200547  A1  8/2008    Peet et al.     
 2008//0200707  A1  8/2008    Shimano et al.     
 2008//0299187  A1  12/2008    Opheim et al.     
 2008//0306154  A1  12/2008    Svensson et al.     
 2008//0319077  A1  12/2008    Suzuki et al.     
 2009//0012167  A1  1/2009    Rongen et al.     
 2009//0018125  A1  1/2009    Mittmann et al.     
 2009//0156675  A1  6/2009    Yokoyama et al.     
 2009//0182049  A1  7/2009    Opheim     
 2009//0227602  A1  9/2009    Griffin et al.     
 2009//0304784  A1  12/2009    Mane et al.     
 2009//0311322  A1  12/2009    Dlugatch et al.     
 2010//0021555  A1  1/2010    Geiringer et al.     
 2010//0063018  A1  3/2010    Pellicciari et al.     
 2010//0069492  A1  3/2010    Geiringen et al.     
 2010//0113506  A1  5/2010    Kawano et al.     
 2010//0113811  A1  5/2010    Yadav et al.     
 2010//0119598  A1  5/2010    Yoshinari et al.     
 2010//0130608  A1  5/2010    Ryan et al.     
 2010//0160261  A1  6/2010    Fortin     
 2010//0233280  A1  9/2010    Driscoll     
 2010//0254951  A1  10/2010    Shido et al.     
 2010//0278879  A1  11/2010    Manku     
 2010//0285121  A1  11/2010    Uchiyama et al.     
 2010//0311834  A1  12/2010    Manku et al.     
 2011//0034555  A1  2/2011    Osterloh et al.     
 2011//0065793  A1  3/2011    Peet et al.     
 2011//0071176  A1  3/2011    Rowe     
 2011//0082119  A1  4/2011    Yano     
 2011//0092592  A1  4/2011    Yano     
 2011//0105510  A1  5/2011    Ishikawa     
 2011//0130458  A1  6/2011    Breivik et al.     
 2011//0178105  A1  7/2011    Gillies et al.     
 2011//0218243  A1  9/2011    Rowe     
 2011//0223158  A1  9/2011    Sacks et al.     
 2011//0236476  A1  9/2011    Manku     
 2011//0268811  A1  11/2011    Minatelli et al.     
 2011//0288171  A1  11/2011    Manku et al.     
 2012//0035105  A1  2/2012    Geho et al.     
 2012//0035262  A1  2/2012    Osterloh et al.     
 2012//0039997  A1  2/2012    Manku et al.     
 2012//0093922  A1  4/2012    Manku et al.     
 2012//0093924  A1  4/2012    Manku et al.     
 2012//0100208  A1  4/2012    Manku     
 2012//0108659  A1  5/2012    Manku et al.     
 2012//0108660  A1  5/2012    Manku et al.     
 2012//0108663  A1  5/2012    Manku et al.     
 2012//0121698  A1  5/2012    Manku et al.     
 2012//0156285  A1  6/2012    Manku et al.     
 2012//0157530  A1  6/2012    Manku et al.     
 2012//0157531  A1  6/2012    Osterloh et al.     
 2012//0172432  A1  7/2012    Manku et al.     
 2012//0184595  A1  7/2012    Macdonald et al.     
 2012//0195963  A1  8/2012    Peet et al.     
 2012//0214771  A1  8/2012    Sampalis     
 2012//0225120  A1  9/2012    Manku et al.     
 2012//0232145  A1  9/2012    Osterloh et al.     
 2012//0237594  A1  9/2012    Manku et al.     
 2012//0264824  A1  10/2012    Mizuguchi et al.     
 2012//0302589  A1  11/2012    Manku et al.     
 2013//0004566  A1  1/2013    Manku et al.     
 2013//0004567  A1  1/2013    Manku et al.     
 2013//0004568  A1  1/2013    Manku et al.     
 2013//0004572  A1  1/2013    Manku et al.     
 2013//0005757  A1  1/2013    Osterloh et al.     
 2013//0005809  A1  1/2013    Manku et al.     
 2013//0011471  A1  1/2013    Manku et al.     
 2013//0011472  A1  1/2013    Manku et al.     
 2013//0012580  A1  1/2013    Osterloh et al.     
 2013//0017256  A1  1/2013    Manku et al.     
 2013//0079409  A1  3/2013    Manku et al.     
 2013//0090383  A1  4/2013    Manku et al.     
 2013//0095178  A1  4/2013    Manku     
 2013//0095179  A1  4/2013    Davidson et al.     
 2013//0096197  A1  4/2013    Manku     
 2013//0102674  A1  4/2013    Manku     
 2013//0131170  A1  5/2013    Manku     
 2013//0156852  A1  6/2013    Manku et al.     
 2013//0158120  A1  6/2013    Manku et al.     
 2013//0164375  A1  6/2013    Manku et al.     
 2013//0165513  A1  6/2013    Manku et al.     
 2013//0171249  A1  7/2013    Manku et al.     
 2013//0171250  A1  7/2013    Manku et al.     
 2013//0171251  A1  7/2013    Manku et al.     
 2013//0172413  A1  7/2013    Manku     
 2013//0189355  A1  7/2013    Manku et al.     
 2013//0195972  A1  8/2013    Manku et al.     
 2013//0252989  A1  9/2013    Manku et al.     
 2013//0252990  A1  9/2013    Manku et al.     
 2013//0253030  A1  9/2013    Osterloh et al.     
 2013//0253031  A1  9/2013    Osterloh et al.     
 2013//0281534  A1  10/2013    Osterloh et al.     
 2013//0295173  A1  11/2013    Machielse et al.     
 2013//0324607  A1  12/2013    Mason     
 2013//0331447  A1  12/2013    Manku et al.     
 2014//0004183  A1  1/2014    Soni et al.     
 2014//0005264  A1  1/2014    Soni et al.     
 2014//0005265  A1  1/2014    Soni et al.     
 2014//0017306  A1  1/2014    Manku     
 2014//0073692  A1  3/2014    Peet     
 2014//0080850  A1  3/2014    Mason     
 2014//0080909  A1  3/2014    Manku     
 2014//0088194  A1  3/2014    Manku     
 2014//0127289  A1  5/2014    Osterloh et al.     
 2014//0128453  A1  5/2014    Mullick et al.     
 2014//0128464  A1  5/2014    Rowe     
 2014//0154310  A1  6/2014    Osterloh et al.     
 2014//0155455  A1  6/2014    Osterloh et al.     
 2014//0155481  A1  6/2014    Osterloh et al.     
 2014//0186438  A1  7/2014    Manku et al.     
 2014//0187633  A1  7/2014    Manku et al.     
 2014//0213648  A1  7/2014    Manku et al.     
 2014//0221358  A1  8/2014    Zakrzewski     
 2014//0221452  A1  8/2014    Zakrzewski     
 2014//0221486  A1  8/2014    Manku et al.     
 2014//0221676  A1  8/2014    Braeckman et al.     
 2014//0235716  A1  8/2014    Manku et al.     
 2014//0243389  A1  8/2014    Zakrzewski     
 2014//0249200  A1  9/2014    Braeckman et al.     
 2014//0249214  A1  9/2014    Braeckman et al.     
 2014//0249220  A1  9/2014    Braeckman et al.     
 2014//0249225  A1  9/2014    Mason     
 2014//0256809  A1  9/2014    Zakrzewski     
 2014//0271841  A1  9/2014    Grandolfi     
 2014//0271907  A1  9/2014    Zakrzewski     
 2014//0275252  A1  9/2014    Zakrzewski     
 2014//0275253  A1  9/2014    Zakrzewski     
 2014//0357717  A1  12/2014    Braeckman et al.     
 2014//0364459  A1  12/2014    Zakrzewski     
 2015//0045431  A1  2/2015    Zakrzewski     
 2015//0051143  A1  2/2015    Harada et al.     
 2015//0051282  A1  2/2015    Zakrzewski     
 2015//0065572  A1  3/2015    Zakrzewski     
 2015//0073050  A1  3/2015    Zakrzewski     
 2015//0141510  A1  5/2015    Kiyohara et al.     
 2015//0164850  A1  6/2015    Osterloh et al.     
 2015//0190361  A1  7/2015    Osterloh et al.     
 2015//0290154  A1  10/2015    Roberts et al.     
 2016//0213639  A1  7/2016    Suzuki et al.     

 
 FOREIGN PATENT DOCUMENTS 
 
       CA       2628305                         5/2007      
       CA       2653787                         12/2007      
       CA       2675836                         7/2008      
       CA       2724983                         11/2009      
       CN       101252837                         8/2008      
       EP       273708                         7/1988      
       EP       277747                         8/1988      
       EP       0302482                         2/1989      
       EP       347509                         12/1989      
       EP       0460917                         12/1991      
       EP       606012                         7/1994      
       EP       0610506                         8/1994      
       EP       0641562       A1                3/1995      
       EP       1125914                         8/2001      
       EP       1157692                         11/2001      
       EP       1296670                         4/2003      
       EP       1549299                         12/2003      
       EP       1743644                         1/2007      
       EP       1 790 339       A1                5/2007      
       EP       1 834 639       A1                9/2007      
       EP       1 982 710       A1                10/2008      
       EP       2022495                         2/2009      
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       EP       2719382       A1                4/2014      
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       FR       2635263                         2/1990      
       GB       2148713                         6/1985      
       GB       2221843                         2/1990      
       GB       2229363                         9/1990      
       GB       9901809                         1/1999      
       JP       61035356                         2/1986      
       JP       04182426                         6/1992      
       JP       2003306690                         10/2003      
       JP       07 238598                         9/2007      
       JP       08 050367                         3/2008      
       KR       10-2006-0109988                         10/2006      
       KR       10-2007-0058460                         6/2007      
       WO       WO 90/04391                         5/1990      
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 OTHER PUBLICATIONS
  
  Aarsland, et al., “On the Effect of Peroximsomal beta-Oxidation and Carnitine Palmitoyltransferase Activity by Eicosapentaenoic Aid in Live and Heart of Rats.” Lipids, 25:546-548, (1990).
  Aas, V., et al., “Eicosapentaenoic acid (20:5 n-3) increases fatty acid and glucose uptake in cultured human skeletal muscle cells.” Journal of Lipid Research, 47:366-374 (2006).
  Abbey, M., et al., “Effect of fish oil on lipoproteins, lecithin:cholesterol acyltransferase, and lipidtransfer protein activity in humans” Arterioscler. Thromb. Vasc. Biol. 10:85-94 (1990).
  Adan, Y, et al., “Effects of docosahexaenoic and eicosapentaenoic acid on lipid metabolism, eicosanoid production, platelet aggregation and atherosclerosis.” Biosci. Biotechnol. Biochem. 63(1), 111-119 (1999).
  Adan, Y., et al., “Concentration of serum lipids and aortic lesion size in female and male apo E-deficient mice fed docosahexaenoic acid.” Biosci. Biotechnol. Biochem. 63(2):309-313 (1999).
  Agren, J.J. et al., “Fatty acid composition of erythrocyte, platelet, and serum lipids in strict vegans.” Lipids 30:365-369 (1995).
  Agren, J.J., et al., “Fish diet, fish oil and docosahexaenoic acid rich oil lower fasting and postprandial plasma lipid levels.” Eur J Clin Nutr., 50:765-771. (1996).
  Ait-Said, et al., “Inhibition by eicosapentaenoic acid of IL-1β-induced PGHS-2 expression in human microvascular endothelial cells: involvement of lipoxygenase-derived metabolites and p38 MAPK pathway.” Biohimicia et Biophysica Acta, 1631:66-85 (2003).
  Alderman, J.D., et al., “Effect of a modified, well-tolerated niacin regimen on serum total cholesterol, high density lipoprotein cholesterol and the cholesterol to high density lipoprotein ratio,” Am. J. Cardio, 64: 725-729.A (1989).
  Alessandri, J-M., et al., “Estradiol favors the formation of eicosapentaenoic acid (20:5n-3) and n-3 docosapentaenoic acid (22:5n-3) from alpha-linolenic acid (18:3n-3) in SH-SY5Y neuroblastoma cells.” Lipids 43:19-28 (2008).
  Allred, C., et al., “PPARγ1 as a molecular target of eicosapentaenoic acid in human colon cancer (HT-29) cells.” J. Nutr. 138:250-256 (2008).
  Amarin Corporation Announces First Patients Enrolled in Two Phase 3 Clinical Trials Assessing AMR101 for the Treatment of Cardiovascular Disease [online], Amarin Corporation, Jan. 11, 2010 [retrieved Apr. 27, 2011], Retrieved from the Internet: <http://inestor.amarincorp.com/releasedetail.cfm?ReleaseID=504380>.
  Ando, M., et al., “Eicosapentanoic acid reduces plasma levels of remnant lipoproteins and prevents in vivo peroxidation of LDL in dialysis patients.” J. Am. Soc. Nephrol., 10:2177-2184 (1999).
  Ando, Y., et al., “Positional distribution of highly unsaturated fatty acids in triacyl-sn-glycerols of Artemia Nauplii enriched with docosahexaenoic acid ethyl ester.” Lipids 36:733-740 (2001).
  Andrade, SE. et al., “Discontinuation of antihyperlipidaemic drugs do rates reported in clinical trials reflect rates in primary care settings?” New Eng. J. Med. 332: 1125-1131. (1995).
  Angerer et al., “n-3 Polyunsaturated Fatty Acids and the Cardiovascular System”, Current Opinion in Lipidology, 11(1):57-63, (2000).
  Anil, Eliz, “The Impact of EPA and DHA on Blood Lipids and Lipoprotein Metabolism: Influence of ApoE Genotype”, Proceedings of the Nutrition Society, 66:60-68, (2007).
  Aoki T et al. “Experience of the use of ethyl eicosapentaenoic acid preparation (Epadel) in patients with arteriosclerosis obliterans complicated with Diabetes mellitus. A study of the long-term effects on glycemic control and blood lipids,” Rinsho to Kenkyu; 70:625-631. (1993) (with English translation).
  Appleton, Katherine M., et al., “Effects of n-3 long-chain polyunsaturated fatty acids on depressed mood: systematic review of published trials”, Am. J. Clin. Nutr., 84(6):1308-1316, (Dec. 2006).
  Arrol, S. et al., “The effects of fatty acids on apolipoprotein B secretion by human hepatoma cells (HEP G2),” Atherosclerosis 150:255-264. (2000).
  Arshad, A., et al., “Sudden cardiac death and the role of medical therapy.” Progress in Cardiovascular Diseases, vol. 50, No. 6, 420-438, (2008).
  Arterburn, L., et al., “Distribution, interconversion, and dose response of n-3 fatty acids in humans.” Am J Clin Nutr., 83:1467S-76S (2006).
  Asano, M., et al., “Eicosapentaenoic acid inhibits vasopressin-activated Ca2q influx and cell proliferation in rat aortic smooth muscle cell lines.” European Journal of Pharmacology 379:199-209 (1999).
  Asano, M., et al., “Inhibitory effects of ω-3 polyunsaturated fatty acids on receptor-mediated non-selective cation currents in rat A7r5 vascular smooth muscle cells.” British Journal of Pharmacology 120:1367-1375, (1997).
  ATP III guidelines, NIH publication No. 01-3305 (2001).
  Ayton, et al., “A pilot open case series of Ethyl-EPA supplementation in the treatment of anorexia nervosa,” Prostaglandins, Leukotrienes and Essential Fatty Acids 71, pp. 205-209. (2004).
  Ayton, et al., “Rapid improvement of severe anorexia nervosa during treatment with ethyl-eicosapentaenoate and micronutrients,” European Psychiatry 19, pp. 317-319. (2004).
  Baigent, C., et al., “Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.” Lancet; 366:1267-1278. (2005).
  Balk, E.M., et al., “Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis.” 189:19-30. (2006).
  Ballantyne et al., Influence of low-high density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S, Circulation, 104:3046-3051. (2001).
  Bang HO, Dyerberg J. “Plasma lipids and Lipoproteins in Greenlandic west coast Eskimos” Acta Med Scand, 192:85-94. (1972).
  Banga, A. et al., “Adiponectin translation is increased by the PPAR? agonists pioglitazone and ?-3 fatty acids.” Am J Physiol Endocrinol Metab 296:480-489 (2009).
  Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM, “Fasting Compared With Nonfasting Triglycerides and Risk of Cardiovascular Events in Women,” JAMA, 298:309-316 (2007).
  Basu, A., et al., “Dietary Factors That Promote or Retard Inflammation.” Arterioscler. Thromb. Vasc. Biol. 26:995-1001 (2006).
  Bays, H., Clinical Overview of Omacor: A Concentrated Formulation of Omega-3 Polyunsaturated Fatty Acids, Am J Cardiol.; 98[suppl]:71i-76i (2006).
  Bays, H., “Rationale for Prescription Omega-3-Acid Ethyl Ester Therapy for Hypertriglyceridemia: A Primer for Clinicians,” Drugs of Today, 44(3); 205-246. (2008).
  Bays, H.E., Eicosapentaenoic Acid Ethyl Ester (AMR101) Therapy in Patients With Very High Triglyceride Levels (from the Multi-center, plAcebo-controlled, Randomized, double-bIINd, 12-week study with an open-label Extension [MARINE] Trial) Am J Cardiol;108:682-690. (2011).
  Bays, H.E., et al., “Long-term up to 24-month efficacy and safety of concomitant prescription omega-3-acid ethyl esters and simvastatin in hypertriglyceridemic patients.” Curr Med Res Opin.; 26:907-915. (2010).
  Beal, M.F., Annals of Neurology, vol. 38, No. 3, “Aging, Energy, and Oxidative Stress in Neurodegenerative Diseases”, pp. 357-366, (Sep. 1995).
  Belmaker et al., “Addition of Omega-3 Fatty Acid to Maintenance Medication Treatment for Recurrent Unipolar Depressive Disorder,” Am. J. Psychiatry, 159:477-479 (2002).
  Belmaker, et al., “Omega-3 Eicosapentaenoic Acid in Bipolar Depression: Report of a Small Open-Label Study,” J Clin Psychiatry; 66:726-729. (2005).
  Bénistant, C., et al., “Docosapentaenoic acid (22:5, n-3): metabolism and effect on prostacyclin production in endothelial cells.” Prostaglandins, Leukotrienes and Essential Fatty Acids, 55(4):287-292, (1996).
  Berge, R.K., et al., “In contrast with docosahexaenoic acid, eicosapentaenoic acid and hypolipidaemic derivatives decrease hepatic synthesis and secretion of triacylglycerol by decreased diacylglycerol acyltransferase activity and stimulation of fatty acid oxidation.” Biochem J.; 343(Pt 1):191-197. (1999).
  Betteridge, D.J., “Diabetic dyslipidaemia: past, present and future.” Practical Diabetes Int, 21(2): 78-85. (2004).
  Black et al., “Effect of intravenous eicosapentaenoic acid on cerebral blood flow, edema, and brain prostaglandins in ischemic gerbils”, Prostaglandins, 28(4), pp. 545-546. (1984).
  Blankenhorn D.H. et al., “Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts.” JAMA 257: 3233-3240. (1987).
  Block, R. C., et al., “EPA and DHA in blood cell membranes from acute coronary syndrome patients and controls.” Atherosclerosis, 197(2):821-828 (2007).
  Blumenthal, Advanced Studies in Medicine, 2:148-157 (2002).
  Bonaa, KH et al., Docosahexaenoic and Eicosapentaenoic acids in plasma phospholipids are divergently associated with high density lipoprotein in humans, Arterioscler. Thromb. Vasc. Biol.;12;675-681 (1992).
  Bousserouel, S., et al., “Different effects of n-6 and n-3 polyunsaturated fatty acids on the activation of rat smooth muscle cells by interleukin-1?.” J. Lipid Res. 44:601-611 (2003).
  Bousserouel, S., et al., “Modulation of cyclin D1 and early growth response factor-1 gene expression in interleukin-1?-treated rat smooth muscle cells by n-6 and n-3 polyunsaturated fatty acids.” Eur. J. Biochem. 271:4462-4473 (2004).
  Brady, L., et al., Increased n-6 polyunsaturated fatty acids do not attenuate the effects of long-chain n-3 polyunsaturated fatty acids on insulin sensitivity or triacylglycerol reduction in Indian Asians. Am J Clin Nutr 79:983-91(2004).
  Breslow, J., “n-3 Fatty acids and cardiovascular disease.” Am J Clin Nutr., 83:1477S-82S (2006).
  Brossard, N., et al., “Retroconversion and metabolism of [13C]22:6n-3 in humans and rats after intake of a single dose of [13C]22:6n-3—3-triacyylglycerols.” Am. J. Clin. Nutr. 64:577-86 (1996).
  Brouwer, I.A., et al., “Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators.” JAMA. 295(22):2613-2619 (2006).
  Brown et al., Simvastatin and Niacin, Antioxidant Vitamins, or the Combination for the Prevention of Coronary Disease, N Engl J Med, vol. 345, No. 22, 1583-1592 (Nov. 29, 2001).
  Brown, A. J., et al., “Administration of n-3 Fatty Acids in the Diets of Rats or Directly to Hepatocyte Cultures Results in Different Effects on Hepatocellular ApoB Metabolism and Secretion.” Arterioscler. Thromb. Vasc. Biol. 19:106-114 (1999).
  Brown, A. J., et al., “Persistent changes in the fatty acid composition of erythrocyte membranes after moderate intake of n-3 polyunsaturated fatty acids: study design and implications.” Am.J. Clin. Nutri. 54:668-73(1991).
  Brown, G., et al., “Regression of coronary artery-disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein,” B., N. Engl. J. Med. 323: 1289-1298. (1990).
  Bryhn, M., et al., “The bioavailability and pharmacodynamics of different concentrations of omega-3 acid ethyl esters.” Prostaglandins, Leukotrienes and Essential Fatty Acids 75:19-24 (2006).
  Budavari, S., Editor, “The Merck Index”, Merck & Co., Inc., 2417:379,4511,725, (1989).
  Bunting et al. “Depression in Parkinson's Disease”. J Neurosci Nurs.; 23(3):158-164. (Abstract Only) (1991).
  Burdge, G.C., et al., “Eicosapentaenoic and docosapentaenoic acids are the principal products of a-linolenic acid metabolism in young men.” British Journal of Nutrition 88:355-363 (2002).
  Burdge, G.C., et al., “Lack of effect of meal fatty acid composition on postprandial lipid, glucose and insulin responses in men and women aged 50-65 years consuming their habitual diets.” British Journal of Nutrition, 96:489-500 (2006).
  Burdge, G.C., et al., “The effect of altering the 20:5n-3 and 22:6n-3 content of a meal on the postprandial incorporation of n-3 polyunsaturated fatty acids into plasma triacylglycerol and non-esterified fatty acids in humans.” Prostaglandins, Leukotrienes and Essential Fatty Acids 77:59-65 (2007).
  Burr, M. L., et al., “Effects of changes in fat, fish and fibre intakes on death and myocardial reinfarction: Diet and reinfarction trial.” The Lancet, 2(8666):757-61 (1989).
  Calabresi, L., et al., “Omacor in familial combined hyperlipidemia: effects on lipids and low density lipoprotein subclasses.” Atherosclerosis 148:387-396 (2000).
  Campos, H., et al., “Lowdensity lipoprotein size, pravastatin treatment, and coronary events.” JAMA, 286:1468-1474 (2001).
  Canner P.L. et al., “Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin,” J. Am. Coll. Cardiol. 8. 1245-1255. (1986).
  Cao, et al., “Cloning, Expression, and Chromosomal Locatlization . . . ”, Genomics, 49:327-331, (1998).
  Cao, J., et al., “Incorporation and Clearance of Omega-3 Fatty Acids in Erythrocyte Membranes and Plasma Phospholipids.” Clinical Chemistry 52(12):2265-2272 (2006).
  Capuzzi, DM et al., “Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.” Am. J. Cardiol. 82: 74U-81U. (1998).
  Carlson, L.A. & Rosenhamer G., “Reduction of mortaility in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid.” Acta Med. Scand. 223, 405-418 (1988).
  Carlson, L.A., “Nicotinic acid: the broad spectrum lipid drug. A 50th Anniversary review”, J. Int. Med., 258:94-114, (2005).
  Carrero et al., “Intake of Fish Oil, Oleic Acid, Folic Acid, and Vitamins B-6 and E for 1 Year Decreases Plasma C-Reactive Protein and Reduces Coronary Heart Disease Risk Factors in Male Patients in a Cardiac Rehabilitation Program”, pp. 384-390 (2007).
  Carroll, D. N., et al., “Evidence for the Cardioprotective Effects of Omega-3 Fatty Acids.” Ann Pharmacother., 36:1950-6 (2002).
  Cazzola, R., et al., “Age- and dose-dependent effects of an eicosapentaenoic acid-rich oil on cardiovascular risk factors in healthy male subjects.” Atherosclerosis 193:159-167 (2007).
  Cefali, E.A., et al., “Aspirin reduces cutaneous flushing after administration of an optimised extended-release niacin formulation”, Int. J. Clin. Pharmacol. & Ther., 45:78-88, (2007).
  Center for Drug Evaluation and Research. Application No. 21-853, 21654s016, (Omacor). Statistical Review and Evaluation: Clinical Studies, Omacor (omega-3 acid ethyl ester) Capsules, 4 grams/day; 2007. Available at: http://www.accessdata.fda.gov/drugsatfdadocs/nda/2007/021853s000;%20021654s016StatR.pdf. (Accessed Jan. 26, 2012).
  Center for Drug Evaluation and Research. Approval Package for: 21-654 (Omacor/Lovaza). Statistical Review; 2004. Available at: http://www.accessdata.fda.gov/drugsatfdadocs/nda/2004/21-654OmacorAdminCorresP1.pdf. Accessed Jan. 26, 2012.
  Chan et al., “Effect of Atorvastatin and Fish Oil on Plasma High-Sensitivity C-Reactive Protein Concentrations in Individuals with Visceral Obesity”, Clin. Chem., vol. 48, pp. 877-883 (2002).
  Chan, D.C., et al., “Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity.” Am J Clin Nutr 77:300-7 (2003).
  Chapman, M.J., et al., “Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors.” Eur Heart J., 31:149-164 (2010).
  Chemical Book, Eicosapentaenoic acid ethyl ester, copyright 2010, printed Jun. 16, 2011 from www.chemicalbook.com. (2010).
  Chen, H., et al., “Eicosapentanoic acid inhibits hypoxia-reoxygenation-induced injury by attenuating upregulation of MMP-1 in adult rat myocytes.” Cardiovascular Research 59:7-13 (2003).
  Chen, H., et al., “EPA and DHA attenuate ox-LDL-induced expression of adhesion molecules in human coronary artery endothelial cells via protein kinase B pathway.” Journal of Molecular and Cellular Cardiology 35:769-775 (2003).
  Chen, I.S., et al., “In vitro clearance of chylomicron triglycerides containing (?-3) eicosapentaenoate.” Atherosclerosis, 65:193-198 (1987).
  Childs, M.T., et al., “Divergent lipoprotein Responses to Fish Oils With Various Ratios of Eicosapentaenoic Acid and Docasahexaenoic Acid”, American Society for Clinical Nutrition, 52:632-9, (1990).
  Christensen, J. H., et al., “Effect of fish oil on heart rate variability in survivors of myocardial infarction: a double blind randomised controlled trial.” BMJ, 312:677-678 (1996).
  Christensen, M.S., et al., “Intestinal absorption and lymphatic transport of eicosapentaenoic (EPA), docosahexaenoic (DHA), and decanoic acids: dependence on intramolecular triacyiglycerol structure.” Am J Clin Nutr 61:56-61 (1995).
  Cleland, L.G., et al., “A Biomarker of n-3 compliance in patients taking fish oil for rheumatoid arthritis.” Lipids 38:419-424 (2003).
  Clinical Trial NCT01047501, Effect of AMR101 (Ethyl Icosapentate) on Triglyceride (Tg) Levels in Patients on Statins With High Tg Levels (>200 and <500 mg/dL) (ANCHOR), ClinicalTrials.gov [database online], U.S. National Institute of Health, Jan. 2010 [retrieved Apr. 27, 2011], Retrieved from the Internet: <http://clinicaltrials.gov/ct2/show/NCT01047501>.
  Cohen, J.D., et al., “30-year trends in serum lipids among United States adults: results from the National Health and Nutrition Examination Surveys II, III, and 1999-2006.” Am J Cardiol., 106:969-975. (2010).
  Colhoun, H. M., et al., “Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.” Lancet 364: 685-9 (2004).
  Collins, N., et al., “Differences between Dietary Supplement and Prescription Drug Omega-3 Fatty Acid Formulations: A Legislative and Regulatory Perspective.” Journal of the American College of Nutrition, 27 (6):659-666 (2008).
  Conklin, S. M., et al., “Serum ?-3 fatty acids are associated with variation in mood, personality and behavior in hypercholesterolemic community volunteers.” Psychiatry Research 152: 1-10 (2007).
  Connor et al., “Seminars in thrombosis and hemostasis,” 14:271-284. (1988).
  Connor, W.E., “Importance of n-3 Fatty Acids in Health and Disease”, Am. J. Clin. Nutr., 71(1(S)):171S-175S, (2000).
  Conquer, J.A., et al., “Effect of supplementation with different doses of DHA on the levels of circulating DHA as non-esterified fatty acid in subjects of Asian Indian background. J Lipid Res.” 39:286-292. (1998).
  Conquer, J.A., et al., “Supplementation with an algae source of docosahexaenoic acid increases (n-3) fatty acid status and alters selected risk factors for heart disease in vegetarian subjects.” J Nutr., 126: 3032-3039. (1996).
  Contacos et al. Effect of pravastatin and omega-3 fatty acids on plasma lipids and lipoproteins in patients with combined hyperlipidemia, pp. 1755-1762 (1993).
  Criqui, M., “Triglycerides and Coronary Heart Disease Revisited (Again),” vol. 147 No. 6, pp. 425-427 (2007).
  Crowe, F. L., et al., “Serum phospholipid n-3 long-chain polyunsaturated fatty acids and physical and mental health in a population-based survey of New Zealand adolescents and adults.” Am J Clin Nutr 86:1278-85 (2007).
  Daggy, B., et al., Dietary fish oil decreases VLDL production rates. Biochimica et Biophysics Acta 920: 293-300 (1987).
  Das, U.N., Essential fatty acids as possible mediators of the actions of statins. Prostaglandins, Leukotrienes and Essential FattyAcids 65(1):37-40, (2001).
  Davidson MH, Stein EA, Bays HE et al. “Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study,” Clin Ther., 29:1354-1367. (2007).
  Davidson MH., “Mechanisms for the hypotriglyceridemic effect of marine omega 3 fatty acids.” Am J Cardiol 98(4A):27i-33i. (2006).
  Davidson, M.H., et al., “Effects of docosahexaenoic acid on serum lipoproteins in patients with combined hyperlipidemia: a randomized, doubleblind, placebo-controlled trial.” J Am Coll Nutr., 16:236-243. (1997).
  De Caterina, R, et al., “Control of Endothelial Leukocyte Adhesion Molecules by Fatty Acids.” Lipids, vol. 31:S57-S63 (1996).
  De Caterina, R., et al., “The Omega-3 fatty acid docosahexaenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells.” Arterioscler. Thromb. Vasc. Biol. 14:1829-1836 (1994).
  Deckelbaum R. J., et al., “Conclusions and recommendations from the symposium, Beyond Cholesterol: Prevention and Treatment of Coronary Heart Disease with n-3 Fatty Acids.” Am J Clin Nutr 87:2010S-12S (2008).
  Dewailly, E. et al., “n-3 Fatty acids and cardiovascular disease risk factors among the Inuit of Nunavik.” Am J Clin Nutr 74:464-73 (2001).
  Diagnostic and Statistical Manual of Mental Disorders, 4.Ed. Text revision, published by the American Psychiatric Assoc., pp. 154-163 and 369-381 (2000).
  Diagnostic and Statistical Manual of Mental Disorders, 4.sup.th Ed., published by the American Psychiatric Assoc., pp. 285-286, (1994).
  Dijan, P., et al., Proc. Natl. Acad. Sci., vol. 93, “Codon repeats in genes associated with human diseases: Fewer repeats in the genes of nonhuman primates and nucleotide substitutions concentrated at the sites of reiteration,” pp. 417-421, (1996).
  Dijk, J. M., et al., “Carotid intima-media thickness and the risk of new vascular events in patients with manifest atherosclerotic disease: the SMART study.” European Heart Journal 27:1971-1978 (2006).
  Dodin, S., et al., “Flaxseed on cardiovascular disease markers in healthy menopausal women: a randomized, double-blind, placebo-controlled trial.” Nutrition 24:23-30 (2008).
  Dolecek, “Epidemiological Evidence of Relationships Between Dietary Polyunsaturated Farry Acids and Morality in the Multiple Risk Factor Intervention Trial”, Society of Experimental Biology and Medicine, 200(2):177-182, (1991).
  Dullenmeijer, C., et al., “n-3 Fatty acid proportions in plasma and cognitive performance in older adults.” Am J Clin Nutr 86:1479-85 (2007).
  Duncan, R. E., et al., “Regulation of HMG-CoA reductase in MCF-7 cells by genistein, EPA, and DHA, alone and in combination with mevastatin.” Cancer Letters 224:221-228 (2005).
  Durrington PN et al. “An omega 3 poly unsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persistent Hypertriglyceridemia,” Heart, 85:544-48 (2001).
  Dwyer, J. H., et al., “Arachidonate 5-Lipoxygenase Promoter Genotype, Dietary Arachidonic Acid, and Atherosclerosis.” N. Engl. J. Med., 350:1 (2004).
  Dyerberg, J., et al., “Marine Oils and Thrombogenesis.” Prog. Lipid Res. 21:255-269 (1982).
  Egert, S., et al., “Dietary alpha-linolenic acid, EPA, and DHA have differential effects on Ldl fatty acid composition but similar effects on serum lipid profiles in normolipidemic humans.” J Nutr., 139:861-868 (2009).
  Eisenberg S, Bilheimer DW, Levy RI, Lindgren FT. “On the metabolic conversion of human plasma very low density lipoprotein to low density lipoprotein,” Biochim Biophys Acta, 326:361-77 (1973).
  Eisenberg S, Rachmilewitz D. “Metabolism of rat plasma very low density lipoprotein. I. Fate in circulation of the whole lipoprotein,” Biochim Biophys Acta, 326:378-90 (1973).
  Elam, M.B., et al., “Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease study: a randomized trial”, The ADMIT [Arterial Disease Multiple Intervention Trial] JAMA, 284:1263-1270, (2000).
  Ei-Sohemy, A., et. al., “Regulation of Mevalonate Synthesis in Low Density Lipoprotein Receptor Knockout Mice Fed n-3 or n-6 Polyunsaturated Fatty Acids.” Lipids, 34 (10): 1037-43 (1999).
  Engler, et al., “Docosahexaenoic acid restores endothelial function in children with hyperlipidemia: results from the EARLY Study.” International Journal of Clinical Pharmacology and Therapeutics, vol. 42—No. 12-2004 (672-679). (2004).
  Engler, M.B., et al., “Mechanisms of vasorelaxation induced by eicosapentaenoic acid (20:5n-3) in WKY rat aorta.” British Journal of Pharmacology 131:1793-1799 (2000).
  Engler, M.M., et al., “The effects of a diet rich in docosahexaenoic acid on organ and vascular fatty acid composition in spontaneously hypertensive rats.” Prostaglandins, Leukotrienes and Essential Fatty Acids 61(5):289-295 (1999).
  Epadel® [Complete prescribing information]. Update (Version 5). Tokyo, Japan: Mochida Pharmaceutical; Jan. 2007. (English translation).
  Faggin, E., et al., “Fish Oil Supplementation Prevents Neointima Formation in Nonhypercholesterolemic Balloon-Injured Rabbit Carotid Artery by Reducing Medial and Adventitial Cell Activation.” Arterioscler. Thromb. Vasc. Biol., 20:152-163 (2000).
  Fer, M., et al., “Metabolism of eicosapentaenoic and docosahexaenoic acids by recombinant human cytochromes P450.” Archives of Biochemistry and Biophysics 471:116-125 (2008).
  Ferns, G., et al., “Investigation and management of hypertriglyceridaemia.” J. Clin. Pathol. 61:1174-1183 (2008).
  Finnen et al., “Purification and characterisation of phospholipase A2 from human epidermis,”, Biochemical Society Trans,19(2):91S, 1991.
  Fischer, R., et al., “Dietary n-3 polyunsaturated fatty acids and direct renin inhibition improve electrical remodeling in a model of high human renin hypertension.” Hypertension 51:540-546 (2008).
  Fisher et al., Journal of Biological Chemistry (2001) 276(3) 27855-27863.
  Flaten, H., et al., “Fish-oil concentrate: effects on variables related to cardiovascular disease.” Am. J. Clin. Nutr. 52:300-306 (1990).
  Ford, E.S. et al., “Hypertriglyceridemia and Its Pharmacologic Treatment Among US Adults.” Arch, Intern. Med., 169(6): 572-78 (2009).
  Frick, MH, et al., “Helsinki Heart Study. Primary prevention trial with gemfibrozil in middle-aged men with dyslipidaemia. Safety of treatment, changes in risk factors and incidence of coronary heart disease”, N. Eng. J. Med., 317:1237-1245, (1987).
  Friedewald, W.T., et al., “Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.” Clin Chem.,18:499-502 (1972).
  Friedman, A. N., et al., “Fish Consumption and Omega-3 Fatty Acid Status and Determinants in Long-Term Hemodialysis.” Amer. J. Kidney Diseases, 47(6):1064-1071 (2006).
  Frøyland, L., et al., “Hypotriacylglycerolemic component of fish oil.” Prostaglandins, Leukotrienes and Essential Fatty Acids 57 (4 & 5):387-388 (1997).
  Garg, R., et al., “Niacin treatment increases plasma homocyst(e)ine levels”, Am. Heart. J., 138:1082-1087, (1999).
  Garnett, “Interactions with Hydroxymethylglutaryl-coenzyme A reductase inhibitors,” Am J Health-Sys Pharm vol. 52, 1639-1645, (1995).
  Genest, JJ, et al., “Familial lipoprotein disorders in patients with premature coronary artery disease”, 85:2025-2033, (1992).
  Geppert, et al. “Microalgal docosahexaenoic acid decreases plasma triacylglycerol in normolipidaemic vegetarians: a randomized trial.” British Journal of Nutrition, 95, 779-786. (2006).
  Gillies, et al. “Effect of a Novel Eicosapentaenoic Acid-Rich Oil on Serum Cholesterol in Man,” DuPont 2010.
  Ginsberg HN. “Hypertriglyceridemia: new insights and new approaches to pharmacologic therapy,” Am J Cardiol, 87:1174-1180 (2001).
  GISSI-Prevenzione Investigators, “Dietary Supplementation with n-3 Polyunsaturated Fatty Acids and Vitamin E after Myocardial Infarction: Results of the GISSI-Prevenzione Trial”, The Lancet, 354:447-455, (Aug. 7, 1999).
  Glod, “Recent Advances in the Pharmacotherapy of Major Depression”, Arch. Psychiatr. Nurs., 10(6):355-364, Abstract (Dec. 1996).
  Goldberg, A C: “Combination therapy of dyslipidemia,” Current Treatment Options in Cardiovascular Medicine 200708 GB, vol. 9, No. 4, pp. 249-258 (2007).
  Gordon, DJ. et al., High density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation. 79: 8-15. (1989).
  Gorriz JL et al., “Rhabdomyolysis and Acute Renal Failure Associated with Gemfibrozil Therapy,” Nephron 74(2): 437-438 (1996).
  Gorriz, JL, “Rhabdomyolysis and Acute Renal Failure Associated with Bezafibrate Treatment,” Nephrol Dial Transplant 10(12):2371-2372 (1995).
  Goto, Y. et al., “Clinical Pharmacological Trial of Ethyl Icosapentate (MND-21)—Dose Finding Study.” Journal of Clinical Therapeutic & Medicines 8:1293-309 (1992).
  Gould, A.L., et al., “Cholesterol reduction yields clinical benefit: impact of statin trials.” Circulation, 97:946-952 (1998).
  Grenyer, Brin F.S., et al., “Fish Oil Supplementation in the Treatment of Major Depression: A Randomised Double-Blind Placebo-Controlled Trial”, Progress in Neuro-Psychopharmacology & Biological Psychiatry, 31:1393-1396, (2007).
  Griffin, M.D., et al., “Effects of altering the ratio of dietary n-6 to n-3 fatty acids on insulin sensitivity, lipoprotein size, and postprandial lipemia in men and postmenopausal women aged 45-70 y: the OPTILIP Study.” Am J Clin Nutr 84:1290-8 (2006).
  Grimsgaard et al., “Effects of Highly Purified Eicosapentaenoic Acid and Docosahexaenoic Acid on Hemodynamics in Humans” American Society for Clinical Nutrition, 68:52-9, (1998).
  Grimsgaard, Kaare H. Bonaa, John-Bjarne Hansen, and Arne Nordoy, “Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids” Am J Clin Nutr, 66:649-59, (1997).
  Grundy S.M et al., Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial. Arch. Intern. Med. 162: 1568-1576 (2002).
  Guallar, E., et al., “Omega-3 fatty acids in adipose tissue and risk of myocardial infarction—The EURAMIC study.” Arterioscler. Thromb. Vasc. Biol., 19:1111-1118 (1999).
  Guillot, et al., “Increasing intakes of the long-chain ?-3 docosahexaenoic acid: effects on platelet functions and redox status in healthy men,” The FASEV Journal, vol. 23, pp. 2909-2916 (2009).
  Guizy, M., et al., “ω-3 and ω-6 Polyunsaturated fatty acids block HERG channels.” Am J Physiol Cell Physiol 289:C1251-C1260 (2005).
  Hall, W. L., et al., “A high-fat meal enriched with eicosapentaenoic acid reduces postprandial arterial stiffness measured by digital volume pulse analysis in healthy men.” J. Nutr. 138: 287-291 (2008).
  Hamazaki et al., “Docosahexaenoic Acid-Rich Fish Oil Does Not Affect Serum Lipid Concentrations of Normolipidemic Young Adults”, American Institute of Nutrition, 126(11):2784-2789, Nov. (1996).
  Hamazaki et al., “Effects of Orally Administered Ethyl Ester of Eicosapentaenoic Acid (EPA: C20:5, omega-3) on PG12-Like Substance Production by Rat Aorta” Prostaglandins, vol. 23 No. 4, pp. 557-567 (1982).
  Hamazaki T. et al., “Reduction of microalbuminuria in diabetics by Eicosapentaenoic acid ethyl ester” Lipids. 25 (9):542-5 (1990).
  Han, J. J., et al., “Enhancement of both reaction yield and rate of synthesis of structured triacylglycerol containing eicosapentaenoic acid under vacuum with water activity control.” Lipids 34:989-995 (1999).
  Hanasaki, K., et al., “Potent modification of low density lipoprotein by group X secretory phospholipase A2 is linked to macrophage foam cell formation.” J. Biol. Chem. 277(32):29116-24 (2002).
  Haney, E.M., et al., “Screening for lipid disorders in children and adolescents; Systematic evidence review for the U.S. Preventive Services Task Force (evidence synthesis).” No. 47. Rockville, MD: Agency for Healthcare Research and Quality, US Department of Health and Human Services; AHRQ Publication No. 07-0598-EF-1; Jul. 2007. Available at: http://www.uspreventiveservicestaskforce.org/uspstf07/chlipid/chlipidsyn.pdf. (Accessed Mar. 23, 2011).
  Hannah, J., et al., “Effect of dietary fatty acids on LDL binding.” Ann N Y Acad Sci., 683:178-182 (1993).
  Hansen, J.B., et al., “Effects of highly purified eicosapentaenoic acid and docosahexaenoic acid on fatty acid absorption, incorporation into serum phospholipids and postprandial triglyeridemia.” Lipids 33:131-38 (1998).
  Harkonarson, H., et al., “Effects of a 5-lipoxygenase—activating protein inhibitor on biomarkers associated with risk of myocardial infarction—a randomized trial.” JAMA, 293(8):2245-56 (2005).
  Harris, W. S. et al. “Safety and efficacy of Omacor in severe hypertriglyceridemia,” Journal of Cardiovascular Risk, 4:385-391 (1997).
  Harris, W. S., “Fish oils and plasma lipid and lipoprotein metabolism in humans: a critical review.” J Lipid Res. 30:785-807 (1989).
  Harris, W. S., “The omega-3 index as a risk factor for coronary heart disease.” Am J Clin Nutr 87:1997S-2002S (2008).
  Harris, W. S., et al., “n-3 Fatty acids and urinary excretion of nitric oxide metabolites in humans.” Am. J. Clin. Nutr., 65:459-64 (1997).
  Harris, W. S., et al., “Influence of n-3 fatty acid supplementation on the endogenous activities of plasma lipases.” Am. J. Clin. Nutr. 66:254-60 (1997).
  Harris, W.S., “Expert opinion: omega-3 fatty acids and bleeding-cause for concern?” The American Journal of Cardiology 99(6A): 45C-46C (2007).
  Harris, W.S., “n-3 Fatty acids and human lipoprotein metabolism: an update.” Lipids 34:S257-S258 (1999).
  Harris, W.S., “n-3 Fatty acids and serum lipoproteins: human studies.” Am J Clin Nutr 65:1645S-54S (1997).
  Harris, W.S., “Omega-3 fatty acids in cardiac biopsies from heart transplantation patients.” Circulation 110;1645-1649 (2004).
  Harris, W.S., et al., “Comparison of the effects of fish and fish-oil capsules on the n-3 fatty acid content of blood cells and plasma phospholipids.” Am J Clin Nutr 86:1621-5 (2007).
  Harris, W.S., et al., “Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives.” Atherosclerosis 197:12-24 (2008).
  Harris, W S et al “Stearidonic acid increases the red blood cell and heart eicosapentaenoic acid content in dogs.” Lipids 42:325-333 (2007).
  Harris, W.S., et al., “Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events.” Atherosclerosis 193:1-10 (2007).
  Hartweg, J., et al., “Potential impact of omega-3 treatment on cardiovascular disease in type 2 diabetes.” Curr Opin Lipidol., 20:30-38 (2009).
  Hawthorne, et al., “High dose eicosapentaenoic acid ethyl ester: effects on lipids and neutrophil leukotriene production in normal volunteers.” Br. J. Clin. Pharmac., vol. 30, 187-194 (1990).
  Hayashi et al., Decreases in Plasma Lipid Content and Thrombotic Activity by Ethyl Icosapentate Purified from Fish Oiles, Current Therapeutic Research, vol. 56, No. 1, pp. 24-31 (1995).
  Hibbeln, J. R., et al., “Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity.” Am J Clin Nutr. 83:1483S-93S (2006).
  Hilpert, K.F., et al., “Postprandial effect of n-3 polyunsaturated fatty acids on apolipoprotein B-containing lipoproteins and vascular reactivity in type 2 diabetes.” Am J Clin Nutr 85:369 -76 (2007).
  Hirafuji, M., et al., “Docosahexaenoic acid potentiates interleukin-1beta induction of nitric oxide synthase through mechanism involving p44/42 MAPK activation in rat vascular smooth muscle cells.” British Journal of Pharmacology 136:613-619 (2002).
  Hirai, A., et al., “The effects of the oral administration of fish oil concentrate on the release and the metabolism of [14C ] arachidonic acid and [14C ] eicosapentaenoic acid by human platelets”, Thromb. Res., 28:285-298, (1982).
  Hirano, R., et al., “Regulation by long-chain fatty acids of the expression of cholesteryl ester transfer protein in HepG2 cells.” Lipids, 36:401-406 (2001).
  Holmeide, A. K., et al., “Oxidative degradation of eicosapentaenoic acid into polyunsaturated aldehydes.” Tetrahedron 59:7157-7162 (2003).
  Holub, B.J., PhD, “Fish Oils and Cardiovascular Disease”, Canadian Medical Association Journal, 141(10):1063 (1989).
  Hombeck, M., et al., “Biosynthesis of the algal pheromone fucoserratene by the freshwater diatom Asterionella formosa (Bacillariophyceae).” Tetrahedron 54:11033-11042 (1998).
  Hoskins et al., “Combination use of statins and omega-3 fatty acids: an emerging therapy for combined hyperlipidemia,” Abstract, 1(5): 579-591(13) (2006).
  Howe, P.R.C., et al., “Equal antithrombotic and triglyceride-lowering effectiveness of eicosapentaenoic acid-rich and docosahexaenoic acid-rich fish oil supplements.” Lipids 34:S307-S308 (1999).
  Huntington's Diesase Drug Works—The DHA Dilemma http://hddrugworks.org/index2.php?option=comcontent&task=view&id=185&pop=1&pa . . . Printed on Aug. 22, 2008.
  Illingworth, DR, et al., “Comparative effects of lovastatin and niacin in primary hypercholesterolemia: A prospective trial”, Arch. Int. Med., 154:1586-1595, (1994).
  Inoue, I., et al., “Expression of peroxisome proliferator-activated receptor ? (PPAR?) in primary cultures of human vascular endothelial cells.” Biochem. Biophys. Res. Comm., 246, 370-374 (1998).
  Ishida, Y., et al., “?-Lipoic Acid and Insulin Autoimmune Syndrome.” Diabeters Care, 30(9): 2240-41 (2007).
  Isley, et al., “Pilot study of combined therapy with w-3 fatty acids and niacin in atherogenic dyslipidemia,” Journal of Clinical Lipidology, 1, 211-217 (2007).
  Jacobson et al. “Hypertriglyceridemia and Cardiovascular Risk Reduction”, Clinical Therapeutics, vol. 29 pp. 763-777 (2007).
  Jacobson, T. Secondary Prevention of Coronary Artery Disease with Omega-3 Fatty Acids. Am J Cardiol; 98 [suppl]: 61i-70i (2006).
  Jacobson, T.A., “Role of n-3 fatty acids in the treatment of hypertriglyceridemia and cardiovascular disease.” Am J Clin Nutr 87:1981S-90S (2008).
  Jacobson, T.A., et al., “Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: A review.” J. Clin. Lipidology, vol. 6, pp. 5-18 (2012).
  Jenner, “Presymptomatic Detection of Parkinson's Disease”. J Neural Transm Suppl., 40:23-36. (Abstract only) (1993).
  Jialal, I., “Editorial: Remnant lipoproteins: measurement and clinical significance.” Clinical Chemistry 48(2):217-219 (2002).
  Jung, U.J., et al., “n-3 Fatty acids and cardiovascular disease: mechanisms underlying beneficial effects.” Am J Clin Nutr 87: 2003S-9S (2008).
  Kanayasu, T., et al., “Eicosapentaenoic acid inhibits tube formation of vascular endothelial cells in vitro.” Lipids 26:271-276 (1991).
  Katan, M. B., et al., “Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes, and adipose tissue: an 18-month controlled study.” J. Lipid Res. 38: 2012-2022 (1997).
  Katayama et al., “Efficacy and Safety fo Ethyl Icosapentate (Epadel) Given for a Long Term Against Hyperlipidemia,” Prog. Med., 21:457-467, translated from Japanese (2001).
  Kato, T., et al., “Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets.” Diabetes, 57(9):2382-2392 (2008) (published online May 5, 2008.).
  Kawano, H., et al., “Changes in aspects such as the collagenous fiber density and foam cell size of atherosclerotic lesions composed of foam cells, smooth muscle cells and fibrous components in rabbits caused by all-cis 5, 8, 11, 14, 17-icosapentaenoic acid”, J. Atheroscler. Thromb., 9:170-177, (2002).
  Kawashima, H., et al., “Oral Administration of Dihomo-?-Linolenic Acid Prevents Development of Atopic Dermatitis in NC/Nga Mice.” Lipids 43:37-43 (2008).
  Kelley, D. S., et al., “Docosahexaenoic Acid Supplementation Decreases Remnant-Like Particle-Cholesterol and Increases the (n-3) Index in Hypertriglyceridemic Men.” J. Nutr. 138: 30-35 (2008).
  Kelley, et al., “Docosahexaenoic acid supplementation improves fasting and postprandial lip profiles in hypertriglyceridemic men.” The American Journal of Clinical Nutrition, 86: 324-333 (2007).
  Kew, S., et al., “Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans.” Am J Clin Nutr 79:674-81 (2004).
  Kimura, F., et al., “Long-term supplementation of docosahexaenoic acid-rich, eicosapentaenoic acid-free microalgal oil in n-3 fatty acid-deficient rat pups.” Biosci. Biotechnol. Biochem., 72(2):608-610 (2008).
  Kinsella, J.E., et al., “Dietary n-3 polyunsaturated fatty acids and amelioration of cardiovascular disease: possible mechanisms.” Am J Clin Nutr 52:1-28 (1990).
  Knopp, R.H., et al., “Contrasting effects of unmodified and time-release forms of niacin on lipoproteins in hyperlipidemic subjects: clues to mechanism of action of niacin”, Metabolism, 34:642-650, (1985).
  Kohno, M., et al., “Inhibition by Eicosapentaenoic Acid of Oxidized-LDL- and Lysophosphatidylcholine-Induced Human Coronary Artery Smooth Muscle Cell Production of Endothelin.” J. Vasc. Res. 38:379-388 (2001).
  Kojima, T,. et al., “Long-term administration of highly purified eicosapentaenoic acid provides improvement of psoriasis.” Dermatologica, 182:225-230 (1991).
  Kosonen, O., et al., “Inhibition by nitric oxide-releasing compounds of E-selectin expression in and neutrophil adhesion to human endothelial cells.” European Journal of Pharmacology 394:149-156 (2000).
  Kris-Ehterton, P. M., et al., “Omega-3 Fatty Acids and Cardiovascular Disease—New Recommendations From the American Heart Association.” Arterioscler Thromb Vasc Biol. 23:151-152 (2003).
  Kris-Etherton, et al., “Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease” Circulation, 106:2747-2757 (2002).
  Ku, K., et al., “Beneficial Effects of to-3 Fatty Acid Treatment on the Recovery of Cardiac Function After Cold Storage of Hyperlipidemic Rats.” Metabolism, 48(10):123-1209 (1999).
  Kurabayashi, T., et al., “Eicosapentaenoic acid effect on hyperlipidemia in menopausal Japanese women.” Obstet Gynecol 96:521-8 (2000).
  Lai, E., et al., “Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1”, Clin. Pharm. & Ther., 81:849-857, (2007).
  Laidlaw, M., et al., “Effects of supplementation with fish oil-derived n-3 fatty acids and ?-linolenic acid on circulating plasma lipids and fatty acid profiles in women.” Am J Clin Nutr 77:37-42 (2003).
  Larsen, L.N., et al., “Heneicosapentaenoate (21:5n-3): Its incorporation into lipids and its effects on arachidonic acid and eicosanoid Synthesis.” Lipids 32:707-714 (1997).
  Law, M.R., et al., “Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.” Br Med J., 326:1423-1427 (2003).
  Leaf, A., “Historical overview of n3 fatty acids and coronary heart disease.” Am J Clin Leaf, Nutr 87:1978S-80S. (2008).
  Lee and G.Y.H. Lip, “The Role of Omega-3 Fatty Acids in the Secondary Prevention of Cardiovascular Disease”, Q J Med, 96:465-480, (2003).
  Lee, J.H., et al., “Omega-3 fatty acids for cardioprotection.” Mayo Clin Proc., 83(3):324-332 (2008).
  Lemaitre, R.N., et al., “n-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study.” Am J Clin Nutr 77:319-25 (2003).
  Leonard, Brian E., “Neurological Aspects”, Fundamentals of Psychopharmacology, 186-187, (1997).
  Leucht, S., et al., Schizophrenia Research, vol. 35, “Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials”, pp. 51-68, (1999).
  Li, D. et al., “Effect of dietary a-linolenic acid on thrombotic risk factors in vegetarian men.” Am J Clin Nutr 69:872-82 (1999).
  Li, H. et al., “EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: Evidence for a PPAR-?-dependent mechanism.” Kidney Int'l. 67:867-74 (2005).
  Lien, E.L., “Toxicology and safety of DHA.” Prostaglandins Leukot Essent Fatty Acids., 81:125-132 (2009).
  Lin, Pao-Yen, M.D., et al., “A Meta-Analytic Review of Double-Blind, Placebo-Controlled Trials of Antidepressant Efficacy of Omega-3 Fatty Acids”, Psychiatry, 1056-1061 (Jul. 2007).
  Lin, Y., et al., “Differential effects of eicosapentaenoic acid on glycerolipid and apolipoprotein B metabolism in primary human hepatocytes compared to HepG2 cells and primary rat hepatocytes.” Biochimica et Biophysica Acta 1256:88-96 (1995).
  Lindsey, S., et al., “Low density lipoprotein from humans supplemented with n-3 fatty acids depresses both LDL receptor activity and LDLr mRNA abundance in HepG2 cells.” J Lipid Res., 33:647-658 (1992).
  Lohmussaar, E., et al., “ALOX5AP Gene and the PDE4D Gene in a Central European Population of Stroke Patients.” Stroke, 36:731-736 (2005).
  Lu, G., et al., “Omega-3 fatty acids alter lipoprotein subfraction distributions and the in vitro conversion of very low density lipoproteins to lowdensity lipoproteins.” J Nutr Biochem., 10:151-158 (1999).
  Lucas, M., et al., “Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women: a double-blind, placebo-controlled, randomized clinical trial.” Am J Clin Nutr 89:641-51 (2009).
  Luria, MH, “Effect of low-dose niacin on high-density lipoprotein cholesterol and total cholesterol/high density lipoprotein cholesterol ratio”, Arch. Int. Med., 148:2493-2495, (1998).
  Madhavi et al., “Effect of n-6 and n-3 fatty acids on the survival of vincristine sensitive and resistant human cervical carcinoma cells in vitro”, Cancer Letters, vol. 84. No. 1, pp. 31-41 (1994).
  Madsen, L., et al., “Eicosapentaenoic and Docosahexaenoic Acid Affect Mitochondrial and Peroxisomal Fatty Acid Oxidation in Relation to Substrate Preference.” Lipids 34:951-963 (1999).
  Maki, K.C., et al., “Baseline lipoprotein lipids and low-density lipoprotein cholesterol response to prescription omega-3 acid ethyl ester added to simvastatin therapy.” Am J Cardiol., 105:1409-1412 (2010).
  Maki, PhD, et al., “Lipid Responses to a Dietary Docosahexaenoic Acid Supplement in Men and Women with Below Average Levels of High Density Lipoprotein Cholesterol.” Journal of the American College of Nutrition, vol. 24, No. 3, 189-199 (2005).
  Mallat, Z., et al., “Apoptosis in the vasculature: mechanisms and functional importance.” British Journal of Pharmacology 130:947-962 (2000).
  Mallat, Z., et al., “Protective role of interleukin-10 in atherosclerosis.” Circ. Res. 85:e17-e24 (1999).
  Marangell, Lauren B., M.D., et al., “A Double-Blind, Placebo-Controlled Stury of the Omega-3 Fatty Acid Docosahexaenoic Acid in the Treatment of Major Depression”, Am. J. Psychiatry, 160(5):996-998, (May 2003).
  Marckmann, P., “Fishing for heart protection.” Am J Clin Nutr, 78:1-2 (2003).
  Martin-Jadraque, R. et al., Effectiveness of low dose crystalline nicotinic acid in men with low density lipoprotein cholesterol levels. Arch. Int. Med. 156: 1081-1088. (1996).
  Mater, M.K., et al., “Arachidonic acid inhibits lipogenic gene expression in 3T3-L1 adipocytes through a prostanoid pathway.” J. Lipid Res. 39:1327-1334 (1998).
  Matsumoto, M., et al., “Orally administered eicosapentaenoic acid reduces and stabilizes atherosclerotic lesions in ApoE-deficient mice.” Atherosclerosis, 197(2):524-533 (2008).
  Matsuzawa, Y., et al., “Effect of Long-Term Administration of Ethyl Icosapentate (MND-21) In Hyperlipaemic Patients,” J. Clin Therapeutic & Medicines, 7: 1801-16 (1991).
  Mayatepek, E., et al., The Lancet, vol. 352, Leukotriene C4-synthesis deficiency: a new inborn error of metabolism linked to a fatal developmental syndrome, pp. 1514-1517 (1998).
  McElroy, S.L., et al., “Clozapine in the Treatment of Psychotic Mood Disorders, Schizoaffective Disorder, and Schizophrenia”, Journal of Clinical Psychiatry, vol. 52, No. 10, pp. 411-414 (1991).
  McKenney, James et al., “Role of prescription omega-3 fatty acids in the treatment of Hypertriglyceridemia,” Pharmacotherapy, LNKD—Pubmed: 17461707, vol. 27, No. 5, pp. 715-728 (2007).
  McMurchie, E.J., et al., “Incorporation and effects of dietary eicosapentaenoate (20 : 5(n-3)) on plasma and erythrocyte lipids of the marmoset following dietary supplementation with differing levels of linoleic acid.” Biochimica et Biophysics Acta, 1045:164-173 (1990).
  Menuet, R. et al., “Importance and management of dyslipidemia in the metabolic syndrome,” American Journal of the Medical Sciences 200512 US, vol. 33, No. 6, pp. 295-302 (2005).
  Merched, A.J., et al., “Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators.” FASEB J. 22:3595-3606 (2008).
  Mesa, M., “Effects of oils rich in Eicosapentaenoic and docosahexaenoic acids on the oxidizability and thrombogenicity of low-density lipoprotein,” Artherosclerosis 175, pp. 333-343 (2004).
  Metcalf, R.G. et al., “Effect of dietary n-3 polyunsaturated fatty acids on the inducibility of ventricular tachycardia in patients with ischemic cardiomyopathy.” Am J Cardiol 101:758-761 (2008).
  Metcalf, R.G., et al., “Effects of fish-oil supplementation on myocardial fatty acids in humans.” Am J Clin Nutr 85:1222-28 (2007).
  Meyer, et al., “Dose-Dependent Effects of Docosahexaenoic Acid Supplementation on Blood Lipids in Statin-Treated Hyperlipidaemic Subjects.” Lipids, 42:109-115 (2007).
  Meyers, et al., “Nicotinic acid induces secretion of prostaglandin D2 in human macrophages: An in vitro model of the niacin-flush”, Atherosclerosis, 192:253-258, (2007).
  Mii S. et al., “Perioperative use of eicosapentaenoic acid and patency of infrainguinal vein'' bypass: a retrospective chart review.” Curr Ther Res Clin Exp. 68:161-174 (2007).
  Miller, M., et al., “Impact of lowering triglycerides on raising HDL-C in hypertriglyceridemic and non-hypertriglyceridemic subjects.” International Journal of Cardiology 119:192-195 (2007).
  Minihane, A.M., et al., “ApoE polymorphism and fish oil supplementation in subjects with an atherogenic lipoprotein phenotype.” Arterioscler. Thromb. Vasc. Biol. 20:1990-1997 (2000).
  Mishra, A., et al., “Oxidized omega-3 fatty acids inhibit NF-?B activation via a PPAR?—Dependent Pathway.” Arterioscler Thromb Vasc Biol. 24:1621-1627 (2004).
  Mita, T. et al., Eicosapentaenoic acid reduces the progression of carotid intima-media thickness in patients with type 2 diabetes, Atherosclerosis 191:162-167 (2007).
  Mizota M, Katsuki Y, Mizuguchi K, Endo S, Miyata H, Kojima M, Kanehiro H et al. “Pharmacological studies of eicosapentaenoic acid ethylester (EPA E) on high cholesterol diet-fed rabbits,” Nippon Yakurigaku Zasshi, 91:255-66 (1988) (with English abstract).
  Mizota M, Katsuki Y, Mizuguchi K, Endo S, Miyata H, Kojima M, Kanehiro H et al. “The effects of eicosapentaenoic acid ethylester (EPA E) on arterial thrombosis in rabbits and vascular lesions in rats,” Nippon Yakurigaku Zasshi, 91:81-9 (1988)(with English abstract).
  Mizuguchi K, Yano T, Kojima M, Tanaka Y, Ishibashi M, Masada A, Sato M et al. “Hypolipidemic effect of ethyl all-cis-5,8,11,14,17-eicosapentaenoate (EPA-E) in rats,” Jpn J Pharmacol., 59:3307-12 (1992).
  Mizuguchi, K., et al., “Ethyl all-cis-5,8,11,14,17-icosapentaenoate modifies the biochemical properties of rat very low-density lipoprotein.” European Journal of Pharmacology, 231:221-227 (1993).
  Mizuguchi, K., et al., “Mechanism of the lipid-lowering effect of ethyl all-cis-5,8,11,14,17-icosapentaenoate.” European Journal of Pharmacology, 231:121-127 (1993).
  Mora, S., et al., “LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA).” Atherosclerosis. 2007;192:211-217 (2007).
  Mori TA, Woodman RJ. “The independent effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular risk factors in humans,” Curr Opin Clin Nutr Metab Care 2006; 9:95-104 (2006).
  Mori, et al., “Purified Eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men,” Am J Clin Nutr 2000; 71:1085-1094 (2000).
  Mori, T. et al., Effect of Eicosapentaenoic acid and docosahexaenoic acid on oxidative stress and inflammatory markers in treated-hypertensive type 2 diabetic subjects, Free Radical Biology & Medicine, vol. 35, No. 7, pp. 772-781 (2003).
  Mori, Trevor A., et al., “Docosahexaenoic Acid but Not Eicosapentaenoic Acid Lowers Ambulatory Blood Pressure and Heart Rate in Humans”, Hypertension, 34(2):253-60 (Aug. 1999).
  Morita, I., et al., “Effects of purified eicosapentaenoic acid on arachidonic acid metabolism in cultured murine aortic smooth muscle cells, vessel walls and platelets.” Lipids 18:42-490 (1983).
  Morrow, JD, “Release of markedly increased quantities of prostaglandin D2 in vivo in humans following the administration of nicotinic acid”, Prostaglandins, 38:263-274, (1989).
  Morton, R.E., “Specificity of lipid transfer protein for molecular species of cholesteryl ester.” J Lipid Res., 27:523-529 (1986).
  Mosher LR et al., “Nicotinic Acid Side Effects and Toxicity: A review,” Am J Psychiat., 126: 1290-1296 (1970).
  Mostad, I.L, et al., “Effects of n-3 fatty acids in subjects with type 2 diabetes: reduction of insulin sensitivity and time-dependent alteration from carbohydrate to fat oxidation.” Am J Clin Nutr 84:540-50 (2006).
  Mozaffarian, “JELIS, fish oil, and cardiac events,” www.thelancet.com vol. 369, pp. 1062-1063 (2007).
  Mozaffarian, D., “Fish and n-3 fatty acids for the prevention of fatal coronary heart disease and sudden cardiac death.” Am J Clin Nutr, 87:1991S-6S (2008).
  Mozaffarian, D. et al., “Dietary fish and ω-3 fatty acid consumption and heart rate variability in US adults.” Circulation, 117:1130-1137 (2008).
  Naba, H., et al., “Improving effect of ethyl eicosapentanoate on statin-induced rhabdomyolysis in Eisai hyperbilirubinemic rats.” Biochemical and Biophysical Research Communications, 340:215-220 (2006).
  Nakamura, et al., “Effects of Eicosapentaenoic Acids on Remnant-like Particles, Cholesterol Concentrations and Plasma Fatty Acid Composition in Patients with Diabetes mellitus.” in vivo 12: 311-314 (1998).
  Nakamura, H., et al., “Evaluation of ethyl icosapentate in the treatment of hypercholesterolemia in kidney transplant recipients.” Transplantation Proceedings, 30:3047-3048 (1998).
  Nakamura, N. et al., “Joint effects of HMG-CoA reductase inhibitors and eicosapentaenoic acids on serum lipid profile and plasma fatty acid concentrations in patients with hyperlipidemia,” International Journal of Clinical and Laboratory Research, Springer, Berlin, DE LNKD-DOI: 10.1007/S005990050057, vol. 29, No. 1, pp. 22-25 (1999).
  Nambi, V., et al., “Combination therapy with statins and omega-3 fatty acids.” Am J Cardiol 98:34i-38i (2006).
  Nasa, et al., “Long-Term Supplementation With Eicosapentaenoic Acid Salvages Cardiomyocytes From Hypoxia/Reoxygenation-Induced Injury in Rats Fed With Fish-Oil-Deprived Diet,” Jpn. J. Pharmacol. 77, 137-146 (1998).
  Nattel, S. et al., “Atrial remodeling and atrial fibrillation: Mechanisms and implications.” Circ Arrhythmia Electrophysiol, 1:62-73 (2008).
  Negre-Salvayre, A., et al., “Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors.” British Journal of Pharmacology 153:6-20 (2008).
  Nelson, G.J., et al., “The Effect of Dietary Docosahexaenoic Acid on Plasma Lipoproteins and Tissue Fatty Acid Composition in Humans”, Lipids, 32(11):1137-1146, (1997).
  Nemets, Boris, M.D., “Addition of Omega-3 Fatty Acid to Maintenance Medication Treatment for Recurrent Unipolar Depressive Disorder”, Am. J. Psychiatry, 159(3):477-479, (Mar. 2002).
  Nenseter, MS et al., “Effect of dietary supplementation with n-3 polyunsaturated fatty acids on physical properties and metabolism of low density lipoprotein in humans,” Arterioscler. Thromb. Vasc. Biol., 12;369-379 (1992).
  Nestel, et al., “The n—3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans,” Am J Clin Nutr., 76:326-30 (2002).
  Nestel, P.J., “Effects of N-3 fatty acids on lipid metabolism.” Ann Rev Nutr., 10:149-167 (1990).
  Nishikawa M. et al., “Effects of Eicosapentaenoic acid (EPA) on prostacyclin production in diabetics. GC/MS analysis of PG12 and PG13 levels” Methods Find Exp Clin Pharmacol. 19(6):429-33 (1997).
  Nobukata, H., et al., “Age-related changes in coagulation, fibrinolysis, and platelet aggregation in male WBN/Kob rats.” Thrombosis Research 98: 507-516 (2000).
  Nobukata, H., et al., “Long-term administration of highly purified eicosapentaenoic acid ethyl ester improves the dysfunction of vascular endothelial and smooth muscle cells in male WBN/Kob rats.” Metabolism, 49(12): 1588-1591 (2000).
  Nobukata, H., et al., “Long-term administration of highly purified eicosapentaenoic acid ethyl ester prevents diabetes and abnormalities of blood coagulation in male WBN/Kob rats.” Metabolism, 49(12): 912-919 (2000).
  Nourooz-Zadeh, J., et al., “Urinary 8-epi-PGF2? and its endogenous ?-oxidation products (2,3-dinor and 2,3-dinor-5,6-dihydro) as biomarkers of total body oxidative stress.” Biochemical and Biophysical Research Communications 330:731-736 (2005).
  Nozaki S. et al., “Effects of purified Eicosapentaenoic acid ethyl ester on plasma lipoproteins in primary hypercholesterolemia” Int J Vitam Nutr Res. 62(3):256-60 (1992).
  Obata, et al., “Eicosapentaenoic acid inhibits prostaglandin D2 generation by inhibiting cyclo-oxygenase in cultured human mast cells”, Clin. & Experimental Allergy, 29:1129-1135, (1999).
  O'Donnell, C.J., et al., “Leukocyte telomere length and carotid artery intimal medial thickness—the Framingham heart study.” Arteriosclerosis, Thrombosis, and Vascular Biology.28:1165-1171 (2008).
  Oh, Robert C et al., Management of Hypertriglyceridemia, American Family Physician, LNKD-PUBMED: 17508532, vol. 75, No. 9, pp. 1365-1371 (2007).
  Okuda, Y. et al., Eicosapentaenoic acid enhances nitric oxide production by cultured human endothelial cells. Biochem. Biophys. Res. Commun. 232: 487-491 (1997).
  Okuda, Y., et al., “Long-term effects of eicosapentaenoic acid on diabetic peripheral neuropathy and serum lipids in patients with type II Diabetes mellitus.” Journal of Diabetes and Its Complications 10:280-287 (1996).
  Okumura, T., et al., “Eicosapentaenoic acid improves endothelial function in hypertriglyceridemic subjects despite increased lipid oxidizability.” Am J Med Sci 324(5):247-253 (2002).
  Oliw, E.H., et al., “Biosynthesis of prostaglandins from 17(18)epoxy-eicosatetraenoic acid, a cytochrome P-450 metabolite of eicosapentaenoic acid.” Biochimica el Biophysica Acta, 1126, 261-268 (1992).
  Ona, V.O., et al., Nature, vol. 399, Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease, pp. 263-267 (1999).
  Ozawa A, Nakamura E, Jinbo H. Fujita T, Hirai A, Terano T, Hamazaki T et al. “Measurement of higher lipids in the fractions of human red blood cell membranes, blood platelets and plasma, using thin layer chromatography and gas chromatography,” Bunseki Kagaku, 32:174-8 (1982).
  Park, Y., et al., “Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance.” J. Lipid Res. 44:455-463 (2003).
  Pedersen RS, Damkier P, Brosen K. The effects of human CYP2C8 genotype and fluvoxamine on the pharmacokinetics of rosiglitazone in healthy subjects. Br. J. Clin. Pharmacol. 2006;62:682-689.
  Peet et al., “A Dose-Ranging Study of the Effects of Ethyl-Eicosapentaenoate in Patients with Ongoing Depression Despite Apparently Adequate Treatment with Standard Drugs”, Arch. Gen. Psychiatry, 59:913-919, (2002).
  Peet, M., et al., Phospholipid Spectrum Disorder in Psychiatry pp. 1-19, (1999).
  Piccini, Monica, et al., Genomics, vol. 47, “FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is deleted in a family with Alport syndrome, elliptocytosis, and mental retardation,” pp. 350-358 (1998).
  Pike, NB, “Flushing out the role of GPR109A (HM74V) in the clinical efficacy of nicotinic acid”, J. Clin. Invest., 115:3400-3403, (2005).
  Pownall, H.J., et al., “Correlation of serum triglyceride and its reduction by ?-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins.” Atherosclerosis 143:285-297 (1999).
  Press Release: Amarin Corporation Says Huntington's Diease Drug Failed in Trials, http://www.fiercebiotech.com/node/6607/print (Apr. 24, 2007) (Printed on Aug. 22, 2008).
  Puri, B., et al., “Eicosapentaenoic Acid in Treatment-Resistant Depression Associated with Symptom Remission, Structural Brain Changes and Reduced Neuronal Phospholipid Turnover,” Int J Clinical Practice, 55:560-563 (2001).
  Puri, B., et al., Archives of General Psychiatry, No. 55, “Sustained remission of positive and negative symptoms of schizophrenia following treatment with eicosapentaenoic acid,” pp. 188-189, (1998).
  Puri, B.K., et al., “Ethyl-EPA in Huntington Disease: A Double-Blind, Randomized, Placebo-Controlled Trial”, Neurology, 65:286-292, (2005).
  Qi, K., et al., “Omega-3 fatty acid containing diets decrease plasma triglyceride concentrations in mice by reducing endogenous triglyceride synthesis and enhancing the blood clearance of triglyceride-rich particles.” Clinical Nutrition 27(8):424-430 (2008).
  Raitt, M.H., et al., “Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators—a randomized controlled trial.” JAMA. 293(23):2884-2891 (2005).
  Rambjor, Gro S., et al., “Elcosapentaenoic Acid is Primarily Responsible for Hypotrigylceridemic Effect of Fish Oil in Humans”, Fatty Acids and Lipids from Cell Biology to Human Disease: Proceedings of the 2nd international Congress of the ISSFAL (International Society for the Study of Fatty Acids and Lipids, AOCS Press, 31:S-45-S-49, (1996).
  Reiffel, J.A., et al., “Antiarrhythmic effects of omega-3 fatty acids.” Am J Cardiol 98:50i-60i (2006).
  Riediger, N.D., et al., “A systemic review of the roles of n-3 fatty acids in health and disease.” J Am Diet Assoc. 109:668-679. (2009).
  Risé, P., et al., “Effects of simvastatin on the metabolism of polyunsaturated fatty acids and on glycerolipid, cholesterol, and de novo lipid synthesis in THP-1 cells.” J. Lipid Res. 38:1299-1307 (1997).
  Roach, P.D. et al., “The effects of dietary fish oil on hepatic high density and low density lipoprotein receptor activities in the rat.” FEBS Lett., 222: 159-162 (1987).
  Robinson, J.G., et al., “Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart risk.” J Am Coll Cardiol., 53: 316-322 (2009).
  Roche, H.M., et al., “Effect of long-chain n-3 polyunsaturated fatty acids on fasting and postprandial triacylglycerol metabolism.” Am J Clin Nutr 71:232S-7S (2000).
  Roche, H.M., et al., “Long-chain n-3 polyunsaturated fatty acids and triacylglycerol metabolism in the postprandial state.” Lipids 34: S259-S265 (1999).
  Rodriguez, Y., et al., “Long-chain ?6 polyunsaturated fatty acids in erythrocyte phospholipids are associated with insulin resistance in non-obese type 2 diabetics.” Clinica Chimica Acta 354:195-199 (2005).
  Rogers, P. J., “No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial” British Journal of Nutrition, 99:421-431, (2008).
  Rubins, HB, et al., “Distribution of lipids in 8,500 men with coronary artery disease: Department of Veterans Affairs HDL Intervention Trial Study Group,” Am. J. Cardiol, 75:1196-1201, (1995).
  Rubins, HB, et al., “Gemfibrozil for the prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs HDL-C Intervention Trial Study Group”, N. Eng. J. Med., 341:410-418, (1999).
  Ruiz-Narváez, E.A., et al., “Abdominal obesity and hyperglycemia mask the effect of a common APOC3 haplotype on the risk of myocardial infarction.” Am J Clin Nutr 87:1932-8 (2008).
  Rustan, A.C., et al., “Eicosapentaenoic acid inhibits cholesterol esterification in cultured parenchymal cells and isolated microsomes from rat liver.” J. Bio. Chem. 263(17):8126-32 (1988).
  Rustan, A.C., et al., “Eicosapentaenoic acid reduces hepatic synthesis and secretion of triacylglycerol by decreasing the activity of acyl-coenzyme A:1,2-diacylglycerol acyltransferase.” J. Lipid Res. 29:1417-1426 (1988).
  Rustan, A.C., et al., “Postprandial decrease in plasma unesterified fatty acids during n-3 fatty acid feeding is not caused by accumulation of fatty acids in adipose tissue.” Biochimica et Biophysica Acta 1390.245-25 (1998).
  Ryan, A.M., et al., “Enteral nutrition enriched with eicosapentaenoic acid (EPA) preserves lean body mass following esophageal cancer surgery: results of a double-blinded randomized controlled trial.” Ann Surg 249:355-363 (2009).
  Ryan, A.S., et al., “Clinical overview of algal-docosahexaenoic acid: effects on triglyceride levels and other cardiovascular risk factors.” Am J Ther., 16:183-192 (2009).
  Sacks, Frank M., “The apolipoprotein story,” Atherosclerosis Supplements, 23-27 (2006).
  Saito et al., “Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: Sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS),” Atherosclerosis, 200:135-140 (2008).
  Saito, J., et al., “Mechanisms of enhanced production of PGI2 in cultured rat vascular smooth muscle cells enriched with eicosapentaenoic acid.” Atherosclerosis 131: 219-228 (1997).
  Sanders, A. Hinds and C.C. Pereira, “Influence of n-3 fatty acids on blood lipids in normal subjects” Journal of Internal Medicine. 225:99-104,(1989).
  Sanders, et al., “Influence of an algal triacylglycerol containing docosahexaenoic acid (22:6n-3) and docosapentaenoic acid (22:5n-6) on cardiovascular risk factors in healthy men and women,” British Journal of Nutrition, 95, 525-531 (2006).
  Sanders, T.A., et al., “Effect of varying the ratio of n-6 to n-3 fatty acids by increasing the dietary intake of α-linolenic acid, eicosapentaenoic and docosahexaenoic acid, or both on fibrinogen and clotting factors VII and XII in persons aged 45-70 y: the OPTILIP Study.” Am J Clin Nutr 84:513-22 (2006).
  Sanders, T.A., et al., “Triglyceride-lowering effect of marine polyunsaturates in patients with hypertriglyceridemia.” Arterioscler. Thromb. Vasc. Biol. 5:459-465 (1985).
  Sasaki, Y.F., et al., “Bio-anticlastogenic effects of unsaturated fatty acids included in fish oil—docosahexaenoic acid, docosapentaenoic acid, and eicosapentaenoic acid—in cultured Chinese hamster cells.” Mutation Research, 320: 9-22 (1994).
  Sato et al., “General Pharmacological Studies on 5 8 11 14 17 Eicosapentaenoic Acid Ethyl Ester EPA-E”, Folia Pharmacol JPN, 94 (1), 35-48. (1989).
  Satoh-Asahara N, Shimatsu A, Sasaki Y, Nakaoka H, Himeno A, Tochiya M, Kono S, Takaya T, Ono K, Wada H, Suganami T, Hasegawa K, Ogawa Y. Highly purified eicosapentaenoic acid increases interleukia-10 levels of peripheral blood monocytes in obese patients with dyslipidemia.Diabetes Care. 2012;35(12):2631-2639.
  Schaefer, E.J., et al., “Effects of eicosapentaenoic acid, docosahexaenoic acid, and olive oil on cardiovascular disease risk factors [abstract 20007].” Circulation, 122:A20007 (2010).
  Schectman, G. & Hiatt, J., “Drug therapy for hypercholesterolemia in patients with cardiovascular disease: factors limiting achievement of lipid goals”, Am. J. Med., 100:197-204, (1996).
  Schectman, G., et al., “Dietary fish oil decreases low-density-lipoprotein clearance in nonhuman primates.” Am J Clin Nutr., 64:215-221 (1996).
  Schectman, G., et al., “Heterogeneity of Low Density Lipoprotein Responses to Fish-Oil Supplementation in Hypertriglyceridemic Subjects.” Arterioscler. Thromb. Vasc. Biol. 9:345-354 (1989).
  Schmidt, E.B., et al., “Lipoprotein-associated phospholipase A2 concentrations in plasma are associated with the extent of coronary artery disease and correlate to adipose tissue levels of marine n-3 fatty acids.” Atherosclerosis 196: 420-424 (2008).
  Schmitz, G., et al., “The opposing effects of n-3 and n-6 fatty acids.” Progress in Lipid Research, 47:147-155 (2008).
  Schwarz, S., et al., “Lycopene inhibits disease progression in patients with benign prostate hyperplasia.” J. Nutr. 138: 49-53 (2008).
  Serhan, C.N., et al., “Resolvins: A family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals.” J. Exp. Med. 196:1025-1037 (2002).
  Shah, S., et al., “Eicosapentaenoic Acid (EPA) as an Adjunct in the Treatment of Schizophrenia”, Schizophrenia Research, vol. 29, No. 1/02 (1998).
  Shan, Z., et al., “A combination study of spin-trapping, LC/ESR and LC/MS on carbon-centred radicals formed from lipoxygenase-catalysed peroxidation of eicosapentaenoic acid.” Free Radical Research, 43(1):13-27 (2009).
  Shimizu, H., et al., “Long-term effect of eicosapentaenoic acid ethyl (EPA-E) on albuminuria of non-insulin dependent diabetic patients.” Diabetes Research and Clinical Practice 28: 35-40 (1995).
  Shinozaki K. et al., “The long-term effect of Eicosapentaenoic acid on serum levels of lipoprotein (a) and lipids in patients with vasciular disease” J Atheroscler Thromb. 2(2):207-9 (1996).
  Sierra, S., et al., “Dietary eicosapentaenoic acid and docosahexaenoic acid equally incorporate as decosahexaenoic acid but differ in inflammatory effects.” Nutrition 24: 245-254 (2008).
  Silvers, Karen M., et al., “Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression”, Prostagandins, Leukotrienes and Essential Fatty Acids, 72:211-218, (2005).
  Simoens, C.M., et al., “Inclusion of 10% fish oil in mixed medium-chain triacylglycerol-induces rapid eicosapentaenoic acid (20:5n-3) incorporation into blood cell phospholipids.” Am J Clin Nutr 88: 282-8 (2008).
  Simon, Joel A., et al., “Serum Fatty Acids and the Risk of Coronary Heart Disease”, American Journal of Epidemiology, 142(5):469-476, (1995).
  Singh, R.B., et al., “Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival—4.” Cardiovascular Drugs and Therapy 11:485-491 (1997).
  Sirtori, C.R., et al., “One-year treatment with ethyl esters of n-3 fatty acids in patients with hypertriglyceridemia and glucose intolerance—Reduced triglyceridemia, total cholesterol and increased HDL-C.” Atherosclerosis 137: 419-427 (1998).
  Skinner JS, Cooper A, & Feder GS and on behalf of the Guideline Development Group. “Secondary prevention for patients following a myocardial infarction; summary of NICE guidance,” Heart, 93:862-864 (2007).
  Smith et al., Pharmacokinetics and Pharmacodynamics of Epoetin Delta in Two Studies in Health Volunteers and Two Studies in Patients with Chronic Kidney Disease, Clinical Therapeutics/vol. 29, pp. 1368-1380 (2007).
  Sohma, R., et al., “Protective effect of n-3 polyunsaturated fatty acid on primary culture of rat hepatocytes without glycemic alterations.” Journal of Gastroenterology and Hepatology 22: 1965-1970 (2007).
  Spector, A.A., “Arachidonic acid cytochrome P450 epoxygenase pathway.” Journal of Lipid Research, 50: S52-S56 (2009) (published online on Oct. 23, 2008.).
  Spector, A.A., et al., “Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function.” Progress in Lipid Research 43: 55-90 (2004).
  Springer, T.A., “Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm.” Cell, 76: 301-314 (1994).
  Squires, RW, et al., “Low-dose, time release nicotinic acid: effects in selected patients with low concentrations of high density lipoprotein cholesterol”, Mayo Clinic Proc., 67:855-860, (1992).
  Srinivas, et al., “Controlled release of lysozyme from succinylated gelatin microspheres,” J. Biomater. Sci., Polymer Ed., vol. 12(2):137-148 (2001).
  Stalenhoef, A.F.H., et al., “The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertrygliceridemia.” Atherosclerosis 153: 129-138 (2000).
  Stark, K.D. & Holub, B.J., Differential eicosapentaenoic acid elevations and altered cardiovascular disease risk factor responses after supplementation with docosahexaenoic acid in postmenopausal women receiving and not receiving hormone replacement therapy, Am. J. Clin. Nutr., vol. 79, pp. 765-773 (2004).
  Stark, K.D., “The percentage of n-3 highly unsaturated fatty acids in total HUFA as a biomarker for omega-3 fatty acid status in tissues.” Lipids 43:45-53 (2008).
  Stark, K.D., et al., “Effect of a fish-oil concentrate on serum lipids in postmenopausal women receiving and not receiving hormone replacement therapy in a placebo-controlled, double-blind trial.” Am J Clin Nutr 72:389-94 (2000).
  Stoll, Andrew L. et al., “Omega 3 Fatty Acids in Bipolar Disorder”, Arch. Gen. Psychiatry, 56:407-412, (May 1999).
  Su, Kuan-Pin, et al., “Omega-3 Fatty Acids in Major Depressive Disorder a Preliminary Double-Blind, Placebo-Controlled Trial”, European Neuropsychopharmacology, 13:267-271, (2003).
  Sugiyama, E., et al., “Eicosapentaenoic acid lowers plasma and liver cholesterol levels in the presence of peroxisome proliferators-activated receptor alpha.” Life Sciences, 83:19-28 (2008).
  Superko et al., “Lipid Management to Reduce Cardiovascular Risk: A New Strategy is Required,” Circulation, 117:560-568 (2008).
  Surette, M.E., et al., “Dependence on dietary cholesterol for n-3 polyunsaturated fatty acidinduced changes in plasma cholesterol in the Syrian hamster.” J Lipid Res., 33:263-271 (1992).
  Tamura, et al., “Study of the Clinical Usefulness of Ethyl Icosapentate (MND-21) in Long-Term Treatment of Hyperlipaemic Patients.” J Clin Thera & Medicines, 7:1817-1834 (1991).
  Tanaka, K.T., et al., “Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients—Subanalysis of the JELIS trial.” Stroke, 39(7):2052-8 (2008).
  Tatarczyk, et al., “Analysis of long-chain ?-3 fatty acid content in fish-oil supplements,” Wien Klin Wochenschr, 119/13-14: 417-422 (2007).
  Taylor, A.J., et al., “Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins”, Circulation, 110:3512-3517, (2004).
  Tedgui, A., et al., “Anti-inflammatory mechanisms in the vascular wall.” Circ. Res. 88:877-887 (2001).
  Terano, et al., “Effect of Oral Administration of Highly Purified Eicosapentaenoic Acid on Platelet Function, Blood Vicosity and Red Cell Deformability in Healthy Human Subjects,” Atherosclerosis, 46, 321-331 (1983).
  Theilla, M., et al., “A diet enriched in eicosapentanoic acid, gamma-linolenic acid and antioxidants in the prevention of new pressure ulcer formation in critically ill patients with acute lung injury: a randomized, prospective, controlled study.” Clinical Nutrition 26: 752-757 (2007).
  Thies, F., et al., “Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial.” Lancet 361: 477-85 (2003).
  Thies, F., et al., “Dietary supplementation with eicosapentaenoic acid, but not with other long-chain n-3 or n-6 polyunsaturated fatty acids, decreases natural killer cell activity in healthy subjects aged >55 y.” Am J Clin Nutr 73:539-48 (2001).
  Tirosh et al., “Changes in Triglyceride Levels and Risk for Coronary Heart Disease in Young Men,” American College of Physicians, pp. 377-385 (2007).
  Torrejon, C. et al., “n-3 Fatty acids and cardiovascular disease: Actions and molecular mechanisms,” Prostaglandins Leukotrienes & Essent. Fatty Acids, doi:10.1016/j.plefa.2007.10.014 (2007).
  TREND-HD Investigators, Randomized controlled trial of ethyl-eicosapentaenoic acid in Huntington disease: the TREND-HD study, Arch Neurol., vol. 65(12): 1582-9 (2008).
  Tsuruta K., et al.,“Effects of purified eicosapentaenoate ethyl ester on fibriolytic capacity in patients with stable coronary artery disease and lower extremity ischaemia” Coron Artery Dis. 7(11):837-42 (Nov. 1996).
  Ullian, M.E., “Fatty acid inhibition of angiotensin II-stimulated inositol phosphates in smooth muscle cells.” Am J Physiol Heart Circ Physiol (1996).
  Urakaze, Masaharu, et al., “Infusion of emulsified trieicosapentaenoylglycerol into rabbits. The effects on platelet aggregation, polymorphonuclear leukocyte adhesion, and fatty acid composition in plasma and platelet phosphollpids”, Thromb. Res., 44(5):673-682 (1986).
  US Food and Drug Administration and Dept of Health and Human Services. Substances affirmed as generally recognized as safe: Menhaden Oil. Fed Register, 62:30751-30757 (1997).
  Vaddadi, K.S., et al., “A Randomised, Placebo-Controlled, Double-Blind Study of Treatment of Huntington's Disease with Unsaturated Fatty Acids”, Clinical Neuroscience and Neuropathology, 13(1):29-33, (Jan. 2002).
  Van der Steeg, W.A., et al., “High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: Significance for cardiovascular risk—the IDEAL and EPIC-Norfolk studies.” J. Am. Coll. Cardiol. 51;634-642 (2008).
  Vasudevan et al., “Effective Use of Combination of Lipid Therapy”, Curr. Atheroscl. Rep., vol. 8, pp. 76-84 (2006).
  Vedin, I., et al., “Effects of docosahexaenoic acid—rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study.” Am J Clin Nutr 87:1616-22 (2008).
  Vidgren, H.M., et al., “Incorporation of n-3 fatty acids into plasma lipid fractions, and erythrocyte membranes and platelets during dietary supplementation with fish, fish oil, and docosahexaenoic acid-rich oil among healthy young men.” Lipids 32: 697-705 (1997).
  Volcik, K.A., et al., “Peroxisome proliferator—activated receptor agenetic variation interacts with n-6 and long-chain n-3 fatty acid intake to affect total cholesterol and LDL-cholesterol concentrations in the Atherosclerosis Risk in Communities Study.” Am J Clin Nutr 87:1926-31 (2008).
  Von Schacky, C., “A review of omega-3 ethyl esters for cardiovascular prevention and treatment of increased blood triglyceride levels.” Vascular Health and Risk Management 2(3): 251-262 (2006).
  Von Schacky, C., et al., “The Effect of Dietary ω-3 Fatty Acids on Cornoray Atherosclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial”, American College of Physicians-American Society of Internal Medicine, 130(7):554-562, (1999).
  Wada, M., et al., “Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products.” J. Biol. Chem. 282(31): 22254-22266 (2007).
  Walldius, G., et al., “Editorial: Rationale for using apolipoprotein B and apolipoprotein A-I as indicators of cardiac risk and as targets for lipid-lowering therapy.” European Heart Journal 26, 210-212 (2005).
  Wander, R.C., et al., “Influence of long.chain polyunsaturated fatty acids on oxidation of low density lipoprotein.” Prostaglandins, Leukotrienes and Essential Fatty Acids 59(2):143-151 (1998).
  Wang, C., et al., “n-3 Fatty acids from fish or fish-oil supplements, but not α-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review.” Am J Clin Nutr 84:5-17 (2006).
  Wang, L., et al., “Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation.” J. Lipid Res. 50:204-213 (2009).
  Warren, Stephen T., “The Expanding World of Trinucleotide Repeats”, Science, 271:1374-1375, (1996).
  Watanabe, Ikuyoshi, et al., “Usefulness of EPA-E (eicosapentaenoic acid ethyl ester) in preventing neointimal formation after vascular injury”, Kokyu to Junkan, 42(7):673-677, (1994).
  Weaver, K.L., et al., “Effect of Dietary Fatty Acids on Inflammatory Gene Expression in Healthy Humans.” J. Biol. Chem., 284(23): 15400-15407 (2009) (published online Apr. 9, 2009).
  Weber, P. “Triglyceride-lowering effect of n-3 long chain polyunsaturated fatty acid: eicosapentaenoic acid vs. docosahexaenoic acid.” Lipids 34: S269 (1999).
  Westerveld H.T. et al., “Effects of low-dose EPA-Eon glycemic control, lipid profile, lipoprotein(a), platelet aggretation, viscosity, and platelet and vessel wall interaction in NIDDM” Diabetes Care 16(5):683-8 (May 1993).
  Westphal, S., et al., “Postprandial chylomicrons and VLDLs in severe hypertriacylglycerolemia are lowered more effectively than are chylomicron remnants after treatment with n23 fatty acids.” Am J Clin Nutr 71:914-20 (2000).
  Whelan, J., et al., “Evidence that dietary arachidonic acid increases circulating triglycerides.” Lipids 30, 425-429 (1995).
  Wierzbicki, A.S., “Editorial: Newer, lower, better? Lipid drugs and cardiovascular disease—the continuing story.” Int J Clin Pract, 61(7):1064-1067 (2007).
  Wierzbicki, A.S., “Editorial: Raising HDL-C: back to the future?” Int J Clin Pract, 61(7): 1069-1071 (2007).
  Willumsen, N. et al., Biochimica et Biophysica Acta. vol. 1369, “On the effect of 2-deuterium- and 2-methyl-eicosapentaenoic acid derivatives on triglycerides, peroxisomal beta-oxidation and platelet aggregation in rats,” pp. 193-203, (1998).
  Willumsen, N., et al., “Eicosapentaenoic acid, but not docosahexaenoic acid, increased, mitochondrial fatty acid oxidation and upregulates 2,3-dienoyl-CoA reductase gene expression in rats.” Lipids, 31:579-592 (1996).
  Wilson Omega 3 fish oil: EPA versus DHA (Dietivity.com, 1-16) (2006).
  Wilt, VM & Gumm, JG, “Isolated low high-density lipoprotein cholesterol”, Ann. Pharmacol., 31:89-97, (1997).
  Wink, J., et al., “Effect of very-low-dose niacin on high-density lipoprotein in patients undergoing long-term statin therapy”, Am. Heart J., 143:514-518, (2002).
  Wojenski, C.M., et al., “Eicosapentaenoic acid ethyl ester as an antithrombotic agent: comparison to an extract of fish oil.” Biochimica et Biophysica Acta. 1081:33-38 (1991).
  Wong, S.H., et al., “Effects of eicosapentaenoic and docosahexaenoic acids on Apoprotein B mRNA and secretion of very low density lipoprotein in HepG2 cells.” Arterioscler. Thromb. Vasc. Biol. 9;836-841 (1989).
  Woodman et al., “Effects of Purified Eicosapentaenoic and Docosahexaenoic Acids on Glycemic Control, Blood Pressure, and Serum Lipids in Type 2 Diabetic Patients with Treated Hypertension”, The American Journal of Clinical Nutrition: Official Journal of the American Society for Clinical Nutrition, Inc., 76(5):1007-1015 (2002).
  Woodman, R.J., et al., “Effects of purified eicosapentaenoic acid and docosahexaenoic acid on platelet, fibrinolytic and vascular function in hypertensive type 2 diabetic patients.” Atherosclerosis 166: 85-93 (2003).
  Wu, W.H., et al., “Effects of docosahexaenoic acid supplementation on blood lipids, estrogen metabolism, and in vivo oxidative stress in postmenopausal vegetarian women.” Eur J Clin Nutr., 60:386-392 (2006).
  Xiao, Y.F., et al., “Inhibitory effect of n-3 fish oil fatty acids on cardiac Na+/Ca2+ exchange currents in HEK293t cells.” Biochemical and Biophysical Research Communications 321: 116-123 (2004).
  Xiao, Y-F., et al., “Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes.” Proc. Natl. Acad. Sci. 92: 11000-11004 (1995).
  Xydakis, A M et al., “Combination therapy for combined dyslipidemia,” American Journal of Cardiology, Nov. 20, 2002 US, vol. 90, No. 10 Suppl. 2, p. 21K-29K (2002).
  Yamamoto, H. et al., Improvement of coronary vasomotion with Eicosapentaenoic acid does not inhibit acetylcholine-induced coronary vasospasm in patients with variant angina: Jpn Cir J. 59(9):608-16 (1995).
  Yamamoto, K., et al., “4-Hydroxydocosahexaenoic acid, a potent Peroxisome Proliferator-Activated Receptor C agonist alleviates the symptoms of DSS-induced colitis.” Biochemical and Biophysical Research Communications 367: 566-572 (2008).
  Yamashita et al., J. Biochem., vol. 122, No. 1, “Acyl-transferases and Transaclyases Involved in Fatty Acid Remoding of Phospholipids and Metabolism of Bioactive Lipids in Mammalian Cells”, pp. 1-16 (1997).
  Yamashita, N., et al., “Inhibition of natural killer cell activity of human lymphocytes by eicosapentaenoic acid.” Biochem. Biophys. Res. Comm. 138(3): 1058-1067 (1986).
  Yamazaki et al., “Changes in fatty acid composition in rat blood and organs after infusion of eicosapentaenoic acid ethyl ester”, Biochim. Biophys. ACTA, 1128(1):35-43, (1992).
  Yamazaki, et. al., “Dissolution tests by RDC method for soft gelatin capsules containing ethyl icosapentate,”, Pharm. Tech. Japan, vol. 15, No. 4, pp. 595-603 Abstract (1999) (with English translation).
  Yang, S.P., et al., “Eicosapentaenoic acid attenuates vascular endothelial growth factor-induced proliferation via inhibiting Flk-1 receptor expression in bovine carotid artery endothelial cells.” J. Cell. Physio. 176:342-349 (1998).
  Yano T, Mizuguchi K, Takasugi K, Tanaka Y, Sato M. “Effects of ethyl all-cis-5,8,11,14,17-icosapentaenoate on low density lipoprotein in rabbits,” Yakugaku Zasshi, 115:843-51 (1995).
  Yano, T., et al., “Effects of ethyl-all-cis-5,8,11,14,17-icosapentaenoate (EPA-E), pravastatin and their combination on serum lipids and intimal thickening of cuff-sheathed carotid artery in rabbits.” Life Sciences, 61(20):2007-2015 (1997).
  Yerram, N.R., et al., “Eicosapentaenoic acid metabolism in brain microvessel endothelium: effect on prostaglandin formation.” J. Lipid Res.30:1747-1757 (1989).
  Yokoyama et al., “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis”, Lancet, vol. 369, pp. 1090-1098 (2007).
  Zaima, N., et al., “Trans geometric isomers of EPA decrease LXRa-induced cellular triacylglycerol via suppression of SREBP-1c and PGC-1?.” J. Lipid Res. 47: 2712-2717 (2006).
  Zanarini, et al., “Omega-3 Fatty Acid Treatment of Women with Borderline Personality Disorder: A Double-Blind, Placebo-Controlled Pilot Study,” Am J Psychiatry, 160:167-169 (2003).
  Zhang, M., et al., “Effects of eicosapentaenoic acid on the early stage of type 2 diabetic nephropathy in KKAy/Ta mice: involvement of anti-inflammation and antioxidative stress.” Metabolism Clinical and Experimental 55:1590-1598 (2006).
  Zhang, Y.W., et al., “Inhibitory effects of eicosapentaenoic acid (EPA) on the hypoxia/reoxygenation-induced tyrosine kinase activation in cultured human umbilical vein endothelial cells.” Prostaglandins, Leukotrienes and Essential FattyAcids 67(4):253-261 (2002).
  Zhang, Y.W., et al., “Pretreatment with eicosapentaenoic acid prevented hypoxia/reoxygenation-induced abnormality in endothelial gap junctional intercellular communication through inhibiting the tyrosine kinase activity.” Prostaglandins, Leukotrienes and Essential Fatty Acids 61(1): 33-40 (1999).
  Zhao, G. et al., “Dietary α-linolenic acid inhibits proinflammatory cytokine production by peripheral blood mononuclear cells in hypercholesterolemic subjects.” Am J Clin Nutr 85:385-91 (2007).
  Zhao, G., et al., “Dietary α-linolenic acid reduces inflammatory and lipid cardiovascular risk factors in hypercholesterolemic men and women.” J. Nutr. 134: 2991-2997 (2004).
  Ziegler, D., et al., “Treatment of symptomatic diabetic polyneuropathy with the antioxidant ?-lipoic acid: A 7-month multicenter randomized controlled trial (ALADIN III Study).” Diabetes Care 22:1296-1301 (1999).
  Zuijdgeest-van Leeuwen, et al., “N-3 Fatty Acids Administered as Triacylglycerols or as Ethyl Esters Have Different Effects on Serum Lipid Concentrations in Healthy Subjects,” N-3 Fatty Acids, Lipid Metabolism and Cancer, pp. 89-100 (2000).
  A study of AMR101 to evaluate its ability to reduce cardiovascular events in high risk patients with hypertriglyceridemia and on statin (REDUCE-IT). Available at: http://clinicaltrials.gov/show/NCT01492361.
  Abela GS, Aziz K. Cholesterol crystals cause mechanical damage to biological membranes: a proposed mechanism of plaque rupture and erosion leading to arterial thrombosis. Clin. Cardiol. 2005;28(9):413-420.
  Abelo A, Andersson TB, Antonsson M, et al. Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. Drug Metab. Dispos. Aug. 28, 2000 (8): 966-72.
  Ackman et al., The “Basic” Fatty Acid Composition of Atlantic Fish Oils: Potential Similarties Useful for Enrichment of Polyunsaturated Fatty Acids by Urea Complexation, JAOCS, vol. 65, 1:136-138 (Jan. 1988).
  Agren JJ, Vaisanen S, Hanninen O, et al. Hemostatic factors and platelet aggregation after a fish-enriched diet or fish oil or docosahexaenoic acid supplementation. Prostaglandins Leukot Essent Fatty Acids Oct. 1997 57 (4-5): 419-21.
  Aguilar-Salinas et al., “High Prevalence of Low HDL Cholesterol Concentrations and Mixed Hyperlipidemia in a Mexican Nationwide Survey,” J Lipid Res., 2001, 42:1298-1307.
  Ai M, Otokozawa S, Asztalos BF, Ito Y, Nakajima K, White CC, Cupples LA, Wilson PW, Schaefer EJ. Small dense LDL cholesterol and coronary heart disease: results from the Framingham Offspring Study. Clin. Chem. 2010;56(6):967-976.
  Allard et al. “Nutritional assessment and hepatic fatty acid composition in non-alcoholic fatty liver disease (NAFLD): a cross-sectional study.” J Hepatol. Feb. 2008;48(2):300-7.
  Almeida et al., “Effect of nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.” Eur J Clin Pharmacol. Oct. 2008;64(10):961-6.
  Amarin Appoints Medpace as CRO for Two Phase 3 Cardiovascular Trials, published Oct. 19, 2009.
  Amarin Presentation “Next Generation Lipid Modification in Cardiovascular Disease,” (Mar. 2010).
  Amarin press release (Jan. 18, 2008).
  Amarin Proceeding to Phase 3 with AMR101 for Hypertriglyceridemia, published Jul. 23, 2008.
  Amarin, Information Sheet, 2010.
  Amarin's SEC filing dated Oct. 12, 2005.
  Amarin's Vascepa® Briefing Document for the Endocrinologic and Metabolic Drugs Advisory Committee Meeting dated Oct. 16, 2013, 117 pages.
  Anber V, Griffin BA, McConnell M, Packard CJ, Shepherd J. Influence of plasma lipid and LDL-subfraction profile on the interaction between low density lipoprotein with human arterial wall proteoglycans. Atherosclerosis. 1996;124(2):261-271.
  Anderson TJ, Gregoire J, Hegele RA, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can. J. Cardiol. 2013;29:151-167.
  Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N. Engl. J. Med. 1995;332:488-493.
  Anderson, “Lipoprotein-Associated Phospholipase A2: An Independent Predictor of Coronary Artery Disease Events in Primary and Secondary Prevention,” 101 Am. J. Cardiology 23-F (2008).
  Andrews HE, Bruckdorfer KR, Dunn RC, Jacobs M. Low-density lipoproteins inhibit endotheliumdependent relaxation in rabbit aorta. Nature. 1987;327:237-239.
  Annex to Rule 161 Response dated Apr. 16, 2012.
  Appendix A to Defendants' Invalidity Contentions, 3:14-CV-02550-MLC-DEA (D.N.J.), 478 pages (Dec. 5, 2014).
  Attie AD, et al., “Relationship between stearoyl-CoA desaturase activity and plasma trigylcerides in human and mouse hypertriglyceridemia,” J. Lipid Res. 2002;43:1899-907.
  Ault, “Prescription omega-3 fatty acid formulation approved,” Ob.Gyn.News, (Jan. 15, 2005).
  Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011.
  Aviram M, Rosenblat M, Bisgaier CL, Newton RS. Atorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation. Atherosclerosis. 1998; 138(2):271-280.
  Baldwin RM, Ohlsson S, Pedersen Rs, et al. Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers. Br. J. Clin. Pharmacol. May 2008 65 (5): 767-74.
  Baldwin SJ, Clarke SE, Chenery RJ. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br. J. Clin. Pharmacol. 1999;48:424-432.
  Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR 101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol Oct. 2012 110 (7): 984-92.
  Ballantyne et al., “Abstract 15071: AMR101 Lowers Triglycerides, Atherogenic Lipoprotein, Phospholipase A2, and High-sensitivity C-reactive Protein Levels in Patients with High Triglycerides and on Background Statin Therapy (the ANCHOR Study),” Circulation, Lippincott Williams and Wilkins, vol. 124, No. 21, Suppl., Nov. 22, 2011.
  Ballantyne et al., “Effects of icosapent ethyl on lipoprotein particle concentration and the fatty acid desaturation index in statiotreated patients with persistent high triglycerides (the ANCHOR study).” Journ. Clin. Lipidology, 2013, 7(3):270-271.
  Bangham et al., “Diffusion of univalent ions across the lamellae of swolloen phospholipids.” J. Mol. Biol. (1965) 13(1):238-252.
  Barter et al., “Effectiveness of Combined Statin Plus Omega-3 Fatty Acid Therapy for Mixed Dyslipidemia.” Am. J. Cardiol. 102(8):1040-1045 (Oct. 15, 2008).
  Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991;40(4):405-412.
  Bays HE et al. “Prescription omega 3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications,” Expert Rev Cardiovasc Ther., 6:391-409. (2008).
  Bays HE, Ballantyne CM, Braeckman RA, Stirtan WG, Soni PN. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am. J. Cardiovasc. Drugs. 2013;13(1):37-46.
  Bays HE, Braeckman RA, Ballantyne CM, et al. Icosapent ethyl, a pure EPA omega-3 fatty acid: Effects on lipoprotein particle concentration and size in patients with very high triglyceride levels (the MARINE study). J. Clin. Lipidol. 2012;6:565-572.
  Bays HE, Safety considerations with omega-3 fatty acid therapy. Am. J. Cardiol. Mar. 2007 99 (6A): 35C-43C.
  Belarbi et al., “A process for high yield and scaleable recovery of high purity eicosapentaenoic acid esters from microalgae and fish oil,” Enzyme and Microbail Technology 26:516-529 (2000).
  Belger et al., “Assessment of prefrontal activation by infrequent visual targets and non-target noval stimuli in schisophrenia: a function MRI study, ” Presented at the 9th Biennial winter workshop on schizophrenia, Davos, Switzerland, Feb. 7-13, 1998, Abstract in Schizophrenia Research. vol. 29. No. 1/02, Jan. 1998.
  Bender NK, Kraynak MA, Chiquette E, et al. Effects of marine fish oils on the anticoagulation status of patients receiving chronic warfarin therapy. J. Thromb. Thrombolysis Jul. 5, 1998 (3): 257-61.
  Benn et al., Improving Prediction of Ischemic Cardiovascular Disease in the General Population Using Apolipoprotein B: The Copenhagen City Heart Study, 27 Arteriosclerosis, Thrombosis, & Vascular Biology 661 (2007).
  Bennett et al., “Treatment of IgA nephropathy with eicosapentanoic acid (EPA): a two-year prospective trial [Abstract Only].” Clin. Nephrol. 31(3):128-131 (Mar. 1989).
  Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. Sep. 2012 97 (9): 2969-89.
  Berliner JA, Watson AD. A role for oxidized phospholipids in atherosclerosis. N. Engl. J. Med. 2005;353(1):9-11.
  Bertelsen M, Anggard EE, Carrier MJ. Oxidative stress impairs insulin internalization in endothelial cells in vitro. Diabetologia. 2001;44(5):605-613.
  Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, IJ McBride R, Teo K, Weintraub W. Niacin in patients with low hdl cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 2011;365:2255-2267.
  Borchman D, Lamba OP, Salmassi S, Lou M, Yappert MC. The dual effect of oxidation on lipid bilayer structure. Lipids. 1992;27(4):261-265.
  Bordin et al., “Effects of fish oil supplementation on apolipoprotein B100 production and lipoprotein metabolism in normolipidaemic males,” Eur. J. Clin. Nutr. 52: 104-9 (1998).
  Borthwick et al., “The effects of an omega-3 ethyl ester concentrate on blood lipid concentrations in pateitns with hyperlipidemia,” Clin. Drug Investig. (1998) 15(5): 397-404.
  Bossaller C, Habib GB, Yamamoto H, Williams C, Wells S, Henry PD. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5′-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. J. Clin. Invest. 1987;79:170-174.
  Braeckman RA, Manku MS, Bays HE, Stirtan WG, Soni PN. Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on plasma and red blood cell fatty acids in patients with very high triglyceride levels (results from the MARINE study). Prostaglandins Leukot Essent Fatty Acids. 2013;89(4):195-201.
  Braeckman RA, Stirtan WG, Soni PN. Pharmacokinetics of eicosapentaenoic acid in plasma and red blood cells after multiple oral dosing with AMR101 (ethyleicosapentaenoic acid) in healthy subjects [abstract]. Presented at: Congress of the International Society for the Study of Fatty Acids and Lipids, Vancouver, Canada, May 26-30, 2012.
  Braeckman RA, Stirtan WG, Soni PN. Pharmacokinetics of eicosapentaenoic acid in plasma and red blood cells after multiple oral dosing with icosapent ethyl in healthy subjects. Clin. Pharmacol. Drug Dev. 2013;3:101-108.
  Braunersreuther V, Steffens S, Arnaud C, Pelli G, Burger F, Proudfoot A, Mach F. A novel rantes antagonist prevents progression of established atherosclerotic lesions in mice. Arterioscler. Thromb. Vasc. Biol. 2008;28:1090-1096.
  Brinton EA, Ballantyne CM, Bays HE, Kastelein JJ, Braeckman RA, Soni PN. Effects of AMR101 on lipid and inflammatory parameters in patients with Diabetes mellitus-2 and residual elevated triglycerides (200-500 mg/dl) on statin therapy at LDL-C goal: the ANCHOR study [abstract 629-P]. Diabetes. 2012;61(suppl 1): A159-A160.
  Brovkovych V, Dobrucki LW, Brovkovych S, Dobrucki I, Do Nascimento CA, Burewicz A, Malinski T. Nitric oxide release from normal and dysfunctional endothelium. J. Physiol. Pharmacol. 1999;50:575-586.
  Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414(6865):813-820.
  Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with Diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2007;30: 162-172.
  Calder PC. The role of marine omega-3 (n-3) fatty acids in inflammatory processes, atherosclerosis and plaque stability. Mol. Nutr. Food Res. 2012;56(7):1073-1080.
  Carulli et al., “Chenodeoxycholic acid and ursodeoxycholic acid effects in endogenous hypertriglyceridemias. A controlled double-blind trial.” J. Clin. Pharmacol., 21(10):436-42 (1981).
  Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler. Thromb. Vasc. Biol. 2004;24(5):816-823.
  Chait A, Brazg RL, Tribble DL, Krauss RM. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am. J. Med. 1993;94(4):350-356.
  Chan et al., Factorial Study of the Effects of Atorvastatin and Fish Oil on Dyslipidaemia in Visceral Obesity, 32 Euro. J. Clinical Investigation. 429 (2002).
  Chatterjee SN, Agarwal S. Liposomes as membrane model for study of lipid peroxidation. Free Radic. Biol. Med. 1988;4(1):51-72.
  Cheng et al., “Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induces vasodilation in mice and humans,” PNAS 103(17):6682-7 (2006).
  Classification of Hyperlipidaemias and Hyperlipoproteinaemias, Bulletin of the World Health Organization, 43(6): 891-915 (1970).
  Cohen AW, Combs TP, Scherer PE, Lisanti MP. Role of caveolin and caveolae in insulin signaling and diabetes. American journal of physiology. Endocrinology and metabolism. 2003;285(6):E1151-1160.
  Cole et al., “Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into capsules for oral administration,” Advanced Drug Delivery Reviews, vol. 60, No. 6, pp. 747-756. (2007).
  Committee Roster for the Oct. 16, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, 2 pages. (2013).
  Coumadin [package insert], Princeton, NJ: Bristol-Myers Squibb; 2011.
  Cox PJ, Ryan DA, Hollis FJ, et al. Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans. Drug Metab. Dispos. 2000;28:772-780.
  Creager MA, Gallagher SJ, Girerd XJ, Coleman SM, Dzau VJ, Cooke JP. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J. Clin. Invest. 1992;90:1248-1253.
  Cruz et al., “The metabolic syndrome in children and adolescents,” Curr. Diab. Rep., vol. 4(1):53-62 (2004).
  Culhane et al., “Rosuvastatin for the treatment of hypercholesterolemia,” Pharmacotherapy, 25(7):990-1000 (2005).
  Dall et al., “Clinical utility of low-density lipoprotein particle measurement in management of cardiovascular disease: a case report,” Research Reports in Clin. Cardiol., vol. 2, pp. 57-62 (2011).
  Davidson MH, Ballantyne CM, Jacobson TA, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J. Clin. Lipidol. 2011;5:338-367.
  Davidson MH, et al., Effects of prescription omega-3-acid ethyl esters on lipo protein particle concentrations, apolipoproteins AI and CIII, and lipoprotein-associated phospholipase A2 mass in statin-treated subjects with hypertrigylceridemia, J.Clin. Lipid., vol. 3(5), pp. 332-340 (2009).
  Davidson MH, Rosenson RS, Maki KC, Nicholls SJ, Ballantyne CM, Mazzone T, Carlson DM, Williams LA, Kelly MT, Camp HS, Lele A, Stolzenbach JC. Effects of fenofibric acid on carotid intima-media thickness in patients with mixed dyslipidemia on atorvastatin therapy: Randomized, placebo-controlled study (first). Arterioscler. Thromb. Vasc. Biol. 2014;34:1298-1306.
  De Graaf J, Hak-Lemmers HL, Hectors MP, Demacker PN, Hendriks JC, Stalenhoef AF. Enhanced V susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects. Arterioscler. Thromb. 1991;11(2):298-306.
  Defendants' Invalidity Contentions, 3:14-CV-02550-MLC-DEA (D.N.J.), 520 pages (Dec. 5, 2014).
  Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 901 pages (Dec. 5, 2014).
  Di Spirito, M., Morelli, G., Doyle, R.T., Johnson, J. & McKenney, J. Effect of omega-3-acid ethyl esters on steady-state plasma pharmacokinetics of atorvastatin in healthy adults. Expert Opin. Pharmacother. 9, 2939-2945 (2008).
  Din et al., “Omega 3 fatty acids and cardiovascular disease—fishing for a natural treatment,” BMJ, vol. 327, No. 7430, pp. 30-35 (2004).
  Draft Agenda for the Oct. 16, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, 2 pages.
  Draft Meeting Roster for the Oct. 16, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, 2 pages.
  Draft Questions for the Oct. 16, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, 1 page.
  Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by !-arginine. Lancet. 1991;338:1546-1550.
  Ehara S, Ueda M, Naruko T, Haze K, Itoh A, Otsuka M, Komatsu R, Matsuo T, Itabe H, Takano T, Tsukamoto Y, Yoshiyama M, Takeuchi K, Yoshikawa J, Becker AE. Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation. 2001;103(15):1955-1960.
  El-Serag HB, Graham DY, Satia JA, et al. Obesity is an independent risk factor for Gerd symptoms and erosive esophagitis. Am. J. Gastroenterol. Jun. 2005 100 (6): 1243-50.
  El-Saadani M, Esterbauer H, El-Sayed M, Gober M, Nassar AY, Jurgens G. A spectrophotometric assay for lipid peroxides in serum lipoproteins using commercially available reagent. J. Lipid Res. 1989;30:627-630.
  Emsley et al., “Randomized, Placebo-Controlled Study of Ethyl-Eicosapentaenoic Acid as Supplemental Treatment in Schizophrenia,” Am. J. Psychiatry, 159:1596-1598 (2002).
  Ennis JL, Cromwell WC. Clinical utility of low-density lipoprotein particles and apolipoprotein Bin patients with cardiovascular risk. J. Fam. Pract. 2013;62:1-8.
  Epadel—PubChem CID 9831415, Retrieved on Apr. 9, 2014 [Retrieved from the Internet] <URL:http://pubchem.ncbi.nlm.nih.gov/compound/9831415>.
  Epadel 1990 and JELIS Study.
  Epadel Capsules 300, Japan Pharmaceutical Reference 369-371 (2nd ed.) (1991).
  Epadel drug information brochure (2000), certified English translation.
  Epadel Package Insert 2007 (with Translation).
  Eritsland J, Arnesen H, Gronseth K, et al. Effect of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency. Am. J. Cardiol. 1996 Jan 77 (1): 31-6.
  Eritsland J, Arnesen H, Seljeflot I, et al. Long-term effects of n-3 polyunsaturated fatty acids on haemostatic variables and bleeding episodes in patients with coronary artery disease. Blood Coagul. Fibrinolysis Feb. 6, 1995 (1): 17-22.
  Errata to the FDA Briefing Document Endocrinologic and Metabolic Drug Advisory Committee Meeting Oct. 16, 2013, 1 page.
  Esposito, “Effect of a Mediterranean-Style Diet on Endothelial Dysfunction and Markers ofVascular Inflammation in the Metabolic Syndrome: A Randomized Trial”, Journal of the American Medical Association, 2004, 292(12), 1440-1446.
  Exhibit A to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 48 pages (Dec. 5, 2014).
  Exhibit B to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 6 pages (Dec. 5, 2014).
  Exhibit C to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 14 pages (Dec. 5, 2014).
  Exhibit D to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 19 pages (Dec. 5, 2014).
  Exhibit E to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 6 pages (Dec. 5, 2014).
  Exhibit F to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 10 pages (Dec. 5, 2014).
  Exhibit G to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 21 pages (Dec. 5, 2014).
  Exhibit H to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 10 pages (Dec. 5, 2014).
  Exhibit I to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 14 pages (Dec. 5, 2014).
  Exhibit J to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 13 pages (Dec. 5, 2014).
  Exhibit K to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 5 pages (Dec. 5, 2014).
  Exhibit L to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 5 pages (Dec. 5, 2014).
  Exhibit M to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 7 pages (Dec. 5, 2014).
  Exhibit N to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 15 pages (Dec. 5, 2014).
  Exhibit O to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 6 pages (Dec. 5, 2014).
  Exhibit P to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 17 pages (Dec. 5, 2014).
  Exhibit Q to Defendants' Joint Invalidity Contentions, 3:14-CV-02550-MLC-TJB (D.N.J.), 64 pages (Dec. 5, 2014).
  FDA Briefing Document, Endocrinologic and Metaboloic Drugs Advisory Committee Meeting, dated Oct. 16, 2013, available publicly at least as of Oct. 16, 2013, 115 pages.
  Feron O, Dessy C, Desager JP, Balligand JL. Hydroxy-methylgluataryl-coenzyme a reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance. Circulation. 2001;103:113-118.
  Final Agenda for the Oct. 16, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, 2 pages.
  Final Meeting Roster for the Oct. 16, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, 2 pages.
  Final Questions for the Oct. 16, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, 1 page.
  Frangou et al., “Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study,” British Journ. Psychiatry, 188, 46-50 (2006).
  Frey R, Muck W, Kirschbaum N, et al. Riociguat (BAY 63/2521) and warfarin: a pharmacodynamic and pharmacokinetic interaction study. J. Clin. Pharmacol. Jul. 2011 51 (7): 1051-60.
  Frøyland et al., “Chronic administration of eicosapentaenoic acid and docosahexaenoic acid as ethyl esters reduced plasma cholesterol and changed the fatty acid composition in rat blood and organs.” Lipids 31(2):169-78 (Feb. 1996).
  Furuta T, Shirai N, Sugimoto M, et al. Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies. Drug Metab. Pharmacokinet Jun. 20, 2005 (3): 153-67.
  Galeano NF, Al-Haideri M, Keyserman F, Rumsey SC, Deckelbaum RJ. Small dense low density lipoprotein has increased affinity for LDL receptor-independent cell surface binding sites: a potential mechanism for increased atherogenicity. J. Lipid Res. 1998;39(6):1263-1273.
  Gallagher et al., “Germline BRCA Mutations Denote a Clinicopathalogic Subset of Prostate Cancer,” Amer. Assoc. Cancer Res. Clin Cancer Res., 16(7):2115-21 (2010).
  Garber AJ, Abrahamson MJ, Barzilay JI, et al. American Association of Clinical Endocrinologists' comprehensive diabetes management algorithm 2013 consensus statement. Endocr. Pract. 2013;19(suppl 2):1-48.
  Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA. 1996;276(11):875-881.
  Ginsberg HN, Elam MB, Lovato LC, Crouse JR, 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC, Jr., Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2 Diabetes mellitus. N. Engl. J. Med. 2010;362:1563-1574.
  Girotti A W. Lipid hydroperoxide generation, turnover, and effector action in biological systems. J. Lipid Res. 1998;39(8):1529-1542.
  Goodman & Gilman (Robert W. Mahley & Thomas P. Bersot) Drug Therapy for Hypercholesterolemia and Dyslipidemia, in Goodman & Gilman's the Pharmacological Basis fo Therapeutics 971 (Hardman et al., eds 10th ed. 2001).
  Gosai, P. et al. Effect of omega-3-acid ethyl esters on the steady-state plasma pharmacokinetics of rosuvastatin in healthy adults. Expert Opin. Pharmacother. 9, 2947-2953 (2008).
  Greenblatt DJ, von Moltke LL. Interaction of warfarin with drugs, natural substances, and foods. J. Clin. Pharmacol. Feb. 2005 45 (2): 127-32.
  Grundy SM, et al. Implications of Recent Clinical Trials for the National Cholesterol Education Prgram Adult Treatment Panel III Guidelines, Circulation. 2004; 110:227-39.
  Grundy, Scott M., “Low-Density Lipoprotein, Non-High-Density Lipoprotein, and Apolipoprotein B as Targets of Lipid-Lowering Therapy” Circulation. 106:2526-2529 (2002).
  Gyarmathy, M., “Selection from the industrial manufacturing. 5th part: Gelatine capsules. 5/2 part: Soft gelatine capsules,” Gyogyszereszet, vol. 38, No. 2, pp. 105-109 (1994).
  Hampel H, Abraham NS, El-Se rag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann. Intern. Med. Aug. 2005 143 (3): 199-211.
  Hansen et al., “Comparative effects of prolonged intake of highly purified fish oils as ethyl ester or triglyceride on lipids, haemostasis and platelet function in normolipaemic men.” Eur. J. Clin. Nutr. 47(7):497-507 (Jul. 1993).
  Harris, “n-3 Fatty acids and lipoproteins: a comparison of results from human and animal studies,” Lipids 31, 243-252 (1996).
  Hata et al, Geriatric Medicine, 30 (5), 799-852, 1992 (with English translation).
  Herbette L, Marquardt J, Scarpa A, Blasie JK. A direct analysis of lamellar x-ray diffraction from hydrated oriented multilayers of fully functional sarcoplasmic reticulum. Biophys. J. 1977;20(2):245-272.
  Hirano T, Ito Y, Koba S, Toyoda M, Ikejiri A, Saegusa H, Yamazaki J, Yoshino G. Clinical significance of small dense low-density lipoprotein cholesterol levels determined by the simple precipitation method. Arterioscler. Thromb. Vase. Biol. 2004;24(3):558-563.
  Hofacer R, et al., Omega-3 fatty acid deficiency increases stearoyl-CoA desaturase expression and activity indices in rat liver: Positive association with non-fasting plasma triglyceride levels, Prostaglandins Leukot. Essent. Fatty Acids. 2012;86:71-7.
  Hohenester, “Primary Biliary Cirrhosis,” Semin Immunopathol. 31L:283-307, 285 (2009).
  Holvoet P, Kritchevsky SB, Tracy RP, Mertens A, Rubin SM, Butler J, Goodpaster B, Harris TB. The metabolic syndrome, circulating oxidized LDL, and risk of myocardial infarction in wellfunctioning elderly people in the health, aging, and body composition cohort. Diabetes. 2004;53(4):1068-1073.
  Horrobin, D.F. The Phospholipid Concept of Psychiatric Disorders and its Relationship to the Neurodevelopmental Concept of Schizophrenia. In M. Peet (ed.) Phospholipid Spectrum Disorder in Psychiatry pp. 1-19 (1999).
  HPs2-thrive Collaborative Group, “randomized placebo-controlled trial in 25 673 high-risk patients of er niacin/laroprant: Trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment.” Eur. Heart J. 2013;34:1279-1291.
  Hruska MW, Amico JA, Langaee TY, Ferrell RE, Fitzgerald SM, Frye RF. The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects. Br. J. Clin. Pharmacol. 2005;59:70-79.
  Hughes et al., “Fish oil produces an atherogenic lipid profile in hypertensive men,” Atherosclerosis, 84, pp. 229-237 (1990).
  Hulthe J, Hulten LM, Fagerberg B. Low adipocyte-derived plasma protein adiponectin CJ concentrations are associated with the metabolic syndrome and small dense low-density lipoprotein particles: atherosclerosis and insulin resistance study. Metab. Clin. Exp. 2003;52(12):1612-1614.
  Ignarro LJ, Buga GM, Wood KS, Byrnes RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc. Natl. Acad. Sci. USA. 1987;84:9265-9269.
  Itoh et al., “Increased adinponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity and human obses subjects,” Arterioscler. Thromb. Vasc. Biol., pp. 1918-1925 (together with online Supplements 1-15) (2007).
  Jacob RF, Mason RP. Lipid peroxidation induces cholesterol domain formation in model membranes. J. Biol. Chem. 2005;280(47):39380-39387.
  Jacob RF, Walter MF, Self-Medlin Y, Mason RP. Atorvastatin active metabolite inhibits oxidative modification of small dense low-density lipoprotein. J. Cardiovasc. Pharmacol. 2013;62(2):160-166.
  Jacobson TA. Opening a new lipid “apo-thecary”: incorporating apolipoproteins as potential risk factors and treatment targets to reduce cardiovascular risk. Mayo Clin. Proc. 2011;86:762-780.
  Jakus V, Rietbrock N. Advanced glycation end-products and the progress of diabetic vascular complications. Physiol. Res. 2004;53(2): 131-142.
  Jialal I, Devaraj S. Antioxidants and atherosclerosis: Don't throw out the baby with the bath water. Circulation. 2003;107:926-928.
  Journal of Practical Pharmacy, 58(4):1303-1324 (2007).
  Journal of the Japanese Diabetes Society, Mar. 30, 2008, 51(3), pp. 233-237.
  Kaminski WE, Jendraschak E, Kiefl R, et al. Dietary omega-3 fatty acids lower levels of platelet-derived growth factor mRNA in human mononuclear cells. Blood Apr. 1993 81 (7): 1871-9.
  Kastelein et al., Omega-3 Free Fatty Acids for the Treatment of Severe Hypertriglyceridemia: The EpanoVa for Lowering Very High Triglycerides (EVOLVE) Trial, J. Clin. Lipidol. (JACL 597) 2013.
  Kawamura et al., “Effects of 4 weeks' intake of polyunsaturated fatty acid ethylester rich in eicosapentaenoic acid (ethylester) on plasma lipids, plasma and platelet phsopholipid fatty acid composition and platelet aggregation; a double blind study,” Nihon Naika Gakkai Zasshi, 72(1):18-24 (1983).
  Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi Y A, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 Diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet. 2005;366:1849-1861.
  Kellner-Weibel G, Yancey PG, Jerome WG, Walser T, Mason RP, Phillips MC, Rothblat GH. Crystallization of free cholesterol in model macrophage foam cells. Arterioscler. Thromb. Vasc. Biol. 1999;19(8):1891-1898.
  Kendall BJ, Macdonald GA, Hayward NK, et al. The risk of Barrett's esophagus associated with abdominal obesity in males and females. Int. J. Cancer May 2013 132 (9): 2192-9.
  Kerr, S., Brosnan MJ, Mcintyre M, Reid JL, Dominiczak AF, Hamilton CA. Superoxide anion production is increased in a model of genetic hypertension role of the endothelium. Hypertension. 1999;33:1353-1358.
  Kim F, Tysseling KA, Rice J, Gallis B, Haji L, Giachelli CM, Raines EW, Corson MA, Schwartz MW. Activation of IKKbeta by glucose is necessary and sufficient to impair insulin signaling and nitric oxide production in endothelial cells. J. Mol. Cell. Cardiol. 2005;39(2):327-334.
  Kim KA, Park PW, Kim HK, Ha JM, Park JY. Effect of quercetin on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in healthy subjects. J. Clin. Pharmacol. 2005;45:941-946.
  Kinoshita, “Anti-hyperlipidemic agents,” Nihon Rinsho, 60(5):968-74 (2002) (Abstract Only).
  Knapp HR. Dietary fatty acids in human thrombosis and hemostasis. Am. J. Clin. Nutr. May 1997 65 (5 Suppl): 1687S-98S.
  Koba S, Hirano T, Ito Y, Tsunoda F, Yokota Y, Ban Y, Iso Y, Suzuki H, Katagiri T. Significance of small dense low-density lipoprotein-cholesterol concentrations in relation to the severity of coronary heart diseases. Atherosclerosis. 2006;189(1):206-214.
  Kojda G, Harrison DG. Interactions between no and reactive oxygen species: Pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure. Cardiovasc. Res. 1999;43:562-571.
  Koroshetz, W.J. Huntington's Disease. In Samuels, M. (ed.) Office Practice of Neurology, pp. 654-661 (1996).
  Krauss RM. Heterogeneity of plasma low-density lipoproteins and atherosclerosis risk. Curr. Opin. Lipidol. 1994;5(5):339-349.
  Krzynowek et al., “Purification of Omega-3 Fatty Acids from Fish Oils Using HPLC: An Overview,” National Marine Fisheries—Proceedings of the first joint conference of the Tropical and Subtropical Fisheries Technological Soceity of the Americas with the Atlantic Fisheries Technological Society, pp. 74-77 (1988).
  Kunimoto M, Inoue K, Nojima S. Effect of ferrous ion and ascorbate-induced lipid peroxidation on liposomal membranes. Biochem. Biophys.Acta. 1981;646(1):169-178.
  Lamb RE, Goldstein BJ. Modulating an Oxidative-Inflammatory Cascade: Potential New Treatment Strategy for Improving Glucose Metabolism, Insulin Resistance, and Vascular Function. Int. J. Clin. Pract. 2008;62(7): 1087-1095.
  Lamharzi N, Renard CB, Kramer F, Pennathur S, Heinecke JW, Chait A, Bomfeldt KE. Hyperlipidemia in concert with hyperglycemia stimulates the proliferation of macrophages in atherosclerotic lesions: potential role of glucose-oxidized LDL. Diabetes. 2004;53(12):3217-3225.
  Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J. Clin. Invest. 2003;111:1201-1209.
  Laufs et al., “Upregulation of endothelial nitric oxide synthase by hmg coa reductase inhibitors,” Circulation (1998) 97:1129-1135.
  Lee C, Sigari F, Segrado T, Horkko S, Hama S, Subbaiah PV, Miwa M, Navab M, Witztum JL, Reaven PD. All ApoB-containing lipoproteins induce monocyte chemotaxis and adhesion when minimally modified. Modulation of lipoprotein bioactivity by platelet-activating factor acetylhydrolase. Arterioscler. Thromb. Vase. Biol. 1999; 19(6): 1437-1446.
  Leigh-Firbank et al., “Eicosapentaenoic acid and docosahexanoic acid from fish oils: differential associations with lipid responses,” Br. J. Nutr. 87:435-445 (2002).
  Libby, “Inflammation and atherosclerosis,” Nature (2002) 420(6917):868-874.
  Lipitor (Pfizer, 2007).
  Lipitor [package insert]. New York, NY: Parke-Davis (2012).
  Liu et al., “Effects of stable fish oil and simvastatin on plasma lipoproteinc in patients with hyperlipidemia,” Nutrion Res. , vol. 23, pp. 1027-1034 (2003).
  Liu X, et al., Stearoyl CoA Desaturase 1: Role in Cellular Inflammation and Stress, Adv. Nutr. 2011;2:15-22.
  Lovaza (omega-3-acid ethyl esters) Capsules, Prescribing information, 9 pages, GlaxoSmithKline (Nov. 2008).
  Lovaza [package insert]. Research Triangle Park, NC: GlaxoSmithKline (2012).
  Lovaza, (omega-3-acid ethyl esters) Capsules, Prescribing information Smith Kline Beechum (Jul. 2009).
  Lovaza, GlaxoSmithKline, Lovaza Prescribing Information, Jun. 2008 [retrieved from the internet Jun. 6, 2012 <http://web/archive/org/web/20090206170311/http://us.gsk/com/products/assets/uslovaza.pdf>]; Table 3, p. 1, section entitled ‘Description;’ p. 3, section entitled ‘Very High Triglycerides: Monotherapy;’ p. 4 section entitled ‘Indications and Usage’ and ‘Information for Patients.’
  Lovaza® (omega-3-acid ethyl esters) Capsules, Prescribing information, 12 pgs., GlaxoSmithKline, (Dec. 2010).
  Lovaza®, Physicians' Desk Reference 2699-2701 (62d ed., 2008).
  Lovegrove et al., “Moderate fish-oil supplementation reverses low-platelet, long chain n-3 polyunsaturated fatty acid status and reduced plasma triacylglycerol concentrations in British Indo-Asians,” Am. J. Clin. Nutr., 79:974-982 (2004).
  Lvovich V, Scheeline A. Amperometric sensors for simultaneous superoxide and hydrogen peroxide detection. Anal. Chern. 1997;69:454-462.
  Mak IT, Weglicki WB. Antioxidant properties of calcium channel blocking drugs. Methods Enzymol. 1994;234:620-630.
  Malinowski et al., “Elevation of Low-Density Lipoprotein Cholesterol Concentration with Over-the-Counter Fish Oil Supplementation.” Annals of Pharmacotherapy 41:1296-1300 (Jul./Aug. 2007).
  Malinski T, Taha Z. Nitric oxide release from a single cell measured in situ by a porphyrinic-based microsensor. Nature. 1992;358:676-678.
  Marder, “An Approach to Treatment Resistance in Schizophrenia,” British Journ. Psychiatry, 37:19-22 (1999).
  Martinez-Gonzalez J, Raposo B, Rodriguez C, Badimon L. 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition prevents endothelial no synthase downregulation by atherogenic levels of native ldls: Balance between transcriptional and posttranscriptional regulation. Arterioscler. Thromb. Vasc. Biol. 2001;21:804-809.
  Martz, “Moving Upstream in Huntington's,” Science-Business eXchange, 2 pgs., 2008.
  Mason et al., “Comparative lipid antioxidant effects of omega-3 fatty acids in combination with HMG-CoA reductase inhibitors,” Journ. Clin. Lipidology (2011) 5(3):20.
  Mason RP, Gonye GE, Chester DW, Herbette LG. Partitioning and location of Bay K 8644, 1,4-dihydropyridine calcium channel agonist, in model and biological membranes. Biophys. J. 1989;55(4):769-778.
  Mason RP, Jacob RF, Kubant R, Walter MF, Bellamine A, Jacoby A, Mizuno Y, Malinski T. Effect of enhanced glycemic control with saxagliptin on endothelial nitric oxide release and CD40 levels in obese rats. J. Atheroscler. Thromb. 2011;18:774-783.
  Mason RP, Jacob RF. Membrane microdomains and vascular biology: Emerging role in atherogenesis. Circulation. 2003; 107:2270-2273.
  Mason RP, Kalinowski L, Jacob RF, Jacoby AM, Malinski T. Nebivolol reduces nitroxidative stress and restores nitric oxide bioavailability in endothelium of black americans. Circulation. 2005;112:3795-3801.
  Mason RP, Kubant R, Heeba G, Jacob RF, Day CA, Medlin YS, Funovics P, Malinski T. Synergistic effect of amlodipine and atorvastatin in reversing ldl-induced endothelial dysfunction. Pharm. Res. 2008;25:1798-1806.
  Mason RP, Walter MF, Day CA, Jacob RF. Active metabolite of atorvastatin inhibits membrane cholesterol domain formation by an antioxidant mechanism. J. Biol. Chem. 2006;281(14):9337-9345.
  Mason RP, Walter MF, Day CA, Jacob RF. Intermolecular differences for HMG-CoA reductase inhibitors contribute to distinct pharmacologic and pleiotropic actions. Am. J Cardiol. 2005;96(5A):11F-23F.
  Mason RP, Walter MF, Jacob RF. Effects of hmg-coa reductase inhibitors on endothelial function: Role of microdomains and oxidative stress. Circulation. 2004;109:II34-II41.
  Mason RP, Walter MF, Mason PE. Effect of oxidative stress on membrane structure: Small angle x-ray diffraction analysis. Free Radic. Biol. Med. 1997;23(3):419-425.
  Mason RP. Molecular basis of differences among statins and a comparison with antioxidant vitamins. Am. J. Cardiol. 2006;98:34P-41P.
  Mataki et al., “Effect of Eicosapentaenoic Acid in Combination with HMG-CoA Reductase Inhibitor on Lipid Metabolism,” Int. Med. J. 5(1):35-36 (Mar. 1998).
  Matsuzaki et al., “Incremental Effects of Eicosapentaenoic Acid on Cardiovascular Events in Statin-Treated Patients with Coronary Artery Disease,” Circ. J. 73:1283-1290 (2009).
  Mattson MP. Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity. Trends Neurosci. 1998;21(2):53-57.
  Mayo Clinic at http://www.mayoclinic.org.diseases-conditions/high-blood-cholesterol/in-depth/cholesterol (2014).
  McIntyre M, Hamilton CA, Rees DD, Reid JL, Dominiczak AF. Sex differences in the abundance of endothelial nitric oxide in a model of genetic hypertension. Hypertension. 1997;30:1517-1524.
  McKenney et al., “Prescription omega-3 fatty acids for the treatment of hypertriglyceridemia,” Am. J. Health Syst. Pharm., 64(6):595-605 (2007).
  McKenney et al., CMRO, “Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin and pravastatin in achieving lipid goals: results from the STELLAR trial”, 689-98 (2003).
  McKenney, J., “Niacin for dyslipidemia: considerations in product selection”, Am. J. Health Syst. Pharm., 60:995-1005, (2003).
  McKenney, J.M. et al. Study of the pharmacokinetic interaction between simvastatin and prescription omega-3-acid ethyl esters. J. Clin. Pharmacol. 46, 785-791 (2006).
  McKeone et al., “Alterations in serum phosphatidylcholine fatty acyl species by eicosapentaenoic and docosahexaenoic ethyl esters in patients with severe hypertriglyceridemia.” J. Lipid Res. 38:429-436 (1997).
  McNamara JR, et al., Remnant-like particle (RLP) Cholesterol is an independent cardiovascular disease risk factor in women: results from the Framingham Heart Study, Atherosclerosis, vol. 154(1), pp. 229-236 (2001).
  Micheletta F, Natoli S, Misuraca M, Sbarigia E, Diczfalusy U, Iuliano L. Vitamin E supplementation in patients with carotid atherosclerosis: Reversal of altered oxidative stress in plasma but not in plaque. Arterioscler. Thromb. Vasc. Biol. 2004;24:136-140.
  Michos et al., “Niacin and Statin Combination Therapy for Atherosclerosis Regression and Prevention of Cardiovascular Disease Events,” Journ. Amer. Coll. Cardiol., vol. 59, No. 23:2058-2064 (2012).
  Miles, et al., “Effect of orlistat in overweight and obese patients with type 2 diabetes treated with metformin,” Diabetes Care, 25(7):1123-1128 (2002).
  Miller AK, DiCicco RA, Freed MI. The effect of ranitidine on the pharmacokinetics of rosiglitazone in healthy adult male volunteers. Clin. Ther. 2002;24:1062-1071.
  Miller AK, Inglis AM, Culkin KT, Jorkasky DK, Freed MI. The effect of acarbose on the pharmacokinetics of rosiglitazone. Eur. J. Clin. Pharmacol. 2001;57:105-109.
  Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123:2292-2333.
  Mochida Press Release, Pharmaceutical Col., Ltd.: Conclusion of Distributorship Agreement Concerning Switch-OTC Drug for Hyperlipidemia Treatment, Epadel, (2009).
  Mochida, Announcement, Mochida Announces Completion of “JELIS” Major Clinical Trial for “Epadel,” 2005.
  Mochida's Epadel Reduces Risk of Stroke Recurrence—New Results of Jelis Major Clinical Trial, JCNNetwork Newswire Nov. 13, 2006.
  Mori et al., “Differential Effects of Eicosapentaenoic Acid and Docosahexaenoic Acid on Vascular Reactivity of the Forearm Microcirculation in Hyperlipidemic, Overweight Men,” Circulation, 102:1264-1269 (2000).
  Mozaffarian et al., “Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways and clinical events,” J. Am. Coll. Cardiol. (2011) 58(2):2047-2067.
  Nagakawa et al., Effect of [EPA] on the Platelet Aggregation and Composition of Fatty Acidin Man: A Double Blind Study, Atherosclerosis 47(1):71-75 (1983).
  Naik H, Wu JT, Palmer R, McLean L. The effects of febuxostat on the pharmacokinetic parameters of rosiglitazone, a CYP2C8 substrate. Br. J. Clin. Pharmacol. 2012;74:327-335.
  Nakamura et al., Remnant lipoproteniemia is a risk factor for endothelial vasomotor dysfuction and coronary artery disease in metabolic syndrome, Atherosclerosis, vol. 181(2), pp. 321-327 (2005).
  Nemoto et al., “Ethyl-eicosapentaenoic Acid Reduces Liver Lipids and Lowers Plasma Levels of Lipids in Mice Fed a High-Fat Diet, in vivo,” 23:685-690 2009).
  Niemi M, Backman JT, Grantors M, Laitila J, Neuvonen M, Neuvonen PJ. Gemfibrozil considerably increases the plasma concentrations of rosiglitazone. Diabetologia. 2003;46: 1319-1323.
  Niemi M, Backman JT, Neuvonen PJ. Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone. Clin. Pharmacol. Ther. 2004;76:239-249.
  Nigon F, Lesnik P, Rouis M, Chapman MJ. Discrete subspecies of human low density lipoproteins are heterogeneous in their interaction with the cellular LDL receptor. J. Lipid Res. 1991;32(11):1741-1753.
  Noguchi et al., “Chemoprevention of DMBA-induced mammary carcinogenesis in rats by low-dose EPA and DHA.” Br. J. Cancer 75(3): 348-353 (1997).
  Nomura et al., “The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients.” Platelets, 20(10:16-22 (2009).
  Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T, Luscher TF. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation. 1998;97:2494-2498.
  Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J. Clin. Invest. 1993;91:2546-2551.
  Olofsson et al., “Apolipoprotein B : a clinically important apolipoprotein which assembles atherogenic lipoproteins and promotes the development of atherosclerosis” Journal of Internal Medicine, 258: 395-410 (2005).
  Omacor® Prescribing Information (Omega-3-acid ethyl esters, capsules) (2004).
  Omacor®, Physicians' Desk Reference 2735 (60th ed. 2006).
  Ooi EM, “Apolipoprotein C-III: Understanding an emerging cardiovascular risk factor”, Clin.Sci. (London), vol. 114, pp. 611-624 (2008).
  Opalinska et al., “Increasing Level of Prostate-Specific Antigen and Prostate Cancer Risk Factors Among 193 Men Examined in Screening Procedure,” Ann. Univ. Curie Sklowoska Med., 58(2):57-63 (Abstract Only)(2003).
  Osher et al., “Omega-3 Eicosapentaenoic Acid in Bipolar Depression: Report of a Small Open-Label Study,” J. Clin. Psych. 66:726-729 (2005).
  Ou Z, Ou J, Ackerman AW, Oldham KT, Pritchard KA, Jr. L-4f, an apolipoprotein a-1 mimetic, restores nitric oxide and superoxide anion balance in low-density lipoprotein-treated endothelial cells. Circulation. 2003;107:1520-1524.
  Ozaki M, Kawashima S, Yamashita T, Hirase T, Namiki M, Inoue N, Hirata K, Yasui H, Sakurai H, Yoshida Y, Masada M, Yokoyama M. Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoe-deficient mice. J. Clin. Invest. 2002; 110:331-340.
  Park JH, Park DI, Kim HJ, et al. Metabolic syndrome is associated with erosive esophagitis. World J. Gastroenterol. Sep. 14, 2008 (35): 5442-7.
  Park JY, Kim KA, Kang MH, Kim SL, Shin JG. Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects. Clin. Pharmacol. Ther. 2004;75:157-162.
  Patel et al., “Rosiglitazone monotherapy improves glycaemic control in patients with type 2 diabetes: a twelve-week, randomized, placebo-controlled study,” Diabetes, Obesity and Metabolism, vol. 1, pp. 165-172 (1999).
  Paton, CM, Ntambi, JM., Biochemical and physiological function of stearoyl-CoA desaturase, Am. J. Physiol. Endocrinol. Metab. 2009;297:E28-E37.
  PCT/GB00/00164 International Search Report dated Oct. 20, 2000.
  PCT/US2011/062247 International Search Report and Written Opinion dated Jun. 14, 2012.
  PCT/US2013/020526 International Search Report dated Mar. 29, 2013.
  PCT/US2013/048241 International Search Report dated Dec. 13, 2013.
  PCT/US2013/048516 International Search Report dated Dec. 20, 2013.
  PCT/US2013/048559 International Search Report dated Dec. 13, 2013.
  PCT/US2013/068647 International Search Report and Written Opinion dated May 13, 2014.
  PCT/US2014/019454 International Search Report and Written Opinion dated Jun. 3, 2014.
  Pedersen, T., et al., “Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastation Survival Study (4S)”, The Lancet, No. 19, vol. 344, 8934, p. 1383-1389 (1994).
  Pejic et al., “Hypertriglyceridimia,” Journ. Amer. Board Fam. Med., vol. 19(3):310-316 (2006).
  Pennathur S, Heinecke JW. Mechanisms for oxidative stress in diabetic cardiovascular disease. Antioxid. Redox Signal. 2007;9(7):955-969.
  Piche, “Tumor Necrosis Factor-Alpha, and Fi brinogen to Abdominal Adipose Tissue, Blood Pressure, and Cholesterol and Triglyceride Levels in Healthy Postmenopausal Women”, American Journal of Cardiology, 2005, 96(1), 92-97.
  PLUSEPA® Product brochure “Super Critically” Different from Other Omega-3 Fish Oil Supplements for Depression and ADHD, by Minami Nutrition (Apr. 2009, pp. 1-6).
  Pritchard KA, Ackerman AW, Ou J, Curtis M, Smalley DM, Fontana JT, Stemerman MB, Sessa WC. Native low-density lipoprotein induces endothelial nitric oxide synthase dysfunction: Role of heat shock protein 90 and caveolin-1. Free Radic. Biol. Med. 2002;33:52-62.
  Pritchard KA, Jr., Groszek L, Smalley DM, Sessa WC, Wu M, Villalon P, Wolin MS, Stemerman MB. Native low-density lipoprotein increases endothelial cell nitric oxide synthase generation of superoxide anion. Circ. Res. 1995;77:510-518.
  Rader, Lipid Disorders, in Eric J. Topol (ed.)Textbook of Cardiovascular Medicine pp. 55-75 (2007).
  Rahimy M, Hallen B, Narang P. Effect of tolterodine on the anticoagulant actions and pharmacokinetics of single-dose warfarin in healthy volunteers. Arzneimittelforschung 2002 52 (12): 890-5.
  Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease. The Scandinavian Simvastatin Survival Study, Lancet. 344: 1383-1389 (1994).
  Rao MN, Mullangi R, Katneni K, et al. Lack of effect of sucralfate on the absorption and pharmacokinetics of rosiglitazone. J. Clin. Pharmacol. 2002;42:670-675.
  Recommendation for lipid plasma levels in Germany.
  Rees DD, Palmer RM, Moncada S. The role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc. Natl. Acad. Sci. USA. 1989;86:3375-3378.
  Reiner Z, Catapano AL, De BG, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur. Heart J. 2011;32:1769-1818.
  Ridker, “C-Reactive Protein : A Simple Test to Help Predict Risk of Heart Attack and Stroke”, Circulation: Journal of the American Heart Association, 2003, 108, e81-e85.
  Rifai, “High-Sensitivity C-Reactive Protein: A Novel and Promising Marker of Coronary Heart Disease”, Clinical Chemistry, 2001, 47(3), 403-411.
  Rizzo M, Bemeis K. Low-density lipoprotein size and cardiovascular risk assessment. Q. J. Med. 2006;99(1): 1-14.
  Rost KL, Roots I. Nonlinear kinetics after high-dose omeprazole caused by saturation of genetically variable CYP2C19. Hepatology Jun. 23, 1996 (6): 1491-7.
  Ruocco MJ, Shipley GG. Interaction of cholesterol with galactocerebroside and galactocerebroside phosphatidylcholine bilayer membranes. Biophys. J. 1984;46:695-707.
  Saito et al., “Results of Clinical Usage of Improved Formulation (MND-21S) Epadel Capsule 300 with Respect to Hyperlipidemia,” 26(12) Jpn. Pharmacol. Ther. 2047-62 (1998).
  Sampath H , Ntambi JM., Role of stearoyl-CoA desaturase in human metabolic disese, Future Lipidol. 2008;3.163-73.
  Sampath H, Ntambi JM., The Role of stearoyl-CoA desaturase in obesity, insulin resistance, and inflammation, Ann. NY. Acad. Sci. 2011; 1243:4 7-53.
  Samuels, Martin A., M. D., et al., “Huntington's Disease”, Office Practice of Neurology, (122):654-655, (1996).
  Sasaki J, Miwa T, Odawara M. Administration of highly purified eicosapentaenoic acid to statintreated diabetic patients further improves vascular function. Endocr. J. 2012;59:297-304.
  Sasaki J, Yokoyama M, Matsuzaki M, et al. Relationship between coronary artery disease and non-HDL-C, and effect of highly purified EPA on the risk of coronary artery disease in hypercholesterolemic patients treated with statins: sub-analysis of the Japan EPA Lipid Intervention Study (JELIS). J. Atheroscler. Thromb. 2012;19:194-204.
  Sato, “Effects of Highly Purified Ethyl All-cis-5,8,11,14,17-icosapentaenoate (EPA-E) on Rabbit Platelets,” Biol. Pharm. Bull., 16(4)362-367 (1993).
  Satoh, N., et al., “Purified eicosapentaenoic acid reduces small dense LDL, remnant lipoprotein particles, and C-reactive protein in metabolic syndrome.” Diabetes Care, 30(1): 144-146 (2007).
  Schmitz PG, McCloud LK, Reikes ST, et al. Prophylaxis of hemodialysis graft thrombosis with fish oil: double-blind, randomized, prospective trial. J. Am. Soc. Nephrol. Jan. 13, 2002 (1): 184-90.
  Schreiner et al., Lipoprotein[a] as a Risk Factor for Preclinical Atherosclerosis, 13 Atherosclerosis, Thrombosis & Vascular Biology 826, 826 (1993).
  Schuirmann, D.J. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J. Pharmacokinet. Biopharm. 15, 657-680 (1987).
  Schwellenbach et al., “The Triglyceride-Lowering Effects of a Modest Dose of Docosahexaenoic Acid Alone Versus in Combination with Low Dose Eicosapentaenoic Acidin Patients with Coronary Artery Disease and Elevated Triglycerides.” J. Am. Coll. Nutr. 25(6):480-485 (2006).
  Segrest et al., Structure of Apolipoprotein B-100 in Low Density Lipoproteins, J. Lipid Res. 42(9):1346-1367 (2001).
  Self-Medlin Y, Byun J, Jacob RF, Mizuno Y, Mason RP. Glucose promotes membrane cholesterol crystalline domain formation by lipid peroxidation. Biochim. Biophys. Acta. 2009; 1788(6): 1398-1403.
  Sevanian A, Ursini F. Lipid peroxidation in membranes and low-density lipoproteins: similarities and differences. Free Radic. Biol. Med. 2000;29(3-4):306-311.
  Shimizu et al., “Effects of Highly Purified Eicosapentaenoic Acid on Erythrocyte Fatty Acid Composition and Leukocyte and Colonic Mucosa Leukotriene B4 Production in Children with Ulcerative Colitis,” J. Pediatr. Gastroenterol. Nutr., vol. 37, No. 5, pp. 581-585 (2003).
  Shimokawa H, Flavahan NA, Vanhoutte PM. Loss of endothelial pertussis toxin-sensitive g protein function in atherosclerotic porcine coronary arteries. Circulation. 1991;83:652-660.
  Shishehbor MH, Brenna ML, Aviles RJ, Fu X, Penn MS, Sprecher DL, Hazen SL. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation. 2003;108(4):426-431.
  Simopoulos, “Omega-3 fatty acids in health and disease and in growth and development,” Am. J. Clin. Nutr. 54:438-63 (1991).
  Singer, Peter, “Fluvastatin plus fish oil are more effective on cardiovascular risk factors than fluvastatin alone,” Letter to the Editor, Prostaglandinis, Leukotrienes and Essential Fatty Acids, vol. 72, pp. 379-380 (2005).
  Slides for the Oct. 16, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, 158 pages.
  Sniderman A, Kwiterovich PO. Update on the detection and treatment of atherogenic low-density lipoproteins. Curr. Opin. Endocrinol. Diabetes Obes. 2013;20:140-147.
  Stampfer MJ, Krauss RM, Ma J, et al. A prospective study of trig lyceride level, lowdensity lipoprotein particle diameter, and risk of myocardial infarction. JAMA. 1996;276:882-888.
  Steinberg D, Witztum JL. Is the oxidative modification hypothesis relevant to human atherosclerosis? Do the antioxidant trials conducted to date refute the hypothesis? Circulation. 2002;105:2107-2111.
  Steinberg D. Lewis A. Conner Memorial Lecture: Oxidative modification of LDL and atherogenesis. Circulation. 1997;95(4):1062-1071.
  Stepp DW, Ou J, Ackerman AW, Welak S, Klick D, Pritchard KA, Jr. Native ldl and minimally oxidized ldl differentially regulate superoxide anion in vascular endothelium in situ. Am. J. Physiol. 2002;283:H750-H759.
  Surette, M.E., et al., “Evidence for mechanisms of the hypotriglyceridemic effect of n-3 polyunsaturated fatty, acids.” Biochimica et Biophysic Acta, 1126: 199-205 (1992).
  Takaki A, Umemoto S, Ono K, Seki K, Ryoke T, Fujii A, Itagaki T, Harada M, Tanaka M, Yonezawa T, Ogawa H, Matsuzaki M. Add-on therapy of epa reduces oxidative stress and inhibits the progression of aortic stiffness in patients with coronary artery disease and statin therapy: A randomized controlled study. J. Atheroscler. Thromb. 2011;18:857-866.
  Takaku et al., Study on the Efficacy and Safety of Ethyl Icosapentate (MND-21) in Treatment of Hyperlipidemia Based on a Long-Term Administration Test, 7 J. Clin. Ther. Med. 191 (1991).
  Talayero BG, Sacks FM. The role of triglycerides in atherosclerosis. Curr. Cardiol. Rep. 2011;13:544-552.
  Tanaka et al., “Genome-Wide Association Study of Plasma Polyunsaturated Fatty Acids in the InCHIANTI Study.” PLoS Genetics 5(1):1-8 (Jan. 2009).
  Tanaka et al., “Suppression of prostaglandin synthesis by arachidonic acid or eicosapentaenoic acid in a macrophage-like cell line, RAW 264.7, treated with LPS,” Biol. Pharm. Bull., 22(10):1057-7 (1999).
  Tatsuno et al., Efficacy and safety of TAK-085 compared with eicosapentaenoic acid in Japanese subjects with hypertriglyceridemia undergoing lifestyle modification: The omega-3 fatty acids randomized double-blind (ORL) study, J. Clin. Lipid; vol. 7(6), pp. 615-625 (2013).
  Teissier E, Nohara A, Chinetti G, Paumelle R, Cariou B, Fruchart JC, Brandes Rp, Shah a, B. Staels Peroxisome proliferator-activated receptor alpha induces Nadph.
  Theobald et al., “Ldl Cholesterol-Raising Effect of Low-Dose Docosahexaenoic Acid in Middle-Aged Men and Women,” Am. J. Clin. Nutr. 79:558-63 (2004).
  Third Report of the Ncep Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel Iii) Final Report, Nih Publication No. Feb. 5215 Sep. 2012.
  Thorwest M, Balling E, Kristensen Sd, et al. Dietary fish oil reduces microvascular thrombosis in a porcine experimental model. Thromb. Res. 2000 Jul 99 (2): 203-8.
  Tilg H, Moschen Ar. Inflammatory Mechanisms in the Regulation of Insulin Resistance. Mol. Med. 2008;14(3-4):222-231.
  Transcript from Oct. 16, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, 76 pp.
  Tribble DL, Holl LG, Wood PD, Krauss RM. Variations in oxidative susceptibility among six low density lipoprotein subfractions of differing density and particle size. Atherosclerosis. 1992;93(3):189-199.
  Tribble DL, Rizzo M, Chait A, Lewis DM, Blanche PJ, Krauss RM. Enhanced oxidative susceptibility and reduced antioxidant content of metabolic precursors of small, dense low-density lipoproteins. Am. J. Med. 2001;110(2):103-110.
  Trilipix Package Insert (2010).
  Tsimikas S, Witztum JL, Miller ER, Sasiela WJ, Szarek M, Olsson AG, Schwartz GG. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-1 00 in patients with acute coronary syndromes in the MIRACL trial. Circulation. 2004;110(11):1406-1412.
  Tulenko TN, Chen M, Mason PE, Mason RP. Physical effects of cholesterol on arterial smooth muscle membranes: Evidence of immiscible cholesterol domains and alterations in bilayer width C during atherogenesis. J. Lipid Res. 1998;39:947-956.
  Tungsiripat, et al., “Dyslipidemia in HIV patients,” Cleveland Clinic Journal of Medicine, v. 72, No. 12 (2005).
  Turini et al., “Short-term fish oil supplementation improved innate immunity, but increased ex vivo oxidation of LDL in man—a pilot study.” Eur. J. Nutr. 40:56-65 (2001).
  U.S. Appl. No. 14/245,499, filed Apr. 4, 2014 (now abandoned).
  U.S. Appl. No. 14/261,160, filed Apr. 24, 2014.
  Urquhart et al., “Profile of eicosanoids produced by human saphenous vein endothelial cells and the effect of dietary fatty acids,” Prostaglandins Leukot. Essent. Fatty Acid, 65(1):15-22 (2001.
  Vaagenes et al., “The Hypolipidaemic Effect of EPA is Potentiated by 2- and 3-Methylation.” In P. Quant & S. Eaton (eds.) Current Views of Fatty Acid Oxidation and Ketogenesis from Organelles to Point Mutations; Advances in Experimental Medicine and Biology, vol. 466 , pp. 221-226 (1999).
  Varbo et al., Remnant Cholesterol as a Causal Risk Factor for Ischemic Heart Disease, J. Am. Coll. Cardiol., vol. 61(4), pp. 427-436 (2013).
  Varbo et al., Remnant cholesterol as a cause of ischemic heart disease: Evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment, Pharmacol. Ther., vol. 141(3), pp. 358-367 (2014).
  Vascepa [package insert], Bedminster, NJ: Amarin Pharma Inc.; 2012.
  Vascepa [package insert]. Bedminster, NJ: Amarin Pharma Inc.; 2013.
  Vergnani L, Hatrik S, Ricci F, Passaro A, Manzoli N, Zuliani G, Brovkovych V, Fellin R, Malinski T. Effect of native and oxidized low-density lipoprotein on endothelial nitric oxide and superoxide production : Key role of 1-arginine availability. Circulation. 2000;101:1261-1266.
  Vidal F, Colome C, Martinez-Gonzalez J, Badimon L. Atherogenic concentrations of native low density lipoproteins down-regulate nitric-oxide-synthase mma and protein levels in endothelial cells. Eur. J. Biochem. 1998;252:378-384.
  Virani et al., “The Role of Lipoprotein-associated Phospholipase A2 as a marker for atherosclerosis” Curr. Atheroscler. Rep. 9[2): 97-103 (2007).
  Von Schacky C, Baumann K, Angerer P. The effect of n-3 fatty acids on coronary atherosclerosis: results from Scimo, an angiographic study, background and implications. Lipids 2001 36 Suppl: S99-102.
  Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M. Improvement of nitric oxide-dependent vasodilation by hmg-coa reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler. Thromb. Vasc. Biol. 2000;20:61-69.
  Walker G, Mandagere A, Dufton C, et al. The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers. Br. J. Clin. Pharmacol. May 2009 67 (5): 527-34.
  Walter MF, Jacob RF, Bjork RE, Jeffers B, Buch J, Mizuno Y, Mason RP. Circulating lipid hydroperoxides predict cardiovascular events in patients with stable coronary artery disease: the PREVENT study. J. Am. Coll. Cardiol. 2008;51(12):1196-1202.
  Walter MF, Jacob RF, Jeffers B, Ghadanfar MM, Preston GM, Buch J, Mason RP. Serum levels of TBARS predict cardiovascular events in patients with stable coronary artery disease: A longitudinal analysis of the PREVENT study. J. Am. Coll. Cardiol. 2004;44(10):1996-2002.
  Wassmann S, Laufs U, Muller K, Konkol C, Ahlbory K, Baumer AT, Linz W, Bohm M, Nickenig G. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler. Thromb. Vasc. Biol. 2002;22:300-305.
  Webcast Information for the Oct. 16, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, 1 page.
  Wei et al., Effects of [EPA] Versus [DHA] on Serum Lipids: A Systematic Review and Meta-Analysis, 13 Current Atherosclerosis Rep. 13(6):474-483 (2011).
  Werner, Hypertriglyceridamie: Ein klinischer Leitfaden, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 2008, front page to page V, pp. 2 to 55, 64 to 85, 90 to 97.
  Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet. 1994;344(8925):793-795.
  Xiao, Y-F., et al., “Fatty acids suppress voltage-gated Na+ currents in HEK293t cells transfected with the a-subunit of the human cardiac Na+ channel.” Proc. Natl. Acad. Sci. 95: 2680-2685 (1998).
  Yacyshyn BR, Thomson AB. The clinical importance of proton pump inhibitor pharmacokinetics. Digestion 2002 66 (2): 67-78.
  Yagi K. Assay for blood plasma or serum. Methods Enzymol. 1984;105:328-331.
  Yates RA, Wong J, Seiberling M, et al. The effect of anastrozole on the single-dose pharmacokinetics and anticoagulant activity of warfarin in healthy volunteers. Br. J. Clin. Pharmacol. May 2001 51 (5): 429-35.
  Yokoyama et al., “Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholeterolemia: Rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS),” Amer. Heart Journal 146(4):613-620 (2003).
  Yorioka, N, “Lipid-lowering therapy and coagulation/fibrinolysis parameters in patients on peritoneal dialysis,” The International Journal of Artificial Organs, vol. 23(1):27-32 2000.
  Yoshimura et al., “Effects of highly purified eicosapentaenoic acid on plasma beta thromboglobulin level and vascular reactivity to angiotensin II”, Artery, 14(5):295-303, (1987).
  Zalewski et al., Role of Lipoprotein-Associated Phospholipase A2 in Atherosclerosis: Biology, Epidemiology, and Possible Therapeutic Target, Arteriosclerosis, Thrombosis, & Vascular Biology 25(5):923-931 (2005).
  Zimmerman JJ, Raible DG, Harper DM, et al. Evaluation of a potential tigecycline-warfarin drug interaction. Pharmacotherapy Jul. 28, 2008 (7): 895-905.
  Zuijdgeest-van Leeuwen, S.D., et al., “Incorporation and washout of orally administered n-3 fatty acid ethyl esters in different plasma lipid fractions.” British Journal of Nutrition 82:481-488 (1999).
  Zuijdgeest-van Leeuwen, SD, et al., “Eicosapentaenoic acid inhibits lipolysis in weight-losing cancer patients as well as in healthy volunteers,” Eur J Gastroenterol & Hepatol., 10(12):A67 (1998).
  Zvyaga T, Chang SY, Chen C, et al. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab. Dispos. Sep. 2012 40 (9): 1698-711.
  Crevel et al., “Allergenicity of Refined Vegetable Oils,” Food and Chemical Toxicology, 38, pp. 385-393 (2000).
  Missouri DUReport, Statin Therapy (Oct./Nov. 2003) Drug Use Review Newsletter 8(6):1-9.
  Sicherer et al., “Prevalence of seafood allergy in the United States determined by a random telephone survey,” J. Allergy Clin. Immunol., 114(1):159-165 (Jul. 2004).
  Amarin Presentation “Next Generation Lipid Modification in Cardiovascular Disease,” (Aug. 2011).
  Ascenta Health “Fish Oil as Triglycerides vs. Ethyl Esters: Why this Matters.” (2015).
  Atovastatin Package Leaflet, Reg. No. LSR-005205/08, Sep. 30, 2016 [retrieved Sep. 30, 2016] retrieved from the internet: academ-clinic.ru/drugs/atorvastatin.
  Beaumont et al., Design of Ester Prodrugs to Enhance Oral Absorption of Poorly Permeable Compounds: Challenges to the Discovery Scientist, Current Drug and Metabolism. (2003) 4:461-485.
  Bild et at., “Multi-Ethnic Study of Atherosclerosis: objectives and design,” Am J Epidemiol 156(9):871-81 (Nov. 1, 2002).
  Braeckman et al., “Effect of Concomitant Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) on Pharmacokinetics of Atorvastatin,” Clinical Drug Investigation. (2015) (3)45-51.
  Carrero, J.J. et al. “Efectos cardiovasculares de los acidos grasos omega-3 y alternativas para incrementar su ingesta,” Nutricion Hospitalaria. (2005) (1) 63-69 [with English abstract].
  Ceci et al., “The effects of oral 5-hydroxytryptophan administration on feeding behavior in obese adult female subjects,” J Neural. Transm (1989) 76:109-117.
  Cromwell et al., “LDL particle number and risk of future cardiovascular disease in the Framingham Offspring Study—Implications for LDL Management,” Journal of Lipidololgy. (2009) 1, 583-592.
  Davies-Tuck et al., “Total cholesterol and triglycerides are associated with development of new bone marrow lesions in asymptomatic middle-aged women—a prospective cohort study,” Arthritis Research & Therapy. (2009) pp. 1-7.
  Essentialis Inc. press release, “Essentialis Meets Primary Endpoint in Phase 2b Trial of DCCR for Treatement of Hypertriglyceridemia and is Granted Extensive Patent Coverage in the US,” PR Newswire (May 17, 2009).
  FDA News Release, “FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder,” U.S. Food and Drug Administration, Protecting and Promoting Your Health (Jan. 29, 2013).
  Higashihara et al. “Effects of Eicosapentaenoic Acid on Biochemical Failure after Radical Prostatectomy for Prostate Cancer,” in vivo 24:561-566 (2010).
  Horn et al., “Soft Gelatin Capsules II: Oxygen Permeability Study of Capsule Shells,” J Pharm Sci. (1975) 64(5):851-857.
  Jong et al., “Role of ApoCs in Lipoprotein Metabolism: Function Differences Between ApoC1, ApoC2, and ApoC3,” Arteriosclerosis, Thrombosis and Vascular Biology. (1999) 19(3):472-484.
  Kamido et al., Lipid Composition of Platelets from Patients with Atherosclerosis:Effect of Purified Eicosapentaenoic Acid Ethyl Ester Administration, 1988, Lipids, 23, pp. 917-923 [Abstract only].
  Kholodov et al., “Clinical Pharmacokinetics,” M. Medicine. (1985) pp. 89-98, 134-138, 160, 378-380 [with English Summary].
  Labor Diagnostik Karlsruhe, “Target Values of Lipid Metabolism [Recommendation for lipid plasma levels in Germany],” (exact publication date unknown; circa 2006) (with English abstract).
  Lada et al., “Associations of Low Density Lipoprotein Particle Compositions with Atherogenicity,” Curr. Opin. Lipidol. (2004) 15(1):19-24.
  Margolis, Simeon “What is Hyperlipidemia?” (http:www.healthcommunities.com/highcholesterol/whatishyperlipidemia.shtml, accessed Oct. 20, 2015, published Aug. 25, 2011).
  Martinez-Gonzalez, Jose et al., “Estatinas y acidos grasos omega-3. Disminucion de la mortalidad cardiovascular dependiente e independiente de la reduccion de la colesterolemia,” (2006) Rev Esp Cardiol Suppl., 6(D):20-30 [with English abstract].
  Mason et al., “Eicosapentaenoic Acid (EPA) inhibits the formation of membrane cholesterol crystalline domains by a potent antioxidant mechanism,” Journ. Clin. Lipid., 7(3): 272-273 (2013) [Abstract only].
  Merkl et al., “Antisense Oligonucleotide Directed to Human Apolipoprotein B-100 Reduces Lipoprotein(a) Levels and Oxidized Phospholipids on Human Apolipoprotein B-100 Particles in Lipoprotein(a) Transgenic Mice,” Circulation, vol. 118, pp. 743-753 (2008).
  Mostad et al., “Effects of Marine N-3 Fatty Acid Supplementation on Lipoprotein Subclasses Measured by Nuclear Magnetic Resonance in Subjects with Type II Diabetes,” European Journ. Clin. Nutr., 62(3):419-429 (2007).
  O'Riordan, “DHA and EPA have differential effects on LDL-cholesterol,” May 24, 2011 [online][Retrieved on Aug. 21, 2015] Retrieved from website: http://www.medscape.com/viewarticle/743305.
  Reich, “Formation and physical properties of soft capsules,” Pharmaceutical capsules. (2004) Chapter 11:201-212.
  Satoh et al., “Highly purified eicosapentaenoic acid reduces cardio-ankle vascular index in association with decreased serum amyloid A-LDL in metabolic syndrome,” Hypertension Research (2009) (32):1004-1008.
  Sternbach “The Glasgow Como Scale.” The Journal of emergency medicine 19.1 (2000): 67-71.
  Stiles, FDA approves EPA-only omega-3 PUFA capsule for high TG, http://www.medscape.com/viewarticle/791268, accessed Dec. 17, 2014.
  Stojancevic et al., “The impact of farnesoid X receptor activation on intestinal permeability in inflammatory bowel disease,” Can. J Gastroenterol. 26(9):631-637 (2012).
  Taylor et al., “Fish allergy: fish and products thereof,” Journal Food Science (2004) 69.8 R175-R180.
  van Wijk et al. Rosiglitazone improves postprandial triglyceride and free fatty acid metabolism in type 2 diabetes. Diabetes Care, vol. 28, No. 4, (2005) pp. 844-849.
  Velliquette et al., “Regulation of human stearoyl-CoA desaturase by omega-3 and omega-6 fatty acids: Implications for the dietary management of elevated serum triglycerides,” Journal of Clinical Lipidology. (2009) 3:281-288.
  Watanabe et al., “Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c,” J Clin Invest. 113(10): 1408-1418 (May 2004).
  Wood et al., “Carbohydrate Restriction Alters Lipoprotein Metabolism by Modifying VLDL, LDL and HDL Subtraction Distribution and Size in Overweight Men,” Journ. of Nutrition, 136(2):384-9 (2006).
 
 
     * cited by examiner
 
     Primary Examiner —Kevin E Weddington
     Art Unit — 1629
     Exemplary claim number — 1
 
(74)Attorney, Agent, or Firm — Perkins Coie LLP

(57)

Abstract

The present disclosure relates to, inter alia, methods of treating mixed dyslipidemia with ethyl eicosapentaenoate.
3 Claims, 2 Drawing Sheets, and 4 Figures


CROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] This application is a continuation of U.S. patent application Ser. No. 14/175,602 filed on Feb. 7, 2014 (now U.S. Pat. No. 9,056,088), which is a continuation of U.S. patent application Ser. No. 13/898,447 filed on May 20, 2013 (now U.S. Pat. No. 8,691,871), which is a continuation of U.S. patent application Ser. No. 13/540,319 filed Jul. 2, 2012 (now U.S. Pat. No. 8,618,166), which is a continuation of U.S. patent application Ser. No. 13/417,899 filed on Mar. 12, 2012 (now U.S. Pat. No. 8,563,608), which is a continuation of U.S. patent application Ser. No. 13/266,085 filed on Jan. 30, 2012, which is a National Stage Entry of Application No. PCT/US10/32948 filed on Apr. 29, 2010, which claims priority from U.S. Provisional Patent Application No. 61/173,759 filed on Apr. 29, 2009, all of which are incorporated herein in their entirety.

BACKGROUND

[0002] Cardiovascular disease is one of the leading causes of death in the United States and most European countries. It is estimated that over 70 million people in the United States alone suffer from a cardiovascular disease or disorder including but not limited to high blood pressure, coronary heart disease, dyslipidemia, congestive heart failure and stroke.

SUMMARY

[0003] In one embodiment, the present invention provides a pharmaceutical composition comprising EPA and optionally one or more additional cardiovascular agents. In another embodiment, the EPA comprises eicosapentaenoic acid ethyl ester. In another embodiment, the composition contains substantially no amount of docosahexaenoic acid or derivative thereof (e.g. ethyl-DHA), if any.
[0004] In other embodiments, the present invention provides methods of treating and/or preventing a cardiovascular-related disease comprising administering to a subject in need thereof a pharmaceutical composition or composition(s) comprising EPA and optionally one or more additional cardiovascular agents.
[0005] In any of the foregoing embodiments, the EPA and additional cardiovascular agent(s) can be co-formulated as a single dosage unit or can be formulated as two to a plurality of dosage units for coordinated, combination or concomitant administration.
[0006] These and other embodiments of the present invention will be disclosed in further detail herein below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 shows effects of EPA, DHA and Combination Treatment on membrane lipid peroxidation at cholesterol-to-phospholipid ratio of 1.0.
[0008] FIG. 2 shows effects of EPA, DHA and Combination Treatment on membrane lipid peroxidation at cholesterol-to-phospholipid ratio of 0.5.
[0009] FIG. 3 shows cholesterol-dependent effects of EPA, DHA and Combination Treatment on membrane lipid peroxidation.
[0010] FIG. 4 EPA, DHA or EPA/DHA with atorvastatin (10:1 Mole Ratio) on lipid peroxide levels in cholesterol enriched membranes (1:1 cholesterol-to-phospholipid ratio).

DETAILED DESCRIPTION

[0011] While the present invention is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the invention, and is not intended to limit the invention to the specific embodiments illustrated. Headings are provided for convenience only and are not to be construed to limit the invention in any manner. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
[0012] The use of numerical values in the various quantitative values specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word “about.” In this manner, slight variations from a stated value can be used to achieve substantially the same results as the stated value. Also, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values recited as well as any ranges that can be formed by such values. Also disclosed herein are any and all ratios (and ranges of any such ratios) that can be formed by dividing a recited numeric value into any other recited numeric value. Accordingly, the skilled person will appreciate that many such ratios, ranges, and ranges of ratios can be unambiguously derived from the numerical values presented herein and in all instances such ratios, ranges, and ranges of ratios represent various embodiments of the present invention.

Eicosapentaenoic Acid

[0013] In one embodiment, compositions of the invention comprise EPA as an active ingredient. The term “EPA” as used herein refers to eicosapentaenoic acid (e.g. eicosa-5,8,11,14,17-pentaenoic acid) and/or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof, or mixtures of any of the foregoing. The term “pharmaceutically acceptable” in the present context means that the substance in question does not produce unacceptable toxicity to the subject or interaction with other components of the composition.
[0014] In one embodiment, the EPA comprises all-cis eicosa-5,8,11,14,17-pentaenoic acid. In another embodiment, the EPA is in the form of an eicosapentaenoic acid ester (also referred to herein as E-EPA or ethyl-EPA). In another embodiment, the EPA comprises a C1-C5 alkyl ester of EPA. In another embodiment, the EPA comprises, eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl ester. In still another embodiment, the EPA comprises all-cis eicosa-5,8,11,14,17-pentaenoic acid ethyl ester.
[0015] In another embodiment, the EPA comprises lithium EPA, mono, di- or triglyceride EPA or any other ester or salt of EPA, or the free acid form of EPA. The EPA may also be in the form of a 2-substituted derivative or other derivative which slows down its rate of oxidation but does not otherwise change its biological action to any substantial degree.
[0016] In one embodiment, EPA present in a composition of the invention comprises ultra-pure EPA. The term “ultra-pure” as used herein with respect to EPA refers to a composition comprising at least 96% by weight EPA (as the term “EPA” is defined and exemplified herein). Ultra-pure EPA can comprise even higher purity EPA, for example at least 97% by weight EPA or at least 98% by weight EPA, wherein the EPA is any form of EPA as set forth herein. Ultra-pure EPA can further be defined (e.g. impurity profile) by any of the description of EPA provided herein.
[0017] In another embodiment, the EPA comprises an EPA-Fatty Acid conjugate wherein EPA is conjugated to another molecule of EPA or to another fatty acid. In one embodiment, the EPA-Fatty Acid conjugate comprises a diester formed between EPA and EPA or between EPA a second fatty acid as shown in structures (I) and (II). In one embodiment, R1 is a fatty acid acyl group derived from EPA and R2 is selected from H, a fatty acid acyl of 12 to 30 carbon atoms with two or more cis or trans double bonds and fatty alcohol groups of 12 to 30 carbon atoms, the same or different than R1. R1 and R2 may both be derived from EPA (EPA-EPA) or one may be derived from EPA and the second from a different fatty acid (EPA-Fatty acid), for example gamma-linolenic acid, dihomo-gammalinolenic acid, arachidonic acid, adrenic acid, stearidonic acid, docosapentaenoic acid n-3, etc.). R3 is generally either hydrogen, fully hydrocarbon, or containing heteroatoms, and in one embodiment is a C1-C4 alkyl group.
[0018]  [see pdf for image]
[0019] Synthesis of a diester conjugate can be accomplished according to methods well known in the art, including for example, using metals, metal-chlorides, or organic acids as catalysts; using fatty acid chlorides such as EPA-chloride, γ-linolenic acid chloride (GLAchloride), dihomo-γ-linolenic acid chloride (DGLA-chloride), linoleic acid chloride (LA-chloride), arachidonic acid chloride (AA-chloride), conjugated linoleic acid chloride (cLA-chloride), ALA-chloride, STA-chloride, ETA-chloride, DPA-chloride, etc.; and the use of immobilized enzymes as catalysts.
[0020] In another embodiment, a composition of the present invention includes a mixture of EPA-Fatty Acid diesters. In a related embodiment, compositions of the present invention include less than 20% EPA-DHA conjugate, less than 15% EPA-DHA conjugate, less than 10% EPA-DHA conjugate, less than 9% EPA-DHA conjugate, less than 8% EPADHA conjugate, less than 7% EPA-DHA conjugate, less than 6% EPA-DHA conjugate, less than 5% EPA-DHA conjugate, less than 4% EPA-DHA conjugate, less than 3% EPA-DHA conjugate, less than 2% EPA-DHA conjugate, less than 1% EPA-DHA conjugate, less than 0.5% EPA-DHA conjugate, or less than 0.1% EPA-DHA conjugate, by weight.
[0021] In another embodiment, a composition of the present invention includes at least 96% EPA-Fatty acid conjugate (e.g. EPA-EPA), at least 97% EPA-Fatty acid conjugate, at least 98% EPA-Fatty acid conjugate, or at least 99% EPA-Fatty acid conjugate. In another embodiment, a composition of the present invention contains no more than 10%, no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, or no more than 0.6%, no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2, or no more than 0.1% of any EPA-Fatty Acid conjugate other than EPA-EPA diester.
[0022] In another embodiment, EPA is present in a composition of the invention in an amount of about 50 mg to about 5000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, or about 2500 mg.
[0023] In one embodiment, a composition of the invention contains not more than about 10%, not more than about 9%, not more than about 8%, not more than about 7%, not more than about 6%, not more than about 5%, not more than about 4%, not more than about 3%, not more than about 2%, not more than about 1%, or not more than about 0.5%, by weight of total fatty acids, docosahexaenoic acid or derivative thereof such as ethyl-DHA (E-DHA), if any. In another embodiment, a composition of the invention contains substantially no docosahexaenoic acid or derivative thereof such as E-DHA. In still another embodiment, a composition of the invention contains no docosahexaenoic acid or E-DHA.
[0024] In another embodiment, EPA represents at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100%, by weight, of all fatty acids present in a composition of the invention.
[0025] In another embodiment, a composition of the invention contains less than 30%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% or less than 0.25%, by weight of the total composition or by weight of the total fatty acid content, of any fatty acid other than EPA, or derivative thereof. Illustrative examples of a “fatty acid other than EPA” include linolenic acid (LA) or derivative thereof such as ethyl-linolenic acid, arachidonic acid (AA) or derivative thereof such as ethyl-AA, docosahexaenoic acid (DHA) or derivative thereof such as ethyl-DHA, alpha-linolenic acid (ALA) or derivative thereof such as ethyl-ALA, stearadonic acid (STA) or derivative thereof such as ethyl-SA, eicosatrienoic acid (ETA) or derivative thereof such as ethyl-ETA and/or docosapentaenoic acid (DPA) or derivative thereof such as ethyl-DPA.
[0026] In another embodiment, a composition of the invention has one or more of the following features: (a) eicosapentaenoic acid ethyl ester represents at least 96%, at least 97%, or at least 98%, by weight, of total fatty acids present in the composition; (b) the composition contains not more than 4%, not more than 3%, or not more than 2%, by weight, of total fatty acids other than eicosapentaenoic acid ethyl ester; (c) the composition contains not more than 0.6%, 0.5%, or 0.4% of any individual fatty acid other than eicosapentaenoic acid ethyl ester; (d) the composition has a refractive index (20° C.) of about 1 to about 2, about 1.2 to about 1.8 or about 1.4 to about 1.5; (e) the composition has a specific gravity (20° C.) of about 0.8 to about 1.0, about 0.85 to about 0.95 or about 0.9 to about 0.92; (f) the composition contains not more than 20 ppm, 15 ppm or 10 ppm heavy metals, (g) the composition contains not more than 5 ppm, 4 ppm, 3 ppm, or 2 ppm arsenic, and/or (h) the composition has a peroxide value not more than 5, 4, 3, or 2 Meq/kg.
[0027] In another embodiment, a composition useful in accordance with the invention comprises, consists essentially of or consists of at least 95% ethyl eicosapentaenoate (EPA-E), about 0.2% to about 0.5% ethyl octadecatetraenoate (ODTA-E), about 0.05% to about 0.25% ethyl nonaecapentaenoate (NDPA-E), about 0.2% to about 0.45% ethyl arachidonate (AA-E), about 0.3% to about 0.5% ethyl eicosatetraenoate (ETA-E), and about 0.05% to about 0.32% ethyl heneicosapentaenoate (HPA-E), each by weight of total fatty acids present in the composition. In another embodiment, the composition is present in a capsule shell. In still another embodiment, the capsule shell contains no chemically modified gelatin.
[0028] In another embodiment, compositions useful in accordance with the invention comprise, consist essentially of, or consist of at least 95%, 96% or 97%, ethyl eicosapentaenoate, about 0.2% to about 0.5% ethyl octadecatetraenoate, about 0.05% to about 0.25% ethyl nonaecapentaenoate, about 0.2% to about 0.45% ethyl arachidonate, about 0.3% to about 0.5% ethyl eicosatetraenoate, and about 0.05% to about 0.32% ethyl heneicosapentaenoate, each by weight of all fatty acids present in the composition. Optionally, the composition contains not more than about 0.06%, about 0.05%, or about 0.04%, by weight of total fatty acids present, DHA or derivative thereof such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative thereof such as ethyl-DHA. The composition further optionally comprises one or more antioxidants (e.g. tocopherol) in an amount of not more than about 0.5% or not more than 0.05%. In another embodiment, the composition comprises about 0.05% to about 0.4%, for example about 0.2% by weight tocopherol. In another embodiment, about 500 mg to about 1 g of the composition is provided in a capsule shell. In another embodiment, the capsule shell contains no chemically modified gelatin.
[0029] In another embodiment, compositions useful in accordance with the invention comprise, consist essentially of, or consist of at least 96% ethyl eicosapentaenoate, about 0.22% to about 0.4% ethyl octadecatetraenoate, about 0.075% to about 0.20% ethyl nonaecapentaenoate, about 0.25% to about 0.40% ethyl arachidonate, about 0.3% to about 0.4% ethyl eicosatetraenoate and about 0.075% to about 0.25% ethyl heneicosapentaenoate, each by weight of total fatty acids present in the composition. Optionally, the composition contains not more than about 0.06%, about 0.05%, or about 0.04%, by weight of total fatty acids present, DHA or derivative thereof such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative thereof such as ethyl-DHA. The composition further optionally comprises one or more antioxidants (e.g. tocopherol) in an amount of not more than about 0.5% or not more than 0.05%. In another embodiment, the composition comprises about 0.05% to about 0.4%, for example about 0.2% by weight tocopherol. In another embodiment, the invention provides a dosage form comprising about 500 mg to about 1 g of the foregoing composition in a capsule shell. In one embodiment, the dosage form is a gel- or liquid-containing capsule and is packaged in blister packages of about 1 to about 20 capsules per sheet.
[0030] In another embodiment, compositions useful in accordance with the invention comprise, consist essentially of or consist of at least 96%, 97% or 98%, by weight, ethyl eicosapentaenoate, about 0.25% to about 0.38% by weight ethyl octadecatetraenoate, about 0.10% to about 0.15% by weight ethyl nonaecapentaenoate, about 0.25% to about 0.35% by weight ethyl arachidonate, about 0.31% to about 0.38% by weight ethyl eicosatetraenoate, and about 0.08% to about 0.20% ethyl heneicosapentaenoate, each by weight of all fatty acids present in the composition. Optionally, the composition contains not more than about 0.06%, about 0.05%, or about 0.04%, by weight of all fatty acids present, DHA or derivative thereof such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative there of such as ethyl-DHA. The composition further optionally comprises one or more antioxidants (e.g. tocopherol) in an amount of not more than about 0.5% or not more than 0.05%. In another embodiment, the composition comprises about 0.05% to about 0.4%, for example about 0.2% by weight tocopherol. In another embodiment, the invention provides a dosage form comprising about 500 mg to about 1 g of the foregoing composition in a capsule shell. In another embodiment, the capsule shell contains no chemically modified gelatin.

Cardiovascular Agents

[0031] In one embodiment, a composition (or co-administration regimen) of the invention comprises one or more additional cardiovascular agents. The one or more additional cardiovascular agents can be co-formulated with EPA or can be co-administered with EPA. The interchangeable terms “cardiovascular agent” or “cardiovascular drug” herein refer to a drug or agent that is capable of treating, preventing, or reducing the risk of developing a cardiovascular disease or disorder, or a risk factor or symptom thereof, in a subject. Cardiovascular agents herein can include, without limitation, cholesterol and triglyceride modulating agents, agents that treat coronary artery disease, agents that treat hypertension or pulmonary arterial hypertension, agents that treat arterial fibrillation or arrhythmia, agents that treat stroke, agents that treat myocardial ischemia and/or agents that treat thrombosis.
[0032] Non-limiting examples of classes from which cardiovascular agents suitable for use in accordance with the present invention can be selected include: Acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT-1, ACAT-2 as well as dual inhibitors of ACAT-1 and ACAT-2, alpha-adrenergic blocking drugs (alpha-blockers), alpha/beta blockers, angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists, angiotensin II receptor antagonists, anti-arrhythmics, anticoagulants, antiplatelet agents, apolipoprotein A-1 (apoA-1) mimetics, beta-blockers, bile acid sequestrants, calcium-channel blockers, ApoB cholesteryl ester transfer protein (CETP) inhibitors, cholesterol absorption inhibitors, diuretics, dyslipidemia agents, endothelin receptor antagonists, fibrates, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, LCAT activators, LDL receptor inducers, lipase inhibitors, lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, platelet aggregation inhibitors, PPAR agonists and activators including PPARγ agonists, PPARα agonists and PPAR dual α/γ agonists, PCSK9 antisense or RNAi, squalene epoxidase inhibitors, squalene synthetase inhibitors, thrombolytics, and thyroid receptor beta activators.

ACAT Inhibitors.

[0033] Acyl-CoA cholesteryl acyl transferase (“ACAT”) is an acyltransferase enzyme. In bile acid biosynthesis, ACAT catalyzes the intracellular formation of cholesterol esters from cholesterol. ACAT promotes accumulation of cholesterol esters in vascular tissues. Agents that inhibit ACAT, therefore, are useful in preventing or treating atherosclerosis. Non-limiting examples of suitable ACAT inhibitors include CI-1011 (Avasimibe, Pfizer), CS-505 (Pactimibe sulfate, Sankyo Pharma), or combinations thereof.
[0034] One or more ACAT inhibitors, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 1 mg to about 1000 mg, for example about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 266 mg, about 275 mg, about 300 mg, about 324 mg, about 325 mg, about 330 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg.

ACE Inhibitors.

[0035] Angiotensin I converting enzyme (“ACE”) converts angiontensin I to angiotensin II and inhibits brakykinin. Because increased angiotensin II and decreased brakykinin levels both promote a variety of cardiovascular diseases and disorders, agents that inhibit ACE are useful in preventing or treating cardiovascular-related diseases such as hypertension, heart failure, diabetic neuropathy, and type 2 diabetes. Non-limiting examples of suitable ACE inhibitors include captopril, enalapril, enaliprilat, trandolapril, moexipril, ramipril, quinapril, perindopril, lisinopril, benazepril, fosinopril, or combinations thereof.
[0036] One or more ACE inhibitors, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 0.5 mg to about 50 mg, for example about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg.

Aldosterone Antagonists.

[0037] Aldosterone is a steroidal hormone that contributes to hypertension by inhibiting kidney function. Agents that compete with aldosterone for mineralo-corticoid receptors are therefore useful in preventing or treating hypertension. Non-limiting examples of suitable aldosterone agents include eplerenone and aldactone, or combinations thereof.
[0038] Aldosterone antagonists, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 5 mg to about 100 mg, for example about 5 mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95, or about 100 mg.

Alpha Blockers.

[0039] Alpha blockers, also called adrenergic alpha-antagonists, compete with adrenaline binding at α-adrenoreceptors. Adrenaline binding at such receptors leads to vasoconstriction and therefore hypertension. Agents that compete with adrenaline or block α-adrenoreceptors are therefore useful in preventing or treating hypertension. Non-limiting examples of suitable alpha blockers include doxazosin, methyldopa, clonidine, prazosin, terazosin, or combinations thereof.
[0040] Alpha blockers, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 0.02 mg to about 0.5 mg, for example about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 2.5 mg, about 0.3 mg, about 3.5 mg, about 0.4 mg, about 4.5 mg, or about 0.5 mg; in an amount of about 0.5 mg to about 15 mg, for example about 0.5 mg, about 0.75 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg; or in an amount of about 100 mg to about 500 mg, for example about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.

Alpha/Beta Blockers.

[0041] One or more alpha/beta blockers, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 1 mg to about 25 mg, for example about 1 mg, about 2 mg, about 3 mg, about 3.125 mg, about 4 mg, about 5 mg, about 6 mg, about 6.25 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24, or about 25 mg. A non-limiting example of an alpha/beta blocker is carvedilol.

Angiotensin II Receptor Antagonists.

[0042] Angiotensin II receptor antagonists, alternately called angiotensin receptor blockers, ARBs, AT1-receptor antagonists, or sartans, are useful in treating hypertension, congestive heart failure, and various other diseases and disorders. Non-limiting examples of angiotensin II receptor antagonists include candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, eprosartan, or combinations thereof.
[0043] One or more angiotensin II receptor antagonists, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 1 mg to about 100 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 15 mg, about 16 mg, about 20 mg, about 24 mg, about 25 mg, about 28 mg, about 30 mg, about 32 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg; in an amount of about 40 mg to about 320 mg, for example, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg; in an amount of about 200 mg to about 800 mg, for example about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg.

Anti-Arrhythmic Agents.

[0044] Anti-arrhythmic drugs act to correct an irregular heartbeat and/or slow a heart that is beating too rapidly. Non-limiting examples of suitable anti-arrhythmic agents include adenosine, amiodarone, digoxin, disopyramide, flecainide, lidocaine, mexiletine, procainamide, quinidine gluconate, propafenone hydrochloride, tocainide, or combinations thereof
[0045] One or more anti-arrhythmics, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 0.1 mg to about 1500 mg, about 1 mg to about 1200 mg, or about 5 mg to about 1000 mg, for example about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 5 mg, about 6 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 266 mg, about 275 mg, about 300 mg, about 324 mg, about 325 mg, about 330 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, or about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, or about 1500 mg.
[0046] In an another embodiment, one or more anti-arrhythmics can be present in an amount of about 1 mg per mL to about 500 mg per mL, for example about 1 mg per mL, about 2 mg per mL, about 3 mg per mL, about 4 mg per mL, about 5 mg per mL, about 6 mg per mL, about 10 mg per mL, about 25 mg per mL, about 50 mg per mL, about 75 mg per mL, about 80 mg per mL, about 100 mg per mL, about 125 mg per mL, about 150 mg per mL, about 175 mg per mL, about 200 mg per mL, about 225 mg per mL, about 250 mg per mL, about 275 mg per mL, about 300 mg per mL, about 325 mg per mL, about 350 mg per mL, about 375 mg per mL, about 400 mg per mL, about 425 mg per mL, about 450 mg per mL, about 475 mg per mL, or about 500 mg per mL.
[0047] In another embodiment, an anti-arrhythmics is present in an amount of about 0.01% to about 5%, for example about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, or about 5% by weight of the total composition.

Antiplatelet Agents.

[0048] Antiplatelet agents inhibit platelet aggregation and therefore combat thrombus development. Non-limiting examples of antiplatelet agents include adeparin, aspirin, clopidogrel, danaparoid, deltaparin, denaparoid, ticlopidine, cilostazol, abciximab, eptifibatide, tirofiban, defibrotide, enoxaparin, dipyridamole, tinzaparin, or combinations thereof.
[0049] One or more antiplatelet agents, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 10 mg to about 100 mg, for example about 10 mg, about 12.5 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg; in an amount of about 50 mg to about 300 mg, for example about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.
[0050] In another embodiment, one or more antiplatelet agents are present in an amount of about 25 μg per mL to about 50 μg per mL, for example about 25 μg per mL, about 30 μg per mL, about 35 μg per mL, about 40 μg per mL, about 45 μg per mL, or about 50 μg per mL; or in an amount of about 1 mg per mL to about 2 mg per mL, for example about 1 mg per mL, about 1.25 mg per mL, about 1.50 mg per mL, about 1.75, or about 2 mg per mL.

apoA-1 Mimetics.

[0051] Apolipoprotein A-1 (“apoA-1”) is the primary protein component of serum HDL cholesterol. Non-limiting examples of apoA-1 mimetics include ETC-216, ETC-588-liposome, ETC-642, trimeric apoA-1, CSL-111, APP018, reverse D-4F, or combinations thereof.
[0052] One or more apoA-1 mimetics, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 0.1 mg to about 1500 mg, about 1 mg to about 1200 mg, or about 5 mg to about 1000 mg, for example about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 5 mg, about 6 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 266 mg, about 275 mg, about 300 mg, about 324 mg, about 325 mg, about 330 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, or about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, or about 1500 mg.

Beta Blockers.

[0053] Beta blockers block responses to the beta nerve receptor which tends to slow heart rate and lower blood pressure. Non-limiting examples of suitable beta blockers include acebutolol, atenolol, metoprolol, nadolol, nebivolol, pindolol, propranolol, or combinations thereof.
[0054] One or more beta blockers, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 1 mg to about 1000 mg, about 1 mg to about 750 mg, or about 1 mg to about 500 mg, for example about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.

Bile Acid Sequestrants.

[0055] Bile acid sequestrants interrupt the enterohepatic circulation of bile acids by binding bile acid components in the gastrointestinal tract, rendering them unabsorbable thereafter. Bile acid sequestrants are thus useful in preventing or treating hyperlipidemia, among other diseases and disorders. Non-limiting examples of bile acid sequestrants include colesevelam Hcl, colestipol, locholest and cholestyramine or combinations thereof.
[0056] One or more bile acid sequestrants, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 4 mg to about 32 mg, for example about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 24 mg, about 32 mg; or in an amount of about 300 mg to about 4000 mg, for example about 300 mg, about 325 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 625 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1250 mg, about 1500 mg, about 1750 mg, about 2000 mg, about 2250 mg, about 2500 mg, about 2750 mg, about 3000 mg, about 3250 mg, about 3500 mg, about 3750, or about 4000 mg.

Calcium Channel Blockers.

[0057] Calcium channel blockers are useful in preventing or treating hypertension by their vasodilating action. Non-limiting examples of calcium channel blockers include nicardipine, diltiazem, clevidipine butyrate, isradipine, nimodipine, nisoldipine, verapamil, and amlodipine besylate, or combinations thereof Non-limiting examples of combination calcium channel blockers include amlodipine, olmesartan, valsartan, or combinations thereof
[0058] One or more calcium channel blockers, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 1 mg to about 10 mg, for example about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; in an amount of about 5 mg to about 34 mg, for example about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 8.5 mg, about 9 mg, about 10 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 25.5 mg, about 27.5 mg, about 30 mg, about 32.5, or about 34 mg; in an amount of about 10 mg to about 60 mg, for example about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg; in an amount of about 20 mg to about 120 mg, for example about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110, or about 120 mg; in an amount of about 60 mg to about 420 mg, for example about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400, or about 420 mg.
[0059] In another embodiment, one or more calcium channel blockers is present in an amount of about 0.05 mg per mL to about 2.5 mg per mL, for example about 0.05 mg per mL, about 0.1 mg per mL, about 0.2 mg per mL, about 0.3 mg per mL, about 0.4 mg per mL, about 0.5 mg per mL, about 0.6 mg per mL, about 0.7 mg per mL, about 0.8 mg per mL, about 0.9 mg per mL, about 1.0 mg per mL, about 1.25 mg per mL, about 1.5 mg per mL, about 1.75 mg per mL, about 2.0 mg per mL, about 2.25 mg per mL, or about 2.5 mg per mL.

CETP Inhibitors.

[0060] Cholesteryl ester transfer protein (“CETP”) plays an important role in transferring cholesteryl esters and triglycerides. Inhibition of CETP, also called plasma lipid transfer protein, is therefore useful in preventing or treating atherosclerosis and other cardiovascular diseases and disorders. Non-limiting examples of CETP inhibitors include torcetrapib, anacetrapib, JTT-705, BAY-60-5521, PF-3185043, and CP-800569, or combinations thereof
[0061] One or more CETP inhibitors, if desired, are present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount sufficient to provide the subject with a dose of about 25 mg per kg body weight (“mg per kg”) to about 100 mg per kg, for example about 25 mg per kg, about 30 mg per kg, about 35 mg per kg, about 40 mg per kg, about 45 mg per kg, about 50 mg per kg, about 55 mg per kg, about 60 mg per kg, about 65 mg per kg, about 70 mg per kg, about 75 mg per kg, about 80 mg per kg, about 85 mg per kg, about 90 mg per kg, about 95 mg per kg, or about 100 mg per kg.
[0062] In another embodiment, one or more CETP inhibitors, if desired, are present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 100 mg to about 10 g, about 500 mg to about 9 g, or about 750 mg to about 5 g.

Cholesterol Absorption Inhibitors.

[0063] Cholesterol absorption inhibitors reduce the cholesterol content of chylomicrons and chylomicron remnants by preventing the uptake of micellar cholesterol from the small intestine. As a result, less cholesterol is delivered to the liver and thereby reduces LDL. Non-limiting examples of cholesterol absorption inhibitors include ezetimibe and simvastatin, or combinations thereof.
[0064] One or more cholesterol absorption inhibitors, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 1 mg to about 10 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; or in an amount of about 10 to about 80 mg, for example about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg.

Diuretics.

[0065] Diuretics increase urination rates forcing diuresis. Some diuretics also provide antihypertensive effects. Non-limiting examples of diuretics include hydrochlorothiazide, torsemide, ethacrynic acid, furosemide, triamterene, indapamide, chlorothiazide sodium, aliskiren, or combinations thereof.
[0066] One or more diuretics, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of: (a) about 0.25 mg to about 2.5 mg, for example about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, or about 2.5 mg; (b) in an amount of about 5 mg to about 25 mg, for example about 5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg; (c) in an amount of about 2 mg to about 100 mg, for example about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg; (d) about 10 mg to about 50 mg, for example about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg; in an amount of about 5 mg to about 60 mg, for example about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, (e) or about 60 mg; in an amount of about 25 mg to about 100 mg, for example about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg; in an amount of about 75 mg to about 300 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg; (f) about 0.1 g to about 0.5 g, for example about 0.1 g, about 0.2 g, about 0.3 g, about 0.4 g, or about 0.5 g; or (g) in an amount of about 1 mg per mL to about 10 mg per mL, for example about 1 mg per mL, about 2 mg per mL, about 3 mg per mL, about 4 mg per mL, about 5 mg per mL, about 6 mg per mL, about 7 mg per mL, about 8 mg per mL, about 9 mg per mL, or about 10 mg per mL.

Dyslipidemia Agents.

[0067] Dyslipidemia is a class of diseases that includes hyperlipidemia. Fredrickson's Type I dyslipidemia (sometimes referred to as Buerger-Gruetz syndrome, primary hyperlipoproteinaemia, or familial hyperchylomicronemia) is characterized by elevated cholesterol levels, subjects with Fredrickson's Type Ila dyslipidemia (also known as familial hypercholesterolemia) exhibit elevated LDL levels. Those with Fredrickson's Type Ilb dyslipidemia (familial combined hyperlipoproteinemia (FCH) or secondary combined hyperlipoproteinemia) show increased LDL and VLDL levels. Fredrickson's Type III dyslipidemia (sometimes called beta disease or dysbetalipoproteinemia) features elevated intermediate density lipoproteins (“IDL”), while Fredrickson's Type IV dyslipidemics (sometimes called “pure hypertriglyceridemics”) have elevated VLDL levels. Subjects with Fredrickson's Type V dyslipidemia have increased VLDL and chylomicron levels.
[0068] Non-limiting examples of dyslipidemia agents include Angptl4 antibody, APA-01 (Phosphagenics), CRD-5 (ImaSight), NCX6560 (NicOx), PCSK9 RNAi (Alnylam), recombinant apoA-1 (SemBioSys Genetics), anti-oxLDL (Genentech), APL180 (Novartis), APP018 (D4F) (Novartis), CER-002 (Cerenis Therapeutics), CP-800,569 (Pfizer), GSK256073 (GlaxoSmithKline), MB07811 (Metabasis), PF-3,185,043 (Pfizer), R7232 (Roche), rilapladib (GlaxoSmithKline), RVX-208 (Resverlogix), Sobetirome (QRX-431 (QuatRx)), anacetrapib (Merk), CSL111 (CSL Limited), darapladib (GlaxoSmithKline), eprotirome (Karo Bio), GFT505 (Genfit), MAHDLO1 (Marzal Plant Pharma), MBX-8025 (Metabolex), PLX204 (Wyeth/Plexxikon), aleglitezar (Roche), dalcetrapib (Roche), SLx4090 (Surface Logix), verespladib (Anthera Pharmaceuticals), AEGR-733 (Aegerion), ABT-335 (Abbott Laboratories), AVE5530 (Sanofi-Aventis), LCP-AtorFen (LifeCycle Pharma), TRIA-662 (Cortria), fenofibrate, choline fenofibrate, ezetimibe, colsevelam, laropiprant, or combinations of any of the foregoing.
[0069] One or more dyslipidemia agents, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 1 mg to about 1000 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 43 mg, about 45 mg, about 48 mg, about 50 mg, about 54 mg, about 55 mg, about 60 mg, about 65 mg, about 67 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 87 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 107 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 134 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 500 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg.

Endothelin Receptor Antagonists.

[0070] Binding of endothelin-1 at endothelin-A (ETA) or endothelin-B (ETB) receptors causes pulmonary vasoconstriction. Endothelin receptor antagonists compete with endothelin-1 binding, thereby attenuating pulmonary vasoconstriction. Endothelin receptor antagonists, therefore, are useful in treating pulmonary hypertension. Non-limiting examples of endothelin receptor antagonists include ambrisentan, bosentan, volibris, thelin, or combinations thereof.
[0071] One or more endothelin receptor antagonists, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 1 mg to about 10 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; in an amount of about 50 mg to about 250 mg, for example about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg.

HMG-CoA Reductase Inhibitors.

[0072] HMG-CoA reductase (also known as HMGR) converts HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) to mevalonic acid (3,5-dihydroxy-3-methyl-pentanoic acid) along the metabolic pathway that produces cholesterol. HMG-CoA reductase inhibitors, also called statins, inhibit HMG-CoA reductase and thereby reduce cholesterol production. As a result, HMG-CoA reductase inhibitors are useful in treating a variety of cardiovascular diseases and disorders including, for example, hypercholesterolemia, hyperlipidemia, mixed dyslipidemia, hypertriglyceridemia, atherosclerosis, Non-limiting examples of HMG-CoA reductase inhibitors include lovastatin, lovastatin+niacin, mevastatin, pitavastatin, pravastatin, rosuvastatin, fluvastatin, atorvastatin, atorvastatin+amlodipine besylate, simvastatin, simvistatin+niacin, ezetimibe, and pravastatin, among others.
[0073] One or more HMG-CoA reductase inhibitors, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 1 mg to about 1000 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg.

LCAT Activators.

[0074] Lecithin-cholesterol acyltransferase (“LCAT”) converts cholesterol into cholesteryl ester. In subjects with deficient levels of LCAT, unesterified cholesterol accumulates in body tissues. This can lead to elevated serum levels of HDL and eventually atherosclerosis. LCAT activators are therefore useful in reducing serum HDL levels and treating or preventing atherosclerosis. Non-limiting examples of LCAT activators include LCAT enzyme, recombinant LCAT, genetic therapy agents that include a nucleic acid sequence coding for expression of LCAT, estrogens, estrogen analogs, and combinations thereof for example as disclosed in U.S. Pat. No. 6,635,614 incorporated by reference herein in its entirety.
[0075] One or more LCAT activators, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount sufficient to raise the serum LCAT level of the subject to a desired level. Subjects with abnormally low LCAT serum levels may be administered an amount of a composition of the invention comprising EPA and LCAT enzyme, estrogen, estrogen analogs, or combinations thereof sufficient to raise the subject's serum LCAT level to normal levels, typically about 5 μg per mL or greater. In another embodiment, subjects with about normal LCAT serum levels may be treated with a composition of the invention comprising EPA and LCAT enzyme, estrogen, estrogen analogs, or combinations thereof in an amount sufficient to raise the LCAT serum level to about 6 μg per mL or more, about 7 μg per mL or more, about 8 μg per mL or more, about 9 μg per mL or more, or about 10 μg per mL or more.

LDL Receptor Inducers.

[0076] LDL receptors are cell surface proteins. Along with adaptin, LDL receptors bind free LDL cholesterol to form clathrin-coated vesicles, reducing serum LDL levels. Thus, agents that induce LDL receptors further reduce serum LDL levels and are useful in preventing or treating atherosclerosis. A non-limiting example of LDL receptor is lactacystin.
[0077] One or more LDL receptor inducers, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 1 mg to about 1000 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg.

Lp-PLA2 Inhibitors.

[0078] Compositions of the invention may comprise one or more lipoprotein associated phospholipase A2 (Lp-PLA2) inhibitors. Lp-PLA2 hydrolyzes oxidized phospholipids in LDL cholesterols. High levels of Lp-PLA2 seem to trigger a cascade of inflammatory events in atherosclerosis and an increased risk of stroke. Lp-PLA2 inhibitors, therefore, are useful in slowing or preventing development of atherosclerosis. Non-limiting examples of Lp-PLA2 inhibitors include rilapladib, darapladib, and combinations thereof.
[0079] One or more Lp-PLA2 inhibitors, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 1 mg to about 1000 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg.

5-Lipoxygenase Inhibitors.

[0080] 5-lipoxygenase inhibitors are useful in accordance with various embodiments of the invention. Non-limiting examples of 5-lipoxygenase inhibitors include VIA-2291, MK-886, CMI 977, ABT-761, ZD2138, lonapalene, zileuton, 5-LO inhibitor 6, L-739,010, CGS 22745, SC 45662, and combinations thereof
[0081] Additional 5-lipoxygenase inhibitors suitable for use in accordance with embodiments of the instant invention are disclosed in the following U.S. patents and patent applications, each of which is hereby incorporated by reference herein in its entirety: U.S. 20050101659, U.S. Pat. No. 7,026,344, U.S. Pat. No. 7,329,682, U.S. 20040198768, U.S. 20090054519, U.S. Pat. No. 5,112,848, U.S. Pat. No. 5,086,052, U.S. 482828, U.S. Pat. No. 5,208,364, U.S. Pat. No. 4,970,210, U.S. Pat. No. 4,794,114, U.S. Pat. No. 4,686,231, U.S. Pat. No. 5,134,150, U.S. Pat. No. 5,639,782, U.S. Pat. No. 6,239,170, U.S. 20060106014, U.S. Pat. No. 5,229,386, U.S. Pat. No. 4,673,684, U.S. Pat. No. 6,136,839, U.S. Pat. No. 6,090,547, U.S. Pat. No. 6,355,434, U.S. 20090042849, U.S. Pat. No. 4,731,382, U.S. Pat. No. 4,877,881, U.S. Pat. No. 5,130,485, U.S. Pat. No. 5,665,752, U.S. Pat. No. 5,723,481, U.S. Pat. No. 5,102,897, U.S. Pat. No. 5,234,939, U.S. Pat. No. 5,143,928, U.S. Pat. No. 5,217,971, U.S. Pat. No. 4,889,941, U.S. Pat. No. 5,234,937, U.S. Pat. No. 5,283,361, U.S. Pat. No. 5,232,939, U.S. Pat. No. 5,086,064, U.S. Pat. No. 5,208,251, U.S. Pat. No. 5,290,800, U.S. Pat. No. 5,006,549, U.S. Pat. No. 5,494,927, U.S. 20040198800, U.S. Pat. No. 4,719,218, U.S. Pat. No. 4,847,270, U.S. Pat. No. 6,121,323, U.S. 20080226758, U.S. 20070218146, U.S. Pat. No. 4,728,656, U.S. Pat. No. 4,835,189, U.S. Pat. No. 5,763,673, U.S. Pat. No. 4,835,190, U.S. Pat. No. 5,162,365, U.S. Pat. No. 5,985,937, U.S. Pat. No. 6,455,541, U.S. Pat. No. 5,534,524, U.S. 20070134341, U.S. 20050267145, U.S. Pat. No. 4,694,018, U.S. Pat. No. 5,260,294, U.S. Pat. No. 5,792,776, U.S. Pat. No. 5,530,141, U.S. Pat. No. 5,780,503, U.S. Pat. No. 5,093,356, U.S. Pat. No. 5,348,957, U.S. Pat. No. 5,384,318, U.S. 568822, U.S. 20010009918, U.S. 20070219206, U.S. 20070225285, U.S. 20050267211, U.S. 20030162193, U.S. 20070173508, U.S. 20070066577, U.S. Pat. No. 5,036,067, U.S. 20030082108, U.S. 20090018170, U.S. 20070105866, U.S. 20070237848, U.S. 20070244185, U.S. 20080227807, U.S. Pat. No. 4,728,735, U.S. Pat. No. 4,803,279, U.S. Pat. No. 4,962,119, U.S. Pat. No. 5,314,898, U.S. 20070123522, U.S. 20070123522, U.S. 20070244128, U.S. 20070093524, U.S. Pat. No. 4,602,023, U.S. Pat. No. 4,943,587, U.S. Pat. No. 6,025,384, U.S. 20090118373, U.S. Pat. No. 5,112,868, U.S. Pat. No. 5,254,553, U.S. Pat. No. 5,312,821, U.S. Pat. No. 5,635,514, U.S. Pat. No. 7,405,302, U.S. Pat. No. 4,624,964, U.S. Pat. No. 4,786,755, U.S. Pat. No. 4,933,351, U.S. Pat. No. 5,059,609, U.S. Pat. No. 5,442,111, U.S. Pat. No. 5,066,668, U.S. Pat. No. 5,292,900, U.S. Pat. No. 5,998,451, U.S. Pat. No. 4,851,586, U.S. Pat. No. 5,314,900, U.S. Pat. No. 5,447,943, U.S. Pat. No. 6,221,880, U.S. Pat. No. 6,262,077, U.S. Pat. No. 6,376,528, U.S. Pat. No. 6,569,895, U.S. Pat. No. 4,663,347, U.S. Pat. No. 4,975,457, U.S. Pat. No. 4,978,679, U.S. Pat. No. 5,703,093, U.S. Pat. No. 5,811,432, U.S. Pat. No. 4,822,803, U.S. Pat. No. 5,356,921, U.S. Pat. No. 5,750,565, U.S. Pat. No. 4,751,310, U.S. Pat. No. 4,816,486, U.S. Pat. No. 5,288,751, U.S. Pat. No. 5,298,512, U.S. Pat. No. 5,909,734, U.S. Pat. No. 4,745,127, U.S. Pat. No. 5,215,986, U.S. Pat. No. 5,270,319, U.S. Pat. No. 5,476,944, U.S. Pat. No. 4,939,169, U.S. Pat. No. 6,166,031, U.S. Pat. No. 6,696,477, U.S. Pat. No. 6,756,399, U.S. Pat. No. 4,931,444, U.S. Pat. No. 5,066,658, U.S. Pat. No. 5,248,685, U.S. Pat. No. 5,240,929, U.S. Pat. No. 4,861,798, U.S. Pat. No. 4,933,329, U.S. Pat. No. 5,008,390, U.S. Pat. No. 5,814,648, U.S. Pat. No. 6,939,674, U.S. Pat. No. 5,696,141, U.S. Pat. No. 5,434,151, U.S. 20030216481, U.S. 20030232763, U.S. 20060177528, U.S. 20030235620, U.S. 20020177723, U.S. Pat. No. 5,036,105, U.S. Pat. No. 5,504,097, U.S. Pat. No. 5,741,809, U.S. Pat. No. 5,459,154, U.S. Pat. No. 5,463,083, U.S. Pat. No. 6,420,392, U.S. Pat. No. 5,358,938, U.S. Pat. No. 5,326,907, U.S. Pat. No. 6,294,574, U.S. Pat. No. 5,648,486, U.S. Pat. No. 5,856,323, U.S. Pat. No. 7,387,797, U.S. Pat. No. 4,801,611, U.S. Pat. No. 5,530,114, U.S. Pat. No. 7,514,469, U.S. 20010025040, U.S. 20020143033, U.S. Pat. No. 5,665,749, U.S. 20010009917, U.S. 20070049621, U.S. 20080280826, U.S. Pat. No. 5,393,923, U.S. Pat. No. 5,114,958, U.S. Pat. No. 5,376,670, U.S. Pat. No. 6,217,875, U.S. Pat. No. 5,155,122, U.S. Pat. No. 5,288,896, U.S. Pat. No. 6,436,924, U.S. Pat. No. 5,256,680, U.S. Pat. No. 7,132,441, U.S. Pat. No. 5,145,860, U.S. Pat. No. 5,354,768, U.S. Pat. No. 5,698,576, U.S. Pat. No. 7,371,874, U.S. Pat. No. 5,068,251, U.S. Pat. No. 5,130,483, U.S. Pat. No. 6,177,415, U.S. Pat. No. 5,541,218, U.S. 20070264361, U.S. Pat. No. 5,284,949, U.S. Pat. No. 4,672,075, U.S. Pat. No. 5,212,189, U.S. Pat. No. 5,302,597, U.S. 20080107757, U.S. Pat. No. 6,620,813, U.S. Pat. No. 5,250,565, U.S. 624012, U.S. Pat. No. 4,732,901, U.S. Pat. No. 5,196,431, U.S. Pat. No. 5,340,815, U.S. Pat. No. 5,504,108, U.S. Pat. No. 5,220,025, U.S. Pat. No. 5,252,562, U.S. Pat. No. 5,420,131, U.S. Pat. No. 5,037,837, U.S. Pat. No. 5,081,126, U.S. Pat. No. 5,105,020, U.S. Pat. No. 5,187,175, U.S. Pat. No. 5,342,838, U.S. Pat. No. 4,755,525, U.S. Pat. No. 5,248,682, U.S. Pat. No. 4,963,576, U.S. Pat. No. 5,514,703, U.S. Pat. No. 6,194,585, U.S. Pat. No. 6,194,585, U.S. Pat. No. 6,291,534, U.S. Pat. No. 4,695,586, U.S. Pat. No. 4,971,979, U.S. Pat. No. 6,653,311, U.S. Pat. No. 4,755,524, U.S. Pat. No. 5,147,893, U.S. Pat. No. 4,711,903, U.S. 20040077691, U.S. Pat. No. 4,695,585, U.S. 2005009084, U.S. Pat. No. 5,516,789, U.S. Pat. No. 5,512,594, U.S. 20070202206, U.S. Pat. No. 6,261,607, U.S. Pat. No. 5,350,754, U.S. Pat. No. 6,344,563, U.S. 20040235807, U.S. Pat. No. 5,064,851, U.S. Pat. No. 5,254,581, U.S. Pat. No. 5,288,742, U.S. Pat. No. 5,403,859, U.S. Pat. No. 5,407,945, U.S. 20030008914, U.S. Pat. No. 5,254,731, U.S. Pat. No. 5,318,970, U.S. Pat. No. 5,519,022, U.S. Pat. No. 6,174,883, U.S. Pat. No. 6,262,073, U.S. 20040170974, U.S. 20070231345, U.S. Pat. No. 4,985,435, U.S. Pat. No. 5,126,365, U.S. Pat. No. 5,234,950, U.S. Pat. No. 5,321,025, U.S. Pat. No. 5,484,805, U.S. Pat. No. 5,221,677, U.S. Pat. No. 5,280,047, U.S. Pat. No. 5,300,655, and U.S. Pat. No. 5,359,063.
[0082] One or more 5-lipoxygenase inhibitors, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 0.01 mg to about 2500 mg, about 0.1 mg to about 1500 mg, about 1 mg to about 1200 mg, or about 5 mg to about 1000 mg, for example about 0.1 mg, about 0.5, about 0.75 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, or about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg or about 2500 mg.

Microsomal Triglyceride Transfer Protein Inhibitors.

[0083] Microsomal triglyceride transfer protein (“MTTP” or “MTP”) is a heterodimeric protein involved in lipoprotein assembly. MTP inhibitors are thus useful in slowing or preventing the production of lipoproteins and therefore cardiovascular diseases and disorders. Non-limiting examples of MTP inhibitors include SLx-4090, AEGR-733, implitapide, BMS-200150, CP-346086, JTT-130, dirlotapide, and combinations thereof.
[0084] Additional MTP inhibitors suitable for use in accordance with embodiments of the instant invention are disclosed in the following U.S. patents and patent applications, each of which is hereby incorporated by reference herein in its entirety: U.S. 20030166590, U.S. Pat. No. 6,492,365, U.S. 20040132779, U.S. 20040132745, U.S. 20050181376, U.S. 20030086912, U.S. Pat. No. 6,767,739, U.S. 20080249130, U.S. 20020028943, U.S. Pat. No. 5,883,099, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279, U.S. Pat. No. 6,034,098, U.S. Pat. No. 5,827,875, U.S. Pat. No. 6,066,650, U.S. Pat. No. 5,885,983, U.S. 20060166999, U.S. 20070027183, U.S. 20020045271, U.S. Pat. No. 6,288,234, U.S. 20030109700, U.S. 20040014748, U.S. Pat. No. 6,878,707, U.S. Pat. No. 6,218,524, U.S. Pat. No. 5,595,872, U.S. 20080253985, U.S. 20080103122, U.S. 20050234073, U.S. 20050090426, U.S. 20040044008, U.S. 20090042835, U.S. 20040058908, U.S. 20060270655, U.S. Pat. No. 6,369,075, U.S. 20080241869, U.S. 20070093468, U.S. 20090054393, U.S. 20020132806, U.S. 20070088089, U.S. 20040033506, U.S. 20080161279, U.S. 20020161233, U.S. 20020042516, U.S. 20070093527, U.S. Pat. No. 6,713,489, U.S. 20060211020, U.S. Pat. No. 6,617,325, U.S. Pat. No. 6,147,214 and U.S. 20020032238.
[0085] In one embodiment, one or more MTP inhibitors, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount sufficient to provide the subject with a dose of about 1 μg per kg of body weight (μg per kg) to about 100 μg per kg, for example about 25 μg per kg, about 30 μg per kg, about 35 μg per kg, about 40 μg per kg, about 45 μg per kg, about 50 μg per kg, about 55 μg per kg, about 60 μg per kg, about 65 μg per kg, about 70 μg per kg, about 75 μg per kg, about 80 μg per kg, about 85 μg per kg, about 90 μg per kg, about 95 μg per kg, or about 100 μg per kg. In another embodiment, one or more MTP inhibitors, if desired, are present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 30 μg to about 20 mg, about 50 μg to about 15 mg, or about 70 μg to about 10 mg.
[0086] In another embodiment, one or more MTP inhibitors, if desired, are present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 0.01 mg to about 2500 mg, about 0.1 mg to about 1500 mg, about 1 mg to about 1200 mg, or about 5 mg to about 1000 mg, for example about 0.1 mg, about 0.5, about 0.75 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, or about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg or about 2500 mg.

PPAR Agonists and Activators.

[0087] Peroxisome proliferator-activated receptors (“PPARs”) are nuclear receptor proteins regulating the expression of genes by acting as transcription factors in combination with the retinoid X receptor (“RXR”). Agents that inhibit or activate PPARs are therefore useful in modifying the expression of certain genes including, for example, genes associated with metabolic disorders such as hypercholesterolemia. Non-limiting examples of PPAR agonists and activators include fenofibrate, bezafibrate, ciprofibrate, clofibrate, gemfibrozil, CER-002, rosiglitazone, GW501516, RWJ 800025, KD-3010, and combinations thereof
[0088] One or more PPAR agonists and/or activators, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 0.5 mg to about 4 mg, for example about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, or about 4 mg; or in an amount of about 20 mg to about 120 mg, for example about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg.

sPLA2 Inhibitors.

[0089] sPLA2 inhibitors are suitable for use in accordance with various embodiments of the present invention. Non-limiting examples of sPLA2 inhibitors include LY 333013, varespladib, WA8242A, WA8242A2, WA8242B, A-0001, A-0002 and combinations thereof.
[0090] Additional sPLA2 inhibitors suitable for use in accordance with embodiments of the instant invention are disclosed in the following U.S. patents and patent applications, each of which is hereby incorporated by reference herein in its entirety: U.S. Pat. No. 6,974,831, U.S. Pat. No. 6,916,840, U.S. Pat. No. 6,992,100, U.S. Pat. No. 6,872,743, U.S.20040063967, U.S.20040063941, U.S.20040092543, U.S.20040077704, U.S. Pat. No. 6,433,001, U.S.20030153770, U.S.20030191175, U.S. Pat. No. 6,706,752, U.S. Pat. No. 6,730,694, U.S.20040059130, U.S. Pat. No. 7,026,348, U.S. Pat. No. 6,608,099, U.S. Pat. No. 6,340,699, U.S. Pat. No. 6,252,084, U.S. Pat. No. 6,635,670, U.S. Pat. No. 6,939,890, U.S. Pat. No. 6,930,123, U.S. Pat. No. 6,713,505, U.S. Pat. No. 6,274,578, U.S. Pat. No. 6,451,839, U.S.20040029948, U.S.20090062369, U.S.20030236232, U.S. Pat. No. 7,160,909, U.S. Pat. No. 6,384,041, U.S. Pat. No. 6,175,021, U.S. Pat. No. 6,214,876, U.S.20090131396, U.S. Pat. No. 6,353,128, U.S. Pat. No. 6,407,104, U.S. Pat. No. 6,274,616, U.S.20030087944, U.S. Pat. No. 5,916,922, U.S.20040198801, U.S.20080249027, U.S. Pat. No. 7,026,318, U.S. Pat. No. 6,933,313, U.S.20040087796, U.S. Pat. No. 6,391,908, U.S.20030181454, U.S. Pat. No. 6,831,095, U.S. Pat. No. 6,177,426, U.S.20060116379, U.S. Pat. No. 6,472,389, U.S. Pat. No. 6,797,708, U.S.20090118503, U.S.20070249008, U.S. Pat. No. 7,087,637, U.S. Pat. No. 5,919,810, U.S. Pat. No. 6,828,344, U.S. Pat. No. 6,916,841, U.S. Pat. No. 5,654,326, U.S. Pat. No. 5,641,800, U.S. Pat. No. 5,733,923, U.S. Pat. No. 6,534,535, U.S.20050026988, U.S. Pat. No. 6,166,062, U.S. Pat. No. 5,684,034, U.S. Pat. No. 7,253,194, U.S.20080045444, U.S.20040033995, U.S.20060235009, U.S.20090088427, U.S. Pat. No. 7,196,103, U.S.20080317809, U.S.20090092595, U.S.20070037253, U.S. Pat. No. 7,098,237, U.S. Pat. No. 6,140,327, U.S. Pat. No. 5,972,972, U.S.20040248898, U.S. Pat. No. 6,967,200, U.S.20030092767, U.S.20040106669, U.S.20040077651, U.S.20050158401, U.S. Pat. No. 6,514,984, U.S.20040102442, U.S. Pat. No. 6,610,728, U.S.20030119860, U.S. Pat. No. 6,436,983, U.S. Pat. No. 6,703,385, U.S. Pat. No. 6,576,654, U.S. Pat. No. 7,101,875, U.S. Pat. No. 6,635,771, U.S. Pat. No. 6,756,376, U.S. Pat. No. 6,984,735, U.S. Pat. No. 6,448,284, U.S. Pat. No. 6,787,545, U.S. Pat. No. 6,265,591, U.S. Pat. No. 6,713,645, U.S. Pat. No. 6,673,781, U.S. Pat. No. 6,214,855, U.S. Pat. No. 6,008,231, U.S. Pat. No. 6,344,467, U.S. Pat. No. 6,177,440, U.S. Pat. No. 6,426,344, U.S. Pat. No. 7,105,514, U.S. Pat. No. 6,214,991, U.S.20020169108, U.S.20060025348, U.S.20030008816, U.S.20090029917, U.S. Pat. No. 6,900,208, U.S. Pat. No. 6,380,397, U.S. Pat. No. 7,205,329, U.S. Pat. No. 5,919,943, U.S. Pat. No. 7,126,010, U.S. Pat. No. 7,109,231, U.S. Pat. No. 6,555,568, U.S. Pat. No. 6,872,557, U.S. Pat. No. 7,030,112, U.S. Pat. No. 7,041,695, U.S. Pat. No. 7,220,756, U.S. Pat. No. 7,396,838, U.S. Pat. No. 6,407,261, U.S. Pat. No. 6,028,116, U.S. Pat. No. 5,965,619, U.S. Pat. No. 6,063,818, U.S. Pat. No. 5,998,477, U.S. Pat. No. 6,121,321, U.S. Pat. No. 6,958,348, U.S. Pat. No. 7,528,112, U.S. Pat. No. 6,903,104, U.S. Pat. No. 6,745,133, U.S. Pat. No. 6,861,436, U.S. Pat. No. 5,650,374, U.S. Pat. No. 6,569,539, U.S. Pat. No. 6,432,987, U.S. Pat. No. 5,762,413, U.S. Pat. No. 7,176,281, U.S. Pat. No. 7,317,009, U.S. Pat. No. 7,153,854, U.S.20020110523, U.S. Pat. No. 6,776,986, U.S. Pat. No. 5,948,779, U.S. Pat. No. 7,449,615, U.S. Pat. No. 7,531,568, U.S. Pat. No. 7,476,746, U.S. Pat. No. 7,491,831, U.S. Pat. No. 6,231,189, U.S. Pat. No. 6,987,105, U.S. Pat. No. 7,300,932, U.S. Pat. No. 6,962,784, U.S. Pat. No. 6,248,553, U.S. Pat. No. 6,255,063, U.S.20070053912, U.S. Pat. No. 6,974,831, U.S.20040063941, U.S.20040077704, U.S.20040248898, U.S.20040063967, U.S. Pat. No. 6,992,100, U.S.20040092543, U.S. Pat. No. 6,916,840, U.S. Pat. No. 6,433,001, U.S.20070249008, U.S.20090092595, U.S. Pat. No. 6,872,743, U.S.20070037253.
[0091] One or more sPLA2 inhibitors, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 0.01 mg to about 2500 mg, about 0.1 mg to about 1500 mg, about 1 mg to about 1200 mg, or about 5 mg to about 1000 mg, for example about 0.1 mg, about 0.5, about 0.75 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, or about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg or about 2500 mg.

Squalene Epoxidase Inhibitors.

[0092] Squalene epoxidase, also called squalene monooxygenase, catalyzes the oxidation of squalene in the cholesterol biosynthesis pathway. Thus, agents that inhibit squalene epoxidase are useful in preventing or slowing the cholesterol production. Non-limiting examples of squalene epoxidase inhibitors include terbinafine, naftifine, amorolfine, butenafine, FR194738, NB-598, resveratrol (trans-3,4′,5-trihydroxystilbene), epigallocatechin-3-O-gallate, S-allylcysteine, selenocysteine, alliin, diallyl trisulfide, diallyl disulfide, and combinations thereof.
[0093] One or more squalene epoxidase inhibitors, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 100 mg to 250 mg, for example about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg; or in an amount of about 0.5% to about 5%, by weight of the composition, for example about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about 3%, about 3.25%, about 3.5%, about 3.75%, about 4%, about 4.25%, about 4.5%, about 4.75%, or about 5%, by weight.

Thrombolytic Agents.

[0094] Thrombolytic agents dissolve blood clots. Thrombolytic agents are therefore useful in treating cardiovascular diseases and disorders including, for example, deep vein thrombosis, pulmonary embolism, ischemic complications, unstable angina, myocardial infarction, and venous thromboembolism, among others. Non-limiting examples of thrombolytic agents include fondoparinux, dalteparin, enoxaparin, apixaban, PD-348292, and combinations thereof.
[0095] One or more thrombolytic agents, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount sufficient to provide a dosage of about 0.5 mg per kg of body weight (“mg per kg”) to about 40 mg per kg, for example about 0.5 mg per kg, about 1 mg per kg, about 2 mg per kg, about 3 mg per kg, about 4 mg per kg, about 5 mg per kg, about 6 mg per kg, about 7 mg per kg, about 8 mg per kg, about 9 mg per kg, about 10 mg per kg, about 11 mg per kg, about 12 mg per kg, about 13 mg per kg, about 14 mg per kg, about 15 mg per kg, about 16 mg per kg, about 17 mg per kg, about 18 mg per kg, about 19 mg per kg, about 20 mg per kg, about 21 mg per kg, about 22 mg per kg, about 23 mg per kg, about 24 mg per kg, about 25 mg per kg, about 26 mg per kg, about 27 mg per kg, about 28 mg per kg, about 29 mg per kg, about 30 mg per kg, about 31 mg per kg, about 32 mg per kg, about 33 mg per kg, about 34 mg per kg, about 35 mg per kg, about 36 mg per kg, about 37 mg per kg, about 38 mg per kg, about 39 mg per kg, or about 40 mg per kg, or in a total amount of about 30 mg to about 3.5 g.
[0096] In another embodiment, one or more thrombolytic agents are present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 0.5 mg to about 2.5 mg, for example 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, or about 2.5 mg; or in an amount sufficient to provide about 60 international units per kg of body weight (“IU per kg”) to about 240 IU per kg, for example 60 IU per kg, about 70 IU per kg, about 80 IU per kg, about 90 IU per kg, about 100 IU per kg, about 110 IU per kg, about 120 IU per kg, about 130 IU per kg, about 140 IU per kg, about 150 IU per kg, about 160 IU per kg, about 170 IU per kg, about 180 IU per kg, about 190 IU per kg, about 200 IU per kg, about 210 IU per kg, about 220 IU per kg, about 230 IU per kg, or about 240 IU per kg.

Other Cardiovascular Agents.

[0097] Other cardiovascular agents are also useful in preventing, inhibiting, or treating cardiovascular diseases or disorders. Non-limiting examples of other cardiovascular agents include gemfibrozil, niaspan, orlistat, GFT14, AZD-2479, ETC-1001, and combinations thereof.
[0098] One or more of these other cardiovascular agents, if desired, can be present in a composition of the invention (or may be co-administered with EPA according to other embodiments of the invention) in an amount corresponding to the recommended or suggested dosage for the particular cardiovascular agent(s). In a related embodiment, the cardiovascular agent(s) may be present in a composition of the invention (or may be co-administered with EPA according to other embodiments of the invention) in an amount less than the recommended or suggested dosage for the particular cardiovascular agent(s). For example, a composition of the invention may comprise EPA and one or more of these other cardiovascular agents in an amount of about 5 mg to about 1500 mg for example about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 266 mg, about 275 mg, about 300 mg, about 324 mg, about 325 mg, about 330 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, or about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, or about 1500 mg.
[0099] Headings used to describe cardiovascular agents herein are not to be construed as limiting in any manner. Many cardiovascular agents can have multiple modes of action and can be described under one or more headings.

Salts and Other Derivatives

[0100] Salts, hydrates, solvate, esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, and derivatives of any of the foregoing drugs may be used in accordance with the invention and may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry. See, e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992); Leonard et al., Advanced Practical Organic Chemistry (1992); Howarth et al., Core Organic Chemistry (1998); and Weisermel et al., Industrial Organic Chemistry (2002).
[0101] “Pharmaceutically acceptable salts,” or “salts,” include the salt of a drug prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, beta-hydroxybutyric, galactaric and galacturonic acids.
[0102] In one embodiment, acid addition salts are prepared from the free base forms using conventional methodology involving reaction of the free base with a suitable acid. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
[0103] In another embodiment, base addition salts are prepared from the free acid forms using conventional methodology involving reaction of the free acid with a suitable base.
[0104] In other embodiments, an acid addition salt is reconverted to the free base by treatment with a suitable base. In a further embodiment, the acid addition salts are halide salts, which are prepared using hydrochloric or hydrobromic acids. In still other embodiments, the basic salts are alkali metal salts, e.g., sodium salt. In other embodiments, a base addition salt is reconverted to the free acid by treatment with a suitable acid.
[0105] In one embodiment, EPA and one or more cardiovascular agent(s) are present in a composition of the invention, or are co-administered in a weight ratio of EPA:cardiovascular agent of about 1:1000 to about 1000:1, about 1:500 to about 500:1, about 1:100 to about 100:1, about 1:50 to about 50:1, about 1:25 to about 25:1, about 1:10 to about 10:1, about 1:5 to about 5:1, about 1:4 to about 4:1 about 1:3 to about 3:1, about 1:2 to about 2:1 or about 1:1.

Antiretroviral Therapy

[0106] In one embodiment, the present invention provides a method of treating a cardiovascular-related disease as defined herein, for example dyslipidemia or hyperlipidemia, in an HIV positive subject. In another embodiment, the method comprises co-administration, or concomitant administration, of a composition or compositions as disclosed herein with one or more HIV-1 protease inhibitors. Non-limiting examples of HIV-1 protease inhibitors include amprenavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir.
[0107] One or more HIV-1 protease inhibitors, if desired, are typically present in a composition of the invention (or co-administered with EPA according to other embodiments of the invention) in an amount of about 100 mg to about 2500 mg, for example about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 625 mg, about 650 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1825 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, or about 2500 mg; in an amount of about 200 mg to about 1000 mg, for example about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg; in an amount of about 50 mg to about 400 mg, for example about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg; in an amount of about 200 mg to about 1066 mg, for example about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 533 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, or about 1066 mg; in an amount of about 50 mg to about 1200 mg, for example about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg; or in an amount of about 15 mg per kg body weight to about 40 mg per kg body weight, for example about 15 mg per kg, about 20 mg per kg, about 25 mg per kg, about 30 mg per kg, about 35 mg per kg, about mg per kg, or about 40 mg per kg.

Dosage Forms

[0108] In one embodiment, compositions of the invention are orally deliverable. The terms “orally deliverable” or “oral administration” herein include any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth of the subject, whether or not the agent or composition is swallowed. Thus “oral administration” includes buccal and sublingual as well as esophageal administration.
[0109] In some embodiments, compositions of the invention are in the form of solid dosage forms. Non-limiting examples of suitable solid dosage forms include tablets (e.g. suspension tablets, bite suspension tablets, rapid dispersion tablets, chewable tablets, melt tablets, effervescent tablets, bilayer tablets, etc), caplets, capsules (e.g. a soft or a hard gelatin capsule filled with solid and/or liquids), powder (e.g. a packaged powder, a dispensable powder or an effervescent powder), lozenges, sachets, cachets, troches, pellets, granules, microgranules, encapsulated microgranules, powder aerosol formulations, or any other solid dosage form reasonably adapted for oral administration.
[0110] EPA and/or any other desired cardiovascular agent(s) can be co-formulated in the same dosage unit, or can be individually formulated in separate dosage units. The terms “dose unit” and “dosage unit” herein refer to a portion of a pharmaceutical composition that contains an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect. Such dosage units may be administered one to a plurality (i.e. 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of times per day, or as many times as needed to elicit a therapeutic response.
[0111] In one embodiment, a composition of the invention comprises one or more cardiovascular agents dispersed or suspended in EPA, wherein the dispersion or suspension is present in a capsule (for example gelatin or HPMC capsule), sachet, or other dosage form or carrier as described herein. In another embodiment, the dispersion or suspension is substantially uniform. In still another embodiment, where co-administration of two or more dosage units is desired, the EPA is present in a first dosage unit, for example a suspension in a capsule, and the cardiovascular agent is present in second dosage unit, for example a tablet. Optionally, any desired additional cardiovascular agent can be present in a third composition.
[0112] In another embodiment, composition(s) of the invention can be in the form of liquid dosage forms or dose units to be imbibed directly or they can be mixed with food or beverage prior to ingestion. Non-limiting examples of suitable liquid dosage forms include solutions, suspension, elixirs, syrups, liquid aerosol formulations, etc.
[0113] In one embodiment, compositions of the invention, upon storage in a closed container maintained at room temperature, refrigerated (e.g. about 5 to about 5-10° C.) temperature, or frozen for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, exhibit at least about 90%, at least about 95%, at least about 97.5%, or at least about 99% of the active ingredient(s) originally present therein.
[0114] In another embodiment, the invention provides a pharmaceutical composition comprising EPA and a cardiovascular agent (fill) encapsulated in a capsule shell, wherein the fill has a baseline peroxide value not greater than about 10 Meq/kg, about 9 Meq/kg, about 8 Meq/kg, about 7 Meq/kg, about 6 Meq/kg, about 5 Meq/kg, about 4 Meq/kg, about 3 Meq/kg or about 2 Meq/kg, wherein upon storage of the composition at 23° C. and 50% RH for a period about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23 or about 24 months, the ultra-pure EPA has a second peroxide value not greater than about 25 Meq/kg, about 24 Meq/kg, about 23 Meq/kg, about 22 Meq/kg, about 21 Meq/kg, about 20 Meq/kg, about 19 Meq/kg, about 18 Meq/kg, about 17 Meq/kg, about 16 Meq/kg, about 15 Meq/kg, about 14 Meq/kg, about 13 Meq/kg, about 12 Meq/kg, about 11 Meq/kg, about 10 Meq/kg, about 9 Meq/kg, about 8 Meq/kg, about 7 Meq/kg, about 6 Meq/kg, about 5 Meq/kg, about 4 Meq/kg, about 3 Meq/kg or about 2 Meq/kg.
[0115] Upon storage, some pharmaceutical compositions degrade over time. Degradation products can alter a composition's efficacy, for example by delivering less active ingredient to a subject than recommended. Degradation products for new drugs above certain thresholds should be reported to the Food & Drug Administration (FDA) in accordance with current Guidance Documents. Degradation products above a certain threshold amount should be identified. A degradation product is “identified” when its structural characterization has been achieved. Degradation products above a certain amount should be qualified. A degradation product is “qualified” when its biological safety is acquired and evaluated.
[0116] In one embodiment, compositions of the invention with a maximum daily dose of less than or equal to 1 gram, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 0.1% of any degradation product not reported to the Food and Drug Administration (FDA). In another embodiment, compositions of the invention with a maximum daily dose of greater than 1 gram, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 0.05% of any degradation product not reported to the FDA.
[0117] In one embodiment, compositions of the invention with a maximum daily dose of less than 1 mg, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 1% of any unidentified degradation product. In another embodiment, compositions of the invention with a maximum daily dose of less than 1 mg, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 5 μg of any unidentified degradation product.
[0118] In one embodiment, compositions of the invention with a maximum daily dose of 1 mg to 10 mg, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 0.5% of any unidentified degradation product. In another embodiment, compositions of the invention with a maximum daily dose of 1 mg to 10 mg, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 20 μg of any unidentified degradation product.
[0119] In one embodiment, compositions of the invention with a maximum daily dose of 10 mg to 2 g, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 0.2% of any unidentified degradation product. In another embodiment, compositions of the invention with a maximum daily dose of 10 mg to 2 g, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 2 mg of any unidentified degradation product.
[0120] In one embodiment, compositions of the invention with a maximum daily dose of greater than 2 g, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 0.1% of any unidentified degradation product.
[0121] In one embodiment, compositions of the invention with a maximum daily dose of less than 10 mg, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 1% of any unqualified degradation product. In another embodiment, compositions of the invention with a maximum daily dose of less than 10 mg, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 50 μg of any unqualified degradation product.
[0122] In one embodiment, compositions of the invention with a maximum daily dose of 10 mg to 100 mg, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 0.5% of any unqualified degradation product. In another embodiment, compositions of the invention with a maximum daily dose of 10 mg to 100 mg, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 200 μg of any unqualified degradation product.
[0123] In one embodiment, compositions of the invention with a maximum daily dose of 100 mg to 2 g, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 0.2% of any unqualified degradation product. In another embodiment, compositions of the invention with a maximum daily dose of 100 mg to 2 g, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 3 mg of any unqualified degradation product.
[0124] In one embodiment, compositions of the invention with a maximum daily dose of greater than 2 g, upon storage under light, heat, humidity, acid/base hydrolytic, and/or oxidative conditions, contain less than about 0.15% of any unqualified degradation product.
[0125] In some embodiments, compositions of the invention comprise a stabilizing agent that suppresses, prevents, hinders, or otherwise attenuates the decomposition of the active ingredient(s) during storage. For example, oxidative decomposition of EPA in compositions of the invention may be prevented or attenuated by the presence of antioxidants. Non-limiting examples of suitable antioxidants include tocopherol, lecithin, citric acid and/or ascorbic acid. One or more antioxidants, if desired, are typically present in a composition in an amount of about 0.01% to about 0.1%, by weight, or about 0.025% to about 0.05%, by weight.

Excipients

[0126] Compositions of the invention optionally comprise one or more pharmaceutically acceptable excipients. The term “pharmaceutically acceptable excipient” herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a unit dose of the composition, and that does not produce unacceptable toxicity or interaction with other components in the composition.
[0127] Compositions of the invention optionally comprise one or more pharmaceutically acceptable diluents as excipients. Suitable diluents illustratively include, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (e.g., Celutab™ and Emdex™); mannitol; sorbitol; xylitol; dextrose (e.g., Cerelose™ 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; celluloses including microcrystalline cellulose, food grade sources of a- and amorphous cellulose (e.g., Rexcel™) and powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like. Such diluents, if present, constitute in total about 5% to about 99%, about 10% to about 85%, or about 20% to about 80%, of the total weight of the composition.
[0128] Compositions of the invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients. Suitable disintegrants include, either individually or in combination, starches, including sodium starch glycolate (e.g., Explotab™ of PenWest) and pregelatinized corn starches (e.g., National™ 1551, National™ 1550, and Colocorn™ 1500), clays (e.g., Veegum™ HV), celluloses such as purified cellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-Sol™ of FMC), alginates, crospovidone, and gums such as agar, guar, xanthan, locust bean, karaya, pectin and tragacanth gums. Such disintegrants, if present, typically comprise in total about 0.2% to about 30%, about 0.2% to about 10%, or about 0.2% to about 5%, of the total weight of the composition.
[0129] Compositions of the invention optionally comprise one or more antioxidants. Illustrative antioxidants include sodium ascorbate and vitamin E (tocopherol). One or more antioxidants, if present, are typically present in a composition of the invention in an amount of about 0.001% to about 5%, about 0.005% to about 2.5%, or about 0.01% to about 1%, by weight.
[0130] Compositions of the invention optionally comprise one or more pharmaceutically acceptable binding agents or adhesives as excipients. Such binding agents and adhesives can impart sufficient cohesion to a powder being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion. Suitable binding agents and adhesives include, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (e.g., National™ 1511 and National™ 1500); celluloses such as, but not limited to, methylcellulose and carmellose sodium (e.g., Tylose™); alginic acid and salts of alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; bentonites; povidone, for example povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (e.g., Klucel™); and ethylcellulose (e.g., Ethocel™). Such binding agents and/or adhesives, if present, constitute in total about 0.5% to about 25%, about 0.75% to about 15%, or about 1% to about 10%, of the total weight of the composition.
[0131] Compositions of the invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients. Non-limiting examples of surfactants that can be used as wetting agents in compositions of the invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., Labrasol™ of Gattefossé), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether, polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate, polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acid esters, for example propylene glycol laurate (e.g., Lauroglycol™ of Gattefossé), sodium lauryl sulfate, fatty acids and salts thereof, for example oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters, for example glyceryl monostearate, sorbitan esters, for example sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof Such wetting agents, if present, constitute in total about 0.25% to about 15%, about 0.4% to about 10%, or about 0.5% to about 5%, of the total weight of the composition.
[0132] Compositions of the invention optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and/or glidants) as excipients. Suitable lubricants include, either individually or in combination, glyceryl behapate (e.g., Compritol™ 888); stearic acid and salts thereof, including magnesium (magnesium stearate), calcium and sodium stearates; hydrogenated vegetable oils (e.g., Sterotex™); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., Carbowax™ 4000 and Carbowax™ 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if present, constitute in total about 0.1% to about 10%, about 0.2% to about 8%, or about 0.25% to about 5%, of the total weight of the composition.
[0133] Suitable anti-adherents include talc, cornstarch, DL-leucine, sodium lauryl sulfate and metallic stearates. Talc is an anti-adherent or glidant used, for example, to reduce formulation sticking to equipment surfaces and also to reduce static in the blend. Talc, if present, constitutes about 0.1% to about 10%, about 0.25% to about 5%, or about 0.5% to about 2%, of the total weight of the composition. Glidants can be used to promote powder flow of a solid formulation. Suitable glidants include colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate.
[0134] Compositions of the present invention optionally comprise one or more flavoring agents, sweetening agents, and/or colorants. Flavoring agents useful in the present invention include, without limitation, acacia syrup, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butter, butter pecan, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, citrus, citrus punch, citrus cream, cocoa, coffee, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, MagnaSweet®, maltol, mannitol, maple, menthol, mint, mint cream, mixed berry, nut, orange, peanut butter, pear, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, and combinations thereof, for example, anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, etc.
[0135] Sweetening agents that can be used in the present invention include, for example, acesulfame potassium (acesulfame K), alitame, aspartame, cyclamate, cylamate, dextrose, isomalt, MagnaSweet®, maltitol, mannitol, neohesperidine DC, neotame, Prosweet® Powder, saccharin, sorbitol, stevia, sucralose, sucrose, tagatose, thaumatin, xylitol, and the like.
[0136] Flavoring agents, sweetening agents, and/or colorants can be present in compositions of the invention in any suitable amount, for example about 0.01% to about 10%, about 0.1% to about 8%, or about 1% to about 5%, by weight.
[0137] Compositions of the invention optionally comprise a suspending agent. Non-limiting illustrative examples of suitable suspending agents include silicon dioxide, bentonite, hydrated aluminum silicate (e.g. kaolin) and mixtures thereof One or more suspending agents are optionally present in compositions of the invention in a total amount of about 0.01% to about 3.0%, about 0.1% to about 2.0%, or about 0.25% to about 1.0%, by weight.
[0138] The foregoing excipients can have multiple roles as is known in the art. For example, starch can serve as a filler as well as a disintegrant. The classification of excipients above is not to be construed as limiting in any manner. Excipients categorized in any manner may also operate under various different categories of excipients as will be readily appreciated by one of ordinary skill in the art.

Therapeutic Methods

[0139] In various embodiments, compositions of the invention are useful for treatment and/or prevention of a cardiovascular-related disease. The term “cardiovascular-related disease” herein refers to any disease or disorder of the heart or blood vessels (i.e. arteries and veins) or any symptom thereof, or any disease or condition that causes or contributes to a cardiovascular disease.” Non-limiting examples of cardiovascular-related diseases and disorders include acute cardiac ischemic events, acute myocardial infarction, angina, angina pectoris, arrhythmia, atrial fibrulation, atherosclerosis, arterial fibrillation, cardiac insufficiency, cardiovascular disease, chronic heart failure, chronic stable angina, congestive heart failure, coronary artery disease, coronary heart disease, deep vein thrombosis, diabetes, diabetes mellitus, diabetic neuropathy, diastolic dysfunction in subjects with diabetes mellitus, edema, essential hypertension, eventual pulmonary embolism, fatty liver disease, heart disease, heart failure, homozygous familial hypercholesterolemia (HoFH), homozygous familial sitosterolemia, hypercholesterolemia, hyperlipidemia, hyperlipidemia in HIV positive subjects, hypertension, hypertriglyceridemia, ischemic complications in unstable angina and myocardial infarction, low blood pressure, metabolic syndrome, mixed dyslipidemia, moderate to mild heart failure, myocardial infarction, obesity management, paroxysmal atrial/arterial fibrillation/fibrulation/flutter, paroxysmal supraventricular tachycardias (PSVT), particularly severe or rapid onset edema, platelet aggregation, primary hypercholesterolemia, primary hyperlipidemia, pulmonary arterial hypertension, pulmonary hypertension, recurrent hemodynamically unstable ventricular tachycardia (VT), recurrent ventricular arrhythmias, recurrent ventricular fibrillation (VF), ruptured aneurysm, sitisterolemia, stroke, supraventricular tachycardia, symptomatic atrial fibrillation/flutter, tachycardia, type-II diabetes, vascular disease, venous thromboembolism, ventricular arrhythmias, and other cardiovascular events.
[0140] The term “treatment” in relation a given disease or disorder, includes, but is not limited to, inhibiting the disease or disorder, for example, arresting the development of the disease or disorder; relieving the disease or disorder, for example, causing regression of the disease or disorder; or relieving a condition caused by or resulting from the disease or disorder, for example, relieving, preventing or treating symptoms of the disease or disorder. The term “prevention” in relation to a given disease or disorder means: preventing the onset of disease development if none had occurred, preventing the disease or disorder from occurring in a subject that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease, and/or preventing further disease/disorder development if already present.
[0141] In some embodiments, compositions of the present invention can be co-administered or administered concomitantly with one or more additional cardiovascular agents. The terms “co-administered,” “concomitant administration,” and “administered concomitantly” are used interchangeably herein and each refer to, for example, administration of two or more agents (e.g., EPA or a derivative thereof and a cardiovascular agent) at the same time, in the same dosage unit, one immediately after the other, within five minutes of each other, within ten minutes of each other, within fifteen minutes of each other, within thirty minutes of each other, within one hour of each other, within two hours of each other, within four hours of each other, within six hours of each other, within twelve hours of each other, within one day of each other, within one week of each other, within two weeks of each other, within one month of each other, within two months of each other, within six months of each other, within one year of each other, etc.
[0142] In one embodiment, the present invention provides a method of treating a cardiovascular-related disease comprising administering to a subject in need thereof a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units), wherein one or more lipid parameters are improved by comparison with lipid parameters achieved by the additive effects of the individual treatments.
[0143] In a related embodiment, upon treatment in accordance with the present invention, for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the subject or subject group exhibits one or more of the following outcomes:
[0144] a) reduced triglyceride levels compared to baseline or a placebo arm;
[0145] b) reduced Apo B levels compared to baseline or a placebo arm;
[0146] c) increased HDL-C levels compared to baseline or a placebo arm;
[0147] d) no increase in LDL-C levels compared to baseline or a placebo arm;
[0148] e) a reduction in LDL-C levels compared to baseline or a placebo arm;
[0149] f) a reduction in non-HDL-C levels compared to baseline or a placebo arm;
[0150] g) a reduction in vLDL levels compared to baseline or a placebo arm;
[0151] h) an increase in apo A-I levels compared to baseline or a placebo arm;
[0152] i) an increase in apo A-I/apo B ratio compared to baseline or a placebo arm;
[0153] j) a reduction in lipoprotein A levels compared to baseline or a placebo arm;
[0154] k) an increase in LDL particle number compared to baseline or a placebo arm;
[0155] l) a reduction in LDL size compared to baseline or a placebo arm;
[0156] m) a reduction in remnant-like particle cholesterol compared to baseline or a placebo arm;
[0157] n) a reduction in oxidized LDL compared to baseline or a placebo arm;
[0158] o) no change or a reduction in fasting plasma glucose (FPG) compared to baseline or a placebo arm;
[0159] p) a reduction in hemoglobin A1c (HbA1c) compared to baseline or a placebo arm;
[0160] q) a reduction in homeostasis model insulin resistance compared to baseline or a placebo arm;
[0161] r) a reduction in lipoprotein associated phospholipase A2 compared to baseline or a placebo arm;
[0162] s) a reduction in intracellular adhesion molecule-1 compared to baseline or a placebo arm;
[0163] t) a reduction in interleukin-6 compared to baseline or a placebo arm;
[0164] u) a reduction in plasminogen activator inhibitor-1 compared to baseline or a placebo arm;
[0165] v) a reduction in high sensitivity C-reactive protein (hsCRP) compared to baseline or a placebo arm;
[0166] w) an increase in serum phospholipid EPA compared to baseline or a placebo arm;
[0167] x) an increase in red blood cell membrane EPA compared to baseline or a placebo arm; and/or
[0168] y) a reduction or increase in one or more of serum phospholipid and/or red blood cell content of docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), arachidonic acid (AA), palmitic acid (PA), staeridonic acid (SA) or oleic acid (OA) compared to baseline or a placebo arm.
[0169] In one embodiment, methods of the present invention comprise measuring baseline levels of one or more markers set forth in (a)-(y) above prior to dosing the subject or subject group. In another embodiment, the methods comprise administering a composition as disclosed herein to the subject after baseline levels of one or more markers set forth in (a)-(y) are determined, and subsequently taking an additional measurement of said one or more markers.
[0170] In another embodiment, upon treatment with a composition of the present invention, for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the subject or subject group exhibits any 2 or more of, any 3 or more of, any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of, any 8 or more of, any 9 or more of, any 10 or more of, any 11 or more of, any 12 or more of, any 13 or more of, any 14 or more of, any 15 or more of, any 16 or more of, any 17 or more of, any 18 or more of, any 19 or more of, any 20 or more of, any 21 or more of, any 22 or more of, any 23 or more, any 24 or more, or all 25 of outcomes (a)-(y) described immediately above.
[0171] In another embodiment, upon treatment with a composition of the present invention, for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the subject or subject group exhibits one or more of the following outcomes:
[0172] a) a reduction in triglyceride level of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median change) as compared to baseline or a placebo arm;
[0173] b) a less than 30% increase, less than 20% increase, less than 10% increase, less than 5% increase or no increase in non-HDL-C levels or a reduction in non-HDLC levels of at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline or a placebo arm;
[0174] c) substantially no change, no change or an increase in HDL-C levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline or a placebo arm;
[0175] d) a less than 60% increase, less than 50% increase, less than 40% increase, less than 30% increase, less than 20% increase, less than 15% increase or no increase in LDL-C levels or a reduction in LDL-C levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline or a placebo arm;
[0176] e) a decrease in Apo B levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline or a placebo arm;
[0177] f) a reduction in vLDL levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0178] g) an increase in apo A-I levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0179] h) an increase in apo A-I/apo B ratio of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0180] i) a reduction in lipoprotein (a) levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0181] j) a reduction in mean LDL particle number of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0182] k) an increase in mean LDL particle size of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0183] l) a reduction in remnant-like particle cholesterol of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0184] m) a reduction in oxidized LDL of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0185] n) substantially no change, no change or a reduction in fasting plasma glucose (FPG) of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0186] o) substantially no change, no change or a reduction in hemoglobin A1c (HbA1c) of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% (actual % change or median % change) compared to baseline or a placebo arm;
[0187] p) a reduction in homeostasis model index insulin resistance of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0188] q) a reduction in lipoprotein associated phospholipase A2 of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0189] r) a reduction in intracellular adhesion molecule-1 of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0190] s) a reduction in interleukin-6 of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0191] t) a reduction in plasminogen activator inhibitor-1 of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0192] u) a reduction in high sensitivity C-reactive protein (hsCRP) of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or a placebo arm;
[0193] v) an increase in serum plasma and/or RBC EPA of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 100%, at least about 200% or at least about 400% (actual % change or median % change) compared to baseline or a placebo arm;
[0194] w) an increase in serum phospholipid and/or red blood cell membrane EPA of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, r at least about 50%, at least about 100%, at least about 200%, or at least about 400% (actual % change or median % change) compared to baseline or a placebo arm;
[0195] x) a reduction or increase in one or more of serum phospholipid and/or red blood cell DHA, DPA, AA, PA and/or OA of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) compared to baseline or a placebo arm; and/or
[0196] y) (y) a reduction in total cholesterol of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) compared to baseline or a placebo arm.
[0197] In one embodiment, methods of the present invention comprise measuring baseline levels of one or more markers set forth in (a)-(y) prior to dosing the subject or subject group. In another embodiment, the methods comprise administering a composition as disclosed herein to the subject after baseline levels of one or more markers set forth in (a)-(y) are determined, and subsequently taking a second measurement of the one or more markers as measured at baseline for comparison thereto.
[0198] In another embodiment, upon treatment with a composition of the present invention, for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the subject or subject group exhibits any 2 or more of, any 3 or more of, any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of, any 8 or more of, any 9 or more of, any 10 or more of, any 11 or more of, any 12 or more of, any 13 or more of, any 14 or more of, any 15 or more of, any 16 or more of, any 17 or more of, any 18 or more of, any 19 or more of, any 20 or more of, any 21 or more of, any 22 or more of, any 23 or more of, any 24 or more of, or all 25 of outcomes (a)-(y) described immediately above.
[0199] Parameters (a)-(y) can be measured in accordance with any clinically acceptable methodology. For example, triglycerides, total cholesterol, HDL-C and fasting blood sugar can be sample from serum and analyzed using standard photometry techniques. VLDL-TG, LDL-C and VLDL-C can be calculated or determined using serum lipoprotein fractionation by preparative ultracentrifugation and subsequent quantitative analysis by refractometry or by analytic ultracentrifugal methodology. Apo A1, Apo B and hsCRP can be determined from serum using standard nephelometry techniques. Lipoprotein (a) can be determined from serum using standard turbidimetric immunoassay techniques. LDL particle number and particle size can be determined using nuclear magnetic resonance (NMR) spectrometry. Remnants lipoproteins and LDL-phospholipase A2 can be determined from EDTA plasma or serum and serum, respectively, using enzymatic immunoseparation techniques. Oxidized LDL, intercellular adhesion molecule-1 and interleukin-2 levels can be determined from serum using standard enzyme immunoassay techniques. These techniques are described in detail in standard textbooks, for example Tietz Fundamentals of Clinical Chemistry, 6th Ed. (Burtis, Ashwood and Borter Eds.), WB Saunders Company.
[0200] In a related embodiment, the reductions or increases of parameters (a)-(y) above are statistically significant.
[0201] In another embodiment, the present invention provides a method of blood lipid therapy comprising administering to a subject in need thereof 1 to a plurality of dosage units comprising a composition or compositions as disclosed herein. In another embodiment, the subject being treated has a baseline triglyceride level, prior to treatment with a composition of the present invention, greater than or equal to about 150 mg/dl, greater than or equal to about 175 mg/dl, greater than or equal to about 250 mg/dl, or greater than or equal to about 500 mg/dl, for example about 200 mg/dl to about 2000 mg/dl, about 300 to about 1800 mg/dl, or about 500 mg/dl to about 1500 mg/dl.
[0202] In one embodiment, methods of the present invention comprise measuring baseline levels of one or more markers set forth in (a)-(y) prior to dosing the subject or subject group. In another embodiment, the methods comprise administering a composition as disclosed herein to the subject after baseline levels of one or more markers set forth in (a)-(y) are determined, and subsequently taking a second measurement of the one or more markers as measured at baseline for comparison thereto.
[0203] In one embodiment, the present invention provides a method of treating or preventing primary hypercholesteremia and/or mixed dyslipidemia (Fredrickson Types IIa and IIb) in a subject in need thereof, comprising administering to the subject a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units) as disclosed herein. In a related embodiment, the present invention provides a method of reducing triglyceride levels in a subject or subjects when treatment with a statin or niacin extended-release monotherapy is considered inadequate (Frederickson type IV hyperlipidemia). Statin or niacin extended-release monotherapy is considered inadequate when, for example, the subject's non-HDL-C level is not lowered or is not lowered to the degree desired, the subject's LDL-C level is not improved or is not improved to the degree desired, the subject's HDL-C level is not improved or is not improved to the degree desired, and/or the subject's triglyceride level is not improved or is not improved to the degree desired.
[0204] In another embodiment, the present invention provides a method of treating or preventing nonfatal myocardial infarction, comprising administering to the subject a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units) as disclosed herein.
[0205] In another embodiment, the present invention provides a method of treating or preventing risk of recurrent nonfatal myocardial infarction in a subject with a history of myocardial infarction, comprising administering to the subject a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units) as disclosed herein.
[0206] In another embodiment, the present invention provides a method of slowing progression of or promoting regression of atherosclerotic disease in a subject in need thereof, comprising administering to the subject a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units) as disclosed herein.
[0207] In another embodiment, the present invention provides a method of treating obesity in a subject in need thereof, comprising administering to a subject in need thereof a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units) as disclosed herein.
[0208] In another embodiment, the present invention provides a method of treating or preventing very high serum triglyceride levels (e.g. Types IV and V hyperlipidemia) in a subject in need thereof, comprising administering to the subject a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units) as disclosed herein.
[0209] In another embodiment, the present invention provides a method of treating subjects having very high serum triglyceride levels (e.g. greater than 1000 mg/dl or greater than 2000 mg/dl) and that are at risk of developing pancreatitis, comprising administering to the subject a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units) as disclosed herein.
[0210] In another embodiment, the present invention provides a method of preventing recurrence of stroke, comprising administering to a subject with a history of stroke a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units) as disclosed herein.
[0211] In another embodiment, the present invention provides a method of preventing onset and/or recurrence of cardiovascular events in a subject who has escaped the unstable period after cardiovascular angioplasty, comprising administering to the subject a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units) as disclosed herein.
[0212] In another embodiment, the present invention provides a method of reducing Apo-B and non-HDL cholesterol levels in a subject group with a baseline LDL-cholesterol level of at least 100 mg/dl, a baseline non-HDL-cholesterol level of at least 130 mg/dl and a baseline triglyceride level of at least 200 mg/dl, and reducing the Apo-B and the non-HDL-cholesterol level of the subject group by administering a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units) as disclosed herein to members of the subject group.
[0213] In another embodiment, the invention provides a method of reducing Apo-B levels in a subject group, comprising measuring LDL-cholesterol, non-HDL-cholesterol, and triglyceride levels in subjects, providing a subject group with a baseline LDL-cholesterol level of at least 100 mg/dL, a baseline non-HDL-cholesterol level of at least 130 mg/dL, and a baseline triglyceride level of at least 200 mg/dL, and reducing the Apo-B levels of the subject group by administering to members of the subject group a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units) as disclosed herein in an amount effective to reduce the Apo-B levels of the subject group in a statistically significant amount as compared to a control treatment, wherein an increase or statistically significant increase of LDL-cholesterol level is avoided.
[0214] In another embodiment, the invention provides a method of reducing Apo-B levels in a subject group, comprising providing a subject group with a baseline LDL-cholesterol level of at least 100 mg/dL, a baseline non-HDL-cholesterol level of at least 130 mg/dL, and a baseline triglyceride level of at least 200 mg/dL, reducing the Apo-B levels of the subject group by administering to members of the subject group a a composition or compositions comprising EPA and one or more additional cardiovascular agents (either as a single dosage unit or as multiple dosage units) as disclosed herein in an amount effective to reduce the Apo-B levels of the subject group in a statistically significant amount as compared to a control treatment, and determining the reduction in the Apo-B levels of the subject group.
[0215] In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily EPA dose of about 1 mg to about 10,000 mg, 25 about 5000 mg, about 50 to about 3000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, or about 2500 mg.
[0216] In the various embodiments of the invention described herein, the EPA and optional one or more additional cardiovascular agents can be administered as a co-formulated single dosage unit, or as individual dosage units. Where the EPA and optional one or more additional cardiovascular agents are co-administered as separate dosage units, each dosage unit can be administered to a subject at substantially the same or substantially different times. In one embodiment, where two or more individual dosage units are to be administered daily, each dosage unit can be administered to the subject within a period of about 24 hours, 18 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, or 0.5 hours.
[0217] In another embodiment, the EPA and one or more optional cardiovascular agents can be administered sequentially. For example, EPA can be administered to a subject as a sole agent during an EPA loading period. The loading period can be, for example, 1 day, 2 days, 4 days, 6 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks or 10 weeks. After any such loading period, one or more additional cardiovascular agents can be initiated together with current EPA administration or in place of EPA treatment.
[0218] In another embodiment, EPA is administered to a subject in the morning, for example from about 4 am to about 10 am, about 5 am to about 9 am, or about 6 am to about 8 am, and the optional one or more cardiovascular agents are administered to the subject in the afternoon or evening, for example from about 1 pm to about 11 pm, about 2 pm to about 10 pm, or about 3 pm to about 9 pm, or vice versa.
[0219] In another embodiment, the invention provides the use of EPA and one or more cardiovascular agents in the manufacture of a medicament for treatment or prevention of a cardiovascular-related disease such as hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, vascular disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction, and other cardiovascular events. In one embodiment, the composition contains not more than 10% DHA, if any. In another embodiment, the composition contains substantially no or no DHA.
[0220] In another embodiment, the invention provides a pharmaceutical composition comprising EPA and one or more cardiovascular agents for the treatment and/or prevention of a cardiovascular-related disease, wherein the composition contains not more than 10% DHA, if any. In a related embodiment, the composition contains substantially no DHA or no DHA.
[0221] In one embodiment, a subject being treated with a composition or regimen set forth herein is a diabetic or pre-diabetic subject.
[0222] In one embodiment, any of the methods disclosed herein are used in treatment or prevention of a subject or subjects that consume a traditional Western diet. In one embodiment, the methods of the invention include a step of identifying a subject as a Western diet consumer or prudent diet consumer and then treating the subject if the subject is deemed to consume a Western diet. The term “Western diet” herein refers generally to a typical diet consisting of, by percentage of total calories, about 45% to about 50% carbohydrate, about 35 to about 40% fat, and about 10% to about 15% protein. A Western diet may further be characterized by relatively high intakes of red and processed meats, sweets, refined grains, and desserts, for example where half or more or 70% or more calories come from these sources.
[0223] It is to be understood that a wide range of changes and modifications to the embodiments described above will be apparent to those skilled in the art and are contemplated. It is, therefore, intended that the foregoing detailed description be regarded as illustrative rather than limiting, and that it be understood that it is the following claims, including all equivalents, that are intended to define the spirit and scope of the invention.
[0224] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.

EXAMPLES

[0225] The following non-limiting examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.

Example 1

[0226] An experiment was conducted to test EPA, DHA, EPA+DHA with and without with atorvastatin in model membranes enriched with PUFAs and cholesterol at levels that reproduce disease or high CV-risk conditions (i.e. hypercholesterimia). As is shown below, EPA exhibits a potent antioxidant benefit in cholesterol-enriched membranes that was superior to that observed with DHA. Moreover, the combination of EPA and atorvastating provided even further antioxidant benefit by comparison to EPA alone.
[0227] EPA and DHA were tested individually at a fixed concentration of 10.0 uM or in combination at 5.65 μM and 4.35 μM (EPA and DHA, respectively), which is a mole ratio of 1.3:1. Separate and combined effects of these agents on lipid peroxide (LOON) formation were examined at cholesterol-to-phospholipid (C/P) mole ratios of 0.5:1, 1.0:1 and 1.5:1. Levels of lipid hydroperoxides were also measured for EPA, DPH and EPA/DPH in cholesterol-enriched membrane prepared in the absence and presence of atorvastatin.
[0228] 1,2-Dilinoleoyl-3-sn-phosphatidylcholine (DLPC) was obtained from Avanti Polar Lipids (Alabaster, Ala.) and stored in chloroform (25 mg/ml) at −80° C. until use. Cholesterol obtained and stored in chloroform (10 mg/ml) at −20° C. CHOD-iodide color reagent (stock) was prepared according to a procedure modified from EI-Saadani et al. (ElSaadani M, Esterbauer H, El-Sayed M, Goher M, Nassar A Y, Jurgens G. A spectrophotometric assay for lipid peroxides in serum lipoproteins using commercially available reagent. J Lipid Res 1989; 30:627-30) consisted of 0.2 M K2HPO4, 0.12 M KI, 0.15 mM NaN3, 10 1 . . . EM ammonium molybdate, and 0.1 g/L benzalkonium chloride. Prior to experimental use, the CHOD reagent was activated by adding 24 μM ethylenediaminetetraacetic acid (EDTA), 20 μM butylated hydroxytoluene (BHT), and 0.2% Triton X-100. Atorvastatin was prepared in ethanol just prior to experimental use and added together with component lipids containing fixed amounts of EPA, DPH or EPA/DPH at equimolar levels. The compounds and lipids were added in combination during membrane sample preparation to ensure full incorporation into the lipid bilayers.
[0229] Membrane samples consisting of DLPC±cholesterol, with cholesterol-to-phospholipid (C/P) mole ratios ranging from 0.5 to 1.5, were prepared as follows. Component lipids (in chloroform) were transferred to 13×100 mm test tubes and shell-dried under a steady stream of nitrogen gas while vortex mixing. The lipid was co-dried with EPA, DPH or EPA/DPH prepared in the absence or presence of the atorvastatin at equimolar levels.
[0230] Residual solvent was removed by drying for a minimum of 3 h under vacuum. After desiccation, each membrane sample was resuspended in diffraction buffer (0.5 mM HEPES, 154 mM NaCl, pH 7.3) to yield a final phospholipid concentration of 1.0 mg/ml. Multilamellar vesicles (MLV) were formed by vortex mixing for 3 minutes at ambient temperature. Bangham A D, Standish M M, Watkins J C. Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 1965; 13:238-52. Immediately after initial MLV preparation, aliquots of each membrane sample will be taken for baseline (0 h) peroxidation analyses.
[0231] All lipid membrane samples were subjected to time-dependent autoxidation by incubating at 37° C. in an uncovered, shaking water bath. Small aliquots of each sample were removed at 24 h intervals and combined with 1.0 ml of active CHOD-iodide color reagent. To ensure spectrophotometric readings within the optimum absorbance range, sample volumes taken for measurement of lipid peroxide formation were adjusted for length of peroxidation and range between 100 and 10 μl. Test samples were immediately covered with foil and incubated at room temperature for >4 h in the absence of light. Absorbances were measured against a CHOD blank at 365 nm using a Beckman DU-640 spectrophotometer.
[0232] The CHOD colorimetric assay is based on the oxidation of iodide (I) by lipid hydroperoxides (LOOH) and proceeds according to the following reaction scheme:
          LOOH+2H++3I→LOH+H2O+I3
[0233] The quantity of triiodide anion (I3) liberated in this reaction is directly proportional to the amount of lipid hydroperoxides present in the membrane sample. The molar absorptivity value (ε) of 13 is 2.46×104 M−1 cm−1 at 365 nm.
[0234] Results are shown in FIGS. 1-4.
(57)

Claims

1. A method of treating hypertriglyceridemia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising eicosapentaenoic acid (EPA) or a derivative of EPA, docosahexaenoic acid (DHA) or a derivative of DHA, and at least one surfactant.
2. The method of claim 1 wherein the pharmaceutical composition is administered to the subject in 1 to about 10 dosage units per day.
3. The method of claim 2 wherein the dosage units comprise capsules.
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