Abstract
Embodiments of the present invention are related to novel therapeutic drugs, drug combinations, and associated methods for treating or preventing pulmonary disease, including pulmonary hypertension, pulmonary fibrosis, asthma and COPD, and heart failure, together with other pulmonary and cardiovascular diseases and their complications. More particularly, aspects of the present invention are related to the use of cicletanine and ruboxistaurin as monotherapies or in combination with other agents for treatment of disease. Cicletanine may be used as pure (+) or () enantiomers or as a racemic or nonracemic mixture of those enantiomers.
Claims
 The use of formulations containing nitric oxide modulating agents and/or PKC inhibitors alone or in combination with other agents in the treatment of pulmonary and cardiac disorders.
 The use in (1), where the nitric oxide modulating agent is a furopyridine compound.
 The use in (2), where the nitric oxide modulating furopyridine compound is cicletanine.
 The use in (1 ), where the formulation is an oral time release formulation.
 The use in (1 ), where the formulation is an injectable formulation, including a depot injectable or a subcutaneously placed extended release device.
 The use in (1 ), where the formulation is a transmucosal or transdermal formulation.
 The use in (1 ), where the formulation is an oral immediate release formulation.
 The use in (1 ), where the formulation is an inhaled formulation.
 The use in (3), where the cicletanine formulation is a racemic mixture of cicletanine isomers.
 The use in (3), where the cicletanine formulation is a nonracemic mixture of cicletanine isomers.
 The use in (3) wherein the cicletanine formulation is a nonracemic mixture of two enantiomers that will yield blood concentrations of approximately equal amounts of + and  enantiomers.
 The use in (3) wherein the cicletanine formulation is a nonracemic mixture of two enantiomers that will yield blood concentrations of the (+) and () enantiomers that will optimize diuretic and nondiuretic effects of cicletanine.
 The use in (3), where the cicletanine formulation is a pure formulation of the (+) cicletanine isomer.
 The use in (3), where the cicletanine formulation is a pure formulation of the () cicletanine isomer.
 The use in (2), where the furopyridine formulation is a racemic mixture of furopyridine isomers.
 The use in (2), where the furopyridine formulation is a nonracemic mixture of furopyridine isomers.
 The use in (2), where the furopyridine formulation is a pure formulation of the (+)furopyridine isomer.
 The use in (2), where the furopyridine formulation is a pure formulation of the ( )furopyridine isomer.
 The use in (2), where the furopyridine is used to treat pulmonary hypertension in adults.
 The use in (2), where the furopyridine is used to treat pulmonary hypertension in children.
 The use in (19), where the pulmonary hypertension treated is WHO Group I (pulmonary arterial hypertension).
 The use in (19), where the pulmonary hypertension treated is WHO Group Il (pulmonary venous hypertension).
 The use in (19), where the pulmonary hypertension treated is WHO Group III (pulmonary hypertension associated with hypoxemia).
 The use in (19), where the pulmonary hypertension treated is WHO Group IV (pulmonary hypertension associated with chronic thrombic and/or embolic disease).
 The use in (19), where the pulmonary hypertension treated is WHO Group V (pulmonary hypertension associated with other/miscellaneous disease, including sarcoidosis, pulmonary Langerhans'cell histiocytosis, lymphangiomatosis, compression of pulmonary vessels [secondary to adenopathy, tumor, fibrosing mediastinitis], etc.)
 The use in (20), where the pulmonary hypertension treated is WHO Group I (pulmonary arterial hypertension).
 The use in (20), where the pulmonary hypertension treated is WHO Group Il (pulmonary venous hypertension).
 The use in (20), where the pulmonary hypertension treated is WHO Group III (pulmonary hypertension associated with hypoxemia).
 The use in (20), where the pulmonary hypertension treated is WHO Group IV (pulmonary hypertension associated with chronic thrombic and/or embolic disease).
 The use in (20), where the pulmonary hypertension treated is WHO Group V (pulmonary hypertension associated with other/miscellaneous disease, including sarcoidosis, pulmonary Langerhans'cell histiocytosis, lymphangiomatosis, compression of pulmonary vessels [secondary to adenopathy, tumor, fibrosing mediastinitis], etc.)
 The use in (21 ), where the furopyridine used is a formulation containing cicletanine.
 The use in (22), where the furopyridine used is a formulation containing cicletanine.
 The use in (23), where the furopyridine used is a formulation containing cicletanine.
 The use in (24), where the furopyridine used is a formulation containing cicletanine.
 The use in (25), where the furopyridine used is a formulation containing cicletanine.
 The use in (26), where the furopyridine used is a formulation containing cicletanine.
 The use in (27), where the furopyridine used is a formulation containing cicletanine.
 The use in (28), where the furopyridine used is a formulation containing cicletanine.
 The use in (29), where the furopyridine used is a formulation containing cicletanine.
 The use in (30), where the furopyridine used is a formulation containing cicletanine.
 The use in (21 ), where the cicletanine formulation is a formulation of pure ( )cicletanine.
 The use in (22), where the cicletanine formulation is a formulation of pure ( )cicletanine.
 The use in (23), where the cicletanine formulation is a formulation of pure ( )cicletanine.
 The use in (24), where the cicletanine formulation is a formulation of pure ( )cicletanine.
 The use in (25), where the cicletanine formulation is a formulation of pure ( )cicletanine.
 The use in (26), where the cicletanine formulation is a formulation of pure ( )cicletanine.
 The use in (27), where the cicletanine formulation is a formulation of pure ( )cicletanine.
 The use in (28), where the cicletanine formulation is a formulation of pure ( )cicletanine.
 The use in (29), where the cicletanine formulation is a formulation of pure ( )cicletanine.
 The use in (30), where the cicletanine formulation is a formulation of pure ( )cicletanine.
 The use in (1 ), where the formulation contains a furopyridine compound and an eNOS cofactor or substrate.
 The use in (51), where the furopyridine is cicletanine.
 The use in (19), where heart failure is involved.
 The use in (20), where heart failure is involved.
 The use in (42), where the pulmonary hypertension of WHO Group Il (pulmonary venous hypertension) being treated involves leftsided heart failure.
 The use in (47), where the pulmonary hypertension of WHO Group Il (pulmonary venous hypertension) being treated involves leftsided heart failure.
 The use in (1 ) where the pulmonary disease involved can be exacerbated by histaminergic activity.
 The use in (1 ) where the pulmonary disease involved is asthma or COPD has an asthmatic component.
 The use in (1 ), where the disease treated is heart failure.
 The use in (59), where the nitric oxide modulating agent is a furopyridine compound.
 The use in (60), where the furopyridine compound is a preparation of cicletanine.
 The use in (61), where the cicletanine preparation is the pure () isomer of cicletanine.
 The use in (61 ), where the cicletanine preparation is a nonracemic mixture of cicletanine isomers.
 The use in (1 ) where there is a combination of a PKC inhibitor with a nitric oxide modulating agent.
 The use in (42) where the eNOScoupling/activating agent is a preparation of pure isomeric cicletanine, racemic cicletanine or a nonracemic mixture of cicletanine isomers.
 The use in (65) where the nonracemic mixture of cicletanine isomers has a predominance of ()cicletanine over (+)cicletanine.
 The use in (1 ) where the PKC inhibitor is a PKCbeta inhibitor.
 The use in (67) where the PKCbeta inhibitor is ruboxistaurin.
 The use in (1 ) where there is a combination of ruboxistaurin with a nitric oxide modulating agent.
 The use in (69) where the eNOScoupling/activating agent is a preparation of pure isomeric cicletanine, racemic cicletanine or a nonracemic mixture of cicletanine isomers.
 The use in (70) where the nonracemic mixture of cicletanine isomers has a predominance of ()cicletanine over (+)cicletanine.
 The use in (21 ), where the cicletanine formulation is a formulation of pure ( )cicletanine.
 The use in (22), where the cicletanine formulation is a nonracemic formulation of pure ()cicletanine and pure (+) cicletanine.
 The use in (23), where the cicletanine formulation is a nonracemic formulation of pure ()cicletanine and pure (+) cicletanine.
 The use in (24), where the cicletanine formulation is a nonracemic formulation of pure ()cicletanine and pure (+) cicletanine.
 The use in (25), where the cicletanine formulation is a nonracemic formulation of pure ()cicletanine and pure (+) cicletanine.
 The use in (26), where the cicletanine formulation is a nonracemic formulation of pure ()cicletanine and pure (+) cicletanine.
 The use in (27), where the cicletanine formulation is a nonracemic formulation of pure ()cicletanine and pure (+) cicletanine.
 The use in (28), where the cicletanine formulation is a nonracemic formulation of pure ()cicletanine and pure (+) cicletanine.
 The use in (29), where the cicletanine formulation is a nonracemic formulation of pure ()cicletanine and pure (+) cicletanine.
 The use in (30), where the cicletanine formulation is a nonracemic formulation of pure ()cicletanine and pure (+) cicletanine.
 The use of metabolic and cofactor enhancement strategies to enhance the therapeutic activity of furopyridines, including Cicletanine for the treatment of pulmonary and cardiac disease and pulmonary hypertension.
 The use in 20 where the diseases treated are heart failure and cor pulmonale.
 The use in 20 where the diseases treated are asthma, COPD and pulmonary fibrosis.
 A method of treating pulmonary hypertension by administering therapeutically effective dosages of cicletanine.
Applicants

Cornett Glenn V
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Page James
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Jones Wayne A
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Page Karen
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Inventors

Cornett Glenn V
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Page James
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Jones Wayne A
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Page Karen
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IPC Classifications

A61K31/4355
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A61K31/436
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Document Preview
 Publication: Jul 17, 2008

Application:
Jan 3, 2008
US 2008/0000093 W

Priority:
Jan 3, 2007
US 88333807 P