US 2009.0054381A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0054381 A1 Letts (43) Pub. Date: Feb. 26, 2009

(54) METHODS FORTREATING RESPIRATORY Related U.S. Application Data DSORDERS (60) Provisional application No. 60/722,961, filed on Oct. 4, 2005. (75) Inventor: L. Gordon Letts, Dover, MA (US) Publication Classification Correspondence Address: (51) Int. Cl. WILMERHALEANTROMED A63L/50 (2006.01) 1875 PENNSYLVANIAAVE, NW A6II 3/56 (2006.01) WASHINGTON, DC 20006 (US) A6IP 9/00 (2006.01) A6IP II/00 (2006.01) (73) Assignee: NitroMed, Inc., Lexington, MA (52) U.S. Cl...... 514/171; 514/247 (US) (57) ABSTRACT The invention provides methods for treating respiratory dis (21) Appl. No.: 12/088,922 orders in a patient in need thereof comprising administering an effective amount of (i) at least one hydralazine compound (22) PCT Filed: Oct. 4, 2006 or a pharmaceutically acceptable salt thereof, (ii) isosorbide dinitrate and/or isosorbide mononitrate, and (iii) optionally at (86). PCT No.: PCT/USO6/38965 least one therapeutic agent. The hydralazine compound may be hydralazine hydrochloride. The respiratory disorders may S371 (c)(1), be chronic obstructive pulmonary disease, pulmonary hyper (2), (4) Date: Jul. 11, 2008 tension, emphysema, asthma, cystic fibrosis and bronchitis. US 2009/0054381 A1 Feb. 26, 2009

METHODS FOR TREATING RESPRATORY obstructive pulmonary disease, pulmonary hypertension, DISORDERS emphysema, asthma, cystic fibrosis and bronchitis. In these embodiments of the invention, the methods can involve (i) RELATED APPLICATIONS administering the hydralazine compound or a pharmaceuti 0001. This application claims priority under 35 USC S 119 cally acceptable salt thereof, and at least one of isosorbide to U.S. application Ser. No. 60/722,961 filed Oct. 4, 2005, the dinitrate and/or isosorbide mononitrate, or (ii) administering disclosure of which is incorporated by reference herein in its the hydralazine compound or a pharmaceutically acceptable entirety. salt thereof, at least one of isosorbide dinitrate and/or isosor bide mononitrate, and therapeutic agents. The hydralazine FIELD OF THE INVENTION compound group, isosorbide dinitrate and/or isosorbide mononitrate and/or therapeutic agents can be administered 0002 The invention provides methods for treating respi separately or as components of the same composition in one ratory disorders in a patient in need thereof comprising or more pharmaceutically acceptable carriers. administering an effective amount of (i) at least one hydrala 0005. The invention provides methods for treating respi Zine compound or a pharmaceutically acceptable salt thereof, ratory disorders in a patient in need thereof comprising (ii) isosorbide dinitrate and/or isosorbide mononitrate, and administering to the patient an effective amount of hydrala (iii) optionally at least one therapeutic agent. The hydralazine zine hydrochloride and isosorbide dinitrate. The methods can compound may be hydralazine hydrochloride. The respira optionally further comprise the administration of at least one tory disorders may be chronic obstructive pulmonary disease, therapeutic agent, such as, for example, antimicrobial com pulmonary hypertension, emphysema, asthma, cystic fibrosis pounds, aldosterone antagonists, alpha-adrenergic receptor and bronchitis. antagonists, f-adrenergic agonists, anti-allergic compounds, antidiabetic compounds, anti-hyperlipidemic drugs, antitus BACKGROUND OF THE INVENTION sive compounds, angiotensin II antagonists, angiotensin-con 0003. The incidence and prevalence of respiratory dis Verting enzyme (ACE) inhibitors, antioxidants, antithrom eases and disorders has increased over the past decade. Also botic and vasodilator drugs, B-adrenergic antagonists, there has been reported an alarming increase in mortality bronchodilators, calcium channel blockers, diuretics, endot associated with respiratory disorders. Current methods for helin antagonists, expectorants, hydralazine compounds, H. treating these disorders are not optimal, as they require fre receptor antagonists, neutral endopeptidase inhibitors, non quent and repeated administration of the appropriate drugs, steroidal antiinflammatory compounds (NSAIDs), phos resulting in issues of compliance. There is a need in the art for phodiesterase inhibitors, potassium channel blockers, plate new and more effective compositions and methods for treat let reducing agents, proton pump inhibitors, renin inhibitors, ingrespiratory disorders. The invention is directed to these, as selective cyclooxygenase-2 (COX-2) inhibitors, steroids, and well as other, important ends. combinations of two or more thereof. In another embodiment the at least one therapeutic agent is selected from the group SUMMARY OF THE INVENTION consisting of antimicrobial compounds, B-adrenergic ago nist, an anti-allergic compound, an antitussive compound, an 0004. The invention provides methods for treating respi antioxidant, a bronchodilator, an expectorant, a nonsteroidal ratory disorders in a patient in need thereof comprising antiinflammatory compound (NSAIDs), a phosphodiesterase administering to the patient an effective amount of (i) a inhibitor, a selective cyclooxygenase-2 (COX-2) inhibitor hydralazine compound or a pharmaceutically acceptable salt and a steroid. In one embodiment the respiratory disorder is thereof, (ii) isosorbide dinitrate and/or isosorbide mononi chronic obstructive pulmonary disease, pulmonary hyperten trate, and (iii) optionally at least one therapeutic agent. In one Sion, emphysema, asthma, cystic fibrosis and bronchitis. In embodiment the therapeutic agents include, but are not lim these embodiments of the invention, the methods can involve ited to, antimicrobial compounds, aldosterone antagonists, (i) administering the hydralazine hydrochloride and isosor cc-adrenergic receptor antagonists, f-adrenergic agonists, bide dinitrate, or (ii) administering the hydralazine hydro anti-allergic compounds, antidiabetic compounds, anti-hy chloride, isosorbide dinitrate and therapeutic agents. The perlipidemic drugs, antitussive compounds, angiotensin II hydralazine hydrochloride, isosorbide dinitrate and/or thera antagonists, angiotensin-converting enzyme (ACE) inhibi peutic agents can be administered separately or as compo tors, antioxidants, antithrombotic and vasodilator drugs, nents of the same composition in one or more pharmaceuti B-adrenergic antagonists, bronchodilators, calcium channel cally acceptable carriers. blockers, diuretics, endothelin antagonists, expectorants, hydralazine compounds, H receptor antagonists, neutral 0006. These and other aspects of the invention are endopeptidase inhibitors, nonsteroidal antiinflammatory described in detail herein. compounds (NSAIDs), phosphodiesterase inhibitors, potas sium channel blockers, platelet reducing agents, proton pump DETAILED DESCRIPTION OF THE INVENTION inhibitors, renin inhibitors, selective cyclooxygenase-2 0007 As used throughout the disclosure, the following (COX-2) inhibitors, steroids, and combinations of two or terms, unless otherwise indicated, shall be understood to have more thereof. In another embodiment the at least one thera the following meanings. peutic agent is selected from the group consisting of an anti 0008 “Patient” refers to animals, preferably mammals, microbial compound, a B-adrenergic agonist, an anti-allergic most preferably humans, and includes males and females. compound, an antitussive compound, an antioxidant, a bron 0009 “Effective amount refers to the amount of the com chodilator, an expectorant, a nonsteroidal antiinflammatory pound and/or composition that is necessary to achieve its compound (NSAIDs), a phosphodiesterase inhibitor, a selec intended purpose. tive cyclooxygenase-2 (COX-2) inhibitor and a steroid. In 0010) “Respiratory disorder” refers to any respiratory dis another embodiment the respiratory disorders is chronic ease or respiratory disorder. Such as, for example, chronic US 2009/0054381 A1 Feb. 26, 2009 obstructive pulmonary disease, pulmonary hypertension, tives thereof, peptides, including di- and tri-peptides, and emphysema, asthma, cystic fibrosis, bronchitis, acute pulmo antibodies to ACE which intervene in the renin-angiotensin nary vasoconstriction, pneumonia, traumatic injury, aspira system by inhibiting the activity of ACE thereby reducing or tion or inhalation injury, fat embolism in the lung, acidosis, eliminating the formation of the pressor Substance angio inflammation of the lung, adult respiratory distress syndrome, tensin II. acute pulmonary edema, acute mountain sickness, post car 0016 “Angiotensin II antagonists' refers to compounds diac Surgery, pulmonary hypertension, persistent pulmonary which interfere with the function, synthesis or catabolism of hypertension of the newborn, perinatal aspiration syndrome, angiotensin II. Angiotensin II antagonists include peptide hyaline membrane disease, acute pulmonary thromboembo compounds and non-peptide compounds, including, but not lism, heparin-protamine reactions, sepsis, status asthmaticus, limited to, angiotensin II antagonists, angiotensin II receptor hypoxia, bronchopulmonary dysplasia, chronic pulmonary antagonists, agents that activate the catabolism of angiotensin thromboembolism, idiopathic pulmonary hypertension, pri II, and agents that prevent the synthesis of angiotensin I from mary pulmonary hypertension, chronic hypoxia, Sarcoidosis, angiotensin II. The renin-angiotensin System is involved in idiopathic pulmonary fibrosis, pneumonitis, postperfusion the regulation of hemodynamics and water and electrolyte lung, dyspnea, acute and chronic cough, pneumothorax, balance. Factors that lower blood volume, renal perfusion alveolar hyperventilation disorders, interstitial lung disease, pressure, or the concentration of Sodium in plasma tend to pneumoconiosis, pneumocystosis, inflammatory respiratory activate the system, while factors that increase these param disease, including, but not limited to (acute) respiratory dis eters tend to Suppress its function. ease syndrome (ARDS), IRDS, severe acute respiratory dis 0017 “Anti-hyperlipidemic compounds’ refers to any ease (SARS), porcine reproductive and respiratory syndrome compound or agent that has the effect of beneficially modi (PRRS), porcine epidemic abortion and respiratory syndrome fying serum cholesterol levels such as, for example, lowering (PEARS), swine infertility and respiratory syndrome (SIRS) serum low density lipoprotein (LDL) cholesterol levels, or and the like. inhibiting oxidation of LDL cholesterol, whereas high den 0011 “Therapeutic agent” includes any therapeutic agent sity lipoprotein (HDL) serum cholesterol levels may be low that can be used to treat or prevent the diseases described ered, remain the same, or be increased. The anti-hyperlipi herein. “Therapeutic agents' include, for example, antimi demic compound may bring the serum levels of LDL crobial compounds, aldosterone antagonists, alpha-adrener cholesterol and HDL cholesterol (and, triglyceride levels) to gic receptor antagonists, f-adrenergic agonists, anti-allergic normal or nearly normal levels. compounds, antidiabetic compounds, anti-hyperlipidemic 0018 “Hydralazine compound” refers to a compound drugs, antitussive compounds, angiotensin II antagonists, having the formula: angiotensin-converting enzyme (ACE) inhibitors, antioxi dants, antithrombotic and vasodilator drugs, B-adrenergic antagonists, bronchodilators, calcium channel blockers, diuretics, endothelin antagonists, expectorants, hydralazine compounds. He receptor antagonists, neutral endopeptidase inhibitors, nonsteroidal antiinflammatory compounds (NSAIDs), phosphodiesterase inhibitors, potassium channel whereina, b and care each independently a single or a double blockers, platelet reducing agents, proton pump inhibitors, bond; R and R2 are each independently a hydrogen, an allyl, renin inhibitors, selective cyclooxygenase-2 (COX-2) inhibi an ester or a heterocyclic ring; R and R are each indepen tors, steroids, and the like. Therapeutic agent includes the dently alone pair of electrons or a hydrogen, with the proviso pharmaceutically acceptable salts thereof, pro-drugs, and that at least one of R. R. R. and R is not a hydrogen. pharmaceutical derivatives thereof including, but not limited Exemplary hydralazine compounds include budralazine, to, the corresponding nitrosated and/or nitrosylated and/or cadralazine, dihydralazine, endralazine, hydralazine, heterocyclic nitric oxide donor derivatives and/or nitric oxide pildralazine, todralazine and the like. enhancing derivatives. Although nitric oxide donors have 0019 "Renin inhibitors’ refers to compounds which inter therapeutic activity, the term “therapeutic agent” does not fere with the activity of renin. include the nitric oxide donors described herein, since nitric (0020) “Phosphodiesterase inhibitor” or “PDE inhibitor” oxide donors are separately defined. refers to any compound that inhibits the enzyme phosphodi 0012 “Prodrug” refers to a compound that is made more esterase. The term refers to selective or non-selective inhibi active in vivo. tors of cyclic guanosine 3',5'-monophosphate phosphodi 0013 Antimicrobial compound” refers to any compound esterases (cGMP-PDE) and cyclic adenosine 3',5'- that alters the growth of bacterial, fungi or virus cells whereby monophosphate phosphodiesterases (cAMP-PDE). growth is prevented, modified, impaired, stabilized, inhibited 0021 “Platelet reducing agents’ refers to compounds that or terminated. Antimicrobial compounds can be microbio prevent the formation of a blood thrombus via any number of cidal or microbiostatic and include, but are not limited to potential mechanisms. Platelet reducing agents include, but antibiotics, chemotherapeutic agents, semisynthetic antibiot are not limited to, fibrinolytic agents, anti-coagulant agents ics, synthetic antibiotics, antifungal compounds, antiviral and any inhibitors of platelet function. Inhibitors of platelet compounds, and the like. function include agents that impair the ability of mature plate 0014) “Antioxidant’ refers to and includes any compound lets to perform their normal physiological roles (i.e., their that can react and quench a free radical. normal function, Such as, for example, adhesion to cellular 00.15 "Angiotensin converting enzyme (ACE) inhibitor and non-cellular entities, aggregation, release of factors such refers to compounds that inhibit an enzyme which catalyzes as growth factors) and the like. the conversion of angiotensin Ito angiotensin II. ACE inhibi 0022 “Proton pump inhibitor refers to any compound tors include, but are not limited to, amino acids and deriva that reversibly or irreversibly blocks gastric acid secretion by US 2009/0054381 A1 Feb. 26, 2009 inhibiting the H/K-ATPase enzyme system at the secretory (NO", NO, NO), such that the biological activity of the Surface of the gastric parietal cell. nitrogen monoxide species is expressed at the intended site of 0023 “NSAID' refers to a nonsteroidal anti-inflamma action. tory compound or a nonsteroidal anti-inflammatory drug. 0033 "Nitric oxide releasing or "nitric oxide donating NSAIDs inhibit cyclooxygenase, the enzyme responsible for refers to methods of donating, releasing and/or directly or the biosyntheses of the prostaglandins and certain autocoid indirectly transferring any of the three redox forms of nitro inhibitors, including inhibitors of the various isozymes of gen monoxide (NO", NO-, NO), such that the biological cyclooxygenase (including but not limited to cyclooxyge activity of the nitrogen monoxide species is expressed at the nase-1 and -2), and as inhibitors of both cyclooxygenase and lipoxygenase. intended site of action. 0024 “Cyclooxygenase-2 (COX-2) selective inhibitor 0034 “Nitric oxide donor or “NO donor refers to com refers to a compound that selectively inhibits the cyclooxy pounds that donate, release and/or directly or indirectly trans genase-2 enzyme over the cyclooxygenase-1 enzyme. In one fera nitrogen monoxide species, and/or stimulate the endog embodiment, the compound has a cyclooxygenase-2 ICso of enous production of nitric oxide or endothelium-derived less than about 2 LM and a cyclooxygenase-1 ICso of greater relaxing factor (EDRF) in vivo and/or elevate endogenous than about 5uM, in the human whole blood COX-2 assay (as levels of nitric oxide or EDRF in vivo and/or are oxidized to described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) produce nitric oxide and/or are substrates for nitric oxide and also has a selectivity ratio of cyclooxygenase-2 inhibition synthase and/or cytochrome P450. "NO donor also includes over cyclooxygenase-1 inhibition of about at least 10, and of compounds that are precursors of L-arginine, inhibitors of the about at least 40. In another embodiment, the compound has enzyme arginase and nitric oxide mediators. a cyclooxygenase-1 ICso of greater than about 1 LM, greater 0035) “Heterocyclic nitric oxide donor” refers to a trisub than 20 uM. The compound can also inhibit the enzyme, stituted 5-membered ring comprising two or three nitrogen lipoxygenase. Such selectivity may indicate an ability to atoms and at least one oxygen atom. The heterocyclic nitric reduce the incidence of common NSAID-induced side oxide donoris capable of donating and/or releasing a nitrogen effects. monoxide species upon decomposition of the heterocyclic 0025. “Transdermal refers to the delivery of a compound ring. Exemplary heterocyclic nitric oxide donors include by passage through the skin and into the blood stream. oXatriazol-5-ones, oXatriazol-5-imines, Sydnonimines, 0026 “Transmucosal” refers to delivery of a compound by furoxans, and the like. passage of the compound through the mucosal tissue and into 0036 “Alky1' refers to a lower alkyl group, a substituted the blood stream. lower alkyl group, a haloalkyl group, a hydroxyalkyl group, 0027 “Penetration enhancement” or “permeation an alkenyl group, a Substituted alkenyl group, an alkynyl enhancement” refers to an increase in the permeability of the group, a bridged cycloalkyl group, a cycloalkyl group or a skin or mucosal tissue to a selected pharmacologically active heterocyclic ring, as defined herein. An alkyl group may also compound Such that the rate at which the compound perme comprise one or more radical species, such as, for example a ates through the skin or mucosal tissue is increased. cycloalkylalkyl group or a heterocyclicalkyl group. 0028 “Carriers' or “vehicles' refers to carrier materials 0037 “Lower alkyl refers to branched or straight chain Suitable for compound administration and include any Such acyclic alkyl group comprising one to about ten carbon material known in the art such as, for example, any liquid, gel. atoms, one to about eight carbon atoms, or one to about six solvent, liquid diluent, solubilizer, or the like, which is non carbon atoms). Exemplary lower alkyl groups include toxic and which does not interact with any components of the methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, Sec-bu composition in a deleterious manner. tyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, and the 0029 “Sustained release” refers to the release of a com like. pound and/or composition such that the blood levels of the 0038. “Substituted lower alkyl refers to a lower alkyl compound are maintained within a desirable range over a group, as defined herein, wherein one or more of the hydrogen period of time. The sustained release formulation can be atoms have been replaced with one or more R' groups, prepared using any conventional method knownto one skilled wherein each R' is independently a hydroxy, an ester, an in the art to obtain the desired release characteristics. amidyl, an oxo, a carboxyl, a carboxamido, a halo, a cyano, a 0030 "Nitric oxide enhancing refers to compounds and nitrate, a nitrite, a thionitrate, a thionitrite oran amino group, functional groups which, under physiological conditions can as defined herein or an amino group, as defined herein. increase endogenous nitric oxide. Nitric oxide enhancing 0039) “Haloalkyl refers to a lower alkyl group, an alkenyl compounds include, but are not limited to, nitric oxide releas group, an alkynyl group, a bridged cycloalkyl group, a ing compounds, nitric oxide donating compounds, radical cycloalkyl group or a heterocyclic ring, as defined herein, to Scavenging compounds and/or reactive oxygen species scav which is appended one or more halogens, as defined herein. enger compounds. In one embodiment the radical scavenging Exemplary haloalkyl groups include trifluoromethyl, chlo compound contains a nitroxide group. romethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the 0031. “Nitroxide group' refers to compounds that have like. the ability to mimic Superoxide dimutase and catalase and act 0040 Alkenyl refers to a branched or straight chain as radical scavengers via a stableaminoxyl radical i.e. N-ox C-Cohydrocarbon, C-Cs hydrocarbon or C-C hydrocar ide. bon that can comprise one or more carbon-carbon double 0032 “Nitric oxide adduct' or “NO adduct refers to com bonds. Exemplary alkenyl groups include propylenyl, buten pounds and functional groups which, under physiological 1-yl, isobutenyl, penten-1-yl, 2.2-methylbuten-1-yl, 3-meth conditions, can donate, release and/or directly or indirectly ylbuten-1-yl, hexan-1-yl, hepten-1-yl, octen-1-yl, and the transfer any of the three redox forms of nitrogen monoxide like. US 2009/0054381 A1 Feb. 26, 2009

0041) “Lower alkenyl refers to a branched or straight Zolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl. chain C-C hydrocarbon that can comprise one or two car morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, pip bon-carbon double bonds. erazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophe 0042 “Substituted alkenyl refers to a branched or nyl, benzimidazolyl, benzothiazolinyl, quinolinyl. 2,6-diox straight chain C-Co hydrocarbon C-Cs hydrocarbon, abicyclo(3.3.0)octane, and the like. C-C hydrocarbon which can comprise one or more carbon 0047. “Heterocyclic compounds’ refer to mono- and poly carbon double bonds, wherein one or more of the hydrogen cyclic compounds comprising at least one aryl or heterocyclic atoms have been replaced with one or more R' groups, ring. wherein each R' is independently a hydroxy, an oxo, a 0048 Aryl refers to a monocyclic, bicyclic, carbocyclic carboxyl, a carboxamido, a halo, a cyano or an amino group, or heterocyclic ring system comprising one or two aromatic as defined herein. rings. Exemplary aryl groups include phenyl, pyridyl, 0043 “Alkynyl” refers to an unsaturated acyclic C-Co napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, inde hydrocarbon (preferably a C-Cs hydrocarbon, more prefer nyl, indoyl, and the like. Aryl groups (including bicyclic aryl ably a C-C hydrocarbon) that can comprise one or more groups) can be unsubstituted or Substituted with one, two or carbon-carbon triple bonds. Exemplary alkynyl groups three substituents independently selected from alkyl, alkoxy, include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1- alkylthio, amino, alkylamino, dialkylamino, arylamino, dia yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl, rylamino, alkylarylamino, halo, cyano, alkylsulfinyl, hexyl-3-yl, 3.3-dimethyl-butyn-1-yl, and the like. hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, 0044 “Bridged cycloalkyl refers to two or more alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxy cycloalkyl groups, heterocyclic groups, or a combination lic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxa thereof fused via adjacent or non-adjacent atoms. Bridged mido, alkylcarboxamido, carbomyl, Sulfonic acid, Sulfonic cycloalkyl groups can be unsubstituted or Substituted with ester, Sulfonamido and nitro. Exemplary Substituted aryl one, two or three substituents independently selected from groups include tetrafluorophenyl, pentafluorophenyl, Sul alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, fonamide, alkylsulfonyl, arylsulfonyl, and the like. halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alky lcarboxylic ester, carboxamido, alkylcarboxamido, oxo and 0049) “Hydroxy” refers to OH. nitro. Exemplary bridged cycloalkyl groups include adaman 0050 “Hydroxyalkyl refers to a hydroxy group, as tyl, decahydronapthyl, quinuclidyl, 2,6-dioxabicyclo(3.3.0) defined herein, appended to an alkyl group, as defined herein. octane, 7-Oxabicyclo(2.2.1)heptyl, 8-azabicyclo(3,2,1)oct-2- 0051. “Alkylcarbonyl refers to Rs C(O)—, wherein enyl and the like. Rs is an alkyl group, as defined herein. 0045 “Cycloalkyl refers to a saturated or unsaturated 0052 “Arylcarbonyl refers to Rs C(O)—, wherein cyclic hydrocarbon comprising from about 3 to about 10 Rss is an aryl group, as defined herein. carbon atoms. Cycloalkyl groups can be unsubstituted or 0053 “Ester” refers to RC(O)O - wherein Rs, is a substituted with one, two or three substituents independently hydrogen atom, an alkyl group, an aryl group, an alkylaryl selected from alkyl, alkoxy, amino, alkylamino, dialky group, or an arylheterocyclic ring, as defined herein. lamino, arylamino, diarylamino, alkylarylamino, aryl, 0054 Alkylaryl refers to an alkyl group, as defined amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, herein, to which is appended an aryl group, as defined herein. alkylcarboxylic ester, carboxamido, alkylcarboxamido, OXo, Exemplary alkylaryl groups include benzyl, phenylethyl, alkylsulfinyl, and nitro. Exemplary cycloalkyl groups include hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex like. enyl, cyclohepta-1,3-dienyl, and the like. 0055 “Arylheterocyclic ring refers to a bi- or tricyclic 0046) “Heterocyclic ring or group' refers to a saturated or ring comprised of an aryl ring, as defined herein, appended unsaturated cyclic hydrocarbon group having about 2 to about via two adjacent carbon atoms of the arylling to a heterocy 10 carbon atoms (preferably about 4 to about 6 carbonatoms) clic ring, as defined herein. Exemplary arylheterocyclic rings where 1 to about 4 carbon atoms are replaced by one or more include dihydroindole, 1,2,3,4-tetra-hydroquinoline, and the nitrogen, oxygen and/or Sulfur atoms. Sulfur may be in the thio, sulfinyl or sulfonyl oxidation state. The heterocyclic ring like. or group can be fused to an aromatic hydrocarbon group. 0056 “Hydrazino” refers to HN N(H)– Heterocyclic groups can be unsubstituted or substituted with 0057. In one embodiment of the invention, the hydralazine one, two or three substituents independently selected from compound is hydralazine, which may be administered in the alkyl, alkoxy, amino, alkylthio, aryloxy, arylthio, arylalkyl, form of a pharmaceutically acceptable salt, such as, for hydroxy, oxo, thial, halo, carboxyl, carboxylic ester, alkyl example, in the form of hydralazine hydrochloride. Hydrala carboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic zine hydrochloride is commercially available from, for acid, arylcarboxylic ester, amidyl, ester, alkylcarbonyl, aryl example, Lederle Standard Products, Pearl River, N.Y.; and carbonyl, alkylsulfinyl, carboxamido, alkylcarboxamido, Par Pharmaceuticals Inc., Spring Valley, N.Y. It is a white to arylcarboxamido, Sulfonic acid, Sulfonic ester, Sulfonamide off-white, crystalline powder and is soluble in water, slightly nitrate and nitro. Exemplary heterocyclic groups include pyr soluble in alcohol and very slightly soluble in ether. rolyl, furyl, thienyl, 3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, 0.058 Isosorbide dinitrate is commercially available, for pyridinyl, 1,4-dihydropyridinyl, pyrazolyl, triazolyl pyrim example, under the trade names DILATRATER-SR idinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, (Schwarz Pharma, Milwaukee, Wis.): ISORDIL(R) and ISOR thiophenyl, furanyl, tetrahydrofuranyl, tetrazolyl, pyrrolinyl, DILR TITRADOSE(R) (Wyeth Laboratories Inc., Philadel pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, imidazolinyl, phia, Pa.); and SORBITRATE(R) (Zeneca Pharmaceuticals, imidazolindinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, Wilmington, Del.). Diluted isosorbide dinitrate (1.4.3,6-di isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadia anhydro-D-glucitol-2,5-dinitrate), USP is a white to off US 2009/0054381 A1 Feb. 26, 2009

white powder. It is freely soluble in organic solvents such as orbide dinitrate and/or isosorbide mononitrate, and at least ethanol, ether and chloroform, but is sparingly soluble in one therapeutic agent. In one embodiment, the hydralazine Water. compound is hydralazine hydrochloride. The hydralazine 0059 Isosorbide mononitrate is commercially available, compound, isosorbide dinitrate and/or isosorbide mononi for example, under the trade names IMDURR (A. B. Astra, trate and/ortherapeutic agents can be administered separately Sweden); MONOKETR) (Schwarz Pharma, Milwaukee, or as components of the same composition in one or more Wis.); and ISMOR (Wyeth-Ayerst Company, Philadelphia, pharmaceutically acceptable carriers. Pa.). 0063. The invention provides methods for treating a res 0060. The isosorbide dinitrate and isosorbide mononitrate piratory disease in a patient in need thereof comprising can be stabilized to prevent explosions by the addition of administering to the patientatherapeutically effect amount of compounds, such as, but not limited to, lactose, arginine, (i) a hydralazine compound (such as, hydralazine hydrochlo mannitol, sorbitol, cellulose (Avicel(R) and the like, and com ride) and (ii) isosorbide dinitrate and/or isosorbide mononi binations of two or more thereof. trate (such as, isosorbide dinitrate). The hydralazine com 0061 The hydralazine compound and at least one of isos pound (such as, hydralazine hydrochloride) and isosorbide orbide dinitrate and isosorbide mononitrate can be adminis dinitrate and/or isosorbide mononitrate (Such as, isosorbide tered as separate components or as components of the same dinitrate) can be administered in the form of a composition or composition. When the hydralazine compound and at least can be administered separately or as components of the same one of isosorbide dinitrate and isosorbide mononitrate are composition. The particular amounts of hydralazine and isos administered as separate components, they may be adminis orbide dinitrate or isosorbide mononitrate can be adminis tered to the patient at about the same time. About the same tered as a single dose once a day; or in multiple doses several time” means that within about thirty minutes of administering times throughout the day; as a Sustained-release oral formu one compound (e.g., the hydralazine compound or isosorbide lation; as an injectable formulation; or as an inhalation for dinitrate/mononitrate) to the patient, the other compound mulation. (e.g., isosorbide dinitrate/mononitrate or the hydralazine 0064. In one embodiment, the hydralazine hydrochloride compound) is administered to the patient. About the same can be administered in an amount of about 30 milligrams per time also includes simultaneous administration of the com day to about 400 milligrams per day; the isosorbide dinitrate pounds. can be administered in an amount of about 10 milligrams per 0062. The invention provides methods for treating respi day to about 200 milligrams per day; or the isosorbide mono ratory disorders in a patient in need thereof comprising nitrate can be administered in an amount of about 5 milli administering to the patient an effective amount of (i) a grams per day to about 120 milligrams per day. In another hydralazine compound or a pharmaceutically acceptable salt embodiment, the hydralazine hydrochloride can be adminis thereof, (ii) isosorbide dinitrate and/or isosorbide mononi tered in an amount of about 50 milligrams per day to about trate, and (iii) optionally at least one therapeutic agent. In one 300 milligrams per day; the isosorbide dinitrate can be embodiment the therapeutic agents include, but are not lim administered in an amount of about 20 milligrams per day to ited to, antimicrobial compounds, aldosterone antagonists, about 160 milligrams per day; or the isosorbide mononitrate C.-adrenergic receptor antagonists, B-adrenergic agonists, can be administered in an amount of about 15 milligrams per anti-allergic compounds, antidiabetic compounds, anti-hy day to about 100 milligrams per day. In another embodiment, perlipidemic drugs, antitussive compounds, angiotensin II the hydralazine hydrochloride can be administered in an antagonists, angiotensin-converting enzyme (ACE) inhibi amount of about 37.5 milligrams to about 75 milligrams one tors, antioxidants, antithrombotic and vasodilator drugs, to four times per day; the isosorbide dinitrate can be admin B-adrenergic antagonists, bronchodilators, calcium channel istered in an amount of about 20 milligrams to about 40 blockers, diuretics, endothelin antagonists, expectorants, milligrams one to four times per day; or the isosorbide mono hydralazine compounds. He receptor antagonists, neutral nitrate can be administered in an amount of about 10 milli endopeptidase inhibitors, nonsteroidal antiinflammatory grams to about 20 milligrams one to four times per day. The compounds (NSAIDs), phosphodiesterase inhibitors, potas particular amounts of hydralazine and isosorbide dinitrate or sium channel blockers, platelet reducing agents, proton pump isosorbide mononitrate can be administered as a single dose inhibitors, renin inhibitors, selective cyclooxygenase-2 once a day; or in multiple doses several times throughout the (COX-2) inhibitors, steroids, and combinations of two or day; as a Sustained-release oral formulation; as an injectable more thereof. In another embodiment the at least one thera formulation; or as an inhalation formulation. peutic agent is selected from the group consisting of an anti 0065. In one embodiment of the methods of the invention, microbial compound, a B-adrenergic agonist, an anti-allergic the patient can be administered a composition comprising compound, an antitussive compound, an antioxidant, a bron about 225 mg hydralazine hydrochloride and about 120 mg chodilator, an expectorant, a nonsteroidal antiinflammatory isosorbide dinitrate once per day (i.e., q.d.). In another compound (NSAIDs), a phosphodiesterase inhibitor, a selec embodiment of the methods of the invention, the patient can tive cyclooxygenase-2 (COX-2) inhibitor and a steroid. In be administered a composition comprising about 112.5 mg one embodiment, the respiratory disease is selected from the hydralazine hydrochloride and about 60 mg isosorbide dini group consisting of chronic obstructive pulmonary disease, trate twice per day (i.e., b.i.d.). In another embodiment of the pulmonary hypertension, emphysema, asthma, cystic fibrosis methods of the invention, the patient can be administered a and bronchitis. In these embodiments of the invention, the composition comprising about 56.25 mg hydralazine hydro methods can involve (i) administering the hydralazine com chloride and about 30 mg isosorbide dinitrate twice per day pound or a pharmaceutically acceptable salt thereof, and at (i.e., b.i.d.). In another embodiment, the patient can be admin least one of isosorbide dinitrate and/or isosorbide mononi istered a composition comprising about 75 mg hydralazine trate, or (ii) administering the hydralazine compound or a hydrochloride and about 40 mg isosorbide dinitrate three pharmaceutically acceptable salt thereof, at least one of isos times per day (i.e., t.i.d.). In another embodiment of the US 2009/0054381 A1 Feb. 26, 2009

methods of the invention, the patient can be administered a ssipirazine, acetyl Sulfamethoxypyrazine, acranil, albenda composition comprising about 37.5 mg hydralazine hydro Zole, alexidine, amatadine, ambazone, amdinocillin, amika chloride and about 20 mg isosorbide dinitrate three times per cin, p-aminosalicylic acid, p-aminosalicylic acid hydrazine, day (i.e., t.i.d.). The particular amounts of hydralazine and amoxicillin, amplicillin, anisomycin, apalcillin, apicyclin, isosorbide dinitrate or isosorbide mononitrate can be admin apramycin, arbekacin, argininsa, aspoxicillin, azidamfenicol, istered as a Sustained-release oral formulation; as an inject azidocillin, azithromycin, azlocillin, aztreonam, bacampicil able formulation; or as an inhalation formulation. lin, benzoylpas, benzyl penicillin acid, benzyl Sulfamide, 0066. In any of the embodiments described herein, the bicoZamycin, bipenam, brodimoprim, capreomycin, carbeni patient can be administered one, two or three compositions cillin, carbomycin, cafaZedone, carindacillin, carumonam, (e.g., two tablets, two capsules, two injections, and the like) at cefcapene pivoxil, cefaclor, cefadroxil, cefafroxil, cefaman any particular time. For example, the patient can be adminis dole, cefatamet, cefatrizine, cefazedone, cefazolin, cefbu tered two separate compositions, wherein each composition peraZone, cefclidin, cefdinir, cefditoren, cefixime, comprises about 112.5 mg hydralazine hydrochloride and cefinenoXime, cefimetazole, cefiminox, cefodizime, about 60 mg isosorbide dinitrate twice per day (i.e., b.i.d.). In cefonicid, cefoperaZone, ceforanide, cefotaxime, cefotetan, another embodiment, the patient can be administered two cefotiam, cefoxitin, cefoZopran, cefpimizole, cefpiramide, separate compositions, wherein each composition comprises cefpirome, cefpodoxime proxetil, cefprozil, cefroxadine, cef about 56.25 mg hydralazine hydrochloride and about 30 mg Sulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftio isosorbide dinitrate twice per day (i.e., b.i.d.). fur, ceftizoxime, ceftriaxone, cefuroxime, cefuZonam, ceph 0067. The invention provides methods for treating chronic acetrile sodium, cephadrine, cephalexin, cephaloglycin, obstructive pulmonary disease, pulmonary hypertension, cephaloridine, cephalosporin C, cephalothin, cephapirin emphysema, asthma, cystic fibrosis and bronchitis in a patient Sodium, cephradine, chloramphenicol, chlorotetracycline, in need thereof comprising administering to the patient a cinoxacin, ciprofloxacin, claritromycin, clavulanic acid, therapeutically effect amount of (i) a hydralazine compound clinafloxacin, clindamycin, clofazimnine, clofoctal, clometo (such as, hydralazine hydrochloride) (ii) isosorbide dinitrate cillin, clomocycline, cloxacillin, cloxyquin, cyclacilline, and/or isosorbide mononitrate (such as, isosorbide dinitrate) cycloserine, danoflaxcin, dapsone, deoxycycline, deoxydihy and (iii) at least one therapeutic agent selected from the group drostreptomycin, dibekacin, dicloxacillin, difloxacin, dihy consisting of antimicrobial compounds, B-adrenergic ago drostreptomycin, dimetridazole, diminaZene, dirirtomycin, nist, an anti-allergic compound, an antitussive compound, an doripenam, eflornithine, enoxacin, enrofloxacin, enviomy antioxidant, a bronchodilator, an expectorant, a nonsteroidal cin, epicillin, erythromycin, etacillin, ethambutol, ethiona antiinflammatory compound (NSAIDs), a phosphodiesterase mide, famcyclovir, fenbecillin, fleroxacin, flomoxe?, flox inhibitor, a selective cyclooxygenase-2 (COX-2) inhibitor acillin, flumequine, furonazide, fortimycin, furazolium and a steroid. The hydralazine compound (such as, hydrala chloride, gentamycin, glyconiazide, grepafloxacin, guame zine hydrochloride) and isosorbide dinitrate and/or isosor cycline, halofluginone, hetacillin, homidium, hydroxyl-Still bide mononitrate (such as, isosorbide dinitrate) can be admin bamidine, ibostamycin, imidocarb, imipenam, ipronidazole, istered in the form of a composition or can be administered isoniazide, iosamycin, inosine, lauroguadine, lenampicillin, separately. levofloxin, lincomycin, lomefloxacin, loracarbef, lymecy 0068. In the invention the at least one hydralazine com clin, mafenide, mebendazole, meclocyclin, meropenem, pound or pharmaceutically acceptable salts thereof, and at metampicillin, metacicline, methacycline, methicillin least one of isosorbide dinitrate and isosorbide mononitrate, Sodium, metronidazole, 4'-(methylsulfamoyl) sulfanilanil are administered as separate components or as components of ide, mezlocillin, meZiocillin, micronomycin, midecamycin the same composition with at least one of the antimicrobial A minocycline, miocamycin, miokamycin, morfaZinamide, compounds, aldosterone antagonists, C.-adrenergic receptor moxalactam, mupirocin, myxin, nadifloxacin, nalidixic acid, antagonists, f-adrenergic agonists, anti-allergic compounds, negamycin, neomycin, netlimycin, nifurfoline, nifurpirinol, antidiabetic compounds, anti-hyperlipidemic drugs, antitus nifurprazine, nimorazole, nitroxoline, norfloxacin, novobio sive compounds, angiotensin II antagonists, angiotensin-con cin, ofloxacin, oleandomycin, opiniazide, oxacillin, oxophe Verting enzyme (ACE) inhibitors, antioxidants, antithrom narsine, oxolinic acid, oxytetracycline, panipenam, paromy botic and vasodilator drugs, B-adrenergic antagonists, cin, paZufloxacin, pefloxacin, penicillin G potassium salt, bronchodilators, calcium channel blockers, diuretics, endot penicillinN, penicillin O, penicillin V, penethamate hydroio helin antagonists, expectorants, hydralazine compounds, H. dide, pentamidine, phenamidine, phenethicillin potassium receptor antagonists, neutral endopeptidase inhibitors, non salt, phenyl aminosalicyclate, pipacycline, pipemidic acid, steroidal antiinflammatory compounds (NSAIDs), phos piperacillin, pirlimycin, piromidic acid, pivampicillin, pivoe phodiesterase inhibitors, potassium channel blockers, plate falexin, profiromycin, propamidine, propicillin, protiona let reducing agents, proton pump inhibitors, renin inhibitors, mide, puraltadone, puromycin, pyrazinamide, selective cyclooxygenase-2 (COX-2) inhibitors, steroids, and pyrimethamine, quinacillin, quinacrine, quinapyramine, combinations of two or more thereof. They can also be admin quintine, ribostamycin, rifabutine, rifamide, rifampin, rifa istered as separate components as single doses once a day; or mycin, rifanpin, rifapentine, rifaxymine, ritipenem, rokita in multiple doses several times throughout the day; The par mycin, rollitetracycline, rosamycin, rufloxacin, Salazosulfadi ticular amounts of hydralazine and isosorbide dinitrate or midine, salinazid, sancycline, Sarafloxacin, Sedacamycin, isosorbide mononitrate can be administered as a single dose secnidazole, Sisomycin, sparfloxacin, spectinomycin, spira once a day; or in multiple doses several times throughout the mycin, spiramycin I, spiramycin II, spiramycin III, stilbami day; as a Sustained-release oral formulation; as an injectable dine, Streptomycin, Streptonicizid, Sulbactam, Sulbenicillin, formulation; or as an inhalation formulation. Succisulfone, Sulfanilamide, Sulfabenzamide, Sulfacetamide, 0069 Suitable antimicrobial compounds, include, but are Sulfachloropyridazine, Sulfachrysoidine, Sulfacytine, Sulfadi not limited to, acediasulfone, aceturate, acetyl Sulfameto azine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sul US 2009/0054381 A1 Feb. 26, 2009

fadrazine, Sulfaetidol, Sulfafenazol, Sulfaguanidine, Sulfagua 0072. In some embodiments, the aldosterone antagonist is nole, Sulfalene, Sulfamerazine, Sulfameter, Sulfamethazine, eplerenone or spironolactone (a potassium sparing diuretic Sulfamethizole, Sulfamethomidine, Sulfamethoxazole, Sul that acts like an aldosterone antagonist). In more particular famethoxypyridazine, Sulfamethyltiazol, Sulfamethylthiaz embodiments, eplerenone is administered in an amount of ole, Sulfametrole, Sulfamidochrysoidine, Sulfamoxole, Sulfa about 25 milligrams to about 300 milligrams as a single dose nilamide, 4-Sulfanilamido salicylic acid, 4-4'- or as multiple doses per day; the spironolactone is adminis Sulfanilylbenzylamine, p-sulfanilylbenzylamine, 2-p- tered in an amount of about 25 milligrams to about 150 Sulfinylanilinoethanol, Sulfanily lurea, Sulfoniazide, milligrams as a single dose or as multiple doses per day. Sulfaperine, Sulfaphenazole, Sulfaproxyline, Sulfapyrazine, 0073 Suitable C.-adrenergic receptor antagonists receptor sulfapyridine, sulfathiazole, sulfaethidole, sulfathiourea, antagonists, include, but are not limited to, phentolamine, Sulfisomidine, Sulfasomizole, Sulfasymazine, Sulfisoxazole, tolazoline, idazoxan, deriglidole, RX 821002, BRL 44408, 4,4'-sulfinyldianiline, N'-sulfanilylsulfanilamide, N-sulfa BRL 44409, BAM 1303, labetelol, ifenprodil, rauwolscine, nillyl-3,4-Xylamide, Sultamicillin, talampicillin, tambutol, corynathine, raubascine, tetrahydroalstonine, apoyohimbine, taurolidine, teiclplanin, temocillin, tetracycline, tetroxoprim, akuammigine, B-yohimbine, yohimbol, yohimbine, thiabendazole, thiazolsulfone, tibeZonium iodide, ticarcillin, pseudoyohimbine, epi-3C-yohimbine, 10-hydroxy-yohim tigemonam, tinidazole, tobramycin, to Sufloxacin, trimethop bine, 11-hydroxy-yohimbine, tamsulosin, benoxathian, ati rim, troleandromycin, trospectomycin, trovafloxacin, tuber pamezole, BE 2254, WB 4101, HU-723, tedisamil, mir cidine, miokamycin, oleandomycin, troleandromycin, van taZipine, Setiptiline, reboxitine, deleguamine, naftopil, comycin, Verazide, viomycin, Virginiamycin and Zalcitabine. saterinone, SL 89.0591, ARC 239, urapidil, 5-methylurapi The contemplated compounds of the invention are described dil, monatepi, haloperidol, indoramin, SB 216469, moxisy more fully in the literature. Such as in Goodman and Gilman, lyte, trazodone, dapiprozole, efaroxan, Recordati 15/2739, The Pharmacological Basis of Therapeutics (9th Edition), SNAP 1069, SNAP 5089, SNAP 5272, RS 17053, SL McGraw-Hill, (1996); Merck Index on CD-ROM, 13" Edi 89.0591, KMD 3213, spiperone, AH 11110A, chloroethyl tion; STN Express, file phar and file registry, the disclosures clonidine, BMY 7378, niguldipine, and the like. Suitable of each of which are incorporated by reference herein in their alpha-adrenergic receptor antagonists are described more entirety. fully in the literature, such as in Goodman and Gilman, The 0070. In one embodiment, the antimicrobial compounds Pharmacological Basis of Therapeutics (9th Edition), are amikacin, azetreonam, azithromycin, ciprofloxacin, McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thir colistin, doripenam, duramycin, gentamycin, tigecycline, teenth Edition; and on STN Express, filephar and file registry. tobramycin, Vancomycin, PA-1806 and PA-2794. In other 0074 Suitable B-adrenergic agonists include, but are not embodiments, the antimicrobial compounds are aztreonam, limited to, albuterol, bambuterol, bitolterol, carbuterol, clen doripenam, duramycin, tobramycin and ciprofloxacin. buterol, dobutamine, fenoterol, formoterol, hexoprenaline, 0071 Suitable aldosterone antagonists include, but are not isoprotenerol, mabuterol, metaproterenol, pirbuterol, prenal limited to, canrenone, potassium canrenoate, drospirenone, terol, procaterol, protokylol, ritodrine, rimiterol, reproterol, spironolactone, eplerenone (INSPRAR), epoxymexrenone, salmeterol, Soterenol, terbutaline, tretoquinol, tulobuterol, fadrozole, pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy and the like. Suitable 3-adrenergic agonists are described 17-hydroxy-3-oxo, Y-lactone, methyl ester, (7C.11C. 17 B.)-; more fully in the literature, such as in Goodman and Gilman, pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hy The Pharmacological Basis of Therapeutics (9th Edition), droxy-3-oxo-dimethyl ester, (7C.11C. 17 B.)-; 3'H-cyclopropa McGraw-Hill, 1995; and the Merck Index on CD-ROM, 13' (6.7)pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7- Edition; and on STN Express, file phar and file registry. dihydro-17-hydroxy-3-oxo-, y-lactone, (6?.7f8,11C. 17(3)-; 0075 Suitable anti-allergic compounds include, but are pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hy not limited to, acrivastine, allociamide, amlexanox, bromex droxy-3-oxo-, 7-(1-methylethyl) ester, monopotassium salt, ine, cetirizine, clobenzepam, chromoglycate, chromolyn, (7C.11C. 17 B.)-; pregn-4-ene-7,21-dicarboxylic acid, 9,11 deslortidine, emedastine, epinastine, feXofenadine, formot epoxy-17-hydroxy-3-oxo-, 7-methyl ester, monopotassium erol, hydroxy Zine, ketotifen, loratadine, levocabastine, salt, (7C.11—17 B.)-; 3'H-cyclopropa(6.7) pregna-1,4,6- lodoxamide, mabuterol, montelukast, nedocromil, repirinast, triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hy salmeterol, Seratrodast, Suplatast tosylate, terfenadine, tiara droxy-3-oxo-, y-lactone, (6,3,7,8,11C.)-; 3'H-cyclopropa(6.7) mide, and the like. Suitable anti-allergic compounds are pregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7- described more fully in the literature, such as in Goodman and dihydro-17-hydroxy-3-oxo-, methyl ester, (6?.7f8,11C. 17(3)-; Gilman, The Pharmacological Basis of Therapeutics (9th 3'H-cyclopropa (6.7)pregna-4,6-diene-21-carboxylic acid, Edition), McGraw-Hill, 1995; and the Merck Index on CD 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-, monopotas ROM, 13" Edition; and on STN Express, file phar and file sium salt, (6?.7f8,11C, 17(3)-;3H-cyclopropa(6.7)pregna-1,4, registry. 6-triene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hy 0076 Suitable antidiabetic compounds include, but are droxy-3-oxo-, y-lactone, (63.7B...11C. 17B)-; pregn-4-ene-7, not limited to, acarbose, acetohexamide, buformin, carbuta 21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-. mide, chlorpropamide, glibornuride, gliclazide, glimepiride, y-lactone, ethyl ester, (7C,11C. 17B)-; pregn-4-ene-7,21-di glipizide, gliquidone, glisoxepid, glyburide, glybuthiazol(e), carboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, y-lactone, glybuzole, glyhexamide, glymidine, glypinamide, insulin, 1-methylethyl ester, (7C,11C. 17 B)-; RU-28318, and the like. metformin, miglitol, nateglinide, phenbutamide, phenformin, Suitable aldosterone antagonists are described more fully in pioglitaZone, repaglinide, rosiglitaZone, tolaZamide, tolbuta the literature, such as in Goodman and Gilman, The Pharma mide, tolcyclamide, troglitaZone, Voglibose, and the like. cological Basis of Therapeutics (9th Edition), McGraw-Hill, Suitable antidiabetic compounds are described more fully in 1995; and the Merck Index on CD-ROM, 13 Edition; and on the literature, such as in Goodman and Gilman, The Pharma STN Express, file phar and file registry. cological Basis of Therapeutics (9th Edition), McGraw-Hill, US 2009/0054381 A1 Feb. 26, 2009

1995; and the Merck Index on CD-ROM, Thirteenth Edition; CP-148130, CL-329167, CV-11194, DA-2079, DE-3489, and on STN Express, file phar and file registry. DMP-811, DuP-167, DuP-532, DuP-753, E-1477, E-4177, 0077 Suitable anti-hyperlipidemic compounds include, E-4188, EMD-66397, EMD-666R4, EMD-73495, EMD but are not limited to, statins or HMG-CoA reductase inhibi 66684, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP tors, such as, for example, atorvastatin (LIPITOR(R), berv 6803, EXP-7711, EXP-9270, EXP-9954, FK-739, FRI astatin, cerivastatin (BAYCOLOR), dalvastatin, fluindostatin 153332, GA-0050, GA-0056, HN-65021, HOE-720, (Sandoz XU-62-320), fluvastatin, glenvastatin, lovastatin HR-720, ICI-D6888, ICI-D7155, ICI-D8731, KRI-1177, (MEVACOR(R), mevastatin, pravastatin (PRAVACHOL(R), KT3-671, KT-3579, KW-3433, L-158809, L-158978, , rosuvastatin (CRESTROR), simvastatin (ZOCORR), L-159282, L-159689, L-159874, L-161177, L-162154, velostatin (also known as synvinolin), VYTORINTM L-162234, L-162441, L-163007, L-163017, LF-70156, (ezetimibe/simvastatin), GR-95.030, SQ 33,600, BMY 22089, BMY 22,566, CI980, and the like;gemfibrozil, choly LRB-057, LRB-081, LRB-087, LY-235656, LY-266099, styramine, colestipol, niacin, nicotinic acid, bile acid seques LY-285.434, LY-301875, LY-302289, LY-315995, ME-3221, trants, such as, for example, cholestyramine, colesevelam, MK-954, PD-123177, PD-123319, PD-126055, PD-150304, colestipol, poly(methyl-(3-trimethylaminopropyl)imino-tri RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, methylene dihalide) and the like; probucol; fibric acid agents SC-51757, SC-54629, SC-52458, SC-52459, SK 1080, or fibrates, such as, for example, bezafibrate (BezalipTM), SL-910102, SR-47436, TAK-536, UP-2696, U-96849, beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, U-97018, UK-77778, UP-275-22, WAY-126227, WK-1260, etofibrate, fenofibrate (LipidilTM, Lipidil MicroTM), gemfi WK-1360, WK-1492, WY 126227, YH-1498, YM-358, brozil (LopidTM.), nicofibrate, pirifibrate, ronifibrate, simfi YM-31472, X-6803, XH-148, XR-510, ZD-6888, ZD-7155, brate, theofibrate and the like; cholesterol ester transfer pro ZD-8731, ZD 8.131, the compounds of ACS registry numbers tein (CETP) inhibitors, such as for example, CGS 25159, 124750-92-1, 133240-46-7, 135070-05-2, 139958-16-0, CP-529414 (torcetrapid), JTT-705, substituted N-3-(1,1,2,2- 145160-84-5, 147403-03-0, 153806-29-2, 439904-54-8P. tetrafluoroethoxy)benzyl-N-(3-phenoxyphenyl)-trifluoro 439904-55-9P,439904-56-0P 439904-57-1P 439904-58-2P 3-amino-2-propanols, N,N-disubstituted trifluoro-3-amino 155918-60-8P, 155918-61-9P, 272438-16-1P. 272446-75-0P, 2-propanols, PD 140195 (4-phenyl-5-tridecyl-4H-1,2,4- 223926-77-OP. 169281-89-4, 439904-65-1P, 165113-01-9P, triazole-3-thiol), SC-794, SC-795, SCH 58149, and the like. 165113-02-0P, 165113-03-1P, 165113-03-2P 165113-05-3P, 0078. In some embodiments, the anti-hyperlipidemic 165113-06-4P, 165113-07-5P, 165113-08-6P, 165113-09-7P. compounds are atorvastatin, fluvastatin, lovastatin, pravasta 165113-10-0P, 165113-11-1P, 165113-12-2P, 165113-17-7P. tin, rosuvastatin or simvastatin. In more particular embodi 165113-18-8P, 165113-19-9P, 165113-20-2P 165113-13-3P, ments, theatorvastatin is administered in an amount of about 165113-14-4P, 165113-15-5P, 165113-16-6P, 165113-21-3P, 10 milligrams to about 80 milligrams as a single dose or as 165113-22-4P, 165113-23-5P, 165113-24-6P, 165113-25-7P. multiple doses per day; the fluvastatin is administered in an 165113-26-8P, 165113-27-9P, 165113-28-OP. 165113-29-1P amount of about 20 milligrams to about 80 milligrams as a 165113-30-4P, 165113-31-5P, 165113-32-6P, 165113-33-7P. single dose or as multiple doses per day; the lovastatin is 165113-34-8P, 165113-35-9P, 165113-36-OP. 165113-37-1P administered in an amount of about 10 milligrams to about 80 165113-38-2P, 165113-39-3P, 165113-40-6P, 165113-41-7P. milligrams as a single dose or as multiple doses per day; the 165113-42-8P, 165113-43-9P, 165113-44-OP. 165113-45-1P pravastatin is administered in an amount of about 10 milli 165113-46-2P, 165113-47-3P, 165113-48-4P 165113-49-5P, grams to about 80 milligrams as a single dose or as multiple 165113-50-8P, 165113-51-9P, 165113-52-OP. 165113-53-1P doses per day; the rosuvastatin is administered in an amount 165113-54-2P, 165113-55-3P, 165113-56-4P 165113-57-5P, of about 5 milligrams to about 40 milligrams as a single dose 165113-58-6P, 165113-59-7P 165113-60-0P, 165113-61-1P or as multiple doses per day; the simvastatin is administered 165113-62-2P, 165113-63-3P, 165113-64-4P 165113-65-5P, in an amount of about 5 milligrams to about 80 milligrams as 165113-66-6P, 165113-67-7P 165113-68-8P, 165113-69-9P, a single dose or as multiple doses per day. 165113-70-2P, 165113-71-3P, 165113-72-4P 165113-73-5P, 0079 Suitable antitussive compounds, include, but are not 165113-74-6P, 114798-27-5, 114798-28-6, 114798-29-7, limited to, dextromethorphan, carbetapentane, caramiphen, 124749-82-2, 114798-28-6, 124749-84-4, 124750-88-5, diphenylhydramine, hydrocodene, codeine and the like. Suit 124750-91-0,124750-93-2, 161946-65-2P 161947-47-3P, able antitussive compounds are described more fully in the 161947-48-4P 161947-51-9P, 161947-52-OP. 161947-55-3P, literature. Such as in Goodman and Gilman, The Pharmaco 161947-56-4P 161947-60-0P 161947-61-1P 161947-68-8P. logical Basis of Therapeutics (9th Edition), McGraw-Hill, 161947-69-9P, 161947-70-2P 161947-71-3P, 161947-72-4P. 1995; and the Merck Index on CD-ROM, 13" Edition; and on 161947-74-6P 161947-75-7P 161947-81-5P, 161947-82-6P. STN Express, file phar and file registry. 161947-83-7P 161947-84-8P 161947-85-9P, 161947-86-OP, 0080 Suitable angiotensin II antagonists include, but are 161947-87-1P 161947-88-2P 161947-89-3P, 161947-90-6P. not limited to, angiotensin, abitesartan, candesartan, cande 161947-91-7P 161947-92-8P 161947-93-9P, 161947-94-OP, Sartan cilexetil, elisartan, embusartan, enoltaSosartan, epro 161947-95-1P 161947-96-2P 161947-97-3P, 161947-98-4P. Sartan, fonsartan, forasartan, glycylosartan, irbesartan, losa 161947-99-5P, 161948-00-1P 161948-01-2P 161948-02-3P, rtan, olmesartan, milfasartan, medoxomil, ripisartan, 168686-32-6P, 167301-42-OP. 166813-82-7P 166961-56-4P. pratosartan, Saprisartan, Saralasin, Sarmesin, tasosartan, telm 166961-58-6P, 158872-96-9P, 158872-97-0P, 158807-14-8P. isartan, Valsartan, Zolasartan, 3-(2'(tetrazole-5-yl)-1,1'-bi 158807-15-9P, 158807-16-0P, 158807-17-1P, 158807-18-2P phen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo(4,5-b) 158807-19-3P, 158807-20-6P, 155884-08-5P, 154749-99-2, pyridine, antibodies to angiotensin II, A-81282, A-81988, 167371-59-7P, 244126-99-6P, 177848-35-OP and 141309 BAY 106734, BIBR-363, BIBS-39, BIBS-222, BMS 82-2P and the like. Suitable angiotensin II antagonists are 180560, BMS-184698, BMS-346567, CGP-38560A, CGP described more fully in the literature, such as in Goodman and 42112A, CGP-48369, CGP-49870, CGP-63170, CI-996, Gilman, The Pharmacological Basis of Therapeutics (9th US 2009/0054381 A1 Feb. 26, 2009

Edition), McGraw-Hill, 1995; and the Merck Index on CD or as multiple doses per day; the quinapril is administered as ROM, 13' Edition; and on STN Express, file phar and file quinapril hydrochloride in an amount of about 5 milligrams to registry. about 40 milligrams as single or multiple doses per day; the 0081. In some embodiments, the angiotensin II antago ramapril is administered in an amount of about 1.25 milli nists are candesartan, eprosartan, irbesartan, losartan, omle grams to about 40 milligrams as single or multiple doses per Sartan, telmisartan or Valsartan. In more particular embodi day; the trandolapril is administered as in an amount of about ments the candesartan is administered as candesartancilexetil 0.5 milligrams to about 4 milligrams as single or multiple in an amount of about 15 milligrams to about 100 milligrams doses per day; the trandolaprilat is administered as in an as a single dose or as multiple doses per day; the eprosartan, amount of about 0.5 milligrams to about 4 milligrams as is administered as eprosartan mesylate in an amount of about single or multiple doses per day. 400 milligrams to about 1600 milligrams as a single dose or as 0084 Suitable antioxidants include, but are not limited to, multiple doses per day; the irbesartan is administered in an Small-molecule antioxidants and antioxidant enzymes. Suit amount of about 75 milligrams to about 1200 milligrams as a able small-molecule antioxidants include, but are not limited single dose or as multiple doses per day; the losartan is admin to, hydralazine compounds, glutathione, Vitamin C, vitamin istered as losartan potassium in an amount of about 25 milli E. cysteine, N-acetyl-cysteine, B-carotene, ubiquinone, grams to about 100 milligrams as a single dose or as multiple ubiquinol-10, tocopherols, coenzyme Q, Superoxide dismu doses per day; the omlesartan is administered as omlesartan tase mimetics, such as, for example, 2.2.6.6-tetramethyl-1- medoxomil in an amount of about 5 milligrams to about 40 piperidinyloxy (TEMPO), DOXYL, PROXYL nitroxide milligrams as a single dose or as multiple doses per day; the compounds; 4-hydroxy-2.2.6.6-tetramethyl-1-piperidiny telmisartan is administered in an amount of about 20 milli loxy (Tempol), M-40401, M-40403, M-40407, M-40419, grams to about 80 milligrams as a single dose or as multiple M-40484, M-40587, M-40588, and the like. Suitable antioxi doses per day; the Valsartan is administered in an amount of dant enzymes include, but are not limited to, Superoxide about 80 milligrams to about 320 milligrams as a single dose dismutase, catalase, glutathione peroxidase, NADPH oxidase or as multiple doses per day. inhibitors, such as, for example, apocynin, aminoguanidine, 0082 Suitable angiotensin-converting enzyme inhibitors ONO 1714, S17834 (benzo(b)pyran-4-one derivative), and (ACE inhibitors) include, but are not limited to, alacepril, the like; Xanthine oxidase inhibitors, such as, for example, benazepril (LOTENSINR), CIBACENR), benazeprilat, cap allopurinol, oxypurinol, amflutizole, diethyldithiocarbamate, topril, ceronapril, cilaZapril, delapril, duinapril, enalapril, 2-styrylchromones, chrysin, luteolin, kaempferol, quercetin, enalaprilat, fasidotril, fosinopril, fosinoprilat, gemopatrilat, myricetin, isorhamnetin, benzophenones such as 2.2',4,4'- glycopril, idrapril, imidapril, lisinopril, moexipril, movel tetrahydroxybenzophenone, 3,4,5,2',3',4'-hexahydroxyben tipril, naphthopidil, omapatrilat, pentopril, perindopril, per Zophenone and 4,4'-dihydroxybenzophenone; benzothiazi indoprilat, quinapril, quinaprilat, ramipril, ramiprilat, rent none analogues such as 2-amino-4H-1,3-benzothiazine-4- ipril, Saralasin acetate, spirapril, temocapril, trandolapril, one, 2-guanidino-4H-1,3-benzothiazin-4-one and rhodanine; trandolaprilat, urapidil, Zofenopril, acylmercapto and mer N-hydroxyguanidine derivative such as, PR5 (1-(3,4- captoalkalnoyl pralines, carboxyalkyl dipeptides, carboxy dimethoxy-2-chlorobenzylideneamino-3-hydroxyguani alkyl dipeptide, phosphinylalkanoyl pralines, registry dine); 6-formylpterin, and the like. The antioxidant enzymes no.796406, AVE 7688, BP1.137, CHF 1514, E 4030, ER can be delivered by gene therapy as a viral vertor and/or a 3295, FPL-66564, MDL 100240, RL 6134, RL 6207, RL non-viral vector. Suitable antioxidants are described more 6893, SA 760, S-5590, Z 13752A, and the like. Suitable fully in the literature, such as in Goodman and Gilman, The angiotensin-converting enzyme inhibitors are described more Pharmacological Basis of Therapeutics (9th Edition), fully in the literature, such as in Goodman and Gilman, The McGraw-Hill, 1995; and the Merck Index on CD-ROM, Thir Pharmacological Basis of Therapeutics (9th Edition), teenth Edition; and on STN Express, file phar and file registry. McGraw-Hill, 1995; and the Merck Index on CD-ROM, I0085. In some embodiments, the antioxidants are apocy Twelfth Edition, Version 12:1, 1996; and on STN Express, file nin, hydralazine compounds, nitroxide compounds and phar and file registry. Superoxide dimutase mimetics. 0083. In some embodiments, the angiotensin-converting I0086) Suitable antithrombotic and vasodilator compounds enzyme inhibitors are benazepril, captopril, enalapril, fosino include, but are not limited to, abciximab, acetorphan, ace pril, lisinopril, moexipril, quinapril, ramipril, trandolapril or tylsalicylic acid, argatroban, bamethan, benfurodil, benzio trandolaprilat. In more particular embodiments the darone, betahistine, bisaramil, brovincamine, bufeniode, citi benazepril is administered as benazepril hydrochloride in an coline, clobenfurol, clopidogrel, cyclandelate, dalteparin, amount of about 5 milligrams to about 80 milligrams as a dipyridamol, droprenilamine, enoxaparin, fendiline, ifen single dose or as multiple doses per day; the captopril is prodil, iloprost, indobufen, isobogrel, isoxSuprine, heparin, administered in an amount of about 12.5 milligrams to about lamifiban, midrodine, nadroparin, nicotinoyl alcohol, nylid 450 milligrams as a single dose or as multiple doses per day; rin, oZagrel, perhexiline, phenylpropanolamine, preny the enalapril is administered as enalapril maleate in an lamine, papaveroline, reviparin Sodium salt, ridogrel, Suloc amount of about 2.5 milligrams to about 40 milligrams as a tidil, tinofedrine, tinzaparin, trifusal, Vintoperol, Xanthinal single dose or as multiple doses per day; the fosinopril is niacinate, and the like. Suitable antithrombotic and vasodila administered as fosinopril sodium in an amount of about 5 tor compounds are described more fully in the literature, such milligrams to about 60 milligrams as a single dose or as as in Goodman and Gilman, The Pharmacological Basis of multiple doses per day; the lisinopril is administered in an Therapeutics (9th Edition), McGraw-Hill, 1995; and the amount of about 12.5 milligrams to about 75 milligrams as a Merck Index on CD-ROM, Thirteenth Edition; and on STN single dose or as multiple doses per day; the moexipril is Express, file phar and file registry. administered as moexipril hydrochloride in an amount of I0087 Suitable f3-adrenergic antagonists include, but are about 7.5 milligrams to about 45 milligrams as a single dose not limited to, acebutolol, alprenolol, amoSulalol, arotinolol. US 2009/0054381 A1 Feb. 26, 2009 atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopin Goodman and Gilman, The Pharmacological Basis of Thera dolol, bucindolol, bucumolol, bufetolol, bufuralol, bunitrolol, peutics (9th Edition), McGraw-Hill, 1995; and the Merck bupranolol, butofilolol, carazolol, capsinolol, carteolol. Index on CD-ROM, 13" Edition; and on STN Express, file carvedilol (COREGR), celiprolol, cetamolol, cindolol, clo phar and file registry. ranolol, dilevalol, diprafenone, epanolol, ersentilide, 0090 Suitable calcium channel blockers include, but are esmolol, esprolol, hedroxalol, indenolol, labetalol, landiolol, not limited to, amlodipine (NORVASCR), anipamil, aranid laniolol, levobunolol, mepindolol, methylpranol, metindol, ipine, amrinone, azelnidipine, barnidipine, bencyclane, beni metipranolol, metrizoranolol, metoprolol, moprolol, nadolol. dipine, bepridil, cilnidipine, cinnarizine, clentiazem, dilt nadoxolol, nebivolol, nifenalol, nipradillol, oXprenolol, pen iazem, dotarizine, efonidipine. elgodipine, fantofarone, butolol, pindolol, practolol, pronethalol, propranolol, Sotalol, felodipine, fendiline, flunarizine, fluspirilene, furnidipine, Sotalolnadolol, sulfinalol, taliprolol, talinolol, tertatolol, til gallopamil, ipenoxazone, isradipine, lacidipine, lemildipine, isolol, timolol, toliprolol, tomalolol, trimepranol, Xamoterol, lercanidipine, lomerizine, manidipine, mibefradil, xibenolol, 2-(3-(1,1-dimethylethyl)-amino-2-hydroxypro monatepil, nicardipine, nifedipine, niguldipine, niludipine, poxy)-3-pyridenecarbonitrilHCl, 1-butylamino-3-(2,5- nilvadipine, nimodipine, nisoldipine, nitrendipine, nival dichlorophenoxy)-2-propanol. 1-isopropylamino-3-(4-(2- dipine, oxodipine, perhexilene, phenytoin, phenytpreny cyclopropylmethoxyethyl) phenoxy)-2-propanol, lamine, pranidipine, ranolazine, ryosidine, semotiadil, tamo 3-isopropylamino-1-(7-methylindan-4-yloxy)-2-butanol, larizine, temiverine hydrochloride, terodiline, tiapamil, 2-(3-t-butylamino-2-hydroxy-propylthio)-4-(5-carbamoyl Vatanidipine hydrochloride, Verapamil, Ziconotide, AE-0047. 2-thienyl)thiazol, 7-(2-hydroxy-3-t-butylaminpropoxy)ph CAI, JTV-519, CHF-1521, L-651582, NS-7, NW-1015, thalide, Acc 9369, AMO-140, BIB-16S, CP-331684, RO-2933, SB-237376, SL-34.0829-08, S-312d, SD-3212, Fr-172516, ISV-208, L-653328, LM-2616, SB-226552, TA-993, YM-430, and the like. Suitable calcium channel SR-58894A, SR-59230A, TZC-5665, UK-1745, YM-430, blockers are described more fully in the literature, such as in and the like. Suitable f3-adrenergic antagonists are described Goodman and Gilman, The Pharmacological Basis of Thera more fully in the literature. Such as in Goodman and Gilman, peutics (9th Edition), McGraw-Hill, 1995; and the Merck The Pharmacological Basis of Therapeutics (9th Edition), Index on CD-ROM. Thirteenth Edition; and on STN Express, McGraw-Hill, 1995; and the Merck Index on CD-ROM, 13' file phar and file registry. Edition; and on STN Express, file phar and file registry. 0091. In some embodiments the calcium channel blockers 0088. In some embodiments, the B-adrenergic antagonists are amlodipine, diltiazem, isradipine, nicardipine, nifedipine, are atenolol, bisoprolol, carvedilol, metoprolol, nebivolol, nimodipine, nisoldipine, nitrendipine, Verapamil. propranolol or timolol. In more particular embodiments the 0092 Suitable diuretics include, but are not limited to, atenolol is administered in an amount of about 50 milligrams thiazides (such as, for example, althiazide, bendroflumethi to about 200 milligrams as a single dose or as multiple doses azide, benzclortriazide, benzhydrochlorothiazide, benzthiaz per day; the bisoprolol is administered as bisoprolol fumarate ide, buthiazide, chlorothiazide, cyclopenethiazide, in an amount of about 2.5 milligrams to about 30 milligrams cyclothiazide, epithiazide, ethiazide, hydrobenzthiazide, as a single dose or as multiple doses per day; the carvedilol is hydrochlorothiazide, hydroflumethiazide, methylclothiaz administered in an amount of about 3.125 milligrams to about ide, methylcyclothiazide, penflutazide, polythiazide, 200 milligrams as a single dose or as multiple doses per day; teclothiazide, trichlormethiazide, triflumethazide, and the the metoprolol is administered as metoprolol tartarate or like); allilusem, ambuside, amiloride, aminometradine, metoprolol Succinate in an amount of about 25 milligrams to aZosemide, bemetizide, bumetanide, butazolamide, butizide, about 300 milligrams as a single dose or as multiple doses per canrenone, carperitide, chloraminophenamide, chlorazanil, day; the nebivolol is administered as nebivolol hydrochloride chlormerodrin, chlorthalidone, cicletanide, clofenamide, clo in an amount of about 2.5 milligrams to about 20 milligrams pamide, clorexolone, conivaptan, daglutril, dichlorophena as a single dose or as multiple doses per day; the nebivolol is mide, disulfamide, ethacrynic acid, ethoXZolamide, etoZolon, administered as nebivolol hydrochloride in an amount of fenoldopam, fenguizone, furosemide, indapamide, mebutiz about 2.5 milligrams to about 20 milligrams as a single dose ide, mefruside, meralluride, mercaptomerin Sodium, mercu or as multiple doses per day; the propranolol is administered mallylic acid, mersalyl, methazolamide, meticane, metola as propranolol hydrochloride in an amount of about 40 mil Zone, moZavaptan, muZolimine, N-(5-1,3,4-thiadiazol-2-yl) ligrams to about 240 milligrams as a single dose or as multiple acetamide, nesiritide, pamabrom, paraflutizide, piretanide, doses per day; the timolol is administered as timolol maleate protheobromine, quinethaZone, scoparius, Spironolactone, in an amount of about 10 milligrams to about 30 milligrams as theobromine, ticrynafen, torsemide, torvaptan, triamterene, a single dose or as multiple doses per day. tripamide, ularitide, Xipamide or potassium, AT 189000, AY 0089 Suitable bronchodilators include, but are not limited 31906, BG9928, BG 9791, C2921, DTI 0017, JDL961, KW to, ambroXol, atropine, bevonium methyl Sulfate, 3902, MCC 134, SLV 306, SR 121463, WAY 140288, ZP bethanechol, chlorprenaline, cyclodrine, daiphenacine, 120, and the like. Suitable diuretics are described more fully N-desethyl-oxybutynin, dicyclomine, emepronium, ephe in the literature, such as in Goodman and Gilman, The Phar drine, epinephrine, etafredine, ethylnorepinephrine, flavox macological Basis of Therapeutics (9th Edition), McGraw ate, flutoprium bromide, hexoprenaline, 2-hydroxy-2.2- Hill, 1995; and the Merck Index on CD-ROM, 13' Edition: diphenyl-N-(1,2,3,6-tetra hydro-pyridin-4-ylmethyl) and on STN Express, file phar and file registry. acetamide, ipratropium bromide, isoetharine, NS 21, 0093. Depending on the diuretic employed, potassium oxybutynin, oxitropium bromide, propanthelin, propiverine, may also be administered to the patient in order to optimize rispenzepine, terbutaline, 1-teobromine actetic acid, the fluid balance while avoiding hypokalemic alkalosis. The terodiline, tiotropium bromide, tolterodine, trospium, Vami administration of potassium can be in the form of potassium camide, Zamiphenacine, and the like. Suitable bronchodila chloride or by the daily ingestion of foods with high potas tors are described more fully in the literature, such as in sium content such as, for example, bananas or orange juice. US 2009/0054381 A1 Feb. 26, 2009

The method of administration of these compounds is hydrochloride in an amount of about 10 milligrams to about described in further detail in U.S. Pat. No. 4,868,179, the 300 milligrams as a single dose or as multiple doses per day. disclosure of which is incorporated by reference herein in its I0100 Suitable H receptor antagonists include, but are not entirety. limited to, burimamide, cimetidine, ebrotidin, famotidine, 0094. In some embodiments the diuretics are amiloride, nizatidine, roXatidine, rantidine, tiotidine, and the like. Suit furosemide, chlorthalidone, hydrochlorothiazide or triam able H receptor antagonists are described more fully in the terene. In more particular embodiments the amiloride is administered as amiloride hydrochloride in an amount of literature. Such as in Goodman and Gilman, The Pharmaco about 5 milligrams to about 15 milligrams as a single dose or logical Basis of Therapeutics (9th Edition), McGraw-Hill, as multiple doses per day; the furosemide is administered in 1995, Pgs. 901-915; the Merck Index on CD-ROM, 13' an amount of about 10 milligrams to about 600 milligrams as Edition; and in WO 00/28988 assigned to NitroMed Inc., the a single dose or as multiple doses per day; the chlorthalidone disclosures of which are incorporated herein by reference in is administered in an amount of about 15 milligrams to about their entirety. 150 milligrams as a single dose or as multiple doses per day; 0101 Suitable neutral endopeptidase inhibitors include, the hydrochlorothiazide is administered in an amount of but are not limited to, atrial natriuretic peptides, diazapins, about 12.5 milligrams to about 300 milligrams as a single azepinones, ecadotril, fasidotril, fasidotrilat, omapatrilat, dose or as multiple doses per day; the triamterene is admin sampatrilat, BMS 189,921, Z 13752A, and the like. Neutral istered in an amount of about 35 milligrams to about 225 endopeptidase inhibitors are described more fully in the lit milligrams as a single dose or as multiple doses per day. erature, such as in Goodman and Gilman, The Pharmacologi 0095 Suitable endothelin antagonists include, but are not cal Basis of Therapeutics (9th Edition), McGraw-Hill, 1995: limited to, atrasentan, bosentan, darusentan, endothelin, enra and the Merck Index on CD-ROM, Thirteenth Edition; and on sentan, Sitaxsentan, Sulfonamide endothelin antagonists, STN Express, file phar and file registry. tezosentan, BMS 193884, BQ-123, SQ 28.608, and the like. Suitable endothelin antagonists are described more fully in 0102 Suitable NSAIDs include, but are not limited to, the literature, such as in Goodman and Gilman, The Pharma acetaminophen, acemetacin, aceclofenac, alminoprofen, cological Basis of Therapeutics (9th Edition), McGraw-Hill, amfenac, bendazac, benoxaprofen, bromfenac, bucloxic acid, 1995; and the Merck Index on CD-ROM, Thirteenth Edition; butibufen, carprofen, cinmetacin, clopirac, diclofenac, etod and on STN Express, file phar and file registry. olac, felbinac, fenclozic acid, fenbufen, fenoprofen, fen 0096 Suitable expectorants include, but are not limited to, tiazac, flunoxaprofen, flurbiprofen, ibufenac, ibuprofen, ambroXol, domiodol, erdosteine, guaiacol, guaifenesin, iodi indomethacin, isofeZolac, isoxepac, indoprofen, ketoprofen, nated glycerol, letosteine, mensa, Sobrerol, Strepronine, ter lonazolac, loxoprofen, metiazinic acid, mofeZolac, miropro pin, tiopronin, and the like. Suitable expectorants are fen, naproxen, oxaprozin, piroZolac, pirprofen, pranoprofen, described more fully in the literature, such as in Goodman and protizinic acid, Salicylamide, Sulindac, Suprofen, SuxibuZone, Gilman, The Pharmacological Basis of Therapeutics (9th tiaprofenic acid, tolmetin, Xenbucin, Ximoprofen, Zaltopro Edition), McGraw-Hill, 1995; and the Merck Index on CD fen, Zomepirac, aspirin, acemetcin, bumadizon, carprofenac, ROM, 13' Edition; and on STN Express, file phar and file clidanac, diflunisal, enfenamic acid, fendosal, flufenamic registry. acid, flunixin, gentisic acid, ketorolac, meclofenamic acid, 0097 Suitable hydralazine compounds include, but are mefenamic acid, mesalamine, prodrugs thereof, and the like. not limited to, compounds having Suitable NSAIDs are described more fully in the literature, Such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617 657; the Merck Index on CD-ROM, 13" Edition; and in U.S. Pat. Nos. 6,057,347 and 6.297.260 assigned to NitroMed Inc., the disclosures of which are incorporated herein by reference in their entirety. the formula: (0103. In some embodiments the NSAIDs are acetami 0098 wherein a, b and c are independently a single or nophen, diclofenac, flurbiprofen, ibuprofen, indomethacin, double bond; R and R are each independently a hydrogen, ketoprofen, naproxen or aspirin. In more particular embodi an alkyl, an ester or a heterocyclic ring, wherein alkyl, ester ments the acetaminophen is administered in an amount of and heterocyclic rind areas defined herein; R and Rare each about 325 milligrams to about 4 grams as a single dose or as independently alone pair of electrons or a hydrogen, with the multiple doses per day; the diclofenac is administered in an proviso that at least one of R. R. R. and R is not a hydrogen. amount of about 50 milligrams to about 250 milligrams as a Exemplary hydralazine compounds include budralazine, single dose or as multiple doses per day; the flurbiprofen is cadralazine, dihydralazine, endralazine, hydralazine, administered in an amount of about 100 milligrams to about pildralazine, todralazine, and the like. Suitable hydralazine 300 milligrams as a single dose or as multiple doses per day; compounds are described more fully in the literature, Such as the ibuprofen is administered in an amount of about 400 in Goodman and Gilman, The Pharmacological Basis of milligrams to about 3.2 grams as a single dose or as multiple Therapeutics (9th Edition), McGraw-Hill, 1995; and the doses per day; the indomethacin is administered in an amount Merck Index on CD-ROM, Thirteenth Edition; and on STN of about 25 milligrams to about 200 milligrams as a single Express, file phar and file registry. dose or as multiple doses per day; the ketoprofen is adminis 0099. In some embodiments the hydralazine compound is tered in an amount of about 50 milligrams to about 300 hydralazine or a pharmaceutically acceptable salt thereof milligrams as a single dose or as multiple doses per day; the Such as hydralazine hydrochloride. In more particular naproxen is administered in an amount of about 250 milli embodiments the hydralazine is administered as hydralazine grams to about 1.5 grams as a single dose or as multiple doses US 2009/0054381 A1 Feb. 26, 2009

per day; the aspirin is administered in an amount of about 10 coumarin, dalteparin Sodium, danaparoid sodium; daZOXiben milligrams to about 2 grams as a single dose or as multiple hydrochloride, desirudin, dicumarol, efegatran Sulfate, enox doses per day. aparin Sodium, ifetroban, ifetroban Sodium, lyapolate 0104 Suitable phosphodiesterase inhibitors, include but Sodium, nafamoStat mesylate, phenprocoumon, Sulfatide, tin are not limited to, filaminast, piclaimilast, rolipram, Org Zaparin Sodium, retaplase; trifenagrel, warfarin, dextrans and 20241, MCI-154, roflumilast, toborinone, posicar, lixazi the like; abciximab, acadesine, anipamil, argatroban, aspirin, none, Zaprinast, sildenafil, pyrazolopyrimidinones, motapi clopidogrel, diadenosine 5'5"-P1-P4-tetraphosphate Zone, pimobendan, Zardaverine, siguaZodan, CI 930, EMD (Ap4A) analogs, difibrotide, dilazep dihydrochloride, dipy 53998, imazodan, saterinone, loprinone hydrochloride, 3-py ridamole, dopamine, 3-methoxytyramine, glucagon, glyco ridinecarbonitrile derivatives, acefylline, albifylline, bami protein IIb/IIIa antagonists, such as, for example, Ro-43 fylline, denbufyllene, diphylline, doxofylline, etofylline, tor 8857, L-700.462, iloprost, isocarbacyclin methyl ester, bafylline, theophylline, nanterinone, pentoxofylline, itazigrel, ketanserin, BM-13.177, lamifiban, lifarizine, mol proxyphylline, cilostazol, cilostamide, MS 857, piroximone, sidomine, nifedipine, oxagrelate, prostaglandins, platelet milrinone, amrinone, tolafentrine, dipyridamole, papavero activating factor antagonists Such as, for example, lexipafant, line, E4021, thienopyrimidine derivatives, triflusal, ICOS prostacyclins, pyrazines, pyridinol carbamate, ReoPro (i.e., 351, tetrahydropiperazino(1.2-b)beta-carboline-1,4-dione abciximab), Sulfinpyrazone, synthetic compounds derivatives, carboline derivatives, 2-pyrazolin-5-one deriva BN-50727, BN-52021, CV-4151, E-5510, FK-409, GU-7, tives, fused pyridazine derivatives, quinazoline derivatives, KB-2796, KBT-3022, KC-404, KF-4939, OP-41483, TRK anthranilic acid derivatives, imidazoquinazoline derivatives, 100, TA-3090, TFC-612, ZK-36374,2,4,5,7-tetrathiaoctane, tadalafil. Vardenafil, and in Goodman and Gilman, The Phar 2,4,5,7-tetrathiaoctane 2,2-dioxide, 2,4,5-trithiahexane, macological Basis of Therapeutics (9th Ed.), McGraw-Hill, theophyllin pentoxifyllin, thromboxane and thromboxane Inc. (1995), The Physician's Desk Reference (49th Ed.), synthetase inhibitors such as, for example, picotamide, Medical Economics (1995), Drug Facts and Comparisons Sulotroban, ticlopidine, tirofiban, trapidil, ticlopidine, (1993 Ed), Facts and Comparisons (1993), and the Merck trifenagrel, trilinolein, 3-substituted 5,6-bis(4-methoxyphe Index on CD-ROM, 13" Edition; and the like. Phosphodi nyl)-1,2,4-triazines; antibodies to glycoprotein IIb/IIIa, anti esterase inhibitors and their nitrosated and/or nitrosylated serotonin drugs, such as, for example, clopridogrel; Sulfin derivatives are also disclosed in U.S. Pat. Nos. 5,932,538, pyrazone and the like; aspirin; dipyridamole; clofibrate; 5,994,294, 5,874,437, 5,958,926 reissued as U.S. Pat. Nos. pyridinol carbamate; glucagon, caffeine; theophyllin pen RE 03772346, 172,060, 6,197,778, 6,177,428, 6,172,068, toxifylling ticlopidine, and the like. 6,221,881, 6,232,321, 6,197,782, 6,133,272, 6,211,179, 0107 Suitable proton pump inhibitors include, but are not 6,316,457 and 6,331,542, the disclosures of each of which are limited to, disulprazole, esomeprazole, lanSoprazole, lemino incorporated herein by reference in their entirety. prazole, omeprazole, pantoprazole, rabeprazole, timopra 0105 Suitable potassium channel blockers include, but Zole, tenatoprazole, 2-(2-benzimidazolyl)-pyridine, tricyclic are not limited to, nicorandil, pinacidil, cromakalim (BRL imidazole, thienopydidine benzimidazole, fluoroalkoxy sub 34915), aprikalim, bimakalim, emakalim, lemakalim, stituted benzimidazole, dialkoxy benzimidazole, N-substi minoxidil, diazoxide, 9-chloro-7-(2-chlorophenyl)-5H-py tuted 2-(pyridylalkenesulfinyl) benzimidazole, cyclohep rimido(5,4-d)(2)-benzazepine, Ribi, CPG-1 1952, CGS tenepyridine, 5-pyrrolyl-2-pyridylmethylsulfinyl 9896, ZD6169, diazixide, Bay X 9227, P1075, Bay X 9228, benzimidazole, alkylsulfinyl benzimidazole, fluoro-pyridyl SDZ PCO 400, WAY-120,491, WAY-120,129, Ro 31-6930, methylsulfinyl benzimidazole, imidazo(4,5-b)pydridine, RO SR 44869, BRL 38226, S 0121, SR 46142A, CGP 42500, SR 18-5362, IY 81149, 4-amino-3-carbonyl quinoline, 4-amino 44994, artilide fumarate, lorazepam, temazepam, ril 3-acylnaphthyride, 4-aminoquinoline, 4-amino-3-acylquino maZafone, nimetazepam, midazolam, lormetazepam, lopra line, 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxy Zolam, ibutilide fumarate, haloxazolam, flunitrazepam, esta ethoxy)guinoline, quinazoline, tetrahydroisoquinolin-2-yl Zolam, doxefazepam, clonazepam, cinolazepam, brotizolam, pyrimidine, YH 1885, 3-substituted 1,2,4-thiadiazolo(4.5-a) and the like. Suitable potassium channel blockers are benzimidazole, 3-substituted imidazo(1,2-d)-thiadiazole, described more fully in the literature, such as in Goodman and 2-sulfinylnicotinamide, pyridylsulfinylbenz, imidazole, Gilman, The Pharmacological Basis of Therapeutics (9th pyridylsulfinyl thieno imidazole, theinoimidazole-toluidine, Edition), McGraw-Hill, 1995; and the Merck Index on CD 4,5-dihydrooxazole, thienoimidazole-toluidine, Hoe-731, ROM. Thirteenth Edition; and on STN Express, file phar and imidazo(1.2-a)pyridine, pyrrolo(2,3-b)pyridine, and the like. file registry. Suitable proton pump inhibitors are described more fully in 0106 Suitable platelet reducing agents include, but are not the literature, such as in Goodman and Gilman, The Pharma limited to, fibrinolytic agents such as for example, ancrod, cological Basis of Therapeutics (9th Edition), McGraw-Hill, anistreplase, bisobrin lactate, brinolase, Hageman factor (i.e. 1995; the Merck Index on CD-ROM, 13° Edition; and in WO factor XII) fragments, plasminogen activators such as, for 00/50037 assigned to NitroMed Inc., the disclosures of which example, Streptokinase, tissue plasminogen activators (TPA), are incorporated herein by reference in their entirety. urokinase, pro-urokinase, recombinant TPA, plasmin, plas 0.108 Suitable renin inhibitors include, but are not limited minogen, and the like; anti-coagulantagents including but are to, aldosterone, aliskiren (SPP-100), ditekiren, enalkrein not limited to, inhibitors of factor Xa, factor TFPI, factor (A-64662), medullipin, terlkiren, tonin, Zankiren, RO VIIa, factor IXc, factor Va, factor VIIIa, inhibitors of other 42-5892 (remikiren), A 62198. A 64662. A 65317. A 69729, coagulation factors, and the like; Vitamin Kantagonists. Such A 72517 (Zankiren), A 74273, CP80794, CGP 29287, CGP as, for example, coumarin, coumarin derivatives (e.g., war 38560A, EMD 47942, ES 305, ES 1005, ES 8891, FK 906, farin Sodium); glycosoaminoglycans Such as, for example, FK 744, H 113, H-142, KRI 1314, pepstatin A, RO 44-9375 heparins both in unfractionated form and in low molecular (ciprokiren), RO 42-5892, RO 66-1132, RO 66-1 168, SP500, weight form; ardeparin Sodium, bivalirudin, bromindione, SP 800, SR-43845, SQ 34017, U 71038, YM-21095, US 2009/0054381 A1 Feb. 26, 2009

YM-26365, urea derivatives of peptides, amino acids con cort, flucloronide, flumethasone, flunisolide, flucinolone nected by nonpeptide bonds, di- and tri-peptide derivatives acetonide, fluocininide, fluocortin butyl, fluocortolone, fluo (e.g., Act-A, Act-B, Act-C, ACT-D, and the like), amino acids rometholone, fluperolone acetate, fluprednidene acetate, flu and derivatives thereof, diol sulfonamides and sulfinyls, prednisolone, flurandrenolide, fluticasone propionate, fluti modified peptides, peptidyl beta-aminoacyl aminodiol car casone propionate, formocortal, halcinonide, halobetasol bamates, monoclonal antibodies to renin. Suitable renin propionate, halometasone, haloprednone acetate, hydrocor inhibitors are described more fully in U.S. Pat. Nos. 5,116, tamate, hydrocortisone and its derivatives (such as phosphate, 835, 5,114,937, 5,106,835, 5,104,869, 5,095,119, 21-sodium Succinate and the like), hydrocortisone terbutate, 5,098,924), 5,095,006, 5,089,471, 5,075451, 5,066,643, isoflupredone, loteprednol etabonate, maZipredone, 5,063,208, 4,845,079, 5,055,466, 4,980,283, 4,885.292), medrysone, meprednisone, methylprednisolone, mometa 4,780,401, 5,071,837, 5,064,965, 5,063,207, 5,036,054, Sone furoate, paremethasone, prednicarbate, prednisolone 5,036,053, 5,034,512, and 4,894,437, the disclosures of each and its derivatives (such as 21-stearoylglycolate, sodium of which are incorporated herein by reference in their phosphate and the like), prednisone, prednival, prednylidene entirety; and in the literature. Such as in Goodman and Gil and its derivatives (such as 21-diethylaminoactetate and the man, The Pharmacological Basis of Therapeutics (9th Edi like), rimexolone, tiXocortol, trimcinolone and its derivatives tion), McGraw-Hill, 1995; and the Merck Index on (such as acetonide, benetonide and the like), and the like. CD-ROM. Thirteenth Edition; and on STN Express, file phar Suitable steroids are described more fully in the literature, and file registry. Such as in Goodman and Gilman, The Pharmacological Basis 0109 Suitable COX-2 inhibitors include, but are not lim of Therapeutics (9th Edition), McGraw-Hill, 1995; the Merck ited to, nimesulide, celecoxib (CELEBREXR), etoricoxib Index on CD-ROM, 13" Edition; the disclosures of which are (ARCOXIAR), flosulide, lumiracoxib (PREXIG(R, COX incorporated herein by reference in their entirety. 189), parecoxib (DYNSTATR), rofecoxib (VIOXX(R), tira 0.112. In some embodiments the steroids are dexametha coxib (JTE-522), valdecoxib (BEXTRAR), ABT 963, BMS Sone, fluorometholone, hydrocortisone, and prednisolone. 347070, CS502, DuP 697, GW-406381, NS-386, SC-57666, 0113. When administered separately, the hydralazine SC-58125, SC-58635, and the like, and combinations of two compounds, isosorbide dinitrate and/or isosorbide mononi or more thereof. Suitable COX-2 inhibitors are in U.S. Pat. trate and/or therapeutic agent can be administered about the Nos. 5,344,991, 5,380,738, 5,393,790, 5,409,944, 5,434,178, same time as part of the overall treatment regimen, i.e., as a 5,436,265, 5,466,823, 5,474,995, 5,510,368, 5,536,752, combination therapy. About the same time' includes admin 5,550,142, 5,552,422, 5,604,253, 5,604,260, 5,639,780, istering the hydralazine compounds, isosorbide dinitrate and/ 5,932,598 and 6,633,272, and in WO 94/03387, WO or isosorbide mononitrate and/or therapeutic agent, simulta 94/15723, WO 94/20480, WO 94/26731, WO 94/27980, WO neously, sequentially, at the same time, at different times on 95/00501, WO95/15316, WO 96/03387, WO 96/03388, WO the same day, or on different days, as long as they are admin 96/06840, WO 96/21667, WO 96/31509, WO 96/36623, WO istered as part of an overall treatment regimen, i.e., combina 97/14691, WO 97/16435, WO 01/45703 and WO 01/87343, tion therapy or a therapeutic cocktail. the disclosures of each of which are incorporated herein by 0114. The compounds and compositions of the invention reference in their entirety; and in the literature, such as in can be administered by any available and effective delivery Goodman and Gilman, The Pharmacological Basis of Thera system including, but not limited to, orally, bucally, parenter peutics (9th Edition), McGraw-Hill, 1995; and the Merck ally, by inhalation, by topical application, by injection, trans Index on CD-ROM. Thirteenth Edition; and on STN Express, dermally, in dosage unit formulations containing conven file phar and file registry. tional nontoxic pharmaceutically acceptable carriers, 0110. In some embodiments the COX-2 inhibitors are adjuvants, and vehicles, as desired. Parenteral includes Sub celecoxib, etoracoxib, lumiracoxib, paracoxib, rofecoxib or cutaneous injections, intravenous, intramuscular, intrasternal Valdecoxib. In more particular embodiments the celecoxib is injection, or infusion techniques. In one embodiment of the administered in an amount of about 100 milligrams to about invention the hydralazine compounds, isosorbide dinitrate 800 milligrams as a single dose or as multiple doses per day; and/or isosorbide mononitrate and/or therapeutic agent can the etoricoxib is administered in an amount of about 50 mil be administered orally, parentally or by inhalation. ligrams to about 200 milligrams as a single dose or as multiple 0115 Solid dosage forms for oral administration can doses per day; the lumiracoxib is administered in an amount include capsules, Sustained-release capsules, tablets, Sus of about 40 milligrams to about 1200 milligrams as a single tained release tablets, chewable tablets, sublingual tablets, dose or as multiple doses per day; the paracoxib is adminis effervescent tablets, pills, powders, granules and gels. In Such tered in an amount of about 20 milligrams to about 100 Solid dosage forms, the active compounds can be admixed milligrams as a single dose or as multiple doses per day; the with at least one inert diluent such as Sucrose, lactose or rofecoxib is administered in an amount of about 12.5 milli starch. Such dosage forms can also comprise, as in normal grams to about 50 milligrams as a single dose or as multiple practice, additional Substances other than inert diluents, e.g., doses per day; the Valdecoxib is administered in an amount of lubricating agents such as magnesium Stearate. In the case of about 10 milligrams to about 40 milligrams as a single dose or capsules, tablets, effervescent tablets, and pills, the dosage as multiple doses per day; forms can also comprise buffering agents. Soft gelatin cap 0111 Suitable steroids include, but are not limited to, Sules can be prepared to contain a mixture of the active 21-acetoxypregnenolone, alcolometaSone, algestone, amci compounds or compositions of the invention and vegetable nonide, beclomethasone, betamethasone, budesonide, chlor oil. Hard gelatin capsules can contain granules of the active prednisone, clobetasol, clobentaSone, clocortolone, clopred compound in combination with a solid, pulverulent carrier nol, corticosterone, cortisine, corticaZol (cortivatol), Such as lactose, Saccharose, Sorbitol, mannitol, potato starch, deflazacort, desonide, desoximetaSone, dexamethasone, corn starch, amylopectin, cellulose derivatives of gelatin. diflorasone, diflucortolone, difluprednate, enoxolone, fluza Tablets and pills can be prepared with enteric coatings. US 2009/0054381 A1 Feb. 26, 2009

0116 Liquid dosage forms for oral administration can resinous crosslinking agent impregnated with the composi include pharmaceutically acceptable emulsions, Solutions, tion and laminated to an impermeable backing. Suspensions, syrups, and elixirs containing inert diluents 0.120. The compositions can also be applied topically commonly used in the art, Such as water. Such compositions using a transdermal system, Such as one of an acrylic-based can also comprise adjuvants, such as wetting agents, emulsi polymer adhesive with a resinous crosslinking agent impreg fying and Suspending agents, and Sweetening, flavoring, and nated with the composition and laminated to an impermeable perfuming agents. backing. In a particular embodiment, the compositions of the 0117 Injectable preparations, for example, sterile inject able aqueous or oleaginous Suspensions can be formulated invention are administered as a transdermal patch, more par according to the known art using Suitable dispersing agents, ticularly as a Sustained-release transdermal patch. The trans wetting agents and/or Suspending agents. The sterile inject dermal patches of the invention can include any conventional able preparation can also be a sterile injectable solution or form such as, for example, adhesive matrix, polymeric Suspension in a nontoxic parenterally acceptable diluent or matrix, reservoir patch, matrix or monolithic-type laminated Solvent, for example, as a solution in 1,3-butanediol. Among structure, and are generally comprised of one or more backing the acceptable vehicles and solvents that can be used are layers, adhesives, penetration enhancers, an optional rate water, Ringer's Solution, and isotonic sodium chloride solu controlling membrane and a release liner which is removed to tion. Sterile fixed oils are also conventionally used as a sol expose the adhesives prior to application. Polymeric matrix Ventor Suspending medium. Parenteral formulations contain patches also comprise a polymeric-matrix forming material. ing compounds of the invention are disclosed in U.S. Pat. Suitable transdermal patches are described in more detail in, Nos. 5,530,006, 5,516,770 and 5,626,588, the disclosures of for example, U.S. Pat. Nos. 5,262,165, 5.948,433, 6,010,715 each of which are incorporated by reference herein in their and 6,071,531, the disclosure of each of which are incorpo entirety. rated herein in their entirety. 0118. Inhaled formulations can be administered, for I0121 The compositions of this invention can further example, as pressurized aerosols and/or nebulized formula include conventional excipients, i.e., pharmaceutically tions to the patient's lungs. Such formulations may contain a acceptable organic or inorganic carrier Substances Suitable for variety of known aerosol propellants useful for endopulmo parenteral application which do not deleteriously react with nary and/or intranasal inhalation administration. In addition, the active compounds. Suitable pharmaceutically acceptable water may be present, with or without any of a variety of carriers include, for example, water, salt Solutions, alcohol, cosolvents, surfactants, stabilizers (such as, for example, anti Vegetable oils, polyethylene glycols, gelatin, lactose, amy oxidants, chelating agents, inert gases, buffers and the like). lose, magnesium Stearate, talc, Surfactants, silicic acid, vis The formulation may also be aerosolized by atomizing which cous paraffin, perfume oil, fatty acid monoglycerides and can produce aerosols and/or dry powderparticles between 1 diglycerides, petroethral fatty acid esters, hydroxymethyl and 5 microns for the efficacious delivery of the inhaled cellulose, polyvinylpyrrolidone, and the like. The pharma formulation. ceutical preparations can be sterilized and if desired, mixed 0119 Transdermal compound administration, which is with auxiliary agents, e.g., lubricants, preservatives, stabiliz known to one skilled in the art, involves the delivery of phar ers, wetting agents, emulsifiers, salts for influencing osmotic maceutical compounds via percutaneous passage of the com pressure, buffers, colorings, flavoring and/or aromatic Sub pound into the systemic circulation of the patient. Topical stances and the like which do not deleteriously react with the administration can also involve the use of transdermal admin active compounds. For parenteral application, particularly istration Such as transdermal patches or iontophoresis Suitable vehicles consist of solutions, such as, oily or aqueous devices. Other components can be incorporated into the trans Solutions, as well as Suspensions, emulsions, or implants. dermal patches as well. For example, compositions and/or Aqueous Suspensions may contain Substances which increase transdermal patches can be formulated with one or more the viscosity of the Suspension and include, for example, preservatives or bacteriostatic agents including, but not lim sodium carboxymethyl cellulose, sorbitol and/or dextran. ited to, methyl hydroxybenzoate, propyl hydroxybenzoate, Optionally, the Suspension may also contain stabilizers. chlorocresol, benzalkonium chloride, and the like. Dosage I0122) Solvents useful in the practice of this invention forms for topical administration of the compounds and com include pharmaceutically acceptable, water-miscible, non positions can include creams, sprays, lotions, gels, ointments, aqueous solvents. In the context of this invention, these sol eye drops, nose drops, ear drops, and the like. In Such dosage vents should be taken to include solvents that are generally forms, the compositions of the invention can be mixed to form acceptable for pharmaceutical use, Substantially water-mis white, Smooth, homogeneous, opaque cream or lotion with, cible, and Substantially non-aqueous. The pharmaceutically for example, benzyl alcohol 1% or 2% (wit/wt) as a preserva acceptable, water-miscible, non-aqueous solvents usable in tive, emulsifying wax, glycerin, isopropyl palmitate, lactic the practice of this invention include, but are not limited to, acid, purified water and sorbitol solution. In addition, the N-methyl pyrrolidone (NMP); propylene glycol; ethyl compositions can contain polyethylene glycol 400. They can acetate; dimethyl sulfoxide; dimethyl acetamide; benzyl be mixed to form ointments with, for example, benzyl alcohol alcohol; 2-pyrrolidone; benzyl benzo ate; C alkanols; 2% (wt/wt) as preservative, white petrolatum, emulsifying 2-ethoxyethanol; alkyl esters such as, 2-ethoxyethyl acetate, wax, and tenox II (butylated hydroxyanisole, propyl gallate, methyl acetate, ethyl acetate, ethylene glycol diethyl ether, or citric acid, propylene glycol). Woven pads or rolls of bandag ethylene glycol dimethylether: (S)-(–)-ethyllactate; acetone: ing material, e.g., gauze, can be impregnated with the com glycerol; allyl ketones such as, methylethyl ketone or dim positions in Solution, lotion, cream, ointment or other Such ethyl sulfone; tetrahydrofuran; cyclic allyl amides such as, form can also be used for topical application. The composi caprolactam, decylmethylsulfoxide, oleic acid; aromatic tions can also be applied topically using a transdermal sys amines such as, N,N-diethyl-m-toluamide; or 1-dodecylaza tem, such as one of an acrylic-based polymer adhesive with a cycloheptan-2-one. US 2009/0054381 A1 Feb. 26, 2009

0123. The pharmaceutically-acceptable, water-miscible, I0127. Various delivery systems are known and can be used non-aqueous solvents include N-methyl pyrrolidone (NMP), to administer the compounds or compositions of the inven propylene glycol, ethyl acetate, dimethyl Sulfoxide, dimethyl tion, including, for example, encapsulation in liposomes, acetamide, benzyl alcohol. 2-pyrrolidone, or benzyl ben microbubbles, emulsions, microparticles, microcapsules and Zoate. Ethanol may also be used as a pharmaceutically-ac the like. The required dosage can be administered as a single ceptable, water-miscible, non-aqueous solvent according to unit or in a Sustained release form. the invention, despite its negative impact on stability. Addi I0128. The bioavailability of the compositions can be tionally, triacetin may also be used as a pharmaceutically enhanced by micronization of the formulations using conven acceptable, water-miscible, non-aqueous solvent, as well as tional techniques such as grinding, milling, spray drying and functioning as a solubilizer in certain circumstances. NMP the like in the presence of suitable excipients or agents such as may be available as PHARMASOLVER from International phospholipids or Surfactants. I0129 Sustained release dosage forms of the invention may Specialty Products (Wayne, N.J.). Benzyl alcohol may be comprise microparticles and/or nanoparticles having a thera available from J.T. Baker, Inc. Ethanol may be available from peutic agent dispersed therein or may comprise the therapeu Spectrum, Inc. Triacetin may be available from Mallinkrodt, tic agent in pure, preferably crystalline, Solid form. For Sus Inc. tained release administration, microparticle dosage forms 0.124. The compositions of this invention can further comprising pure, preferably crystalline, therapeutic agents include solubilizers. Solubilization is a phenomenon that are administered. The therapeutic dosage forms of this aspect enables the formation of a solution. It is related to the pres of the invention may be of any configuration suitable for ence of amphiphiles, that is, those molecules that have the Sustained release. dual properties of being both polar and non-polar in the solu 0.130 Nanoparticle sustained release therapeutic dosage tion that have the ability to increase the solubility of materials forms can be biodegradable and, optionally, bind to the vas that are normally insoluble or only slightly soluble, in the cular Smooth muscle cells and enter those cells, primarily by dispersion medium. Solubilizers often have surfactant prop endocytosis. The biodegradation of the nanoparticles occurs erties. Their function may be to enhance the solubility of a over time (e.g., 30 to 120 days; or 10 to 21 days) in prelyso Solute in a solution, rather than acting as a solvent, although in Somic vesicles and lysosomes. Larger microparticle thera exceptional circumstances, a single compound may have both peutic dosage forms of the invention release the therapeutic solubilizing and solvent characteristics. Solubilizers useful in agents for Subsequent target cell uptake with only a few of the the practice of this invention include, but are not limited to, smaller microparticles entering the cell by phagocytosis. A triacetin, polyethylene glycols (such as, for example, PEG practitioner in the art will appreciate that the precise mecha 300, PEG 400, or their blend with 3350, and the like), nism by which a target cell assimilates and metabolizes a polysorbates (such as, for example, Polysorbate 20, Polysor dosage form of the invention depends on the morphology, bate 40, Polysorbate 60, Polysorbate 65, Polysorbate 80, and physiology and metabolic processes of those cells. The size of the like), poloxamers (such as, for example, Poloxamer 124. the particle Sustained release therapeutic dosage forms is also Poloxamer 188, Poloxamer 237, Poloxamer 338, Poloxamer important with respect to the mode of cellular assimilation. 407, and the like), polyoxyethylene ethers (such as, for For example, the smaller nanoparticles can flow with the example, Polyoxyl 2 cetyl ether, Polyoxyl 10 cetyl ether, and interstitial fluid between cells and penetrate the infused tis Polyoxyl 20 cetyl ether, Polyoxyl 4 lauryl ether, Polyoxyl 23 Sue. The larger microparticles tend to be more easily trapped lauryl ether, Polyoxyl 2 oleyl ether, Polyoxyl 10 oleyl ether, interstitially in the infused primary tissue, and thus are useful Polyoxyl 20oleylether, Polyoxyl 2 stearyl ether, Polyoxyl 10 to deliver anti-proliferative therapeutic agents. stearyl ether, Polyoxyl 20 stearyl ether, Polyoxyl 100 stearyl I0131 Particular sustained release dosage forms of the ether, and the like), polyoxylstearates (such as, for example, invention comprise biodegradable microparticles or nanopar Polyoxyl 30 stearate, Polyoxyl 40 stearate, Polyoxyl 50 stear ticles. More particularly, biodegradable microparticles or ate, Polyoxyl 100 stearate, and the like), polyethoxylated nanoparticles are formed of a polymer containing matrix that Stearates (such as, for example, polyethoxylated 12-hydroxy biodegrades by random, nonenzymatic, hydrolytic Scission stearate, and the like), and Tributyrin. ing to release therapeutic agent, thereby forming pores within 0.125. Other materials that may be added to the composi the particulate structure. tions of the invention include cyclodextrins, and cyclodextrin 0.132. In a particular embodiment, the compositions of the analogs and derivatives, and other Soluble excipients that invention are administered by inhalation. For example, the could enhance the stability of the inventive composition, inhaled formulations can comprise a therapeutically effective maintain the product in solution, or prevent side effects asso amount of at least one hydralazine compound or pharmaceu ciated with the administration of the inventive composition. tically acceptable salt thereof, isosorbide dinitrate and/or Cyclodextrins may be available as ENCAPSINR) from Jans isosorbide mononitrate, and, optionally at least one therapeu Sen Pharmaceuticals. tic agent 0126 The composition, if desired, can also contain minor I0133. The compounds and compositions of the invention amounts of wetting agents, emulsifying agents and/or pH can be formulated as pharmaceutically acceptable salt forms. buffering agents. The composition can be a liquid solution, Pharmaceutically acceptable salts include, for example, Suspension, emulsion, tablet, pill, capsule, Sustained release alkali metal salts and addition salts of free acids or free bases. formulation, or powder. The composition can be formulated The nature of the salt is not critical, provided that it is phar as a Suppository, with traditional binders and carriers such as maceutically acceptable. Suitable pharmaceutically-accept triglycerides. Oral formulations can include standard carriers able acid addition salts may be prepared from an inorganic Such as pharmaceutical grades of mannitol, lactose, starch, acid or from an organic acid. Examples of Such inorganic magnesium Stearate, sodium saccharine, cellulose, magne acids include, but are not limited to, hydrochloric, hydrobro sium carbonate, and the like. mic, hydroiodic, nitric, carbonic, Sulfuric and phosphoric US 2009/0054381 A1 Feb. 26, 2009 acid and the like. Appropriate organic acids include, but are compound (NSAIDs), a phosphodiesterase inhibitor, a selec not limited to, aliphatic, cycloaliphatic, aromatic, heterocy tive cyclooxygenase-2 (COX-2) inhibitor and a steroid. clic, carboxylic and Sulfonic classes of organic acids, such as, 4. The method of claim 1, wherein the at least one hydrala for example, formic, acetic, propionic, succinic, glycolic, Zine compound or a pharmaceutically acceptable salt thereof, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, the isosorbide dinitrate and/or isosorbide mononitrate, and, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthra optionally, the at least one therapeutic agent are administered nilic, mesylic, Salicylic, p-hydroxybenzoic, phenylacetic, orally or by inhalation or parenterally. mandelic, embonic (pamoic), methanesulfonic, ethane 5. The method of claim 1, wherein the respiratory disease is Sulfonic, benzenesulfonic, pantothenic, toluenesulfonic, selected from the group consisting of chronic obstructive 2-hydroxyethanesulfonic, Sulfanilic, Stearic, algenic, B-hy pulmonary disease, pulmonary hypertension, emphysema, droxybutyric, cyclohexylaminosulfonic, galactaric and asthma, cystic fibrosis and bronchitis. galacturonic acid and the like. Suitable pharmaceutically 6. A method for treating a respiratory disease in a patient in acceptable base addition salts include, but are not limited to, a patient in need thereof comprising administering to the metallic salts made from aluminum, calcium, lithium, mag patient hydralazine hydrochloride in an amount of 30 milli nesium, potassium, Sodium and Zinc or organic salts made grams to 400 milligrams per day and isosorbide dinitrate in an from primary, secondary and tertiary amines, cyclic amines, amount of 10 milligrams to 200 milligrams per day. N,N'-dibenzylethylenediamine, chloroprocaine, choline, 7. The method of claim 6, further comprising at least one diethanolamine, ethylenediamine, meglumine (N-methylglu therapeutic agent selected from the group consisting of an camine) and procaine and the like. All of these salts may be antimicrobial compound, a B-adrenergic agonist, an anti-al prepared by conventional means from the corresponding lergic compound, an antitussive compound, an antioxidant, a compound by reacting, for example, the appropriate acid or bronchodilator, an expectorant, a nonsteroidal antiinflamma base with the compound. tory compound (NSAIDs), a phosphodiesterase inhibitor, a 0134. While individual needs may vary, determination of selective cyclooxygenase-2 (COX-2) inhibitor and a steroid. optimal ranges for effective amounts of the compounds and/ 8. The method of claim 6, wherein the respiratory disease is or compositions is within the skill of the art and can be selected from the group consisting of chronic obstructive determined by standard clinical techniques, including refer pulmonary disease, pulmonary hypertension, emphysema, ence to Goodman and Gilman, supra: The Physician's Desk asthma, cystic fibrosis and bronchitis. Reference, Medical Economics Company, Inc., Oradell, N.J., 9. The method of claim 6, wherein the hydralazine hydro 1995; and DrugFacts and Comparisons, Inc., St. Louis, Mo., chloride and the isosorbide dinitrate are administered orally, 1993. Generally, the dosage required to provide an effective by inhalation or parenterally. amount of the compounds and compositions, which can be 10. The method of claim 6, comprising administering 37.5 adjusted by one of ordinary skill in the art, will vary depend mg hydralazine hydrochloride and 20 milligrams isosorbide ing on the age, health, physical condition, sex, diet, weight, dinitrate. extent of the dysfunction of the recipient, frequency of treat 11. The method of claim 6, comprising administering 75 ment and the nature and scope of the dysfunction or disease, mg hydralazine hydrochloride and 40 milligrams isosorbide medical condition of the patient, the route of administration, dinitrate. pharmacological considerations such as, the activity, efficacy, 12. The method of claim 6, comprising administering pharmacokinetic and toxicology profiles of the particular 112.5 mg hydralazine hydrochloride and 60 milligrams isos compound used, whether a drug delivery system is used, and orbide dinitrate. whether the compound is administered as part of a drug 13. The method of claim 6, comprising administering 225 combination. mg hydralazine hydrochloride and 120 milligrams isosorbide 0135 The disclosure of each patent, patent application dinitrate. and publication cited or described in the present specification 14. The method of claim 6, wherein the hydralazine hydro is hereby incorporated by reference herein in its entirety. chloride and the isosorbide dinitrate are separately adminis 0.136 Although the invention has been set forth in detail, tered to the patient. one skilled in the art will appreciate that numerous changes 15. The method of claim 6, wherein the hydralazine hydro and modifications can be made to the invention, and that Such chloride and the isosorbide dinitrate are administered to the changes and modifications can be made without departing patient in the form of a composition. from the spirit and scope of the invention. 16. A method for treating a respiratory disease in a patient in need thereof comprising administering in a patient in need What is claimed is: thereof comprising administering orally, by inhalation or 1. A method for treating a respiratory disease in a patient in parenterally to the patient a pharmaceutical composition need thereof comprising administering to the patient (i) at comprising 37.5 mg hydralazine hydrochloride and 20 mg least one hydralazine compound or a pharmaceutically isosorbide dinitrate; or a pharmaceutical composition com acceptable salt thereof, (ii) isosorbide dinitrate and/or isosor prising 75 mg hydralazine hydrochloride and 40 mg isosor bide mononitrate, and (iii) optionally at least one therapeutic bide dinitrate. agent. 17. The method of claim 16, wherein the pharmaceutical 2. The method of claim 1, wherein the hydralazine com composition is administered orally, by inhalation or parenter pound is hydralazine hydrochloride. ally to the patient once, twice, or three times per day. 3. The method of claim 1, wherein the at least one thera 18. The method of claim 16, further comprising at least one peutic agent is selected from the group consisting of an anti therapeutic agent selected from the group consisting of an microbial compound, a B-adrenergic agonist, an anti-allergic antimicrobial compound, a B-adrenergic agonist, an anti-al compound, an antitussive compound, an antioxidant, a bron lergic compound, an antitussive compound, an antioxidant, a chodilator, an expectorant, a nonsteroidal antiinflammatory bronchodilator, an expectorant, a nonsteroidal antiinflamma US 2009/0054381 A1 Feb. 26, 2009 17 tory compound (NSAIDs), a phosphodiesterase inhibitor, a tive pulmonary disease, pulmonary hypertension, emphy selective cyclooxygenase-2 (COX-2) inhibitor and a steroid. sema, asthma, cystic fibrosis and bronchitis. 19. The method of claim 16, wherein the respiratory dis ease is selected from the group consisting of chronic obstruc- ck