Method and compositions for treatment or prevention of inflammatory conditions

Abstract

Pharmaceutical compositions and methods for treating or preventing an inflammatory condition in a patient are disclosed. The pharmaceutical compositions and methods include the use of vincamine or a vincamine derivative, either alone or in combination with one or more additional therapeutic agents, including a steroid (preferably a corticosteroid), an angiotensin II receptor (type 1) antagonist, an angiotensin-converting enzyme (ACE) inhibitor, and a non-steroidal anti-inflammatory drug.

1 . A method of treating or preventing an inflammatory condition comprising administering vincamine or a vincamine derivative to a patient under conditions effective to treat or prevent an inflammatory condition. 
   
   
       2 . The method according to  claim 1  wherein the vincamine derivative is selected from the group consisting of 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where R 1  is a halogen, R 2  can be a hydroxy group whereas R 3  can be hydrogen, or R 2  and R 3  together form an additional bond between the carbon atoms which carry them, or salts thereof; 
     
       
         
         
             
             
         
       
     
     where the compound is formed by a cis-fusion of the D/E rings, and either (i) Y is hydrogen, in which case Z 1  and Z 2  together represent simultaneously an oxygen atom or Z 1  is a methoxycarbonyl radical and Z 2  is a hydroxy radical, or (ii) where Y and Z 2  together form a carbon-carbon bond and Z 1  is a methoxycarbonyl radical, or salts thereof; 
     
       
         
         
             
             
         
       
     
     where R 4  is hydrogen or a hydroxyl group, and R 5  is an alkyl group, or salts thereof; 
     
       
         
         
             
             
         
       
     
     where R 6  is hydrogen or methoxy, X and Y are hydrogen or are together are a double bond between the ring carbon atoms to which they are bonded, or salts thereof; and
 combinations of any two or more of the above compounds or salts thereof. 
 
   
   
       3 . The method according to  claim 1  wherein the administering is effective to treat symptoms of a pre-existing inflammatory condition. 
   
   
       4 . The method according to  claim 1  wherein the administering is carried out prior to onset of the inflammatory condition. 
   
   
       5 . The method according to  claim 4  further comprising repeating the administering after onset of the inflammatory condition. 
   
   
       6 . The method according to  claim 1  wherein the inflammatory condition is selected from the group consisting of atherosclerosis, acute and chronic lung inflammation, inflammation of virus-infected tissues, ulcerative colitis, endotoxic shock, arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, insulin dependent diabetes mellitus, injury independent type II diabetes, ischemia induced inflammation, otitis media, gout, multiple sclerosis, cachexia, and Ataxia Telangiestasia. 
   
   
       7 . The method according to  claim 1  further comprising repeating the administering of vincamine or the vincamine derivative. 
   
   
       8 . The method according to  claim 1  further comprising co-administering to the patient a therapeutically effective amount of one or more of a corticosteroid, an angiotensin II receptor (type 1) antagonist, an angiotensin-converting enzyme inhibitor, and a non-steroidal anti-inflammatory drug. 
   
   
       9 . The method according to  claim 1  wherein the patient is a mammal. 
   
   
       10 . The method according to  claim 9  wherein the mammal is a human, a non-human primate, a rodent, a cow, a horse, a sheep, or a pig. 
   
   
       11 . The method according to  claim 1  wherein administration of the vincamine derivative antagonizes activity of inhibitor of NF-κB kinase (IKK) and the inflammatory condition is an NF-κB mediated inflammatory condition. 
   
   
       12 . The method according to  claim 1  wherein the vincamine derivative, as administered, is in the form of a prodrug, which is metabolized to a form that has antagonist activity on inhibitor of NF-κB kinase (IKK), and wherein the inflammatory condition is an NF-κB mediated inflammatory condition. 
   
   
       13 . The method according to  claim 1  wherein the administering is carried out orally, by inhalation, by intranasal or airway instillation, optically, intranasally, by middle ear injection, by ear drops, topically, transdermally, parenterally, subcutaneously, intravenous injection, intra-arterial injection, injection to a site of inflammation, intradermal injection, intramuscular injection, intrapleural instillation, intraperitoneally injection, intraventricularly, intralesionally, by application to mucous membranes, or implantation of a sustained release vehicle. 
   
   
       14 . The method according to  claim 1  wherein the inflammatory condition involves lung tissue and the administering is carried out via airway instillation or inhalation. 
   
   
       15 . The method according to  claim 14 , wherein the vincamine derivative is present in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. 
   
   
       16 . The method according to  claim 15  wherein the pharmaceutical composition is a lung surfactant composition or a powder mixture suitable for nebulization. 
   
   
       17 . The method according to  claim 1  wherein the inflammatory condition is arthritis and the administering is carried out via direct injection, transdermally via transdermal patch, or topically. 
   
   
       18 . The method according to  claim 1  wherein the vincamine derivative is administered in an amount of about 0.01 to about 2 mg/kg, preferably 0.05 to about 1 mg/kg, most preferably about 0.05 to about 0.5 mg/kg. 
   
   
       19 . The method according to  claim 1  wherein the vincamine derivative is vinpocetine and the vinpocetine is either administered alone or in combination with another agent that is not a COX-2 inhibitor; and wherein the inflammatory condition to be treated does not involve a gastrointestinal inflammatory condition. 
   
   
       20 . A pharmaceutical composition comprising vincamine or a vincamine derivative, wherein the pharmaceutical composition is in the form of a lung surfactant formulation or an inhalable formulation. 
   
   
       21 . The pharmaceutical composition according to  claim 20  wherein the vincamine derivative has antagonist activity on inhibitor of NF-κB kinase (IKK). 
   
   
       22 . The pharmaceutical composition according to  claim 20  wherein the vincamine derivative, as administered, is in the form of a prodrug, which is metabolized to a form that has antagonist activity on inhibitor of NF-κB kinase (IKK). 
   
   
       23 . The pharmaceutical composition according to  claim 20  wherein the vincamine derivative is selected from the group consisting of 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where R 1  is a halogen, R 2  can be a hydroxy group whereas R 3  can be hydrogen, or R 2  and R 3  together form an additional bond between the carbon atoms which carry them, or salts thereof; 
     
       
         
         
             
             
         
       
     
     where the compound is formed by a cis-fusion of the D/E rings, and either (i) Y is hydrogen, in which case Z 1  and Z 2  together represent simultaneously an oxygen atom or Z 1  is a methoxycarbonyl radical and Z 2  is a hydroxy radical, or (ii) where Y and Z 2  together form a carbon-carbon bond and Z 1  is a methoxycarbonyl radical, or salts thereof; 
     
       
         
         
             
             
         
       
     
     where R 4  is hydrogen or a hydroxyl group, and R 5  is an alkyl group, or salts thereof; 
     
       
         
         
             
             
         
       
     
     where R 6  is hydrogen or methoxy, X and Y are hydrogen or are together are a double bond between the ring carbon atoms to which they are bonded, or salts thereof; and
 combinations of any two or more of the above compounds or salts thereof. 
 
   
   
       24 . The pharmaceutical composition according to  claim 20  further comprising a steroid. 
   
   
       25 . The pharmaceutical composition according to  claim 20  wherein the steroid is a corticosteroid. 
   
   
       26 . The pharmaceutical composition according to  claim 25  wherein the corticosteroid is selected from triamcinolone, fluocinolone, cortisone, hydrocortisone, ciclesonide, fluticasone, flunisolide, mometasone, betamethasone, depomedrol, dexamethasone, budesonide, beclomethasone, prednisone, methylprednisolone, prednisolone, and combinations thereof. 
   
   
       27 . The pharmaceutical composition according to  claim 20  further comprising an effective amount of one or more of a corticosteroid, an angiotensin II receptor (type 1) antagonist, an angiotensin-converting enzyme inhibitor, and a non-steroidal anti-inflammatory drug. 
   
   
       28 . A pharmaceutical composition comprising vincamine or a vincamine derivative, and one or more of a corticosteroid, angiotensin II receptor (type 1) antagonist, and an angiotensin-converting enzyme (ACE) inhibitor. 
   
   
       29 . The pharmaceutical composition according to  claim 28  wherein the corticosteroid is selected from triamcinolone, fluocinolone, cortisone, hydrocortisone, ciclesonide, fluticasone, flunisolide, mometasone, betamethasone, depomedrol, dexamethasone, budesonide, beclomethasone, prednisone, methylprednisolone, prednisolone, and combinations thereof. 
   
   
       30 . The pharmaceutical composition according to  claim 28  wherein the angiotensin II receptor (type 1) antagonist is selected from the group consisting of saralasin acetate, candesartan cilexetil, CGP-63170, EMD-66397, KT3-671, LR-B/081, valsartan, A-81282, BIBR-363, BIBS-222, BMS-184698, candesartan, CV-11194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, PD-150304, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, L-159282, ME-3221, SL-91.0102, tasosartan, telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-159689, L-162234, L-162441, L-163007, PD-123177, A-81988, BMS-180560, CGP-38560A, CGP48369, DA-2079, DE-3489, DuP-167, EXP-063, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, isoteoline, KR1-1177, L-158809, L-158978, L-159874, LR B087, LY-285434, LY-302289, LY-315995, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, saprisartan, saralasin, Sarmesin, WK-1360, X-6803, ZD-6888, ZD-7155, ZD-8731, BIBS39, C1-996, DMP-811, DuP-532, EXP-929, L-163017, LY-301875, XH-148, XR-510, zolasartan, PD-123319, and combinations thereof. 
   
   
       31 . The pharmaceutical composition according to  claim 28  wherein the ACE inhibitor is selected from the group consisting of AB-103, ancovenin, benazeprilat, BRL-36378, BW-A575C, CGS-13928C, CL242817, CV-5975, Equaten, EU4865, EU-4867, EU-5476, foroxymithine, FPL 66564, FR-900456, Hoe-065, 15B2, indolapril, ketomethylureas, KR1-1177, KR1-1230, L681176, libenzapril, MCD, MDL-27088, MDL-27467A, moveltipril, MS41, nicotianamine, pentopril, phenacein, pivopril, rentiapril, RG-5975, RG-6134, RG-6207, RGH0399, ROO-911, RS-10085-197, RS-2039, RS 5139, RS 86127, RU-44403, S-8308, SA-291, spiraprilat, SQ26900, SQ-28084, SQ-28370, SQ-28940, SQ-31440, Synecor, utibapril, WF-10129, Wy-44221, Wy-44655, Y-23785, Yissum, P-0154, zabicipril, Asahi Brewery AB-47, alatriopril, BMS 182657, Asahi Chemical C-111, Asahi Chemical C-112, Dainippon DU-1777, mixanpril, Prentyl, zofenoprilat, I (-(1-carboxy-6-(4-piperidinyl)hexyl)amino)-1-oxo-propyl octahydro-1H-indole-2-carboxylic acid, Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564, idrapril, perindoprilat and Servier S-5590, alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, saralasin acetate, temocapril, tranolapril, trandolaprilat, ceranapril, moexipril, quinaprilat, spirapril, and combinations thereof. 
   
   
       32 . The pharmaceutical composition according to  claim 28  wherein the vincamine derivative is selected from the group consisting of 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where R 1  is a halogen, R 2  can be a hydroxy group whereas R 3  can be hydrogen, or R 2  and R 3  together form an additional bond between the carbon atoms which carry them, or salts thereof; 
     
       
         
         
             
             
         
       
     
     where the compound is formed by a cis-fusion of the D/E rings, and either (i) Y is hydrogen, in which case Z 1  and Z 2  together represent simultaneously an oxygen atom or Z 1  is a methoxycarbonyl radical and Z 2  is a hydroxy radical, or (ii) where Y and Z 2  together form a carbon-carbon bond and Z 1  is a methoxycarbonyl radical, or salts thereof; 
     
       
         
         
             
             
         
       
     
     where R 4  is hydrogen or a hydroxyl group, and R 5  is an alkyl group, or salts thereof; 
     
       
         
         
             
             
         
       
     
     where R 6  is hydrogen or methoxy, X and Y are hydrogen or are together are a double bond between the ring carbon atoms to which they are bonded, or salts thereof; and
 combinations of any two or more of the above compounds or salts thereof. 
 
   
   
       33 . The pharmaceutical composition according to  claim 28  wherein the vincamine derivative antagonizes activity of inhibitor of NF-κB kinase (IKK). 
   
   
       34 . The pharmaceutical composition according to  claim 28  wherein the vincamine derivative, as administered, is in the form of a prodrug, which is metabolized to a form that has antagonist activity on inhibitor of NF-κB kinase (IKK). 
   
   
       35 . The pharmaceutical composition according to  claim 28  wherein composition comprises vinpocetine as the vincamine derivative and dexamethasone as the corticosteroid. 
   
   
       36 . The pharmaceutical composition according to  claim 28  wherein the pharmaceutical composition is in the form of or present in a lung surfactant formulation, an inhalable formulation, an injectable formulation, a transdermal formulation, a topical formulation, or a polymeric matrix. 
   
   
       37 . A pharmaceutical composition comprising vincamine or a vincamine derivative other than vinpocetine, and an effective amount of one or more of a corticosteroid, an angiotensin II receptor (type 1) antagonist, an angiotensin-converting enzyme inhibitor, and a non-steroidal anti-inflammatory drug. 
   
   
       38 . The pharmaceutical composition according to  claim 37  wherein the corticosteroid is selected from triamcinolone, fluocinolone, cortisone, hydrocortisone, ciclesonide, fluticasone, flunisolide, mometasone, betamethasone, depomedrol, dexamethasone, budesonide, beclomethasone, prednisone, methylprednisolone, prednisolone, and combinations thereof. 
   
   
       39 . The pharmaceutical composition according to  claim 37  wherein the angiotensin II receptor (type 1) antagonist is selected from the group consisting of saralasin acetate, candesartan cilexetil, CGP-63170, EMD-66397, KT3-671, LR-B/081, valsartan, A-81282, BIBR-363, BIBS-222, BMS-184698, candesartan, CV-11194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, PD-150304, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, L-159282, ME-3221, SL-91.0102, tasosartan, telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-159689, L-162234, L-162441, L-163007, PD-123177, A-81988, BMS-180560, CGP-38560A, CGP48369, DA-2079, DE-3489, DuP-167, EXP-063, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, isoteoline, KR1-1177, L-158809, L-158978, L-159874, LR B087, LY-285434, LY-302289, LY-315995, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, saprisartan, saralasin, Sarmesin, WK-1360, X-6803, ZD-6888, ZD-7155, ZD-8731, BIBS39, C1-996, DMP-811, DuP-532, EXP-929, L-163017, LY-301875, XH-148, XR-510, zolasartan, PD-123319, and combinations thereof. 
   
   
       40 . The pharmaceutical composition according to  claim 37  wherein the ACE inhibitor is selected from the group consisting of AB-103, ancovenin, benazeprilat, BRL-36378, BW-A575C, CGS-13928C, CL242817, CV-5975, Equaten, EU4865, EU-4867, EU-5476, foroxymithine, FPL 66564, FR-900456, Hoe-065, 15B2, indolapril, ketomethylureas, KR1-1177, KR1-1230, L681176, libenzapril, MCD, MDL-27088, MDL-27467A, moveltipril, MS41, nicotianamine, pentopril, phenacein, pivopril, rentiapril, RG-5975, RG-6134, RG-6207, RGH0399, ROO-911, RS-10085-197, RS-2039, RS 5139, RS 86127, RU-44403, S-8308, SA-291, spiraprilat, SQ26900, SQ-28084, SQ-28370, SQ-28940, SQ-31440, Synecor, utibapril, WF-10129, Wy-44221, Wy-44655, Y-23785, Yissum, P-0154, zabicipril, Asahi Brewery AB-47, alatriopril, BMS 182657, Asahi Chemical C-111, Asahi Chemical C-112, Dainippon DU-1777, mixanpril, Prentyl, zofenoprilat, I (-(1-carboxy-6-(4-piperidinyl)hexyl)amino)-1-oxo-propyl octahydro-1H-indole-2-carboxylic acid, Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564, idrapril, perindoprilat and Servier S-5590, alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, ramiprilat, saralasin acetate, temocapril, tranolapril, trandolaprilat, ceranapril, moexipril, quinaprilat, spirapril, and combinations thereof. 
   
   
       41 . The pharmaceutical composition according to  claim 37  wherein the NSAID is selected from the group consisting of ibuprofen (2-(isobutylphenyl)-propionic acid); methotrexate (N-[4-(2,4 diamino 6-pteridinyl-methyl]methylamino]benzoyl)-L-glutamic acid); aspirin (acetylsalicylic acid); salicylic acid; diphenhydramine (2-(diphenylmethoxy)-N,N-dimethylethylamine hydrochloride); naproxen (2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, (−)); ketorolac (1H-Pyrrolizine-1-carboxylic acid, 2,3-dihydro-5-benzoyl-, (+−)); phenylbutazone (4-butyl-1,2-diphenyl-3,5-pyrazolidinedione); sulindac-(2)-5-fluoro-2-methyl-1-[[p-(methylsulfinyl)phenyl]methylene-]-1H-indene-3-acetic acid; diflunisal (2′,4′,-difluoro-4-hydroxy-3-biphenylcarboxylic acid; piroxicam (4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-2-carboxamide 1,1-dioxide, an oxicam; indomethacin (1-(4-chlorobenzoyl)-5-methoxy-2-methyl-H-indole-3-acetic acid); meclofenamate sodium (N-(2,6-dichloro-m-tolyl)anthranilic acid, sodium salt, monohydrate); ketoprofen (2-(3-benzoylphenyl)-propionic acid; tolmetin sodium (sodium 1-methyl-5-(4-methylbenzoyl-1H-pyrrole-2-acetate dihydrate); diclofenac sodium (2-[(2,6-dichlorophenyl)amino]benzeneatic acid, monosodium salt); hydroxychloroquine sulphate (2-{[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino}ethanol sulfate (1:1); penicillamine (3-mercapto-D-valine); flurbiprofen ([1,1-biphenyl]-4-acetic acid, 2-fluoroalphamethyl-, (+−)); cetodolac (1-8-diethyl-13,4,9, tetrahydropyrano-[3-4-13]indole-1-acetic acid; mefenamic acid (N-(2,3-xylyl)anthranilic acid; and diphenhydramine hydrochloride (2-diphenyl methoxy-N,N-di-methylethamine hydrochloride). 
   
   
       42 . The pharmaceutical composition according to  claim 37  wherein the vincamine derivative is selected from the group consisting of 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where R 1  is a halogen, R 2  can be a hydroxy group whereas R 3  can be hydrogen, or R 2  and R 3  together form an additional bond between the carbon atoms which carry them, or salts thereof; 
     
       
         
         
             
             
         
       
     
     where the compound is formed by a cis-fusion of the D/E rings, and either (i) Y is hydrogen, in which case Z 1  and Z 2  together represent simultaneously an oxygen atom or Z 1  is a methoxycarbonyl radical and Z 2  is a hydroxy radical, or (ii) where Y and Z 2  together form a carbon-carbon bond and Z 1  is a methoxycarbonyl radical, or salts thereof; 
     
       
         
         
             
             
         
       
     
     where R 4  is hydrogen or a hydroxyl group, and R 5  is an alkyl group, or salts thereof 
     
       
         
         
             
             
         
       
     
     where R 6  is hydrogen or methoxy, X and Y are hydrogen or are together are a double bond between the ring carbon atoms to which they are bonded, or salts thereof and
 combinations of any two or more of the above compounds or salts thereof. 
 
   
   
       43 . The pharmaceutical composition according to  claim 37  wherein the vincamine derivative antagonizes activity of inhibitor of NF-κB kinase (IKK). 
   
   
       44 . The pharmaceutical composition according to  claim 37  wherein the vincamine derivative, as administered, is in the form of a prodrug, which is metabolized to a form that has antagonist activity on inhibitor of NF-κB kinase (IKK). 
   
   
       45 . The pharmaceutical composition according to  claim 37  wherein the pharmaceutical composition is in the form of or present in a lung surfactant formulation, an inhalable formulation, an injectable formulation, a transdermal formulation, a topical formulation, or a polymeric matrix.