Treating or preventing the early stages of degeneration of articular cartilage or subchondral bone in mammals using carprofen and derivatives

Abstract

Treating or preventing the early stages of degeneration of articular cartilage or subchondral bone in the affected joint of a mammal is accomplished by administering a chondroprotective compound of Formula (I): where A is hydroxy, (C 1 -C 4 )alkoxy, amino, hydroxy-amino, mono-(C 1 -C 2 )alkylamino, di-(C 1 -C 2 )alkylamino; X and Y are independently H or (C 1 -C 2 )alkyl; and n is 1 or 2; R 6 is halogen, (C 1 - C 3 )alkyl, trifluoromethyl, or nitro; R 9 is H; (C 1 -C 2 )alkyl; phenyl or phenyl-(C 1 - C 2 )alkyl, where phenyl is optionally mono-substituted by fluoro or chloro; —C(═O)—R, where R is (C 1 -C 2 )alkyl or phenyl, optionally mono-substituted by fluoro or chloro; or —C(═O)—O—R 1 , where R 1 is (C 1 - C 2 )alkyl. This treatment ameliorates, diminishes, actively treats, reverses or prevents any injury, damage or loss of articular cartilage or subchondral bone subsequent to said early stage of said degeneration. Whether or not a mammal needs such treatment is determined by whether or not it exhibits a statistically significant deviation from normal standard values in synovial fluid or membrane from the affected joint, with respect to at least five of the following substances: increased interleukin-1 beta (IL-1β), increased tumor necrosis factor alpha (TNFα); increased ratio of IL-1β to IL-1 receptor antagonist protein (IRAP); increased expression of p55 TNF receptors (p55 TNF-R), increased interleukin-6 (IL-6); increased leukemia inhibitory factor (LIF); decreased insulin-like growth factor-1 (IGF-1); decreased transforming growth factor beta (TGFβ); decreased platelet-derived growth factor (PDGF); decreased basic fibroblast growth factor (b-FGF); increased keratan sulfate; increased stromelysin; increased ratio of stromelysin to tissue inhibitor of metalloproteases (TIMP); increased osteocalcin; increased alkaline phosphatase; increased cAMP responsive to hormone challenge; increased urokinase plasminogen activator (uPA); increased cartilage oligomeric matrix protein; and increased collagenase.

What is claimed is:  
     
         1 . A method of treating or preventing the early stages of degeneration of articular cartilage or subchondral bone in one or more joints of a mammal in need of such treatment, comprising (1) establishing the status of said mammal as presently or prospectively being in said early stages and thus in need of such treatment; and thereupon (2) administering to said mammal an amount therapeutically effective for treating or preventing said early stages of degeneration of articular cartilage or subchondral bone, of a chondroprotective compound of Formula (I):  
       
         
           
           
               
               
           
         
       
       where A is hydroxy, (C 1 - C 4 )alkoxy, amino, hydroxy-amino, mono-(C 1  -C 2 )alkylamino, di-(C 1 -C 2 )alkylamino; X and Y are independently H or (C 1 - C 2 )alkyl; and n is 1 or 2; 
 R 6  is halogen, (C 1 - C 3 )alkyl, trifluoromethyl, or nitro;  
 R 9  is H; (C 1 - C 2 )alkyl; phenyl or phenyl-(C 1 -C 2 )alkyl, where phenyl is optionally mono-substituted by fluoro or chloro; —C(═O)—R, where R is (C 1  - C 2 )alkyl or phenyl, optionally mono-substituted by fluoro or chloro; or —C(═O)—O—R 1 , where R 1  is (C 1 - C 2 )alkyl;  
 where X and Y are different, the (−)(R) and (+)(S) enantiomers thereof; and all pharmaceutically acceptable salt forms, prodrugs and metabolites thereof which are therapeutically active for treating or preventing said early stages of degeneration of articular cartilage or subchondral bone.  
 
     
     
         2 . A method according to  claim 1  wherein said chondroprotective compound of Formula (I) exists as (−)(R) and (+)(S) enantiomers, and said (+)(S) enantiomer is used alone.  
     
     
         3 . A method according to  claim 1  wherein said mammal is a cat, dog or horse, and said treatment or prevention ameliorates, diminishes, actively treats, reverses or prevents any injury, damage or loss of articular cartilage or subchondral bone subsequent to said early stage of said degeneration.  
     
     
         4 . A method according to  claim 1  wherein said status of said mammal as presently or prospectively being in said early stages and thus in need of such treatment is determined by one or more of the following: 
 (A) positive results from the clinical examination and evaluation of the joints of said mammal, including measurement of hip dysplasia progression;  
 (B) performance of any invasive surgical procedure on one or more joints of said mammal;  
 (C) positive results from an examination of one or more joints of said mammal using noninvasive procedures including radiographic and magnetic resonance imaging (MRI); and  
 (D) positive results from any biochemical test performed on body fluids or joint tissue of said mammal with respect to one or more of the following substances: 
 (1) increased interleukin-1 beta (IL-1β);  
 (2) increased tumor necrosis factor alpha (TNFα);  
 (3) increased ratio of IL-1β to IL-1 receptor antagonist protein (IRAP);  
 (4) increased expression of p55 TNF receptors (p55 TNF-R);  
 (5) increased interleukin-6 (IL-6); increased leukemia inhibitory factor (LIF);  
 (6) unchanged or decreased insulin-like growth factor-1 (IGF-1);  
 (7) decreased transforming growth factor beta (TGFβ); unchanged or decreased platelet-derived growth factor (PDGF),  
 (8) unchanged or decreased basic fibroblast growth factor (b-FGF);  
 (9) increased keratan sulfate;  
 (10) increased matrix metalloproteases (MMPs) including stromelysin;  
 (11) increased ratio of matrix metalloproteases (MMPs) including stromelysin, to tissue inhibitor of metalloproteases (TIMP),  
 (12) increased osteocalcin;  
 (13) increased alkaline phosphatase;  
 (14) increased cAMP responsive to hormone challenge;  
 (15) increased urokinase plasminogen activator (uPA);  
 (16) increased cartilage oligomeric matrix protein;  
 (17) presence of type-II specific collagen neoepitopes and  
 (18) increased collagenase.  
 
 
     
     
         5 . A method according to  claim 1  additionally including administering combinations of compounds, comprising: 
 (A) more than one member selected from the group of chondroprotective compounds of Formula (I); or  
 (B) one or more of said chondroprotective compounds of Formula (I) administered together with one or more members selected from the group consisting essentially of polysulfated glycosaminoglycan (PSGAG), glucosamine, chondroitin sulfate (CS), hyaluronic acid (HA), pentosan polysulfate (PPS), doxycycline, and minocycline.  
 
     
     
         6 . A method according to  claim 1  wherein said chondroprotective compound is 6-chloro-a-methyl-9H-carbazole-2-acetic acid and said administered amount is about 2.0 mg/kg/day to about 4.0 mg/kg/day.  
     
     
         7 . A pharmaceutical composition for treating or preventing the early stages of degeneration of articular cartilage or subchondral bone in one or more joints of a mammal in need of such treatment, comprising: 
 (A) an amount therapeutically effective for treating or preventing said early stages of degeneration of articular cartilage or subchondral bone, of a chondroprotective compound of Formula (I):                          where A is hydroxy, (C 1 -C 4 )alkoxy, amino, hydroxy-amino, mono-(C 1 -C 2 )alkylamino, di-(C 1 -C 2 )alkylamino; X and Y are independently H or (C 1 -C 2 )alkyl; and n is 1 or 2;    R 6  is halogen, (C 1 -C 3 )alkyl, trifluoromethyl, or nitro;    R 9  is H; (C 1 -C 2 )alkyl; phenyl or phenyl-(C 1 -C 2 )alkyl, where phenyl is optionally mono-substituted by fluoro or chloro; —C(═O)—R, where R is (C 1 -C 2 )alkyl or phenyl, optionally mono-substituted by fluoro or chloro; or —C(═O)—O—R 1 , where R 1  is (C 1 -C 2 )alkyl;    where X and Y are different, the (−)(R) and (+)(S) enantiomers thereof; and all pharmaceutically acceptable salt forms, prodrugs and metabolites thereof which are therapeutically active for treating or preventing said early stages of degeneration of articular cartilage or subchondral bone; and    (B) a pharmaceutically acceptable carrier therefor.    
     
     
         8 . A pharmaceutical composition according to  claim 7  wherein said chondroprotective compound is 6-chloro-α-methyl-9H-carbazole-2-acetic acid, and said therapeutically effective amount provides dosing at a rate of from about 2.0 mg/kg/day to about 4.0 mg/kg/day.  
     
     
         9 . A pharmaceutical composition according to  claim 7  comprising solid peroral dosage forms selected from the group consisting of delayed-release oral tablets, capsules, caplets, and multiparticulates which prevent release and absorption in the stomach to facilitate delivery distal to the stomach of the mammal, and sustained-release oral tablets, capsules and microparticulates which provide systemic delivery of the active ingredient in a controlled manner up to a 24-hour period.  
     
     
         10 . A pharmaceutical composition according to  claim 7  additionally including combinations of compounds, comprising 
 (A) more than one member selected from the group of chondroprotective compounds of Formula (I); or  
 (B) one or more of said chondroprotective compounds of Formula (I) together with one or more members selected from the group consisting essentially of polysulfated glycosaminoglycan (PSGAG), glucosamine, chondroitin sulfate (CS), hyaluronic acid (HA), pentosan polysulfate (PPS), doxycycline, and minocycline.  
 
     
     
         11 . A pharmaceutical composition according to  claim 7  additionally including combinations of one or more other therapeutically active agents together with said chondroprotective compounds of Formula (I) comprising: 
 (A) where said one or more joints has become seriously infected at the same time by microorganisms comprising bacteria, fungi, protozoa, or virus, said chondroprotective compound in combination with one or more antibiotic, antifungal, antiprotozoal, or antiviral therapeutic agents;  
 (B) in combination with one or more members selected from the group consisting essentially of H 1  -receptor antagonists; kinin-B 1  - and B 2  -receptor antagonists; leukotriene LTC 4  -, LTD 4 /LTE 4  -, and LTB 4  -inhibitors; PAF-receptor antagonists; gold in the form of an aurothio group together with hydrophilic groups; immunosuppressive agents selected from cyclosporine, azathioprine, and methotrexate; anti-inflammatory glucocorticoids, e g., dexamethasone; broad-spectrum antiparasitic antibiotics, e.g., the avermectins and the milbemycins; penicillamine; hydroxychloroquine; the anti-gout agent colchicine; the xanthine oxidase inhibitor allopurinol; and uricosuric agents selected from probenecid, sulfinpyrazone, and benzbromarone; and  
 (C) in combination with therapeutic agents intended for the treatment of disease conditions, syndromes and symptoms found in older mammals, comprising one or more members selected from the group consisting essentially of cognitive therapeutics to counteract memory loss and impairment, antidyskinetic/antiparkinsonian agents, e g., selegeline; cardiovascular drugs intended to offset the consequences of atherosclerosis, including hypertension, myocardial ischemia including angina, congestive heart failure, and myocardial infarction, selected from diuretics, vasodilators, β-adrenergic receptor antagonists, angiotensin-II converting enzyme inhibitors (ACE-inhibitors) used to treat geriatric mammals with mitral insufficiency, enalapril alone and in combination with neutral endopeptidase inhibitors, angiotensin II receptor antagonists, renin inhibitors, calcium channel blockers, sympatholytic agents, α 2 -adrenergic agonists, a-adrenergic receptor antagonists, and HMG-CoA-reductase inhibitors (anti-hypercholesterolemics); antineoplastic agents; antimitotic drugs including vinblastine and vincristine; growth hormone secretagogues, strong analgesics, local and systemic anesthetics; and H 2  -receptor antagonists and other gastroprotective agents  
 
     
     
         12 . A package suitable for use in commerce for treating or preventing the early stages of degeneration of articular cartilage or subchondral bone in one or more joints of a mammal in need of such treatment, comprising a suitable outer carton and an inner container removably housed therein; enclosed in said container a suitable dosage form of a chondroprotective compound of Formula (I) according to  claim 1 , and associated with said carton or container printed instructional and informational material, which is attached to said carton or to said container enclosed in said carton, or displayed as an integral part of said carton or container, said instructional and informational material stating in words which convey to a reader thereof that said active ingredient, when administered to a mammal in the early stages of degeneration of articular cartilage or subchondral bone in one or more joints thereof, will ameliorate, diminish, actively treat, reverse or prevent any injury, damage or loss of articular cartilage or subchondral bone subsequent to said early stages of said degeneration.