US 2005.0049256A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0049256A1 LOrton et al. (43) Pub. Date: Mar. 3, 2005 (54) TREATMENT OF INFLAMMATORY Publication Classification AUTOIMMUNE DISEASES WITH ALPHA-ADRENERGIC ANTAGONSTS AND BETA-ADRENERGICAGONSTS (51) Int. Cl." ...................... A61K 31/517; A61K 31/137 (76) Inventors: Dianne Lorton, Avondale, AZ (US); (52) U.S. Cl. ..................... 514/252.17; 514/649; 514/651 Cheri Lubahn, Glendale, AZ (US) Correspondence Address: JENNINGS, STROUSS & SALMON, P.L.C. (57) ABSTRACT 201 E. WASHINGTON ST, 11TH FLOOR PHOENIX, AZ 85004 (US) The present invention discloses a novel compound and (21) Appl. No.: 10/928,437 method for the treatment of inflammatory autoimmune dis eases, for example, rheumatoid arthritis, using C.-adrenergic (22) Filed: Aug. 27, 2004 antagonists and B-adrenergic agonists in combination. Treat ment of animals, namely humans, with an O-adrenergic Related U.S. Application Data antagonist, preferably, phentolamine, and a B-adrenergic agonist, preferably terbutaline, in combination can Signifi (60) Provisional application No. 60/498.367, filed on Aug. cantly Suppress the joint destruction and inflammation due to 27, 2003. disease in these animals. Patent Application Publication Mar. 3, 2005 Sheet 1 of 5 US 2005/0049256A1 Patent Application Publication Mar. 3, 2005 Sheet 2 of 5 US 2005/0049256A1 e \ s o o (ulu) pA ped)00 IBuedos. IOC Patent Application Publication Mar. 3, 2005 Sheet 3 of 5 US 2005/0049256A1 as o N w N o et N O CY) c5 O t al L cN Y D. a s t is r s re y (uu) supW pedoo Patent Application Publication US 2005/004925.6 A1 |0*>d 0|| eIOOS 3 guide foupe Patent Application Publication Mar. 3, 2005 Sheet 5 of 5 US 2005/0049256A1 w { Z w t n e (%) (Sudawn,0A US 2005/0049256 A1 Mar. 3, 2005 TREATMENT OF INFLAMMATORY DMARDS. Use of one second-line drug followed by another AUTOIMMUNE DISEASES WITH once the drug being used is no longer effective or is not ALPHA-ADRENERGIC ANTAGONSTS AND tolerated well by the patient, is most widely practiced by BETA-ADRENERGICAGONSTS rheumatologists. Methotrexate and other immunosuppres Sive drugs, Such as cycloSporin and leflunomide were major CLAIM TO DOMESTIC PRIORITY advancements of the 1980s in treating rheumatoid arthritis. Methotrexate is currently the gold standard for treatment of 0001. This Application claims the benefit of priority of aggressive rheumatoid arthritis. However, its effectiveness U.S. Application Ser. No. 60/498.367, filed Aug. 27, 2003. wanes over time and can cause troublesome side effects, including liver damage, Sepsis, Severe anemia and bleeding. FIELD OF THE INVENTION 0007. The approved immunosuppressive drug, lefluno 0002 The present invention relates to an improved mide, was introduced for treating rheumatoid arthritis. This method for the treatment of inflammatory autoimmune dis drug relieves joint tenderneSS and Swelling, decreases joint ease, and more Specifically to a treatment for inflammatory pain and reduces indicators of global disease activity. While autoimmune disease, including rheumatoid arthritis, using leflunomide does not make patients more Susceptible to C.-adrenergic antagonists and B-adrenergic agonists in com infections, it can cause hair loSS, weight loss, hypertension, bination. diZZiness, and gastrointestinal Side effects. Advances in management of rheumatoid arthritis include the use of BACKGROUND OF THE INVENTION corticosteroids as anti-inflammatory and immunosuppres Sive agents. The main disadvantage of corticosteroids is that 0003 Rheumatoid arthritis (RA) is a chronic inflamma long-term use is limited due to adverse effects including tory autoimmune disease of the joints, producing pain and Weight gain, hyperglycemia, cataracts, Osteoporosis, and ultimate destruction of the joints. Rheumatoid arthritis is characterized by a chronic inflammatory response in the Stomach ulcers. joint that is directed by macrophages and T cells which 0008 Thus, treatment for patients with rheumatoid arthri invade affected joints. Production of proinflammatory cytok tis is imperfect. Accordingly, there is an urgent need for ines and other immune cell mediators by these immune cells treatments which have few if any side effects and that will results in the development of a proliferative invasive con be effective in Suppressing not only the inflammation but nective tissue derived from the Synovial membrane and its also prevent the bone and cartilage degeneration associated microvasculature that slowly erodes away the cartilage and with rheumatoid arthritis. bone tissues of joints. SUMMARY OF THE INVENTION 0004. While destruction of joint tissue is the most com mon feature of RA, the disease can exhibit significant 0009. The present invention discloses a method for the extra-articular manifestations, including cutaneous lesions, treatment of inflammatory autoimmune diseases by admin vasculitis, blood abnormalities, peripheral neuropathy, peri istering B-adrenergic agonists in combination with C.-adren carditis, arteritis of the Viscera, and pulmonary disease. This ergic antagonists. The present invention further discloses a indicates that RA is a Systemic disease that affects the compound useful in treating inflammatory autoimmune dis connective tissueS of major organs Systems. The Specific eases comprising B-adrenergic agonists in combination with etiology of RA remains elusive. Dysregulation of both C.-adrenergic antagonists. cell-mediated and humoral immunity are associated with 0010. In certain embodiments, the present invention con RA. The pathophysiology of RA intimately involves defects cerns a compound and method for treating rheumatoid in immune cell regulation. Although the exact mechanisms arthritis or other autoimmune diseases, Such as inflammatory have not been delineated, the functional activities of mac bowel disease, Krohn's disease, thyroiditis, fibromyalgia, rophages, B cells and T cells from both the joint and Systematic erythermatus, lupus, chronic fatigue Syndrome, lymphoid tissue are affected. and Type 1 diabetes, by the application of a therapeutically 0005. Unfortunately, current treatment strategies for RA effective dose of a f-adrenergic agonist, preferably a f-adr and other inflammatory autoimmune diseases are relatively energic agonist Such as terbutaline, coupled with a thera ineffective in preventing bone destruction. Conventional peutically effective dose of an O-adrenergic antagonist, anti-rheumatic drugs are classified into anti-inflammatory preferably C-, C., and C2-adrenergic receptor Subtypes Such drugs, Slow-acting drugs and corticosteroids. Only the slow as phentolamine, praZosin or yohimbine, to human Subjects acting drugs are thought to be capable of modifying the with the disease. Therapeutically effective doses of particu disease course of rheumatoid arthritis and are referred to as lar agonists or antagonists and the frequency of dosage disease modifying anti-rheumatic drugs (DMARD). Drugs administration are to be determined according to protocols from each of these classes are currently being used for understood by those skilled in the art. treatment of rheumatic diseases. Of these, the central focus 0011. Other B-adrenergic agonists useful in this novel has been and remains the DMARDS and nonsteroidal anti method of treatment include: metaproterenol, albuterol, iso inflammatory drugs (NSAID). NSAIDs effectively abolish etharine, pributerol, bitolterol, ritodrine, and Salmeterol. the Signs and Symptoms of joint inflammation and reduce Other C.-adrenergic antagonists useful in this novel method pain. They are not effective in preventing bone and cartilage of treatment include: yohimbine, regitine, prazosin, dox loss. The value of NSAIDs for treating rheumatic diseases is aZosin, tamsulosin, teraZosin, octopamine, phenoxyben limited by their side effects. Zamine, phentolamine, hydrochlorothiazide, 5-methyl ura 0006 Aggressive rheumatoid arthritis or early onset of pidil, chloroethylclonidine, bunazosin, alfuzosin, RS17053, joint destruction indicates the need for rapid treatment with BMY 7378, urapidil, L-765,314, nicergoline, ABT-866, US 2005/0049256 A1 Mar. 3, 2005 cyclazosin, A322312, A 119637, fiduxosin, JTH-601, imi 0018 FIG. 2 is a graph depicting the decreased dor loxan, 2 idopropoxyidazoxan, 2-methoxyidazoxan (RX Soplantar Swelling by day 28 in animals treated with vehicle, 821002), idazoxan, piperoxan, BRL 44408, beditin, atipam phentolamine and/or trebutaline. eZole, rawolscine, ARC 239, RS-79948, MK912, RS 79948, 0019 FIG. 3 illustrates the results of continuous treat UIC 14304 and ethoxyidazoxan. ment with vehicle, combination phentolamine/terbutaline, 0012. The f-adrenergic agonists and C.-adrenergic combination yohimbine/terbutaline or combination pra antagonists of the present invention may be administered to ZoSine/terbutiline drug therapies from initiated at disease a patient in a dosage form Selected from the group consisting onset, day 12 post-CFA challenge, and continued through of pills, tablets, capsules, caplets, Solutions, Suspensions, day 28, that reduced dorsoplantar footpad widths in arthritic Syrups, Suppositories, and aerosols. Additionally, the dosage rats when compared with vehicle treated controls. of the ?- (or f3-) and C.- (or C- or Cl-) adrenergic agonist 0020 FIGS. 4A-E shows the radiographic analysis of and antagonist, respectively, used may be in a Sustained ankle joints treated with vehicle and adrenergic drug com release form. The dosage form of the B-adrenergic agonist