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Use of an Antidiarrheal for the Manufacture of a Medicament for the Treatment of Inflammatory Conditions

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Use of an Antidiarrheal for the Manufacture of a Medicament for the Treatment of Inflammatory Conditions ^ ^ ^ ^ I ^ ^ ^ ^ ^ ^ II ^ ^ ^ II ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ I ^ European Patent Office Office europeen des brevets EP 0 937 460 A2 EUROPEAN PATENT APPLICATION (43) Date of publication: (51) |nt C|.6: A61 K 31/445 25.08.1999 Bulletin 1999/34 (21) Application number: 99201333.4 (22) Date of filing: 11.04.1995 (84) Designated Contracting States: (72) Inventor: Mak, Vivien Hw. AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL Menlo Park, CA 94025 (US) PT SE (74) Representative: (30) Priority: 12.04.1994 US 225991 Crump, Julian Richard John et al 06.07.1994 US 271287 FJ Cleveland, 03.03.1995 US 400234 40-43 Chancery Lane London WC2A1JQ(GB) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: Remarks: 95917009.3 /0 757 558 This application was filed on 28 - 04 - 1999 as a divisional application to the application mentioned (71) Applicant: Adolor Corporation under INID code 62. Malvern, PA 19355 (US) (54) Use of an antidiarrheal for the manufacture of a medicament for the treatment of inflammatory conditions (57) The present invention provides the use of an the treatment of a pathological condition mediated by antidiarrheal for the manufacture of a medicament for TNF production in a mammal, wherein the pathologic condition is an inflammatory one. CM < O CO ^> Is- CO O) o a. LU Printed by Jouve, 75001 PARIS (FR) EP 0 937 460 A2 Description [0001] This application is a continuation-in-part of Serial No. 08/271 ,287, filed July 6, 1 994, which is a continuation- in-part of Serial No. 08/225,991 , filed April 12, 1994, the full disclosures of which are incorporated herein by reference. 5 FIELD OF THE INVENTION [0002] The present invention relates to the field of inflammation and immunology. More particularly, the present invention provides screening methods for the identification of agents which are capable of suppressing cytokine pro- 10 duction. Additionally, the present invention provides compositions which are useful as medicaments in the treatment of a variety of acute and chronic, systemic or skin conditions having an inflammatory and/or immunological component. BACKGROUND OF THE INVENTION 75 [0003] Inflammation represents a cascade of physiological and immunological reactions that nature has designed as the first cellular response to noxious stimuli in an effort to localize toxic materials or prevent tissue injury. Clinically, inflammation is a primary disease under acute conditions or is a manifestation of underlying pathophysiological abnor- malities in chronic disease, characterized by classic signs of redness, pain, swelling and loss of function. Inflammatory diseases are a significant cause of morbidity and mortality in humans. 20 [0004] Regardless of the etiology, most forms of inflammation are propagated as a result of the recruitment of humoral and cellular components of the immune system. Current research indicates that a class of proteins known as cytokines, products of immune-competent cells including macrophages, T-lymphocytes, endothelial cells, etc., are crucial in the initiation and maintenance of inflammation. Cytokines are small- to medium-sized (usually less than 30 kDa), hormone- like proteins governing numerous biological responses such as cell growth, cell maturation, and defense against in- 25 fection. The major cytokines include interferons (IFNs), colony stimulating factors (CSFs), interleukins (ILs), and tumor necrosis factors (TNF and lymphotoxin). Due to their unique biological and extremely potent pharmacological proper- ties, several cytokines have also been considered as therapeutic agents since their discovery in the 1950s. The im- portance of cytokines biologically and as potential therapeutic agents is well-recognized by the medical and pharma- ceutical communities. 30 [0005] With respect to inflammation, TNF, IL-1 and IL-8 have all been characterized as proinflammatory cytokines. The release of these cytokines triggers a cascade of multiple cellular and molecular events including the expression of adhesion molecules, i.e. intercellular adhesion molecule-1 (ICAM-1), E-selectin, etc., the production of secondary inflammatory mediators (prostaglandins, leukotrienes), and growth factors (transforming growth factor alpha, TGF-a). Under acute inflammatory conditions (e.g., endotoxemia), it is well known that TNF is one of the earliest mediators 35 produced, appearing earlier than IL-1 or other cytokines (see, Michalek, etal., J. Inf. Dis. 141:55-63 (1980); Freuden- berg, etal., Inf. Immun. 51:891-895 (1986); Beutler, etal., J. Immunol. 135:3972-3977 (1985) and Fong, etal., J. Exp. Med. 170:1627-1633 (1989)). Furthermore, administration of TNF to animals reproduces the pathologic effects of en- dotoxin (see Tracey, etal., Surg. Gyn. Obstet. 164:415-422 (1987) and Tracey, etal., Science 234:470-474 (1986)). In other correlative studies, the level of TNF observed is a predictive indicator of the outcome in endotoxin shock (see 40 Waage, etal., Lancet (1)8529:355-357 (1987)). There are significant overlaps between the current understanding of the pathophysiology leading to the development of acute skin disorders and acute systemic inflammatory conditions like endotoxemia. In both scenarios, TNF production by hematopoietic cells is the primary event which initiates and orchestrates the inflammatory cascade. [0006] In chronic inflammatory conditions, elevated tissue levels of several mediators including the cytokines IL-1, 45 IL-8, GM-CSF, and TNF have been found in the inflamed joints of patients with rheumatoid arthritis (RA) (see Yocum, etal., Cellular Immunol. 122:131-145 (1989) and Hopkins, etal., Clin. Exp. Immunol. 73:88-92 (1988)). With synovial culture systems, it was demonstrated that TNF regulated the production of GM-CSF and IL-1 in addition to expression of more TNF receptors making TNF seminal in this disease pathogenesis. Similarly, there is an increased level of TNF in the intestinal mucosa (Olson, etal., J. Pediatric Gastroenterology and Nutrition 16:241 -246 (1993)) and in the feces so (Nicholls, etal., J. Clin. Pathol. 46:757-760 (1993)) in patients with inflammatory bowel diseases (IBD, includes Crohn's disease and ulcerative colitis). While it is generally recognized that chronic inflammation is a complex cellular and molecular event, it has been suggested that cytokine mediators do not act in parallel, but in series. This view has been verified recently by clinical results demonstrating a clear resolution of both severe RA (Elliott, etal., Arthritis and Rheu- matism 36:1681-1690 (1993)) and IBD upon administration of anti-TNF antibody. Thus, TNF is found to be the key 55 mediator in these two diseases and, in various other inflammatory conditions including psoriasis, asthma, cancer, infection, and cachexia associated with AIDS and cancer. [0007] In principle, the inflammatory response can be regulated through the use of drugs. Unfortunately, anti-inflam- matory drugs presently available produce cytotoxic effects which reflect their initial employment as cancer chemother- 2 EP 0 937 460 A2 apeutics, typically anti-neoplastics. Such drugs effectively kill cells indiscriminately. Corticosteroids are also mainstay anti-inflammatory agents but manifest significant adverse effects, such as inducing Cushingoid features, skin thinning, increased susceptibility to infection, and suppression of the hypothalamic-pituitary-adrenal axis. The use of other im- munosuppressive agents such as cyclosporin A also may induce the development of severe side effects, e.g., hyper- 5 tension and nephrotoxicity. [0008] What is needed in the art are new and more effective methods of treating inflammation which specifically target TNF production and which carry fewer significant and undesirable side effects. Methods which suppress TNF production will find application not only in inflammation of the skin, but also in systemic inflammation. Surprisingly, the present invention provides such methods of suppressing TNF production and treating inflammation. 10 BRIEF DESCRIPTION OF THE DRAWINGS [0009] Figure 1 illustrates the ability of verapamil to suppress inflammation in TPA-treated mouse skin. [0010] Figure 2 illustrates the ability of loperamide to suppress inflammation in TPA-treated mouse skin. is [0011] Figure 3 illustrates the ability of verapamil to suppress inflammation in DNCB-treated mouse skin. [0012] Figure 4 illustrates the ability of amiloride to suppress inflammation in DNCB-treated mouse skin. [0013] Figure 5 illustrates the ability of verapamil to suppress TNF expression in a skin inflammation model in man. [0014] Figure 6 illustrates the ability of verapamil to suppress epidermal swelling in a skin inflammation model in man. 20 SUMMARY OF THE INVENTION [0015] The present invention provides screening assays to identify new immune modulating agents, compounds which are effective immune modulating agents and compositions and methods for modulating the inflammatory re- sponse. 25 [0016] In one embodiment, the present invention provides a method of screening for skin immune or inflammation modulating agents. In this method, keratinocytes are stimulated to produce at least one cytokine or MHC Class II molecule. A portion of the keratinocytes are then exposed to a putative skin inflammation modulating agent, and a determination is made as to whether the putative agent is effective to modulate the production of the cytokine or MHC Class II molecule in the exposed keratinocytes as opposed to keratinocytes not exposed to the agent. 30 [0017] In a preferred embodiment, the determination
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