(12) United States Patent (10) Patent No.: US 8.242,110 B2 Deregnaucourt Et Al
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USOO824211 OB2 (12) United States Patent (10) Patent No.: US 8.242,110 B2 Deregnaucourt et al. (45) Date of Patent: Aug. 14, 2012 (54) USE OF ANTIHISTAMINEAGENTS FOR THE FOREIGN PATENT DOCUMENTS PREVENTIVE OR EARLY TREATMENT OF FR 2802 101 A1 6, 2001 INFLAMMATORY SYNDROMES, IN JP 4-89428 A 3, 1992 PARTICULAR THOSE TRIGGERED BY JP 2001-151677 A 6, 2001 TOGAVIRUSES WO WO-96,04787 A1 2, 1996 (75) Inventors: Jean Deregnaucourt, Paris (FR): OTHER PUBLICATIONS Etienne Andre, Seyssinet-Pariset (FR): Wilson, Annals of Rheumatic Diseases, 1953; 12(1):38-39.* Jacky Tisne-Versailles, Castres (FR) Storms, Journal of Allergy and Clinical Immunology, 2004; 114:S146-153.* (73) Assignee: Pierre Fabre Medicament, Satake et al., Journal of Cardiovascular Pharmacology, Boulogne-Billancourt (FR) 1994:23(4):669-673 (abstract only).* Toovey et al., Travel Medicine and Infectious Disease, vol.2, No. 3-4, (*) Notice: Subject to any disclaimer, the term of this 2004, pp. 189-191. patent is extended or adjusted under 35 Suhrbier et al., Current Opinion in Rheumatology, vol. 16, No. 4. U.S.C. 154(b) by 809 days. 2004, pp. 374-379. Stocks et al., Australian Family Physician, vol. 26, No. 6, Jun. 1997. (21) Appl. No.: 12/224,830 pp. 710-717. Paganin et al., Presse Medicale 2006, vol. 35. No. 4 II, 2006, pp. (22) PCT Filed: Mar. 9, 2007 641-646. Ware et al., Medical Care, vol. 34, No. 3, 1996, pp. 220-233. (86). PCT No.: PCT/EP2007/052237 Bruce et al., The Journal of Rheumatology, vol. 30, No. 1, 2003, pp. S371 (c)(1), 167-178. (2), (4) Date: Oct. 8, 2008 * cited by examiner (87) PCT Pub. No.: WO2007/101884 PCT Pub. Date: Sep. 13, 2007 Primary Examiner — San-Ming Hui (74) Attorney, Agent, or Firm — Birch, Stewart, Kolasch & (65) Prior Publication Data Birch, LLP US 2009/OO693O8A1 Mar. 12, 2009 (57) ABSTRACT (30) Foreign Application Priority Data The present invention relates to the use of at least one anti Mar. 9, 2006 (FR)...................................... O6 O2O87 histamine agent for the preparation of a medicament for use in the preventive or early treatment of inflammatory syndromes (51) Int. Cl. of viral origin, in particular arthritis of the distal joints, more A6 IK3I/54 (2006.01) particularly those triggered by togaviruses. The invention (52) U.S. Cl. .................................................... S14/227.8 also relates to a combination product of at least one antihis (58) Field of Classification Search ................ 514/227.8 tamine agent and of at least one antiserotonin agent for its See application file for complete search history. simultaneous, separate or sequential use in preventive or early therapy for inflammatory syndromes of viral origin, in par (56) References Cited ticular arthritis of the distal joints, more particularly those triggered by togaviruses. U.S. PATENT DOCUMENTS 3,726,976 A * 4, 1973 Glasser ......................... 514, 186 6,720,318 B2 4/2004 Dib et al. 12 Claims, No Drawings US 8,242,110 B2 1. 2 USE OF ANTHSTAMINEAGENTS FOR THE or viral infections. Acute infectious arthritis is generally of PREVENTIVE OR EARLY TREATMENT OF bacterial or viral origin. With regard to bacterial arthritis, the INFLAMMATORY SYNDROMES, IN bacteria involved are gonococchi, staphylococci, strepto PARTICULAR THOSE TRIGGERED BY cocci, pneumococci, Haemophilus, Spirochetes. Non-gono TOGAVIRUSES coccal arthritis is usually caused by Staphylococcus aureus, Spirochetes, streptococci or other gram-bacteria. With The present invention concerns the novel use of antihista respect to acute viral arthritis, the chief identified causes are minic agents to prepare a medicinal product intended for the B19 parvoviruses, flaviviruses, Hepatitis B and C viruses, the preventive or early treatment of inflammatory syndromes, rubella and measles viruses, togaviruses (including alphavi more specifically in arthritis of viral origin. 10 In general, Subsequent to localized or diffuse tissue attack, ruses). Other pathologies are also associated with arthralgia whether by trauma or infection, a complex cascade of reac and arthritis. These are chicken pox, mumps, adenovirus ill tions is set up by the body to eliminate the infectious agent nesses, Coxsackie A9, B2, B3, B4 and B6 viruses, and and to initiate a repair process. This sequence of events is Epstein-Barr mononucleosis. called the inflammatory reaction and associates local phe 15 In all these situations, the infection leads to an inflamma nomena with the production of systemic signals. The trigger tory reaction at the joints following a process similar to that ing of the cascade of inflammatory reactions can have a large described above. number of causes: bacterial, viral, parasitic, mycotic, The clinical signs of infectious arthritis are joint pain and tumoral, traumatic, physical and/or immunological. The sys tumefaction at the site of inflammation. This may affect sev temic, biological and clinical anomalies ascertained at this eral joints. These signs are usually of Sudden onset, accom time form an inflammatory response syndrome. The produc panied by fever and shivering. Infections of viral origin are tion of cytokines by macrophages plays a central role in also accompanied by feelings of generalized faintness. orchestrating the mechanisms which contribute towards the Treatments currently available have recourse to non-ste setting up of an inflammatory reaction. The systemic circu roid anti-inflammatory drugs (NSAIDs) in particular to lation of the three chief cytokines of inflammation (IL1, IL6 25 relieve pain, Swelling and stiffness caused by infectious and TNFC) whose production is excessive when the inflam arthritis, but they do not contribute towards preventing joint matory response is exacerbated, leads to what is known as the lesions and their consequences. In stronger doses NSAIDs systemic inflammatory response syndrome (SIRS). also help to relieve inflammation. For infectious arthritis of The present invention more particularly concerns inflam bacterial origin antibiotics are used, but for arthritis of viral matory syndromes in which it is chiefly lesions of joint tissue 30 origin generally no medication is prescribed so as to treat the which are observed. Rheumatoid arthritis is an example cause of the pathology. In most cases the infection Subsides thereof. Other tissues may marginally be affected e.g. the spontaneously. heart, lungs, skeletal muscles, peripheral vessels or the cen There is therefore a need for active pharmacological sub tral nervous system. The aetiology of this disorder, even stances, capable of acting at an early stage even preventively, though largely researched, remains obscure. The triggering 35 to avoid the harmful consequences on the joints of the inflam factors include infectious agents, heredity, food factors, but matory process set up at the time of bacterial or viral infec also auto-immune reactions. In this latter case, the starting tions. point of response to outside attack is an antigen/antibody The Applicant has evidenced that some antihistaminic reaction leading to an immune complex which is the trigger agents can fulfill this purpose. ing factor of a sequence of biological phenomena. Alongside 40 Antihistamines are Substances which oppose the activity of this cascade of phenomena intended to combat attack, the histamine on its specific receptors, and therefore oppose the immune complexes have pathological potential. Whereas various reactions caused by this activity. These inhibitors antibodies have two combining sites with antigens for IgG only act selectively, even specifically, on a sub-type receptor, immunoglobulins or five combining sites for IgM immuno hence there are several classes of antihistamines: H1 antihis globulins, the antigens are multivalent. The complexes thus 45 tamines, H2 antihistamines, H3 antihistamines. formed at the time of this antigen/antibody association have H2 antihistamines are powerful inhibitors of gastric secre different sizes and solubilities, and their pathological poten tion, and are used for ulcer conditions and secondarily against tial depends on their relative proportions. The mechanisms gastro-oesophageal reflux and pyrosis. via which the immune complexes can lead to lesions at Some H1 antihistamines act against the vascular effects of hista tissues have been the Subject of numerous studies. In particu 50 mine and reactions of hyper-sensitivity. These are intended to lar, it has been evidenced that they can influence the release of treat the symptoms of a certain number of allergic signs, in vasoactive agents of platelets, neutrophils and mast cells, particular of the skin and mucous membrane. They are pre both by complement-dependent action and non-complement scribed for the main indications of allergic rhinitis, allergic dependent action. Amongst these agents, vasoactive amines dermatosis (papulo-Oedematous forms), Quincke oedema, increase vascular permeability, which causes extravasation 55 against the side effects of desensitisation treatment, to treat and the depositing of a large quantity of antigen/antibody serum sickness and allergic reactions to medicines. complexes at peri- and extra-vascular membranes. An inflam These anti-H1s are grouped under a classification derived matory process is then triggered if polymorphonuclear leu from their chemical structure. A distinction is made between kocytes are recruited and accumulate. Lesions may also occur five main classes: if the antigenfantibody complexes precipitate. Activation of 60 ethylene diamines the resulting complement sequence, after phagocytosis