Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1994-12-06
1996-04-09
Criares, Theodore J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
560 56, 560 10, A61K 3119, C07C32100, C07C 6976
Patent
active
055062652
DESCRIPTION:
BRIEF SUMMARY
This application is filed under 35 USC 371 of PCT/DE93/00013 filed Jan. 9, 1995.
This invention relates to agents for the treatment of multiple sclerosis, a primary inflammatory disease of the central nervous system with localized demyelination.
The agents contain prostacyclin and carbacyclin derivatives and common auxiliary agents and vehicles. The invention also relates to the use of these prostacyclin and carbacyclin derivatives for the production of the above-mentioned agents.
The pharmacological effects of prostacyclin and carbacyclin derivatives, which can be mainly attributed to their cardiovascular and thrombocyte aggregation-inhibiting action, are already known from EP 11591, EP 55208, EP 99538, EP 119949 and EP 84856. It has been found that agents containing prostacyclin and carbacyclin derivatives are suitable for the treatment of multiple sclerosis which is accompanied by various neurological symptoms with a primarily intermittent course, partial remission but chronic progression.
The salts of these prostacyclin and carbacyclin derivatives with physiologically well tolerated bases and their .beta.-cyclodextrin clathrates can also be used for the treatment of the above-mentioned disease.
Multiple sclerosis always has a chronic, recurrent course. The association with immunological defects can be attributed to both the T cell level (W. W. Tourtellotte et al., J. Neuroimmunol 1988; 20:217-27) and the B cell level (B. H. Waksman et al.; Proc. Soc. Exp. Biol. Med. 1984, 175:282-94). In the active foci in the brain, in most cases perivascularly located, dense cellular infiltrates consisting of lymphocytes and macrophages, with at the same time selective demyelination (later gliosis-like scarring) have been described histologically (S. L. Hauser et al.; Ann Neurol 1968, 19:578-87).
Both cell types secrete a tumor necrosis factor (TNF.alpha.), a cytokine which is an important mediator in primary inflammatory diseases including those in the central nervous system area (M. M. Mustafa et al.; Pediatr. Infect Dis. J. 1989; 8:907-7; M. M. Mustafa et al.; J. Pediatr. 1989; 115:208-13; M. Mintz et al.; Am. J. Dis. Child 1989; 143:771-4). K. W. Selmaj et al.; Ann. Neurol. 1988; 23:339-46 report that TNF.alpha. can induce a selective cytotoxicity with respect to oligodendrocytes and the myelin sheath "in vitro". A clinical study of 32 patients (M. K. Sharif et al.; New Engl. J. of Med. Vol. 325, 7 476-470) shows that an elevated TNF synthesis takes place intrathecally in patients with M.S. and that the TNF.alpha. level of the cerebrospinal liquor is correlated with the severity and progression of the disease.
Surprisingly, it has now been found that the above-mentioned prostacyclin and carbacyclin derivatives, as a function of dosage, inhibit the synthesis of TNF at the TNF-messenger RNA stage.
Prostacyclins and carbacyclins inhibit TNF synthesis on the mRNA level. Thus they are preferable as therapeutic agents to monoclonal antibodies, which are aimed only TNF that is already present. The monoclonal antibodies act only on already secreted TNF. The TNF-.alpha.TNF immunocomplexes that are formed must, in turn, be catabolized, which can lead to clinical complications. In addition, the above-mentioned prostacyclins and carbacyclins are used prophylactically in cases involving these diseases; this cannot be done with monoclonal antibodies.
The advantage of the new agents over PGE.sub.2 lies in the marked reduction of side-effects. PGE 2 causes, e.g., itself fever, leads to elevated constriction of the smooth muscles and, in addition, has an abortive action. By contrast, the new agents exert a vessel-protective and antiedematous effect.
Iloprost, Cicaprost, Eptaloprost, Beraprost, and Ciprosten have proved to be especially suitable prostacyclin and carbacyclin derivatives.
Inorganic and organic bases are suitable for forming salts with the free acids as they are known to the specialist for the formation of physiologically well-tolerated salts. Alkali hydroxides, such as sodium hydroxide and potassium hydroxide, alkal
REFERENCES:
patent: 4788319 (1988-11-01), Hazato et al.
Sharief et al., "Association Between Tumor Necrosis Factor-alpha and Disease Progression in Patients with Multiple Sclerosis," The New England Journal of Medicine, vol. 325, No. 7, Aug. 15, 1991, pp. 467-472.
R. Benvenuto et al., "Increased Synthesis of Tumor Necrosis Factor by Cerebrospinal Fluid Derived T-Cell Clones from Patients with Multiple Sclerosis," J. Neurol., vol. 237, No. SUP1, 1990, p. 83.
Sliwa et al., "Prevention of Murine Cerebral Malaria by a Stable Prostacyclin Analog," Infection and Immunity, vol. 59, No. 10, Oct. 1991, pp. 3846-3848.
Kirby et al., "Prostacyclin Increases Cyclic-Nucleotide Responsiveness of Lymphocytes from Patients with Systemic Sclerosis," The Lancet, vol. 2, No. 8192, Aug. 30, 1980, pp. 453-454.
Criares Theodore J.
Schering Aktiengesellschaft
LandOfFree
Prostacyclin and carbacyclin derivatives as agents for the treat does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Prostacyclin and carbacyclin derivatives as agents for the treat, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Prostacyclin and carbacyclin derivatives as agents for the treat will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-139589