NEW USE OF PROSTAGLANDIN BIOSYNTHESIS INHIBITORS

Abstract: A use of prostaglandin biosynthesis inhibitor for the manufacture of a medicament for the treatment of the diseases caused by the AIDS virus.

Description: The present invention relates to the use of prostaglandin biosynthesis inhibitors for the prevention and therapy of AIDS (acquired immunodeficiency syndrome). World-wide interests have been focused on AIDS due to its unfavorable prognosis. It is a clinical syndrome known to occur more frequently among the male homosexuals, and is characterized by the clinical syndromes such as pnemocystis carinii pneumonia and Kaposi's sarcoma, and induces a high mortality of more than 70 % by disregulation of the immune system. It is also known that helper-T cells are specifically destroyed by the infection of the AIDS virus (e.g. HTLV-III). As a result of the extensive study on the properties of the AIDS viruses, the present inventors have found that prostaglandins E₂ and D₂ accelerate the proliferation or replication of the AIDS virus. (Proc. Natl. Acad. Sci. USA, 83 , 3487 - 3490, May, 1986). In view of this fact, the present inventors have thought of a possibility of inhibiting the replication of AIDS viruses by inhibiting, conversely, the biosynthesis of prostaglandins. Based on the above thought, the present inventors have conducted an experiment to see if Diclofenac sodium, one of the non-steroidal anti-inflammatory substances, would inhibit the replication of AIDS viruses. As a result, it has been confirmed that the replication of the virus is inhibited in vitro when the above substances are incubated with AIDS virus producing cells. It has also been confirmed that other non-steroidal anti-inflammatory substances exhibit similar activities. The present invention has been completed on the basis of such findings. It is well known that prostaglandins are biosynthesized in a living body from arachidonic acid which is released from arachidonic acid-fatty acid phospholipoglyceride by phospholipase, and which is cyclized by the action of cyclooxygenase to form prostaglandins. The over-all process of biosynthesis of prostaglandins and related compounds is called "arachidonic acid cascade" (see Kirk-Othmer Encyclopedia of Chemical Technology, 3rd Ed., Supplement Volume, 1984, pages 714-719, John Willy & Sons, New York, U.S.A). It is also known that the latter process, i.e., the conversion of arachidonic acid to prostaglandins, is inhibited by non-steroidal anti-inflammatory substances (see. for example, Modern Chemistry (Gendai Kagaku), Extra Edition 1, "Prostaglandins And Pathema" (Purosutaguranzin To Byotai) pages 29 and 52). In one aspect, the present invention provides a use of a prostaglandin biosynthesis inhibitor for the manufacture of a medicament for the treatment of infection by the AIDS virus. BRIEF EXPLANATION OF THE DRAWINGS Figures 1 and 2 show the viable cells(%) of the AIDS virus-infected established cell line Molt-4/HTLV-III cells and the non-infected established cell line Molt-4 cells, respectively, with or without the addition of Diclofenac sodium. The term "treatment" herein is intended to cover all the controls of the disease including prevention, sustention (i.e. prevention of aggravation), reducing (i.e. alleviation of conditions) and therapy. The term "AIDS" is intended to cover all diseases resulting from the infection of so-called AIDS viruses(e.g. HTLV-III, LAV1, LAV2, ARV). In the biosynthesis,of prostaglandins (to be abbreviated as PG), it is known that arachidonic acid is converted firstly into PGG₂ by the action of cyclooxygenase, and said PGG₂ in turn is converted into PGH₂ and further to PGD₂, PGE₂ PHI₂, etc. Therefore, if the first step of this cascade is inhibited, the biosynthesis of prostaglandins would be entirely inhibited. Accordingly, the term "prostaglandins" to be referred to in the phrase as "prostaglandin biosynthesis inhibitors(s)" used herein is intended to include all prostaglandins which may be biologically synthesized. The term "prostaglandin biosynthesis inhibitors" used herein includes compounds which inhibit the formation of arachidonic acid from arachidonic acid glyceride (phospholipase inhibitor) and those which inhibit the formation of prostaglandin from arachidonic acid. The former includes lipomodulin(also known as macrocortin, or lipocortin), a kind of protein, and the latter includes non-steroidal anti-inflammatory substances (especially acidic ones). Specific examples of the latter are salicylic acid derivatives such as acetylsalicylic acid, salicyl salicylic acid and DL-lysine monoacetyl salicylate, pyrazolone derivatives such as Phenopyrazone, Nifenazone, Phenylbutazone, Oxyphenbutazone, Ketophenylbutazone, Clofezone and Difenamizole, anthranilic acid derivatives such as Mefenamic acid, Fulfenamic acid and Niflumic acid, phenyl acetic acid derivatives such as Diclofenac, Ibufenac, Ibuprofen, Alclofenac, Kotoprofen, Fenbufen and Flurbiprofen, indol or indazole derivatives such as Indomethacin, Sulindac and Benzydamine, and further Naproxen, Tiaramide, Bucolome, Metopyrimazole and Azapropazone and their salts. The dosage of the above prostaglandin biosynthesis inhibitor to be administered may be approximately the same as that used generally in the anti-inflammatory therapy. For example for salicylic acid agent, 0.5 - 5 g/day, for pyrazolone derivative, 0.1 - 2 g/day, for anthranilic acid derivative, 0.3 - 2 g/day, for phenyl acetic acid derivative, 0.2 - 3 g/day, and for indole derivative, 0.2 - 2 g/day, may be administered in 1 - 4 divisions a day, or as a sustained release formulation. The administration route may be optional such as peroral, rectal and by injection and suitably selected according to the effective ingredient. For administration, the effective ingredient may be mixed with a pharmaceutical carrier such as organic or inorganic solid or liquid excipient, e.g., suitable for oral administration, intrarectal administration or injection, and administered in the form of the conventional pharmaceutical preparation. Such a preparation includes solids (e.g., tablet, granule, powder and capsule) and liquids (e.g., liquid, emulsion and suspension). The above carriers include starch, lactose, glucose, sucrose, dextran, cellulose, paraffin, fatty acid glyceride, water, alcohol and gum arabic. If necessary, auxiliary, stabilizer, wetting agent, emulsifier, lubricant, binder, and other conventional additives may be added. The present invention is illustrated in further detail by way of Examples. Example 1 Diclofenac sodium 25 mg Magnesium stearate 5 mg Corn starch 20 mg Lactose 150 mg The above ingredients are mixed and pressed into tablets according to the conventional procedure. Example 2 Indomethacin 25 mg Magnesium stearate 2 mg Lactose 223 mg The above ingredients are mixed and filled in hard gelatine capsules. Example 3 Oxyphenbutazone 50 mg Fatty acid glyceride 1950 mg The above ingredients are melted and mixed according to the conventional procedure to make suppositories. Example 4 Mefenamic acid 250 mg Magnesium stearate 5 mg Lactose 230 mg Corn starch 15 mg The above ingredients are mixed and filled in hard gelatine capsules. Example 5 DL-Lysine monoacetyl salicylate 900 mg Glycine 100 mg Calcium chloride 50 mg The above ingredients are filled in vials according to the conventional procedure to make intravenous injections. Example 6 The cell line Molt-4, established from the lymphocytes of a patient of human acute lymphatic leukemia is susceptible to HTLV-III. The cell line Molt-4/HTLV-III, established from Molt-4 cells infected with HTLV-III, can continuously produce viruses during cell proliferation. This viral producer cells Molt-4/HTLV-III were cultured in a medium containing 100µM Diclofenac sodium. In this experiment, the viability of the viral producer cells decreased markedly and on day 4 almost all cells were killed as shown in Fig. 1. In a control without Diclofenac sodium, hardly any change was seen in cell viability. In contrast to the results shown in Fig. 1, Fig 2 indicates that the viability of Molt-4 cells (HTLV-III uninfected) was not changed irrespective of presence or absence of Diclofenac sodium. The above results demonstrate that Diclofenac sodium shows cytotoxicity specifically to the cells infected with the AIDS virus, and accordingly is usable for the treatment of AIDS.

Claims: The use of a prostaglandin biosynthesis inhibitor for the manufacture of a medicament for the treatment of infection by the AIDS-virus. The use according to claim 1, wherein the prostaglandin biosynthesis inhibitor is a cyclooxygenase inhibitor. The use according to claim 1 or 2, wherein the prostaglandin biosynthesis inhibitor is a non-steroidal anti-inflammatory active substance. The use according to anyone of claims 1 to 3 wherein the prostaglandin biosynthesis inhibitor is a phenylacetic acid derivative. The use according to anyone of claims 1 to 4, wherein the prostaglandin biosynthesis inhibitor is Diclofenac or a pharmaceutical acceptable salt thereof.

Inventors: HAYAISHI,OSAMU, KUNO, SACHIKO, UENO, RYUJI
Applicants: JAPAN RES DEV CORP, UENO SEIYAKU KK
Application year: 1987
Main classification: A61K31
IPC codes: G01N33, A61K38, A61P29, A61K31, A61P43, A61P31, A61K45, A61P37