ANTHRACYCLINE ANTIBIOTICS AS ANTI-RETROVIRAL AGENTS

Abstract: Anti-retroviral agents comprising, as active ingredient, an antibiotic of anthracycline family (e.g., daunorubicin and doxorubicin) have higher effect with less toxicity, compared with conventional anti-­ retroviral substances, such as azidothymidine and bleomycin.

Description: This invention relates to a drug for the treatment of Feline leukaemia virus. Antimonious tungstate, suramin, ribavirin, isoprinosine and azidothymidine are known as anti-retroviral agents. But all of these are unsatisfactory in terms of antiviral activity and toxicity, and there is a great demand for better anti-retroviral agents. The object of this invention is to provide new anti-retroviral agent free of the above-mentioned problems associated with the conventional agents. We discovered that antibiotics of the anthracycline family, such as daunorubicin (daunomycin), which are known to show anti-tumor activity, also have anti-retroviral activity. This invention was accomplished on the basis of these findings. Thus, this invention relates to anti-retroviral agents comprising an antibiotic of the anthracycline family as active ingredient. The anthracycline antibiotics used in this invention is daunorubicin. As stated above, this compound is commercially available as an anti-tumor agent, with the acute toxicity (LD50 value) being 14.3 to 19.0 mg/kg for daunorubicin (intraperitoneal injection in rats). The anti-retroviral agent of this invention comprise an antibiotic of the anthracycline family may be used as parenteral injections (e.g., for intramuscular and intravenous injection and for intravenous instillation), oral preparations (e.g., capsules, tablets, granules, powders and solutions), or external preparations (e.g. ointments, suppositories and tinctures). The suitable dose of the active ingredient (antibiotic of the anthracycline family) may vary with the activity, toxicity, administration method and dosage form of the compound used, the condition, sex and age of the patient and other factors, but is generally in the range of 4 to 800 mg per day for adults. The agent of this invention is effective not only for patients infected with retroviruses, but also for retrovirus carriers (those who have been infected but show no symptoms yet). The anti-retroviral agent of this invention can be prepared by usual methods using additives commonly employed in pharmaceutical manufacturing. Parenteral injections may be manufactured by charging ampules with a solution containing the active ingredient. The solution may be freeze-dried in a vial, and the frozen product is dissolved before use. Oral preparations can be manufactured by mixing the active ingredient with an excipient, stabilizer, preservative, dispersant, luburicant and other necessary components, and treating the mixture into a desired dosage form. External preparations can be manufactured by combining the active ingredient with a base material, stabilizer, preservative, surfactant and others. Described below is the anti-retroviral action of the antibiotics of the anthracycline family. Among the viruses isolated from patients infected by retroviruses are HIV (human immunodeficiency virus) and HTLV-I (human T-lymphotrophic virus-I), which are both retroviruses. Furthermore, FeLV (feline leukemia virus), which is known to cause AIDS and T-cell leukemia in cats, is also a kind of retrovirus having properties very similar to those of HTLV-I and very closely related thereto in viral taxonomy. Hence, we conducted a screening test for anti-retroviral agents using FeLV-producing cells and found that daunorubicin and doxorubicin have outstandingly high activity against retroviruses. FL74 cells (FeLV-producing cells) were dispersed in a liquid medium containing 10% fetal bovine serum to a concentration of 1 x 10⁶ cell/ml, the drug being tested was added to the dispersion at a predetermined concentration, and the reaction was allowed to proceed at 37°C for 1 to 6 hours. The reaction mixture was then diluted to a concentration of 1 x 10⁵ cell/ml, the diluted samples were transferred to a microplate and incubated at 37°C, and the production of the virus was checked by the enzyme-linked immunosorbent assay (ELISA) after 24, 48 and 72 hours. The results are shown in Table 1. As can be seen from the table, daunorubicin and doxorubicin showed higher anti-retroviral activity compared with azidothymidine and bleomycin. Drug Concentration (µg/ml) Treating Time (hrs) Production of Virus Daunorubicin 1 1 ± 5 1 - 0.05 6 - 0.1 5 - 0.2 5 - 0.5 5 - Doxorubicin 0.1 5 + 0.1 6 - Azidothymidine 10 1 + Bleomycin 50 6 + The above results clearly indicate that the anti-retroviral agents of this invention have a higher effect with less toxicity, compared with conventional drugs. Described below are typical examples for pharmaceutical preparations of the agents of this invention. Example 1 (preparations for intravenous injection) Daunorubicin hydrochloride was dispensed in vials with 20 mg contained in each (the content is dissolved before use by addition of physiological saline). Example 2 (capsules) Daunorubicin hydrochloride 20 parts Lactose 60 parts Magnesium stearate 5 parts The above components were well mixed and the mixture was charged in capsules with 20 mg of the active agent contained in each. Example 3 (suppositories) Daunorubicin hydrochloride 20 parts Macrogol 4000 260 parts Macrogol 1500 1240 parts The above components were well mixed, and the mixture was shaped into suppositories with 20 mg of the active agent contained in each.

Claims: Use of daunorubicin for the manufacture of a medicament for the treatment of feline leukaemia virus.

Inventors: KURAMOCHI, TSUNEO
Applicants: MEIJI SEIKA KAISHA LTD.
Application year: 1988
Main classification: A61K31
IPC codes: A61K31, A61P31, C07H15