[Toxicological Evaluation of Intravenous Formulation of Rifapentine.]

Rifapentine belongs to the most potent antituberculosis drugs. Nevertheless, there are some limitations for its clinical use because of the low aqueous solubility and side effects. A technological approach to development of rifapentine intravenous formulation based on human serum albumin was described earlier and its efficacy against experimental tuberculosis was estimated. Toxicological evaluation of that water-compatible form of rifapentine revealed its low acute toxicity (LD50 340 mg/kg). Chronic toxicity tests of both the oral substance and the injectable formulation of rifapentine demonstrated similar adverse effects. However, in contrast to the conventional oral formulations, the intravenous formulation of rifapentine had no gastrointestinal toxic effects or cardiotoxicity, thus suggesting its usefulness for clinical application.

[Anthracycline antibiotics and their derivatives--inhibitors of topoisomerase I].

The relationship between the structure of new semisynthetic derivatives of doxorubicin, daunorubicin, and carminomycin and their ability to inhibit topoisomerase 1 were studied. The new derivatives inhibit the activity of topoisomerase 1 at low concentrations, induce the death of K-562 leukemia cells in culture, and produce an antitumor effect in experimental animals with P388 leukemia.

Potential mutagenicity, embryotoxicity, and teratogenicity of calcium ketopantoyl aminobutyrate.

We studied mutagenic, embryotoxic, and teratogenic properties of calcium ketopantoyl aminobutyrate, a preparation proposed as a new drug. Long-term oral administration of calcium ketopantoyl aminobutyrate produced no mutagenic, embryotoxic, and teratogenic effects.

Allergic and immunotoxic effects of calcium ketopantoyl aminobutyrate.

We studied the allergic and immunotoxic effects of a new promising medicinal preparation calcium ketopantoyl aminobutyrate. Calcium ketopantoyl aminobutyrate produced no negative effects on general mechanisms of humoral and cellular immunity. This preparation did not modulate the anaphylactic reaction to bovine serum, exhibited no mitostatic and lymphotoxic properties, had no effect on the delayed-type hypersensitivity response, and did not produce active cutaneous anaphylactic reaction.

[Comparative analysis of in vitro antifungal activity and in vivo acute toxicity of the nystatin analogue S44HP produced via genetic engineering].

New polyene macrolide S44HP was purified from the culture of recombinant Streptomyces noursei strain with engineered nystatin polyketide synthase. S44HP, nystatin (NYS), and amphotericin B (Amph-B) were tested against 19 clinical fungal isolates in agar diffusion assay, which demonstrated clear differences in antifungal activities of these antibiotics. Sodium deoxycholate suspensions of all three antibiotics were subjected to acute toxicity studies in vivo upon intravenous administration in mice. NYS exhibited the lowest acute toxicity in mice in these experiments, while both Amph-B and S44HP were shown to be 4 times more toxic as judged from the LD50 values. While the acute toxicity of S44HP was higher than that of Amph-B, the data analysis revealed a significantly increased LD10 to LD50 dose interval for S44HP compared to Amph-B. The data revealed structural features of polyene macrolides, which might have an impact on both the activity and toxicity profiles of these antibiotics. These results represent the first example of preclinical evaluation of an "engineered" polyene macrolide, and can be valuable for rational design of novel antifungal drugs with improved pharmacological properties.

Effects of T-activin and vitamin E on toxicity and antitumor activity of cyclophosphamide.

We studied the effect of combination treatment with T-activin and vitamin E on acute toxicity and antitumor activity of cyclophosphamide in mice. Combined administration of these preparations 1.37-fold increased the maximum permissible dose of cyclophosphamide without affecting its LD(50)and delayed mouse death from cyclophosphamide toxicity. Most mice died only 3 days after combination treatment with the test preparations and cyclophosphamide in doses of LD(16)-LD(84). The second peak of death from hematologic toxicity of cyclophosphamide was absent under these conditions. T-activin and vitamin E did not abolish the antitumor effect of cyclophosphamide on mice with subcutaneously implanted P-388 lympholeukemia. Tumor growth was suppressed by 100%.

Effect of a novel antineoplastic drug olipifat on antitumor immunity in mice.

Olipifat is an antineoplastic drug containing pyrophosphate and a product of special lignin processing. Donor C57Bl/6J mice with syngeneic B16 melanoma received a single 5-day course of olipifat. Effect of olipifat on antitumor resistance was evaluated by local neutralization test [3]. In animals with rapid melanoma growth, splenic cells from intact donors stimulated tumor growth. Olipifat abolished this growth-stimulating effect of splenocytes. In animals with slow melanoma growth, splenocytes had no effect on the growth of melanoma or Lewis lung cancer. In this case, splenocytes from olipifat-treated donors completely arrested the growth of melanoma B16 and decelerated the growth of Lewis lung carcinoma.

[The preclinical assessment of the activity and pharmacological action of native human interleukin-2]. / Predklinicheskaia otsenka aktivnosti i farmakologicheskogo deistviia nativnogo interleikina-2 cheloveka.

It was demonstrated in in vivo and in vitro experiments that interleukin-2, obtained by cultivation of donor lymphocytes and purified by gel filtration, induces the production of mouse and human killer lymphocytes possessing high cytolytic activity against tumor cells. Interleukin-2 does not cause irreversible changes of the physiological and morphologic indices of vital activity in mice.

[Antitumor and toxic effects of amotin]. / Izuchenie protivoopukholevogo i toksicheskogo deistviia amotina.

An indole alkaloid isolated from Catharanthus roseus in the Soviet Union and named amotin differs in terpenoid moiety structure of the indole part of the molecule from the foreign preparation vinblastine and its Soviet analog rosevine. In experimental study amotin has exhibited a high antileukemic activity which was more expressed than that of vinblastine. Tolerant doses of amotin cause moderate reversible morphological alterations in hematopoietic organs, gastrointestinal mucosa, liver, kidney, adrenals, testes, ovaries.