Effects of thiol compounds on methotrexate uptake by murine lymphocytes from thymus and thymic lymphosarcoma.

The characteristics of methotrexate (MTX) uptake and the effects of exogenous sulfhydryl compounds (i.e. reduced glutathione and cysteine) on MTX accumulation in thymocytes and thymic lymphosarcoma cells has been studied. Significant differences in the rate and the extent of MTX uptake between normal and neoplastic cells were demonstrated. MTX accumulation was found to be more efficient in thymic lymphosarcoma cells as compared with parental cells. In the cells examined, MTX uptake was not affected by membrane impermeable GSH. In contrast, short-term exposure to cysteine revealed heterogeneity in MTX uptake systems between normal and neoplastic thymocytes. Thus, cysteine was demonstrated to enhance the rate and extent of MTX accumulation exclusively in thymic lymphosarcoma cells. The results obtained indicate that in neoplastic thymocytes biochemical changes had developed in the membrane redox state around the MTX uptake system. These alterations are chemically distinguishable by their characteristic response to cysteine. The findings suggest that the plasma membrane changes could be exploited for preferential enhancement of MTX uptake by neoplastic thymocytes.

Influence of insulin on pharmacokinetics of mannosulfan in rats.

The purpose of the present study was to investigate the possibilities of potentiation of the antitumor action of mannosulfan after its administration together with insulin. The pharmacokinetics of mannnosulfan were investigated after its administration separately and together with insulin. Concentrations of mannosulfan in the plasma were determined by gas chromatography. Insulin enhanced the rate of absorption of mannosulfan from the peritoneal cavity and prolonged its elimination from the body. It may be assumed that insulin enhances not only passage of mannosulfan from the peritoneal cavity to blood, but also from blood to tissues. Since increased antitumor effectiveness of mannosulfan was accompanied by its decreased toxicity, it may be concluded that insulin causes selective cummulation of the cytostatic only in some tissues, among others, in the tumor.

The effect of sulfhydryl compounds on 5-fluorouracil toxicity and distribution.

The investigations performed revealed that sulfhydryl compounds (reduced glutathione, cysteine and mesna) reduced the acute and subacute toxicity of 5-fluorouracil in mice. The above compounds changed pharmacokinetics of 5-fluorouracil increasing its accumulation in tissue compartment. The studies on 5-Fu distribution revealed its increased concentration in certain organs after administration of only certain sulfhydryl-containing compounds and only after certain doses.

The effect of sodium-2-mercaptoethane-sulphonate, N-acetylcysteine and cysteine on the uptake of cytosine arabinoside by normal and neoplastic thymus cells of mice.

The effect of some sulfhydryl compounds on the uptake of cytosine arabinoside (Ara-C) by normal and neoplastically transformed mouse thymus cells was studied. Sodium 2-mercaptoethanesulphonate (Mesna) was found to greatly inhibit (in 80%) the uptake of Ara-C by normal cells. Two other SH-compounds (cysteine and N-acetyl-cysteine) displayed no such effect. None of the three compounds reduced the uptake of Ara-C by neoplastic thymus cells. The possible pharmacological implications of these findings are discussed.

Modulation of anticancer drug toxicity by solcoseryl.

The studies of the effect of solcoseryl on toxicity of selected anticancer drugs were performed in mice. The observed differential influence of solcoseryl was dependent on the type of anticancer drug as well as on the schedule of solcoseryl administration. The protective effect of the biostimulator was noticed exclusively against 5-FU toxicity. The results of our studies could provide possible implications for therapeutic approach.

Influence of some sulfhydryl compounds on the antineoplastic effectiveness of 5-fluorouracil and 6-mercaptopurine.

The influence of three chosen model sulfhydryl groups containing compounds, characterized by increasing size of molecule--cysteine, glutathione and insulin on antineoplastic activity of 5-fluorouracil (5-FU) and 6-mercaptopurine (6-MP) against murine leukemia L-1210 5-FU and 6-MP and murine sarcoma Sa 180, was studied. Sulfhydryl compounds failed to change in most cases the therapeutic (antineoplastic) effect of 5-FU and 6-MP. However, certain doses of these sulfhydryl compounds enhanced the cytostatic effect of 6-MP in respect to Sa-180.

Clinical studies of Ukrain in healthy volunteers (phase 1).

Phase I of a clinical study of Ukrain was performed in 19 healthy outpatient volunteers. Their general clinical conditions were evaluated, as well as the following parameters: biochemical, haematological, immunological, electrolyte and trace elements, neopterin, immune complexes and non specific blocking factors. Ukrain was administered intramuscularly (i.m.) or intravenously (i.v.) every one, two or three days in doses of 5 to 50 mg for 7 to 40 days. In one case the drug was administered for three years in the dose of 5 to 50 mg/injection in repeated courses. During the investigation no significant changes were found in clinical states. During the intramuscular injections the volunteers felt only localized pain; some reported drowsiness, increased thirst and polyurea. There was a slight, insignificant increase in body temperature and negligible decrease of blood pressure in some cases. In conclusion, it can be said that Ukrain is well tolerated in healthy volunteers in the doses of 5, 10, 20, and 50 mg/injection, even during prolonged (up to three years) administration.

Effect of solcoseryl on antitumour action and acute toxicity of some antineoplastic drugs.

The in vivo effect of Solcoseryl on the antitumour activity and acute toxicity of some antineoplastic drugs was examined. It was found that Solcoseryl does not inhibit the antineoplastic effectiveness of the drugs against transplantable P 388 leukaemia in mice. Studies of the effect of Solcoseryl on acute toxicity of selected antineoplastic drugs in mice revealed that the biostimulator could exert a modifying influence. The prior administration of Solcoseryl significantly decreases the acute toxicity of methotrexate but has no effect on acute toxicity of 5-fluorouracil, increases the acute toxicity of bleomycin and vinblastine and has no effect on acute toxicity of methotrexate and mitoxantron. On the other hand, Solcoseryl administered simultaneously with the antineoplastic drugs increases acute toxicity of 5-fluorouracil, bleomycin and mitoxantron. The protective effect of the biostimulator noted exclusively against acute toxicity of 5-fluorouracil was also observed after multiple administration of this anticancer drug.

Pharmacological effects of Ukrain in rats and rabbits.

The effect of Ukrain administered in various doses on mean blood pressure (MAP) and breathing rate in rats and rabbits was evaluated. It was found that MAP was reduced and breathing rate increased significantly in both animal species. Maximum tolerated dose (MTD) of Ukrain was 10-fold higher in rats than in rabbits, and it amounted to 3.5 mg x kg(-1) and 0.35 mg x kg(-1), respectively. Possible clinical implications of these findings were discussed.

[The influence of RS-Timolol in comparison with R-Timolol and S-Timolol on the intraocular pressure in water-loaded rabbits]. / Wplyw racematu RS-timololu w porównaniu z enancjomerami S-timololu i R-timololu na cisnienie sródgalkowe królików w modelu obciazenia wodnego.

PURPOSE: It is assumed that S-timolol can produce more severe systemic adverse reactions than R-timolol. The aim of this study was to estimate the intraocular pressure-lowering effect of RS-timolol in comparison to R-timolol and S-timolol in water-loaded rabbits. MATERIAL AND METHODS: Ocular hypertension was provoked in rabbits by orogastric water loading. Topical administration of one of three timolol solutions: 0.85%, RS-timolol, or 3% R-timolol, or 0.5% S-timolol was performed to the right eyes 40 min before starting the water loading procedure. Left eyes served as a control group. Intraocular pressure was measured before and 30, 60, 90, 120 min after the water loading. RESULTS: Intraocular pressure-lowering effect of all three timolol solutions was comparable. CONCLUSION: RS-timolol can be effective for lowering intraocular pressure in rabbits.