minocycline and Toxoplasmosis--Animal

The efficacy of clarithromycin combined with either pyrimethamine or minocycline for treatment of experimental Toxoplasma gondii infection was investigated. Mice were infected intraperitoneally with 2 x 10(3) to 2 x 10(4) T. gondii strain RH or TS4 tachyzoites. Mortality was recorded for 35 days postinfection. Latency was evaluated by inoculation of brain homogenates from surviving mice into naive untreated mice. The combination of clarithromycin and pyrimethamine therapy caused a significantly greater reduction in mortality than did either drug alone. Similar synergy was observed between clarithromycin and minocycline. A 100% cure rate of active and latent infection was achieved in mice treated with the clarithromycin based combinations. Clarithromycin in combination with either pyrimethamine or minocycline produced efficacy comparable to combined therapy of pyrimethamine with sulfamethoxazole. The in vitro potency of clarithromycin, pyrimethamine, or minocycline against T. gondii on a mouse macrophage monolayer was not predictive of the in vivo efficacy in mice. Clarithromycin combined with minocycline or pyrimethamine could allow greater flexability for treatment of patients predisposed to the toxicity associated with standard pyrimethamine-sulfonamide or pyrimethamine-nonsulfonamide therapy. This therapy could be especially useful since clarithromycin-based therapy provides safe and effective treatment against Mycobacterium avium complex infections associated with AIDS patients.

Topics: AIDS-Related Opportunistic Infections; Animals; Clarithromycin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Mice; Minocycline; Pyrimethamine; Sulfamethoxazole; Toxoplasma; Toxoplasmosis, Animal

The efficacy of atovaquone alone or combined with pyrimethamine, sulfadiazine, clarithromycin, and minocycline was examined in vitro and in a murine model of acute toxoplasmosis. In vitro studies were performed with MRC5 fibroblast tissue cultures, with quantification of Toxoplasma growth by an enzyme-linked immunosorbent assay. For in vivo studies, mice were acutely infected intraperitoneally with 10(4) tachyzoites of the virulent RH strain and then treated perorally for 10 days from day 1 postinfection. The following drug regimens were investigated: atovaquone at 100 and 50 mg/kg of body weight per day and the combinations of atovaquone at 50 mg/kg with sulfadiazine at 200 mg/kg, pyrimethamine at 12.5 mg/kg, clarithromycin at 200 mg/kg, or minocycline at 50 mg/kg. Efficacy was assessed by determination of survival rates and sequential determination of parasite burdens in blood, brain, and lungs. In vitro, atovaquone inhibited Toxoplasma growth at a concentration of > or = 0.02 mg/liter; the 50% inhibitory concentration was estimated to be 0.023 mg/liter. No synergistic effect was observed when it was combined with sulfadiazine, clarithromycin, or minocycline, whereas a significant antagonistic effect was noted for the combination of atovaquone with pyrimethamine. In vivo, administration of atovaquone at 100 or 50 mg/kg/day for 10 days resulted in prolonged survival compared with that in untreated mice; this survival was associated with a reduction of parasite burdens in blood and tissues during the course of treatment. The combinations of atovaquone with pyrimethamine, clarithromycin, or sulfadiazine were more efficient than each drug administered alone, in terms of survival, but parasite burdens in blood and organs were not reduced compared with those in mice treated with any of the agents alone. These experimental results confirmed the activity of atovaquone against Toxoplasma gondii, but no marked improvement in efficacy was observed in vitro and in vivo when this drug was combined with pyrimethamine, sulfadiazine, minocycline, or clarithromycin.

Topics: Animals; Antiprotozoal Agents; Atovaquone; Clarithromycin; Coccidiostats; Drug Combinations; Drug Interactions; Enzyme-Linked Immunosorbent Assay; Kinetics; Mice; Minocycline; Naphthoquinones; Pyrimethamine; Sulfadiazine; Toxoplasma; Toxoplasmosis, Animal

The efficacy of clarithromycin in a murine model of acute toxoplasmosis was studied. Clarithromycin was administered alone and concurrently with minocycline, and efficacy was assessed by survival rates and sequential determination of parasite burden in blood, brains, and lungs. Limited protection resulted from administration of each drug alone, whereas a remarkable synergistic effect followed concurrent administration. Survival of mice treated with 200 mg of clarithromycin plus 20 mg of minocycline per kg of body weight daily was 95%; that of mice treated with 50 mg of clarithromycin plus 50 mg of minocycline per kg daily was 93%. The parasite burden in the blood and organ tissues of these mice was markedly reduced compared with that in mice treated with a single agent. In mice treated with 200 mg of clarithromycin plus 50 mg of minocycline per kg per day, survival was 100% during the 30-day experiment; no parasites were found in blood and tissues.

Topics: Animals; Clarithromycin; Drug Synergism; Drug Therapy, Combination; Mice; Minocycline; Toxoplasmosis, Animal

Topics: Animals; Clarithromycin; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Erythromycin; Mice; Minocycline; Toxoplasmosis, Animal

The chemotherapeutic activity of minocycline, a semi-synthetic tetracycline analogue, was evaluated in a murine model of toxoplasmosis. A lethal acute toxoplasmosis was produced by injecting 10(5) tachyzoites of the RH strain of Toxoplasma gondii into the peritoneal cavities of Swiss-Webster mice. When infected mice were treated once daily for 12 days, starting 2 h after challenge, the survival and cure rates were 100% and 40% respectively after minocycline alone (100 mg/kg per day), 0% and 0% after pyrimethamine alone (8.5 mg/kg per day), and 100% and 50% after combination of the two drugs at the same dosages. Absolute survival and cure with minocycline were observed when mice were treated with two daily doses of 100 mg/kg for 12 days. Mice chronically infected with a low virulent strain of T. gondii (Me49) showed a significant reduction in the number of brain cysts after three weeks of treatment with 50 mg/kg per day of minocycline. Minocycline serum levels after a single oral administration of 50 mg/kg or 100 mg/kg to normal mice, peaked at 1.8 mg/l and 10 mg/l after 1 h, respectively, and showed an extended half-life.

Topics: Acute Disease; Animals; Chronic Disease; Drug Evaluation, Preclinical; Female; Mice; Minocycline; Pyrimethamine; Remission Induction; Toxoplasmosis, Animal

The effects of minocycline alone or in combination with sulphadiazine were evaluated against acute murine toxoplasmosis and compared with the efficacy of pyrimethamine and sulphadiazine. The date presented show that mice could be protected from acute toxoplasmosis by minocycline, in spite of using a virulent strain of Toxoplasma gondii, a large inoculum, and a delay in the administration of the drug. Acute toxoplasmic infection in mice could be eradicated by aminocycline--sulphadiazine combination, which was found to be as effective as pyrimethamine--sulphadiazine combination therapy.

Topics: Animals; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Male; Mice; Minocycline; Pyrimethamine; Sulfadiazine; Tetracyclines; Toxoplasmosis, Animal