We investigated the effects of doxycycline on Toxoplasma gondii infections in vitro and in vivo. Resident peritoneal macrophages were infected with the virulent RH strain of T. gondii and exposed to doxycycline at different concentrations. The antitoxoplasmic activity of doxycycline was first assessed with [3H]uracil, which is incorporated by the parasite but not the host cell. The concentration of doxycycline that inhibited 50% of the radioactive uptake was calculated to be 6.4 ,Ig/ml (95% confidence limits, 5.07 to 8.06 ,ug/ml); the concentration of doxycycline that inhibited 90% of the radioactive uptake was 14 pg/ml. Tetracycline was ineffective up to 40 ,ug/ml. Furthermore, microscopic examination of the infected macrophages after treatment with doxycycline confirmed the inhibition of intracellular growth of T. gondui. Mice acutely infected by the intraperitoneal route with 5 x 103 tachyzoites of T. gondii were protected against death with a dose of 300 mg of doxycycline per kg (body weight) administered by the oral route for 10 days, starting 24 h after challenge. When mice were infected with 105 tachyzoites of T. gondii and treated 12 days starting 2 h after challenge, the protection and the cure rates were, respectively, 100 and 0% after doxycycline alone (300 mg/kg per day), 0 and 0% after pyrimethamine alone (12.5 mg/kg per day), and 100 and 60% after the combination of these two drugs at the same dosages given above. These results suggest that doxycycline may prove to be useful in the treatment of toxoplasmic infections.Infection with Toxoplasma gondii is a potential hazard for immunocompromised patients, such as those suffering from the acquired immune deficiency syndrome (AIDS) (30). Currently, the treatment of choice for toxoplasmosis is the synergistic combination of pyrimethamine with sulfonamides (20,29,43). The treatment of patients with AIDS suffering from toxoplasmic encephalitis with this combination entails a significant mortality rate, usually associated with relapse after withdrawal of therapy for reasons of toxicity, mainly because of the sulfonamide component of the combination (27,30). Moreover, it has been proposed that patients with AIDS suffering from toxoplasmic encephalitis should be maintained on a chronic suppressive (clinical prophylactic) regimen to avoid relapses (23). Thus, the development of effective and safer compounds for treating this disease is critically needed. As alternative treatments, the experimental in vitro and in vivo activities of some new macrolides have been assessed (1,5,(7)(8)(9), but their efficacies in human toxoplasmosis, however, remain to be confirmed in clinical trials. Clindamycin has been shown to have activity in animal models of toxoplasmosis (2, 32, 41), and its use as an alternative drug in the treatment of patients who do not tolerate sulfonamides has been reported recently (12).Among the other possible therapies, the antitoxoplasmic activities of tetracyclines have been studied in animal models. The results of those studies with tetracycl...
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/1 and 10 mg/1 after 1 h, respectively, and showed an extended half-life.
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