Two phenothiazine compounds, trifluoperazine and chlorpromazlnej inhibited growth in vitro of the five niost common pathogenic yeasts, with MICs ranging from 10 to 40 uLg/ml. Daily intraperitoneal injections of trifluoperazine (4 to 7 mg/kg of body weight) increased the survival of mice experimentally infected with Candida albicans or Cryptococcus neoformans. The potential use of these drugs against fungal meningitis is discussed.The increasing occurrence of mycoses caused by opportunistic systemic infections (2, 3, 7) and the lack of effective and safe drugs (8) led to the search for new antifungal drugs with low toxicity. In previous studies in our laboratory, we investigated the effects and the mechanism of action of compounds from the phenothiazine group on the yeast Saccharomyces cerevisiae (4-6). It was found that trifluoperazine (TFP) and chlorpromazine (CPZ) cause a quick and massive K+ efflux leading to membrane hyperpolarization, Ca2' influx, and inhibition of the plasma membrane H+-ATPase. The results led to the suggestion that these substances, which are currently used as tranquilizers and in antipsychotic therapy (1), may be used as drugs against pathogenic yeasts in systemic infections. Since the phenothiazines accumulate in the central nervous system (1, 2), these drugs may be specifically effective against fungal meningitis and encephalitis. In the present study, we investigate the activity of TFP and CPZ against five medically important yeasts.The yeasts used in the experiments were isolated from clinical specimens taken from different body sites of patients before treatment. Only one isolate per patient was studied. The yeasts were identified to the species level by current conventional methods (11). The isolates were maintained on Sabouraud dextrose agar until tested. In each in vitro experiment, at least five isolates of each species were tested. The mice used for in vivo experiments were Sabra white female mice 20 to 25 g in weight, and each experiment was repeated three times.MICs were determined by the agar dilution method as described previously (10), with the exception that HEPES buffer (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid; 20 mM, pH 7.2) was included in the agar medium. For examining the pH effect, plates with acidic pH values were prepared by the addition of MES (4-morpholineethanesulfonic acid) at the required pH.For the susceptibility test by the broth dilution method, yeast suspensions were prepared from overnight growth on Sabouraud dextrose agar at 30TC and added, at a density of 5 X 105 cells per ml, to test tubes each containing 10 ml of yeast nitrogen base (YNB) broth supplemented with glucose (100 mM), HEPES buffer (20 mM, pH 7.2), and the required concentration of the drug being tested. The loosely capped test tubes were incubated at 30°C in a shaker. Every 2 h, the * Corresponding author. optical densities at 530 nm were determined. MIC,b) was the concentration of the drug at which the increase in the optical density at 530 nm after 8 h was less than 20% of t...
Combination of ketoconazole and trifluoperazine or chlorpromazine yielded an in vitro synergistic effect on growth inhibition of Candida albicans, Torulopsis glabrata, Cryptococcus neoformans, Candida parapsilosis and Candida tropicalis. The optimal pH range for the synergistic effects was 7.0–7.6. At pH 5.0 the drug combination was antagonistic. (Application for patent protection has been filed.)
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