Use of Terbinafine in Mouse and Rat Models ofPneumocystis cariniiPneumonia

Abstract

Terbinafine, an allylamine used to treat onychomycosis, has been reported to be active against rat Pneumocystis carinii in vitro and in vivo. By contrast, our in vitro data showed that the 50% inhibitory concentration of terbinafine against rat P. carinii is 3.7 g/ml, a level that cannot be clinically achieved in serum. In the present study, terbinafine administered orally at doses of 20 to 400 mg/kg/day and 50 to 250 mg/kg/day was ineffective therapy for mouse and rat models of pneumocystosis, respectively. These results emphasize the complexities of P. carinii drug testing and the need for caution before considering studies in humans.Despite improved treatment of human immunodeficiency virus, pneumonia caused by Pneumocystis carinii remains an important clinical problem in human immunodeficiency virus patients and other immunocompromised hosts. Anti-P. carinii drugs in clinical use are hampered by toxicity, limited effectiveness, and emerging resistance (10,17,24). The lack of interest among pharmaceutical companies in developing new agents for P. carinii has stimulated efforts to test existing drugs marketed for other purposes for activity against the organism. Terbinafine, a member of the allylamines which has been marketed for the treatment of onychomycosis, is one of these agents. Terbinafine has activity against dermatophytes, other fungi, and trypanosomes (19).Two studies have shown that terbinafine is active against rat and human P. carinii infection at concentrations of 300 g/ml and 0.4 to 0.8 g/ml, respectively, in tissue culture (3, 5). The investigators also found that terbinafine given at oral doses of 15 to 80 mg/kg/day had efficacy that was equal to or greater than that of known anti-P. carinii drugs in rats with P. carinii pneumonia (5, 6). These provocative reports led to interest in possibly using terbinafine to treat pneumocystosis in humans. Before clinical studies can be contemplated, these findings should be confirmed by other investigators using different experimental approaches. Using an ATP cytotoxicity assay to screen candidate anti-P. carinii drugs, our group found that terbinafine has a 50% inhibitory concentration of 3.7 g/ml against rat P. carinii at 72 h (16). Although this concentration indicates moderate activity on our rating scale (7, 28), it exceeds levels of terbinafine in serum that can be achieved in humans (1 to 2 g/ml) or rodents (2 to 2.5 g/ml) with oral administration of the drug (9,13,15,18,19,20). Here we have analyzed the efficacy of terbinafine in our mouse and rat models of pneumocystosis.Adult C3H/HeN mice and Lewis rats (Charles River) were housed under barrier conditions with infected mice and rats, respectively, and administered corticosteroids to induce the development of pneumocystosis as previously described (25,26,27,28). After 6 to 7 weeks of immunosuppression, when the infection reached moderate intensity, the animals were randomly divided into treatment and control groups. Terbinafine (Lamsil; Novartis), which was obtained commercially, and trimethoprim...

The Effect Of Combinations Of Antimycotics In A Mouse Model Of Systemic Candidiasis

“…It may because 100 mg/ kg/day terbinafine was toxic, even if an 80 mg/kg/day dose was not. Concerning this, Walzer et al [17] tested terbinafine in mouse and rat models of Pneumocystis carinii pneumonia in doses of 20-50-150 mg/kg/day in mice and 50-250 mg/kg/day in rats. The authors found that these therapies were ineffective.…”

“…Beginning 1 day after infection, one group remained untreated (the control group), three other groups were treated with fluconazole (Pfizer) at 100mg/kg/day in 0.2 ml i.p., with amphotericin B 1 mg/kg/day ip, and with terbinafine 100mg/kg/day by oral gavages. [1,2,13,17] The remaining two groups were treated with terbinafine with amphotericin B and terbinafine with fluconazole at the same doses. Treatment was continued up to day 10.…”

“…[2,3,15] Amphotericin B (Fungizone, Bristol-Myers Squibb), and fluconazole (Triflucan 100mg, Pfizer) were used, and prepared for injection as recommended by the manufacturer and terbinafine (Lamsil, Novartis) dissoluting in polyethylene glycol 200 and diluted in sterile distilled water. [17,18] The MICs for amphotericin B, fluconazole and terbinafine were determined by the broth microdilution method described by the National Committee for Clinical Laboratory Standards M27 A. [19] The median MIC of fluconazole, amphotericin B, and terbinafine after 48 h incubation were 4, 0.5, and 8 g/ml respectively.…”

Evaluation Of Terbinafine Activity On Pneumocystis Carinii At The Rat Model

“…[4] The investigators of two studies found that terbinafine given at oral doses of 15 to 80 mg/kg/day had an efficacy equal to or greater than that of known anti-P. carinii drugs in rats with PCP. [5,6] In another study Walzer et al [1] showed that terbinafine administered orally at doses of 20 to 400 mg/kg/day and 50 to 250 mg/kg/day was ineffective therapy for mouse and rat models of pneumocystosis, respectively.…”

“…Drugs used in PCP in clinical use are hampered by toxicity, limited effectiveness, and emerging resistance. [1,2] The lack of interest among pharmaceutical companies in developing new agents for Pneumocystis has stimulated efforts to test existing drugs marketed for other purposes for activity against the organism. Terbinafine is an allylamine antifungal agent which appears to act by preventing fungal ergosterol biosynthesis via specific and selective inhibition of fungal squalene epoxidase.…”