Activities of Sordarins in Experimental Models of Candidiasis, Aspergillosis, and Pneumocystosis

Abstract

Sordarin derivatives represent a new class of antifungal agents that act as potent inhibitors of fungal protein synthesis and possess a broad spectrum of activity. The in vivo activity of GM193663 and GM237354 was studied in mouse models of disseminated candidiasis and aspergillosis and in a rat model of pneumocystosis. The pharmacokinetic behavior of both sordarin derivatives was studied in mice and rats. In all studies, compounds were administered by the subcutaneous route. After a subcutaneous dose of 50 mg/kg of body weight to mice, the maximum level in serum, area under the concentration-time curve, half-life, and clearance for GM193663 and GM237354 were 51.8 and 23 g/ml, 79.5 and 46 g ⅐ h/ml, 0.8 and 0.85 h, and 21 and 25 ml/h, respectively. Systemic candidiasis and aspergillosis were established in CD-1 male mice infected with Candida albicans or Aspergillus fumigatus. For systemic candidiasis, compounds were given three times per day for seven consecutive days at 15, 30, 60, or 120 mg/kg/day. GM193663 and GM237354 showed dose-related efficacy against C. albicans, with 50% effective doses, 1 month after infection, of 25.2 and 10.7 mg/kg/dose, respectively. In experimental infections with A. fumigatus, GM237354 was given three times per day at 30, 60, or 120 mg/kg/day for five consecutive days. Animals treated with GM237354 demonstrated irregular responses. The survival of animals treated with GM237354 was 0, 30, and 0% at 30, 60, and 120 mg/kg/day, respectively. The therapeutic efficacy of GM193663 and GM237354 against Pneumocystis carinii was studied in an experimental P. carinii pneumonia (PCP) rat model. After a subcutaneous dose of 10 mg/kg given to rats, the maximum level in serum, area under the concentration-time curve, half-life, and clearance for GM193663 and GM237354 were 6.6 and 7.2 g/ml, 8.5 and 11.8 g ⅐ h/ml, 0.7 and 0.8 h, and 230 and 133 ml/h, respectively. To induce spontaneous PCP, rats were chronically immunosuppressed with dexamethasone. Infected animals were treated twice daily for 10 days at 0.2, 2, or 10 mg/kg/day. The therapeutic effect was estimated by the reduction in the number of cysts in the lungs of treated versus untreated animals. GM193663 and GM237354 significantly reduced the mean (؎ standard deviation) log number of cysts from 7.6 ؎ 0.2 in the untreated group to 4.7 ؎ 0.2 and 4.6 ؎ 0.1, respectively, when the drugs were administered at a dose of 2 mg/kg/day. The log number of cysts was also reduced in infected animals given lower doses of the compounds (0.2 mg/kg/day). In summary, GM193663 and GM237354 are new sordarin derivatives that may potentially play a major role in the treatment of candidiasis and PCP. Further testing with Aspergillus in other animal models is warranted.

Antifungal Activities of Two New Azasordarins, GW471552 and GW471558, in Experimental Models of Oral and Vulvovaginal Candidiasis in Immunosuppressed Rats

“…Furthermore, oral and vaginal candidiasis models have been shown to afford a simple, reliable, and highly reproducible method for studying the efficacies of new antifungal agents (17,20). On the other hand, strain-related differences in C. albicans pathogenicity in the rat mucosa have been described; consequently, we have used a well-characterized C. albicans strain that has been widely used in previous therapeutic and pharmacodynamic studies in rodents, where its pathogenic properties have been well demonstrated (1,13,14). In the present study, immunosuppression in the VVC model ensured homogeneous and chronic infection in the rats.…”

“…Therapeutic efficacy studies were performed against C. albicans 4711E, a clinical isolate used in previous in vivo studies (1,13,14). C. albicans 4711E was stored at Ϫ80°C in Sabouraud dextrose broth containing 15% glycerol in our laboratory until used.…”

“…Sordarin derivatives have demonstrated potent and relatively broadspectrum antifungal activity in several in vitro (10) and in vivo (1,13,14) studies. A further evolution of this class of compounds has led to a new family of substances called azasordarins.…”

Evaluation Of Terbinafine Activity On Pneumocystis Carinii At The Rat Model

“…Tetracycline (1mg/lt) was added to the drinking water to minimize bacterial infections. [7][8][9] All animals remained on immunosuppression therapy with dexamethasone throughout the study. Food and water were ad libitum.…”

“…The filtrate was centrifuged at 2,900 X g for 10 min, and the pellet was resuspended in phosphate-buffered saline, and stained with cresyl echt violet, which selectively stains the cell wall of the cyst. [7,8,10] The number of cysts was determined by visual assessment under light microscope (20 microscopic fields).…”