sm-8668 and Coccidioidomycosis

A new oral triazole antifungal, SCH 39304, was administered to 54 patients with progressive infections due to Coccidioides immitis from six collaborating centers. Patients were grouped according to site of infection including chronic pulmonary (25), bone/joint (17) and skin/soft tissue (12). The median age was 40 years; 83% were male, 52% white, 13% HIV-infected and 35% had failed previous therapy. The majority of patients were treated with either 100 mg or 200 mg day-1. One patient on renal dialysis received 300 mg day-1. Baseline abnormalities were reassessed for evidence of efficacy every 4 months and expressed in a standardized scoring system. Cumulative overall response rates at 4, 8 and 12 months were 7%, 36% and 66% respectively. Twelve month response rates by disease were 77% (pulmonary), 62% (skin/soft tissue) and 31% (bone/joint). Fifteen patients failed therapy although seven of these were still on treatment when the study was discontinued. Two failed due to toxicity. Possible symptoms or signs of toxicity occurred in 24 (44%) patients and were generally mild. SCH 39304 is an effective and well tolerated therapy for progressive forms of coccidioidomycosis.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antifungal Agents; Coccidioidomycosis; Dermatomycoses; Drug Administration Schedule; Female; HIV Infections; Humans; Joint Diseases; Lung Diseases, Fungal; Male; Middle Aged; Treatment Outcome; Triazoles

To assess the efficacy of amphotericin B lipid complex (ABLC) in the treatment of coccidioidal meningitis, we compared a wide range of doses (0.35-15 mg kg-1, intravenously (IV)) of ABLC with amphotericin B deoxycholate (AmB) (0.3-7 mg kg-1, intraperitoneally (IP)) and (IV) and a new triazole, SCH 39304 (SCH), in an experimental murine model. Survival data showed high dose ABLC to be of equal efficacy to IV and high dose IP AmB and SCH. Quantitative studies confirmed this outcome. No acute toxicity with ABLC, at the doses employed, was found. We conclude that ABLC is effective in the treatment of murine coccidioidal meningitis.

Topics: Amphotericin B; Animals; Antifungal Agents; Coccidioidomycosis; Drug Carriers; Liposomes; Meningitis, Fungal; Mice; Triazoles

SCH 39304 (304) and its isomers, SCH 42426 (426) and SCH 42427 (427), are new orally administered antifungal azole derivatives. In this study, we compared the efficacy of 304 with that of 426 and 427 in murine models of cryptococcal and coccidioidal meningitis. On day 18 postinfection with Cryptococcus neoformans, controls showed 80% mortality. The 50% protective doses calculated at this day were 0.56 mg of 304 per kg of body weight, 23.5 mg of 426 per kg, and 0.11 mg of 427 per kg. Controls with coccidioidal meningitis all succumbed, and treated mice at the same time point showed 50% protective doses of 10.8 mg/kg for 304, 200 mg/kg for 426, and 2.1 mg/kg for 427. We conclude that isomer 427 is five times as potent, whereas 426 is 1/50th as potent as 304 in these experimental mycoses.

Topics: Administration, Oral; Animals; Antifungal Agents; Azoles; Coccidioides; Coccidioidomycosis; Cryptococcus neoformans; Culture Techniques; Isomerism; Meningitis, Cryptococcal; Mice; Triazoles

The triazole SCH39304 was compared with itraconazole and fluconazole for treatment of murine coccidioidal meningitis. Mice were treated for 30 days with 1, 5, 10, or 30 mg of each drug per kg of body weight. Survival and brain tissue counts were measured. At equivalent doses, SCH39304 was more effective than the other triazoles.

Topics: Animals; Antifungal Agents; Coccidioidomycosis; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Fluconazole; Itraconazole; Ketoconazole; Meningitis; Mice; Mice, Inbred BALB C; Triazoles

The efficacies of SCH39304 (SCH) and fluconazole (FLU) were tested in a murine model of coccidioidomycosis. CD-1 mice were infected with Coccidioides immitis and dosed with SCH at 2, 10, 25, or 50 mg/kg per day or FLU at 10 or 100 mg/kg per day. Survival was enhanced (P less than 0.001) by both drugs at all doses. Residual burdens of C. immitis in the organs of mice treated with SCH at 25 or 50 mg/kg per day were lower than in mice treated with FLU at 100 mg/kg per day (P less than 0.001). These results indicate that SCH is an effective therapy for coccidioidomycosis and is superior to FLU in this comparison.

Topics: Animals; Antifungal Agents; Coccidioidomycosis; Fluconazole; Male; Mice; Triazoles