Efficacy of diaminodiphenylsulfone and other drugs in murine Pneumocystis carinii pneumonitis

Abstract

The purpose of this study was to identify new drugs for the prevention and treatment of Pneumocystis carinii pneumonitis (PCP) induced in rats by continuous daily dosage with dexamethasone. Initially, test drugs were administered prophylactically as a screen for efficacy. Drugs were selected because of their known activity against certain protozoa and their tolerance in human usage. Doses were based on previous studies in rats or estimated from usage in humans and lower animals. Allopurinol (50 mg/kg per day), ketoconazole (25 mg/kg per day), difluoromethylornithine (2.5 g/kg per day), diloxanide (125 mg/kg per day, nifurtimox (100 mg/kg per day), suramin (20 mg/kg per day), melarsoprol (20 mg/kg per day), gentian violet (0.5 mg/kg per week, 5 and 50 mg/kg per day), primaquine (5.6 mg/kg per day) and chloroquine (37.5 mg/kg per day) were ineffective, whereas diaminodiphenylsulfone (daspone) (25 mg/kg per day) was totally effective in preventing the infection. Diaminodiphenylsulfone was then evaluated at dose levels of 5, 25, and 125 mg/kg per day and compared with trimethoprim-sulfamethoxazole (TMP-SMZ), given at 50 per 250 mg/kg per day orally. The two highest dose levels of diaminodiphenylsulfone and TMP-SMZ prevented the infection in all of the animals, and the lowest dose of diaminodiphenylsulfone prevented it in 40% of the rats. All of the untreated controls developed PCP. To determine therapeutic efficacy, animals with extensive PCP were treated for 2.5 weeks with diaminodiphenylsulfone or TMP-SMZ. Based on residual extensive pneumonitis at the completion of treatment, the pneumonitis was reduced to 50% by TMP-SMZ and to 25% by diaminodiphenylsulfone, whereas 100% of untreated controls had extensive PCP. When treatment was begun earlier in the course of the pneumonitis, diaminodiphenylsulfone was totally effective in eradicating the infection. These results suggest that diaminodiphenylsulfone is an effective drug for the treatment and prevention of murine PCP and that it is at least as effective as TMP-SMZ.