EFFICACY OF COMBINATION THERAPY WITH TUBERCIDIN AND NITROBENZYLTHIONOSINE 5'-MONOPHOSPHATE AGAINST CHRONIC AND ADVANCED STAGES OF SCHISTOSOMIASIS

The efficacy of the highly selective antischistosomal combination chemotherapy with tubercidin (7-deazaadenosine) plus nitrobenzylthioinosine 5'-monophosphate (NBMPR-P), [el Kouni et al., Proc Natl Acad Sci USA 80: 6667-6670, 1983; el Kouni et al., Biochem Pharmacol 36: 3815-3821, 1987] was examined against chronic and advanced stages of schistosomiasis in mice. Administration of four successive daily doses of tubercidin (5 mg/kg/day) plus NBMPR-P (25 mg/kg/day) to Schistosoma mansoni-infected mice beginning 5, 6, 7 and 8 weeks post-infection and monitored for 22 weeks was very effective against the parasite. It resulted in a marked increase in survivorship of treated mice. Repetition of the dose-regimen after a 10-day rest period was even more effective. However, survivorship of infected animals decreased with the delay of therapy. Early treatment (5 weeks post-infection) resulted in 100% survival compared to 13% only for untreated animals. If therapy was instituted at 8 weeks post-infection, only 70% of the treated mice survived. Treated animals appeared healthy and were found to have less splenomegaly and hepatomegaly. Combination therapy also caused a significant reduction in the number of worms as well as the number of eggs in the liver and small intestine. However, these differences diminished as the treatment was delayed. The number of eggs in the liver was reduced from an average of 120,000 eggs per liver in untreated animals to approximately 16,000 eggs per liver when treated at 5 weeks post-infection. When treatment was delayed to 8 weeks post-infection, the reduction in liver egg count was not as dramatic (88,000 eggs per liver). Similarly, the number of eggs was reduced in the intestine from 1,759 to an average of 58 and 860 eggs per cm2 of the intestine when the mice were treated at 5 and 8 weeks post-infection respectively. However, some worms survived and resumed egg production after an extended period of recuperation. Histological examination indicated that combination therapy was effective in preventing the formation of new egg granulomas but not on pre-existing granulomas.