thioinosine and Schistosomiasis

Host toxicity of the dose regimen of tubercidin (7-deazaadenosine) plus nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) used in combination therapy of schistosomiasis (M. H. el Kouni, D. Diop, and S. Cha, Proc. Natl. Acad. Sci. USA 80:6667-6670, 1983; M. H. el Kouni, N. J. Messier, and S. Cha, Biochem. Pharmacol. 36:3815-3821, 1987) was examined in vivo in mice and in vitro with human bone marrow progenitor cells. Four successive daily intraperitoneal injections of tubercidin at 5 mg/kg per day produced 100% mortality in mice within 3 to 5 days following the first injection, with massive peritonitis and intestinal obstruction secondary to abdominal adhesions. Coadministration of NBMPR-P (25 mg/kg per day) protected the mice from the lethality of tubercidin and allowed the repetition of the regimen for a second time with 100% survival until the mice were sacrificed 22 days following the first injection. Blood chemistry, hematological studies, and histological examinations showed no evidence for injury to the liver, kidney, spleen, pancreas, mesentery, or peritoneal mesothelium. In vitro, tubercidin alone had a direct dose-dependent inhibitory effect on myeloid and erythroid human bone marrow progenitor cells, and consistent inhibition (50%) of granulocyte-macrophage CFU (CFU-GM) and erythroid burst-forming units (BFU-E) occurred at 2 to 3 nM tubercidin. At higher doses, BFU-E were more sensitive to tubercidin toxicity than CFU-GM. Complete inhibition (99%) of BFU-E colonies occurred at 10 nM tubercidin, while complete inhibition of CFU-GM occurred at 100 nM. NBMPR-P at 10 to 100 nM protected CFU-GM and BFU-E from tubercidin toxicity in a dose-dependent matter.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Colony-Forming Units Assay; Female; Hematopoietic Stem Cells; Humans; In Vitro Techniques; Inosine; Mice; Schistosomiasis; Thioinosine; Thionucleotides; Tubercidin

In contrast to their effects on mammalian cells, the nucleoside transport inhibitors nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) dilazep, benzylacyclouridine (BAU), and to a lesser extent, dipyridamole have no significant effect on the in vitro uptake of adenosine analogues by Schistosoma mansoni [el Kouni and Cha, Biochem. Pharmac. 36, 1099 (1987)]. Coadministration of either NMBPR-P or dilazep with potentially lethal doses of tubercidin (7-deazaadenosine), nebularine or 9-deazaadenosine protected mice from the toxicity of these adenosine analogues. Dipyridamole caused partial protection, whereas BAU did not protect the animals from this toxicity. Toyocamycin caused delayed mortality (after 16 weeks) which could not be prevented by coadministration of NBMPR-P. In S. mansoni infected mice, treated with the combination of NBMPR-P and 9-deazaadenosine was not effective against the parasite. On the other hand, the combinations of NBMPR-P or dilazep with either tubercidin or nebularine were highly toxic to the parasite but not the host. Combination therapy caused a marked reduction in the number of pairing of worms. Effectiveness of combination therapy could also be noted by a drastic decrease in the number of eggs in the liver and small intestine. All eggs found were dead, indicating a direct effect on ovigenesis. Although dipyridamole was less effective than NBMPR-P or dilazep in protecting the host from the toxicity of tubercidin or nebularine, the combinations with dipyridamole produced similar significant therapeutic effects in animals that survived. Mice receiving the combination of tubercidin (or nebularine) plus NBMPR-P or dilazep, as well as those that survived the combination with dipyridamole, appeared healthy and were found to have normal size livers and spleens. These results suggest that highly selective toxicity against schistosomes can be achieved by coadministration of various nucleoside transport inhibitors with adenosine analogues.

Topics: Adenosine; Animals; Biological Transport; Dilazep; Dipyridamole; Drug Therapy, Combination; Female; Mice; Purine Nucleosides; Ribonucleosides; Schistosoma mansoni; Schistosomiasis; Thioinosine; Thionucleotides; Toyocamycin; Tubercidin; Uracil

Nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) inhibits the transport of nucleosides, including tubercidin, in mammalian systems but not in Schistosoma mansoni. Administration of NBMPR-P with high doses of tubercidin (lethal doses if injected alone) by intraperitoneal injection into S. mansoni-infected mice was highly toxic to the parasite but not to the host. Combination therapy resulted in a striking decrease in the number and copulation of worms. The few worms that could be found were so stunted that it was difficult to identify their sex. Mice receiving the combination of tubercidin plus NBMPR-P appeared healthy and had normal-sized livers and spleens. Combination therapy also caused a drastic decrease in the number of eggs in the liver (from 32,500 to 1,800 eggs per liver) and in the intestine (from 1,295 to 2 eggs per cm2). All eggs found were dead, indicating the termination of oviposition. Very few granulomas were detected in livers of treated animals. Sections of these livers showed lesions containing dead worms and what appeared to be a process of regeneration of normal tissue around old granulomas. Thus, combination therapy reduced the number and the progress of the primary pathological lesions associated with schistosomiasis. These results demonstrate that through combination therapy, highly selective toxicity against a parasite can be achieved. The effectiveness, simplicity, and practicality of host protection afforded by this method may yield a promising chemotherapeutic approach for the treatment of schistosomiasis and other parasitic diseases.

Topics: Animals; Biological Transport; Disease Models, Animal; Drug Therapy, Combination; Female; Inosine; Mice; Ribonucleosides; Schistosomiasis; Thioinosine; Thionucleotides; Tubercidin