Treatment of schistosomiasis by purine nucleoside analogues in combination with nucleoside transport inhibitors.
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.
Division of Biology and Medicine, Brown University, Providence, RI 02912.
M H
MH
el Kouni
N J
NJ
Messier
S
S
Cha
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004109:Dilazep / Q000627:therapeutic use; D004176:Dipyridamole / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D051379:Mice; D011684:Purine Nucleosides / Q000627:therapeutic use* / Q000633:toxicity; D012263:Ribonucleosides / Q000633:toxicity; D012550:Schistosoma mansoni / Q000378:metabolism; D012552:Schistosomiasis / Q000188:drug therapy*; D013868:Thioinosine / Q000031:analogs & derivatives / Q000627:therapeutic use; D013873:Thionucleotides / Q000627:therapeutic use; D014127:Toyocamycin / Q000633:toxicity; D014372:Tubercidin / Q000633:toxicity / Q000031:analogs & derivatives; D014498:Uracil / Q000031:analogs & derivatives / Q000627:therapeutic use
D011684:Purine Nucleosides; D012263:Ribonucleosides; D013873:Thionucleotides; C034753:5-benzylacyclouridine; D013868:Thioinosine; D014498:Uracil; D004176:Dipyridamole; C028318:nitrobenzylthioinosine 5'-monophosphate; C038031:9-deazaadenosine; C005248:nebularine; D004109:Dilazep; D000241:Adenosine; D014127:Toyocamycin; D014372:Tubercidin