Combination therapy of schistosomiasis by tubercidin and nitrobenzylthioinosine 5'-monophosphate.

Abstract

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.

Adenosine Kinase ofTrypanosoma bruceiand Its Role in Susceptibility to Adenosine Antimetabolites

“…Within the adenosine kinases, the T. brucei enzyme forms a significantly distinct branch together with the AK homologues from Trypanosoma cruzi and Leishmania donovani (LdAK), with which TbAK shares 77% and 74% similarity, respectively. All the charged residues that are indispensable for catalysis in LdAK (Asp 16 , Arg 69 , Arg 131 , and Asp 299 ) (12, 13) are conserved in TbAK (Asp 17 , Arg 70 , Arg 132 , and Asp 299 , respectively). However, with a predicted pI of 5.5, TbAK does not share with LdAK its unusually high pI of 8.8 (11).…”

“…Tubercidin (7-deazaadenosine) is another natural adenosine analogue of potent antitrypanosomal activity. In vivo, its therapeutic window may be widened by the coadministration of NBMPR to block uptake by host cells (16,39). Here we clone and characterize TbAK and investigate by functional expression in the yeast Saccharomyces cerevisiae its potential for the activation (i.e., phosphorylation) of cordycepin, tubercidin, and other adenosine analogues.…”

Cytotoxic Nucleosides and Parasitic Diseases: A New Therapeutic Approach

“…17,18 The same appears to apply to S. haematobium, 19 and a similar drug combination resulted in therapeutic effects in experimentally induced trypanosomiasis. 20 This new approach to the treatment of parasitic organisms is not only interesting from an intellectual point of view but promises to be of practical therapeutic significance.…”

“…It would be useful to have available at least one of the two drugs in an orally applicable, longacting form. Experimental protocols in the treatment of schistosomiasis inmice and in host protection experiments [16][17][18][19] have involved parenteral (intraperitoneal) administration of all drugs used.…”

Flavonoids and Related Compounds as Nucleoside Transporter Inhibitors

“…Nucleoside transporter inhibitors have been used for host tissue protection during experimental treatment of schistosomiasis, [131][132][133] trypanosomiasis, 134 and leishmaniasis 135 . However, certain parasites are known to induce the expression of new inhibitor resistant transporters in the infected mammalian host cells which has been best demonstrated in mammalian erythrocytes infected with malarial parasites.…”