formycins and Leishmaniasis

A single dose of the adenosine analogue Formycin A (FoA) (20 mg/kg), combined with nitrobenzyl mercaptopurine ribonucleoside 5'-monophosphate (NBMPR-P) (10 mg/kg), a prodrug of nitrobenzylthioinosine (NBMPR), was effective in reducing the size of the foot pad lesions from 7.4 +/- 0.2 to 3.9 +/- 0.2 of Syrian golden hamsters infected with Leishmania major. There was a statistical difference (p < 0.01) in the size of the foot pad by the fifth day between the infected groups that received treatment and the controls, as well as between the groups that were treated with combined drugs and FoA only. The initial reduction in size of the foot pad noted in the group that received only FoA was transient. The effect of FoA or FoA combined with NBMPR on the in vitro cultured promastigotes was similar, indicating that the transport inhibitor might be manipulating the availability of FoA in the host's macrophages where the leishmania amastigotes are resident. The results further indicate the need to explore the usefulness of combining cytotoxic nucleoside analogues with host protecting nucleoside transport inhibitors in the treatment of protozoan parasitic infections.

Topics: Animals; Cricetinae; Drug Combinations; Female; Foot; Formycins; Leishmania; Leishmaniasis; Mesocricetus; Microbial Sensitivity Tests; Thioinosine

Using foot-pad infection of female C57BL/6, DBA/2J and NMRI-IVIC mice as an animal model for American cutaneous leishmaniasis (ACL), we evaluated the inhibitory effect of Formycin B (FoB) on the infection produced by 7 different Leishmania isolates. When treatment was initiated some days, or even some weeks, after infection a significant leishmanistatic effect was detected on mice infected with all Leishmania isolates, which reached 30-55 weeks for some isolates. The optimal dose schedule was 1.25 mg/kg body weight/day, injected intraperitoneally for 20 consecutive days. Significant differences in the sensitivity of various Leishmania spp. to FoB were found, either in vivo, or in vitro where a high [3H]FoB incorporation rate was found only for certain Leishmania isolates. The low toxicity of this drug and the sensitivity of the 7 Leishmania isolates tested suggest that FoB could be useful in the treatment of ACL.

Topics: Animals; Antibiotics, Antineoplastic; Cricetinae; Female; Formycins; Leishmania; Leishmania braziliensis; Leishmania mexicana; Leishmaniasis; Mesocricetus; Mice; Mice, Inbred C57BL; Mice, Inbred DBA

Allopurinol and allopurinol ribonucleoside tested in vitro and in vivo for activity against Leishmania donovani. Activity in vitro was low against the amastigote form of this parasite with ED50 values of the order of 54 and 96 microM and 86 and 213 microM respectively for the two compounds. In vivo inhibition of up to 47% was achieved with allopurinol ribonucleoside given in the drinking water. However, low blood levels were found in the mouse relative to those in man. Low in vivo activity was also seen with allopurinol ribonucleoside against L. major and other species of Leishmania causing cutaneous lesions. The metabolism of allopurinol ribonucleoside in aldehyde oxidase deficient mice (inbred strains DBA/1, DBA/2) resembled that of man, but the antileishmanial activity remained low. Other compounds, formycin B, sinefungin and the lepidine WR6026 were highly active against mice infected with L. donovani or L. major.

Topics: Adenosine; Allopurinol; Aminoquinolines; Animals; Antiprotozoal Agents; Cricetinae; Female; Formycins; Leishmania; Leishmaniasis; Leishmaniasis, Visceral; Macrophages; Mice; Mice, Inbred Strains; Ribonucleosides; Thionucleosides

Formycin B is a potent inhibitor of growth of the promastigote forms of Leishmania tropica, L. mexicana, L. braziliensis, and L. donovani. The metabolic products formed in these organisms are formycin B 5'-monophosphate and formycin A 5'-mono-, di-, and triphosphates, with formycin A 5'-triphosphate predominating. In addition, formycin A is extensively incorporated into RNA. From the metabolic profile, we conclude that formycin B is first converted to the 5'-monophosphate by the nucleoside phosphotransferase found in Leishmania and is subsequently converted to cytotoxic adenosine nucleotide analogs of formycin A that become incorporated into RNA. The metabolism and mechanism of formycin B appears to be qualitatively similar to that of allopurinol riboside, but quantitative differences and species selectivity suggest that these agents may have a different spectrum of activity as potential anti-leishmanial agents.

Topics: Antibiotics, Antineoplastic; Formycins; Leishmania; Leishmaniasis; Ribonucleotides

Topics: Amphotericin B; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antimony; Formycins; Humans; Imidazoles; Ketoconazole; Leishmaniasis; Pentamidine; Piperazines

Topics: Adenylosuccinate Synthase; Animals; Antibiotics, Antineoplastic; Cricetinae; Formycins; Kinetics; Leishmania; Leishmaniasis; Mesocricetus; Phosphorylation; Ribonucleotides; Species Specificity