formycins and Leishmaniasis--Visceral

The dose of orally administered 9-deazainosine calculated to suppress 50% of Leishmania donovani amastigotes in hamster livers was 19 mg/kg (body weight) per day; 96 to 99% of Leishmania organisms were eliminated from the liver and spleen of squirrel monkeys by 50 mg/kg per day. Because these activities were greater than that of the experimental clinical agent allopurinol and comparable to that of the classical agent parenteral pentavalent antimony, 9-deazainosine should be considered for clinical development for visceral leishmaniasis.

Topics: Administration, Oral; Allopurinol; Animals; Cricetinae; Formycins; Guanosine; Injections, Intramuscular; Inosine; Leishmania donovani; Leishmaniasis, Visceral; Liver; Male; Meglumine; Meglumine Antimoniate; Mesocricetus; Organometallic Compounds; Saimiri; Spleen

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, a structural analog of inosine, was evaluated as an orally administrable antileishmanial agent. Against Leishmania donovani in hamsters, it achieved an 85-92% reduction in numbers of parasites in livers of infected animals after oral administration at 13 mg/kg/day for 4 days. Its efficacy by oral administration was approximately four to eight times that by intramuscular administration and four times that of the positive control drug Glucantime by intramuscular administration. The levels of formycin B in serum after the final oral administration of 26 mg/kg/day were 1.4 micrograms/ml at 1 hr and 0.3 microgram/ml at 2 hr. The concentration in liver was greater (9.0 micrograms/ml at 1 hr) and declined more slowly. With this latter dosage or with 104 mg/kg/day there was no acute toxicity of formycin B to bone marrow or formed elements of the blood. The only statistically significant toxicity to the liver was a doubling of serum total bilirubin levels. Comparison of the in vivo efficacy of formycin B against L. donovani to the mild acute toxicity of the drug suggests that formycin B has potential as an oral agent against visceral leishmaniasis.

Topics: Administration, Oral; Animals; Antibiotics, Antineoplastic; Antimony; Bilirubin; Bone Marrow; Cricetinae; Drug Evaluation, Preclinical; Formycins; Leishmaniasis, Visceral; Liver; Meglumine; Meglumine Antimoniate; Mesocricetus; Organometallic Compounds