formycins and Chagas-Disease

The inosine analog formycin B was examined for in vitro and in vivo activities against Trypanosoma cruzi. concentration of formycin B as low as 0.1 microgram/ml markedly inhibited intracellular multiplication of T. cruzi strains both in macrophages and in L929 cells. Mice infected with 10(5) blood form trypomastigotes of the highly virulent strain Y of T. cruzi were completely protected against death by treatment with 11.8 or 5.9 mg of formycin B per kg administered intraperitoneally each day for 19 days. Four different strains of T. cruzi were used, and each was susceptible to formycin B administered either intraperitoneally or orally. Parasitological cure, however, was not achieved with any of the treatments used, including prolonged treatment for up to 10 weeks. Formycin B has a remarkable capacity for inhibiting the in vitro intracellular replication of T. cruzi and protecting mice against death due to the acute infection with the organism. It does not appear, however, to be able to completely eliminate T. cruzi from infected mice.

Topics: Animals; Antibiotics, Antineoplastic; Chagas Disease; Female; Formycins; Mice; Phagocytosis; Time Factors; Trypanosoma cruzi

The anti-Trypanosoma cruzi effect of allopurinol ribonucleoside and formycin B was examined against infections of the sensitive Y and Peru strains in inbred mice, strain DBA/1. Allopurinol ribonucleoside given in the drinking water at doses calculated to be 239, 511 and 929 mg/kg/day for 28 days, prevented the death of the mice but did not eradicate the infection. Formycin B given orally at 100 and 10 mg/kg/day X 5 days, showed a similar effect.

Topics: Allopurinol; Animals; Antibiotics, Antineoplastic; Chagas Disease; Formycins; Mice; Mice, Inbred DBA; Ribonucleosides; Trypanocidal Agents

Strains of Trypanosoma cruzi differ in their susceptibilities to and metabolism of pyrazolopyrimidines. Allopurinol riboside can control but not eliminate infections with a sensitive strain in both tissue culture and mice. Formycin B, which proved to be greater than 10-fold more effective on a weight basis, showed a similar strain specificity but could eliminate an infection with a sensitive strain from tissue culture. However, this drug, unlike allopurinol riboside, was converted to toxic analogues of adenosine mono-, di-, and triphosphate by uninfected tissue culture cells. Thiopurinol and its riboside were effective against all strains unless culture was performed in purine-defined medium. Thus formycin B and allopurinol riboside appear to be good models for the design of antitrypanosomal agents. Suitable modification of the molecule may provide an effective chemotherapeutic agent.

Topics: Adenine; Allopurinol; Animals; Antiprotozoal Agents; Chagas Disease; Drug Resistance; Formycins; Inosine; Mice; Mice, Inbred DBA; Ribonucleosides; Thionucleosides; Trypanosoma cruzi