New potent 5-nitroindazole derivatives as inhibitors of Trypanosoma cruzi growth: synthesis, biological evaluation, and mechanism of action studies.

New 5-nitroindazole derivatives were developed and their antichagasic properties studied. Eight compounds (14-18, 20, 26 and 28) displayed remarkable in vitro activities against Trypanosoma cruzi (T. cruzi). Its unspecific cytotoxicity against macrophages was evaluated being not toxic at a concentration at least twice that of T. cruzi IC(50), for some derivatives. The electrochemical studies, parasite respiration studies and ESR experiment showed that 5-nitroindazole derivatives not be able to yield a redox cycling with molecular oxygen such as occurs with nifurtimox (Nfx). The study on the mechanism of action proves to be related to the production of reduced species of the nitro moiety similar to that observed with benznidazole.

Influence of atropine on the acute toxicity of isometamidium.

The effectiveness of atropine in blocking the acute toxic effects of the antitrypanosomal drug isometamidium (ISMM) was evaluated in mice and goats using lethality as the primary index. The median lethal dose (LD50) of ISMM in nonatropinized mice was 45.3 mg/kg bodyweight (SE +/- 5.3 mg/kg bodyweight), whereas the LD50 of ISMM in mice pre-treated with atropine was 71.7 mg/kg bodyweight (SE +/- 13.2 mg/kg bodyweight). The increase in LD50 was about 60%. The ratio of the slope of the dose-response curve for ISMM in non-atropinized mice to that in atropinized mice was about 4:1. The results showed that atropine was effective in considerably reducing the lethal effect of ISMM in mice. In contrast, experiments in goats showed markedly different results; atropine was not effective in reducing the lethality of ISMM. It was concluded that in mice atropine has some beneficial action in cases of overdosage or poisoning by ISMM. Treatment with atropine should be attempted as an antidotal measure in humans accidentally poisoned with ISMM.

Some observations on the toxicosis of isometamidium chloride (samorin) in camels.

Healthy camels were experimentally infected with Trypanosoma evansi and then treated with isometamidium chloride (samorin) at single intravenous doses of 0.5 or 1.0 mg/kg. Five to 10 min after the drug administration, the camels at both dosages showed lacrimation, salivation, trembling, restlessness, frequent urination and defecation, followed by diarrhea. Moreover, the camels at the higher dose showed an unsteady gait for about an hour with hindleg weakness and walking backward. The animals fell to the ground, laid on their sides, and bent their necks into an "S" shaped curve. Three hours after the drug administration all the animals stood up and remained quiet. The treatment increased the concentration of plasma ammonia and total protein. No significant change was found in the plasma bilirubin concentration. Two hours after treatment, the activity of plasma cholinesterase was significantly reduced. The enzyme activity recovered 24 h after drug administration, but was still significantly below the control value. The treatment did not produce statistically significant changes in the hemogram of the infected camels. The results suggest that the drug should not be used clinically against T evansi infection due to its low margin of safety. If the drug is to be used at all in camels, pretreatment with an anticholinergic agent might be considered.