Anticancer agents suppressive for adult parasites of filariasis in Mongolian jirds.

Eight chemical structures not previously reported to possess antifilarial activity have been identified. A total of 79 compounds with anticancer properties were evaluated for possible macrofilaricidal activity against Brugia pahangi and Acanthocheilonema viteae transplanted into male Mongolian jirds (Meriones unguiculatus). All eight active compounds were suppressive for the onchocerciasis type (Acanthocheilonema viteae) of the disease. None was macrofilaricidal for the lymphatic form (Brugia pahangi). These new structures may represent a nucleus around which effective drugs can be synthesized.

Polyamines: agents with macrofilaricidal activity.

There is a need for effective macrofilaricidal drugs. The polyamine metabolism of filarial worms has been recognized as a possible target for effective drug action. In an attempt to identify agents that might provide leads in developing an effective macrofilaricide, 78 polyamine compounds were selected from among > 250,000 structures that have been amassed by the Walter Reed Army Institute of Research, in the U.S.A. These thousands of agents have been chosen principally for drug-development programmes for other parasitic diseases. The 78 prospective drugs selected were evaluated for their macrofilaricidal activity against Brugia pahangi and Acanthocheilonema viteae, in male Mongolian jirds (Meriones unguiculatus). The animal models using these two parasites were designed to mimic, in so far as possible, human lymphatic filariasis and onchocerciasis, respectively. Thirteen of the compounds were found to be active although none of these has been previously reported to be macrofilaricidal. Two were suppressive for B. pahangi and 11 for A. viteae. These active agents may represent a nucleus around which highly effective drugs can be synthesised.

Activity of anticancer compounds against Trypanosoma cruzi-infected mice.

Chagas' disease, which is caused by Trypanosoma cruzi, remains essentially incurable. Due principally to a lack of profit incentive, the pharmaceutical industry has had limited interest in developing new antichagasic drugs. Thus, a search for agents that exhibit activity against T. cruzi, although medicaments have been developed for the treatment of other diseases, seems justifiable. Responding to evidence that the principal biochemical differences between mammalian cells and African trypanosomes apply equally to T. cruzi, our evaluations were conducted. Previous work showed the effectiveness of anticancer agents against T. rhodesiense. In the present studies, 76 anticancer compounds were assessed for their ability to suppress the trypomastigotes of T. cruzi- infected mice. Five compounds were found to be active. The most effective was cycloheximide, which was more than six times as effective as the standard, nifurtimox.

In pursuit of drugs for American trypanosomiasis: evaluation of some "standards" in a mouse model.

Forty-nine "standard" compounds known to be useful in the treatment of other diseases were tested for their suppressive activity against the trypomastigotes of Trypanosoma cruzi-infected mice. The most active was the antidepressant protriptyline, which was almost three times as effective as the reference drug, nifurtimox. A major value of the present data is to demonstrate the refractoriness of the T. cruzi parasite against many of the drug standards that have known biological activity.

Chagas' disease: a search for treatment and a question--should the disease be of military concern?

If military forces are required to operate in areas that are endemic for Chagas' disease, the occupation should be of critical concern. These areas, located in Central and South America, are many. The matter is of particular importance because no suitable drug exists to treat individuals who contract the disease. We examined 60 compounds of a chemical class, thiosemicarbazones, known to have some activity against the disease. The work was carried out using Trypanosoma cruzi-infected mice. Of the 60 potential drugs evaluated, 12 showed significant suppressive activity. One of these compounds was almost 50% greater than the reference drug used in the test system.

Evidence that certain 8-aminoquinolines are potentially effective drugs against Chagas disease.

Forty 8-aminoquinolines (a chemical class with members having some activity against Trypanosoma cruzi infections) were evaluated for their effectiveness in reducing the 14-day parasitaemias of 4-6 week-old, female, albino mice infected with a Brazilian strain of T. cruzi. Six of the compounds were more active or as active as the reference drug, nifurtimox, and one was > 13-fold as efficacious. Certain members of the series tested warrant further evaluation.

Primaquine analogues that are potent anti-Trypanosoma cruzi agents in a mouse model.

Seventy-seven primaquine analogues were evaluated for their effectiveness in reducing the parasitaemias in female albino mice (aged 4-6 weeks) which had been infected with a Brazilian strain of Trypanosoma cruzi 15 days earlier. Of the analogues tested, 23 were more effective than the reference drug, nifurtimox, and one was > 14-fold as effective as the standard and almost four times as active as primaquine itself. Certain members of the series tested warrant further evaluation.

Filariasis testing in a jird model: new drug leads from some old standbys.

A total of 65 compounds, most of which were from chemical classes having members known to be active against one or more parasitic organisms, were evaluated against Brugia pahangi and Acanthocheilonema viteae for macrofilaricidal activity in male Mongolian jirds (Meriones unguiculatus). Sixteen of the 65 compounds tested suppressed the number of parasites. Of these 16, three were suppressive for B. pahangi, 10 for A. viteae, and three for both parasites. The antibiotic nigericin and the antihistaminic isothipendyl were found to be most active.

A new class of anti-filariasis compounds: a preliminary look.

Parasitic nematode worms which produce filariasis in humans place approximately one billion people at risk in more than 75 countries. More than 100 million people are infected with these diseases and are recognized as being of significant military importance. During World War II, filariasis was among the leading causes of medical evacuation from the entire South Pacific area. Agents available to treat the diseases exhibit significant toxicity. Better drugs are urgently needed. Data are reported from work using a Mongolian jird animal model on a new class of potential drugs, thiosemicarbazones. These compounds exhibit activity against the parasites which cause both lymphatic filariasis and the "onchocerciasis type" of the disease.