Kenneth E. Kinnamon

Activity of Antitumor Drugs Against African Trypanosomes

Of 49 compounds known to have antitumor properties, 6 were found to have significant activity against Trypanosoma rhodesiense infections in mice. Activity against the African trypanosomes has not been reported previously for any of these six compounds. In order of decreasing activity these compounds were: (i) imidazole-4-carboxamide, 5-(3,3-dimethyl-1,1-triazene), (ii) inosine diglycolaldehyde, (iii) cis-diamminedichloro-platinum, (iv) streptozotocin, (v) coralyne sulfate, and (vi) 5-fluoro-2′-deoxyuridine. The percentage of “hits” (12.2%) from these known antitumor agents was approximately twice as great as when other means are employed for the selection of compounds for this test system.

Leishmania donovani, Plasmodium berghei, Trypanosoma rhodesiense: antiprotozoal effects of some amidine types.

Abstract A series of 39 diamidines and cyclic congeners was investigated for antiprotozoal effects in standard animal models. The test systems employed were the following: Leishmania donovani in hamsters, Plasmodium berghei (trophozoite) in mice, and Trypanosoma rhodesiense in mice. None of the compounds was found to exhibit appreciable antimalaria or antileishmanial activity. One compound, 2,5-bis(4-guanylphenyl)furan dihydrochloride, was identified as having antitrypanosomal activity in the same range as pentamidine, and deemed worthy of further study.

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.

Mouse Endogenous Spleen Counts as a Means of Screening for Anti-Radiation Drugs

Abstract Using eight radioprotective compounds, a comparison was made between the “standard” survival method and a method employing the counting of macroscopic spleen colonies in assessing the degree of radioprotection. The two methods yielded similar assessments of the degree of radioprotection afforded and required about the same amount of man-hours to conduct the procedure. The spleen colony method offers the advantage of completing the assessment after 10 days rather than 30 and yielding fresh tissues from all scored test animals. The use of a system in which macroscopic spleen colonies are counted offers an alternative to employing the method of animal survival in the quantitative assessment of compounds for radioprotective activity.

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.

Plasmodium berghei: Combining folic acid antagonists for potentiation against malaria infections in mice

Abstract The drugs 2,4-diamino-6-(2-naphthyl-sulfonyl)-quinazoline (WR 158,122)and its tetrahydro analog (WR 180,872) were found to act synergistically in reducing the parasitemia of Plasmodium berghei infected mice. Evidence was found that both the drugs which are potent folic acid antagonists were acting at different sites in the folic acid metabolic pathway, neither of which was at the action site of p -aminobenzoic acid (PABA)inhibitors. Advantages of drug combinations in malaria chemotherapy are discussed.

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.

Survival of Bone Marrow-Engrafted Mice Subsequent to Protection from Lethal Radiation by WR 2721

For the first time data are presented for animals treated with bone marrow cells after lethal radiation exposure while protected with WR 2721 (the single radioprotective chemical compound with the highest known dose reduction factor). The LD/sub 50/ /sub 30/ (lethal dose to 50% in 30 days) for mice exposed to whole-body /sup 60/Co radiation was elevated from 824 +- 8 rad in unprotected and untreated mice to (a) 1181 +- 33 rad in animals which received syngeneic bone marrow cells after exposure; (b) 1342 +- 27 rad in animals which received WR 2721 before radiation exposure; and (c) 1608 +- 33 rad in animals receiving both the radioprotective agent before exposure and bone marrow engraftment after exposure.

Plasmodium cynomolgi: Folic acid antagonist combinations for treatment of malaria in rhesus monkeys

Abstract The dihydrofolate reductase inhibitor 2,4-diamino-6-(2-naphthyl-sulfonyl)-quinazoline and its tetrahydro analog 2,4-diamino-6-(2-naphthyl-sulfonyl)-5,6,7,8-tetrahydroquinazoline were evaluated for possible synergism in treating trophozoite-induced Plasmodium cynomolgi var. bastianellii malaria of rhesus monkeys. The degree of synergism, if it exists, was found to be not nearly as great as observed previously with this combination of drugs against Plasmodium berghei infections of mice.