Chemotherapy of Babesia microti infections in Mongolian Jirds.

For identifying drugs which might be effective in the treatment of human Babesia microti infections, 20 selected antiprotozoal agents or combinations of agents were tested for activity against B. microti in Mongolian jirds (meriones unguiculatus). 4-Methyl-primaquine and aromatic diamidines, including diminazene and pentamidine, were the most effective compounds tested.

Leishmaniasis: in search of new chemotherapeutic agents.

Members of a class of compounds designated lepidines (8-amino-6-methoxy-4-methylquinoline derivatives) were tested in a hamster-Leishmania donovani model and found to have activity many-fold that of a reference drug meglumine antimoniate. One of them, 8-(7-isopropylaminoheptylamino)-6-methoxy-4-methylquinoline, was found to be 138 times as effective as the standard antimonial drug used.

Anticancer agents and antitrypanosomiasis activity in mice.

Of 303 compounds (66 active against cancer and 237 inactive against cancer) obtained from the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland, 25 were found to be active against Trypanosoma rhodesiense infections of ICR/Ha Swiss mice. Fifteen of these 25 compounds also had anticancer properties. The percentage of anticancer compounds found to have antitrypanosomiasis properties was 22.7. This percentage compares with 6% antitrypanosomiasis compounds among compounds selectecd by other methods.

Sporozoite-induced malaria: therapeutic effects of glycolipids in liposomes.

Liposomes containing neutral glycolipids with a terminal glucose or galactose, when injected intravenously, prevented the appearance of erythrocytic forms of malaria (Plasmodium berghei) in mice previously injected with sporozoites. Inhibitory glycolipids included glucosyl, galactosyl, or lactosyl ceramide. Inhibition was not observed with liposomes containing ceramide, phosphocholine ceramide, sulfogalactosyl ceramide (sulfatide), or ganglioside GM1. Liposomes containing glycolipids did not inhibit infection transmitted by injecting blood containing erythrocytic stages of malaria. These results may have therapeutic implications in the treatment of malaria. Analysis of the mechanism of interference with the life cycle of malaria by liposomal glycolipids may yield information about the interactions of parasites with cellular membranes.

A new chemical series active against African trypanosomes: benzyltriphenylphosphonium salts.

Antitrypanosomal activity for benzyltriphenylphosphonium salts is reported for the first time. Testing was conducted using Trypanosoma rhodesiense infected mice. Of 70 phosphorus-containing compounds tested, 21 were active. Sixteen of these active chemical species were benzyltriphenylphosphonium salts. Four were nonbenzyl triphenyl compounds. The remaining active drug was a benzyldiphenylphosphonium salt.

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.

The antileishmanial activity of lepidines.

A series of lepidines (6-methoxy-4-methyl-8-aminoquinoline derivatives) was studied in a hamster-Leishmania donovani model. Members of this class were found to have activity many-fold that of the standard, meglumine antimoniate (Glucantime). One of them, 8-(6-diethylamino-hexylamino)-6-methoxy-4-methylquinoline, designated WR 6026, when given orally was over 700 times as effective as the standard antimonial drug.

Therapy of leishmaniasis: superior efficacies of liposome-encapsulated drugs.

Liposomes containing antimonial compounds trapped in the aqueous phase were tested in the treatment of experimental leishmaniasis. The rationale of this approach was based on the hypothesis that the liposomes and the parasite are taken up by the same cell, the reticuloendothelial cell, and we present electron microscopic evidence that supports this hypothesis. Suppression of leishmaniasis was quantified by determining the total number of parasites per liver from impression smears. When two antimonials, meglumine antimoniate and sodium stibogluconate, were encapsulated within liposomes, each was more than 700 times more active compared to either of the free (unencapsulated) drugs. After infection, if untreated, all of the hamsters eventually would die from the disease. Liposome-encapsulated meglumine antimoniate was about 330-640 times more effective in causing a drop in the death rate than was the free antimonial. The efficacy of treatment was influenced by the lipid composition and charge of the liposomes. For example, positively charged liposomes containing egg phosphatidylcholine were much less effective than negatively charged ones. In contrast, positively and negatively charged sphingomyelin liposomes were equally effective. Liposomes containing phosphatidylserine (which were negatively charged, but also had a much higher charge density) were among the less-effective preparations. Among those tested, the most consistently efficacious liposomes contained highly saturated long-chain phospholipids (eg., dipalmitoyl phosphatidylcholine), cholesterol, and a negative charge. We conclude that liposomes may be useful as carriers of drugs to treat infectious diseases involving the reticuloendothelial system. The toxicities of antimony are very similar to those of arsenic. Encapsulation of antimonial drugs and reduction of the dose required for effective therapy should minimize such systemic toxicities as acute cardiomyopathy and toxic nephritis.

In search of anti-Trypanosoma cruzi drugs: new leads from a mouse model.

Nine of 25 carefully selected compounds (from a stock of more than 200 000 chemical species amassed principally as a result of testing against other parasitic diseases) were found to have significant suppressive activity against the parasites in the blood of a Trypanosoma cruzi mouse model. Eight of these compounds evaluated in this model had suppressive activity equal to or greater than the reference compound, nifurtimox. For the first time, suppressive activity against T. cruzi is reported for a 7-aminoquinoline, a phosphonium salt, and TAC pamoate; The biological model is believed to be able to serve as a means of identifying other new "leads* in seeking drugs broadly effective against T=ruzi infections in man.