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 lipo somes, 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.

Berberine, a quaternary alkaloid, and several of its derivatives were tested for efficacy against Leishmania donovani and Leishmania braziliensis panamensis in golden hamsters. Tetrahydroberberine was less toxic and more potent than berberine against L. donovani but was not as potent as meglumine antimonate (Glucantime), a standard drug for the treatment of leishmaniasis. Only berberine and 8-cyanodihydroberberine showed significant activity (greater than 50% suppression of lesion size) against L. braziliensis panamensis.

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.

No abstract

Standard therapy of human visceral leishmaniasis with parenteral pentavalent antimonial agents is generally curative but has the disadvantages of a 28-day treatment course, occasional treatment failures, and toxicity.The antifungal and antileishmanial agent amphotericin B has been complexed with lipids to develop a less toxic formulation of amphotericin B. Because lipid particles are phagocytized by the reticuloendothelial system, lipid-associated amphotericin B should be concentrated in infected macrophages and be very effective against visceral leishmaniasis. One formulation, amphotericin B cholesterol dispersion (ABCD) (Amphocil), was tested for antileishmanial activity in Leishmania donovani-infected hamsters. In the first experiment, hamsters were infected, administered with the drug 3 days later, and then sacrificed after a further 4 days. ABCD {dose needed to suppress 99%o of hepatic parasites compared with controls [SD (99) Leishmaniasis results from infection with protozoal parasites of the genus Leishmania. Insect-transmitted forms of leishmaniae are inoculated into the skin via the bite of a female sandfly. The insect-transmitted forms cannot survive long in a mammalian host: within a few hours, the only parasites to be seen are within mononuclear phagocytes. Throughout the rest of the interaction between the parasite and its human host, leishmaniae are obligate intramacrophage microorganisms. Visceral leishmaniasis results from infection of the macrophages of the liver, spleen, and bone marrow with leishmaniae. The symptoms of established disease are fever, weight loss, hepatosplenomegaly, and pancytopenia. If untreated, established disease is characteristically fatal because of intercurrent infections such as diarrhea and pneumonia.The first antileishmanial chemotherapeutic agents with a favorable therapeutic index, the pentavalent antimonial agents (Sb), were introduced in the 1940s and are still the primary therapy for all forms of leishmaniasis. The formulations available then and now are sodium stibogluconate (Pentostam), in which Sb is reacted with gluconic acid to form an unknown number of compounds of unknown structure (3), and meglumine antimonate (Glucantime), in which pentavalent antimony is reacted with the sugar meglumine to form a similarly unknown set of products. Although Sb will heal approximately 90% of patients with visceral disease (10), there are several disadvantages to Sb therapy: the standard regimen is 28 days (40 days in India) of parenteral injections, modest to intolerable toxicity occurs, and a small percentage of cases (-10%) tive agent for treatment of the leishmaniases but is little employed because of the side reactions of fever and phlebitis during infusion, anemia, kidney dysfunction, and hypokalemia. The reason that this antifungal agent is also an antileishmanial agent is that both leishmaniae and fungi contain a 24-substituted sterol (ergosterol or episterol) as the major membrane sterol (2, 9), whereas in mammalian cells the major sterol is cholesterol. Amphot...