Activity of amphotericin B cholesterol dispersion (Amphocil) in experimental visceral leishmaniasis

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...

Lycopodium clavatum and Lycopodium complanatum subsp. chamaecyparissus ekstrelerinin antiprotozoal aktivitesi ve sitotoksisitesi

“…We also reported the isolation of some non-polar compounds; namely palmitic acid, cerotic acid, tetradecyl acetate, and 24-alpha-methylcholest-5-enol, and a serratane-type triterpene, alpha-onocerin [33,34]. It has been reported that amphotericin B complexed with cholesterol is at least four times more active than amphotericin B alone in L. donovani-infected hamsters [35]. Moreover, some fatty acid derivatives have been reported with antileishmanial and antimalarial activity [36][37][38][39].…”

Treatment of experimental visceral leishmaniasis in a T-cell-deficient host: response to amphotericin B and pentamidine

“…The latter finding suggests that amphotericin B, traditionally considered a second-line antileishmanial agent (2,8,11,12), may be worth testing as primary therapy for the T-celldeficient patient with visceral infection. Lipid-associated amphotericin B preparations (3,5,6) may prove even more useful.…”

“…Therefore, we have extended our analysis to two other experimentally and clinically active antileishmanial agents, amphotericin B and pentamidine (3,5,6,8,(11)(12)(13), and tested their efficacies in L. donovani-infected nude mice.…”

In vitro and in vivo activity of amphotericin B-lipid formulations against experimental Trypanosoma cruzi infections.

“…Recently, lipid formulations that have lower toxicity have been developed for the treatment of systemic mycoses. 12,14,15 Three commercially available lipid formulations, the liposome AmBisome (NeXtar, San Dimas, CA), the colloidal dispersion Amphocil (Liposome Technology, Inc., Menlo Park, CA), and the lipid complex Abelcet (The Liposome Company, Ltd., London, United Kingdom), have also been shown to be effective against experimental [16][17][18][19] and clinical visceral leishmaniasis, [20][21][22] as well as against experimental cutaneous leishmaniasis. 23 In this study, the experimental activities of these three commercial lipid formulations of amphotericin B were compared with the parent drug, amphotericin B deoxycholate (Fungizone ; E. R. Squibb and Sons, Hounslow, United Kingdom) and the standard drug benznidazole, against experimental infections of T. cruzi in vitro and in vivo.…”