Antileishmanial activity of liposome-encapsulated amphotericin B in hamsters and monkeys

130

This study was designed to examine the antileishmanial activity of the oxygenated chalcone licochalcone A in mice and hamsters infected with Leishinunia parasites. Intraperitoneal administration of licochalcone A at doses of 2.5 and 5 mg/kg of body weight per day completely prevented lesion development in BALB/c mice infected with Leishmania major. Treatment of hamsters infected with L. donovani with intraperitoneal administration of licochalcone A at a dose of 20 mg/kg of body weight per day for 6 consecutive days resulted in a >96% reduction of parasite load in the liver and the spleen compared with values for untreated control animals. The [3H]thymidine uptake by the parasites isolated from the treated hamsters was only about 1% of that observed in parasites isolated from the controls. Oral administration of licochalcone A at concentrations of 5 to 150 mg/kg of body weight per day for 6 consecutive days resulted in >65 and 85% reductions ofL. donovani parasite loads in the liver and the spleen, respectively, compared with those of untreated control hamsters. These data clearly demonstrate that licochalcone A is a promising lead for the development of a new drug against leishmaniases.The World Health Organization has identified leishmaniases as a major and increasing public health problem (23,26). The visceral form of the disease, known as kala-azar, is widely distributed in many parts of the world, particularly Africa, Asia, Latin America, the Middle East, and the Mediterranean Basin (13,23,26

Section: Resultsmentioning

confidence: 99%

Antileishmanial activity of licochalcone A in mice infected with Leishmania major and in hamsters infected with Leishmania donovani

Chen

Christensen

Theander

et al. 1994

130

“…A cell-targeting phenomenon forms the basis for the enhanced antileishmanial activity observed with liposomal amphotericin B compared to that observed with free drug (1,2). At this stage, there is as yet no evidence to suggest that MB-III would also have a similar cell-targeting potential, but its selective toxicity toward reticuloendothelial cells at least suggests this possibility (10).…”

Section: Discussionmentioning

confidence: 98%

Comparative Activities of the Triterpene Saponin Maesabalide III and Liposomal Amphotericin B (AmBisome) againstLeishmania donovaniin Hamsters

Maes

Germonprez

Quirijnen³

et al. 2004

Maesabalide III (MB-III), an oleane triterpene saponin isolated from the Vietnamese plant Maesa balansae, is a new antileishmanial lead compound whose activity against Leishmania donovani (MHOM/ET/67/L82) in groups of five golden hamsters was evaluated after administration of a single subcutaneous dose on either day 1 (prophylactic treatment) or day 28 (curative treatment) after infection. Liposomal amphotericin B (AmBisome), administered intravenously at 5 mg/kg of body weight, was used as the reference drug. Amastigote burdens in liver, spleen, and bone marrow were determined either 7 days (early effects) or 56 days (late effects) after treatment. Prophylactic administration of MB-III at 0.2 mg/kg reduced liver amastigote burdens by 99.8 and 83% within 7 and 56 days after treatment, respectively. In the latter group, however, all animals became ill and some died. Among other tropical diseases, insufficient resources are being allocated to tackle leishmaniasis (15). The emergence of resistance to the first-line drugs (19) and the fact that the drugs available at present do not adequately cover the prime requirements for effective disease control (4) explain why new drug discovery must remain a pivotal objective (9). We recently demonstrated that olenane triterpene saponins (PX-6518) are promising new antileishmanial lead structures (10). By using the Leishmania donovani-infected BALB/c mouse model, administration of a single subcutaneous dose at 0.4 mg/kg of body weight day 1 after infection reduced liver amastigote burdens by about 95% within 7 days of treatment. Although the BALB/c model is highly validated for drug screening purposes, it does not reproduce the progressive disease features that are seen in human visceral leishmaniasis (VL) (14). The golden hamster is regarded to be more sensitive to progressive VL and is a better model for prediction of the effects of drugs on progressive VL (11, 16) and was therefore selected as the experimental host in the present study. From advanced characterization of the individual constituents of PX-6518, maesabalide III (MB-III) (Fig. 1) was retained as a potential drug development candidate (10). Although multiple-dose treatment schedules are adopted in standard clinical practice, single-dose regimens for MB-III and liposomal amphotericin B (AmBisome) were envisaged in the present study because a high degree of efficacy is already obtained after administration of a single dose (10) and because this provided a more accurate basis for comparative assessment of their efficacies. Among the commercial liposomal formulations of amphotericin B, AmBisome was shown to have the best antileishmanial potential under experimental conditions (20) and in clinical practice as a low, single-dose treatment (18). MATERIALS AND METHODSParasite. Amastigotes of a drug-sensitive L. donovani strain (MHOM/ET/67/ L82) were harvested from the spleens of 6-week-infected donor hamsters (Mesocrisetus auratus). The inoculum for infection was prepared as described previously (10) and involved purif...

“…In animals administered with dextrose and sacrificed 2 days later (12 days after infection with parasites), there were more organisms (1.7 x 109 per liver) than in the lightly infected animals in experiment 1 (4) or when amphotericin B in the form of distearoylphosphatidylglycerol was used in a mouse model (5), the experiments were performed at different times or in different models and the results are noncomparable.…”

Section: Methodsmentioning

confidence: 99%

“…Hamsters were infected with Leishmania donovani (WR# 378) and administered with drugs exactly as described previously (4,8). In brief, 60-to 80-g hamsters (Mesocricetus auratus) were administered intracardiac injections of approximately 107 L. donovani amastigotes (Khartoum strain).…”

Section: Methodsmentioning

confidence: 99%

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

Berman

Ksionski

Chapman

et al. 1992

Self Cite

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...