Efficacious Treatment of Experimental Leishmaniasis with Amphotericin B-Arabinogalactan Water-Soluble Derivatives
- 1 September 1999
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 43 (9), 2209-2214
- https://doi.org/10.1128/aac.43.9.2209
Abstract
In this study, we tested the efficacy of amphotericin B (AmB)-arabinogalactan (AmB-AG) conjugates for the treatment of experimental leishmaniasis. Chemical conjugation of AmB to a water-soluble, biodegradable, and biocompatible polymer could present many advantages over presently available AmB formulations. Two conjugates were tested, a reduced (rAmB-AG) form and an unreduced (uAmB-AG) form. In vitro, the drug concentrations which lower the values of parasites (for promastigotes) or infected macrophages (for amastigotes) to 50% of the untreated values (ED 50 s) of uAmB-AG and rAmB-AG were 0.19 and 0.34 μg/ml, respectively, for Leishmania major promastigotes and 0.17 and 0.31 μg/ml, respectively, for amastigotes. The effect on Leishmania infantum -infected macrophages was more marked, with ED 50 s of 0.035 μg/ml for rAmB-AG and 0.027 μg/ml for uAmB-AG. In in vivo experiments, BALB/c mice injected with L. major were treated from day 2 onwards on alternate days for 2 weeks. Both conjugates, as well as liposomal AmB (all at 6 mg/kg of body weight) and Fungizone (1 mg/kg), significantly delayed the appearance of lesions compared to that in untreated mice. In addition, both conjugates, but not liposomal AmB, were significantly more effective than Fungizone. Subcutaneous injection of the conjugates (6 mg/kg) was significantly more effective than liposomal AmB in delaying the appearance of lesions. Higher AmB concentrations of up to 12 mg/kg could be administered by this route. When an established infection was treated, uAmB-AG was somewhat more effective than liposomal AmB. In summary, water-soluble polymeric AmB derivatives were found effective and safe for the treatment of leishmanial infections. The conjugates, which are stable and can be produced relatively cheaply (compared to lipid formulations), can be used in the future for the treatment of leishmaniasis infections.Keywords
This publication has 19 references indexed in Scilit:
- A Novel Injectable Water-Soluble Amphotericin B-Arabinogalactan ConjugateAntimicrobial Agents and Chemotherapy, 1999
- Liposomal Amphotericin BDrugs, 1998
- Amphotericin B is superior to sodium antimony gluconate in the treatment of Indian post kala azar dermal leishmaniasisPathogens and Global Health, 1997
- Release of Amphotericin B from Delivery Systems and its Action Against Fungal and Mammalian CellsJournal of Drug Targeting, 1997
- Lipid Formulations of Amphotericin B: Recent Progress and Future DirectionsClinical Infectious Diseases, 1996
- Amphotericin versus sodium stibogluconate in first-line treatment of Indian kala-azarThe Lancet, 1994
- Pharmacokinetics and Toxicity of Continuous Infusion Amphotericin B in Cancer PatientsJournal of Pharmaceutical Sciences, 1989
- The in vitro Susceptibility of Macrophages Infected with Amastigotes of Leishmania spp. to Pentavalent Antimonial Drugs and Other Compounds with Special Relevance to Cutaneous IsolatesPublished by Springer Nature ,1989
- A Review of Complications of Amphotericin-B Therapy: Recommendations for Prevention and ManagementDrug Intelligence & Clinical Pharmacy, 1980
- Studies on Larch Arabogalactan IIJournal of Pharmaceutical Sciences, 1961