Treatment of experimental visceral leishmaniasis with amphotericin B in stable albumin microspheres.
Hydrophilic albumin microspheres are proposed as a new delivery system for amphotericin B (AMB; AMB microspheres). The acute toxicity of AMB microspheres was lower than that of the AMB-deoxycholate (AMB-Doc) reference formulation in hamsters. Lethal doses in healthy and infected animals were improved at least eight times. Intravenous bolus administration of doses of AMB microspheres up to 40 mg/kg of body weight did not produce acute symptoms of toxicity. The efficacy of this new formulation was tested against Leishmania infantum-infected hamsters at doses of 2, 10, 20, and 40 mg/kg. With the 2-mg/kg dose, the activity of AMB, as assessed through the parasite load reductions in the liver and spleen and the evolution of antibody levels, was also improved (P < 0.05) by use of the AMB microsphere system. At the higher doses of 10, 20, and 40 mg/kg, reductions in parasite levels of more than 99% were achieved in the liver and spleen after the administration of AMB microspheres. A pharmacokinetic study was performed to study the serum, liver, and spleen AMB concentrations after administration of AMB microspheres and the reference formulation. Interestingly, a significant accumulation of AMB in the spleen and liver was observed after AMB microsphere administration. Our results suggest that this new formulation is a promising alternative to the conventional AMB-Doc formulation for the treatment of visceral leishmaniasis.
Department of Pharmacy and Pharmaceutical Technology, Universidad Complutense, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.
J A
JA
Sánchez-Brunete
M A
MA
Dea
S
S
Rama
F
F
Bolás
J M
JM
Alunda
R
R
Raposo
M T
MT
Méndez
S
S
Torrado-Santiago
J J
JJ
Torrado
D000666:Amphotericin B / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000953:Antigens, Protozoan / Q000032:analysis; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D006224:Cricetinae; D016503:Drug Delivery Systems; D007275:Injections, Intravenous; D007674:Kidney Diseases / Q000139:chemically induced; D018314:Leishmania infantum / Q000187:drug effects; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008099:Liver / Q000469:parasitology; D008297:Male; D008647:Mesocricetus; D008863:Microspheres; D010316:Particle Size; D012709:Serum Albumin; D013154:Spleen / Q000469:parasitology
D000953:Antigens, Protozoan; D000981:Antiprotozoal Agents; D012709:Serum Albumin; D000666:Amphotericin B