Visceral Leishmaniasis: Drug Carrier System Characteristics and the Ability to Clear Parasites from the Liver, Spleen and Bone Marrow in Leishmania donovani Infected BALB/c Mice

Abstract

The efficacy of various sodium stibogluconate formulations against Leishmania donovani has been investigated using a BALB/c mouse model of visceral leishmaniasis. Only one therapy, multiple dosing with drug loaded sonicated vesicles, liposomes or niosomes, was found to be effective against parasites in the liver, spleen and bone marrow. Other treatments significantly reduced parasite liver burdens but either failed to effect spleen and bone marrow parasites, or were effective but toxic. Prophylactic treatment with sodium stibogluconate preparations, six days before infection, reduced parasite multiplication in the liver (free, niosomal and liposomal drug) and the spleen (sonicated, drug loaded niosomes only), but had no suppressive effect on bone marrow parasite burdens compared with controls. These results indicate that in-vivo sodium stibogluconate persists in some compartments at parasiticidal concentrations and that failure to reach this concentration at some sites of infection such as bone marrow, is the cause of treatment failure and relapse.

Pharmacokinetic and parasitological evaluation of the bone marrow of dogs with visceral leishmaniasis submitted to multiple dose treatment with liposome-encapsulated meglumine antimoniate

“…Although 10-fold higher and multiple doses were given in the present study, antimony levels in the bone marrow still remained relatively low. These low antimony levels may be attributed to the large size (1.2 µm) of the liposomes used in the present study when compared to that of the liposomes previously used (0.12 µm) (8), and to the fact that bone marrow is expected to be more accessible to smaller liposomes (9).…”

Clinical and Experimental Advances in Treatment of Visceral Leishmaniasis

“…Liver, spleen, and bone marrow are particularly rich in sinusoidal and resident macrophages capable of phagocytizing circulating material; thus, encapsulation or carrier vehicles facilitate rapid, high-level tissue uptake and favor intracellular drug accumulation. The remarkable clinical efficacy and good tolerability of the lipid formulations of amphotericin B certainly attest to this approach, and well illustrate interdigitating benefits suggested by early experimental studies of targeted agents (7,20,32,44,136), including (i) use of lower total drug doses with comparable or greater efficacy, (ii) selective tissue uptake and reduced systemic toxicity, (iii) improved tolerability permitting higher daily doses and, in turn, short-course therapy, and (iv) likely persistence of drug in targeted tissues and/or within parasitized macrophages themselves.…”

Combination Therapy Using Sodium Antimony Gluconate in Stearylamine-Bearing Liposomes against Established and Chronic Leishmania donovani Infection in BALB/c Mice

“…In most of these studies the efficacy demonstrated by neutral and negatively charged liposomal formulations of SAG was determined purely on the basis of liver parasite burdens (2,5,21). These formulations either failed to contain parasites in the spleen (6) or required multiple doses for a significant clearance in an acute-infection model (7,13). The spleen is a site of persistent infection with Leishmania donovani (1,12,32), and parasite removal from this organ is more difficult than parasite removal from liver (6,8,31,32).…”