Sodium stibogluconate: therapeutic use in the management of leishmaniasis

Leishmaniasis causes significant morbidity and mortality worldwide. The disease is endemic in developing countries of tropical regions, and in recent years economic globalization and increased travel has also spread to people in developed countries. In the absence of effective vaccines and vector-control measures, the main line of defense against the disease is chemotherapy. Organic pentavalent antimonials, including sodium stibogluconate have been the first-line drug for the treatment of leishmaniasis for the last several decades, and clinical resistance to these drugs has emerged as a primary obstacle to successful treatment and control. The present review describes the structure, activity, mode of action of sodium stibogluconate and mechanism of resistance towards this drug in leishmaniasis

Sodium Stibogluconate: Therapeutic use in the Management of Leishmaniasis

16-22Leishmaniasis causes significant morbidity and mortality worldwide. The disease is endemic in developing countries of tropical regions, and in recent years economic globalization and increased travel has also spread to people in developed countries. In the absence of effective vaccines and vector-control measures, the main line of defense against the disease is chemotherapy. Organic pentavalent antimonials, including sodium stibogluconate have been the first-line drug for the treatment of leishmaniasis for the last several decades, and clinical resistance to these drugs has emerged as a primary obstacle to successful treatment and control. The present review describes the structure, activity, mode of action of sodium stibogluconate and mechanism of resistance towards this drug in leishmaniasis

Stearylamine-Bearing Cationic Liposomes Kill Leishmania parasites through Surface Exposed Negatively Charged Phosphatidylserine

Leishmania parasites are the causative agents for cutaneous and visceral leishmaniasis (VL) with �2 million cases annually and a prevalence rate of 12 million, respectively. VL, principally caused by Leishmania donovani, is fatal if left untreated.1 Pentavalent antimonials, though toxic, remain the first-line drugs for leishmaniasis. Emergence of drug resistance has pushed in second-line drugs such as amphotericin B and pentamidine, which cause toxic side effects.2–4 Miltefosine, the most recent oral drug for VL, is potentially teratogenic.2 Moreover, clinical trials have identified occasional gastrointestinal toxicity that requires treatment withdrawa

Cationic Liposomal Sodium Stibogluconate (SSG), a Potent Therapeutic Tool for Treatment of Infection by SSG-Sensitive and -Resistant Leishmania donovani

Pentavalent antimonials have been the first-line treatment for leishmaniasis for decades. However, the development of resistance to sodium stibogluconate (SSG) has limited its use, especially for treating visceral leishmaniasis (VL). The present work aims to optimize a cationic liposomal formulation of SSG for the treatment of both SSG-sensitive (AG83) and SSG-resistant (GE1F8R and CK1R) Leishmania donovani infections. Parasite killing was determined by the 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide (MTT) assay and microscopic counting of Giemsa-stained macrophages. Macrophage uptake studies were carried out by confocal microscopic imaging. Parasite-liposome interactions were visualized through transmission electron microscopy. Toxicity tests were performed using assay kits. Organ parasite burdens were determined by microscopic counting and limiting dilution assays. Cytokines were measured by enzyme-linked immunosorbent assays (ELISAs) and flow cytometry. Although all cationic liposomes studied demonstrated leishmanicidal activity, phosphatidylcholine (PC)-dimethyldioctadecylammonium bromide (DDAB) vesicles were most effective, followed by PC-stearylamine (SA) liposomes. Since entrapment of SSG in PC-DDAB liposomes demonstrated enhanced ultrastructural alterations in promastigotes, PC-DDAB-SSG vesicles were further investigated in vitro and in vivo. PC-DDAB-SSG could effectively alleviate SSG-sensitive and SSG-resistant L. donovani infections in the liver, spleen, and bone marrow of BALB/c mice at a dose of SSG (3 mg/kg body weight) not reported previously. The parasiticidal activity of these vesicles was attributed to better interactions with the parasite membranes, resulting in direct killing, and generation of a strong host-protective environment, necessitating a very low dose of SSG for effective cures

Immunomodulatory activity of free and vesicular SSG on splenocytes of normal BALB/c mice.

<p>Splenocytes of normal healthy mice were incubated with various concentrations of (A) free SSG, (B) PC-SA-SSG, and (C) PC-Chol-SSG with or without LPS (2.5 µg/ml) for 48 h at 37°C with 5% CO₂. IL-10 was measured from culture supernatants by enzyme-linked immunosorbent assay (ELISA). Each symbol represents mean cytokine level ± SEM, representative of three independent experiments.</p

Differential pattern of cytokine and NO production following therapy with antileishmanial formulations in infected BALB/c mice.

<p>Splenocytes isolated from GE1F8R and CK1R-infected mice after indicated treatments were plated aseptically, and stimulated with LAg (12.5<i> µ</i>g/ml) for 72 h. (A, C) IFN-γ, IL-12, TNF-α and (B, D) IL-10, TGF-β, IL-4 cytokine levels in supernatants of splenocyte cultures were assayed by ELISA. Total, and CD4⁺ and CD8⁺ T cell-depleted splenocytes were stimulated as above and (E) IFN-γ and (F) IL-10 levels were measured after 72 h. Values represent the mean ± SEM (3–5 mice/group). (G) Leishmanicidal NO generation determined by Greiss assay method in supernatants of splenocytes derived from indicated groups. Data represent the mean ± SEM (3–5 mice/group). * p<0.05 compared to (A, C) PBS or (B, D,G) AmB therapy.</p

Humoral and antigen-specific proliferative response following treatment with PC-SA-SSG.

<p>(A, B) Sera from treated mice were analyzed individually by ELISA for detection of IgG1 and IgG2a antibodies in GE1F8R and CK1R-infected groups of mice (3-5 mice/group). The results are representative of two independent experiments and data represent mean ± SEM. * p<0.05 compared to PBS treatment. (C, D) Total, and CD4⁺ and CD8⁺ T cell-depleted splenocytes from treated groups were stimulated in vitro with <i>Leishmania</i> membrane antigen (LAg) (12.5<i> µ</i>g/ml). After 48 h, [³H] thymidine was added and cells were harvested subsequently. Proliferative index was measured as [³H] thymidine incorporation in counts per minute. Data represent mean ± SEM (3 mice/group) in triplicates. * p<0.05 compared to AmB therapy.</p

Intracellular retention of free and liposomal rhodamine 123 in <i>L.donovani</i> promastigotes.

<p>Rhodamine 123 (Rh123) uptake and retention study was performed in AG83 and GE1F8R strains with Rh123. Parasites were incubated with (A) different concentrations of free Rh123 for 4 h and (B) for different time periods. At indicated time points parasites were washed, lysed and fluorescence intensity of the cell lysates measured. Data reperesent mean ± SEM of two independent experiments performed in triplicates and expressed as ng of Rh123/10⁵ cells. (C, D) In another set of experiments, parasites incubated for 4 h with 250 ng/ml of either free or liposomal Rh123 were washed and reincubated in medium free of Rh 123 for different times followed by lysis. The percent retention of Rh123 was calculated for each group compared to respective controls. Data represent mean ± SEM of three independent experiments each performed in duplicate. * p<0.05; *** p<0.001</p