The therapeutic effect of sodium stibogluconate in BALB/c mice infected with <i>Leishmania donovani</i> is organ-dependent

Carter, K C; Baillie, A. J.; Alexander, James; Dolan, Thomas F.

doi:10.1111/j.2042-7158.1988.tb05271.x

Cited by 68 publications

(49 citation statements)

References 14 publications

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“…following the administration of a pentavalent antimonial drug such as SSG or meglumine antimonate in animal models (2,4,6,9,17), but only one looked at the concentrations of this metal in skin in addition to other tissues and serum (2). Thus, our study is the first to examine the pharmacokinetics of Sb in skin biopsies of patients treated with SSG for cutaneous leishmaniasis.…”

Section: Discussionmentioning

confidence: 99%

Skin uptake, distribution, and elimination of antimony following administration of sodium stibogluconate to patients with cutaneous leishmaniasis

Jaser

El-Yazigi

Kojan

et al. 1995

Antimicrob Agents Chemother

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We examined in this study the pharmacokinetics of Sb in the affected skin and normal skin of patients treated with sodium stibogluconate for cutaneous leishmaniasis and compared the results with those for the blood. The procedure was fully explained, and a written consent was obtained from each of nine patients. After a dose of sodium stibogluconate equivalent to 600 mg of Sb was administered intramuscularly, small skin biopsies were collected under local anesthesia at different time intervals from the circumferences of the lesions and simultaneously from normal skin. Antimony was measured in these biopsies after suitable ashing and processing by flameless atomic absorption spectrophotometry. The means (with standard errors of the means in parentheses) of the peak concentration, time to peak concentration, area under the curve, half-life, and mean residence time in lesions were 5.02 (1.43) g/g, 2.1 (0.4) h, 32.8 (6.1) g ⅐ h/g, 6.88 (0.54) h, and 10.4 (1.2) h, respectively, and those in normal skin were 6.56 (2.01) g/g, 2.6 (0.8) h, 44.0 (15.8) g ⅐ h/g, 5.44 (0.83) h, and 8.08 (1.34) h, respectively. There was no significant difference in any of these parameters between lesions and normal skin, whereas the differences in peak concentration, half-life, and mean residence time between lesions and whole blood were significant (P Յ 0.05). The penetration of Sb into skin, either affected or normal, as measured by the skin/blood area under the curve ratio appears to be complete, but the disposition is slow compared with that from the blood.The best treatment for leishmaniasis is currently achieved with pentavalent antimonials in the form of sodium stibogluconate (SSG) or meglumine antimonate. However, because of the rapid blood clearance of these drugs (5,13,14,17), an increase in dose and dosing frequency has been recommended by the World Health Organization (18). The amount of exposure of the infectious parasite to pentavalent antimony is believed to be an important factor in eradicating the cutaneous leishmania disease. Thus, delivering the dose by intralesion injections of SSG has recently been advocated (8,10,15). When the drug is administered intramuscularly, the contact with the parasite is undoubtedly controlled by the rate and extent at which this metal reaches and leaves the lesions following the administration of SSG. Therefore, knowledge of the kinetics of the uptake and disposition of this metal in affected skin is vital for optimization of the dosage regimens of these drugs in the treatment of cutaneous leishmaniasis. Although these drugs have been in use for more than four decades (11,16), no such study has yet been reported for SSG. Plasma kinetic data are clinically relevant to the extent that they reflect those of the site of action.We undertook to examine in this study the kinetics of Sb in the affected skin and normal skin of patients treated intramuscularly with sodium stibogluconate for cutaneous leishmaniasis and to compare the results with those for the blood samples of these patients. The impac...

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Section: Discussionmentioning

confidence: 99%

Skin uptake, distribution, and elimination of antimony following administration of sodium stibogluconate to patients with cutaneous leishmaniasis

Jaser

El-Yazigi

Kojan

et al. 1995

Antimicrob Agents Chemother

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“…In contrast, vaccination with SLA ϩ IL-12 failed to make any impact on the course of infection in the spleen. Parasites in the spleen are also more resistant to various immunological interventions (5,6), and to T cell-dependent chemotherapy (62). We have yet to make a formal comparison of the T cell response induced by rHASPB1 vs SLA ϩ IL-12 in these two sites.…”

Section: Discussionmentioning

confidence: 99%

Immunization with a Recombinant Stage-Regulated Surface Protein fromLeishmania donovaniInduces Protection Against Visceral Leishmaniasis

Stäger

Smith

Kaye

2000

The Journal of Immunology

174

134

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Vaccination against visceral leishmaniasis has received limited attention compared with cutaneous leishmaniasis, although the need for an effective vaccine against visceral leishmaniasis is pressing. In this study, we demonstrate for the first time that a recombinant stage-specific hydrophilic surface protein of Leishmania donovani, recombinant hydrophilic acylated surface protein B1 (HASPB1), is able to confer protection against experimental challenge. Protection induced by rHASPB1 does not require adjuvant and, unlike soluble Leishmania Ag + IL-12, extends to the control of parasite burden in the spleen, an organ in which parasites usually persist and are refractory to a broad range of immunological and chemotherapeutic interventions. Both immunohistochemistry (for IL-12p40) and enzyme-linked immunospot assay (for IL-12p70) indicate that immunization with rHASPB1 results in IL-12 production by dendritic cells, although an analysis of Ab isotype responses to rHASPB1 suggests that this response is not sufficient in magnitude to induce a polarized Th1 response. Although both vaccinated and control-infected mice have equivalent frequencies of rHASPB1-specific CD4+ T cells producing IFN-γ, vaccine-induced protection correlates with the presence of rHASPB1-specific, IFN-γ-producing CD8+ T cells. Thus, we have identified a novel vaccine candidate Ag for visceral leishmaniasis, which appears to operate via a mechanism similar to that previously associated with DNA vaccination.

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“…L. donovani strains 200011 and 20016, which were clinically derived from patients in India and collected under the regulations of the Bihar University Ethical Committee (3), were used in this study. The mice were infected by intravenous injection (tail vein, no anesthetic) with 1 ϫ 10 7 to 2 ϫ 10 7 L. donovani amastigotes (2). The day of parasite administration to the mice was designated day 0 of the experiment.…”

Section: Methodsmentioning

confidence: 99%

“…Animals were killed at 7 days posttreatment; and parasite burdens in the spleens, livers, and bone marrow were determined microscopically by blindly counting the number of parasites per 1,000 host nuclei from randomly chosen slides. Organ weights were used to calculate the Leishman donovan units (LDU) for spleen and liver parasite burdens (2). In order to determine the importance of glutathione in SSG susceptibility, the animals were treated intravenously on day 7 postinfection with PBS (controls), free SSG (70.4 to 300 mg of Sb v /kg), free BSO, or BSO-NIV mixed 1:1 with free SSG or water.…”

Section: Methodsmentioning

confidence: 99%

The In Vivo Susceptibility of Leishmania donovani to Sodium Stibogluconate Is Drug Specific and Can Be Reversed by Inhibiting Glutathione Biosynthesis

Carter¹,

Sundar

Spickett³

et al. 2003

Antimicrob Agents Chemother

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The therapeutic effect of sodium stibogluconate in BALB/c mice infected with Leishmania donovani is organ-dependent

Cited by 68 publications

References 14 publications

Skin uptake, distribution, and elimination of antimony following administration of sodium stibogluconate to patients with cutaneous leishmaniasis

Skin uptake, distribution, and elimination of antimony following administration of sodium stibogluconate to patients with cutaneous leishmaniasis

Immunization with a Recombinant Stage-Regulated Surface Protein fromLeishmania donovaniInduces Protection Against Visceral Leishmaniasis

The In Vivo Susceptibility of Leishmania donovani to Sodium Stibogluconate Is Drug Specific and Can Be Reversed by Inhibiting Glutathione Biosynthesis

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