Pentostam® (sodium stibogluconate); a 50-year personal reminiscence

Goodwin, L. G.

doi:10.1016/0035-9203(95)90572-3

Cited by 68 publications

(33 citation statements)

References 7 publications

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“…Previous reports suggest that SbIII is the active form of SbV that is toxic to the promastigotes of different Leishmania species (32). The relatively nontoxic drug SbV is considered a prodrug that is converted to highly toxic SbIII either in macrophages (21) or near the site of action (33). In agreement with these findings, we showed, using the Dd8 transfectants, that intracellular amastigotes are much more susceptible to SbV (SAG), with the IC 50 being almost ninefold less than that for the promastigotes (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Use of Leishmania donovani Field Isolates Expressing the Luciferase Reporter Gene in In Vitro Drug Screening

Ashutosh¹,

Gupta

Ramesh

et al. 2005

Antimicrob Agents Chemother

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Currently available primary screens for the selection of candidate antileishmanial compounds are not ideal. These techniques are time-consuming, laborious, and difficult to scale and require macrophages, which limit their use for high-throughput screening. We have developed Leishmania donovani field isolates that constitutively express the firefly luciferase reporter gene (luc) as a part of an episomal vector. An excellent correlation between parasite number and luciferase activity was observed. luc expression was stable, even in the absence of drug selection, for 4 weeks. The transfectants were infective to macrophages, and intracellular amastigotes exhibited luciferase activity. The suitability of these recombinant field isolates for in vitro screening of antileishmanial drugs was established. The luciferase-expressing sodium stibogluconate-resistant cell lines offer a model for the screening of compounds for resistance. The system is in routine use at the Central Drug Research Institute, Lucknow, India, for high-throughput screening of newly synthesized compounds.

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Section: Discussionmentioning

confidence: 99%

Use of Leishmania donovani Field Isolates Expressing the Luciferase Reporter Gene in In Vitro Drug Screening

Ashutosh¹,

Gupta

Ramesh

et al. 2005

Antimicrob Agents Chemother

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“…Sodium stibogluconate is of Sb(V) form which transforms inside cells into Sb(III) form that can affect Leishmania growth (38). We therefore determined the activity of potassium antimonyl tartrate of Sb(III) form in inhibiting PTPases in vitro and in vivo.…”

Section: The Sb(iii) Form Of Potassium Antimonyl Tartrate Lacks Inhibmentioning

confidence: 99%

Sodium Stibogluconate Is a Potent Inhibitor of Protein Tyrosine Phosphatases and Augments Cytokine Responses in Hemopoietic Cell Lines

Pathak

2001

The Journal of Immunology

178

168

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Using in vitro protein tyrosine phosphatase (PTPase) assays, we found that sodium stibogluconate, a drug used in treatment of leishmaniasis, is a potent inhibitor of PTPases Src homology PTPase1 (SHP-1), SHP-2, and PTP1B but not the dual-specificity phosphatase mitogen-activated protein kinase phosphatase 1. Sodium stibogluconate inhibited 99% of SHP-1 activity at 10 μg/ml, a therapeutic concentration of the drug for leishmaniasis. Similar degrees of inhibition of SHP-2 and PTP1B required 100 μg/ml sodium stibogluconate, demonstrating differential sensitivities of PTPases to the inhibitor. The drug appeared to target the SHP-1 domain because it showed similar in vitro inhibition of SHP-1 and a mutant protein containing the SHP-1 PTPase domain alone. Moreover, it forms a stable complex with the PTPase: in vitro inhibition of SHP-1 by the drug was not removed by a washing process effective in relieving the inhibition of SHP-1 by the reversible inhibitor suramin. The inhibition of cellular PTPases by the drug was suggested by its rapid induction of tyrosine phosphorylation of cellular proteins in Baf3 cells and its augmentation of IL-3-induced Janus family kinase 2/Stat5 tyrosine phosphorylation and proliferation of Baf3 cells. The augmentation of the opposite effects of GM-CSF and IFN-α on TF-1 cell growth by the drug indicated its broad activities in the signaling of various cytokines. These data represent the first evidence that sodium stibogluconate inhibits PTPases and augments cytokine responses. Our results provide novel insights into the pharmacological effects of the drug and suggest potential new therapeutic applications.

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“…The mode of action of pentavalent antimonials remains poorly understood (3,4,5). An in vivo metabolic conversion of pentavalent antimonial [Sb(V)] into trivalent ones [Sb(III)] was suggested more than 50 years ago by Goodwin and Page (15,16). This hypothesis was supported by the high toxicity of trivalent antimony against both parasite stages of different Leishmania species (10,14,26,31,34).…”

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confidence: 99%

Antimonial-Mediated DNA Fragmentation inLeishmania infantumAmastigotes

Sereno

Holzmüller

Mangot

et al. 2001

Antimicrob Agents Chemother

140

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The basic treatment of leishmaniasis consists in the administration of pentavalent antimonials. The mechanisms that contribute to pentavalent antimonial toxicity against the intracellular stage of the parasite (i.e., amastigote) are still unknown. In this study, the combined use of several techniques including DNA fragmentation assay and in situ and cytofluorometry terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling methods and YOPRO-1 staining allowed us to demonstrate that potassium antimonyl tartrate, an Sb(III)-containing drug, was able to induce cell death associated with DNA fragmentation in axenic amastigotes of Leishmania infantum at low concentrations (10 g/ml). This observation was in close correlation with the toxicity of Sb(III) species against axenic amastigotes (50% inhibitory concentration of 4.75 g/ml). Despite some similarities to apoptosis, nuclease activation was not a consequence of caspase-1, caspase-3, calpain, cysteine protease, or proteasome activation. Altogether, our results demonstrate that the antileishmanial toxicity of Sb(III) antimonials is associated with parasite oligonucleosomal DNA fragmentation, indicative of the occurrence of late events in the overall process of apoptosis. The elucidation of the biochemical pathways leading to cell death could allow the isolation of new therapeutic targets.Leishmaniasis is a significant cause of morbidity and mortality in several countries. A vertebrate host is infected with flagellated extracellular promastigote forms via the bite of a sand fly. Promastigotes are rapidly transformed into nonflagellated amastigotes dividing actively within the mononuclear phagocytes of the vertebrate host. The basic treatment consists in the administration of sodium stibogluconate (Pentostam), meglumine (Glucantime), pentamidine, or amphotericin B. Treatment failure, especially for kala-azar, mucosal leishmaniasis, and diffuse cutaneous leishmaniasis is becoming a common problem in many areas where leishmaniasis is endemic. Immunological, physiological, or pharmacological deficiencies in the host are possible explanations for variations in clinical response (29). But there is evidence that inherent lack of susceptibility and (or) the development of resistance can also contribute to parasite unresponsiveness to drugs (13,18,23,28,39,40). The mode of action of pentavalent antimonials remains poorly understood (3, 4, 5). An in vivo metabolic conversion of pentavalent antimonial [Sb(V)] into trivalent ones [Sb(III)] was suggested more than 50 years ago by Goodwin and Page (15,16). This hypothesis was supported by the high toxicity of trivalent antimony against both parasite stages of different Leishmania species (10,14,26,31,34). Recently, we and other investigators have shown that axenically grown amastigotes of Leishmania represent a powerful model to investigate drug activity on the active and dividing population of the mammalian parasite stage (7, 34). We have shown that potassium antimonyl tartrate [containing Sb(III)] was generally...

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Pentostam® (sodium stibogluconate); a 50-year personal reminiscence

Cited by 68 publications

References 7 publications

Use of Leishmania donovani Field Isolates Expressing the Luciferase Reporter Gene in In Vitro Drug Screening

Use of Leishmania donovani Field Isolates Expressing the Luciferase Reporter Gene in In Vitro Drug Screening

Sodium Stibogluconate Is a Potent Inhibitor of Protein Tyrosine Phosphatases and Augments Cytokine Responses in Hemopoietic Cell Lines

Antimonial-Mediated DNA Fragmentation inLeishmania infantumAmastigotes

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