Disease relevance of LS-2383

• Pentostam, a Sb(V)-containing drug that is one of the first-line therapeutic agents for treatment of leishmaniasis, inhibited uptake after reaction with GSH [1].
• Also, in promastigotes of both wild-type L. donovani and the Pentostam-resistant mutant L. donovani Ld1S.20, Sb(V) inhibited the toxicity of Sb(III) but not of As(III) [2].
• In the present report, the oral antifungal agent ketoconazole (600 mg/day for 28 days) was compared to a recommended regimen of intramuscular Pentostam (20 mg antimony/kg, with a maximum of 850 mg antimony/day, for 20 days) in a randomized study of the treatment of Panamanian cutaneous leishmaniasis due to Leishmania braziliensis panamensis [3].
• Thirty-five golden hamsters infected with Leishmania donovani were treated with Pentostam and followed up to determine the effect of treatment on the development of secondary amyloidosis [4].
• In a model of visceral leishmaniasis, infected mice were treated with ineffective concentrations of rIFN-gamma (10(4) U) plus suboptimal doses of Pentostam (10 or 50 mg/kg) [5].

High impact information on LS-2383

• We report that treatment with interleukin 12 (IL-12), in combination with the antimony-based leishmanicidal drug Pentostam, induces healing in L. major-infected mice and that healing is associated with a switch from a Th2 to a Th1 response [6].
• Switch from a type 2 to a type 1 T helper cell response and cure of established Leishmania major infection in mice is induced by combined therapy with interleukin 12 and Pentostam [6].
• Transfection of LmAQP1 in a Pentostam-resistant field isolate also sensitized the parasite in the macrophage-associated amastigote form [7].
• Leishmania major LmACR2 is a pentavalent antimony reductase that confers sensitivity to the drug pentostam [8].
• An IFN-secreting T cell line derived from the spleen of a chronically infected mouse, after boosting with leishmanial Ag and treatment with Pentostam to kill residual parasites, was able to activate macrophages to kill amastigotes in vitro [9].

Chemical compound and disease context of LS-2383

• Sodium stibogluconate (Pentostam) potentiates oxidant production in murine visceral leishmaniasis and in human blood [10].
• The toxicity of potassium antimonyl tartrate trihydrate, which is generally higher than that of Pentostam, seemed to indicate that pentavalent antimony can be metabolized in vivo to compounds, possibly trivalent in nature, which are more active against the amastigote organisms [11].
• A prospective randomized trial of three dosage regimens of sodium stibogluconate (Pentostam; Wellcome Foundation, London) to treat visceral leishmaniasis was conducted [12].
• We compared generic stibogluconate to Pentostam and Glucantime for the treatment of cutaneous leishmaniasis patients in Bolivia and Colombia [13].
• Sixty four Kenyan patients with visceral leishmaniasis were treated with sodium stibogluconate (Pentostam) (40 patients) or various combinations of Pentostam and allopurinol (24 patients) [14].

Biological context of LS-2383

• Dose-response curve analyses show that Leishmania promastigotes are susceptible to Pentostam, with the 50% inhibitory concentration (IC50) being 104 microg/ml, while amastigotes are more susceptible, with the IC50 being 24 microg/ml [15].
• Parasites were transfected with an episomal ODC construct, and these ODC overexpressers exhibited significant resistance to APA and were concomitantly resistant to sodium antimony gluconate (Pentostam), indicating a role for ODC overexpression in antimonial drug resistance [16].
• An in vitro cell-viability assay demonstrated that Pentostam is not toxic to human mononuclear cells [17].
• Because zoster has been associated with depressed cellular immunity, we prospectively followed serial lymphocyte subpopulations in eight patients with cutaneous leishmaniasis who received Pentostam [17].
• Pharmacokinetics of pentavalent antimony (Pentostam) in hamsters [18].

Anatomical context of LS-2383

• Partial or complete activation of macrophages as judged by killing of tumor cells significantly enhanced the efficacy of sodium antimony gluconate (Pentostam) [19].
• The PENT0400 and PENT03200 cell lines were isolated after prolonged exposure to 0.4 mg/ml and 3.2 mg/ml Pentostam (Sb concentration), respectively [20].
• Concentration of Pentostam in human breast milk [21].
• In Pentostam-treated cultures, some organisms exhibited diminished definition of mitochondrial and other membranes, while other organisms had completely disintegrated [22].

Associations of LS-2383 with other chemical compounds

• Leishmania tarentolae promastigotes were selected step by step for resistance to sodium stibogluconate (Pentostam) [23].
• Sodium stibogluconate (Pentostam) inhibition of glucose catabolism via the glycolytic pathway, and fatty acid beta-oxidation in Leishmania mexicana amastigotes [24].
• We report that in vitro sensitivity to pentavalent antimony (Sb5) of 35 Leishmania isolates as determined by the semiautomated microdilution technique (SAMT) showed an 89% and 86% correlation with clinical outcome after Pentostam and Glucantime treatment, respectively [25].
• In vitro, allopurinol (5 micrograms/ml) augmented the antileishmanial effect of a low concentration of Pentostam (5 micrograms/ml) but not of a higher concentration of Pentostam (20 micrograms/ml) [26].
• LmACR2 is the first identified antimonate reductase responsible for the reduction of pentavalent antimony in pentostam to the active trivalent form of the drug in Leishmania [27].

Gene context of LS-2383

• In order to investigate the role of the expanding parasite population on the Th2 response, mice infected for 2 weeks with L. major, which exhibited a Th2-like cytokine profile, were treated with a leishmanicidal agent (Pentostam) and/or various doses of anti-IL-4 antibody [28].
• However, in 8 of 10 mice treated with this dose of anti-IL-4 antibody plus Pentostam lesion development was arrested and lesions were either controlled or eventually healed [28].
• Activities of hexadecylphosphocholine (miltefosine), AmBisome, and sodium stibogluconate (Pentostam) against Leishmania donovani in immunodeficient scid mice [29].
• Synergism of IL-2-stimulated splenocytes and Pentostam enhances the killing of Leishmania donovani in vitro [30].
• A complicated case of ACL, which showed feverish and widely disseminated ulcers over the face was successfully treated with systemic antibiotic and pentostam as intralesional injections [31].

Analytical, diagnostic and therapeutic context of LS-2383

• One hundred and thirty lesions of cutaneous leishmaniasis in 60 patients were treated with intralesional injections of Pentostam and 30 lesions were left untreated as controls [32].
• Three of these patients responded to liposomal amphotericin B, two responded to splenectomy in association with Pentostam therapy, and three died [33].
• The use of Pentostam liposomes in the chemotherapy of experimental leishmaniasis [34].
• This study shows that intralesional pentostam injection was effective than cryotherapy [35].
• In this study parasitologically proven patients with CL. were treated with Pentostam (57) or Cryosurgery (38) [36].

References