Sodium Stibogluconate (Pentostam) Potentiates Oxidant Production in Murine Visceral Leishmaniasis and in Human Blood

Abstract

Sodium stibogluconate (Sbb), a leishmanicidal drug, was studied for its in vivo effect on the formation of reactive oxygen species (ROS), assessed by chemiluminescence (CL) in the whole blood of mice infected with Leishmania infantum. Stimulation of ROS formation induced ex vivo by zymosan particles or the protein kinase C activator phorbol myristate acetate (PMA) was reduced by approximately 25% (P < 0.05) after infection of mice. Treatment of infected mice with Sbb (50 to 400 mg/kg of body weight) enhanced the blood CL induced by zymosan and PMA (47 to 96%, P < 0.01). The drug potentiation effect also occurred in uninfected mice. In vitro treatment of normal human blood with Sbb (1, 10, or 100 g/ml) for 1 h primed the CL response to PMA (29 to 54%). The priming effect of Sbb was also observed on the production of superoxide by isolated polymorphonuclear leukocytes stimulated either by PMA and zymosan or by the chemoattractants N-formylMet-Leu-Phe and platelet-activating factor. These data provide the first evidence of priming of the phagocyte respiratory burst by Sbb. This novel property of Sbb may contribute to the drug's leishmanicidal effect.

Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis

“…There is some evidence that chronic arsenic exposure leads to immunosuppression (29,30). This could have contributed to the decreased efficacy of in vivo antimonials in our model because part of their mode of action is driven by the immune system (28). However, the current literature is sporadic and can be contradictory (31,32), so no concrete conclusions can be drawn without further work in this area.…”

“…In the case of antimonial drugs specifically, this lack of clinical correlation may be due to the dual mechanism of action of Pentostam, which exerts its direct toxic effects on the Leishmania parasite not only after reduction to Sb III but also via indirect effects on the host immune system leading to increased oxidative and nitrosative stress (28). Therefore, the results of the in vivo treatment with Pentostam provide important confirmation that the resistance developed by the arsenic-exposed Leishmania parasites is relevant within a physiological system.…”

Antimonial-induced Increase in Intracellular Ca2+ through Non-selective Cation Channels in the Host and the Parasite Is Responsible for Apoptosis of Intracellular Leishmania donovani Amastigotes

“…Even though there is no clear consensus in the literature as to how the ROS brings about pathogen death inside the host cell, it is known that anti-leishmanicidal drugs generate ROS in blood (21). Therefore, it was checked whether the cellular response to the drug was generation of ROS.…”

“…To investigate early changes induced by PAT, we checked ROS generation within the macrophages as these cells can ingest and kill invading microorganisms using microbicidal mechanisms that include generation of ROS (31) and PAT is known to induce ROS production in blood (21 to the drug (Fig. 4A (a-c)).…”

“…Therefore, it is possible that ROS generation might have a direct bearing on apoptotic death of intracellular parasites, but this phenomenon has not been examined adequately. ROS is also generated by anti-leishmanial drugs like antimonials in blood (21), but it is not known whether this is directly linked to apoptotic death of amastigote forms of Leishmania spp. It remains to be shown whether apoptotic pathway of death is an inherent feature of intracellular parasitic life style because the features and mechanisms of apoptotic death in intracellular parasitic forms have not been sufficiently described.…”