<i>In vitro</i> and <i>in vivo</i> anti-leishmanial activity of chlorpromazine alone and combined with N-meglumine antimonate

El‐On, Joseph; Rubinstein, N; Kernbaum, S

doi:10.1080/00034983.1986.11812057

Cited by 18 publications

(7 citation statements)

References 11 publications

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“…Chlorpromazine at 0.2 mM concentration likewise inhibited transplasma membrane electron transport of hepatocytes only 42%, whereas at the same concentration clo‐fazimine failed to inhibit promastigotes transplasma membrane electron transport. Chlorpromazine can effectively inhibit the growth of Leishmania promastigotes and amastigotes in vivo and in vitro (El‐On et al 1986; Hewlett and Pearson 1985). However, Zilberstein and Dwyer (1985) also reported that the proton translocating ATPase in Leishmania plasma membrane is the site of inhibition by chlorpromazine.…”

Section: Discussionmentioning

confidence: 99%

Transplasma Membrane Electron Transport in Leishmania donovani Promastigotes

Datta

Bera

2002

J Eukaryotic Microbiology

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Leishmania donovani promastigotes are capable of reducing certain electron acceptors with redox potential at pH 7 down to -125 mV; outside the plasma membrane promastigotes can reduce ferricyanide. Ferricyanide has been used as an artificial electron acceptor probe for studying the mechanism of transplasma membrane electron transport. Transmembrane ferricyanide reduction by L. donovani promastigotes was not inhibited by such mitochondrial inhibitors as antimycin A or cyanide, but it responded to inhibitors of glycolysis. Transmembrane ferricyanide reduction by Leishmania appears to involve a plasma membrane electron transport chain dissimilar to that of hepatocyte cells. As with other cells, transmembrane electron transport is associated with proton release, which may be involved in internal pH regulation. The Leishmania transmembrane redox system differs from that of mammalian cells in being 4-fold less sensitive to chloroquine and 12-fold more sensitive to niclosamide. Sensitivities to these drugs suggest that transplasma membrane electron transport and associated proton pumping may be targets for the drugs used against leishmaniasis.

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Section: Discussionmentioning

confidence: 99%

Transplasma Membrane Electron Transport in Leishmania donovani Promastigotes

Datta

Bera

2002

J Eukaryotic Microbiology

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“…Chlorpromazine, trifluoropromazine, thioridazine, trifluoperazine and prochlorperazine are reported to inhibit the energy-dependent effux of pirarubicin, an anthracycline derivative, in L. braziliensis, L. guyanensis and L. mexicana [62]. A synergistic effect between chlorpromazine and Nmeglumine antimonate is observed in multidrug resistant L. donovani and L. major cells in vitro [89]. The effect of phenothiazine derivatives on the Leishmania active efflux systems may be explained by their ability to inhibit the activity of trypanothione reductase [90,91].…”

Section: -Transporter Inhibitors and Modulators Of Multidrug Resistancementioning

confidence: 99%

“…Indeed, if we consider that the reduced form of trypanothione is an important co-factor for the function of the Leishmania drug transporter, in the same way as reduced glutathione is required for the MRP1 function [65,92], phenothiazines may inhibit the transport activity by decreasing the intracellular level of reduced trypanothione [62]. However, no significant effect is observed in vivo against amastigotes of L. major and L. mexicana, in cutaneous lesions of mice [89]. The toxic effects reported with the most frequently studied phenothiazine, that is chlorpromazine, has impaired the investigation of other phenothiazines as potentially clinical agents.…”

Section: -Transporter Inhibitors and Modulators Of Multidrug Resistancementioning

confidence: 99%

Chemosensitizers in Drug Transport Mechanisms Involved in Protozoan Resistance

Pradines

Pages²,

Barbe³

2005

CDTID

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The emergence and spread of antiparasitic drug resistance pose a severe and increasing public health threat. Failures in prophylaxis or those in treatment with quinolines, hydroxynaphtoquinones, sesquiterpenic lactones, antifolate drugs, arsenic and antimony containing drugs sulfamides induce reemergence of parasitic-related morbidity and mortality. Resistance is often associated with alteration of drug accumulation into parasites, which results from a reduced uptake of the drug, an increased efflux or, a combination of the two processes. Resistance to quinolines, artemisinin derivatives and arsenicals and expression of an active efflux mechanism are more or less correlated in protozoa like Plasmodium spp., Leishmania spp., and Trypanosoma spp. Various parasite candidate genes have been proposed to be involved in drug resistance, each concerned in membrane transport. Genes encoding membrane glycoproteins, orthologue to the P-glycoproteins identified in MDR human cancer cells, have been described in these resistant pathogens in addition to various membrane proteins involved in drug transport. Several compounds have demonstrated, in the past decade, promising capability to reverse the drug resistance in parasite isolates in vitro, in animal models and for human malaria. These drugs belong to different pharmacological classes such as calcium channel blockers, tricyclic antidepressants, antipsychotic calmodulin antagonists, histamine H1-receptor antagonists, analgesic antipyretic drugs, non-steroidal anti-inflammatory drugs, and to different chemical classes such as synthetic surfactants, alkaloids from plants used in traditional medicine, pyrrolidinoaminoalkanes and derivatives, and anthracene derivatives. Here, are summarized the molecular bases of antiparasitic resistance emphasizing recent developments with compounds acting on trans-membrane proteins involved in drug efflux or uptake.

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“…Calmodulin antagonists have been shown to reverse drugs resistance in parasites. Phenothiazine derivates such as chlorpromazine increased sensitivity to antimonials in multidrug resistant L. donovani and L. major strains in vitro ( el-On et al, 1986 ). These compounds have antiprotozoal activity per se ( Pearson et al, 1984 ; Werbovetz et al, 1992 ).…”

Section: Strategies To Specifically Overcome Transport Related Drug Rmentioning

confidence: 99%

New Approaches to Overcome Transport Related Drug Resistance in Trypanosomatid Parasites

et al. 2016

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Leishmania and Trypanosoma are members of the Trypanosomatidae family that cause severe human infections such as leishmaniasis, Chagas disease, and sleeping sickness affecting millions of people worldwide. Despite efforts to eradicate them, migrations are expanding these infections to developing countries. There are no vaccines available and current treatments depend only on chemotherapy. Drug resistance is a major obstacle for the treatment of these diseases given that existing drugs are old and limited, with some having severe side effects. Most resistance mechanisms developed by these parasites are related with a decreased uptake or increased efflux of the drug due to mutations or altered expression of membrane transporters. Different new approaches have been elaborated that can overcome these mechanisms of resistance including the use of inhibitors of efflux pumps and drug carriers for both active and passive targeting. Here we review new formulations that have been successfully applied to circumvent resistance related to drug transporters, opening alternative ways to solve drug resistance in protozoan parasitic diseases.

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In vitro and in vivo anti-leishmanial activity of chlorpromazine alone and combined with N-meglumine antimonate

Cited by 18 publications

References 11 publications

Transplasma Membrane Electron Transport in Leishmania donovani Promastigotes

Transplasma Membrane Electron Transport in Leishmania donovani Promastigotes

Chemosensitizers in Drug Transport Mechanisms Involved in Protozoan Resistance

New Approaches to Overcome Transport Related Drug Resistance in Trypanosomatid Parasites

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