Nonylphenolethoxylates as Malarial Chloroquine Resistance Reversal Agents

Crandall, Ian; Charuk, Jeffrey H. M.; Kain, Kevin C.

doi:10.1128/aac.44.9.2431-2434.2000

Cited by 11 publications

(10 citation statements)

References 25 publications

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“…Nonylphenolethoxylate Surfactants (Table 7) Nonylphenolethoxylates (NPEs) are synthetic surfactants used as intestinal permeability enhancers to improve oral drug delivery. They have synergistic effects in combination with chloroquine [191]. Nevertheless, there is a subset of P. falciparum isolates that displays a polyethoxylated nonylphenol (NP30) insensitive CQ resistance [192].…”

Section: Phenothiazines (Antipsychotic Drugs) (Table 4)mentioning

confidence: 99%

Chloroquine Resistance Reversal Agents as Promising Antimalarial Drugs

Henry¹,

Alibert²,

Orlandi-Pradines³

et al. 2006

CDT

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The development and spread of resistance to antimalarial drugs poses a severe and increasing public health threat. Failures of prophylaxis or treatment with quinolines, hydroxynaphthoquinones, sesquiterpene lactones, antifolate drugs and sulfamides are involved in a return malaria-related morbidity and mortality. Resistance is associated with a decrease in accumulation of drugs into the vacuole, which results from a reduced uptake of the drug, an increased efflux or a combination of both. A number of candidate genes in P. falciparum have been proposed to be involved in antimalarial resistance, each concerned in membrane transport. Weaker or stronger associations are seen in P. falciparum between the resistance to quinolines or artemisinin derivatives and codon changes in Pfmdr1, a gene which encodes Pgh-1, an ortholog of one of the P-glycoproteins expressed in multi-drug resistant human cancer cells (ABC transporter). Further analysis has revealed a new gene, Pfcrt, encoding a PfCRT protein, which resembles an anion channel. Codon changes found in the Pfcrt sequence in drug resistant isolates could facilitate the drug efflux through a putative channel. It has been proposed that the reversal of quinoline resistance by verapamil is due to hydrophobic binding to the mutated PfCRT protein. Several compounds have demonstrated in the past decade a promising capability to reverse the antimalarial drug resistance in vitro in parasite isolates, in animal models and in human malaria. These drugs belong to different pharmacological classes such as calcium channel blockers, tricyclic antidepressants, antipsychotic calmodulin antagonists, histamine H1-receptor antagonists, analgesic and 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 anthracenic derivatives. Here we summarize the progress made in biochemical and genetic basis of antimalarial resistance, emphasizing the recent developments on drugs, which interfere with trans membrane proteins involved in drug efflux or uptake.

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Section: Phenothiazines (Antipsychotic Drugs) (Table 4)mentioning

confidence: 99%

Chloroquine Resistance Reversal Agents as Promising Antimalarial Drugs

Henry¹,

Alibert²,

Orlandi-Pradines³

et al. 2006

CDT

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“…We have previously determined that NP30 both has anti-P. falciparum effects and can reverse CQ resistance in some isolates (8). To test the hypothesis that NP30 and verapamil interacted with a common site, we determined whether the presence of 2 M verapamil enhanced the anti-P. falciparum effects of NP30.…”

Section: Resultsmentioning

confidence: 99%

“…1), appears to belong to a novel class of resistance reversal agents since its structure does not contain a nitrogen atom and the surfactant has no ionizable groups (7,8). We therefore wished to determine if NP30 had quinoline sensitization properties that were similar to or different from those of verapamil, the agent most frequently used to examine CQ resistance in vitro.…”

mentioning

confidence: 99%

Reversal of Mefloquine and Quinine Resistance in Plasmodium falciparum with NP30

Ciach

Zong

Kain

et al. 2003

Antimicrob Agents Chemother

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Quinoline resistance in malaria is frequently compared with P-glycoprotein-mediated multidrug resistance (mdr) in mammalian cells. We have previously reported that nonylphenolethoxylates, such as NP30, are potential Plasmodium falciparum P-glycoprotein substrates and drug efflux inhibitors. We used in vitro assays to compare the ability of verapamil and NP30 to sensitize two parasite isolates to four quinolines: chloroquine (CQ), mefloquine (MF), quinine (QN), and quinidine (QD). NP30 was able to sensitize (reversal, >80%) P. falciparum to MF, QN, QD, and, to a lesser extent, CQ. The presence of 2 M verapamil had no effect on mefloquine resistance; however, the presence of verapamil modulated the activities of QN and QD in a manner parallel to that observed for CQ. Genetic analysis of putative quinoline resistance genes did not suggest an association between known point mutations in pfcrt and pfmdr1 and NP30 sensitization activity. We conclude that the sensitization action of NP30 is distinct both phenotypically and genotypically from that of verapamil.

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“…Nonylphenolethoxylates (NPEs), synthetic surfactants which are used as intestinal permeability enhancers to improve oral drug delivery, have synergistic effects in combination with chloroquine [305]. Nevertheless, there is a subset of P. falciparum isolates that display CQ resistance that is insensitive to a polyethoxylated nonylphenol (NP30) [306].…”

Section: -Transporter Inhibitors and Modulators Of The Multidrug Resimentioning

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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Nonylphenolethoxylates as Malarial Chloroquine Resistance Reversal Agents

Cited by 11 publications

References 25 publications

Chloroquine Resistance Reversal Agents as Promising Antimalarial Drugs

Chloroquine Resistance Reversal Agents as Promising Antimalarial Drugs

Reversal of Mefloquine and Quinine Resistance in Plasmodium falciparum with NP30

Chemosensitizers in Drug Transport Mechanisms Involved in Protozoan Resistance

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