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At least 19 recordsLinked to original sources
PubMed1992

Rapid chloroquine efflux phenotype in both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum. A correlation of chloroquine sensitivity with energy-dependent drug accumulation.

Recent reports suggest that lower levels of chloroquine accumulation in chloroquine-resistant isolates of Plasmodium falciparum are achieved by energy-dependent chloroquine efflux from resistant parasites. In support of this argument, a rapid chloroquine efflux phenotype has been observed in some chloroquine-resistant isolates of P. falciparum. In this study, no relationship was found between chloroquine sensitivity and the rate of [3H]chloroquine efflux from four isolates of P. falciparum with a greater than 10-fold range in sensitivity to chloroquine. All the isolates tested displayed the rapid efflux phenotype, irrespective of sensitivity. However, chloroquine sensitivity of these isolates was correlated with energy-dependent rate of drug accumulation into these parasites. Verapamil and a variety of other compounds reverse chloroquine resistance. The reversal mechanism is assumed to result from competition between verapamil and chloroquine for efflux protein translocation sites, thus causing an increase in steady-state accumulation of chloroquine and hence a return to sensitivity. Verapamil accumulation at a steady-state is increased by chloroquine, possibly indicating competition for efflux of the two substrates. Increases in steady-state verapamil concentrations caused by chloroquine were identical in sensitive and resistant strains, suggesting that similar capacity efflux pumps may exist in these isolates. These data suggest that differences in steady-state chloroquine accumulation seen in these isolates can be attributed to changes in the chloroquine concentrating mechanism rather than the efflux pump. It seems likely that chloroquine resistance generally in P. falciparum, results at least in part from a change in the drug concentrating mechanism and that changes in efflux rates per se are insufficient to explain chloroquine resistance.

Animals↗
PubMed2006

Chloroquine-resistant isoforms of the Plasmodium falciparum chloroquine resistance transporter acidify lysosomal pH in HEK293 cells more than chloroquine-sensitive isoforms.

The emergence of chloroquine-resistant Plasmodium falciparum malaria imperils the lives of millions of people in Africa, Southeast Asia and South America. Chloroquine resistance is associated with mutations in the P. falciparum chloroquine resistance transporter (PfCRT). We expressed chloroquine-sensitive (HB3) and resistant (Dd2) pfcrt alleles in HEK293 human embryonic kidney cells. PfCRT localized to the lysosomal limiting membrane and was not detected in the plasma membrane. We observed significant acidification of lysosomes containing PfCRT HB3 and Dd2, with Dd2 acidifying significantly more than HB3. A mutant HB3 allele expressing the K76T mutation (earlier found to be key for chloroquine resistance) acidified to the same extent as Dd2, whereas the acidification by a Dd2 allele expressing the T76K "back mutation" was significantly less than Dd2. Thus, the amino acid at position 76 is both an important determinant of chloroquine resistance in parasites and of lysosomal acidification following heterologous expression. PfCRT may be capable of modulating the pH of the parasite digestive vacuole, and thus chloroquine availability. Chloroquine accumulation and glycyl-phenylalanine-2-naphthylamide-induced release of lysosomal Ca(2+) stores were unaffected by PfCRT expression. Cytoplasmic domain mutations did not alter PfCRT sorting to the lysosomal membrane. This heterologous expression system will be useful to characterize PfCRT protein structure and function, and elucidate its molecular role in chloroquine resistance.

Animals↗
PubMed2003

Recovery of chloroquine sensitivity and low prevalence of the Plasmodium falciparum chloroquine resistance transporter gene mutation K76T following the discontinuance of chloroquine use in Malawi.

In 1993, Malawi stopped treating patients with chloroquine for Plasmodium falciparum malaria because of a high treatment failure rate (58%). In 1998, the in vitro resistance rate to chloroquine was 3% in the Salima District of Malawi; in 2000, the in vivo resistance rate was 9%. We assayed two genetic mutations implicated in chloroquine resistance (N86Y in the P. falciparum multiple drug resistance gene 1 and K76T in the P. falciparum chloroquine resistance transporter gene) in 82 P. falciparum isolates collected during studies in 1998 and 2000. The prevalence of N86Y remained similar to that in neighboring African countries that continued to use chloroquine. In contrast, the prevalence of K76T was substantially lower than in neighboring countries, decreasing significantly from 17% in 1998 to 2% in 2000 (P < 0.02). However, neither mutation was significantly associated with in vivo or in vitro resistance (P > 0.29). Withdrawal of the use of chloroquine appears to have resulted in the recovery of chloroquine efficacy and a reduction in the prevalence of K76T. However, other polymorphisms are also expected to contribute to resistance.

ATP-Binding Cassette Transporters↗
PubMed2000

The disposition of chloroquine and its main metabolite desethylchloroquine in volunteers with and without chloroquine-induced pruritus: evidence for decreased chloroquine metabolism in volunteers with pruritus.

The pharmacokinetics of chloroquine and its main metabolite desethylchloroquine have been carried out in volunteers with and without chloroquine-induced pruritus. It was shown that the volunteers with pruritus tended to metabolize chloroquine slower than the volunteers without pruritus because the metabolic ratio was lower in the volunteers with pruritus than that in the volunteers without pruritus. However, the overall pharmacokinetic patterns were comparable between the two groups and agreed with published data. The 24-hour urinary collections in the two groups of volunteers indicated that the volunteers with pruritus excreted more chloroquine (although not statistically significant) than the volunteers without pruritus. This also indicates that they metabolized less chloroquine. There were no side effects of note in any of the volunteers. The volunteers who gave positive histories of chloroquine-induced pruritus had mild episodes of itching after intake of the drug; the pruritus subsided within 48 hours in all instances.

Adult↗
PubMed2005

Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride.

Literature data on the properties of chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride related to the Biopharmaceutics Classification System (BCS) are reviewed. The available information indicates that these chloroquine salts can be classified as highly soluble and highly permeable, i.e., BCS class I. The qualitative composition of immediate release (IR) tablets containing these Active Pharmaceutical Ingredients (APIs) with a Marketing Authorization (MA) in Belgium (BE), Germany (DE), Finland (FI), and The Netherlands (NL) is provided. In view of these MA's and the critical therapeutic indication of chloroquine, it is assumed that the registration authorities had evidence that these formulations are bioequivalent to the innovator. It is concluded that IR tablets formulated with these excipients are candidates for a biowaiver.

Antimalarials↗
PubMed1984

Failure of chloroquine-erythromycin and chloroquine-tetracycline combinations in treatment of chloroquine-resistant falciparum malaria in eastern Thailand.

In Eastern Thailand the increasing resistance of Plasmodium falciparum to all available antimalarial drugs prompted a reassessment of chloroquine in combination with either erythromycin or tetracycline. Both combinations had produced encouraging results in vitro, in experimental animal models, or in preliminary clinical trials. In patients with uncomplicated falciparum malaria presenting with moderate parasitaemia the trial of chloroquine and tetracycline was abandoned after RIII resistance with clinical deterioration was encountered in 2 out of the first 5 patients studied. Of 16 patients treated with chloroquine+erythromycin, 11 showed resistance (RI-RIII). These regimens appear ineffective and potentially dangerous in Eastern Thailand.

Adolescent↗
PubMed1998

[Accumulation and effluxion of chloroquine in chloroquine-sensitive and chloroquine-resistant Plasmodium berghei].

AIM: To explore whether the difference in the amount of chloroquine (CQ) accumulated in CQ-resistant (CR) and in CQ-sensitive (CS) P. berghei is involved in the infected erythrocytes (RBC) or in the parasites. METHODS: The concentration of CQ in infected RBC and parasites following ig administration of CQ to CS and CR infected mice was determined by HPLC method (extra standard). RESULTS: 3 h after 4.06 mg/kg and 400 mg/kg administration, the accumulation of CQ in both infected RBC was similar, but in CR was 54.0% and 42.1% less than in CS (P < 0.001) respectively. The CQ accumulation in CS 3 h and 7 h after ig administration of CQ 400 mg/kg was similar (0.780 +/- 0.128 nmol/protein and 0.760 +/- 0.180 nmol/mg protein), while in CR the CQ-accumulation was higher at 7 h than that at 3 h after CQ administration (0.452 +/- 0.079 nmol/mg protein and 0.559 +/- 0.124 nmol/mg protein P < 0.02). CONCLUSION: The low CQ accumulation in CR is attributable to the parasite rather than to the infected RBC, and CR was not found to excrete CQ more rapidly than CS.

Animals↗
PubMed1969

Chloroquine resistance in malaria: a deficiency of chloroquine binding.

Chloroquine-(14)C was used to study the processes which concentrate chloroquine in mouse red blood cells infected with chloroquine-sensitive or with chloroquine-resistant Plasmodium berghei. The initial rates of uptake and exchange of chloroquine-(14)C were both too fast to measure, yet large concentration gradients were maintained by the cells. When red blood cells were exposed to 10(-8)M chloroquine at 22 degrees C, with pH between 7.2 and 7.4, steady-state gradients of chloroquine-(14)C were approximately 600:1 (cells:medium) for cells infected with chloroquine-sensitive parasites, 100:1 for cells comparably infected with chloroquine-resistant parasites, and 14:1 for uninfected cells. The processes responsible for these gradients were saturable, in agreement with the proposal of chloroquine binding to cellular constituents. No degradation of chloroquine was detected. The major difference between the chloroquine-sensitive and -resistant parasites was deficiency of high-affinity binding of chloroquine by cells infected with chloroquine-resistant parasites. This deficiency explains the reduced ability of chloroquine-resistant parasites to concentrate chloroquine, and it suggests that chloroquine resistance is due to a decrease in the number, affinity, or accessibility of chloroquine receptor sites on a constituent of the malaria parasite.

Animals↗
PubMed1990

Plasmodium chabaudi: in vivo effects of Ca2+ antagonists on chloroquine-resistant and chloroquine-sensitive parasites.

The effects of Ca2+ antagonists, verapamil, nicardipine, and diltiazem, on susceptibility to chloroquine were examined in mice infected with chloroquine-sensitive and chloroquine-resistant lines of Plasmodium chabaudi. In mice that received no chloroquine, daily injections of 50 mg/kg of verapamil, nicardipine, or diltiazem did not affect the growth of both sensitive and resistant parasites. When mice were injected daily with verapamil plus 2 to 3 mg/kg chloroquine, the chloroquine-sensitive parasite became more susceptible to chloroquine than the parasite in mice given chloroquine alone. On the other hand, in mice infected with chloroquine-resistant parasites, verapamil severely suppressed the growth of the parasite when accompanied by daily injections of 2 to 3 mg/kg of chloroquine, at which doses resistant parasites grew steadily in the absence of verapamil, indicating reversal of chloroquine resistance. This reversal was dose-dependent between 5 and 50 mg/kg of verapamil. Daily injections of nicardipine or diltiazem at 50 mg/kg also reversed resistance to chloroquine in resistant parasites. These results indicate that Ca2+ antagonists increase the susceptibility to chloroquine in a sensitive line of P. chabaudi and reverse chloroquine resistance in a resistant line.

Animals↗
PubMedDate not supplied

Chloroquine disposition in hypersensitive and non-hypersensitive subjects and its significance in chloroquine-induced pruritus.

Twenty-one healthy Nigerian volunteers distributed into four groups participated in a study to determine the significance of chloroquine disposition in chloroquine-induced pruritus. It involved the administration of chloroquine with or without promethazine pre-administration to the subjects. Group I consisted of 8 chloroquine non-hypersensitive subjects receiving 2 tablets of chloroquine sulphate (300 mg base); Group II consisted of 5 chloroquine non-hypersensitive subjects receiving 2 tablets of chloroquine sulphate 30 minutes after 25 mg promethazine tablet pre-administration; Group III consisted of 5 chloroquine hypersensitive subjects treated as in Group II; Group IV consisted of 3 hypersensitive subjects treated as in Group I. Blood (5 ml) and urine samples were collected periodically for up to 6 days post-dose. The samples were analysed for chloroquine and some of its oxidation metabolites by a specific HPLC method. Probit plots of cumulative drug/metabolite ratios were done to determine if there is polymorphism in chloroquine metabolism. There was bimodality only in the distribution of chloroquine/monodesethylchloroquine ratios, suggesting polymorphism in the metabolic oxidation of chloroquine in these subjects. Higher levels of monodesethylchloroquine were obtained in Group IV subjects when compared with any of the other groups. The oral clearance rate, elimination half-life, and volume distribution at steady state of chloroquine in the study groups were not significantly different (P greater than 0.05). In the absence of promethazine there appears to be an extensive metabolism of chloroquine in hypersensitive individuals to produce monodesethylchloroquine which probably determines the degree of pruritus experienced by an individual.

Adult↗
PubMed1983

Distribution of chloroquine and its metabolite desethyl-chloroquine in human blood cells and its implication for the quantitative determination of these compounds in serum and plasma.

The amount of chloroquine and desethyl-chloroquine was determined in samples of total blood and in blood cell fractions from three normal subjects after one oral dose of 1000 mg of chloroquine diphosphate. About 70-85% of the total whole blood content of chloroquine and its metabolite desethyl-chloroquine were recovered in blood cells isolated from whole blood, indicating that these compounds have a high cell/plasma concentration ratio. They were mainly present in thrombocytes and granulocytes. A study of 40 patients taking chloroquine regularly as a treatment for rheumatoid arthritis showed significantly higher concentrations of chloroquine and desethyl-chloroquine in serum than in plasma. The concentration of chloroquine was about two times higher in serum than in plasma and for desethyl-chloroquine the concentration was about four times higher in serum than in plasma. These differences may be explained by a release of chloroquine and desethyl-chloroquine from thrombocytes during the coagulation of blood. The practical implication of the results is that the samples taken for chloroquine determination must be clearly identified as serum or plasma.

Arthritis, Rheumatoid↗
PubMed2003

Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi.

In 1993, Malawi became the first African country to replace chloroquine with sulfadoxine-pyrimethamine nationwide in response to high rates of chloroquine-resistant falciparum malaria. To determine whether withdrawal of chloroquine can lead to the reemergence of chloroquine sensitivity, the prevalence of the pfcrt 76T molecular marker for chloroquine-resistant Plasmodium falciparum malaria was retrospectively measured in Blantyre, Malawi. The prevalence of the chloroquine-resistant pfcrt genotype decreased from 85% in 1992 to 13% in 2000. In 2001, chloroquine cleared 100% of 63 asymptomatic P. falciparum infections, no isolates were resistant to chloroquine in vitro, and no infections with the chloroquine-resistant pfcrt genotype were detected. A concerted national effort to withdraw chloroquine from use has been followed by a return of chloroquine-sensitive falciparum malaria in Malawi. The reintroduction of chloroquine, ideally in combination with another antimalarial drug, should be considered in areas where chloroquine resistance has declined and safe and affordable alternatives remain unavailable.

Animals↗
PubMed2000

Chloroquine or amodiaquine combined with sulfadoxine-pyrimethamine for treating uncomplicated malaria.

BACKGROUND: Amodiaquine and chloroquine give fast relief from malaria symptoms, particularly fever. When used alone in areas where there is some parasite resistance they do not completely clear parasites from the blood in all cases, and so not all patients are cured of infection. The major disadvantage of using sulfadoxine-pyrimethamine alone is that it takes a relatively long time to relieve fever. OBJECTIVES: To assess the effectiveness of chloroquine or amodiaquine given with sulfadoxine-pyrimethamine to treat uncomplicated falciparum malaria. SEARCH STRATEGY: The Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE, Science Citation Index, African Index Medicus and LILACS were searched. Experts in the field and drug companies were contacted. SELECTION CRITERIA: Randomised and quasi-randomised trials of chloroquine or amodiaquine given with sulfadoxine-pyrimethamine compared with either drug alone in adults or children with confirmed uncomplicated falciparum malaria. DATA COLLECTION AND ANALYSIS: Two people independently applied the inclusion criteria. Data were extracted by the reviewer and checked independently by another person. MAIN RESULTS: Five trials were included. Fever clearance time was reduced by combination therapy compared with sulfadoxine-pyrimethamine alone. Parasite clearance at day seven follow-up was not significantly different for chloroquine or amodiaquine treatment with or without sulfadoxine-pyrimethamine. Parasite clearance at day 28 was better with combination therapy compared with chloroquine or amodiaquine alone (odds ratio 14.28, 95% confidence interval 6.76 to 30.19), but not significantly better than sulfadoxine-pyrimethamine alone (odds ratio 3.17, 95% confidence interval 0.96 to 10.43). There was no evidence from the included trials of serious side effects with combination treatment. REVIEWER'S CONCLUSIONS: In areas where chloroquine or amodiaquine are still effective, despite some degree of resistance, using these drugs in combination with sulfadoxine-pyrimethamine, rather than sulfadoxine-pyrimethamine alone, may make people feel better faster and improve sustained parasites clearance.

Adult↗
PubMed1987

Comparison of proteases from chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum.

An aminopeptidase and four hemoglobin-degrading acid proteases have been isolated from cloned strains of chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum. Amino-peptidases from both strains showed similar properties including molecular weights of 63,000 and non-competitive inhibition by chloroquine; Ki = 535 and 410 microM for enzymes from the sensitive and resistant strains respectively. The acid proteases from the chloroquine-sensitive strain included a low molecular weight enzyme in the soluble fraction (protease S), an enzyme weakly associated with membrane (protease M2), and two enzymes strongly associated with membrane (proteases M3 and M4). The acid proteases from the chloroquine-resistant strain included protease S, protease M2, a second enzyme weakly associated with membrane (protease M1), and protease M3. All of the acid proteases were inhibited by ferriprotoporphyrin IX and by the chloroquine-ferriprotoporphyrin IX complex, I50 = 5-25 microM. The data were consistent with a model for chloroquine action wherein chloroquine acts to divert ferriprotoporphyrin IX from sequestration into malarial pigment, leaving ferriprotoporphyrin IX (or its chloroquine complex) to interfere with digestion of host cytosol by inhibiting hemoglobin-degrading proteases. However, the similarities among the proteases from chloroquine-sensitive and chloroquine-resistant strains of parasites suggest that chloroquine resistance does not result from changes in parasite proteases.

Aminopeptidases↗
PubMed1993

Stereoselective pharmacokinetic properties of chloroquine and de-ethyl-chloroquine in humans.

Stereoselective pharmacokinetic properties of chloroquine were investigated in humans after a single oral dose of the separate enantiomers. The study was carried out according to a crossover experimental design with a washout period between the administration of each enantiomer. Total blood chloroquine concentrations were measured using an achiral high performance liquid chromatography method. Terminal half-life (t1/2 lambda z) and mean residence time (MRT) were longer for (R)-chloroquine (294h and 388h, respectively) than for (S)-chloroquine (236h and 272h, respectively). The total body clearance was lower for the (R)-enantiomer [136 +/- 38 ml/min (8.16 +/- 2.28 L/h)] than for the (S)-enantiomer [237 +/- 71 ml/min (14.22 +/- 4.26 L/h)]. Although the (R)-stereoisomer remained longer in the body, its volume of distribution (3410 +/- 720L) was lower than than that of (S)-chloroquine (4830 +/- 1490L). Protein binding was different for both chloroquine stereoisomers, with opposite preferential binding to human albumin and alpha 1-acid glycoprotein. Binding to total human plasma amounted to 66.6 +/- 3.3% for (S)-chloroquine and to 42.7 +/- 2.1% for the (R)-enantiomer. De-ethyl-chloroquine concentrations were also different for both enantiomers, resulting in a statistically significant increase in the AUC of (S)-de-ethyl-chloroquine (12.9 +/- 7.4 mg/L.h) compared with (R)-de-ethyl-chloroquine (6.29 +/- 2.18 mg/L.h). With a daily dosage regimen, the divergent pharmacokinetic behaviour of chloroquine enantiomers generates a calculated R:S ratio of blood concentrations amounting to 1:0.7 at steady-state. Insufficient information about stereoselective activity and toxicity of chloroquine stereoisomers prevent further conclusions about the clinical consequences of these pharmacokinetic differences.

Administration, Oral↗
PubMed1994

Uptake and efflux of chloroquine by chloroquine-resistant Plasmodium falciparum clones recently isolated in Africa.

In recently isolated African Plasmodium falciparum clones, the intracellular chloroquine concentration at steady-state, under standard culture conditions, could not differentiate chloroquine-sensitive from resistant parasites. However, under an atmosphere of air the chloroquine-resistant P. falciparum clones released pre-accumulated [3H]chloroquine more rapidly than sensitive clones. The very fast efflux of the pre-accumulated drug from chloroquine-resistant (CQR) parasites resulted in a differential in the drug retained by resistant and sensitive parasites. The chloroquine-sensitive parasites retained 2-3 times more chloroquine than resistant parasites. The steady-state uptake of [3H]chloroquine appeared to be enhanced by verapamil and desipramine in the chloroquine-resistant clones, while the opposite was observed with sensitive clones. This confirmed the suggestion that verapamil inhibits the rapid efflux in CQR parasites resulting in a readily detectable increase in chloroquine accumulation. These observations indicate that the biochemical phenotypes of African chloroquine-resistant P. falciparum are similar to those reported from S.E. Asia and Latin America and are consistent with a common molecular basis for the phenomenon.

Africa↗
PubMed1975

Chloroquine resistance in malaria: variations of substrate-stimulated chloroquine accumulation.

The response of [14C]chloroquine accumulation to the provision of substrate was evaluated using washed erythrocytes infected with Plasmodium berghei CS (chloroquine-susceptible), with P. berghei CR (chloroquine-resistant), with Plasmodium vinckei CS, with P. vinckei CR, or with a strain of P. berghei spontaneously resistant to chloroquine, Plasmodium berghei yoelii 17X. Erythrocytes infected with chloroquine-resistant parasites had a blunted response, particularly to low glucose concentrations. In the presence of 0.5 mM glucose in one set of experiments, for example, chloroquine accumulation increased by a factor of 8 in erythrocytes infected with P. berghei CS whereas there was no increase in erythrocytes infected with P. berghei CR or with P. berghei yoelii 17X; the difference between P. vinckei CS and P. vinckei CR was less dramatic. In every case except for P. berghei CR, the process of chloroquine accumulation in the presence of 5 mM glucose exhibited a component which became saturated at low concentrations of chloroquine in the medium. For P. berghei CR, plotting steady-state accumulation of chloroquine as a function of the concentration of chloroquine in the medium yielded a sigmoid curve, revealing that higher concentrations of chloroquine (above 100 mM) somehow relieve the blunted response to glucose and suggesting that the variation is in the process of accumulation rather than in substrate utilization.

Animals↗
PubMed1997

Identification of a chloroquine importer in Plasmodium falciparum. Differences in import kinetics are genetically linked with the chloroquine-resistant phenotype.

We demonstrate that uptake of the antimalarial drug chloroquine is temperature-dependent, saturable, and inhibitable in Plasmodium falciparum. These features are indicative of carrier-mediated transport and suggest that a P. falciparum-encoded protein facilitates chloroquine import. Although both chloroquine-resistant and susceptible parasite isolates exhibit facilitated chloroquine uptake, the kinetics differ. Chloroquine-resistant parasite isolates consistently have an import mechanism with a lower transport activity and a reduced affinity for chloroquine. These differences in uptake kinetics are linked with chloroquine resistance in a genetic cross. These data suggest that changes in chloroquine import kinetics constitute a minimal and necessary event in the generation of the resistant phenotype. Competitive inhibition of chloroquine uptake by amiloride derivatives further suggests that chloroquine import is mediated by a plasmodial Na+/H+ exchanger.

Amiloride↗