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PubMed2004

Variations in the sequence and expression of the Plasmodium falciparum chloroquine resistance transporter (Pfcrt) and their relationship to chloroquine resistance in vitro.

Chloroquine has been widely used for malaria treatment and prophylaxis for several decades, but its usefulness has now declined with the emergence of chloroquine resistance. Recent studies showed that the K76T mutation in the PfCRT protein, initially associated to chloroquine-resistant parasites, is sometimes also present in susceptible parasites, suggesting that other factors control the expression of the resistance phenotype. Here, we sought new mutations in the Pfcrt gene and used real-time PCR to investigate variations in the expression level of this gene with respect to the in vitro response to chloroquine. About 40 Cambodian isolates of Plasmodium falciparum were selected on the basis of their response to chloroquine in vitro. The Pfcrt gene was characterised by amplifying and sequencing the full-length cDNA. Twelve point mutations--M74I, N75D/E, K76T, A144F, L148I, I194T, A220S, Q271E, N326S, T333S, I356T and R371I--were detected. Mutations identified at positions 144, 148, 194 and 333 had never been described before. These mutations define six distinct haplotypes, distributed heterogeneously throughout Cambodia. Only the mutations at positions 74-76, 220 and 271 were significantly associated with the in vitro response to chloroquine. Three major haplotypes--MNK/A/Q, IDT/S/E and IET/S/E--accounted for all the isolates examined. The MNK/A/Q haplotype corresponded to susceptible isolates whereas parasites with the IDT/S/E haplotype displayed an intermediate response to chloroquine and those with the IET/S/E haplotype displayed the highest IC50 values. Phylogenic analysis suggested that the IDT and IET haplotypes (positions 74-76) arose independently from the wild-type MNK sequence. We found that the expression level of Pfcrt, evaluated by real-time PCR, had no effect on the response of the parasite to the drug in vitro. Similarly, in a CQ-resistant strain short-term cultured in the presence of CQ, no change was observed in the level of transcripts. These results are discussed in light of recent finding suggesting the possible involvement of other transporters in CQ-resistance.

Animals↗
PubMed1990

The effects of chloroquine on the infectivity of chloroquine-sensitive and -resistant populations of Plasmodium yoelii nigeriensis to mosquitoes.

Subtherapeutic doses of chloroquine have been reported to enhance infectivity of drug-resistant Plasmodium species to their vectors. In this investigation, Plasmodium yoelii nigeriensis N67 strain showed enhanced infectivity to mosquitoes when stimulated by chloroquine. Both sensitive and resistant clones were derived from the N67 strain by dilution, showing that this strain is polymorphic for the resistant trait. A resistant subline was derived by selection under drug pressure from a chloroquine-sensitive clone, but neither the sensitive nor the resistant clones or sublines showed enhancement of infectivity in the presence of chloroquine. This suggests that the enhancement of infectivity shown by the N67 strain is a response to chloroquine stimulation shown only by certain of the genotypes within it, and that this response to chloroquine is not a trait causally connected with the genes coding for chloroquine resistance.

Animals↗
PubMed1995

Treatment of chloroquine-resistant Plasmodium vivax with chloroquine and primaquine or halofantrine.

Optimal therapy for infection by chloroquine-resistant Plasmodium vivax has not been established. From 1992 to 1994 during three separate studies, 147 Javanese residents of Irian Jaya infected by P. vivax were treated with either chloroquine (25 mg of base/kg during 3 days or 10 mg of base/kg in one dose) plus primaquine (10 mg/kg during 28 days or 2.5 mg/kg during 3 days) (n = 78), chloroquine plus placebo (n = 50), or halofantrine (24 mg base/kg in 12 h; n = 19). There was no difference in tolerance to or side effects of any of the regimens. Within 14 days of starting therapy, therapeutic failure among these patients was 44% for chloroquine, 5% for chloroquine plus primaquine (P < .001), and 0 for halofantrine (P < .001). After 28 days, therapeutic failure was 78%, 15%, and 6%, respectively. Thus, chloroquine plus primaquine in combination and halofantrine alone are effective therapies for chloroquine-resistant P. vivax.

Adolescent↗
PubMed1985

Chloroquine uptake by Plasmodium falciparum-infected human erythrocytes during in vitro culture and its relationship to chloroquine resistance.

Chloroquine uptake by Plasmodium falciparum-infected human erythrocytes (RBC) was studied in vitro before and during culture by measuring the chloroquine gradient between the cells and medium (C/M) by high-pressure liquid chromatography. The C/M values were 5.9 +/- 2.7 (n = 23) for uninfected RBC, 13 to 34 for six chloroquine-susceptible isolates (concentration required to inhibit 50% of parasite growth, less than 100 nmol/liter) in partially infected RBC (parasitemia from 0.3 to 5%) (n = 28), and 8.4 to 4.9 for four chloroquine-resistant isolates (concentration required to inhibit 50% of parasite growth, 320 to 1,500 nmol/liter) in partially infected RBC (parasitemia from 0.4 to 5%) (n = 26). Two isolates were studied before and after adaptation to continuous culture. C/M was found to decrease (34.2 to 2.1 and 19.3 to 4.9), whereas the concentration required to inhibit 50% of parasite growth increased (35 to 1,400 and 54 to 1,500 nmol/liter), thus indicating the acquisition of chloroquine resistance. These results demonstrate that chloroquine uptake decreased in RBC in which the infective strain, initially susceptible, became resistant in culture and imply that the drug is bound to ferriprotoporphyrin IX to a lesser extent or that a parasite protein competes with ferriprotoporphyrin IX to a greater extent. We suggest that genotypic modifications in the mechanism of chloroquine uptake might occur in the parasite.

Chloroquine↗
PubMed1991

Chloroquine inhibits the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. A potential new mechanism for the therapeutic effect of chloroquine against intracellular pathogens.

Chloroquine and ammonium chloride, by virtue of their basic properties, have been shown to raise endocytic and lysosomal pH and thereby interfere with normal iron metabolism in a variety of cell types, including mononuclear phagocytes. Cellular iron metabolism is of critical importance to Legionella pneumophila, an intracellular bacterial pathogen whose capacity to multiply in human mononuclear phagocytes is dependent upon the availability of intracellular iron. In view of this, we have studied the effects of chloroquine and ammonium chloride on L. pneumophila intracellular multiplication in human monocytes. Chloroquine, at a concentration of 20 microM, and ammonium chloride, at a concentration of 20 mM, inhibited L. pneumophila intracellular multiplication by 1.4 +/- 0.2 (SEM) logs and 1.5 +/- 0.2 logs, respectively. Chloroquine- and ammonium chloride-induced inhibition of L. pneumophila intracellular multiplication was completely reversed by iron nitrilotriacetate, an iron compound which is soluble in the neutral to alkaline pH range, but not by iron transferrin, which depends upon acidic intracellular conditions to release iron. Chloroquine had no major direct effect on L. pneumophila multiplication in artificial media except at extremely high concentrations (15,000-fold that which inhibited L. pneumophila multiplication in mononuclear phagocytes), and inhibition at such concentrations was not reversed by iron nitrilotriacetate. This study demonstrates that chloroquine and ammonium chloride inhibit the intracellular multiplication of L. pneumophila by limiting the availability of iron to the bacterium. It is possible that such a mechanism of action underlies chloroquine's antimicrobial effect against other intracellular pathogens, such as the agents of malaria and tuberculosis.

Adult↗
PubMedDate not supplied

Reported side effects to chloroquine, chloroquine plus proguanil, and mefloquine as chemoprophylaxis against malaria in Danish travelers.

BACKGROUND: The aim of the study was to provide data on the relative frequency of reported symptoms in travelers using chloroquine, chloroquine plus proguanil, and mefloquine. METHOD: The study was an open, nonrandomized study recording self-reported events in travelers recruited consecutively from two travel clinics in Copenhagen, Denmark. The main outcome measures were the relative proportion of travelers reporting particular symptoms in the three prophylaxis groups, compliance, hospitalization and premature termination of the travel. RESULTS: From May 1996 to April 1998 5, 446 travelers were included and 4,158 questionnaires (76.3%) returned. Compliance was significantly better in mefloquine users with 83.3% of short term travelers compared to 76.3% in chloroquine plus proguanil users. Also, 84.8%, 59.3% and 69.5% using chloroquine, chloroquine plus proguanil, and mefloquine respectively reported no symptoms and 0.6%, 1.1% and 2.8% reported "unacceptable" symptoms. Compared to chloroquine, mefloquine users had a significantly higher risk of reporting depression, RR 5.06 (95% CI 2.71 - 9.45), "strange thoughts," RR 6.36 (95% CI 2.52 - 16.05) and altered spatial perception, RR 3.00 (95% CI 1.41 - 6.41). CONCLUSION: Overall mefloquine is tolerated at least as well as chloroquine plus proguanil and shows better compliance, however, symptoms related to the central nervous system are more prevalent in mefloquine users and when symptoms develop, they are perceived as more severe.

Antimalarials↗
PubMed1992

[Alteration in resistance of Plasmodium falciparum to chloroquine after cessation of chloroquine medication for twelve years].

In view of the fact the resistance of Plasmodium falciparum to chloroquine occurred extensively in Hainan, a decision was made in 1979 that the use of chloroquine should be quit in the whole province. A longitudinal survey on chloroquine-sensitivity of P. falciparum was carried out during 1981-1991 to observe the variation in resistance of the parasite after the cessation of the chloroquine medication for every 2-3 years. A tendency of progressive decline of resistance was revealed. By using in vitro test, the rate of chloroquine-resistant P. falciparum dropped from 97.9% in 1981 to 60.9% in 1991 (P < 0.001). The mean dosage of chloroquine for complete inhibition of schizont formation declined from 10.46 pmol/microliters in 1981 to 3.02 pmol/microliters in 1991 (P < 0.001). The percentage of population requiring larger dosage (6.4 pmol/microliters to completely inhibit schizont formation declined from 83.3% in 1981 to 17.4% in 1991 (P < 0.001); whereas those requiring small dosage (1.6 pmol/microliters), increased from 4.2% in 1981 to 60.8% in 1991 (P < 0.001). In in vivo test, the rate of chloroquine-resistant P. falciparum decreased from 84.2% in 1981 to 40% in 1991 (P < 0.001). The proportion of RII plus RIII cases of the total resistant cases dropped from 59.4% in 1981 to 37.5% in 1991 (0.02 > P > 0.01).

Animals↗
PubMed2003

Short report: association between chloroquine and amodiaquine resistance and allelic variation in the Plasmodium falciparum multiple drug resistance 1 gene and the chloroquine resistance transporter gene in isolates from the upper Nile in southern Sudan.

Amodiaquine, a 4-aminoquinoline compound, is being considered as an alternative to chloroquine and pyrimethamine/sulfadoxine where resistance in Plasmodium falciparum to both drugs has been selected. Although amodiaquine is more potent than chloroquine, its effectiveness is reduced in areas where chloroquine resistance is high. We report an association of the P. falciparum chloroquine resistance transporter (pfcrt) gene and the P. falciparum multiple drug resistance 1 (pfmdr1) gene, two chloroquine resistance markers, with chloroquine and amodiaquine efficacy in vivo in southern Sudan. The data show that the allele of the pfcrt gene with a lysine to threonine change at codon 76 is strongly associated with both chloroquine and amodiaquine resistance. No such association was observed with the pfmdr1 gene.

ATP-Binding Cassette Transporters↗
PubMed1989

Response of Plasmodium falciparum to chloroquine treatment: relation to whole blood concentrations of chloroquine and desethylchloroquine.

A standard treatment with 25 mg chloroquine base per kilogram body weight was given to 39 semi-immune asymptomatic Tanzanian schoolchildren with Plasmodium falciparum parasitaemia. Whole blood chloroquine and desethylchloroquine concentrations were monitored 12 times during 30 days of follow-up using 100 microliters capillary blood dried on filter-paper. All but three children had detectable amounts of chloroquine (greater than or equal to 10 nmol/l) in their blood before treatment. The interindividual variations in concentrations during the first week were 3.3 to 5.1-fold for chloroquine and 3.5 to 6.3-fold for desethylchloroquine. In seven children with RII response in vivo, the highest determined chloroquine concentration was lower (P = 0.029) than in the others. After treatment, a rough approximation of the minimum inhibitory concentration in vivo was made by calculating the average of the chloroquine concentrations before and after the time when parasites increased or reappeared again. RII-resistant parasites increased in number when the median residual whole blood concentration in the children was approximately 790 (range, 444-869) nmol/l. Parasites reappeared when the median residual whole blood concentrations was approximately 147 (range, 44-673) nmol/l. We conclude that interindividual variations of chloroquine concentrations have an impact on the outcome of treatment and the classification of resistance in vivo.

Adolescent↗
PubMed1984

Residual chloroquine and metabolites in man as a sequel of previous chloroquine medications: a urinary excretion study and its significance.

In malaria-endemic areas like Nigeria, chloroquine is used frequently and extensively in the management of attacks. In this investigation urine samples of six different adult subjects showed a significantly wide range of excretion of total chloroquine and metabolites (10.01 to 0.021 mg) in 12 h due to residual levels of the drug in the subjects as a function of time of last medication with the drug. Two subjects representing extreme users of the drug--a naive subject and a frequent user--were given 300 mg of chloroquine each and the excretion rate profile monitored for 24 h. The first-time user of chloroquine showed a typical cumulative excretion pattern with total excretion of 16 mg while the frequent user showed a bimodal cumulative excretion curve with the second phase tending to a higher plateau effect and a total excretion of 21 mg in 24 h. These different levels of total excretion could be attributed to the influence of protein binding and tissue accumulation of the drug in the frequent user, and a second-phase excretion related to release of some bound chloroquine and metabolites. These effects are considered in relation to accumulation of chloroquine in the body resulting from frequent medication with the drug. Information regarding the time of last medication, and residual levels of chloroquine and metabolites is necessary for instituting the appropriate therapeutic regimen. The assay techniques involving single selective solvent extraction, thin-layer chromatography and spectrophotometric measurements, have been found adequately quantitative, simple and quick for use in routine clinical laboratory investigation.

Adult↗
PubMedDate not supplied

[Chloroquine resistance of Plasmodium falciparum. Study of a surveillance method based on placental apposition and determination of blood chloroquine in pregnant women].

We investigated placental malaria infection and blood chloroquine concentration in pregnant women to assess a new method of monitoring the chloroquine resistance (CQ-R) of Plasmodium falciparum. We studied two groups of women: 96 women taking the usual prophylactic treatment of 300 mg chloroquine per week and 108 controls given no treatment. We carried out placental apposition, a thick smear and determination of blood chloroquine concentration after delivery. Malarial infection of the placenta was more frequent and the density of parasites higher in controls than in women given prophylaxis. Blood chloroquine concentrations were adequate in all women given prophylaxis (above 200 ng/ml, with a mean of 500 ng/ml). Twenty-six per cent of placentas in the treated group and 51% of placentas in the control group were infected. The placental infection rates for the two groups were compared. The frequency of chloroquine-resistant strains was about 50% (2 or 3 times higher than the CQ-R frequencies obtained in studies using in vivo tests). The simplicity of placental apposition makes this technique potentially valuable. However, determination of blood chloroquine concentration is also required and can only be carried out in a reference center.

Adult↗
PubMed2003

Combination effects of chloroquine with the febrifugine and isofebrifugine mixture against a blood-induced infection with chloroquine-resistant Plasmodium berghei NK65 in ICR mice.

The combination effects of chloroquine with a mixture of febrifugine and isofebrifugine were evaluated against a blood-induced infection with chloroquine-resistant P. berghei NK65 in ICR mice. Mice in the untreated control showed a progressively increasing parasitemia leading to mouse death. A two-day dosage of 20 mg base/kg of chloroquine alone showed little effect against P. berghei NK65 infection, and all mice died from day 13 to 14 with an increasing parasitemia. A four-day dosage of 1 mg/kg of the febrifugine and isofebrifugine mixture alone showed a little antimalarial activity, but all mice died from day 19 to 27 with an increasing parasitemia. On the other hand, mice treated with chloroquine plus alkaloids survived during the experiment. All mice treated with chloroquine alone or the alkaloid mixture alone showed low parasitemia levels during a drug administration and following a few days, but then malaria parasites increased in the bloodstream of the treated mice until death. On the other hand, malaria parasites in the mice given chloroquine plus alkaloids decreased on day 6 and then were not detected by a microscopic examination during observation period.

Animals↗
PubMed1987

Double-blind study to assess the efficacy of chlorproguanil given alone or in combination with chloroquine for malaria chemoprophylaxis in an area with Plasmodium falciparum resistance to chloroquine, pyrimethamine and cycloguanil.

In this study the efficacy of chlorproguanil (20 mg base weekly) was compared in schoolchildren with that of chloroquine (200 mg base weekly) and that of both drugs combined (20 mg base + 200 mg base weekly). The double blind trial was performed in the rice field area of the Ruzizi valley in Burundi, where Plasmodium falciparum is widely resistant to chloroquine, and where pyrimethamine resistance with cycloguanil cross-resistance had been demonstrated. After 17 weeks, when the trial was ended, 60% breakthroughs had been observed among the children taking chloroquine, 72% among those under chlorproguanil and 61% among those under chlorproguanil and chloroquine. In children weighing between 15 and 24 kg, the failure rate was significantly higher in those treated with chlorproguanil than in the group treated with chloroquine. No difference in efficacy was observed in children weighing 25 to 39 kg. There was no significant increase of efficacy when chlorproguanil was given in association with chloroquine. The mean titre of fluorescent antibodies was the same in each treated group on week 5 and week 15. The comparison of these data with the infection rates in non-protected children suggests that malaria could not be prevented with any of the drug regimens utilized in the study.

Adolescent↗
PubMed1996

Chloroquine bioassay of plasma specimens obtained from soldiers on chloroquine plus doxycycline for malaria prophylaxis.

In this study we describe the application of a bioassay for measuring chloroquine equivalent concentrations in plasma samples obtained from soldiers on chloroquine (300 mg weekly) and doxycycline (50 or 100 mg daily) for malaria prophylaxis. Chloroquine, its principal metabolite monodesethylchloroquine and doxycycline were also measured by high performance liquid chromatography (HPLC). Physiological concentrations of doxycycline did not interfere with the measurement of chloroquine equivalent concentrations. The correlation between bioassay and HPLC was rs = 0.88, with a median bioassay/HPLC chloroquine concentration ration of 1.1 (range 0.6-2.4, n = 26). The bioassay is a valuable method, particularly under field conditions, for measuring chloroquine concentrations and can be very helpful in distinguishing drug failures from either poor compliance or inadequate drug absorption.

Antimalarials↗
PubMed2003

Chloroquine resistance modulated in vitro by expression levels of the Plasmodium falciparum chloroquine resistance transporter.

Plasmodium falciparum malaria is increasingly difficult to treat and control due to the emergence of parasite resistance to the major antimalarials, notably chloroquine. Recent work has shown that the chloroquine resistance phenotype can be conferred by multiple amino acid mutations in the parasite digestive vacuole transmembrane protein PfCRT. Here, we have addressed whether chloroquine resistance can also be affected by changes in expression levels of this protein. Transient transfection reporter assays revealed that truncation of the pfcrt 3'-untranslated region just prior to putative polyadenylation sites resulted in a 10-fold decrease in luciferase expression levels. Using allelic exchange on a chloroquine-resistant line (7G8 from Brazil), this truncated 3'-untranslated region was inserted downstream of the pfcrt coding sequence, in the place of the endogenous 3'-untranslated region. The resulting pfcrt-modified "knockdown" clones displayed a marked decrease in pfcrt transcription and an estimated 30-40% decrease in PfCRT protein expression levels. [3H]hypoxanthine incorporation assays demonstrated up to a 40% decrease in chloroquine with or without verapamil IC50 levels of pfcrt knockdown clones, relative to the 7G8 parent. Single-cell photometric analyses were consistent with an altered intracellular pH in the knockdown clones, providing further evidence for a relationship between PfCRT, pH regulation, and chloroquine resistance. Genetic truncation of 3'-untranslated regions provides a useful approach for assessing the impact of candidate genes on drug resistance or other quantifiable phenotypes in P. falciparum.

3' Untranslated Regions↗
PubMed1983

Plasma chloroquine and desethylchloroquine concentrations in children during and after chloroquine treatment for malaria.

Twelve children with acute falciparum malaria were treated with 25 mg/kg chloroquine orally in three divided doses at 24 h intervals. Concentrations of chloroquine and its metabolite, desethylchloroquine, were measured in plasma from the beginning of treatment for up to 7 days using a high pressure liquid chromatography (h.p.l.c.) technique. Chloroquine was detectable in plasma within 30 min of giving the drug. Peak level was reached in 1-8 h after the first dose of 10 mg/kg and the peak concentrations ranged between 65 and 263 ng/ml. Chloroquine concentration declined slowly in plasma after stopping drug administration so that the concentration at the seventh day was 37.5% of the concentration on the third day. The apparent half-life was 3-4 days. Desethylchloroquine was detectable in plasma within 30 min of giving chloroquine and peak levels were reached in 2-12 h. Peak concentration after the first dose of chloroquine ranged between 9 and 62 ng/ml. Desethylchloroquine was also slowly cleared from plasma and mean concentration at the end of 7 days was 49% of the mean concentration at the end of 3 days.

Child↗
PubMed1996

Response of childhood malaria to chloroquine and Fansidar in an area of intermediate chloroquine resistance in Côte d'Ivoire.

The parasitological, clinical and haematological responses to chloroquine treatment were studied in children during a 28-day follow-up in an area of Côte d'Ivoire with intermediate chloroquine resistance. The parasitological, clinical and haematological responses to Fansidar were also investigated in patients who returned to the health centre within 28 days with symptoms of malaria. Of 82 children aged 0-9 years who completed the study, only 67% were parasite-negative on thick blood film on day 7, which decreased to 21% by day 28. While chloroquine treatment still produced clinical remission at day 7 in 95% of the children, 35% had recurrent fever with concomitant parasitaemia before day 28. All fever cases subsequently treated with Fansidar remained parasite-negative over a period of 28 days. On day 28 the haematocrit levels were higher in those children who responded successfully to treatment with either chloroquine or Fansidar than in the children who were still parasite-positive but without fever (two-tailed t-test, P = 0.02). The rate of resistance to chloroquine was most pronounced among the younger children (< 5 years), 18% of whom showed clinical failure by day 14. This study underlines the importance of monitoring the durability of response to chloroquine treatment for at least 14 days in young children in Côte d'Ivoire.

Animals↗
PubMed1997

WR 238605, chloroquine, and their combinations as blood schizonticides against a chloroquine-resistant strain of Plasmodium vivax in Aotus monkeys.

The compound WR 238605 is a primaquine analog being developed by the U.S. Army as an antimalarial drug. Currently, there is no established treatment for Plasmodium vivax parasitemias that are not cured by chloroquine. This study tested WR 238605, chloroquine, and their combinations against a chloroquine-resistant strain of P. vivax (AMRU 1) in Aotus monkeys. A total dose of 3 mg/kg of WR 238605 given at a dosage of 1 mg/kg/day for three days cleared patent parasites in all eight monkeys but recrudescence of parasitemia occurred 15-25 days after initiation of treatment. A total dose of 9 mg/kg of WR 238605 over a three-day period cured all three monkeys of their infections. A total dose of 30 mg/kg of chloroquine did not clear patent infections in three monkeys, whereas a total dose of 60 mg/kg generally (two of three) cleared patent parasitemia but did not cure. Whereas total doses of 30 mg/kg of chloroquine or 3 mg/kg of WR 238605 given alone failed to cure, both drugs given in combination at these dosages cured two of three infections. These results indicate that WR 238605 may be an alternative treatment for chloroquine-resistant vivax malaria.

Aminoquinolines↗