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PubMed2002

Molecular epidemiology of malaria in Cameroon. XIV. Plasmodium falciparum chloroquine resistance transporter (PFCRT) gene sequences of isolates before and after chloroquine treatment.

Laboratory studies have strongly suggested that the gene coding for Plasmodium falciparum chloroquine resistance transporter (PFCRT) may play a determinant role in chloroquine resistance. A clinical study in Mali also found evidence for selection of the key PFCRT amino acid substitution, Lys76Thr, in patients who fail to respond to chloroquine treatment. To test the hypothesis that in vivo selection of mutant PFCRT alleles occurs after chloroquine treatment, PFCRT and merozoite surface antigen 2 (msa-2) polymorphisms were compared between 61 pretreatment and posttreatment paired samples from children with either clinical or parasitologic failure. There were six wild-type PFCRT alleles, 44 mutant alleles, and 11 mixed alleles among pretreatment isolates. All posttreatment parasites had mutant PFCRT alleles. Recrudescence accounted for 42 of 61 posttreatment infections, while 19 posttreatment infections were due to new infection (including all isolates with Lys-76 before treatment and Thr-76 after treatment). Seven pretreatment isolates with mixed PFCRT alleles had only Thr-76 on recrudescence, providing a direct evidence for in vivo selection for mutant PFCRT. Although the presence of mutant PFCRT alleles in pretreatment isolates is not predictive of chloroquine treatment failure, our data support the hypothesis that in vivo selection for recrudescent parasites carrying mutant PFCRT alleles occurs. These results may have important implications for the future surveillance of chloroquine resistance by the use of molecular markers.

Animals↗
PubMed2003

New haplotypes of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene among chloroquine-resistant parasite isolates.

Mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene were examined to assess their associations with chloroquine resistance in clinical samples from Armopa (Papua) and Papua New Guinea. In Papua, two of the five pfcrt haplotypes found were new: SVIET from Armopa and CVIKT from an isolate in Timika. There was also a strong association (P < 0.0001) between the pfcrt 76T allele and chloroquine resistance in 50 samples. In Papua New Guinea, mutations in the pfcrt gene were observed in 15 isolates with chloroquine minimum inhibitory concentrations (MICs) of 16-64 pmol, while the remaining six isolates, which had a wild-type pfcrt gene at codon 76, had MICs of 2-8 pmol. These observations confirm that mutations at codon 76 in the pfcrt gene are present in both in vivo and in vitro cases of chloroquine resistance, and that detection of the pfcrt 76T allele could predict potential chloroquine treatment failures.

Animals↗
PubMed2005

Decreased prevalence of the Plasmodium falciparum chloroquine resistance transporter 76T marker associated with cessation of chloroquine use against P. falciparum malaria in Hainan, People's Republic of China.

The use of chloroquine treatment for Plasmodium falciparum malaria was abandoned in China in 1979 because of widespread drug resistance. Subsequent studies found decreases in the prevalence of chloroquine-resistant strains. To evaluate these decreases and assess the current status of chloroquine sensitivity in Hainan, China, we determined the prevalence of the P. falciparum chloroquine resistance transporter (PfCRT) 76T marker in the DNA of blood samples collected from 1978 to 2001. Results showed the presence of PfCRT 76T in 101 of 112 samples (90%) from 1978 to 1981, 30 of 43 samples (70%) from 1986, 22 of 34 samples (65%) from 1997 to 1998, and 37 of 68 samples (54%) from 2001. The prevalence of PfCRT 76T thus progressively decreased after chloroquine was discontinued as a treatment for P. falciparum malaria (chi(2) = 5.2, P < 0.022 [1978-1981 versus 1986]; chi(2) = 7.4, P < 0.006 [1978-1981 versus 1997-1998]; and chi(2) = 28.8, P < 0.0001 [1978-1981 versus 2001]). Reduced prevalence of the PfCRT 76T marker is consistent with greater rates of chloroquine sensitivity from in vitro drug assays of blood samples in 1997 and 2001. Monitoring for continued decreases will provide valuable information for future drug-use policies in China.

Animals↗
PubMed1998

Efficacy of chloroquine plus chlorpheniramine in chloroquine-resistant falciparum malaria during pregnancy in Nigerian women: a preliminary study.

The efficacy of chloroquine plus chlorpheniramine, a histamine H receptor antagonist, which reverses chloroquine 1 insensitivity in Plasmodium falciparum in vitro and in vivo , was evaluated in 30 pregnant women with recrudescent chloroquine-resistant Plasmodium falciparum malaria. All patients had at least one or more treatment failures with one or more courses of chloroquine or pyrimethamine-sulphadoxine. There was a prompt response to treatment with parasitaemia and fever clearing in all patients within 48 and 96 hours respectively of commencement of therapy with the combination. The cure rate on day 14 was 77%. Parasitaemia recurred in seven patients after day 14 and was successfully treated with oral mefloquine. The combination was well tolerated; pruritus and drowsiness were the only noticeable adverse effects. The progress of pregnancy and its outcome were not adversely affected by treatment with the combination. When fully developed, the combination of chloroquine plus chlorpheniramine may be an alternative in the treatment of chloroquine-resistant malaria during pregnancy in Nigerian women.

Journal Article↗
PubMed1998

Pfmdr1 Asn1042Asp and Asp1246Tyr polymorphisms, thought to be associated with chloroquine resistance, are present in chloroquine-resistant and -sensitive Brazilian field isolates of Plasmodium falciparum.

Parasite resistance to antimalarial drugs, particularly chloroquine, is the most disturbing problem of malaria chemotherapy. There is evidence that the codon 86Tyr polymorphism of the Pfmdr1 gene is associated with chloroquine resistance in West African Plasmodium falciparum. The association of this and four other coding alterations of the Pfmdr1 gene with chloroquine resistance has not been extensively investigated in South American isolates. In this study, we examined 51 Brazilian P. falciparum isolates for the presence or absence of Asn86Tyr, Asn1042Asp, and Asp1246Tyr polymorphisms. While these isolates were all sensitive in vitro to mefloquine, amodiaquine, and quinine, only 2 (4%) were chloroquine-sensitive. The findings reported here provide the first observations of this kind on a large number of field parasite samples from South America. We show that in vitro chloroquine-resistant and -sensitive strains carry the Asn1042Asp and Asp1246Tyr polymorphisms and provide support for earlier suggestions that Asn86Tyr may be rare or absent in South American P. falciparum.

Amodiaquine↗
PubMed1988

Chloroquine treatment of falciparum malaria in an area of Kenya of intermediate chloroquine resistance.

106 children aged 1-10 years who had pure Plasmodium falciparum infections and temperatures greater than or equal to 38 degrees C were treated with chloroquine base, 25 mg/kg body weight. 29% of the infections were sensitive in vivo, 41% recurred within 4 weeks (RI), 26% were RII resistant, and 4% were RII resistant. Rieckmann micro in vitro tests were successful in 64% of isolates obtained from these children; 63% were resistant to chloroquine. In 58 paired isolates obtained before and after treatment, the level of chloroquine sensitivity was lower in the parasites persisting or recurring after treatment. All children except 2 of the 4 with RIII resistance became afebrile an average of 1.4 d after starting treatment and their other symptoms resolved in an average of 1.8 d. By day 28, 57% of the children with RI resistance and 78% of those with RII resistance had recurrence of fever and other symptoms, compared with 19% of children with sensitive infections. No relationship was observed between the clinical or parasitological response and age, nutritional status, haematocrit, splenomegaly, presence of sickle-cell trait, or seropositivity to malaria by enzyme-linked immunosorbent assay. The study demonstrates that, in most children with malaria in an area of intermediate chloroquine resistance, fever and other symptoms resolve at least temporarily when treated with chloroquine.

Animals↗
PubMed2006

Why does chloroquine impair renal function?: chloroquine may modulate the renal tubular response to vasopressin either directly by inhibiting cyclic AMP generation, or indirectly via nitric oxide.

Chloroquine is one of the antimalaria drugs, also used to treat rheumatoid arthritis and systemic lupus erythematosus (SLE). Although well tolerated in most individuals, it was suggested that chloroquine can exert a profound influence on renal function, especially in individuals with compromised body fluid status. However, epidemiological studies are still lacking. The renal actions of chloroquine are further exacerbated by co-administration of other commonly used drugs such as paracetamol. The following discussion will focus on the evidence that chloroquine is a stimulator of nitric oxide (NO), which mediates many of its renal actions (diuresis, natriuresis and an increase in both glomerular filtration rate (GFR) and plasma vasopressin). Chloroquine appears to modulate the renal tubular response to vasopressin either by directly inhibiting cAMP generation or indirectly via NO.

Animals↗
PubMed2000

Interaction between chloroquine and diverse pharmacological agents in chloroquine resistant Plasmodium yoelii nigeriensis.

The effect of a number of pharmacological agents on the enhancement of antimalarial activity of chloroquine was evaluated against chloroquine resistant line of Plasmodium yoelii nigeriensis (N-67). The response after combination therapy was monitored on the basis of alteration in the course of parasitaemia, the extension of mean survival time and the percent cure rate in different groups. The study was designed to compare the in vivo efficacy of a number of resistance modulating agents found effective in several in vitro studies against chloroquine resistant P. falciparum isolates. Based on their efficacy in this rodent model, the response of combination of chloroquine with agents representing diverse chemical moieties has been categorised as curative, moderately active and inactive. Out of the 22 agents evaluated, only cyproheptadine-chloroquine combination produced curative response. Ketotifen, azatadine, pheniramine, amitriptyline, fluoxetine, verapamil, penfluridol and trifluoperazine demonstrated moderate activity while loratadine, terfenadine, promethazine, ranitidine, nifedipine, diltiazem, chlorpromazine, amiodarone, tamoxifen, dipyridamol, propranolol, acyclovir and amantidine were inactive. The study advocates the suitability of proposed rodent model to shortlist potential resistance reversal agents.

Animals↗
PubMed1998

Chloroquine in Africa: critical assessment and recommendations for monitoring and evaluating chloroquine therapy efficacy in sub-Saharan Africa.

Chloroquine-resistant malaria is a major public health threat in sub-Saharan Africa. While a few countries have already replaced chloroquine as the first-line therapy for uncomplicated malaria or are in the process of doing so, other countries are faced with the complicated task of assessing the current status of drug resistance, making national policy-level decisions about whether to replace chloroquine or not, and initiating a monitoring system to track changes in the efficacy of malaria therapy. There is currently no standardized approach for collecting and interpreting data on therapy efficacy. There is also no agreement as to how much chloroquine resistance or treatment failure is acceptable and how much warrants a change in treatment policy. Using data collected in 10 sites in eastern and southern Africa between 1990 and 1996, we have assessed the therapeutic response to chloroquine and investigated predictors of clinical success or failure. Based on these experiences and analyses, a standardized protocol for in vivo studies of the efficacy of malaria therapy and for approaches to designing monitoring systems are proposed. The process of making policy-level decisions based on data collected by these systems is also discussed.

Antimalarials↗
PubMed1989

[Chloroquine-resistant Plasmodium falciparum malaria confirmed by semi-micro sensitivity test for chloroquine seen in a person returned from Nigeria to Japan].

A 39-year-old Japanese male engineer who stayed in Nigeria from August 17, 1987 through January 22, 1988, presented chloroquine-resistant Plasmodium falciparum malaria. He was taking oral chloroquine prophylactically. But he suffered from P. falciparum malaria in November, 1987 and early January, 1988. He was treated in Nigeria. After his return to Japan, he was admitted to our hospital with a fever of 39 degrees C on January 29, 1988. The peripheral blood smear on admission showed the presence of ring form P. falciparum. He was diagnosed as recrudescence of P. falciparum malaria. Laboratory examination revealed severe thrombocytopenia and biologic false-positive serological tests of syphilis. The level of 50% inhibitory concentration was 0.44 nmol/ml by in vitro chloroquine sensitivity test of the strain of P. falciparum obtained from this patient. Clinically, chloroquine was not effective. The patient was treated with intravenous quinine dihydrochloride followed by sulfadoxine/pyrimethamine tablets and recovered completely. As far as we know through our survey this patient was the first case of chloroquine-resistant P. falciparum malaria brought to Japan from Nigeria.

Adult↗
PubMed1973

Chloroquine-resistant Plasmodium falciparum: difference in the handling of 14C-amodiaquin and 14C-chloroquine.

(14)C-amodiaquin and (14)C-chloroquine were used to study drug binding by preparations of owl monkey erythrocytes infected either with a chloroquine-susceptible (CS) or with a chloroquine-resistant (CR) strain of P. falciparum. Both of these drugs are derivatives of 4-aminoquinoline, but they differ in their side chains, and there are differences in the way they are handled by preparations of erythrocytes infected with malaria parasites. Although the apparent association constant for the binding of either drug is approximately 10(7) mol(-1), two to three times more radioactivity was bound from (14)C-amodiaquin than from (14)C-chloroquine. Furthermore, there was no apparent difference between CS and CR parasites with respect to (14)C-amodiaquin binding, whereas erythrocytes infected with CR parasites have a deficiency of (14)C-chloroquine binding. This difference in the handling of amodiaquin probably accounts for its superiority in the treatment of the owl monkey and of humans infected with CR P. falciparum.

Amodiaquine↗
PubMed1975

Evidence for a relationship between chloroquine and complement from studies with lymphocyte mitogens: possible implications for the mechanism of action of chloroquine in disease.

Chloroquine increases the inhibition of cultured lymphocytes by high concentrations of phytohemagglutinin (PHA) or concanavalin A (Con A). The inhibition is also increased by complement. Thus chloroquine and complement have similar effects. Time-course studies show that chloroquine increases the rate of onset of the complement-dependent inhibition. In serum preheated to inactivate complement, chloroquine can partially simulate the effect of complement. It is suggested that at certain stages in malaria or autoimmune disease the rate of clearance of parasitized erythrocytes or autoreactive lymphocytes is limited by the concentration of complement. Under these conditions a drug such as chloroquine, which could enhance or simulate the action of complement, might be of therapeutic value.

Animals↗
PubMed2003

Absorption, distribution and excretion of 14C-chloroquine after single oral administration in albino and pigmented rats: binding characteristics of chloroquine-related radioactivity to melanin in-vivo.

Chloroquine is an antimalarial agent that has been reported to have distinct affinity to melanin. After single oral administration of 14C-chloroquine at a dose of 20mg kg-1 under non-fasting conditions, the absorption, distribution and excretion of 14C-chloroquine-related radioactivity were studied in albino and pigmented rats. The objectives of the study were to investigate differences in the disposition of chloroquine between albino and pigmented rats and to define its in-vivo binding characteristics to melanin-containing ocular tissues. Extensive uptake of radioactivity into tissues was indicated by higher concentrations in most tissues compared with serum and there was no quantitative differences in the distribution of radioactivity found between albino and pigmented rats except for melanin-containing tissues, such as the uveal tract of the eye and perhaps hair follicles. There was selective and strong binding of drug-related compounds to these tissues in pigmented rats. The uveal tract concentrations reached the maximum value of 158.42 +/- 7.86 micrograms equiv g-1 (mean+/-s.e.) at 1 week and decreased very slowly with a terminal half life of 4476 h (187 day). The uveal tract concentrations at 24 weeks were still high (67.75 +/- 6.19 micrograms equiv g-1). The AUC for uveal tract was 842.3 mg.h g-1. A relatively high concentration was still determined in the uveal tract even at 48 weeks after single oral dosing by whole-body autoradiography. The uveal tracts separated from one eye of each rat were extracted with 0.067 M phosphate buffer (pH 7.4) and 1 M HCl-EtOH (30:70) successively. In pigmented rats, almost all radioactivity was released from the tissue with 1 M HCl-EtOH (30:70), indicating that the strong binding by melanin was reversible, and that hydrophobic or electrostatic interaction would play a critical role in the binding of chloroquine and its metabolites with the melanin-containing ocular tissues. Approximately 70% of the radioactivity given was recovered in urine and faeces up to 144 h after dosing both in pigmented and albino rats. The excretion pattern in pigmented rats was similar to that seen in albino rats.

Administration, Oral↗
PubMed1986

In vitro activity of chloroquine, the two enantiomers of chloroquine, desethylchloroquine and pyronaridine against Plasmodium falciparum.

A 48 h in vitro test was conducted to compare the susceptibility of two strains of Plasmodium falciparum to chloroquine, the two enantiomers of chloroquine, desethylchloroquine and the new antimalarial drug pyronaridine. The five compounds similarly inhibited the chloroquine sensitive strain. However, desethylchloroquine was less active and pyronaridine was much more active than chloroquine and its enantiomers against the chloroquine resistant strain.

Antimalarials↗
PubMed1995

Response of Plasmodium falciparum to chloroquine and Fansidar in vivo and chloroquine and amodiaquine in vitro in Uganda.

The response of P. falciparum to chloroquine and pyrimethamine-sulfadoxine in vivo and chloroquine and amodiaquine in vitro was investigated in parasitaemic school children from six locations. Mean parasite sensitivity to chloroquine at day 7 was 74% (range 61-97) with parasite clearance rates between 2-3 days and complete defervescence in 85% of febrile children. Sensitivity declined in the four sites followed up to day 14 to 45% (range 37-53). Parasites were significantly more sensitive to pyrimethamine/sulfadoxine at 5/6 sites (100% day 7) but 5% of subjects became parasitaemic by day 14. In vitro isolates were significantly less sensitive to chloroquine than to amodiaquine with a mean 99% effective concentration of 348 mumol/L compared to 6.44 mumol/L. Clearly the role of chloroquine as the primary therapy for uncomplicated P. falciparum malaria should be reconsidered especially in the light of increasing disease severity and resurgence. Amodiaquine may be suitable alternative with pyrimethamine/sulfadoxine as second line and for more severe malaria prior to referral. The cost of alternative antimalarials and the dynamic and deteriorating pattern of resistance are powerful arguments for more objective slide diagnosis to minimise drug pressure and a regular drug sensitivity surveillance system. We believe that the latter should concentrate on measuring clinical drug efficacy in symptomatic outpatients rather than in asymptomatic children while the former needs more pragmatic and economical strategies possibly centred on seasonality and risk.

Amodiaquine↗
PubMed1994

Chloroquine and sulfadoxine/pyrimethamine sensitivity in Burkina Faso. In vivo sensitivity of Plasmodium falciparum to chloroquine and sulfadoxine/pyrimethamine in Burkina Faso.

Plasmodium falciparum susceptibility to chloroquine and sulfadoxine/pyrimethamine was investigated in children living in an urban district of Ouagadougou, Burkina Faso, in August 1992. A modified WHO Standard Field in vivo test was used, with follow-up on days 2, 4, 7, and 14 after treatment with 25 mg chloroquine per kg body weight given over 3 days, or with standard doses of sulfadoxine/pyrimethamine in children from 2 to 8 years old with P. falciparum monospecific infection, asexual parasitaemia > 800/microliters of blood and negative Bergqvist and Lignin urine tests. Out of a total of 515 children screened, 152 were selected and randomized into treatment with chloroquine (86 children) or sulfadoxine/pyrimethamine (66 children). With the chloroquine regimen, parasitaemia did not clear by day 7 in 7 cases (8.1%), and there was recurrence of parasitaemia in 21 subjects (24.4%) on day 14, while all the children who had received sulfadoxine/pyrimethamine were fully sensitive on day 7 and day 14. It can be concluded that sulfadoxine/pyrimethamine is a good alternative for the treatment of falciparum malaria in areas of Burkina Faso with established chloroquine resistance.

Animals↗
PubMed2001

In vitro and in vivo antimalarial activity of ferrochloroquine, a ferrocenyl analogue of chloroquine against chloroquine-resistant malaria parasites.

Previous studies have shown that ferrochloroquine (FQ) exhibited an antimalarial activity against Plasmodium spp. The present work confirmed this activity, described the curative effect on P. vinckei and investigated the FQ toxicity in vitro and in vivo. The in vitro and in vivo growth inhibition of P. falciparum and P. berghei N, respectively, showed that FQ antimalarial activity was 1.5-10 times more potent than chloroquine. FQ completely inhibited the in vivo development of both chloroquine-susceptible and resistant P. vinckei strains and protected mice from lethal infection at a dose of 8.4 mg kg(-1) day(-1) given for 4 days subcutaneously or orally. This curative effect was 5-20 times more potent than chloroquine, according to the strains' resistance to chloroquine. At this curative dose, no clinical changes were observed in mice up to 14 days after the last administration. Nevertheless, the acute toxicity and lethality of ferrochloroquine seemed to be dependent on gastric surfeit. The FQ security index determined in vitro confirmed that it might be a promising compound.

Administration, Oral↗
PubMed1984

Absence of malaria mortality in villagers with chloroquine-resistant Plasmodium falciparum treated with chloroquine.

We carried out a series of malaria studies in Robek , Flores, Indonesia, a coastal village of 900 farmers and fishermen where malaria is hyperendemic by parasite rate and holoendemic by spleen rate. The studies showed that: (i) 28 of 31 isolates (90%) of Plasmodium falciparum were resistant to chloroquine in vitro, (ii) 3 of 12 isolates (25%) were resistant at the R-11 level in vivo, (iii) 376 P. falciparum infections occurred in 301 individuals during one year, (iv) no villagers who were treated with chloroquine for P. falciparum infections during the year died, and (v) increasing the dosage of chloroquine base from 15 to 25 to 37.5 mg/kg led to improved clearing of parasitaemia. We conclude that chloroquine can still be used as the primary antimalarial in Robek , but the dosage may have to be increased to clear parasitaemia.

Adolescent↗