Original Article
A Molecular Marker for Chloroquine-Resistant Falciparum Malaria
N Engl J Med 2001; 344:257-263January 25, 2001
- Abstract
Background
Chloroquine-resistant Plasmodium falciparum malaria is a major health problem, particularly in sub-Saharan Africa. Chloroquine resistance has been associated in vitro with point mutations in two genes, pfcrt and pfmdr 1, which encode the P. falciparum digestive-vacuole transmembrane proteins PfCRT and Pgh1, respectively.
Methods
To assess the value of these mutations as markers for clinical chloroquine resistance, we measured the association between the mutations and the response to chloroquine treatment in patients with uncomplicated falciparum malaria in Mali. The frequencies of the mutations in patients before and after treatment were compared for evidence of selection of resistance factors as a result of exposure to chloroquine.
Results
The pfcrt mutation resulting in the substitution of threonine (T76) for lysine at position 76 was present in all 60 samples from patients with chloroquine-resistant infections (those that persisted or recurred after treatment), as compared with a base-line prevalence of 41 percent in samples obtained before treatment from 116 randomly selected patients (P< 0.001), indicating absolute selection for this mutation. The pfmdr 1 mutation resulting in the substitution of tyrosine (Y86) for asparagine at position 86 was also selected for, since it was present in 48 of 56 post-treatment samples from patients with chloroquine-resistant infections (86 percent), as compared with a base-line prevalence of 50 percent in 115 samples obtained before treatment (P<0.001). The presence of pfcrt T76 was more strongly associated with the development of chloroquine resistance (odds ratio, 18.8; 95 percent confidence interval, 6.5 to 58.3) than was the presence of pfmdr 1 Y86 (odds ratio, 3.2; 95 percent confidence interval, 1.5 to 6.8) or the presence of both mutations (odds ratio, 9.8; 95 percent confidence interval, 4.4 to 22.1).
Conclusions
This study shows an association between the pfcrt T76 mutation in P. falciparum and the development of chloroquine resistance during the treatment of malaria. This mutation can be used as a marker in surveillance for chloroquine-resistant falciparum malaria.
Media in This Article
Figure 1
Prevalence of Alleles with the pfcrt T76, cg2 κ, cg2 Ω, or pfmdr 1 Mutations Associated with Resistance to Chloroquine, Wild-Type Alleles Associated with Sensitivity to Chloroquine, or Both in Samples from Patients with a Persistent or Recurrent Infection after Chloroquine Treatment.Table 1
Prevalence of Mutations in Samples Obtained from Patients before Chloroquine Treatment and from Patients with Persistent or Recurrent Infection after Treatment.Article Activity
- Article
Falciparum malaria remains a major cause of disease and death among children and pregnant women in sub-Saharan Africa. During the second half of the 20th century, chloroquine was the antimalarial treatment of choice, because it was safe, inexpensive, and highly effective against susceptible malaria parasites. Chloroquine resistance arose more than 40 years ago in Southeast Asia and South America, and in these regions chloroquine has now been largely abandoned as a treatment for falciparum malaria. Increasing rates of chloroquine resistance contribute to the rising morbidity and mortality from malaria in Africa.1,2 Given the lack of affordable alternatives, chloroquine remains the first-line antimalarial agent in most African countries.
Chloroquine acts by interfering with heme metabolism in the digestive vacuole of Plasmodium falciparum. In resistant parasites, the accumulation of chloroquine inside the vacuole is diminished.3-7 Verapamil, which inhibits P-glycoprotein–mediated multidrug resistance (encoded by mdr) in mammalian tumor cells, partly reverses chloroquine resistance in malaria parasites grown in vitro.8 In P. falciparum, mdr homologues encoding P-glycoprotein–like molecules have been proposed as determinants of chloroquine resistance, and associations have been reported between chloroquine resistance and amplification or mutation of the mdr-like gene pfmdr 1, which encodes Pgh1.9-11 However, the chloroquine-resistance phenotype was dissociated from inheritance of the pfmdr 1 gene in genetic studies.12 Some field studies have found an association between pfmdr 1 mutations and chloroquine resistance13 and others have not.14-17 In recent transformation experiments, chloroquine-sensitive P. falciparum parasites that acquire pfmdr 1 mutations did not become resistant to chloroquine.18
The locus governing chloroquine resistance in a P. falciparum genetic cross has been mapped to a 36-kb segment of chromosome 7. Polymorphisms in one gene, cg2, were highly associated with chloroquine resistance,19-21 but allelic modification experiments have ruled out a role for this gene in chloroquine resistance.22
Recently pfcrt, a gene with 13 exons, was identified near cg2 on chromosome 7.23 This gene encodes PfCRT, a transmembrane protein in the digestive vacuoles of malaria parasites. Sets of point mutations in pfcrt were associated with chloroquine resistance in vitro in laboratory lines of P. falciparum from Africa, South America, and Southeast Asia. One mutation, the substitution of threonine (T76) for lysine (K76) at position 76 (K76T), was present in all resistant isolates and absent from all sensitive isolates tested in vitro. Furthermore, genetic-transformation experiments with plasmids expressing mutant forms of pfcrt conferred chloroquine resistance on three different chloroquine-sensitive clones. These studies point to a key role for the pfcrt T76 mutation in conferring in vitro chloroquine resistance. The role of these mutations in the failure of chloroquine treatment has not been evaluated in clinical settings.
We conducted haplotype analyses of chloroquine-sensitive and chloroquine-resistant parasites from a drug-efficacy trial in Mali, assessing the relation between chloroquine resistance and mutations in pfcrt and pfmdr 1 in parasites from patients with falciparum malaria.
Methods
Measurement of Chloroquine Efficacy
The study was approved by institutional review boards at the University of Mali, Bamako; the National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; and the University of Maryland, Baltimore. Subjects were enrolled from August through December 1997 in Mopti (population, 60,000) and Bandiagara (population, 12,000) in central Mali, areas where P. falciparum is endemic, with intense seasonal peaks.24 Eligible patients were at least two years of age, had a positive blood smear for asexual forms of P. falciparum, and were seeking treatment for symptoms consistent with the presence of malaria (fever, chills, headache, and aches). Patients were excluded if they were allergic to chloroquine, had a concurrent nonmalarial febrile illness, had severe malnutrition or another chronic illness, or had severe malaria, defined by the presence of coma, obtundation, seizures, prostration, respiratory distress, shock, protracted vomiting, severe parasitemia (more than 105 parasites per cubic millimeter), a hematocrit of less than 15 percent, or a serum glucose level of less than 40 mg per deciliter (2.2 mmol per liter).
Chloroquine phosphate was administered orally at a dose of 10 mg per kilogram of body weight per day for two days, followed by a dose of 5 mg per kilogram on day 3. The patients were observed after each dose, and they were given another full dose if they vomited within 30 minutes and a half dose if they vomited within 31 minutes to 1 hour. Clinical follow-up occurred on days 1, 2, 3, 7, and 14 after treatment, with microscopical examination of blood on days 3, 7, and 14 and whenever symptoms were reported or fever (defined as an axillary temperature of at least 37.5°C) was detected.
The outcome of treatment was assessed with the use of classic parasitologic definitions of resistance and sensitivity.25 Class III resistance was defined as persistent parasitemia with no reduction in the level of parasitemia or with a reduction to 25 percent or more of the initial (pretreatment) level by the third day after treatment. Class II resistance was defined as persistent parasitemia with reduction to less than 25 percent of the initial level by day 3. Class I resistance was defined as the initial clearance of parasites, with recurrence of parasitemia by day 14. An organism was considered to be sensitive to chloroquine if there was clearance of parasites, with no recurrence of parasitemia by day 14.
Molecular Analysis
After DNA had been extracted from dried filter papers that had been soaked in blood obtained from patients before and after treatment, nested mutation-specific polymerase chain reaction (PCR) or nested PCR followed by mutation-specific restriction-endonuclease digestion was used to detect mutations in pfcrt and pfmdr 1. Repeat polymorphisms in the κ region and the Ω region of cg2 were detected by agarose-gel electrophoresis on the basis of the size of amplified products. The samples were analyzed for the following substitutions and polymorphisms: T76, the substitution of serine (S220) for alanine at position 220 (A220S), the substitution of glutamic acid (E271) for glutamine at position 271 (Q271E), the substitution of serine (S326) for asparagine at position 326 (N326S), the substitution of threonine (T356) for isoleucine at position 356 (I356T), and the substitution of isoleucine (I371) for arginine at position 371 (R371I) in pfcrt ; the substitution of tyrosine (Y86) for asparagine at position 86 (N86Y), the substitution of tyrosine (Y184) for phenylalanine at position 184 (F184Y), the substitution of cysteine (C1034) for serine at position 1034 (S1034C), the substitution of asparagine (N1042) for aspartic acid at position 1042 (D1042N), and the substitution of tyrosine (Y1246) for aspartic acid at position 1246 (D1246Y) in pfmdr 1; and size polymorphisms in the cg2 κ and cg2 Ω repeats. Direct DNA sequencing was used to detect mutations for which these assays were not available and to confirm results. Microsatellite analysis26-28 was performed to determine whether there was genetic similarity among chloroquine-sensitive parasites and among chloroquine-resistant parasites with the use of primers and methods described elsewhere.29 Detailed information on these techniques is available on the Internet at http://medschool.umaryland.edu/CVD/plowe.html.
Statistical Analysis
We analyzed samples taken before and after treatment for all patients with chloroquine-resistant infections. Base-line frequencies of mutations were determined from samples taken before treatment that were selected randomly and analyzed without knowledge of the clinical outcome. All samples with class I, II, or III resistance were grouped for analysis. The chi-square test or Fisher's exact test for two-tailed significance (P=0.05) was used for univariate comparisons. Multiple logistic-regression analysis was performed with the use of a software program (Stata, College Station, Tex.).
Results
Of the 514 patients who were enrolled, 469 completed follow-up and had an outcome that could be evaluated. The infection was sensitive to chloroquine in 86 percent of the infections, resistant at the class I level in 11 percent, resistant at the class II level in 2 percent, and resistant at the class III level in 1 percent. The median age of the patients was 10 years. The median parasite density was 12,800 per cubic millimeter.
Prevalence of pfcrt T76 and pfmdr 1 Mutations
The prevalence of pfcrt T76 and pfmdr 1 Y86 was compared in parasites from randomly selected patients before treatment and in parasites from patients whose infections persisted or recurred 4 to 14 days after treatment. Table 1Table 1
Prevalence of Mutations in Samples Obtained from Patients before Chloroquine Treatment and from Patients with Persistent or Recurrent Infection after Treatment. shows that these mutations, as well as cg2 polymorphisms, were more prevalent in samples obtained from patients with a post-treatment infection. Other previously described pfmdr 1 mutations (F184Y, S1034C, D1042N, and D1246Y) either were not detected or were not more common in samples from patients with a post-treatment infection (data not shown).The pfcrt T76 mutation was present in all 60 samples from patients with a post-treatment infection that were analyzed for this mutation (Figure 1Figure 1
Prevalence of Alleles with the pfcrt T76, cg2 κ, cg2 Ω, or pfmdr 1 Mutations Associated with Resistance to Chloroquine, Wild-Type Alleles Associated with Sensitivity to Chloroquine, or Both in Samples from Patients with a Persistent or Recurrent Infection after Chloroquine Treatment.). In contrast, 14 percent of the 56 samples analyzed from patients with post-treatment infections carried only the wild-type allele at position 86 of pfmdr 1 (N86) and 16 percent carried a mixture of the wild-type and the mutant allele.We performed microsatellite analysis in 8 samples from patients with chloroquine-sensitive infections in which the parasites had the K76 pfcrt allele and in 22 samples from patients with chloroquine-resistant infections in which the parasites had the T76 mutant allele. This analysis (data not shown) confirmed the diversity of the genetic backgrounds of P. falciparum parasites in all infections, and there was no evidence that a clone or strain of parasite was responsible for either sensitive or resistant infections.
Prevalence of Other pfcrt Mutations in Association with T76
Seven other pfcrt mutations have been identified in association with T76 in parasites from Africa and Asia: I74, E75, S220, E271, S236, T356, and I371.23 In randomly selected samples obtained from patients before treatment and patients with post-treatment infections, all but the T356 mutation were significantly selected for in vivo by chloroquine treatment (Table 1). This result is consistent with the lack of association of T356 with in vitro chloroquine resistance.23
In most pretreatment infections with chloroquine-sensitive parasites that had the K76 pfcrt allele, which is associated with sensitivity to chloroquine, the parasite also carried wild-type pfcrt alleles at other positions that are associated with sensitivity type at A220 (30 of 31 samples), Q271 (35 of 35), N326 (29 of 34), I356 (35 of 36), and R371 (27 of 29).23 Among parasites with the T76 mutation, there was no significant difference in the prevalence of pfcrt I74, E75, S220, E271, S326, T356, or I371 mutations in the infections that cleared after chloroquine treatment and those that did not clear after chloroquine treatment. In all parasites tested for their presence, the pfcrt mutations I74, E75, S220, and I371 accompanied T76.
Association between pfcrt and pfmdr 1 Mutations and Treatment Outcome
To determine whether the presence of pfcrt and pfmdr 1 mutations at the time of treatment was associated with subsequent treatment failure, we compared the prevalence of these mutations in infections that failed to clear and in infections that cleared with chloroquine treatment. The mutations pfcrt T76 and pfmdr 1 Y86, as well as the polymorphisms in cg2 κ and cg2 Ω repeats that are associated with resistance, were all associated with in vivo chloroquine resistance in univariate analyses. Overall, parasites carrying pfcrt T76 were the most likely to be resistant to chloroquine treatment (odds ratio, 18.8; 95 percent confidence interval, 6.5 to 58.3). The additional presence of pfmdr 1 Y86 and of polymorphisms in cg2 that are associated with resistance did not strengthen the association between pfcrt T76 and in vivo resistance. Adjustment for age showed in almost all cases that the strongest associations between genotypes and resistant infections were found in children younger than 10 years of age, which was the median age of the patients (Table 2Table 2
Univariate Analysis of the Association between the Presence of Various Mutations before Treatment and the Likelihood of Clinical Chloroquine Resistance, According to Age.).Multiple logistic-regression analysis confirmed that pfcrt T76 (odds ratio for resistance, 16.1; 95 percent confidence interval, 5.7 to 45.7) and pfmdr 1 Y86 (odds ratio, 2.5; 95 percent confidence interval, 1.1 to 5.8) were independently associated with an increased likelihood of resistance, although there was no interaction between these two mutations. The cg2 polymorphisms were not associated with outcome independently of pfcrt T76. Increasing age was confirmed to be protective against resistance, whereas the presence or absence of fever and the level of parasitemia were not significantly associated with outcome.
Effect of Age on the Association between Mutations and Outcome
The base-line prevalence of pfcrt T76 was higher than that of clinical chloroquine resistance: 41 percent of the parasites obtained from 116 randomly selected patients before treatment had T76, whereas the parasites from only 14 percent of 469 patients exhibited in vivo resistance. Partial immunity develops with prolonged exposure to malaria, and older persons in endemic areas have protection against the disease.30 To determine whether immunity contributed to the ability to clear infections by parasites carrying pfcrt T76, we compared the proportion of infections by parasites carrying T76 that cleared in children younger than 10 years with the proportion of infections by parasites carrying T76 that cleared in older children and adults. In the younger group, 68 percent of 73 pretreatment infections by parasites with the T76 mutation failed to clear, whereas in older patients, only 34 percent of 35 pretreatment infections with the T76 mutation failed to clear (P< 0.001).
Discussion
The T76 mutation in pfcrt, which encodes a transporter protein of the P. falciparum digestive vacuole, was found in 60 samples from patients with falciparum malaria infections that recurred or persisted after treatment with oral chloroquine, indicating the absolute selection for this mutation in parasites capable of surviving in the presence of chloroquine. Parasites harboring pfcrt K76, which is associated with chloroquine sensitivity in vitro,23 were not detected in any of these post-treatment infections. In contrast to the total absence of pfcrt K76, pfmdr 1 N86, the form associated with sensitivity, was detected in parasites from 30 percent of patients whose infections persisted or recurred after chloroquine treatment. The presence of PfCRT T76 at the time of treatment was also strongly associated with subsequent resistance to chloroquine in vivo. These data, combined with the genetic evidence of Fidock et al.,22,23 support the idea that pfcrt is an essential determinant of chloroquine resistance in clinical falciparum malaria.
Chloroquine therapy cleared some infections by parasites carrying pfcrt T76. This result is consistent with those of previous field studies in which in vitro drug resistance was more common than in vivo resistance.31-33 The association we observed between age and successful treatment reflects the gradual acquisition of partial immunity in this highly endemic area, and this immunity helps in the clearance of resistant parasites.
In some infections that were resistant to chloroquine treatment, pfcrt T76 was not detected at the time of treatment but was detected in the parasites that survived treatment. Although this result could have been due to reinfection or to the failure to achieve adequate chloroquine levels in blood, reinfection should be rare during a 14-day follow-up period, and subtherapeutic chloroquine levels owing to poor compliance are unlikely with directly observed therapy. A more likely explanation is that these were mixed infections consisting predominantly of sensitive parasites along with minute populations of resistant parasites whose levels were below the threshold of detection by PCR or restriction-endonuclease methods. During exposure to chloroquine, sensitive parasites would have been cleared as the resistant parasite population expanded, resulting in treatment failure.
All parasites with the pfcrt T76 mutation also had the pfcrt I74, E75, S220, and I371 mutations. The presence of several of these mutations may be required to maintain native PfCRT function and at the same time confer chloroquine resistance. Simultaneous acquisition of several mutations by a single PfCRT molecule would be an extremely rare event. This may explain the slow rate of emergence and contiguous pattern of the geographic spread of chloroquine resistance in South America and Southeast Asia34 and the different sets of pfcrt mutations found in chloroquine-resistant isolates from these regions.23 Among chloroquine-sensitive parasites without the T76 mutation, some had the S220, S236, T356, or I371 mutation or more than one of these mutations. This result is consistent with the finding of Fidock et al. that some chloroquine-sensitive clones do not have the T76 mutation but do have other pfcrt mutations,23 and it further supports the idea that T76 has an essential role in chloroquine resistance.
Our finding of a significant association between cg2 polymorphisms and chloroquine resistance is consistent with the findings of others,20,21 but in the light of recent genetic-transformation studies,22 this result is almost certainly due to the proximity of cg2 and pfcrt on chromosome 7 and not to any causal role of cg2 in chloroquine resistance.
We found that the pfmdr 1 mutation Y86 was significantly selected for by chloroquine treatment, as previously reported.13 Because pfmdr 1 and PfCRT are on different chromosomes, their coselection cannot be attributed to physical linkage. Rather, pfmdr 1 Y86 may confer some advantage to the parasite in the presence of chloroquine, either by compensating for fitness lost because of pfcrt mutations or by augmenting the level of resistance.
Our study does not support the idea that pfmdr 1 has a primary role in conferring chloroquine resistance in P. falciparum. This result is consistent with those of previous studies, which reported the absence of an association between the presence of other pfmdr 1 mutations and chloroquine resistance in vivo14-17 and showed that resistant infections in vivo can be due to parasites with no pfmdr 1 mutations at position 86.14,19,35 Although there is some evidence that pfmdr 1 may modulate the level of in vitro resistance,18 the presence of pfmdr 1 Y86 in parasites obtained from patients before treatment did not strengthen the association between pfcrt T76 and treatment failure. Since these two mutations could affect each other only if they occurred in the same parasite, these data do not rule out the possibility that pfmdr 1 modulates chloroquine resistance in areas where polyclonal infections are common. However, because most parasites in our study had only mutant forms of both pfcrt and pfmdr 1, any strong interaction should have been detected. It is possible that any additive or epistatic effects of pfmdr 1 Y86 or other genetic factors on chloroquine resistance would be more apparent in areas where the level of immunity, the prevalence of chloroquine resistance, or the genetic complexity of infections is different.
Molecular assays for detecting pfcrt mutations are potentially important tools for identifying chloroquine-resistant P. falciparum malaria. Our results suggest that pfcrt T76 will be most predictive of clinical chloroquine resistance in nonimmune populations, such as travelers or residents of areas with low or unstable rates of malaria transmission. In areas such as our study site, where the prevalence of pfcrt T76 exceeds that of clinical resistance, indicating low specificity of pfcrt T76 as a clinical test, determining the ratio of the prevalence of T76 mutations to the prevalence of chloroquine resistance may permit the prediction of clinical resistance rates. Surveys to determine the prevalence of pfcrt T76 will be useful not only in areas that still rely on chloroquine, but also in regions where the failure rates of drugs that replaced chloroquine are now increasing. The finding of a decreasing prevalence of pfcrt mutations in these areas would provide a rationale for considering the reintroduction of chloroquine, ideally in combination with other antimalarial drugs, so as to prevent the reemergence of resistance.36 A better understanding of the specific host factors that contribute to the clearance of parasites with resistance-conferring pfcrt mutations will be needed in order to improve the ability of molecular markers to predict in vivo resistance in semi-immune populations.
Supported by a contract (N01-AI-85346) with and a grant (5P50AI39469) from the National Institutes of Health (NIH); by the U.S. Agency for International Development (USAID) through its Health and Human Resources Analysis for Africa Program; by direct support from the USAID Mission, Bamako, Mali, for the development of the Malaria Research and Training Center; by a grant (980152) from the United Nations Development Program, World Bank, World Health Organization Special Program for Research and Training in Tropical Diseases/Multilateral Initiative on Malaria; and by the Department of Technical Co-operation of the Energy Agency. Dr. Djimdé is supported by an NIH Research Fellowship and a Research Training Grant from the United Nations Development Program, World Bank, World Health Organization Special Program for Research and Training in Tropical Diseases.
We are indebted to Chiaka Diakité, Robert Gwadz, Richard Sakai, Akouni Dougnon, Ibrahim Ouologuem, Idrissa Cissé, Dramane Coulibaly, Sekou Touré, and Fabian Mendez; to the directors of the Bandiagara and Mopti Health Centers and the Mopti Regional Malaria Control Program; and to the Bandiagara Traditional Healers Association.
Source Information
From the Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore (A. Djimdé, J.F.C., A. Dicko, C.V.P.); the Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Dentistry, University of Mali, Bamako, Mali (A. Djimdé, O.K.D., K.K., S.D., Y.D., A. Dicko); and the Malaria Genetics Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md. (A. Djimdé, A. Dicko, X.S., T.N., D.A.F., T.E.W.).
Address reprint requests to Dr. Plowe at the Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, 685 W. Baltimore St., HSF 480, Baltimore, MD 21201, or at cplowe@medicine.umaryland.edu.
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Citing Articles
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O.A. Folarin, C. Bustamante, G.O. Gbotosho, A. Sowunmi, M.G. Zalis, A.M.J. Oduola, C.T. Happi. (2011) In vitro amodiaquine resistance and its association with mutations in pfcrt and pfmdr1 genes of Plasmodium falciparum isolates from Nigeria. Acta Tropica 120:3, 224-230
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S. Mharakurwa, T. Kumwenda, M. A. P. Mkulama, M. Musapa, S. Chishimba, C. J. Shiff, D. J. Sullivan, P. E. Thuma, K. Liu, P. Agre. (2011) Malaria antifolate resistance with contrasting Plasmodium falciparum dihydrofolate reductase (DHFR) polymorphisms in humans and Anopheles mosquitoes. Proceedings of the National Academy of Sciences
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Adele M. Lehane, Christopher A. McDevitt, Kiaran Kirk, David A. Fidock. (2011) Degrees of chloroquine resistance in Plasmodium – Is the redox system involved?. International Journal for Parasitology: Drugs and Drug Resistance
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Wasiq Faraz Rawasia, Sankar Sridaran, Jaymin C. Patel, Joseph Abdallah, Najia Karim Ghanchi, John W. Barnwell, Ananias A. Escalante, Venkatachalam Udhayakumar, Mohammad Asim Beg. (2011) Genetic backgrounds of the Plasmodium falciparum chloroquine resistant transporter (pfcrt) alleles in Pakistan. Infection, Genetics and Evolution
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Erasmus Kamugisha, Ioana Bujila, Mona Lahdo, Samtou Pello-Esso, Mercy Minde, Gilbert Kongola, Halima Naiwumbwe, Steven Kiwuwa, Mark Kaddumukasa, Fred Kironde, Göte Swedberg. (2011) Large differences in prevalence of Pfcrt and Pfmdr1 mutations between Mwanza, Tanzania and Iganga, Uganda—A reflection of differences in policies regarding withdrawal of chloroquine?. Acta Tropica
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Irene Zeile, Jean-Bosco Gahutu, Cyprien Shyirambere, Christian Steininger, Andre Musemakweri, Fidèle Sebahungu, Corine Karema, Gundel Harms, Teunis A. Eggelte, Frank P. Mockenhaupt. (2011) Molecular markers of Plasmodium falciparum drug resistance in southern highland Rwanda. Acta Tropica
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Mandana Afsharpad, Sedigheh Zakeri, Sakineh Pirahmadi, Navid Dinparast Djadid. (2011) Molecular monitoring of Plasmodium falciparum resistance to antimalarial drugs after adoption of sulfadoxine–pyrimethamine plus artesunate as the first line treatment in Iran. Acta Tropica
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Mandana Afsharpad, Sedigheh Zakeri, Sakineh Pirahmadi, Navid D. Djadid. (2011) Molecular assessment of dhfr/dhps mutations among Plasmodium vivax clinical isolates after introduction of sulfadoxine/pyrimethamine in combination with artesunate in Iran. Infection, Genetics and Evolution
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R Matthew Chico, Daniel Chandramohan. (2011) Azithromycin plus chloroquine: combination therapy for protection against malaria and sexually transmitted infections in pregnancy. Expert Opinion on Drug Metabolism & Toxicology 7:9, 1153-1167
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Berlin Londono-Renteria, Thomas P. Eisele, Joseph Keating, Adam Bennett, Donald J. Krogstad. (2011) Genetic diversity in the merozoite surface protein 1 and 2 genes of Plasmodium falciparum from the Artibonite Valley of Haiti. Acta Tropica
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Saad M. Bin Dajem, Adel Ali H. Al-Sheikh, Marie Fe Bohol, Mohammad Alhawi, Mohammed N. Al-Ahdal, Ahmed Al-Qahtani. (2011) Detecting mutations in PfCRT and PfMDR1 genes among Plasmodium falciparum isolates from Saudi Arabia by pyrosequencing. Parasitology Research 109:2, 291-296
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Mamadou Wélé, Abdoulaye A. Djimdé, Aldiouma Guindo, Abdoul H. Beavogui, Isaac Z. Traoré, Aboubacar Sadou, Dackouo Blaise, Dapa A. Diallo, Thomas E. Wellems, Ogobara K. Doumbo. (2011) High frequency of PfCRT 76T in two Malian villages and its prevalence in severe relative to non-severe malaria. Acta Tropica 119:1, 11-13
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R. Matthew Chico, Daniel Chandramohan. (2011) Intermittent preventive treatment of malaria in pregnancy: at the crossroads of public health policy. Tropical Medicine & International Health 16:7, 774-785
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Case McNamara, Elizabeth A Winzeler. (2011) Target identification and validation of novel antimalarials. Future Microbiology 6:6, 693-704
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Ines Petersen, Richard Eastman, Michael Lanzer. (2011) Drug-resistant malaria: Molecular mechanisms and implications for public health. FEBS Letters 585:11, 1551-1562
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Jean Bernard Lekana-Douki, Sylvatrie Danne Dinzouna Boutamba, Rafika Zatra, Sonya Estelle Zang Edou, Hervé Ekomy, Ulrick Bisvigou, Fousseyni S. Toure-Ndouo. (2011) Increased prevalence of the Plasmodium falciparum Pfmdr1 86N genotype among field isolates from Franceville, Gabon after replacement of chloroquine by artemether–lumefantrine and artesunate–mefloquine. Infection, Genetics and Evolution 11:2, 512-517
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Abdulsalam M Al-Mekhlafi, Mohammed AK Mahdy, Hesham M Al-Mekhlafi, Ahmed A Azazy, Mun Fong. (2011) High frequency of Plasmodium falciparum chloroquine resistance marker (pfcrt T76 mutation) in Yemen: An urgent need to re-examine malaria drug policy. Parasites & Vectors 4:1, 94
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Samir Ranjitkar, Mette L Schousboe, Thomas Thomsen, Madhav Adhikari, Christian MO Kapel, Ib C Bygbjerg, Michael Alifrangis. (2011) Prevalence of molecular markers of anti-malarial drug resistance in Plasmodium vivax and Plasmodium falciparum in two districts of Nepal. Malaria Journal 10:1, 75
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Reem A Mubjer, Ahmed A Adeel, Michael L Chance, Amir A Hassan. (2011) Molecular markers of anti-malarial drug resistance in Lahj Governorate, Yemen: baseline data and implications. Malaria Journal 10:1, 245
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Wanna Chaijaroenkul, Stephen A Ward, Mathirut Mungthin, David Johnson, Andrew Owen, Patrick G Bray, Kesara Na-Bangchang. (2011) Sequence and gene expression of chloroquine resistance transporter (pfcrt) in the association of in vitro drugs resistance of Plasmodium falciparum. Malaria Journal 10:1, 42
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J. Ursing, P.-E. Kofoed, A. Rodrigues, D. Blessborn, R. Thoft-Nielsen, A. Bjorkman, L. Rombo. (2011) Similar Efficacy and Tolerability of Double-Dose Chloroquine and Artemether-Lumefantrine for Treatment of Plasmodium falciparum Infection in Guinea-Bissau: A Randomized Trial. Journal of Infectious Diseases 203:1, 109-116
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Patricia Mula, Amalia Fernández-Martínez, Aida de Lucio, Jose Ramos, Francisco Reyes, Vicenta González, Agustín Benito, Pedro Berzosa. (2011) Detection of high levels of mutations involved in anti-malarial drug resistance in Plasmodium falciparum and Plasmodium vivax at a rural hospital in southern Ethiopia. Malaria Journal 10:1, 214
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Mahamadou Diakite, Eric A Achidi, Olivia Achonduh, Rachel Craik, Abdoulaye A Djimde, Marie-Solange B Evehe, Angie Green, Christina Hubbart, Muntasir Ibrahim, Anna Jeffreys, Baldip K Khan, Francis Kimani, Dominic P Kwiatkowski, Wilfred F Mbacham, Sabah Jezan, Jean Ouedraogo, Kirk Rockett, Kate Rowlands, Nawal Tagelsir, Mamadou M Tekete, Issaka Zongo, Lisa C Ranford-Cartwright. (2011) Host candidate gene polymorphisms and clearance of drug-resistant Plasmodium falciparum parasites. Malaria Journal 10:1, 250
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Véronique Sinou, Le Quang, Stéphane Pelleau, Vu Huong, Nguyen Huong, Le Tai, Lionel Bertaux, Marc Desbordes, Christine Latour, Lai Long, Nguyen Thanh, Daniel Parzy. (2011) Polymorphism of Plasmodium falciparum Na+/H+ exchanger is indicative of a low in vitro quinine susceptibility in isolates from Viet Nam. Malaria Journal 10:1, 164
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Anne EP Frosch, Meera Venkatesan, Miriam K Laufer. (2011) Patterns of chloroquine use and resistance in sub-Saharan Africa: a systematic review of household survey and molecular data. Malaria Journal 10:1, 116
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Matthias Frank, Nicola Lehners, Pembe I Mayengue, Julian Gabor, Matthias Dal-Bianco, David U Kombila, Ghyslain Mombo Ngoma, Christian Supan, Bertrand Lell, Francine Ntoumi, Martin P Grobusch, Klaus Dietz, Peter G Kremsner. (2011) A thirteen-year analysis of Plasmodium falciparum populations reveals high conservation of the mutant pfcrt haplotype despite the withdrawal of chloroquine from national treatment guidelines in Gabon. Malaria Journal 10:1, 304
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Ingrid B Müller, John E Hyde. (2010) Antimalarial drugs: modes of action and mechanisms of parasite resistance. Future Microbiology 5:12, 1857-1873
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Jigar J. Patel, Drew Thacker, John C. Tan, Perri Pleeter, Lisa Checkley, Joseph M. Gonzales, Bingbing Deng, Paul D. Roepe, Roland A. Cooper, Michael T. Ferdig. (2010) Chloroquine susceptibility and reversibility in a Plasmodium falciparum genetic cross. Molecular Microbiology 78:3, 770-787
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Sanjeev Krishna, Serena Pulcini, Farrah Fatih, Henry Staines. (2010) Artemisinins and the biological basis for the PfATP6/SERCA hypothesis. Trends in Parasitology 26:11, 517-523
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David C. Smithson, W. Armand Guiguemde, R. Kiplin Guy. 2010. Antimalarials. .
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T. H. Davis. (2010) Profile of Thomas E. Wellems. Proceedings of the National Academy of Sciences 107:31, 13567-13569
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Mathirut Mungthin, Nantana Suwandittakul, Wanna Chaijaroenkul, Kanchana Rungsrihirunrat, Pongchai Harnyuttanakorn, Aree Seugorn, Kesara Na Bangchang. (2010) The patterns of mutation and amplification of Plasmodium falciparum pfcrt and pfmdr1 genes in Thailand during the year 1988 to 2003. Parasitology Research 107:3, 539-545
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Aminatou Kone, Marga van de Vegte-Bolmer, Rianne Siebelink-Stoter, Geert-Jan van Gemert, Antoine Dara, Hamidou Niangaly, Adrian Luty, Ogobara K. Doumbo, Robert Sauerwein, Abdoulaye A. Djimde. (2010) Sulfadoxine–pyrimethamine impairs Plasmodium falciparum gametocyte infectivity and Anopheles mosquito survival. International Journal for Parasitology 40:10, 1221-1228
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Aung Swi Prue Marma, Toshihiro Mita, Hideaki Eto, Takahiro Tsukahara, Sumon Sarker, Hiroyoshi Endo. (2010) High prevalence of sulfadoxine/pyrimethamine resistance alleles in Plasmodium falciparum parasites from Bangladesh. Parasitology International 59:2, 178-182
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Nadja Oster, Petra Rohrbach, Cecilia P. Sanchez, Katharine T. Andrews, Judith Kammer, Boubacar Coulibaly, Gabriele Stieglbauer, Heiko Becher, Michael Lanzer. (2010) Apparent bias for P. falciparum parasites carrying the wild-type pfcrt allele in the placenta. Parasitology Research 106:5, 1065-1070
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Arjen M. Dondorp, Shunmay Yeung, Lisa White, Chea Nguon, Nicholas P.J. Day, Duong Socheat, Lorenz von Seidlein. (2010) Artemisinin resistance: current status and scenarios for containment. Nature Reviews Microbiology
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Wanna Chaijaroenkul, Raewadee Wisedpanichkij, Kesara Na-Bangchang. (2010) Monitoring of in vitro susceptibilities and molecular markers of resistance of Plasmodium falciparum isolates from Thai-Myanmar border to chloroquine, quinine, mefloquine and artesunate. Acta Tropica 113:2, 190-194
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Richard T. Eastman, David A. Fidock. (2009) Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nature Reviews Microbiology
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Praveen Kumar Bharti, Mohammad Tauqeer Alam, Robert Boxer, Man Mohan Shukla, Sant P. Gautam, Yagya D. Sharma, Neeru Singh. (2009) Therapeutic efficacy of chloroquine and sequence variation in pfcrt gene among patients with falciparum malaria in central India. Tropical Medicine & International Health
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G. Q. Zhang, Y. Y. Guan, B. Zheng, S. Wu, L. H. Tang. (2009) Molecular assessment of Plasmodium falciparum resistance to antimalarial drugs in China. Tropical Medicine & International Health 14:10, 1266-1271
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Virginie Sauvage, Dominique Aubert, Sandie Escotte-Binet, Isabelle Villena. (2009) The role of ATP-binding cassette (ABC) proteins in protozoan parasites. Molecular and Biochemical Parasitology 167:2, 81-94
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Daniel J. Bridges, Malcolm Molyneux, Standwell Nkhoma. (2009) Low level genotypic chloroquine resistance near Malawi’s northern border with Tanzania. Tropical Medicine & International Health 14:9, 1093-1096
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Toshihiro Mita, Kazuyuki Tanabe, Kiyoshi Kita. (2009) Spread and evolution of Plasmodium falciparum drug resistance. Parasitology International 58:3, 201-209
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Kesara Na-Bangchang, Juntra Karbwang. (2009) Current status of malaria chemotherapy and the role of pharmacology in antimalarial drug research and development. Fundamental & Clinical Pharmacology 23:4, 387-409
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Catherine E. James, Amanda L. Hudson, Mary W. Davey. (2009) Drug resistance mechanisms in helminths: is it survival of the fittest?. Trends in Parasitology 25:7, 328-335
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H. C. Hapuarachchi, S. Abeysundara, M. Y. D. Dayanath, A. Manamperi, W. Abeyewickreme, N. R. de Silva. (2009) Molecular markers of chloroquine resistance in <I>Plasmodium falciparum</I> in Sri Lanka: frequency before revision of the antimalarial drug policy. Annals of Tropical Medicine and Parasitology 103:4, 351-356
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Toshimitsu Hatabu, Moritoshi Iwagami, Shin-ichiro Kawazu, Nao Taguchi, Aleyla D. Escueta, Elena A. Villacorte, Pilarita T. Rivera, Shigeyuki Kano. (2009) Association of molecular markers in Plasmodium falciparum crt and mdr1 with in vitro chloroquine resistance: A Philippine study. Parasitology International 58:2, 166-170
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MARK A. TRAVASSOS, MIRIAM K. LAUFER. (2009) Resistance to Antimalarial Drugs: Molecular, Pharmacologic, and Clinical Considerations. Pediatric Research 65:Supplement, 64R-70R
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J. I. Thwing, C. O. Odero, F. O. Odhiambo, K. O. Otieno, S. Kariuki, R. Ord, C. Roper, M. McMorrow, J. Vulule, L. Slutsker, R. D. Newman, M. J. Hamel, M. Desai. (2009) In-vivo efficacy of amodiaquine-artesunate in children with uncomplicated Plasmodium falciparum malaria in western Kenya. Tropical Medicine & International Health 14:3, 294-300
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Benoit Witkowski, Antoine Berry, Françoise Benoit-Vical. (2009) Resistance to antimalarial compounds: Methods and applications. Drug Resistance Updates 12:1-2, 42-50
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Mirabeau Youtchou Tatfeng, Dennis Edokpaibe Agbonlahor, Adesola Olufunmilayo Olalekan, Faith Oviasogie, Jonathan Isibor. (2009) Chloroquine resistance molecular markers in Falciparum malaria in Edo state. Tropical Medicine and Health 37:2, 37-41
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Kanchana Rungsihirunrat, Wanna Chaijareonkul, Aree Seugorn, Kesara Na-Bangchang, Sodsri Thaithong. (2009) Association between chloroquine resistance phenotypes and point mutations in pfcrt and pfmdr1 in Plasmodium falciparum isolates from Thailand. Acta Tropica 109:1, 37-40
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Miriam K. Laufer. (2009) Monitoring antimalarial drug efficacy: Current challenges. Current Infectious Disease Reports 11:1, 59-65
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Henglin Yang, Yaming Yang, Pinfang Yang, Xingliang Li, Baihe Gao, Zhiyong Zhang, Zhaoqing Yang, Liwang Cui. (2008) Monitoring Plasmodium falciparum chloroquine resistance in Yunnan Province, China, 1981–2006. Acta Tropica 108:1, 44-49
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Christian Mouala, Sandrine Houzé, Marguerite Guiguet, Philippe Abboud, Gilles Pialoux, Nathalie Viget, Dominique Costagliola, Sophie Matheron. (2008) Imported Malaria in HIV-Infected Patients Enrolled in the ANRS CO4 FHDH Study. JAIDS Journal of Acquired Immune Deficiency Syndromes 49:1, 55-60
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Ousmane Sarr, Ambroise D. Ahouidi, Omar Ly, Johanna P. Daily, Daouda Ndiaye, Omar Ndir, Souleymane Mboup, Dyann F. Wirth. (2008) Mutations in PFCRT K76T do not correlate with sulfadoxine–pyrimethamine–amodiaquine failure in Pikine, Senegal. Parasitology Research 103:4, 765-769
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P. K. Sahu, S. S. Pati, R. Satpathy. (2008) Association of <I>msp-1, msp-2</I> and <I>pfcrt</I> genes with the severe complications of <I>Plasmodium falciparum</I> malaria in children. Annals of Tropical Medicine and Parasitology 102:5, 377-382
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Alfredo Mayor, Elisa Serra‐Casas, Sergi Sanz, John J. Aponte, Eusebio Macete, Inacio Mandomando, Laura Puyol, Pedro Berzosa, Carlota Dobaño, Pedro Aide, Jahit Sacarlal, Agustín Benito, Pedro Alonso, Clara Menéndez. (2008) Molecular Markers of Resistance to Sulfadoxine‐Pyrimethamine during Intermittent Preventive Treatment for Malaria in Mozambican Infants. The Journal of Infectious Diseases 197:12, 1737-1742
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Halima Kaddouri, Abdoulaye Djimdé, Souleymane Dama, Aly Kodio, Mamadou Tekete, Véronique Hubert, Aminatou Koné, Hamma Maiga, Oumar Yattara, Bakary Fofana, Bakary Sidibe, Cheick P.O. Sangaré, Ogobara Doumbo, Jacques Le Bras. (2008) Baseline in vitro efficacy of ACT component drugs on Plasmodium falciparum clinical isolates from Mali. International Journal for Parasitology 38:7, 791-798
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Daniel Dive, Christophe Biot. (2008) Ferrocene Conjugates of Chloroquine and other Antimalarials: the Development of Ferroquine, a New Antimalarial. ChemMedChem 3:3, 383-391
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Johan Ursing, Berit Aydin Schmidt, Marianne Lebbad, Poul-Erik Kofoed, Fransisco Dias, José Pedro Gil, Lars Rombo. (2007) Chloroquine resistant P. falciparum prevalence is low and unchanged between 1990 and 2005 in Guinea-Bissau: An effect of high chloroquine dosage?. Infection, Genetics and Evolution 7:5, 555-561
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Xinzhuan Su, Karen Hayton, Thomas E. Wellems. (2007) Genetic linkage and association analyses for trait mapping in Plasmodium falciparum. Nature Reviews Genetics 8:7, 497-506
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Ole Wichmann, Teunis A. Eggelte, Sabine Gellert, Maha Elhadi Osman, Franziska Mylius, Stephan Ehrhardt, Sylvester D. Anemana, Ulrich Bienzle, Frank P. Mockenhaupt. (2007) High residual chloroquine blood levels in African children with severe malaria seeking healthcare. Transactions of the Royal Society of Tropical Medicine and Hygiene 101:7, 637-642
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Vannan Kandi Vijayan. (2007) How to diagnose and manage common parasitic pneumonias. Current Opinion in Pulmonary Medicine 13:3, 218-224
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Vivian N. Hawkins, Hema Joshi, Kanchana Rungsihirunrat, Kesara Na-Bangchang, Carol Hopkins Sibley. (2007) Antifolates can have a role in the treatment of Plasmodium vivax. Trends in Parasitology 23:5, 213-222
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Standwell Nkhoma, Malcolm Molyneux, Stephen Ward. (2007) Molecular surveillance for drug-resistant Plasmodium falciparum malaria in Malawi. Acta Tropica 102:2, 138-142
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Maman Laminou Ibrahim, Françoise Gay-Andrieu, Eric Adehossi, Veronique Lacroix, Milijaona Randrianarivelojosia, Jean-Bernard Duchemin. (2007) Field-based evidence for the linkage of pfcrt and pfdhfr drug-resistant malaria genotypes and clinical profiles of severe malaria in Niger. Microbes and Infection 9:5, 599-604
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Pembe Issamou Mayengue, Yvonne Kalmbach, Saadou Issifou, Peter G. Kremsner, Francine Ntoumi. (2006) No variation in the prevalence of point mutations in the Pfcrt and Pfmdr1 genes in isolates from Gabonese patients with uncomplicated or severe Plasmodium falciparum malaria. Parasitology Research 100:3, 487-493
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Xavier de Radiguès, Kandian I. Diallo, Mouctar Diallo, Paul Akisa Ngwakum, Hamma Maiga, Abdoulaye Djimdé, Massambou Sacko, Ogobara Doumbo, Jean-Paul Guthmann. (2006) Efficacy of chloroquine and sulfadoxine/pyrimethamine for the treatment of uncomplicated falciparum malaria in Koumantou, Mali. Transactions of the Royal Society of Tropical Medicine and Hygiene 100:11, 1013-1018
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