Atovaquone-proguanil for treating uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The World Health Organization (WHO) in 2015 stated atovaquone-proguanil can be used in travellers, and is an option in malaria-endemic areas in combination with artesunate, as an alternative treatment where first-line artemisinin-based combination therapy (ACT) is not available or effective. This review is an update of a Cochrane Review undertaken in 2005. OBJECTIVES: To assess the efficacy and safety of atovaquone-proguanil (alone and in combination with artemisinin drugs) versus other antimalarial drugs for treating uncomplicated Plasmodium falciparum malaria in adults and children. SEARCH METHODS: The date of the last trial search was 30 January 2020. Search locations for published trials included the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, and LILACS. To include recently published and unpublished trials, we also searched ClinicalTrials.gov, the metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform Search Portal. SELECTION CRITERIA: Randomized controlled trials (RCTs) reporting efficacy and safety data for atovaquone-proguanil or atovaquone-proguanil with a partner drug compared with at least one other antimalarial drug for treating uncomplicated Plasmodium falciparum infection. DATA COLLECTION AND ANALYSIS: For this update, two review authors re-extracted data and assessed certainty of evidence. We meta-analyzed data to calculate risk ratios (RRs) with 95% confidence intervals (CI) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Outcome measures include unadjusted treatment failures and polymerase chain reaction (PCR)-adjusted treatment failures. PCR adjustment differentiates new infection from recrudescent infection. MAIN RESULTS: Seventeen RCTs met our inclusion criteria providing 4763 adults and children from Africa, South-America, and South-East Asia. Eight trials reported PCR-adjusted data to distinguish between new and recrudescent infection during the follow-up period. In this abstract, we report only the comparisons against the three WHO-recommended antimalarials which were included within these trials. There were two comparisons with artemether-lumefantrine, one trial from 2008 in Ethiopia with 60 participants had two failures with atovaquone-proguanil compared to none with artemether-lumefantrine (PCR-adjusted treatment failures at day 28). A second trial from 2012 in Colombia with 208 participants had one failure in each arm (PCR-adjusted treatment failures at day 42). There was only one comparison with artesunate-amodiaquine from a 2014 trial conducted in Cameroon. There were six failures with atovaquone-proguanil at day 28 and two with artesunate-amodiaquine (PCR-adjusted treatment failures at day 28: 9.4% with atovaquone-proguanil compared to 2.9% with artesunate-amodiaquine; RR 3.19, 95% CI 0.67 to 15.22; 1 RCT, 132 participants; low-certainty evidence), although there was a similar number of PCR-unadjusted treatment failures (9 (14.1%) with atovaquone-proguanil and 8 (11.8%) with artesunate-amodiaquine; RR 1.20, 95% CI 0.49 to 2.91; 1 RCT, 132 participants; low-certainty evidence). There were two comparisons with artesunate-mefloquine from a 2012 trial in Colombia and a 2002 trial in Thailand where there are high levels of multi-resistant malaria. There were similar numbers of PCR-adjusted treatment failures between groups at day 42 (2.7% with atovaquone-proguanil compared to 2.4% with artesunate-mefloquine; RR 1.15, 95% CI 0.57 to 2.34; 2 RCTs, 1168 participants; high-certainty evidence). There were also similar PCR-unadjusted treatment failures between groups (5.3% with atovaquone-proguanil compared to 6.6% with artesunate-mefloquine; RR 0.8, 95% CI 0.5 to 1.3; 1 RCT, 1063 participants; low-certainty evidence). When atovaquone-proguanil was combined with artesunate, there were fewer treatment failures with and without PCR-adjustment at day 28 (PCR-adjusted treatment failures at day 28: 2.16% with atovaquone-proguanil compared to no failures with artesunate-atovaquone-proguanil; RR 5.14, 95% CI 0.61 to 43.52; 2 RCTs, 375 participants, low-certainty evidence) and day 42 (PCR-adjusted treatment failures at day 42: 3.82% with atovaquone-proguanil compared to 2.05% with artesunate-atovaquone-proguanil (RR 1.84, 95% CI 0.95 to 3.56; 2 RCTs, 1258 participants, moderate-certainty evidence). In the 2002 trial in Thailand, there were fewer treatment failures in the artesunate-atovaquone-proguanil group compared to the atovaquone-proguanil group at day 42 with PCR-adjustment. Whilst there were some small differences in which adverse events were more frequent in the atovaquone-proguanil groups compared to comparator drugs, there were no recurrent associations to suggest that atovaquone-proguanil is strongly associated with any specific adverse event. AUTHORS' CONCLUSIONS: Atovaquone-proguanil was effective against uncomplicated P falciparum malaria, although in some instances treatment failure rates were between 5% and 10%. The addition of artesunate to atovaquone-proguanil may reduce treatment failure rates. Artesunate-atovaquone-proguanil and the development of parasite resistance may represent an area for further research.

Trouble from the tropics: challenges in managing malaria in Rhode Island.

The authors present a case of severe falciparum malaria diagnosed in a traveler after he returned to Rhode Island from a visit to the Dominican Republic. They then review aspects of the case pertinent to our local practice environment that make diagnosis and management especially challenging.

Different patterns of pfcrt and pfmdr1 polymorphisms in P. falciparum isolates from Nigeria and Brazil: the potential role of antimalarial drug selection pressure.

The effect of antimalarial drug selection on pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from two distinct geographical locations was determined in 70 and 18 P. falciparum isolates from Nigeria and Brazil, respectively, using nested polymerase chain reaction and direct DNA sequencing approaches. All isolates from Brazil and 72% from Nigeria harbored the mutant SVMNT and CVIET pfcrt haplotype, respectively. The pfcrt CVMNT haplotype was also observed in (7%) of the Nigerian samples. One hundred percent (100%) and 54% of the parasites from Brazil and Nigeria, respectively, harbored wild-type pfmdr1Asn86. We provide first evidence of emergence of the CVMNT haplotype in West Africa. The high prevalence of pfcrt CVIET and SVMNT haplotypes in Nigeria and Brazil, respectively, is indicative of different selective pressure by chloroquine and amodiaquine. Continuous monitoring of pfcrt SVMNT haplotype is required in endemic areas of Africa, where artesunate-amodiaquine combination is used for treatment of acute uncomplicated malaria.

Efficacy of different primaquine-based antimalarial regimens against Plasmodium falciparum gametocytemia.

This study compared the efficacy against Plasmodium falciparum gametocytes of four regimens: amodiaquine-sulfadoxine/pyrimethamine (AQ-SP) and mefloquine-artesunate (MQ-AS), with and without primaquine (PQ) administered with the second dose of the schizonticide (AQ-SP; AQ-SP-PQ; MQ-AS; MQ-AS-PQ). Efficacy was determined by thick smear on days 1, 4 and 8 after the beginning of treatment. A total of 82 patients (19-23/group) were recruited. After AQ-SP administration, gametocytemia steadily increased until day 8. With AQ-SP-PQ, a marked decline in gametocytemia was detected on days 4 and 8. MQ-AS treatment resulted in reduced gametocytemia on days 4 and 8, and with MQ-AS-PQ it was reduced even further. None of the treatments cleared gametocytemia by day 8. Currently, artemisinin-based combination therapies plus PQ are the recommended treatment option against falciparum malaria; however, further studies are required to optimize the use of PQ. Issues to be addressed include the optimal time of administration, treatment duration, optimal daily and total dose, and day of evaluation of the gametocytocidal effect. In falciparum malaria, the WHO recommends a maximum of 4days of treatment; consequently, an effective regimen must clear asexual parasites and symptoms within this time frame. The same criteria should be taken into account when evaluating the anti-gametocyte activity.

Evaluation of artemisone combinations in Aotus monkeys infected with Plasmodium falciparum.

Artemisone (single oral dose, 10 mg/kg of body weight) cured nonimmune Aotus monkeys of their Plasmodium falciparum infections when combined with mefloquine (single oral dose, 5 and 10 mg/kg but not 2.5 mg/kg). In combination with amodiaquine (20 mg/kg/day), artemisone (10 mg/kg/day) given orally for 3 days cured all infected monkeys. Three days of treatment with artemisone (30 mg/kg/day) and clindamycin (100 mg/kg/day) was also curative.

Some features of primary and recrudescent amodiaquine-resistant Plasmodium falciparum infections in Nigerian children

Characteristics of primary and recrudescent Plasmodium falciparum infections were evaluated in 25 children who did not recover after amodiaquine (AQ) treatment. Recrudescence was detected by a thick blood smear and confirmed by polymerase chain reaction. Over half of recrudescent events occurred after 14 days of initiation of treatment and were associated with relatively low asexual parasitaemia. We examined the gametocyte sex ratio (GSR) in these children and in age and gender-matched controls that had AQ-sensitive (AQ-S) infections (n = 50). In both AQ-S and AQ-resistant (AQ-R) infections, the GSR was female-biased pre-treatment and became male-biased by the third day after treatment initiation. However, gametocyte males persisted after this period in children with AQ-R infections. AQ-recrudescent infections are relatively low (25 of 612.4 percent) in children from this endemic area.

[Gametocytemia in falciparum malaria treated with amodiaquine or artesunate]. / Gametocitemia en malaria por Plasmodium falciparum tratada con amodiaquina o artesunato.

INTRODUCTION: Antimalarial treatment effects on Plasmodium falciparum gametocytemia has been the focus of few studies in the Americas. OBJECTIVE: Relationships are described that occur between falciparum gametocytemia and the treatment with amodiaquine-sulfadoxine-pyrimethamine, artesunate-sulfadoxine-pyrimethamine or amodiaquine-artesunate. MATERIALS AND METHODS: The experimental design consisted of a randomized selection of patients not balanced or blinded. A total of 241 patients were evaluated, residents of Turbo, El Bagre and Zaragoza (Antioquia, Colombia). The follow up occurred 21-28 days after antimalarial treatment. The World Health Organization (1998) protocol was used. RESULTS: The therapeutic efficacy of amodiaquine-sulfadoxine-pyrimethamine, artesunate-sulfadoxine-pyrimethamine and amodiaquine-artesunate were equal at day 21 of the follow up. Four cases (1.7%) were therapeutic failures. Amodiaquine-sulfadoxine-pyrimethamine was less effective than the artesunate treatments in reducing the gametocyte load. On day 7, none of the three treatments had eliminated completely the gametocytes. Most patients (56.0%) were observed not to have circulating gametocytes pre-treatment and did not develop them later. CONCLUSION: The three treatment schemes were similar in their therapeutic efficacy and in their incapacity to eliminate gametocytes at day seven.

[Efficacy of the amodiaquine+sulfadoxine-pyrimethamine combination and of chloroquine for the treatment of malaria in Córdoba, Colombia, 2006]. / Eficacia de la combinación amodiaquina más sulfadoxina-pirimetamina y de la cloroquina para el tratamiento del paludismo en Córdoba, Colombia, 2006.

INTRODUCTION: The decrease in the efficacy of antimalarial drugs in the world and in Colombia hampers its control. OBJECTIVE: The in vivo therapeutic efficacy of the amodiaquine+sulfadoxine-pyrimethamine combination was evaluated in the treatment of uncomplicated Plasmodium falciparum malaria and of chloroquine for P. vivax malaria. MATERIALS AND METHODS: From May to November 2006, in vivo efficacy studies of malaria treatments were undertaken in Tierralta, Córdoba, northeastern Colombia. Standard protocols were followed as recommended by the World Health Organization/Panamerican Health Organization, with some modifications. Patients older than two years with single P. falciparum or P. vivax infection, with asexual parasitemia between 500 and 50,000 parasites/microl, were selected according to established inclusion and exclusion criteria. Supervised treatment was administered, and clinical and parasitological follow-up was carried out on days 0 (inclusion), 1, 2, 3, 7, 14, 21 and 28. The outcome was defined as adequate clinical and parasitological response, early therapeutic failure, or late therapeutic failure. RESULTS: Of 53 subjects selected, 50 (94.3%; CI 70%-100%) presented adequate clinical and parasitological response to the amodiaquine+sulfadoxine-pyrimethamine treatment for uncomplicated falciparum malaria. One patient presented early therapeutic failure, and two developed late therapeutic failure. All of the 50 patients (95%CI: 74%-100%) in the invivo efficacy study of chloroquine for vivax malaria presented adequate clinical and parasitological response. CONCLUSION: In Cordoba, the amodiaquine+sulfadoxine-pyrimethamine combination and chloroquine show a high efficacy for the treatment of uncomplicated falciparum and vivax malaria, respectively.

Some features of primary and recrudescent amodiaquine-resistant Plasmodium falciparum infections in Nigerian children.

Characteristics of primary and recrudescent Plasmodium falciparum infections were evaluated in 25 children who did not recover after amodiaquine (AQ) treatment. Recrudescence was detected by a thick blood smear and confirmed by polymerase chain reaction. Over half of recrudescent events occurred after 14 days of initiation of treatment and were associated with relatively low asexual parasitaemia. We examined the gametocyte sex ratio (GSR) in these children and in age and gender-matched controls that had AQ-sensitive (AQ-S) infections (n = 50). In both AQ-S and AQ-resistant (AQ-R) infections, the GSR was female-biased pre-treatment and became male-biased by the third day after treatment initiation. However, gametocyte males persisted after this period in children with AQ-R infections. AQ-recrudescent infections are relatively low (25 of 612.4%) in children from this endemic area.

[Polymorphisms of the pfmdr1 gene in field samples of Plasmodium falciparum and their association with therapeutic response to antimalarial drugs and severe malaria in Colombia]. / Polimorfismos del gen pfmdr1 en muestras clínicas de Plasmodium falciparum y su relación con la respuesta terapéutica a antipalúdicos y paludismo grave en Colombia.

INTRODUCTION: The pfmdr1 gene of Plasmodium falciparum has been described as a gene conferring resistance to several antimalarial drugs. In particular, polymorphisms on specific codons have been associated with resistance and treatment failure with cloroquine, amodiaquine and mefloquine. However, the role of these polymorphisms in treatment response to antimalarials remains unexplored in Colombia. Furthermore, the relationship of these polymorphisms to severe malaria is unknown. OBJECTIVE: This work studied the association of the Asn 86Tyr and Asp1246Tyr pfmdr1 polymorphisms with response to cloroquine, amodiaquine and mefloquine treatment in three municipalities of Antioquia, and severe malaria cases from the municipality Tumaco. MATERIALS AND METHODS: The polymorphisms were assessed by nucleic acid amplification followed by restriction length polymorphism analysis. RESULTS: The wild-type codon Asn 86 was detected in 97% of the clinical samples from the treatment response study. No association was detected between this polymorphism and treatment failure to the three antimalarials administered. The 1246Tyr polymorphism was detected with a higher frequency in the samples from Antioquia 92% (130/141) than in those from Tumaco 22% (20/89). However, again, no association was found between the presence of a specific polymorphism and the presence of severe malaria in the municipality of Tumaco. CONCLUSIONS: The 86Tyr and 1246Tyr polymorphisms of the pfmdr1 gene are not useful as predictors of treatment failure or severe malaria in the municipalities studied. In addition, we report for the first time, the presence of the mutant codon 86Tyr in field samples in South America.

[Assessment of the efficacy of antimalarial drugs in Tarapacá, in the Colombian Amazon basin]. / Evaluación de la eficacia de los medicamentos antimaláricos en Tarapacá, Amazonas colombiano.

INTRODUCTION: The current antimalarial drug policy in Colombia has been based on studies conducted in Antioquia and the Pacific Coast. However, the efficacy of antimalarial drugs in other endemic regions is unknown. OBJECTIVE: The therapeutic efficacy of three monotherapies was assessed: amodiaquine and sulfadoxine/pyrimethamine for uncomplicated Plasmodium falciparum malaria, and chloroquine for Plasmodium vivax malaria in the municipality of Tarapacá, located in the Colombian province of Amazonas. MATERIALS AND METHODS: Treatment was supervised and clinical/parasitological follow-up was undertaken through a 28-day period following to World Health Organization standard protocols for subjects with a single P. falciparum or P. vivax infection. RESULTS: Due to a decrease in malaria transmission at the time of the study, the sample size was very small. The treatment failed for two subjects who received amodiaquine, and treatment with sulfadoxine/pyrimethamine was discontinued due to a high frequency of therapeutic failures (7/8). Most subjects (18/20) with P. vivax infections showed an adequate therapeutic response. CONCLUSIONS: The use of sulfadoxine/pyrimethamine in Tarapacá, and possibly in the Amazon region of Colombia, needs to be reviewed. Therapeutic efficacy studies in other endemic areas in the Amazon and Orinoco regions in Colombia are desirable but not feasible. Alternative methods such as in vitro assays or detection of molecular markers for resistance in the parasite can provide a basis for decisions concerning antimalarial drug policy for the Amazon and Orinoco regions in Colombia.

Artemisinin-based combination therapy for uncomplicated Plasmodium falciparum malaria in Colombia.

BACKGROUND: Artemisinin-based combination therapy (ACT) is being widely promoted as a strategy to counteract the increase in Plasmodium falciparum antimalarial drug resistance. METHODS: A randomized, double-blind, placebo-controlled, clinical trial of the efficacy, effect on gametocytes and safety of the addition of artesunate/placebo (4 mg/kg/day x 3 d) to amodiaquine (10 mg/kg/day x 3 d) was conducted in Choco department, a low intensity transmission area in northwest Colombia. RESULTS: From 2,137 screened subjects, 85 entered the study: 43 in the amodiaquine plus placebo and 42 in the amodiaquine plus artesunate groups. Potentially eligible cases failed to qualify mostly because they were not available for follow-up visits (73%). Based on a per protocol analysis, the therapeutic response to both treatments was high: amodiaquine/placebo 35/36, 97.2% (95% CI 85.5-99.9), and amodiaquine/artesunate 32/32, 100% (89.1-100) after PCR genotyping. The Kaplan-Meier survival estimates based on all eligible patients enrolled (amodiaquine/placebo: n = 42; amodiaquine/artesunate: n = 41) were similar in the two study groups (P = 0.3). The addition of artesunate significantly decreased gametocyte carriage on Day 4 (OR = 0.1 95% CI 0.02-0.6), Day 7 (OR = 0.2 95%CI 0.04-0.9), Day 14 (OR = 0.09 95% CI 0-0.8), and Day 21 (OR95%CI 0-0.9). Most subjects in both groups (81% in amodiaquine/placebo and 75.6% in amodiaquine/artesunate) reported at least one drug related adverse event. Symptoms were generally mild and self-limiting and there was no serious adverse event. Two patients on amodiaquine/artesunate voluntarily withdrew from study because they could not tolerate the medication. CONCLUSION: Both drug regimens were effective in this area of Colombia. The addition of artesunate reduced gametocyte carriage and did not adversely affect tolerability. In this set of patients, the rate of adverse events was higher than in other studies. Patients' follow-up is problematic in areas with dispersed population and affects the conduct of clinical studies and monitoring of treatment effects. The results are discussed in the light of concurrent increase resistance to amodiaquine in other endemic areas in Colombia and the factors that may influence a change in the national antimalarial drug policy.

[Cytochrome P-450 and the response to antimalarial drugs]. / El citocromo P-450 y la respuesta terapéutica a los antimaláricos.

OBJECTIVES: To assess the relationship between the genetic and phenotypic factors linked to the cytochrome P-450 enzyme system and the response to the antimalarial drugs chloroquine, amodiaquine, mefloquine, and proguanil, as well as to determine how certain biological and social factors of the host influence the behavior of this enzymatic complex. METHODS: We performed a systematic review of the medical bibliographic databases PubMed, Excerpta Medica, LILACS, and SciELO by using the following Spanish and English descriptors: "CYP-450" and "citocromo P-450" in combination with "proguanil" (and with "mefloquina," "cloroquina," and "amodiaquina"), "farmacocinética de proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina"), "resistencia a proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina"), "metabolismo," "farmacogenética," "enfermedad," "inflamación," "infección," "enfermedad hepática," "malaria," "nutrición," and "desnutrición." The same terms were used in English. The search included only articles published in Spanish, English, and Portuguese on or before 30 June 2005 that dealt with only four antimalarial drugs: amodiaquine, chloroquine, mefloquine, and proguanil. RESULTS: Some genetic factors linked to human cytochrome P-450 (mainly its polymorphism), as well as other biological and social factors (the presence of disease itself, or of inflammation and infection, the use of antimalarials in their various combinations, and the patient's nutritional status) influence the behavior of this complex enzymatic system. It has only been in the last decade that the genetics of the cytochromes has been explored and that the mechanisms underlying some therapeutic interactions and aspects of drug metabolism have been uncovered, making it possible to characterize the biotransformation pathway of amodiaquine and chloroquine. Hopefully new research will help answer the questions that still remain, some of which pertain to the metabolism of other antimalarial drugs, the distribution in the population of the genetic alleles linked to the enzymes involved in their metabolism, the contribution of these genetic mutations to therapeutic failure, and the possibility of predicting the response to antimalarial therapy. CONCLUSIONS: The therapeutic response to antimalarial drugs is a multifactorial process that is poorly understood, so that it is not possible to ascribe to a specific phenotype or genotype a role in the response to antimalarial therapy. Attention should be given to biological and social factors, such as diet, nutritional status, and inflammatory and infectious processes that are often present in areas where malaria is endemic.

El citocromo P-450 y la respuesta terapéutica a los antimaláricos / Cytochrome P-450 and the response to antimalarial drugs

OBJETIVOS: Evaluar la relación entre los factores genéticos y fenotípicos del sistema enzimático del citocromo P-450 y la respuesta terapéutica antimalárica a la cloroquina, la amodiaquina, la mefloquina y el proguanil, así como determinar la influencia de algunos factores biológicos y sociales del hospedero en el comportamiento de este complejo enzimático. MÉTODOS: Revisión sistemática de las bases de literatura biomédica PubMed, Excerpta Medica, LILACS y SciELO mediante descriptores en español e inglés. Se usaron los siguientes descriptores: "CYP-450" y "citocromo P-450" y sus combinaciones con "proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "farmacocinética de proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "resistencia a proguanil" (y lo mismo con "mefloquina", "cloroquina" y "amodiaquina"), "metabolismo", "farmacogenética", "enfermedad", "inflamación", "infección", "enfermedad hepática", "malaria", "nutrición" y "desnutrición". Estos mismos términos se usaron en inglés. La búsqueda se limitó a los artículos publicados en español, inglés y portugués hasta el 30 de junio de 2005 y a cuatro medicamentos antimaláricos: amodiaquina, cloroquina, mefloquina y proguanil. RESULTADOS: Algunos factores genéticos del citocromo P-450 humano (principalmente su polimorfismo), así como otros de tipo biológico y social (la propia presencia de enfermedad, inflamación o infección, la administración de medicamentos antimaláricos y su combinación, y el estado nutricional del paciente), influyen en la actividad de ese complejo enzimático. Solo en la última década se ha abordado el estudio de las bases genéticas de los citocromos y se han podido dilucidar los mecanismos de algunas interacciones entre fármacos y del metabolismo de estos, lo que ha permitido caracterizar el proceso de biotransformación de la amodiaquina y de la cloroquina. Se espera que nuevas investigaciones permitan responder a las interrogantes que aún subsisten, entre ellas cuál es la ruta metabólica de otros medicamentos antimaláricos, la distribución en la población de los alelos de las enzimas que participan en su metabolismo, y la contribución de tales mutaciones al fracaso terapéutico, y predecir la respuesta a los tratamientos antimaláricos. CONCLUSIONES. La respuesta terapéutica a los medicamentos antimaláricos es un proceso multifactorial y poco comprendido, por lo que no es posible asignar a un fenotipo o a un genotipo una determinada responsabilidad en la respuesta terapéutica antimalárica. Se debe contemplar la influencia de factores biológicos y sociales, tales como la alimentación, el estado nutricional y cualquier proceso inflamatorio e infeccioso concomitante, que puedan ser frecuentes en las zonas con malaria endémica.

OBJECTIVES. To assess the relationship between the genetic and phenotypic factors linked to the cytochrome P-450 enzyme system and the response to the antimalarial drugs chloroquine, amodiaquine, mefloquine, and proguanil, as well as to determine how certain biological and social factors of the host influence the behavior of this enzymatic complex. METHODS. We performed a systematic review of the medical bibliographic databases PubMed, Excerpta Medica, LILACS, and SciELO by using the following Spanish and English descriptors: "CYP-450" and "citocromo P-450" in combination with "proguanil" (and with "mefloquina," "cloroquina," and "amodiaquina"), "farmacocinética de proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina"), "resistencia a proguanil" (and the same using "mefloquina," "cloroquina," and "amodiaquina"), "metabolismo," "farmacogenética," "enfermedad," "inflamación," "infección," "enfermedad hepática," "malaria," "nutrición," and "desnutrición." The same terms were used in English. The search included only articles published in Spanish, English, and Portuguese on or before 30 June 2005 that dealt with only four antimalarial drugs: amodiaquine, chloroquine, mefloquine, and proguanil. RESULTS. Some genetic factors linked to human cytochrome P-450 (mainly its polymorphism), as well as other biological and social factors (the presence of disease itself, or of inflammation and infection, the use of antimalarials in their various combinations, and the patient's nutritional status) influence the behavior of this complex enzymatic system. It has only been in the last decade that the genetics of the cytochromes has been explored and that the mechanisms underlying some therapeutic interactions and aspects of drug metabolism have been uncovered, making it possible to characterize the biotransformation pathway of amodiaquine and chloroquine. Hopefully new research will help answer the questions that still remain, some of which pertain to the metabolism of other antimalarial drugs, the distribution in the population of the genetic alleles linked to the enzymes involved in their metabolism, the contribution of these genetic mutations to therapeutic failure, and the possibility of predicting the response to antimalarial therapy. CONCLUSIONS. The therapeutic response to antimalarial drugs is a multifactorial process that is poorly understood, so that it is not possible to ascribe to a specific phenotype or genotype a role in the response to antimalarial therapy. Attention should be given to biological and social factors, such as diet, nutritional status, and inflammatory and infectious processes that are often present in areas where malaria is endemic.

[Efficacy of amodiaquine and sulfadoxine/pyrimethamine in the treatment of malaria not complicated by Plasmodium falciparum in Nariño, Colombia, 1999-2002]. / Eficacia de amodiaquina y sulfadoxina/pirimetamina en el tratamiento de malaria no complicada por Plasmodium falciparum en Nariño, Colombia, 1999-2002.

The resurgence and spread of antimalarial drug resistance is one of the causes of the worldwide increase of malaria. In Colombia, uncomplicated Plasmodium falciparum malaria has been treated with a combination of amodiaquine (AQ) and sulfadoxine/pyrimethamine (SP) since 2000. The efficacy of these two antimalarials was evaluated after the implementation of the new malaria treatment scheme. In the municipalities of El Charco and Tumaco (Nariño) on the Pacific Coast region, the standard PAHO protocol was used to evaluate antimalarial efficacy in areas of low to moderate malaria transmission. Patients were randomly allocated to treatment regime in two cities of Nariño, El Charco (n = 48) and Tumaco (n = 50). After 14 days none of El Charco patients presented therapeutic failure to either antimalarial. However, in Tumaco after 28 days, 12 of 24 (95% CI: 30.6-69.4) patients presented AQ treatment failure while 4 of 26 (95% CI: 5.1-33.1) patients had SP treatment failure. The high level of AQ treatment failure in Tumaco was unexpected because it had been introduced only recently as an antimalarial treatment in Colombia. The results suggest that the use of the current dose of AQ in combination with SP will be therapeutically useful for less time than expected. Use of combined therapies is a key strategy to delay antimalarial resistance. Unfortunately, its success depends on the efficacy of antimalarial drugs individually.

In vivo and vitro Plasmodium falciparum resistance to chloroquine, amodiaquine and quinine in the Brazilian Amazon

Com o proposito de avaliar a resistencia do Plasmodium falciparum as drogas antimalaricas, rotineiramente empregadas no Brasil, os autores acompanham dez pacientes com malaria falciparum adquirida na Amazonia brasileira. Os pacientes foram submetidos a estudo in vivo de sensibilidade a drogas, apos tratamento com derivados 4-aminoquinoleinicos (cloroquina e amodiaquina) ou quinino. A absorcao das drogas foi verificada atraves de testes padronizados de excrecao urinaria de antimalaricos. Oito pacientes puderam ser seguidos por 28 dias...

Drug susceptibility of Plasmodium falciparum in the western Amazon region State of Acre, Brazil

Estudos de campo na Amazonia ocidental (Estado do Acre, Brasil) indicam que as 4-aminoquinolinas, assim como a sua combinacao com sulfadoxina-pirimetamina nao podem mais ser recomendadas para o tratamento e profilaxia das infeccoes pelo P. falciparum nesta regiao. A quinina permanece como droga efetiva quando usada corretamente. Entretanto, problemas podem surgir devido aos efeitos colaterais durante a sua aplicacao por periodo de 10 dias. Possibilidades de ultrapassar estes problemas combinando curto espaco de administracao da quinina com outras drogas estao no momento limitadas devido a falta de um composto associado adequado. Por esta razao, a combinacao quinina/clindamicina parece ser a terapeutica mais adequada para a malaria pelo P. falciparum. Nossos estudos in vitro sugerem que a mefloquina e outra alternativa efetiva para o tratamento da malaria falciparum nesta regiao da Amazonia.

Low response of Colombian strains of Plasmodium vivax to classical antimalarial therapy.

This report describes 11 cases of Plasmodium vivax infection of Colombian origin that relapsed 49-166 days following treatment with chloroquine or amodiquine (1.5 g in 3 days) plus primaquine (15 mg daily for 14 days) a regimen widely used to effect radical cure of infections with this parasite. Relapses occurred under conditions that precluded reinfection. The fact that most of the relapses occurred within the last two years suggest that P. vivax drug resistance may be developing in Colombia and possibly other regions of South America.

[Malaria in Guiana. I. General status of the endemic]. / Le paludisme en Guyane. I. Situation générale de l'endémie.

Before 1949 malaria was highly prevalent in the whole territory of French Guiana. When malaria control based on house-spraying and drug prophylaxis was implemented in 1950 the disease sharply dropped below 20 cases per year. Since 1976 despite vector control malaria is rising again. In 1987, 3,269 cases have been notified giving an incidence of 37.6 per thousand for the whole country population; only four deaths were recorded. All the age groups were concerned but the transmission was restricted to some foci along the Oyapock river (prevalence rate 25%), along the Maroni river (prevalence 2.3%) and in a few places of the coastal area. The main cities remain malaria free. In vivo resistance to chloroquine was observed in 22% of the cases which could be cleared by amodiaquine or quinine.