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.

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.

Drug resistant falciparum malaria and the use of artesunate-based combinations: focus on clinical trials sponsored by TDR.

Antimalarial drug resistance has now become a serious global challenge and is the principal reason for the decline in antimalarial drug efficacy. Malaria endemic countries need inexpensive and efficacious drugs. Preserving the life spans of antimalarial drugs is a key part of the strategy for rolling back malaria. Artemisinin-based combinations offer a new and potentially highly effective way to counter drug resistance. Clinical trials conducted in African children have attested to the good tolerability of oral artesunate when combined with standard antimalarial drugs. The cure rates of the different combinations were generally dependent on the degree of resistance to the companion drug. They were high for amodiaquine-artesunate, variable for sulfadoxine/pyrimethamine-artesunate, and poor for chloroquine-artesunate.

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...

Chloroquine versus amodiaquine in the treatment of Plasmodium falciparum malaria in northeast India.

Amodiaquine is being used in India for presumptive treatment as an alternative to chloroquine in areas with chloroquine resistant P. falciparum. Keeping in view the toxicity of amodiaquine, studies have been undertaken to evaluate the advantage of the drug over chloroquine in the treatment of P. falciparum malaria. In vivo drug resistance studies were carried out in the states of Assam and Meghalaya in India. A total of 388 subjects have been studied to compare the efficacy of chloroquine and amodiaquine. The overall cure rate, degree of resistance, mean parasite clearance time and mean parasite recrudescence time were comparable for both the drugs, the differences being not statistically significant. The results indicate no advantage of amodiaquine in the treatment of patients with P. falciparum infection in chloroquine resistant areas of northeast India and development of cross resistance in P. falciparum to these 4-aminoquinolines is complete and parallel.

Comparative efficacy of chloroquine and amodiaquine in Plasmodium falciparum strain of north-eastern India.

The present study describes the comparative efficacy of chloroquine and amodiaquine in two different presumptive therapy areas of north eastern India. The study recorded insignificant differences in respect of Mean Parasite Clearance Time (MPCT) of sensitive cases, MPCT and Mean Parasite Recrudescence Time (MPRT) of RI resistant cases and recrudescence rate in chloroquine and amodiaquine therapy areas. It is concluded that amodiaquine is not a superior drug as compared to chloroquine. In the chloroquine resistance area, Plasmodium falciparum developed cross resistance to amodiaquine and this phenomenon appears to be unidirectional. However, amodiaquine may help to slow-down the rate of precipitation of higher grade of resistance.

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.

Falciparum malaria and pregnancy: relationship and treatment response.

Fifty-two patients with falciparum malaria during pregnancy were studied in Taunggyi, Shan States, Burma, during the period of April 1985 through December 1986. Severely ill cases were all treated with quinine, but uncomplicated cases were randomised to receive either quinine or amodiaquine. Fifty-one age-matched non-pregnant female patients were also randomised to receive either quinine or amodiaquine. All clinical and laboratory parameters were comparable between pregnant and non-pregnant group of patients. Falciparum malaria was most frequent among primigravidae, and occurred most frequently in the second trimester for all parities. There were no differences in parasite density, fever clearance and parasite clearance between groups with different parity or gestational period. Quinine and amodiaquine treatment were equally effective. The outcome of pregnancy with and without anti-malarial prophylaxis is discussed.

Resistência in vivo do Plasmodium falciparum às 4-aminoquinoleínas e à associaçäo sulfadoxina-pirimetamina: II. Estudo de Imperatriz, Maranhäo, 1983-1984 / Resistance in vivo of Plasmodium falciparum to 4-aminoquinolines and the association sulphadoxine-pyrimethamine: II. Study in Imperatriz, Maranhäo state, 1983-1984

Através da prova de 7 dias foram estudadas as respostas terapêuticas de 96 pacientes com malária falciparum näo grave atendidos pela SUCAM em Imperatriz, Maranhäo. Esses pacientes foram distribuídos aleatoriamente em três grupos de estudo, tendo o primeiro recebido cloroquina, o segundo amodiaquina e o terceiro a associaçäo sulfadoxina-pirimetamina. Mesmo sem evidenciar significância estatística ao nível de 5% de probabilidade, as diferenças observadas nas respostas as 3 drogas apontam para a associaçäo sulfadoxina-pirimetamina como a que produziu melhores resultados terapêuticos. Recomenda-se a monitorizaçäo contínua da resistência nas áreas malarígenas críticas

Resistência in vivo do Plasmodium falciparum as 4-aminoquinoleínas e a associaçäo sulfadoxina-pirimetamina: II- estudo de Manaus, Amazonas 1983-1984 / In vivo resistence of plasmodium falciparum to 4-aminoquinolines and sulfadoxine-pyrimethamine combination: II. Study of Manaus Amazonas 1983-1984

Estudaram-se as respostas terapêuticas de 97 pacientes com malária näo grave por P. falciparum atendidos pela SUCAM em Manaus, Amazonas, submetidos a tratamento com cloroquina, amodiaquina e associaçäo sulfadoxina-pirimetamina. Os pacientes foram alocados aleatoriamente em três grupos distintos de tratamento e foram avaliados através da prova de 7 dias de acompanhamento. Ainda que apresentando uma melhor resposta dentre os pacientes que permaneceram sob estudo, o esquema sulfa-pirimetamina näo necessáriamente representou a melhor alternativa terapêutica em funçäo do elevado número de afastamento por agravamento do quadro clínico. As 4-aminoquinoleínas apresentaram respostas inferiores e semelhantes com elevada proporçäo de graus avançados de resistência. Reitera-se a necessidade de monitorizaçäo contínua de resistência em áreas malarígenas críticas