الملخص
INTRODUCTION: In Colombia, there are no published studies for the treatment of uncomplicated Plasmodium falciparum malaria comparing artemisinin combination therapies. Hence, it is intended to demonstrate the non-inferior efficacy/safety profiles of artesunate + amodiaquine versus artemether-lumefantrine treatments. METHODS: A randomized, controlled, open-label, noninferiority (Δ≤5%) clinical trial was performed in adults with uncomplicated P. falciparum malaria using the 28‑day World Health Organization validated design/definitions. Patients were randomized 1:1 to either oral artesunate + amodiaquine or artemether-lumefantrine. The primary efficacy endpoint: adequate clinical and parasitological response; secondary endpoints: - treatment failures defined per the World Health Organization. Safety: assessed through adverse events. RESULTS: A total of 105 patients was included in each group: zero censored observations. Mean (95%CI - Confidence interval) adequate clinical and parasitological response rates: 100% for artesunate + amodiaquine and 99% for artemether-lumefantrine; the noninferiority criteria was met (Δ=1.7%). There was one late parasitological therapeutic failure (1%; artemether-lumefantrine group), typified by polymerase chain reaction as the MAD20 MSP1 allele. The fever clearance time (artesunate + amodiaquine group) was significantly shorter (p=0.002). Respectively, abdominal pain for artesunate + amodiaquine and artemether-lumefantrine was 1.9% and 3.8% at baseline (p=0.68) and 1% and 13.3% after treatment (p<0.001). CONCLUSIONS: Uncomplicated P. falciparum malaria treatment with artesunate + amodiaquine is noninferior to the artemether-lumefantrine standard treatment. The efficacy/safety profiles grant further studies in this and similar populations.
INTRODUÇÃO: Na Colômbia não existem estudos publicados sobre o tratamento da malária não complicada por Plasmodium falciparum comparando as terapias combinadas com artemisinina. Destarte, quer se demonstrar a não inferioridade dos perfis de eficácia/segurança dos tratamentos com artesunato+amodiaquina versus artemeter-lumefantrina. MÉTODOS: Foi realizado um estudo clínico de não inferioridade (∆≤5%), aleatório, controlado, aberto, em adultos com malária não complicada por P. falciparum usando o desenho validado de 28 dias e os desenhos validados/definidos pela Organização Mundial da Saúde. Os pacientes foram aleatorizados (1:1) para ambos artesunato+amodiaquina ou artemeter-lumefantrina orais. Critérios primários de eficácia: resposta clínica e parasitológica adequada; Criterios de eficácia secundários: as falhas de tratamento definidos pela Organização Mundial da Saúde. A segurança: avaliada através de eventos adversos. RESULTADOS: Foram incursos 105 pacientes em cada grupo: zero observações censuradas. As taxas médias da resposta clínica e parasitológica adequada (95% IC - intervalo de confiança): 100% para artesunato+amodiaquina e 99% para artemeter-lumefantrina; atingiu-se o critério de não inferioridade (∆=1.7%). Houve uma falha terapêutica parasitológica tardia (1%; grupo artemeter-lumefantrina), caracterizada mediante reação em cadeia da polimerase como o alelo MAD20 MSP1. Tempo de remissão da febre (grupo artesunato+amodiaquina), foi significativamente mais curto (p=0.002). Dor abdominal, para artesunato+amodiaquina e artemeter-lumefantrina, respectivamente, 1.9% e 3.8% (p=0.68) na linha de base, 1% e 13.3% pós-tratamento (p<0.001). CONCLUSÕES: O tratamento com artesunato+amodiaquina da malária não complicada por P. falciparum é não inferior ao tratamento normal com artemeter-lumefantrina. Os perfis de eficácia/segurança justificam estudos adicionais nesta e outras populações semelhantes.
الموضوعات
Adult , Female , Humans , Male , Amodiaquine/administration & dosage , Antimalarials/administration & dosage , Artemisinins/administration & dosage , Ethanolamines/administration & dosage , Fluorenes/administration & dosage , Malaria, Falciparum/drug therapy , Amodiaquine/adverse effects , Antimalarials/adverse effects , Artemisinins/adverse effects , Colombia , Drug Combinations , Drug Therapy, Combination/methods , Ethanolamines/adverse effects , Fluorenes/adverse effects , Treatment Outcomeالملخص
Chloroquine (CQ) resistance in Plasmodium falciparum contributes to increasing malaria-attributable morbidity and mortality in Sub-Saharan Africa. Despite a change in drug policy, continued prescription of CQ did not abate. Therefore the therapeutic efficacy of CQ in uncomplicated falciparum malaria patients was assessed in a standard 28-day protocol in 116 children aged between six and 120 months in Osogbo, Southwest Nigeria. Parasitological and clinical assessments of response to treatment showed that 72 (62.1 percent) of the patients were cured and 44 (37.9 percent) failed the CQ treatment. High initial parasite density and young age were independent predictors for early treatment failure. Out of the 44 patients that failed CQ, 24 received amodiaquine + sulphadoxine/pyrimethamine (AQ+SP) and 20 received chlorpheniramine + chloroquine (CH+CQ) combinations. Mean fever clearance time in those treated with AQ+SP was not significantly different from those treated with CH+CQ (p = 0.05). There was no significant difference in the mean parasite density of the two groups. The cure rate for AQ+SP group was 92 percent while those of CH+CQ was 85 percent. There was a significant difference in parasite clearance time (p = 0.01) between the two groups. The 38 percent treatment failure for CQ reported in this study is higher than the 10 percent recommended by World Health Organization in other to effect change in antimalarial treatment policy. Hence we conclude that CQ can no more be solely relied upon for the treatment of falciparum malaria in Osogbo, Nigeria. AQ+SP and CH+CQ are effective in the treatment of acute uncomplicated malaria and may be considered as useful alternative drugs in the absence of artemisinin-based combination therapies.
الموضوعات
Animals , Child , Child, Preschool , Female , Humans , Infant , Male , Antimalarials/administration & dosage , Histamine H1 Antagonists/administration & dosage , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Amodiaquine/administration & dosage , Clinical Protocols , Chloroquine/administration & dosage , Chlorpheniramine/administration & dosage , Drug Combinations , Drug Resistance , Drug Therapy, Combination , Malaria, Falciparum/parasitology , Nigeria , Pyrimethamine/administration & dosage , Sulfadoxine/administration & dosage , Treatment Outcomeالملخص
Resistance in Plasmodium falciparum to amodiaquine (AQ) can be reversed in vitro with with antihistaminic and tricyclic antidepressant compounds, but its significance in vivo is unclear. The present report presents the enhancement of the antimalarial efficacy of AQ by chlorpheniramine, an H1 receptor antagonist that reverses chloroquine (CQ) resistance in vitro and enhances its efficacy in vivo, in five children who failed CQ and/or AQ treatment, and who were subsequently retreated and cured with a combination of AQ plus CP, despite the fact that parasites infecting the children harboured mutant pfcrtT76 and pfmdr1Y86 alleles associated with AQ resistance. This suggests a potential clinical appliation of the reversal phenomenon.
الموضوعات
Humans , Animals , Infant , Child, Preschool , Child , Adolescent , Amodiaquine/administration & dosage , Antimalarials/administration & dosage , Chloroquine/administration & dosage , Chlorpheniramine/administration & dosage , Histamine H1 Antagonists/administration & dosage , Malaria, Falciparum/drug therapy , Membrane Transport Proteins/genetics , Protozoan Proteins/genetics , Drug Synergism , Drug Therapy, Combination , Malaria, Falciparum/parasitology , Plasmodium falciparum/drug effects , Plasmodium falciparum/geneticsالملخص
The effects of pyrimethamine-sulphadoxine (PS), chloroquine plus chlorpheniramine, a H1 receptor antagonist that reverses chloroquine resistance in Plasmodium falciparum in vitro and in vivo (CQCP), and amodiaquine plus pyrimethamine-sulphadoxine (AQPS) on gametocyte production were evaluated in 157 children with acute, symptomatic, uncomplicated falciparum malaria who were treated with these drugs. PS was significantly less effective than CQCP or AQPS at clearing asexual parasitaemia or other symptoms of malaria. Gametocyte carriage on days 3, 7, and 14 were significantly higher in those treated with PS. The ratio of the density (per æl blood) of peripheral young gametocyte (PYG), that is, < stage III to peripheral mature gametocyte (PMG), that is, stage IV and V, an index of continuing generation of gametocytes, rose to 1 by day 7 of treatment in those treated with PS, but remained consistently below 1 in the other treatment groups. PYG-PMG density ratio increased significantly from day 0-14 in those treated with PS and CQCP (chi2 = 76, P = 0.000001 and chi2 = 42.2, P = 0.00001, respectively) but decreased significantly in those treated with AQPS (chi2 = 53.2, P = 0.000001). Both PS-sensitive and -resistant infections generated PYG (18 of 29 vs 13 of 20, chi2 = 0.04, P = 0.93) but PYG was present only in those with resistant response to CQCP. Combination of PS with amodiaquine (AQ), that is, (AQPS) resulted in less production of PYG, but in this setting, PYG was not indicative of response to AQPS. These data indicate that PS enhanced production or release of young gametocytes when used alone, but generated less young gametocytes when used in combination with AQ. PYG may be used as an indicator of response to CQCP but not PS or PS-based combination drugs.
الموضوعات
Humans , Animals , Child, Preschool , Child , Antimalarials/administration & dosage , Gametogenesis/drug effects , Histamine H1 Antagonists/administration & dosage , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Acute Disease , Amodiaquine/administration & dosage , Chloroquine/administration & dosage , Chlorpheniramine/administration & dosage , Drug Combinations , Drug Therapy, Combination , Pyrimethamine/administration & dosage , Sulfadoxine/administration & dosage , Time Factors , Treatment Outcomeالملخص
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...
الموضوعات
Humans , Animals , Child , Adult , Mice , Rats , Antimalarials/therapeutic use , /genetics , /metabolism , Malaria, Falciparum/drug therapy , Malaria/drug therapy , Administration, Oral , Amodiaquine/administration & dosage , Amodiaquine/metabolism , Amodiaquine/pharmacokinetics , Amodiaquine/therapeutic use , Antimalarials/administration & dosage , Antimalarials/metabolism , Antimalarials/pharmacokinetics , Biotransformation , Proguanil/administration & dosage , Proguanil/metabolism , Proguanil/pharmacokinetics , Proguanil/therapeutic use , Chloroquine/administration & dosage , Chloroquine/metabolism , Chloroquine/pharmacokinetics , Chloroquine/therapeutic use , Databases as Topic , Disease Models, Animal , Genotype , Malaria, Falciparum/metabolism , Malaria/metabolism , Mefloquine/administration & dosage , Mefloquine/metabolism , Mefloquine/pharmacokinetics , Mefloquine/therapeutic use , Murinae , Mutation , Nutritional Status , Phenotype , Plasmodium berghei , Polymorphism, Geneticالملخص
Blood schizontocidal effect of antimalarials were compared by 4-day suppressive test with an extended observation period of 31 days. On a drug-sensitive Plasmodium berghei ANKA strain, pyronaridine (PND) exhibited the best effect, followed by amodiaquine (ADQ), mefloquine (MFQ), and qinghaosu (QHS). On a moderately chloroquine-resistant P. berghei NS line, the order of effects was the same, PND greater than ADQ greater than MFQ greater than QHS. On a highly pyronaridine-resistant P. berghei RP line, ADQ, MFQ and QHS showed cross resistance with PND.
الموضوعات
Amodiaquine/administration & dosage , Animals , Antimalarials/administration & dosage , Artemisinins , Drug Administration Schedule , Drug Evaluation, Preclinical , Drug Resistance , Female , Malaria/drug therapy , Male , Mefloquine/administration & dosage , Mice , Naphthyridines/administration & dosage , Plasmodium berghei , Sesquiterpenes/administration & dosageالملخص
In view of the emergence of chloroquine resistant Plasmodium falciparum from more and more geographical areas profiling of the responses to other available antimalarials by in vitro methods have become essential. A preliminary study undertaken in two Primary Health Centres of Karnataka State, India show the presence of strains of P. falciparum resistant to chloroquine and amodiaquine. The response for amodiaquine was poor as compared to chloroquine. The isolates were, however, sensitive to mefloquine and quinine.
الموضوعات
Amodiaquine/administration & dosage , Animals , Chloroquine/administration & dosage , Drug Resistance, Microbial , Malaria/blood , Mefloquine/administration & dosage , Microbial Sensitivity Tests , Plasmodium falciparum , Quinine/administration & dosageالملخص
Se describen 3 casos de malaria en ninos incluyendo el diagnostico y tratamiento, la evolucion y las complicaciones. El primer caso corresponde a una lactante menor con un avanzado estado de desnutricion y una infeccion post-transfusional por Plasmodium Vivax. La respuesta a la cloroquina no fue adecuada requiriendo 2 ciclos adicionales para eliminar los parasitos circulantes. El segundo caso describe un neonato de 25 dias de edad con una infeccion por Plasmodium vivax cuyo mecanismo de transmision natural. La madre fue positiva para Plasmodium Vivax durante el embarazo y puerperio. El paciente presento ademas una metahemoglobinemia como complicacion del tratamiento con primaquina. Finalmente se presenta el caso de un escolar con una malaria por Plasmodium Falciparum resistente a la cloroquina tratada en forma inadecuada con 4 esquemas terapeuticos diferentes, que incluyen quinina intravenosa, trimetoprim-sulfametoxazol y sulfadoxina-pirimetamina