Treatment of Chloroquine-Resistant Plasmodium vivax Malaria in India

Background: Treatment failure in P. vivax Malaria is a major dilemma that faces health care workers. True drug resistance is one of the causes after ruling out compliance and drug quality issues. The other two causes are re-infection during the treatment period or the release of hypnozoites from the liver. Objectives: To find out what antimalarials can be prescribed in India for treating Chloroquine-resistant P. vivax Malaria. Methods: By reviewing documents prepared by the National Center for Vector-Borne Diseases Control (NCVBDC) and doing a PUBMED search for articles that deal with Chloroquine-resistant P. vivax Malaria treatment. Results: It was found that a fixed-dose combination of oral Artemether and Lumefantrine can be given for Chloroquine-resistant P. vivax Malaria. Conclusions: There is a lack of awareness among health care providers on how to treat Chloroquine-resistant P. vivax Malaria. This paper addresses this concern.

Therapeutic failure after regimen with artemether-lumefantrine combination therapy: a report of three cases in Benin City, Nigeria

Abstract Artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated malaria. Currently, there appears to be a downward trend in the efficacy of ACT in some parts of sub-Saharan Africa because some patients have been positive for Plasmodium parasite 3 days after artemether-lumefantrine treatment. We reported three cases of possible parasite resistance to artemether-lumefantrine therapy. All subjects had complete parasite clearance when treated with other antimalarial drugs. This observation necessitates the urgent need to re-evaluate artemether-lumefantrine medication in Nigeria since it is one of the most commonly used ACT drug.

Artemeter-Lumefantrine therapeutic efficacy, safety and plasma levels in patients with uncomplicated falciparum malaria from the Colombian Pacific region / Eficacia terapéutica, seguridad y niveles plasmáticos del Artemeter-Lumefantrine en pacientes con malaria falciparum no complicada de la región del Pacifico Colombiano

Introduction: In Colombia, the published studies for the treatment of uncomplicated Plasmodium falciparum malaria with Artemether-Lumefantrine are scarce. The aim of the study was to evaluate the therapeutic efficacy and safety profile of this combination. Methods: A clinical trial was performed in adults with uncomplicated P. falciparum malaria using the 28‑day World Health Organization validated protocol. Patients received supervised antimalarial treatment and the primary efficacy endpoint was the clinical and parasitological response. Safety was assessed through adverse events surveillance and plasmatic levels of antimalarial drugs were measured. Results: 88 patients were included. Adequate clinical and parasitological response rate of 100% on day 28 was achieved in 84 patients, diagnosed by thick blood smear examination. There were four parasitological therapeutic failures (5%) detected by polymerase chain reaction. Discusion: Therapeutic efficacy similar to previous studies was established with a slight increase in therapeutic failure. The serum levels of the antimalarials were adequate and the few cases of therapeutic failure were not related. Conclusion: Treatment of uncomplicated P. falciparum malaria with Artemeter-Lumefantrine was effective and safe in the study population. All patients reached adequate plasma concentrations of the drugs; therapeutic failures were not associated with low blood levels of the drug clinical trial.

Introducción: Son escasos los estudios en Colombia sobre eficacia del tratamiento para Plasmodium falciparum con la combinación Artemeter-Lumefantrina. El objetivo de este estudio fue evaluar la eficacia terapéutica y el perfil de seguridad de este tratamiento combinado. Métodos: Se realizó un ensayo clínico en adultos con malaria por P. falciparum no complicada, utilizando el esquema de 28 días recomendado por la Organización Mundial de la Salud (OMS). Los pacientes recibieron el tratamiento supervisado y el desenlace primario evaluado fue la respuesta clínica y parasitológica. La seguridad fue evaluada a través de vigilancia de efectos adversos y medición de niveles plasmáticos del medicamento. Resultados: Se incluyeron 88 pacientes. La tasa de curación clínica y parasitológica fue del 100% en 84 pacientes que tuvieron examen de gota gruesa al día 28. Hubo cuatro (5%) fallas parasitológicas detectada por reacción en cadena de polimerasa. Discusión: La eficacia terapéutica fue similar a la reportada en estudios previos con un ligero aumento de falla terapéutica. Los niveles plasmáticos de los antimalaricos fueron adecuados y no relacionados con la falla terapéutica. Conclusión: El tratamiento de malaria por P. falciparum no complicada con Artemeter-Lumefantrina fue efectiva y segura en la población estudiada. Todos los pacientes alcanzaron niveles en plasma adecuados y no se encontró asociación de falla terapéutica con bajos niveles en sangre.

In vitro effects of co-incubation of blood with artemether/lumefantrine & vitamin C on the viscosity & elasticity of blood.

Background & objectives: The antimalarial combination drug artemether/lumefantrine has been shown to be effective against malaria parasite through its haemolytic action. This drug is sometimes co-administered with vitamin C in patients with malaria. Vitamin C is associated with antioxidant properties which would be expected to protect against haemolytic effects of this antimalarial drug. This study was designed to investigate in vitro effects of co-incubation of artemether/lumefantrine with vitamin C on the viscosity and elasticity of blood. Methods: Blood was collected from 12 healthy female volunteers with normal haemoglobin genotype (HbAA). A Bioprofiler was used to measure the viscosity and elasticity of untreated blood samples (control) and samples exposed to artemether/lumefantrine (0.06/0.36 mg/ml) alone and with low or high dose vitamin C (equivalent to adult doses of 100 or 500 mg). Results: Artemether/lumefantrine significantly (P<0.05) reduced viscosity of blood from 4.72 ± 0.38 to 3.78 ± 0.17 mPa.s. Addition of vitamin C (500 mg) further reduced blood viscosity to 2.67 ± 0.05 mPa.s. The elasticity of blood was significantly (P<0.05) reduced from 0.33 ± 0.04 mPa.s to 0.24 ± 0.03 mPa.s by the antimalarial drug, and further reduced to 0.13 ± 0.02 mPa.s in the presence of vitamin C (500 mg). Interpretation & conclusions: Co-incubation of blood with vitamin C and antimalarial combination drug potentiates the haemolytic effects of the latter on reducing blood viscosity and elasticity in vitro. This may possibly have implications in relation to haemolysis in patients receiving vitamin C supplementation with artemether/lumefantrine during malaria therapy.

Prevalence of Pfmdr 1 N86Y and Y184F Alleles is Associated with Recurrent Parasitemia following Treatment of Uncomplicated Malaria with Artemether-Lumefantrine in Nigerian Patients.

We investigated and compared genetic variations in Plasmodium falciparum multidrug resistance 1 gene (Pfmdr 1) in patients showing good therapeutic response (GTR) and artemisinin resistance (AR) following artemether-lumefantrine (AL) treatment of uncomplicated malaria in Nigeria. Some 150 malaria patients were subjected to AL treatment and therapeutic efficacy was monitored for 28 days. Parasite genomic DNA was isolated followed by nested polymerase chain reaction (PCR). Genotyping of Pfmdr 1 gene for specific genetic variants: N86Y, Y184F, S1034C and N1042D were done using PCR-restriction fragment length polymorphism (PCR-RFLP).Out of 121 patients that were P. falciparum positive, 46 % (56) and 54 % (65) showed good therapeutic response and artemisinin resistance respectively, with 5.4 % and 98.3 % being mutated in the GTR and AR group respectively. The most prevalent mutations were Y184F (44.1 %) and N86Y (40.7 %). There was significant increase (p<0.001) in the prevalence of Pfmdr 1 mutation in the post treatment compared to the pre-treatment group.Prevalence of Pfmdr1 86Y and 184F alleles is associated with artemisinin resistance and presence of AL drug significantly induced genetic variation in the plasmodial gene.

Efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Northeast Ethiopia.

Background: The impact of resistance to antimalarials is insidious and unless efficacy studies are conducted, resistance may go unrecognized. The aim of this study was to assess the efficacy of artemether/lumefantrine, for the treatment of uncomplicated Plasmodium falciparum infections in Kemisie Health Center, Northeast Ethiopia. Methods: Artemether/lumefantrine efficacy study was conducted in Kemisie Health Center, Northeast Ethiopia from September, 2012 to May, 2013. The study participants were febrile people above the age of 6 months with confirmed uncomplicated P. falciparum infection. Patients were treated with artemether/lumefantrine. Clinical and parasitological parameters were monitored over a 28 days follow-up period to evaluate drug efficacy. The Kaplan–Meier method was used for statistical analysis of data on drug efficacy. Results: Among the 66 enrolled participants 72.7% were 15 and above years of age while 15.3% were less than 5 years old. Of these study participants, 53% were male. There was 89.4% fever clearance and 84.8% parasite clearance on day 1, whereas, there was 100% fever clearance and 96.8% parasite clearance on day 3 from the 62 participants who carried on the study. Among 66 participants who had started 28 days of follow-up one patient had an early parasitological failure (parasitemia on day 3) and another patient had a late parasitological failure (parasitemia on day 21). Conclusions: In general, this study discovered good clinical and parasitological response of P. falciparum to artemether/lumefantrine. Further polymeric chain reaction and plasma drug concentration based effectiveness study of artemether/ lumefantrine should be conducted throughout the country.

Determination of Related Substances in Lumefantrine by Gradient Elution RP￣HPLC / 医药导报

Objective To establish a gradient RP￣HPLC method for determining the related substances in lumefantrine. Methods The HPLC analysis was performed on an Agilent nucleosil 100￣5 C18(4.0 mm×125 mm,5 μm) column;the mobile phase was consisted of solution A,B and C,which included phosphate buffer solutions (consisting sodium hexane sulfonate,pH was adjusted to 2. 3 )￣water￣acetonitrile￣propanol with different proportion, with a gradient elution at the flow rate of 2.0 mL.min-1 , the detection wavelength was 265 nm, and the column temperature was 35 ℃ . Results An excellent separation achieved for lumefantrine from its related substances.Lumefantrine had a good linear relationship with the peak area within the range of 0.173 4-0.693 2 μg.mL-1(r= 0.999 6).The limit of determination was 0.06 μg.mL-1 . Conclusion The method is sensitive,reproducible and specific for the separation and determination of related substances in lumefantrine.

Possible artemisinin-based combination therapy-resistant malaria in Nigeria: a report of three cases

Artemisinin-based combination therapy-resistant malaria is rare in Sub-Saharan Africa. The World Health Organization identifies monitoring and surveillance using day-3 parasitaemia post-treatment as the standard test for identifying suspected artemisinin resistance. We report three cases of early treatment failure due to possible artemisinin-based combination therapy-resistant Plasmodium falciparum malaria. All cases showed adequate clinical and parasitological responses to quinine. This study reveals a need to re-evaluate the quality and efficacy of artemisinin-based combination therapy agents in Nigeria and Sub-Saharan Africa.

Aspectos farmacológicos do antimalárico lumefantrina / Pharmacological aspects of antimalarial lumefantrine

Objetivo: conhecer as características farmacológicas do antimalárico Lumefantrina, o qual estásendo utilizado na malaria falciparum resistente aos antigos tratamentos, tal como: estruturaquímica e propriedades fisico-químicas, farmacocinética, mecanismo de ação entre outros, poisatravés delas pode-se observar se o fármaco é bem tolerado, seguro e eficaz. Esta revisãoobjetiva ampliar e incentivar os conhecimentos sobre os aspectos farmacológicos dalumefantrina, servindo como apoio para futuros estudos sobre este fármaco. Método: foirealizada uma pesquisa na literatura sobre as características farmacológicas desse fármaco.Considerações finais: pode-se observar que a lumefantrina é bem tolerada, de ação rápida eeficaz em crianças e adultos

Objective: to understand the pharmacology of antimalarial Lumefantrine, which is being usedin falciparum malaria resistant to older treatments, such as chemical structure and physicochemicalproperties, pharmacokinetics, mechanism of action among others, because throughthem we can see if the drug is well tolerated, safe and effective. This review aims to encourageand expand the knowledge about the pharmacological aspects of lumefantrine, serving assupport for future studies on this drug. Methods: we performed a literature search on thepharmacology of this drug. Final Thoughts: it can be observed that lumefantrine is welltolerated, fast acting and effective in children and adults

Artesunate + amodiaquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in the Colombian Pacific region: a noninferiority trial / Artesunato + amodiaquina versus artemether-limefantrina para o tratamento da malaria não complicada por Plamodium falciparum no Pacifico Colombiano: um estudo de não inferioridade

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.

Evaluation of biochemical indices following administration of artemether, halofantrine and a combination of artemether and lumefantrine in guinea pigs.

Combination of artemether and lumefantrine (artemether-lumefantrine) is an orally effective artemisinin-based combination therapy, used widely in the treatment of Plasmodium falciparum infections. The present study investigates the comparative effects of artemether, halofantrine and artemether-lumefantrine on biochemical indices in the male guinea pig. Half, normal and double therapeutic doses of the drugs were given to different groups of animals (n=5) by oral gavage. After the drug treatments, serum levels of biochemical parameters were measured using standard methods. Artemether significantly (p<0.05) reduced uric acid (UA) level (10.44%), but produced no significant effects on the other parameters measured. Halofantrine and artemether-lumefantrine significantly increased acid phosphatase- ACPT (56.13 and 26.45%) and prostatic acid phosphatase-ACPP (100.00 and 78.95%) respectively, while alkaline phosphatase (ALP) was not affected. In addition, halofantrine and artemether-lumefantrine significantly and dose-dependently decreased UA, while urea and creatinine levels were increased. UA was decreased by 12.15 and 17.92%; urea was increased by 84.42 and 53.25%; and creatinine was increased by 42.15 and 30.25%, respectively. Furthermore, both drugs had no significant effects on serum levels of total protein and cholesterol. The results show that halofantrine and artemether-lumefantrine may cause toxicity to renal and reproductive functions in the male guinea pig, halofantrine likely to cause more of these effects.

Malaria healthcare policy change in Kenya: Implications on sales and marketing of antimalarials.

Background & objectives: Malaria healthcare policy change in Kenya aimed at improving the control of malaria but faced a number of challenges in implementation related to marketing of the drugs. This research investigated the effect of the change of the national malaria policy on drug sales and strategic marketing responses of antimalarial pharmaceutical companies in Kenya. Study design: A descriptive cross-sectional design was employed to describe the existing state of antimalarials market in Kenya after the change of the malaria healthcare policy. Results & conclusion: Policy change did result in an increase in the sales of Coartem®. Novartis Pharma recorded a 97% growth in sales of Coartem® between 2003 and 2004. However, this increase was not experienced by all the companies. Further, SPs (which had been replaced as first-line therapy for malaria) registered good sales. In most cases, these sales were higher than the sales of Coartem®. Generally, the sales contribution of SPs and generic antimalarial medicines exceeded that of Coartem® for most distributors. The most common change made to marketing strategies by distributors (62.5%) was to increase imports of antimalarials. A total of 40% of the manufacturers preferred to increase their budgetary allocation for marketing activities. In view of the fact that continued sale of SP drugs and limited availability of AL poses the risk of increasing the incidence of malaria in Kenya, it is therefore, recommended that pharmacy surveillance systems be strengthened to ensure drugs that have been rendered non-viable or that prescription-only medicines are not sold contrary to the national guidelines.

Robustness evaluation of the chromatographic method for the quantitation of lumefantrine using youden's test / Avaliação da robustez do método cromatográfico para quantificação de lumefantrina utilizando o teste de youden

Youden's test is a reliable method to evaluate the robustness of analytical methods, by means of an experiment design which involves seven analytical parameters combined in eight tests. In the present study, we assessed the robustness of a chromatographic method to quantify lumefantrine in raw material samples, using Youden's test. Hence, it was possible to determine the effect of each analytical parameter in the final analysis results. Youden's test showed to be a simple and feasible procedure to evaluate the robustness of chromatographic methods.

O teste de Youden constitui um método confiável para avaliação da robustez de métodos analíticos, por meio de um delineamento que envolve sete parâmetros analíticos combinados em oito experimentos. No presente estudo, a robustez de um método cromatográfico para quantificação de lumefantrina em matéria-prima farmacêutica foi avaliada utilizando-se o teste de Youden. Assim, foi possível determinar o efeito de cada parâmetro analítico nos resultados finais das análises. O teste de Youden se mostrou um procedimento simples e confiável para a avaliação da robustez de métodos cromatográficos.

Clinical efficacy of chloroquine versus artemether-lumefantrine for Plasmodium vivax treatment in Thailand

Chloroquine remains the drug of choice for the treatment of vivax malaria in Thailand. Mixed infections of falciparum and vivax malaria are also common in South-East Asia. Laboratory confirmation of malaria species is not generally available. This study aimed to find alternative regimens for treating both malaria species by using falciparum antimalarial drugs. From June 2004 to May 2005, 98 patients with Plasmodium vivax were randomly treated with either artemether-lumefantrine (n = 47) or chloroquine (n = 51). Both treatments were followed by 15 mg of primaquine over 14 days. Adverse events and clinical and parasitological outcomes were recorded and revealed similar in both groups. The cure rate was 97.4% for the artemether-lumefantrine treated group and 100% for the chloroquine treated group. We concluded that the combination of artemether-lumefantrine and primaquine was well tolerated, as effective as chloroquine and primaquine, and can be an alternative regimen for treatment of vivax malaria especially in the event that a mixed infection of falciparum and vivax malaria could not be ruled out.