Plasmodium vivax malaria elimination: should innovative ideas from the past be revisited?

In the 1950s, the strategy of adding chloroquine to food salt as a prophylaxis against malaria was considered to be a successful tool. However, with the development of Plasmodium resistance in the Brazilian Amazon, this control strategy was abandoned. More than 50 years later, asexual stage resistance can be avoided by screening for antimalarial drugs that have a selective action against gametocytes, thus old prophylactic measures can be revisited. The efficacy of the old methods should be tested as complementary tools for the elimination of malaria.

Metemoglobinemia em pacientes com malária por Plasmodium vivax em uso oral de primaquina / Methemoglobinemia in patients with Plasmodium vivax receiving oral therapy with primaquine

INTRODUÇÃO: A primaquina pode acarretar sérios eventos adversos, com destaque para a toxicidade ao sangue. O objetivo deste trabalho é determinar a metemoglobinemia de 20 pacientes com malária por Plasmodium vivax tratados com primaquina, comparando-os segundo o sexo e a expressão da glicose-6-fosfato desidrogenase. MÉTODOS: Quantificação da metemoglobina por espectrofotometria visível e avaliação qualitativa da glicose-6-fosfato desidrogenase. RESULTADOS: A metemoglobinemia variou de 2,85 a 5,45 por cento nos pacientes do sexo masculino e de 3,77 a 7,34 por cento no feminino. CONCLUSÕES: A instituição da terapia aumentou de maneira significativa os teores de metemoglobina, sem manifestação clínica evidente e independente do sexo e da atividade enzimática.

INTRODUCTION: Primaquine can produce adverse reactions as toxicity to blood when used in the treatment of vivax malaria. This work aimed to determine methemoglobinemia in patients with vivax malaria receiving oral therapy with primaquine. METHODS: Spectrophotometric quantification of methemoglobinemia and qualitative assay for glucose-6-phosphate dehydrogenase. RESULTS: Methemoglobinemia ranged from 2.85 to 5.45 percent in male patients and 3.77 to 7.34 percent in female patients. CONCLUSIONS: A statistically significant increase in methemoglobinemia was observed following oral therapy with primaquine, with no clinical manifestations, and independent of sex and the qualitative expression of glucose-6-phosphate dehydrogenase.

Plan de mejoramiento del control de la malaria hacia su eliminación en Mesoamérica / Plan to improve malaria control towards its elimination in Mesoamerica

Desarrollar un plan de fortalecimiento del control de la mala-ria hacia su eliminación. En 2009, bajo la coordinación del Instituto Nacional de Salud Pública, se integró un equipo técnico transdisciplinario para hacer un diagnóstico situacional de la malaria y de los programa de control y para la selección de prácticas efectivas de intervención que serían incorporadas al plan, en el marco de un ejercicio de teoría de cambio. Se establecieron criterios de estratificación de las localidades con base en sus condiciones de transmisión. Se identificaron limitaciones estructurales y operativas de los programas de control. Se elaboró un plan de intervenciones para mejorar la cobertura de vigilancia epidemiológica, intervenciones antimaláricas y diagnóstico y tratamiento oportunos de casos. El plan delinea con fases progresivas de implementación: reorganización, intensificación de intervenciones y evaluación de la factibilidad de eliminación. La adopción de un plan estratégico único brindará lineamientos y elementos administrativos para conformar un sistema que coordine las actividades de los programas nacionales de control y facilite la eliminación de la malaria en la región.

To develop a plan to strengthen the control of malaria towards its elimination. In 2009, under the coordination of the National Public HealthInstitute ofMexico, atransdisciplinary equipment of technical and operative experts was conformed to carry out a situational analysis of malaria and control programs and for the selection of effective practices of intervention that would be incorporated to the plan, within the framework of an exercise in Theory of Change. Criteria for thestratificationof thelocalities, based ontheirtransmission characteristics were established. The structural and operative limitations of the control programs were identified. A plan of interventions was elaborated to improve the coverage of epidemiological surveillance, anti-malaria interventions and opportune diagnosis and treatment of cases. The plan delineates progressive phases of implementation: reorganization, intensification of interventions and evaluation of elimination feasibility. The adoption of a regional strategic plan will provide guidance and administrative elements to conform a system that coordinates the activities of the national control programs and facilitate the elimination of malaria in the region.

Subdoses of primaquine in overweight patients and malaria vivax relapses: report of two cases in the Federal District, Brazil / Subdoses de primaquina associadas a recaídas de malária vivax em pacientes com peso elevado: relato de dois casos no Distrito Federal

Two cases of malaria by Plasmodium vivax relapsed after treatment with drugs in doses recommended by the Ministry of Health are presented. Both patients were overweight and were followed in the Federal District, an area considered free from vector transmission of the disease. Radical cure was obtained after medication with the same drugs in weight proportional doses.

São apresentados dois casos de pacientes com malária por Plasmodium vivax que apresentaram recaídas após tratamento com medicamentos em doses indicadas pelo Ministério da Saúde. Ambos os pacientes tinham pesos elevados e foram acompanhados no Distrito Federal, área considerada sem transmissão vetorial da doença. A cura radical foi obtida após medicação em dose proporcional ao peso corpóreo dos pacientes.

Malaria vivax en niños: recurrencia con dosis total estándar de primaquina administrada durante 3 frente a 7 días / Vivax malaria in children: recurrences with standard total dose of primaquine administered in 3 vs. 7 days

Introducción: se ha evaluado poco en el mundo la eficacia del tratamiento con cloroquinaprimaquina para el ataque agudo y, sobre todo, para las recurrencias del paludismo vivax en niños; esos estudios en América Latina son muy escasos y casi inexistentes en Colombia.Objetivo: evaluar la eficacia de dos dosificaciones de primaquina en menores de 18 años.Materiales y métodos: estudio clínico controlado, no enmascarado, con asignación aleatoria del tratamiento. Se evaluaron dos grupos según la dosis de primaquina: 0,50 mg/kg/día por 7 días (0,50-7) frente a 1,17 mg/kg/día por 3 días (1,17-3).Resultados: A. Curación del ataque agudo: eficacia del 100% en los dos grupos; B. Prevención de las recurrencias durante 120 días: ocurrieron recurrencias en 68,4% de los niños tratados con el esquema 1,17-3, y en 34,2% de los que recibieron el régimen 0,50-7.Conclusiones: 1. La proporción de recurrencias a los 120 días en niños tratados con el esquema 0,50-7 (34,2%) fue significativamente menor que la de los niños que recibieron el régimen 1,17-3 (68,4%). 2. El tiempo de administración de una misma dosis total de primaquina influye en su eficacia contra las recurrencias: a menos días, menor eficacia.

Introduction: Worldwide, the efficacy of cloroquine-primaquine for treating acute Plasmodiumvivax malarious attacks has not been thoroughly evaluated. In Latin America such studies arescarce, and in Colombia, almost nonexisting. Objective: To assess the efficacy of two regimens foradministration of primaquine in children aged less than18 years. Methodology: A clinical, controlled, unmasked studywas carried out, with randomized administration of twoprimaquine regimens, namely: 0.50 mg/kg/day for 7days (0.50-7) vs. 1.17 mg/kg/day for 3 days (1.17-3). Results: A. Healing of the acute attack: efficacy was100% in both groups. B. Prevention of recurrencesduring 120 days: recurrences occurred in 68.4% ofchildren treated with the 1.17-3 regimen, and in 34.2%of those receiving the 0.5-7 one. Conclusions: 1. Proportion of recurrences during the120 days follow-up was significantly lower (34.2%) inchildren receiving the 0.50-7 regimen than in thosetreated with the 1.17-3 one (68.4%). The length ofadministration of the same total dose of primaquineinfluenced its efficacy against recurrences: shorterperiods of administration were associated with lesserefficacy.

Efficacy of Artequick versus artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria in Thailand.

To determine the efficacy, safety and tolerability of an alternative short-course, artemisinin-based combination therapy for acute uncomplicated Plasmodium falciparum malaria, we compared Artequick--a fixed-dosed combination of artemisinin (80 mg), piperaquine (400 mg), and primaquine (4 mg), per tablet--with a standard regimen of artesunate-mefloquine. A total of 130 patients were randomly assigned to treatment with an orally administered, once-daily, 3-day regimen of either Artequick (Group A: 3.2 mg/Kg/day of artemisinin, 16 mg/Kg/day of piperaquine, and 0.16 mg/Kg/day of primaquine) or artesunate-mefloquine (Group B: artesunate, 4 mg/Kg/day, with mefloquine, 8 mg/Kg/day). Patients receiving each regimen had a rapid clinical and parasitological response. All treatments were well tolerated, and no serious adverse effects occurred. No significant differences were found in fever- and parasite-clearance times between the two study groups. The 28-day cure rates were similarly high, at 98.5% and 100%, in groups A and B, respectively. We conclude that Artequick was as effective and well tolerated as artesunate-mefloquine and could be used as an alternative treatment for multidrug-resistant Plasmodium falciparum malaria in Southeast Asia.

Operational feasibility of rapid diagnostic kits & blister packs use for malaria control in high transmission areas of Orissa & Chhattisgarh.

BACKGROUND & OBJECTIVE: Early diagnosis and prompt treatment of cases with malaria are two important components of malaria control strategy. The independent assessment of the operational feasibility of rapid diagnostic kits and blister packs for malaria in some selected high transmission areas of Orissa and Chhattisgarh was done with the objectives to assess the knowledge and skills of the paramedical personnel and their acceptability by the paramedical personnel and the community, and to assess improvement in patients' health seeking behaviour. METHODS: The basic information regarding malaria situation, epidemiological divisions, distribution data of rapid diagnostic kits and blister packs, etc., was collected from State and district headquarters. The subcentres from the primary health centres/community health centres were selected on the basis of supply of rapid diagnostic kits and blister packs. The subcentres were visited and health personnel interviewed about their knowledge and skills on the use of rapid diagnostic kits and blister packs. A cross-sectional survey was conducted to assess the public opinion about rapid diagnostic kits and blister packs. RESULTS: We found that the paramedicals were well trained in the use of rapid diagnostic kits and blister pack administration and the acceptance was good by both paramedicals and general public. The compliance rate of radical treatment with blister packs was 100 per cent and no adverse events were reported. INTERPRETATION & CONCLUSION: Our findings showed that rapid diagnostic kits and blister packs under remote and inaccessible highly malarious areas can be introduced that will have significant impact in reducing malaria morbidity and mortality.

Assessment of therapeutic efficacy of chloroquine for vivax malaria in Thailand.

Chloroquine-resistant Plasmodium vivax has been reported in some Asian countries. In 2003, 161 patients infected with vivax malaria were treated according to the Thai National Drug Policy, with oral chloroquine (approximately 25 mg base/kg body weight, administered over 3 days) followed by primaquine on day 28 (15 mg daily for 14 days). All the patients were initially cured after chloroquine treatment, clearing their parasitemias within 7 days. Only one patient presented with parasitemia at 28 days. These data indicate that chloroquine is still effective for the treatment of patients with vivax malaria in Thailand.

Declining mefloquine sensitivity of Plasmodium falciparum along the Thai-Myanmar border.

Mefloquine sensitivity of Plasmodium falciparum along the Thai-Myanmar border, both in vitro and in vivo, following different first-line treatments for uncomplicated falciparum malaria patients in these areas during the period 1997--2003 were studied. Standard in vitro micro tests and in vivo efficacy according to World Health Organization methodologies were performed. P. falciparum isolates along the Thai-Myanmar border with in vitro sensitivity to mefloquine have had up to a ten-fold decrease in sensitivity compared to a baseline done in 1986, conducted one year after the drug was first introduced to Thailand. The reduction in the mefloquine sensitivity of P. falciparum isolates in Tak Province developed rapidly, with the highest IC50 of 1,254 nM in 1997. The IC50 declined to 1,067 and 737 nM in 1999 and 2001, respectively, but there was no statistically significant difference in the sensitivity. The sensitivity of P. falciparum isolates from Mae Hong Son, Kanchanaburi, and Ranong, where the first line treatment was mefloquine 15 mg/kg single dose, continued to decline, where in 2001 the IC50 were 1,087, 941, and 1,116 nM, respectively, in these provinces. The difference in sensitivities of P. falciparum isolates in Mae Hong Son and Ranong in 2001, compared to 1997, was statistically significant (p<0.05). Good therapeutic efficacy of the artesunate-mefloquine combination in Tak Province was observed. Adequate clinical responses (ACR) were 89.5% and 92.3% in 1997 and 2002, respectively. The efficacy of mefloquine alone in Mae Hong Son, Kanchanaburi, and Ranong has significantly dropped. ACR in 1997 and 2001 in Mae Hong Son were 87.8% and 73.2%, respectively, in Kanchanaburi were 82% and 59.6%, respectively, and in Ranong were 96% and 31.6%, respectively.

Monitoring the therapeutic efficacy of antimalarials against uncomplicated falciparum malaria in Thailand.

Increasing antimalarial drug-resistance is an important problem in Thailand. The results of monitoring the antimalarial efficacy are used in decision-making about using antimalarials to treat uncomplicated falciparum malaria in Thailand. In 2002, 552 patients with uncomplicated malaria were treated according to the Thai National Drug Policy, with mefloquine 25 mg/kg plus artesunate 12 mg/kg and primaquine 30 mg in divided doses for 2 days in high-mefloquine-resistant areas; mefloquine 15 mg/kg plus primaquine 30 mg in non- or low-mefloquine-resistant areas; mefloquine 15 mg/kg plus artesunate 12 mg/kg and primaquine 30 mg in divided doses for 2 days or Coartem (6-dose regimen for adult contains 480 mg artemether and 2880 mg lumefantrine) plus primaquine 30 mg given over 3 days in moderate-mefloquine-resistant areas. The study shows that mefloquine, artesunate plus mefloquine, and artemether plus lumefantrine are effective in the treatment of uncomplicated malaria in most areas of Thailand except for Ranong and Kanchanaburi, where the first-line treatment regimen should be revised.

Esquemas terapêuticos encurtados para o tratamento de malária por Plasmodium vivax / Short course schemes for vivax malaria treatment

Visando avaliar esquemas terapêuticos encurtados eficazes no tratamento de malária vivax, foi realizado um estudo aberto, prospectivo, alocando 234 pacientes com malária por P. vivax, distribuídos aleatoriamente em 8 grupos terapêuticos. Seis grupos usaram como esquizonticida sangüíneo o artesunato via oral em diferentes dosagens por um dia e aos outros dois grupos foi administrada a cloroquina em dose única. Como hipnozoiticida, foi utilizada a primaquina em dose diária de 30mg dia durante cinco ou sete dias, em ambos os grupos. O desaparecimento da parasitemia nos pacientes tratados com artesunato (independente da dose) foi mais rápido quando comparados aos que fizeram uso de cloroquina (p<0,01). Cura ocorreu em 92,3 por cento e 80,2 por cento, respectivamente nos pacientes tratados com primaquina por sete e cinco dias (p=0,0372), independente do esquizonticida sanguíneo utilizado

Effect of primaquine standard dose (15 mg/day for 14 days) in the treatment of vivax malaria patients in Thailand.

Primaquine (8-aminoquinoline), the only effective drug to prevent relapses of the persistent liver forms of Plasmodium vivax and Plasmodium ovale, can induce hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The severity varies considerably among affected individuals. Three hundred and sixty-four Plasmodium vivax cases (342 G6PD-normal and 22 G6PD-deficient) were given a 3-day course of chloroquine (total dose 1,500 mg) followed by primaquine 15 mg a day for 14 days and completed a 28-day follow-up. All G6PD-deficient patients were male; there were no relapses or serious adverse events during the study. Although a significant decrease in hematocrit levels and an increase in the percent reduction of hematocrit levels were observed on day 7 (34.9+/-5.0 vs 26.7+/-5.4; (-1.2)+/-14.4 vs (-24.5) +/-13.9 respectively) and on day 14 (35.7+/-4.3 vs 30.9+/-3.1; 1.6+/-17.8 vs (-11.0) +/-19.3 respectively) blood transfusion was not required. Daily doses of 15 mg of primaquine for 14 days following a full course of chloroquine when prescribed to Thai G6PD deficient patients where Mahidol variant is predominant, are relatively safe.

Malaria: tratamiento y quimioprofilaxis / Malaria: treatment and prophylaxis

Malaria es una patología reemergente en el mundo y en América en particular; se revisan aspectos epidemiológicos de la enfermedad en Perú. Las nuevas medidas de control propuestas por la OMS para reducir la mortalidad por malaria y su impacto socio-económico son: diagnóstico y tratamiento precoz de los pacientes; control del vector; detección y contención de epidemias; investigación local básica y aplicada que permita evaluar periódicamente la situación de malaria. Se describen los fármacos y esquemas terapéuticos y profilácticos recomendados para el manejo de la malaria

Is primaquine useful and safe as true exo-erythrocytic merontocidal, hypnozoitocidal and gametocidal antimalarial drug? / ¿Es la primaquine útil y segura como medicamanto antimalárico y verdaderamente merontocida exo-eritrocítico, hipnozoiticidad y gametocitocida?

El objetivo principal de este ensayo es poner a disposición en un documento único, una secuencia de eventos que han sido publicados sobre la biología de los parásitos del paludismo y su interacción con el huésped humano, buscando argumentos para el tratamiento eficaz y seguro; ¿qué sabemos y qué nos gustaría saber sobre los efectos de la primaquina para justificar su uso en la práctica clínica y de salud pública? El profesional debe estar atento a que tanto la actividad antipalúdica, como los efectos deletéreos hemolíticos y metahemoglobinémicos y de detoxificación de la primaria dependen de varios productos de biotransformación de la droga. No obstante el uso universal durante seis décadas, el sitio y mecanismo de formación y degradación y sus efectos biológicos específicos en los seres humanos aún permanecen poco comprendidos. Los gametocitos maduros de Plasmodium falciparum son naturalmente resistentes a la cloroquina y a otras drogas merontocidas sanguíneas, pero son usualmente eliminados con dosis única de 1.315 mg/kg per os (p.o) de fosfato de primaquina (equivalente a 0.75 mg base). En relación con la frecuencia de recaídas, en vez de empíricamente, los esquemas de tratamiento deberían determinarse considerando la farmacodinamia de la droga y su efecto sobre los esporozoitos, merontes pre-exo-eritrocíticos, hipnozoitos y gametocitos p. vivax. Donde no hay servicios de atención médica disponibles, o éstos no están capacitados para identifica deficiencias de glucosa -6- fosfato dehidrogenasa (G6PD) ni efectos deletéreos de la droga, recomendamos que no se use primaquina. Tanto los ataques clínicos primarios como las recaídas de las infecciones por P. vivax como y cuando se presenten deben tratarse con 10 mg/kg de cloroquina base p.o. La prevención de las recaídas por P. vivax está problemente relacionada con la cepa y las características de las poblaciones de hipnozoitos de P.vivax involucrados. Si los trabajadores de salud bien informados y calificados deciden usar primaquina en ausencia de deficiencias de enzimas y están dispuestos a hacer el seguimiento clínico, toxicológico y parasitológico, pueden administrar con seguridad una dosis diaria de 0.25 mg/kg de primaquina-base durante 14 días para la posible prevención de las recaídas por P.vivax

Paludismo en niños: experiencia del Hospital Universitario de Caracas / Paludismo in childrens: experience of the Hospital Universitario de Caracas

El Paludismo es una de las principales causas de mortalidad en los niños de los Países Tropicales y en Venezuela es todavía un problema importante de salud. Se notificaron 28.055 casos de parasitosis en el país en 1997. Durante un período de diez años, 45 niños con Paludismo fueron incluídos en un estudio prospectivo, efectuado en el Hospital Universitario de Caracas, con el propósito de describir y evaluar el comportamiento de la enfermedad en este grupo poblacional. 16 por ciento fueron lactantes, 33 por ciento preescolares y 45 por ciento escolares. 78 por ciento de los niños adquirieron la enfermedad durante un viaje a un área endémica de la enfermedad. 44 por ciento procedía del Estado Sucre. Plasmodium Vivax ocasióno el 82 por ciento de los casos y P. Falciparum el 13 por ciento. Todos los Pacientes referían una historia de fiebre y dos tercios tenían esplenomegalía. Anemia (84 por ciento), Linfocitosis (45 por ciento) y Monocitosis (27 por ciento) fueron las variables de laboratorio resaltantes. Dos niños presentaron recaídas por P. Vivax y fueron tratados con nuevas dosis de cloroquina y primaquina y a uno de ellos al tener una segunda recaída , se le administró Cloroquina y se le duplicó la dosis de Primaquina. Quinina y Clindamicina fueron empleadas para tratamientos de niños co P. Falciparum resistente a la Cloroquina. La fiebre y la Parasistemia desaparecieron en el 90 por ciento de los pacientes en el transcurso de las primeras 50 horas de iniciado el tratamiento específico

Early diagnosis and treatment of malaria in a refugee population in Sri Lanka.

To provide early diagnosis and prompt treatment for malaria, two interventions were compared in refugee camps in Kalpitiya, Sri Lanka. Community health volunteers (HV's) were trained in diagnosis and management of malaria on clinical grounds, while a field laboratory was established in another group of camps providing treatment after laboratory confirmation of a malarial infection. Patients with fever sought treatment from HV's on average after 2.74 days and from the field laboratory after 3.20 days. Although acceptance of both interventions was high, the effective catchment areas, especially of the HV's were small. Large numbers of health volunteers would be needed to cover all families, making it difficult to sustain supervision and necessary logistic support. For every malaria patient treated by HV's, three others would receive anti-malarial drugs unnecessarily. The maintenance of a field laboratory with a microscopist of the Anti-Malaria Campaign is not an economically viable option. Training of HV's in microscopy with a mechanism for cost recovery should be given serious consideration. HV's and diagnosis and treatment centers should be able to handle a wide spectrum of common diseases. A better option for Sri Lanka in the short term might be to improve existing general health facilities that are accessible to the refugee population.

Paludismo y embarazo / Malarie and pregnancy

Se presentan tres casos de paludismo y embarazo atendidos en el Hospital General Dr. José Gregorio Hernández de Caracas entre diciembre de 1973 y diciembre de 1992. Se encuentra una incidencia de 0,003 por ciento, es decir, de 1 caso por 33.221 casos atendidos. Todas las pacientes fueron referidas de zonas endémicas. En todos los casos se demostró la presencia de plasmodium vivax, acompañado de falciparum en dos de ellos. Ninguna paciente asistió a control prenatal. Todas recibieron tratamiento con cloroquina y primaqina en esquema curativo. Los recien nacidos no presentaron morbilidad

Humoral immune response of normal rhesus monkeys during primaquine administration.

Humoral immune response of normal rhesus monkeys was studied after giving a standard dose of primaquine. The drug did not effect the level of complement (C3) and its haemolytic activity. Levels of Immunoglobulin i.e. IgG, IgM & IgA and number of immunoglobulin secreting cells also remained unaffected. Results of this study suggested that primaquine did not suppress the immune status of the host and could be given safely to the malaria patients.