Efficacy and safety of chloroquine plus primaquine for the treatment of Plasmodium vivax malaria in Hamusit site, Northwestern Ethiopia.

BACKGROUND: Plasmodium vivax malaria is still an important public health problem in Ethiopia. Unlike Plasmodium falciparum, P. vivax has a dormant liver stage (hypnozoite) that can be a risk of recurrent vivax malaria unless treated by radical cure with primaquine. Drug resistance to chloroquine is threatening malaria control and elimination efforts. This study assessed the therapeutic efficacy and safety of chloroquine plus 14 days of primaquine on P. vivax infection based on parasitological, clinical, and haematological parameters. METHODS: A single-arm in vivo prospective therapeutic efficacy study was conducted to assess the clinical and parasitological response to the first-line treatment of P. vivax in Ethiopia, chloroquine plus 14 days low dose of (0.25 mg/kg/day) primaquine between December 2022 and March 2023 at Hamusit Health Centre using the standard World Health Organization (WHO) protocol. A total of 100 study participants with P. vivax mono-infection who were over 6 months old were enrolled and monitored for adequate clinical and parasitological responses for 42 days. The WHO double-entry Excel sheet and SPSS v.25 software were used for Kaplan-Meier survival analysis, and a paired t-test was used for analysis of haemoglobin improvements between follow up days. RESULTS: A total of 100 patients were enrolled among those, 96% cases were rural residents, 93% had previous malaria exposure, and predominant age group was 5-15 years (61%). 92.6% (95% CI 85.1-96.4%) of enrolled patients were adequate clinical and parasitological response, and 7.4% (95% CI 3.6-14.9%) recurrences were observed among treated patients. The fever and parasite clearance rate on day 3 were 98% and 94%, respectively. The baseline haemoglobin levels improved significantly compared to those days 14 and 42 (p < 0.001). No serious adverse event was observed during the study period. CONCLUSIONS: In this study, co-administration of chloroquine with primaquine was efficacious and well-tolerated with fast resolution of fever and high parasites clearance rate. However, the 7.4% failure is reported is alarming that warrant further monitoring of the therapeutic efficacy study of P. vivax.

The effect of single low-dose primaquine treatment for uncomplicated Plasmodium falciparum malaria on haemoglobin levels in Ethiopia: a longitudinal cohort study.

BACKGROUND: To interrupt residual malaria transmission and achieve successful elimination of Plasmodium falciparum in low-transmission settings, the World Health Organization (WHO) recommends the administration of a single dose of 0.25 mg/kg (or 15 mg/kg for adults) primaquine (PQ) combined with artemisinin-based combination therapy (ACT), without glucose-6-phosphate dehydrogenase (G6PD) testing. However, due to the risk of haemolysis in patients with G6PD deficiency (G6PDd), PQ use is uncommon. Thus, this study aimed to assess the safety of a single low dose of PQ administered to patients with G6PD deficiency. METHODS: An observational cohort study was conducted with patients treated for uncomplicated P. falciparum malaria with either single-dose PQ (0.25 mg/kg) (SLD PQ) + ACT or ACT alone. Microscopy-confirmed uncomplicated P. falciparum malaria patients visiting public health facilities in Arjo Didessa, Southwest Ethiopia, were enrolled in the study from September 2019 to November 2022. Patients with uncomplicated P. falciparum malaria were followed up for 28 days through clinical and laboratory diagnosis, such as measurements of G6PD levels and haemoglobin (Hb) concentrations. G6PD levels were measured by a quantiative CareSTART™ POCT S1 biosensor machine. Patient interviews were also conducted, and the type and frequency of clinical complaints were recorded. Hb data were taken on days (D) 7, 14, 21, and 28 following treatment with SLD-PQ + ACT or ACT alone. RESULTS: A total of 249 patients with uncomplicated P. falciparum malaria were enrolled in this study. Of these, 83 (33.3%) patients received ACT alone, and 166 (66.7%) received ACT combined with SLD-PQ treatment. The median age of the patients was 20 (IQR 28-15) years. G6PD deficiency was found in 17 (6.8%) patients, 14 males and 3 females. There were 6 (7.2%) and 11 (6.6%) phenotypic G6PD-deficient patients in the ACT alone and ACT + SLD-PQ arms, respectively. The mean Hb levels in patients treated with ACT + SLD-PQ were reduced by an average of 0.45 g/dl (95% CI = 0.39 to 0.52) in the posttreatment phase (D7) compared to a reduction of 0.30 g/dl (95% CI = 0.14 to - 0.47) in patients treated with ACT alone (P = 0.157). A greater mean Hb reduction was observed on day 7 in the G6PDd ACT + SLD-PQ group (- 0.60 g/dL) than in the G6PDd ACT alone group (- 0.48 g/dL); however, there was no statistically significant difference (P = 0.465). Overall, D14 losses were 0.10 g/dl (95% CI = - 0.00 to 0.20) and 0.05 g/dl (95% CI = - 0.123 to 0.22) in patients with and without SLD-PQ, respectively (P = 0.412). CONCLUSIONS: This study's findings indicate that using SLD-PQ in combination with ACT is safe for uncomplicated P. falciparum malaria regardless of the patient's G6PD status in Ethiopian settings. Caution should be taken in extrapolating this finding in other settings with diverse G6DP phenotypes.

Bioequivalence of a new coated 15 mg primaquine formulation for malaria elimination.

BACKGROUND: With only one 15 mg primaquine tablet registered by a stringent regulatory authority and marketed, more quality-assured primaquine is needed to meet the demands of malaria elimination. METHODS: A classic, two sequence, crossover study, with a 10-day wash out period, of 15 mg of IPCA-produced test primaquine tablets and 15 mg of Sanofi reference primaquine tablets was conducted. Healthy volunteers, aged 18-45 years, without glucose-6-phosphate dehydrogenase deficiency, a baseline haemoglobin ≥ 11 g/dL, creatinine clearance ≥ 70 mL/min/1.73 ms, and body mass index of 18.5-30 kg/m2 were randomized to either test or reference primaquine, administered on an empty stomach with 240 mL of water. Plasma primaquine and carboxyprimaquine concentrations were measured at baseline, then 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 h by liquid chromatography coupled to tandem mass spectrometry. Primaquine pharmacokinetic profiles were evaluated by non-compartmental analysis and bioequivalence concluded if the 90% confidence intervals (CI) of geometric mean (GM) ratios of test vs. reference formulation for the peak concentrations (Cmax) and area under the drug concentration-time (AUC0-t) were within 80.00 to 125.00%. RESULTS: 47 of 50 volunteers, median age 33 years, completed both dosing rounds and were included in the bioequivalence analysis. For primaquine, GM Cmax values for test and reference formulations were 62.12 vs. 59.63 ng/mL, resulting in a GM ratio (90% CI) of 104.17% (96.92-111.96%); the corresponding GM AUC0-t values were 596.56 vs. 564.09 ngxh/mL, for a GM ratio of 105.76% (99.76-112.08%). Intra-subject coefficient of variation was 20.99% for Cmax and 16.83% for AUC0-t. Median clearances and volumes of distribution were similar between the test and reference products: 24.6 vs. 25.2 L/h, 189.4 vs. 191.0 L, whilst the median half-lives were the same, 5.2 h. CONCLUSION: IPCA primaquine was bioequivalent to the Sanofi primaquine. This opens the door to prequalification, registration in malaria endemic countries, and programmatic use for malaria elimination. Trial registration The trial registration reference is ISRCTN 54640699.

Effectiveness, Safety, and Acceptability of Primaquine Mass Drug Administration in Low-Endemicity Areas in Southern Thailand: Proof-of-Concept Study.

BACKGROUND: A challenge in achieving the malaria-elimination target in the Greater Mekong Subregion, including Thailand, is the predominance of Plasmodium vivax malaria, which has shown extreme resilience to control measures. OBJECTIVE: This proof-of-concept study aimed to provide evidence for implementing primaquine mass drug administration (pMDA) as a strategy for P. vivax elimination in low-endemicity settings. METHODS: The study employed a mixed-methods trial to thoroughly evaluate the effectiveness, safety, acceptability, and community engagement of pMDA. The quantitative part was designed as a 2-period cluster-crossover randomized controlled trial. The intervention was pMDA augmented to the national prevention and control standards with directly observed treatment (DOT) by village health volunteers. The qualitative part employed in-depth interviews and brainstorming discussions. The study involved 7 clusters in 2 districts of 2 southern provinces in Thailand with persistently low P. vivax transmission. In the quantitative part, 5 cross-sectional blood surveys were conducted in both the pMDA and control groups before and 3 months after pMDA. The effectiveness of pMDA was determined by comparing the proportions of P. vivax infections per 1000 population between the 2 groups, with a multilevel zero-inflated negative binomial model adjusted for cluster and time as covariates and the interaction. The safety data comprised adverse events after drug administration. Thematic content analysis was used to assess the acceptability and engagement of stakeholders. RESULTS: In the pre-pMDA period, the proportions of P. vivax infections in the pMDA (n=1536) and control (n=1577) groups were 13.0 (95% CI 8.2-20.4) and 12.0 (95% CI 7.5-19.1), respectively. At month 3 post-pMDA, these proportions in the pMDA (n=1430) and control (n=1420) groups were 8.4 (95% CI 4.6-15.1) and 5.6 (95% CI 2.6-11.5), respectively. No statistically significant differences were found between the groups. The number of malaria cases reduced in all clusters in both groups, and thus, the impact of pMDA was inconclusive. There were no major safety concerns. Acceptance among the study participants and public health care providers at local and national levels was high, and they believed that pMDA had boosted awareness in the community. CONCLUSIONS: pMDA was associated with high adherence, safety, and tolerability, but it may not significantly impact P. vivax transmission. As this was a proof-of-concept study, we decided not to scale up the intervention with larger clusters and samples. An alternative approach involving a targeted primaquine treatment strategy with primaquine and DOT is currently being implemented. We experienced success regarding effective health care workforces at point-of-care centers, effective collaborations in the community, and commitment from authorities at local and national levels. Our efforts boosted the acceptability of the malaria-elimination initiative. Community engagement is recommended to achieve elimination targets. TRIAL REGISTRATION: Thai Clinical Trials Registry TCTR20190806004; https://www.thaiclinicaltrials.org/show/TCTR20190806004.

Optimal balance of benefit versus risk for tafenoquine in the treatment of Plasmodium vivax malaria.

A single 300 mg dose of tafenoquine (an 8-aminoquinoline), in combination with a standard 3-day course of chloroquine, is approved in several countries for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged ≥ 16 years. Despite this, questions have arisen on the optimal dose of tafenoquine. Before the availability of tafenoquine, a 3-day course of chloroquine in combination with the 8-aminoquinoline primaquine was the only effective radical cure for vivax malaria. The World Health Organization (WHO)-recommended standard regimen is 14 days of primaquine 0.25 mg/kg/day or 7 days of primaquine 0.5 mg/kg/day in most regions, or 14 days of primaquine 0.5 mg/kg/day in East Asia and Oceania, however the long treatment courses of 7 or 14 days may result in poor adherence and, therefore, low treatment efficacy. A single dose of tafenoquine 300 mg in combination with a 3-day course of chloroquine is an important advancement for the radical cure of vivax malaria in patients without glucose-6-phosphate dehydrogenase (G6PD) deficiency, as the use of a single-dose treatment will improve adherence. Selection of a single 300 mg dose of tafenoquine for the radical cure of P. vivax malaria was based on collective efficacy and safety data from 33 studies involving more than 4000 trial participants who received tafenoquine, including over 800 subjects who received the 300 mg single dose. The safety profile of single-dose tafenoquine 300 mg is similar to that of standard-dosage primaquine 0.25 mg/kg/day for 14 days. Both primaquine and tafenoquine can cause acute haemolytic anaemia in individuals with G6PD deficiency; severe haemolysis can lead to anaemia, kidney damage, and, in some cases, death. Therefore, relapse prevention using an 8-aminoquinoline must be balanced with the need to avoid clinical haemolysis associated with G6PD deficiency. To minimize this risk, the WHO recommends G6PD testing for all individuals before the administration of curative doses of 8-aminoquinolines. In this article, the authors review key efficacy and safety data from the pivotal trials of tafenoquine and argue that the currently approved dose represents a favourable benefit-risk profile.

Population pharmacokinetics of primaquine and its metabolites in African males.

BACKGROUND: Primaquine (PQ) is the prototype 8-aminoquinoline drug, a class which targets gametocytes and hypnozoites. The World Health Organization (WHO) recommends adding a single low dose of primaquine to the standard artemisinin-based combination therapy (ACT) in order to block malaria transmission in regions with low malaria transmission. However, the haemolytic toxicity is a major adverse outcome of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient subjects. This study aimed to characterize the pharmacokinetic properties of primaquine and its major metabolites in G6PD-deficient subjects. METHODS: A single low-dose of primaquine (0.4-0.5 mg/kg) was administered in twenty-eight African males. Venous and capillary plasma were sampled up to 24 h after the drug administration. Haemoglobin levels were observed up to 28 days after drug administration. Only PQ, carboxy-primaquine (CPQ), and primaquine carbamoyl-glucuronide (PQCG) were present in plasma samples and measured using liquid chromatography mass spectrometry. Drug and metabolites' pharmacokinetic properties were investigated using nonlinear mixed-effects modelling. RESULTS: Population pharmacokinetic properties of PQ, CPQ, and PQCG can be described by one-compartment disposition kinetics with a transit-absorption model. Body weight was implemented as an allometric function on the clearance and volume parameters for all compounds. None of the covariates significantly affected the pharmacokinetic parameters. No significant correlations were detected between the exposures of the measured compounds and the change in haemoglobin or methaemoglobin levels. There was no significant haemoglobin drop in the G6PD-deficient patients after administration of a single low dose of PQ. CONCLUSIONS: A single low-dose of PQ was haematologically safe in this population of G6PD-normal and G6PD-deficient African males without malaria. Trial registration NCT02535767.

Population pharmacokinetic modelling of primaquine exposures in lactating women and breastfed infants.

Current guidelines advise against primaquine treatment for breastfeeding mothers to avoid the potential for haemolysis in infants with G6PD deficiency. To predict the haemolytic risk, the amount of drug received from the breast milk and the resulting infant drug exposure need to be characterised. Here, we develop a pharmacokinetic model to describe the drug concentrations in breastfeeding women using venous, capillary, and breast milk data. A mother-to-infant model is developed to mimic the infant feeding pattern and used to predict their drug exposures. Primaquine and carboxyprimaquine exposures in infants are <1% of the exposure in mothers. Therefore, even in infants with the most severe G6PD deficiency variants, it is highly unlikely that standard doses of primaquine (0.25-1 mg base/kg once daily given to the mother for 1-14 days) would cause significant haemolysis. After the neonatal period, primaquine should not be restricted for breastfeeding women (Clinical Trials Registration: NCT01780753).

Artemether-lumefantrine with or without single-dose primaquine and sulfadoxine-pyrimethamine plus amodiaquine with or without single-dose tafenoquine to reduce Plasmodium falciparum transmission: a phase 2, single-blind, randomised clinical trial in Ouelessebougou, Mali.

BACKGROUND: Artemether-lumefantrine is widely used for uncomplicated Plasmodium falciparum malaria; sulfadoxine-pyrimethamine plus amodiaquine is used for seasonal malaria chemoprevention. We aimed to determine the efficacy of artemether-lumefantrine with and without primaquine and sulfadoxine-pyrimethamine plus amodiaquine with and without tafenoquine for reducing gametocyte carriage and transmission to mosquitoes. METHODS: In this phase 2, single-blind, randomised clinical trial conducted in Ouelessebougou, Mali, asymptomatic individuals aged 10-50 years with P falciparum gametocytaemia were recruited from the community and randomly assigned (1:1:1:1) to receive either artemether-lumefantrine, artemether-lumefantrine with a single dose of 0·25 mg/kg primaquine, sulfadoxine-pyrimethamine plus amodiaquine, or sulfadoxine-pyrimethamine plus amodiaquine with a single dose of 1·66 mg/kg tafenoquine. All trial staff other than the pharmacist were masked to group allocation. Participants were not masked to group allocation. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. The primary outcome was the median within-person percent change in mosquito infection rate in infectious individuals from baseline to day 2 (artemether-lumefantrine groups) or day 7 (sulfadoxine-pyrimethamine plus amodiaquine groups) after treatment, assessed by direct membrane feeding assay. All participants who received any trial drug were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT05081089. FINDINGS: Between Oct 13 and Dec 16, 2021, 1290 individuals were screened and 80 were enrolled and randomly assigned to one of the four treatment groups (20 per group). The median age of participants was 13 (IQR 11-20); 37 (46%) of 80 participants were female and 43 (54%) were male. In individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 2 days after treatment was 100·0% (IQR 100·0-100·0; n=19; p=0·0011) with artemether-lumefantrine and 100·0% (100·0-100·0; n=19; p=0·0001) with artemether-lumefantrine with primaquine. Only two individuals who were infectious at baseline infected mosquitoes on day 2 after artemether-lumefantrine and none at day 5. By contrast, the median percentage reduction in mosquito infection rate 7 days after treatment was 63·6% (IQR 0·0-100·0; n=20; p=0·013) with sulfadoxine-pyrimethamine plus amodiaquine and 100% (100·0-100·0; n=19; p<0·0001) with sulfadoxine-pyrimethamine plus amodiaquine with tafenoquine. No grade 3-4 or serious adverse events occurred. INTERPRETATION: These data support the effectiveness of artemether-lumefantrine alone for preventing nearly all mosquito infections. By contrast, there was considerable post-treatment transmission after sulfadoxine-pyrimethamine plus amodiaquine; therefore, the addition of a transmission-blocking drug might be beneficial in maximising its community impact. FUNDING: Bill & Melinda Gates Foundation.

Operational effectiveness of tafenoquine and primaquine for the prevention of Plasmodium vivax recurrence in Brazil: a retrospective observational study.

BACKGROUND: Prevention of Plasmodium vivax malaria recurrence is essential for malaria elimination in Brazil. We evaluated the real-world effectiveness of an updated treatment algorithm for P vivax radical cure in the Brazilian Amazon. METHODS: In this non-interventional observational study, we used retrospective data from the implementation of a P vivax treatment algorithm at 43 health facilities in Manaus and Porto Velho, Brazil. The treatment algorithm consisted of chloroquine (25 mg/kg over 3 days) and point-of-care quantitative glucose-6-phosphate dehydrogenase (G6PD) testing followed by single-dose tafenoquine 300 mg (G6PD normal, aged ≥16 years, not pregnant and not breastfeeding), 7-day primaquine 0·5 mg/kg per day (G6PD intermediate or normal, aged ≥6 months, not pregnant, and not breastfeeding or breastfeeding for >1 month), or primaquine 0·75 mg/kg per week for 8 weeks (G6PD deficient, aged ≥6 months, not pregnant, and not breastfeeding or breastfeeding for >1 month). P vivax recurrences were identified from probabilistic linkage of routine patient records from the Brazilian malaria epidemiological surveillance system. Recurrence-free effectiveness at day 90 and day 180 was estimated using Kaplan-Meier analysis and hazard ratios (HRs) by multivariate analysis. This clinical trial is registered with ClinicalTrials.gov, NCT05096702, and is completed. FINDINGS: Records from Sept 9, 2021, to Aug 31, 2022, included 5554 patients with P vivax malaria. In all treated patients of any age and any G6PD status, recurrence-free effectiveness at day 180 was 75·8% (95% CI 74·0-77·6) with tafenoquine, 73·4% (71·9-75·0) with 7-day primaquine, and 82·1% (77·7-86·8) with weekly primaquine. In patients aged at least 16 years who were G6PD normal, recurrence-free effectiveness until day 90 was 88·6% (95% CI 87·2-89·9) in those who were treated with tafenoquine (n=2134) and 83·5% (79·8-87·4) in those treated with 7-day primaquine (n=370); after adjustment for confounding factors, the HR for recurrence following tafenoquine versus 7-day primaquine was 0·65 (95% CI 0·49-0·86; p=0·0031), with similar outcomes between the two treatments at day 180 (log-rank p=0·82). Over 180 days, median time to recurrence in patients aged at least 16 years who were G6PD normal was 92 days (IQR 76-120) in those treated with tafenoquine and 68 days (52-94) in those treated with 7-day primaquine. INTERPRETATION: In this real-world setting, single-dose tafenoquine was more effective at preventing P vivax recurrence in patients aged at least 16 years who were G6PD normal compared with 7-day primaquine at day 90, while overall efficacy at 180 days was similar. The public health benefits of the P vivax radical cure treatment algorithm incorporating G6PD quantitative testing and tafenoquine support its implementation in Brazil and potentially across South America. FUNDING: Brazilian Ministry of Health, Municipal and State Health Secretariats; Fiocruz; Medicines for Malaria Venture; Bill & Melinda Gates Foundation; Newcrest Mining; and the UK Government. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

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.

¿Cuánta primaquina es necesaria para erradicar los hipnozoitos de Plasmodium vivax? / How much primaquine is needed to eradicate Plasmodium vivax hypnozoites?

Introducción. La terapia con primaquina es, hasta el momento actual, la única disponible para el tratamiento radical de la malaria por Plasmodium vivax. La dosis óptima de primaquina para evitar las recaídas de P. vivax es un tema aún en discusión. Casos clínicos. Se describen 3 casos de malaria por P. vivax de diferentes áreas geográficas en los que se constató tolerancia a las dosis convencionales de primaquina y en algún caso incluso a dosis elevadas. Comentario. La tolerancia de P. vivax a la primaquina es un problema creciente en la práctica diaria por lo que es necesario reevaluar la dosis necesaria para erradicar los hipnozoitos intrahepáticos de P. vivax (AU)

Introduction. Primaquine is now the only drug available to eradicate Plasmodium vivax malaria. The optimal dose of primaquine to prevent relapses of P. vivax remains under discussion. Clinical cases. We describe three cases of P. vivax malaria from different geographical areas, in which a tolerance to standard doses of primaquine and, in some cases, to much higher doses has been observed. Comments. P. vivax tolerance to primaquine is an emerging problem in daily practice. Reassessment of the primaquine dose required to eradicate P. vivax intrahepatic hypnozoites is needed (AU)

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

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

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