SciCombinator

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Concept: Glucose-6-phosphate dehydrogenase deficiency

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Malaria, caused by parasites of the genus Plasmodium, leads to over half a million deaths per year, 90% of which are caused by Plasmodium falciparum. P. vivax usually causes milder forms of malaria; however, P. vivax can remain dormant in the livers of infected patients for weeks or years before re-emerging in a new bout of the disease. The only drugs available that target all stages of the parasite can lead to severe side effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; hence, there is an urgent need to develop new drugs active against blood and liver stages of the parasite. Different groups have demonstrated that triclosan, a common antibacterial agent, targets the Plasmodium liver enzyme enoyl reductase. Here, we provide 4 independent lines of evidence demonstrating that triclosan specifically targets both wild-type and pyrimethamine-resistant P. falciparum and P. vivax dihydrofolate reductases, classic targets for the blood stage of the parasite. This makes triclosan an exciting candidate for further development as a dual specificity antimalarial, which could target both liver and blood stages of the parasite.

Concepts: Immune system, Malaria, Plasmodium falciparum, Plasmodium, Plasmodium vivax, Quinine, Liver, Glucose-6-phosphate dehydrogenase deficiency

177

Primaquine is a key drug for malaria elimination. In addition to being the only drug active against the dormant relapsing forms of Plasmodium vivax, primaquine is the sole effective treatment of infectious P. falciparum gametocytes, and may interrupt transmission and help contain the spread of artemisinin resistance. However, primaquine can trigger haemolysis in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd). Poor information is available about the distribution of individuals at risk of primaquine-induced haemolysis. We present a continuous evidence-based prevalence map of G6PDd and estimates of affected populations, together with a national index of relative haemolytic risk.

Concepts: Malaria, Plasmodium falciparum, Plasmodium, Plasmodium vivax, Hemolytic anemia, Hemolysis, Glucose-6-phosphate dehydrogenase deficiency, Primaquine

169

In areas of low malaria transmission, it is currently recommended that a single dose of primaquine (0.75 mg base/kg; 45 mg adult dose) be added to artemisinin combination treatment (ACT) in acute falciparum malaria to block malaria transmission. Review of studies of transmission-blocking activity based on the infectivity of patients or volunteers to anopheline mosquitoes, and of haemolytic toxicity in glucose 6-dehydrogenase (G6PD) deficient subjects, suggests that a lower primaquine dose (0.25 mg base/kg) would be safer and equally effective. This lower dose could be deployed together with ACTs without G6PD testing wherever use of a specific gametocytocide is indicated.

Concepts: Malaria, Plasmodium falciparum, Plasmodium, Plasmodium vivax, Anopheles, Apicomplexa, Glucose-6-phosphate dehydrogenase deficiency, Artemisinin

169

After sixty years of continuous use, primaquine remains the only therapy licensed for arresting transmission and relapse of malaria. The US Army developed primaquine for soldiers in a wartime crisis setting. Dosing strategies suited to that narrow population were adopted without modification or validation for the broader population of humans exposed to risk of malaria. The poor suitability of these strategies in populations exhibiting greater vulnerability to hemolytic toxicity among glucose-6-phosphate dehydrogenase deficient patients has not been addressed. Primaquine requires chemotherapeutic reinvention delivering less threatening doses by leveraging unexplored co-drug synergies.

Concepts: Malaria, Population, Glucose-6-phosphate dehydrogenase deficiency, Dose, World population, United States Army, Military, Primaquine

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BACKGROUND: Indonesia has set 2030 as its deadline for elimination of malaria transmission in the archipelago, with regional deadlines established according to present levels of malaria endemicity and strength of health infrastructure. The Municipality of Sabang which historically had one of the highest levels of malaria in Aceh province aims to achieve elimination by the end of 2013. METHOD: From 2008 to 2010, baseline surveys of malaria interventions, mapping of all confirmed malaria cases, categorization of residual foci of malaria transmission and vector surveys were conducted in Sabang, Aceh, a pilot district for malaria elimination in Indonesia. To inform future elimination efforts, mass screening from the focal areas to measure prevalence of malaria with both microscopy and PCR was conducted. G6PD deficiency prevalence was also measured.Result: Despite its small size, a diverse mixture of potential malaria vectors were documented in Sabang, including Anopheles sundaicus, Anopheles minimus, Anopheles aconitus and Anopheles dirus. Over a two-year span, the number of sub-villages with ongoing malaria transmission reduced from 61 to 43. Coverage of malaria diagnosis and treatment, IRS, and LLINs was over 80%. Screening of 16,229 residents detected 19 positive people, for a point prevalence of 0.12%. Of the 19 positive cases, three symptomatic infections and five asymptomatic infections were detected with microscopy and 11 asymptomatic infections were detected with PCR. Of the 19 cases, seven were infected with Plasmodium falciparum, 11 were infected with Plasmodium vivax, and one subject was infected with both species. Analysis of the 937 blood samples for G6PD deficiency revealed two subjects (0.2%) with deficient G6PD. DISCUSSION: The interventions carried out by the government of Sabang have dramatically reduced the burden of malaria over the past seven years. The first phase, carried out between 2005 and 2007, included improved malaria diagnosis, introduction of ACT for treatment, and scale-up of coverage of IRS and LLINs. The second phase, from 2008 to 2010, was initiated to eliminate the persist residual transmission of malaria, consisted of development of a malaria database to ensure rapid case reporting and investigation, stratification of malaria foci to guide interventions, and active case detection to hunt symptomatic and asymptomatic malaria carriers.

Concepts: Malaria, Plasmodium falciparum, Plasmodium, Plasmodium vivax, Anopheles, Apicomplexa, Glucose-6-phosphate dehydrogenase deficiency, Aceh

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Background. Artemisinin-based combination therapy (ACT) is very effective in clearing asexual stages of malaria and reduces gametocytemia, but may not affect mature gametocytes. Primaquine is the only commercially available drug that eliminates mature gametocytes.Methods and objectives. We conducted a two-arm open-label randomized controlled trial to evaluate the efficacy of single dose primaquine (0.75 mg/kg) following treatment with dihydroartemisinin-piperaquine on P. falciparum’s gametocytemia, in Indonesia. Patients with symptomatic uncomplicated falciparum malaria, normal glucose-6-phosphate dehydrogenase (G6PD) enzyme levels, aged ≥5 years and hemoglobin levels ≥8 g/dL were assigned by computerized-generating sequence to receive either a standard 3-day course dihydroartemisinin-piperaquine alone (n=178) or combined with a single dose of primaquine on Day-3 (n=171). Patients were seen on days 1, 2, 3, 7 and then weekly for 42 days to assess the presence of gametocytes and asexual parasites by microscopy. Survival analysis was stratified by the presence of gametocytes on Day-3.Results. DHP prevented development of gametocytes in 277 patients without gametocytes on Day-3. In the gametocytemic patients (n=72), primaquine was associated with faster clearance of gametocytes (HR=2.42, 95% CI 1.39- 4.19, P= 0.002) and reduced gametocyte densities (geometric mean area-under-the-curve 157 vs 330, P= 0.018). The Day-42 cure rate of asexual stages in the DHP-PQ and DHP-alone arms were: PCR-unadjusted: 98.7% vs 99.4% respectively; PCR-adjusted:100% for both. Primaquine was well tolerated.Conclusion. Addition of a single dose of primaquine shortens the infectivity period of DHP treated patients with acute uncomplicated malaria and should be considered in low transmission regions that aim to control and ultimately eliminate falciparum malaria.Clinical Trial Registration. NCT01392014.

Concepts: Pharmacology, Malaria, Plasmodium falciparum, Plasmodium, Randomized controlled trial, Plasmodium vivax, Glucose-6-phosphate dehydrogenase deficiency, Artemisinin

25

Acute hemolytic anemia (AHA) due to glucose 6-phosphate dehydrogenase (G6PD) deficiency has rarely been recognized as a contributor to the development of frostbite. We discuss a case of frostbite in a 32-year-old male Marine with G6PD deficiency during military training on Mount McKinley in Alaska, which eventually led to a permanent disability. In this report, the pathophysiology of G6PD deficiency, the effects of hemolytic anemia, and factors that contribute to frostbite will be discussed, as well as the clinical findings, treatment course, and the outcome of this case. The patient was evacuated and admitted to Alaska Regional Hospital. He was treated for fourth-degree frostbite, ultimately resulting in the complete or partial amputation of all toes. Although it cannot be proved that AHA occurred in this patient, this case potentially adds frostbite to the list of rare but possible clinical presentations of G6PD deficiency.

Concepts: Hemolytic anemia, Hemolysis, Hematology, Glucose-6-phosphate dehydrogenase deficiency, Pentose phosphate pathway, Glucose-6-phosphate dehydrogenase, Primaquine, Haemolytic anaemias

7

In spite of significant progress towards malaria control and elimination achieved in South America in the 2000s, this mosquito-transmitted tropical disease remains an important public health concern in the region. Most malaria cases in South America come from Amazon rain forest areas in northern countries, where more than half of malaria is caused by Plasmodium vivax, while Plasmodium falciparum malaria incidence has decreased in recent years. This review discusses current malaria data, policies and challenges in four South American Amazon countries: Brazil, Colombia, Peru and the Bolivarian Republic of Venezuela. Challenges to continuing efforts to further decrease malaria incidence in this region include: a significant increase in malaria cases in recent years in Venezuela, evidence of submicroscopic and asymptomatic infections, peri-urban malaria, gold mining-related malaria, malaria in pregnancy, glucose-6-phosphate dehydrogenase (G6PD) deficiency and primaquine use, and possible under-detection of Plasmodium malariae. Some of these challenges underscore the need to implement appropriate tools and procedures in specific regions, such as a field-compatible molecular malaria test, a P. malariae-specific test, malaria diagnosis and appropriate treatment as part of regular antenatal care visits, G6PD test before primaquine administration for P. vivax cases (with weekly primaquine regimen for G6PD deficient individuals), single low dose of primaquine for P. falciparum malaria in Colombia, and national and regional efforts to contain malaria spread in Venezuela urgently needed especially in mining areas. Joint efforts and commitment towards malaria control and elimination should be strategized based on examples of successful regional malaria fighting initiatives, such as PAMAFRO and RAVREDA/AMI.

Concepts: Malaria, Plasmodium falciparum, Plasmodium, Plasmodium vivax, Glucose-6-phosphate dehydrogenase deficiency, Brazil, South America, Amazon Rainforest

7

Resistance to the artemisinin derivatives in Plasmodium falciparum has emerged in Cambodia and is now spreading throughout South-East Asia. The rapid elimination of P. falciparum seems to be the only viable option to avoid a public health disaster but this is difficult because even in low transmission settings many residents have asymptomatic parasitaemias.

Concepts: Epidemiology, Malaria, Plasmodium falciparum, Plasmodium, Plasmodium vivax, Anopheles, Glucose-6-phosphate dehydrogenase deficiency, Artemisinin

6

Primaquine is the only antimalarial drug available to clinicians for the treatment of relapsing forms of malaria. Primaquine development and usage dates back to the 1940s and has been administered to millions of individuals to treat and eliminate malaria infections. Primaquine therapy is not without disadvantages, however, as it can cause life threating hemolysis in humans with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In addition, the efficacy of primaquine against relapsing malaria was recently linked to CYP 2D6 mediated activation to an active metabolite, the structure of which has escaped definitive identification for over 75years. CYP 2D6 is highly polymorphic among various human populations adding further complexity to a comprehensive understanding of primaquine pharmacology. This review aims to discuss primaquine pharmacology in the context of state of the art understanding of CYP 2D6 mediated 8-aminoquinoline metabolic activation, and shed light on the current knowledge gaps of 8-aminoquinoline mechanistic understanding against relapsing malaria.

Concepts: Pharmacology, Malaria, Quinine, Glucose-6-phosphate dehydrogenase deficiency, Pentose phosphate pathway, Primaquine