1. Modelling primaquine-induced haemolysis in G6PD deficiency
- Author
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James A Watson, Sim Kheng, Nicholas J. White, Didier Menard, Walter Rj Taylor, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Mahidol Oxford Tropical Medicine Research Unit, and University of Oxford [Oxford]-Mahidol University [Bangkok]
- Subjects
MESH: Cell Death ,Male ,Pediatrics ,Primaquine ,Erythrocytes ,Plasmodium vivax ,global health ,in silico modelling ,radical cure ,computational biology ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Recurrence ,G6PD deficiency ,Epidemiology ,Global health ,030212 general & internal medicine ,Biology (General) ,education.field_of_study ,biology ,Cell Death ,MESH: Erythrocytes ,General Neuroscience ,systems biology ,General Medicine ,MESH: Primaquine ,Haemolysis ,MESH: Hemolysis ,MESH: Plasmodium vivax ,3. Good health ,MESH: Glucosephosphate Dehydrogenase Deficiency ,Parasitic disease ,Medicine ,epidemiology ,Female ,medicine.drug ,Research Article ,Computational and Systems Biology ,Human ,medicine.medical_specialty ,Anemia, Hemolytic ,primaquine ,QH301-705.5 ,MESH: Bayes Theorem ,Science ,030231 tropical medicine ,Population ,Hemolysis ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Antimalarials ,parasitic diseases ,medicine ,Malaria, Vivax ,Humans ,education ,MESH: Anemia, Hemolytic ,MESH: Humans ,Models, Statistical ,General Immunology and Microbiology ,business.industry ,MESH: Malaria, Vivax ,Bayes Theorem ,medicine.disease ,biology.organism_classification ,MESH: Antimalarials ,MESH: Male ,MESH: Recurrence ,Glucosephosphate Dehydrogenase Deficiency ,Epidemiology and Global Health ,Immunology ,business ,MESH: Female ,MESH: Models, Statistical ,Malaria - Abstract
Primaquine is the only drug available to prevent relapse in vivax malaria. The main adverse effect of primaquine is erythrocyte age and dose-dependent acute haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd). As testing for G6PDd is often unavailable, this limits the use of primaquine for radical cure. A compartmental model of the dynamics of red blood cell production and destruction was designed to characterise primaquine-induced haemolysis using a holistic Bayesian analysis of all published data and was used to predict a safer alternative to the currently recommended once weekly 0.75 mg/kg regimen for G6PDd. The model suggests that a step-wise increase in daily administered primaquine dose would be relatively safe in G6PDd. If this is confirmed, then were this regimen to be recommended for radical cure patients would not require testing for G6PDd in areas where G6PDd Viangchan or milder variants are prevalent. DOI: http://dx.doi.org/10.7554/eLife.23061.001, eLife digest Malaria is the most important parasitic disease that affects humans. Over half of the malaria cases in Asia and South America are caused by a species of malaria parasite called Plasmodium vivax (known as vivax malaria). This form of malaria results in repeated illness because dormant parasites in the liver wake at intervals to infect the blood. The only available drug that can stop these relapses is a drug called primaquine, which was developed seventy years ago. Unfortunately, primaquine causes dangerous side effects in certain individuals who are deficient in an enzyme called G6PD, which helps defend red blood cells against stresses. Primaquine damages these cells so that they burst, leading to anaemia. This is a major problem because G6PD deficiency is common in regions where malaria is present: in some areas up to 30% of the population may be G6PD deficient. Since G6PD testing is not widely available, doctors often avoid prescribing primaquine to treat malaria, which results in more cases of disease relapse. Failing to prevent vivax relapses causes extensive illness and hinders efforts to eliminate malaria. Is there a way to give this drug to patients that would be safer for people with G6PD deficiency? Primaquine destroys older rather than younger red blood cells. Watson et al. used mathematical modelling to see whether it is possible to develop a primaquine treatment strategy that would allow a gradual destruction of older red blood cells in individuals with G6PD deficiency, which would be safer. The mathematical model incorporates data from previous studies in malaria patients and healthy volunteers with G6PD deficiency and combines this with knowledge of how red blood cells are produced and destroyed. Watson et al. predicted that giving primaquine over 20 days in a steadily increasing dose was safer than current recommendations. Mathematical models are simplifications of real world processes. The only way to test these findings properly will be to run a clinical trial that gives healthy volunteers who are G6PD deficient a course of primaquine treatment with a steadily increasing dose. DOI: http://dx.doi.org/10.7554/eLife.23061.002
- Published
- 2017
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