scholarly journals The risk of adverse clinical outcomes following treatment of Plasmodium vivax malaria with and without primaquine in Papua, Indonesia

2020 ◽  
Vol 14 (11) ◽  
pp. e0008838
Author(s):  
Kamala Thriemer ◽  
Jeanne-Rini Poespoprodjo ◽  
Enny Kenangalem ◽  
Nicholas M. Douglas ◽  
Paulus Sugiarto ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
G6pd Deficiency ◽  
Cox Regression ◽  
Artemisinin Combination Therapy ◽  
Morbidity And Mortality ◽  
Radical Cure ◽  
Drug Induced ◽  
Routine Administration ◽  
Plasmodium Vivax Malaria ◽  
Glucose 6 Phosphate Dehydrogenase

The widespread use of primaquine (PQ) radical cure for P. vivax, is constrained by concerns over its safety. We used routinely collected patient data to compare the overall morbidity and mortality in patients treated with and without PQ without prior testing of Glucose-6-Phosphate-Dehydrogenase (G6PD) deficiency in Papua, Indonesia, where there is a low prevalence of G6PD deficiency. Records were collated from patients older than 1 year, with P. vivax infection, who were treated with an artemisinin combination therapy (ACT). The risks of re-presentation, hospitalization, major fall in haemoglobin and death within 30 days were quantified and compared between patients treated with and without PQ using a Cox regression model. In total 26,216 patients with P. vivax malaria presented to the hospital with malaria during the study period. Overall 27.56% (95% Confidence Interval (95%CI): 26.96–28.16) of 21,344 patients treated with PQ re-presented with any illness within 30 days and 1.69% (1.51–1.88) required admission to hospital. The corresponding risks were higher in the 4,872 patients not treated with PQ; Adjusted Hazard Ratio (AHR) = 0.84 (0.79–0.91; p<0.001) and 0.54 (0.41–0.70; p<0.001) respectively. By day 30, 14.15% (12.45–16.05) of patients who had received PQ had a fall in haemoglobin (Hb) below 7g/dl compared to 20.43% (16.67–24.89) of patients treated without PQ; AHR = 0.66 (0.45–0.97; p = 0.033). A total of 75 (0.3%) patients died within 30 days of treatment with a mortality risk of 0.27% (0.21–0.35) in patients treated with PQ, compared to 0.38% (0.24–0.60) without PQ; AHR = 0.79 (0.43–1.45; p = 0.448). In Papua, Indonesia routine administration of PQ radical cure without prior G6PD testing, was associated with lower risk of all cause hospitalization and other serious adverse clinical outcomes. In areas where G6PD testing is not available or cannot be delivered reliably, the risks of drug induced haemolysis should be balanced against the potential benefits of reducing recurrent P. vivax malaria and its associated morbidity and mortality.

scholarly journals Protective effect of Mediterranean-type glucose-6-phosphate dehydrogenase deficiency against Plasmodium vivax malaria

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Ghulam R Awab ◽  
Fahima Aaram ◽  
Natsuda Jamornthanyawat ◽  
Kanokon Suwannasin ◽  
Watcharee Pagornrat ◽  
...  
Keyword(s):  
Protective Effect ◽  
Plasmodium Vivax ◽  
G6pd Deficiency ◽  
Vivax Malaria ◽  
Malaria Incidence ◽  
Large Population ◽  
Credible Interval ◽  
Radical Cure ◽  
Plasmodium Vivax Malaria ◽  
Glucose 6 Phosphate Dehydrogenase

X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. The severe Mediterranean variant (G6PD Med) found across Europe and Asia is thought to confer protection against malaria, but its effect is unclear. We fitted a Bayesian statistical model to observed G6PD Med allele frequencies in 999 Pashtun patients presenting with acute Plasmodium vivax malaria and 1408 population controls. G6PD Med was associated with reductions in symptomatic P. vivax malaria incidence of 76% (95% credible interval [CI], 58–88) in hemizygous males and homozygous females combined and 55% (95% CI, 38–68) in heterozygous females. Unless there is very large population stratification within the Pashtun (confounding these results), the G6PD Med genotype confers a very large and gene-dose proportional protective effect against acute vivax malaria. The proportion of patients with vivax malaria at risk of haemolysis following 8-aminoquinoline radical cure is substantially overestimated by studies measuring G6PD deficiency prevalence in healthy subjects.

scholarly journals Molecular Epidemiology of G6PD Genotypes in Different Ethnic Groups Residing in Saharan and Sahelian Zones of Mauritania

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 931
Author(s):  
Oum Kelthoum Mamadou Djigo ◽  
Mohamed Salem Ould Ahmedou Salem ◽  
Sileye Mamadou Diallo ◽  
Mohamed Abdallahi Bollahi ◽  
Boushab Mohamed Boushab ◽  
...  
Keyword(s):  
G6pd Deficiency ◽  
African Ancestry ◽  
Population Based ◽  
Black African ◽  
Plasmodium Vivax Malaria ◽  
The Mediterranean ◽  
Linguistic Groups ◽  
Study Sites ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Genotype Screening

Plasmodium vivax malaria is endemic in Mauritania. Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency may develop acute hemolytic anemia when exposed to 8-aminoquinoline antimalarial drugs, which are indispensable for a complete cure. The prevalence of G6PD allelic variants was assessed in different ethno-linguistic groups present in Mauritania. A total of 996 blood samples (447 males and 549 females; 499 white Moors and 497 individuals of black African ancestry) were collected from febrile patients in 6 different study sites: Aleg, Atar, Kiffa, Kobeni, Nouakchott, and Rosso. The presence of the African-type G6PD A- (G202A, A376G, A542T, G680T, and T968C mutations) and the Mediterranean-type G6PD B- (C563T) variants was assessed by PCR followed by restriction fragment length polymorphism and/or DNA sequencing. The prevalence of African-type G6PD A- genotype was 3.6% (36/996), with 6.3% (28/447) of hemizygote (A-) males and 1.5% (8/549) of homozygous (A-A-) females. Forty of 549 (7.3%) women were heterozygous (AA-). The following genotypes were observed among hemizygous men and/or homozygous women: A376G/G202A (22/996; 2.2%), A376G/T968C Betica-Selma (12/996; 1.2%), and A376G/A542T Santamaria (2/996; 0.2%). The Mediterranean-type G6PD B- genotype was not observed. The prevalence rates of G6PD A- genotype in male (10/243; 4.1%) and heterozygous female (6/256; 2.3%) white Moors were lower (p < 0.05) than those of males (18/204; 8.8%) and heterozygous females (34/293; 11.6%) of black African ancestry. There were only a few homozygous women among both white Moors (3/256; 1.2%) and those of black African ancestry (5/293; 1.7%). The prevalence of G6PD deficiency in Mauritania was comparable to that of neighboring countries in the Maghreb. Because of the purportedly close ethnic ties between the Mauritanian white Moors and the peoples in the Maghreb, further investigations on the possible existence of the Mediterranean-type allele are required. Moreover, a surveillance system of G6PD phenotype and/or genotype screening is warranted to establish and monitor a population-based prevalence of G6PD deficiency.

scholarly journals The impact of using primaquine without prior G6PD testing: a case series describing the obstacles to the medical management of haemolysis

2019 ◽  
Vol 4 ◽  
pp. 25 ◽  
Author(s):  
Cindy S. Chu ◽  
Germana Bancone ◽  
Nay Lin Soe ◽  
Verena I. Carrara ◽  
Gornpan Gornsawun ◽  
...  
Keyword(s):  
Health Care Providers ◽  
G6pd Deficiency ◽  
Case Series ◽  
Radical Cure ◽  
Care Providers ◽  
Medical Treatments ◽  
Normal Individuals ◽  
High Index Of Suspicion ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
The Impact

Radical cure of Plasmodium vivax malaria in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals employs weekly primaquine dosing. This is the only recommended regimen for this patient sub-group. If national malaria programs mandate daily primaquine dosing (the recommended regimen for G6PD normal individuals), then G6PD testing before prescription is necessary to avoid iatrogenic haemolysis in G6PD deficient individuals. In this case series, two P. vivax infected patients with unknown G6PD status from two different countries were prescribed primaquine as per national malaria program guidelines. During treatment both patients presented to the clinic with symptoms of anaemia after taking primaquine incorrectly. The clinical management of the iatrogenic severe haemolysis that occurred in these patients demonstrates the various adverse effects primaquine can cause, that other common medical treatments also have haemolytic potential, and how the diagnosis of G6PD deficiency can be elusive during acute haemolysis. Health care providers should provide careful instructions about primaquine dosing, be watchful for haemolysis, and have a high index of suspicion for G6PD deficiency in the presence of haemolysis if the G6PD status is previously unknown.

scholarly journals Clinical spectrum and severity of hemolytic anemia in glucose 6-phosphate dehydrogenase–deficient children receiving dapsone

Blood ◽  
2012 ◽  
Vol 120 (20) ◽  
pp. 4123-4133 ◽  
Author(s):  
Allan Pamba ◽  
Naomi D. Richardson ◽  
Nick Carter ◽  
Stephan Duparc ◽  
Zul Premji ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Hemolytic Anemia ◽  
G6pd Deficiency ◽  
Case Reports ◽  
Drug Induced ◽  
Once Daily ◽  
Maximum Decrease ◽  
Life Threatening ◽  
The Mean ◽  
Glucose 6 Phosphate Dehydrogenase

AbstractDrug-induced acute hemolytic anemia led to the discovery of G6PD deficiency. However, most clinical data are from isolated case reports. In 2 clinical trials of antimalarial preparations containing dapsone (4,4′-diaminodiphenylsulfone; 2.5 mg/kg once daily for 3 days), 95 G6PD-deficient hemizygous boys, 24 G6PD-deficient homozygous girls, and 200 girls heterozygous for G6PD deficiency received this agent. In the first 2 groups, there was a maximum decrease in hemoglobin averaging −2.64 g/dL (range −6.70 to +0.30 g/dL), which was significantly greater than for the comparator group receiving artemether-lumefantrine (adjusted difference −1.46 g/dL; 95% confidence interval −1.76, −1.15). Hemoglobin concentrations were decreased by ≥ 40% versus pretreatment in 24/119 (20.2%) of the G6PD-deficient children; 13/119 (10.9%) required blood transfusion. In the heterozygous girls, the mean maximum decrease in hemoglobin was −1.83 g/dL (range +0.90 to −5.20 g/dL); 1 in 200 (0.5%) required blood transfusion. All children eventually recovered. All the G6PD-deficient children had the G6PD A− variant, ie, mutations V68M and N126D. Drug-induced acute hemolytic anemia in G6PD A− subjects can be life-threatening, depending on the nature and dosage of the drug trigger. Therefore, contrary to current perception, in clinical terms the A− type of G6PD deficiency cannot be regarded as mild. This study is registered at http://www.clinicaltrials.gov as NCT00344006 and NCT00371735.

scholarly journals The enzymopathy of G6PD deficiency in Jordan: a demographic and biochemical analysis

2018 ◽  
Vol 10 (1) ◽  
pp. 25-32
Author(s):  
Ahmed Al-Imam
Keyword(s):  
G6pd Deficiency ◽  
Liver Enzymes ◽  
Clinical Manifestations ◽  
University Hospital ◽  
Drug Induced ◽  
Mean Values ◽  
Significant Difference ◽  
Wbc Count ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Blood Grouping

Background: G6PD deficiency is an inherited X-linked recessive condition leading to insufficient levels of glucose-6-phosphate dehydrogenase, thus causing hemolytic anaemia under certain circumstances. Materials and Methods: Our study is explorative for cases admitted to Jordan University Hospital. The studied parameters include demographics, clinical manifestations, biochemical markers including Hb level, WBC count, liver enzymes, and blood grouping. Results: Most of the patients were admitted to the emergency unit (53.13%). Individuals who were Rh-positive represented 57.81%, while patients of AB blood group accounted for 75%. The mean values were 4.81 years (age), 29.06 hours (time-to-hospital admission), 38.10 degree Celsius (temperature), 6.11 gm/dl (Hb), 13242.19 (WBC count), 343.20 U/L (S. ALP), and 50.98 IU/L (S. ALT). There was no significant difference between males and females or between favism-induced versus drug-induced hemolytic episodes. AB and Rh positive blood groups are of a protective effect in relation to liver enzymes. Patients who were admitted to the hospital within 24 hours from having clinical manifestations had a better prognosis. Conclusion: This study is the first inferential research on G6PD deficiency from the Middle East to explore cases from one of the largest healthcare centres in Jordan. The role of blood grouping should be investigated prospectively.

scholarly journals Implementing Radical Cure Diagnostics for Malaria: User Perspectives on G6PD Testing in Bangladesh

2020 ◽  
Author(s):  
Nora Engel ◽  
Cristian Ghergu ◽  
Mohammad Abdul Matin ◽  
Mohammad Golam Kibria ◽  
Kamala Thriemer ◽  
...  
Keyword(s):  
Health Care Providers ◽  
G6pd Deficiency ◽  
New Technologies ◽  
Routine Practice ◽  
Radical Cure ◽  
Care Providers ◽  
Structured Interviews ◽  
Drug Induced ◽  
User Perspectives ◽  
The Impact

Abstract Background: The radical cure of Plasmodium vivax requires treatment with an 8-aminoquinoline drug, such as primaquine and tafenoquine, to clear the liver of parasites which can reactivate to cause relapsing infections. Safe treatment regimens require prior screening of patients for glucose-6-phosphate dehydrogenase (G6PD) deficiency to avoid potential life-threatening drug induced hemolysis. Testing is rarely available in malaria endemic countries, but will be needed to support routine use of radical cure. This study investigates end-user perspectives in Bangladesh on the introduction of a quantitative G6PD test (SD Biosensor STANDARD™ G6PD analyser) to support malaria elimination.Methods: The perspectives of users on the SD Biosensor test were analysed using semi-structured interviews and focus group discussions with health care providers and malaria programme officers in Bangladesh. Key emerging themes regarding the feasibility of introducing this test into routine practice, including perceived barriers, were analysed.Results: In total 63 participants were interviewed. Participants emphasized the life-saving potential of the biosensor, but raised concerns including the impact of limited staff time, high workload and some technical aspects of the device. Participants highlighted that there are both too few and too many P. vivax patients to implement G6PD testing owing to challenges of funding, workload and complex testing infrastructure. Implementing the biosensor would require flexibility and improvisation to deal with remote sites, overcoming a low index of suspicion and mutual interplay of declining patient numbers and reluctance to test. This approach would generate new forms of evidence to justify introduction in policy and carefully consider questions of deployment given declining patient numbers. Conclusions: The results of the study show that, in an elimination context, the importance of malaria needs to be maintained for both policy makers and the affected communities, in this case by ensuring P. vivax, PQ treatment, and G6PD deficiency remain visible. Availability of new technologies, such as the biosensor, will fuel ongoing debates about priorities for allocating resources that must be adapted to a constantly evolving target. Technical and logistical concerns regarding the biosensor should be addressed by future product designs, adequate training, strengthened supply chains, and careful planning of communication, advocacy and staff interactions at all health system levels.

scholarly journals Determinants of primaquine and carboxyprimaquine exposures in children and adults with Plasmodium vivax malaria

2021 ◽  
Author(s):  
Cindy S Chu ◽  
James A Watson ◽  
Aung Pyae Phyo ◽  
Htun Htun Win ◽  
Widi Yotyingaphiram ◽  
...  
Keyword(s):  
Young Children ◽  
Plasmodium Vivax ◽  
Plasma Concentrations ◽  
Radical Cure ◽  
Pharmacokinetic Properties ◽  
Daily Dose ◽  
Plasmodium Vivax Malaria ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
To Receive ◽  
Cyp 2D6

Background Primaquine is the only widely available drug for radical cure of Plasmodium vivax malaria. There is uncertainty whether the pharmacokinetic properties of primaquine are altered significantly in childhood or not. Methods Glucose-6-phosphate dehydrogenase normal patients with uncomplicated P. vivax malaria were randomized to receive either chloroquine (25mg base/kg) or dihydroartemisinin-piperaquine (dihydroartemisinin 7mg/kg and piperaquine 55mg/kg) plus primaquine; given either as 0.5 mg base/kg/day for 14 days or 1 mg/kg/day for 7 days. Pre-dose day 7 venous plasma concentrations of chloroquine, desethylchloroquine, piperaquine, primaquine and carboxyprimaquine were measured. Methemoglobin levels were measured on day 7. Results Day 7 primaquine and carboxyprimaquine concentrations were available for 641 patients. After adjustment for the primaquine mg/kg daily dose, day of sampling, partner drug, and fever clearance, there was a significant non-linear relationship between age and trough primaquine and carboxyprimaquine concentrations, and day methemoglobin levels. Compared to adults 30 years of age, children 5 years of age had trough primaquine concentrations 0.53 (95% CI: 0.39- 0.73) fold lower, trough carboxyprimaquine concentrations 0.45 (95% CI: 0.35- 0.55) fold lower, and day 7 methemoglobin levels 0.87 (95% CI: 0.58-1.27) fold lower. Increasing concentrations of piperaquine and chloroquine and poor metabolizer CYP 2D6 alleles were associated with higher day 7 primaquine and carboxyprimaquine concentrations. Higher blood methemoglobin concentrations were associated with a lower risk of recurrence. Conclusion Young children have lower primaquine and carboxyprimaquine exposures, and lower levels of methemoglobinemia, than adults. Young children may need higher weight adjusted primaquine doses than adults.

scholarly journals 787Multistate modelling to investigate the impact of recurrent malaria episodes on hospital admissions and mortality

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Saber Dini ◽  
Nicholas Douglas ◽  
Jeanne Rini Poespoprodjo ◽  
Enny Kenangalem ◽  
Paulus Sugiarto ◽  
...  
Keyword(s):  
Vivax Malaria ◽  
Hospital Admissions ◽  
Cox Regression ◽  
Early Death ◽  
Morbidity And Mortality ◽  
Radical Cure ◽  
Liver Stage ◽  
Recurrent Malaria ◽  
The Impact ◽  
Malaria Episodes

Abstract Background Inadequate prevention and treatment of malaria can lead to reinfections and recurrent episodes, and for vivax malaria, further recurrences from the dormant liver stage. This study quantified the impact of recurrent malaria episodes on morbidity and mortality. Methods Routinely collected data were available from 68,381 malaria patients presenting to the primary referral hospital in Papua, Indonesia. A multi-state modelling framework, with Cox regression for transition rates, was employed to determine the risks of re-presentation to hospital, receiving in-patient treatment, and early (≤14 days post treatment)/late death following multiple malaria episodes. Results The risk of re-presentation to hospital increased from 34.7% (95%CI: 34.4%–35.1%) at first episode to 58.6% (57.5%–59.6%) following the third episode. Infection with vivax malaria increased the rate of re-presentation to hospital by 1.48-fold (Hazard Ratio 1.48; 95%CI 1.44–1.51) and late hospital in-patient admission by 1.17-fold (1.11–1.22), compared to falciparum. Falciparum malaria caused a higher overall rate of early death (1.54 (1.25–1.92)), however, after multiple episodes, there was a trend towards a greater rate of early death for vivax infection (1.91 (0.73–4.97)). Conclusions Recurrent episodes of malaria can cause substantial morbidity and mortality, highlighting the importance of prevention and effective treatments for both falciparum and vivax malaria. Key messages To achieve elimination of malaria in South-East Asia, where prevalence of vivax malaria is high, we must prioritise the radical cure of vivax to eliminate the liver-stage of this species that causes relapses of infection.

scholarly journals PO 8609 PREVALENCE AND RISK FACTORS FOR GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY IN TWO P. VIVAX MALARIA-ENDEMIC AREAS IN SUDAN

2019 ◽  
Vol 4 (Suppl 3) ◽  
pp. A62.2-A62
Author(s):  
Muzamil Mahdi Abdel Hamid ◽  
Musab Albsheer ◽  
Mohamed Muneer ◽  
Lina Altinae ◽  
Andrew A Lover
Keyword(s):  
Risk Factors ◽  
G6pd Deficiency ◽  
Demographic Data ◽  
Univariate Analysis ◽  
G6pd Activity ◽  
Radical Cure ◽  
Major Health Problem ◽  
Significant Difference ◽  
Endemic Areas ◽  
Glucose 6 Phosphate Dehydrogenase

BackgroundPlasmodium vivax malaria is a major health problem in Sudan and the parasite has become widely distributed in the recent years. The WHO recommends the use of primaquine as radical cure for liver dormant stage, the hypnozoite. However, prior its use, a test for Glucose-6-phosphate Dehydrogenase (G6PD) should be performed. The objective of the current study was to determine prevalence and risk factors for G6PD deficiency in two P. vivax malaria-endemic areas in Sudan.MethodsA cross-sectional study recruiting 557 subjects from two malaria-endemic areas in Sudan was conducted. Demographic data and blood samples were collected. G6PD activity was measured by spectrometry using SPINREACT enzymatic-UV kit.ResultsThe measured G6PD activities for both sites ranged from 0.6 to 37.7 U/g Hb, with a median value of 12.8 U/g Hb. There was a significant difference in enzyme activity by study site (p<0.001), but not by sex (p=0.91). Overall, across the two study sites, 22 (3.9%) is G6PDd (<30%). Prevalence of G6PDd (<30%) in Khartoum is 1.8% (4/230) compared to 4.8% (16/327) in New Hafla. In univariate analysis predictors of G6PDd were study site (odds ratio of G6PD activity <3.8, Khartoum relative to New Halfa=0.22 (95% CI: 0.08 to 0.66), p=0.006), and recent antibiotic use (OR=2.45 (95% CI: 1.1 to 5.5), p=0.027). In multivariate analysis, the only factor that was significant was the individual’s weight in kilograms, with an OR of 0.97 (95% CI 0.95 to 0.99, p=0.014).ConclusionG6PD deficiency is less prevalent among Sudanese population and this indicates that the use of primaquine for radical cure of P. vivax malaria is safe.

scholarly journals Determinants of primaquine and carboxyprimaquine exposures in children and adults with Plasmodium vivax malaria

2021 ◽  
Author(s):  
Cindy S Chu ◽  
James Andrew Watson ◽  
Aung Pyae Phyo ◽  
Htun Htun Win ◽  
Widi Yotyingaphiram ◽  
...  
Keyword(s):  
Young Children ◽  
Plasmodium Vivax ◽  
Vivax Malaria ◽  
Plasma Concentrations ◽  
Radical Cure ◽  
Pharmacokinetic Properties ◽  
Plasmodium Vivax Malaria ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
To Receive ◽  
Cyp 2D6

Background: Primaquine is the only widely available drug for radical cure of Plasmodium vivax malaria. There is uncertainty whether the pharmacokinetic properties of primaquine are altered significantly in childhood or not. Methods: Glucose-6-phosphate dehydrogenase normal patients with uncomplicated P. vivax malaria were randomized to receive either chloroquine (25mg base/kg) or dihydroartemisinin-piperaquine (dihydroartemisinin 7mg/kg and piperaquine 55mg/kg) plus primaquine; plus either 0.5 mg base/kg/day for 14 days or 1 mg/kg/day for 7 days. Pre-dose day 7 venous plasma concentrations of chloroquine, desethylchloroquine, piperaquine, primaquine and carboxyprimaquine were measured. Methemoglobin levels were measured on days 1, 4, 7. Results: Day 7 primaquine and carboxyprimaquine concentrations were available for 641 patients. After adjustment for the primaquine mg/kg daily dose, day of sampling, partner drug, and fever clearance, there was a significant non-linear relationship between age and trough primaquine and carboxyprimaquine concentrations, and day methemoglobin levels. Compared to adults 30 years of age, children 5 years of age had trough primaquine concentrations 0.55 (95% CI: 0.39- 0.78) fold lower, trough carboxyprimaquine concentrations 0.43 (95% CI: 0.34- 0.55) fold lower, and day 7 methemoglobin levels 0.87 (95% CI: 0.58-1.27) fold lower. Increasing concentrations of piperaquine and chloroquine and poor metabolizer CYP 2D6 alleles were also associated with higher day 7 primaquine and carboxyprimaquine concentrations. Increased methemoglobin concentrations were associated with a lower risk of recurrence. Conclusion: Young children have lower primaquine and carboxyprimaquine exposures, and lower levels of methemoglobinemia, than adults. Young children may need higher weight adjusted primaquine doses than adults.

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