The Association between Glucose 6-Phosphate Dehydrogenase Deficiency and Attention Deficit/Hyperactivity Disorder.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, impacting 4.9% of the population and more prevalent in Mediterranean communities, is a common enzymopathy with potential relevance to Attention Deficit/Hyperactivity Disorder (ADHD). This study investigated this association. METHODS: The clinical characteristics of 7473 G6PD-deficient patients and 29,892 matched case-controls (selected at a 1:4 ratio) from a cohort of 1,031,354 within the Leumit Health Services database were analyzed using Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables. RESULTS: In total, 68.7% were male. The mean duration of follow-up was 14.3 ± 6.2 years at a mean age of 29.2 ± 22.3 years. G6PD deficiency was associated with an increased risk of being diagnosed with ADHD (Odds Ratio (OR) = 1.16 [95% CI, 1.08-1.25], p < 0.001), seeking care from adult neurologists (OR = 1.30 [95% CI, 1.22-1.38], p < 0.001), and consulting adult psychiatrists (OR = 1.12 [95% CI, 1.01-1.24], p = 0.048). The use of stimulant medications among G6PD-deficient individuals was 17% higher for the methylphenidate class of drugs (OR = 1.17 [95% CI, 1.08, 1.27], p < 0.001), and there was a 16% elevated risk for amphetamine use (OR = 1.16 [95% CI, 1.03, 1.37], p = 0.047). CONCLUSIONS: G6PD deficiency signals an increased risk of ADHD diagnosis, more severe presentations of ADHD and a greater need for psychiatric medications to treat ADHD.

Severe Hemolysis during Primaquine Radical Cure of Plasmodium vivax Malaria: Two Systematic Reviews and Individual Patient Data Descriptive Analyses.

Primaquine (PQ) kills Plasmodium vivax hypnozoites but can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We conducted two systematic reviews. The first used data from clinical trials to determine the variety of definitions and frequency of hematological serious adverse events (SAEs) related to PQ treatment of vivax malaria. The second used data from prospective studies and case reports to describe the clinical presentation, management, and outcome of severe PQ-associated hemolysis necessitating hospitalization. In the first review, SAEs were reported in 70 of 249 clinical trials. There were 34 hematological SAEs among 9,824 patients with P. vivax malaria treated with PQ, nine of which necessitated hospitalization or blood transfusion. Criteria used to define SAEs were diverse. In the second review, 21 of 8,487 articles screened reported 163 patients hospitalized after PQ radical cure; 79.9% of whom (123 of 154) were prescribed PQ at ≥ 0.5 mg/kg/day. Overall, 101 patients were categorized as having probable or possible severe PQ-associated hemolysis, 96.8% of whom were G6PD deficient (< 30% activity). The first symptoms of hemolysis were reported primarily on day 2 or 3 (45.5%), and all patients were hospitalized within 7 days of PQ commencement. A total of 57.9% of patients (77 of 133) had blood transfusion. Seven patients (6.9%) with probable or possible hemolysis died. Even when G6PD testing is available, enhanced monitoring for hemolysis is warranted after PQ treatment. Clinical review within the first 5 days of treatment may facilitate early detection and management of hemolysis. More robust definitions of severe PQ-associated hemolysis are required.

A pharmacokinetic-pharmacodynamic model for chemoprotective agents against malaria.

Chemoprophylactics are a vital tool in the fight against malaria. They can be used to protect populations at risk, such as children younger than the age of 5 in areas of seasonal malaria transmission or pregnant women. Currently approved chemoprophylactics all present challenges. There are either concerns about unacceptable adverse effects such as neuropsychiatric sequalae (mefloquine), risks of hemolysis in patients with G6PD deficiency (8-aminoquinolines such as tafenoquine), or cost and daily dosing (atovaquone-proguanil). Therefore, there is a need to develop new chemoprophylactic agents to provide more affordable therapies with better compliance through improving properties such as pharmacokinetics to allow weekly, preferably monthly, dosing. Here we present a pharmacokinetic-pharmacodynamic (PKPD) model constructed using DSM265 (a dihydroorotate dehydrogenase inhibitor with activity against the liver schizonts of malaria, therefore, a prophylaxis candidate). The PKPD model mimics the parasite lifecycle by describing parasite dynamics and drug activity during the liver and blood stages. A major challenge is the estimation of model parameters, as only blood-stage parasites can be observed once they have reached a threshold. By combining qualitative and quantitative knowledge about the parasite from various sources, it has been shown that it is possible to infer information about liver-stage growth and its initial infection level. Furthermore, by integrating clinical data, the killing effect of the drug on liver- and blood-stage parasites can be included in the PKPD model, and a clinical outcome can be predicted. Despite multiple challenges, the presented model has the potential to help translation from preclinical to late development for new chemoprophylactic candidates.

Safety of age-dosed, single low-dose primaquine in children with glucose-6-phosphate dehydrogenase deficiency who are infected with Plasmodium falciparum in Uganda and the Democratic Republic of the Congo: a randomised, double-blind, placebo-controlled, non-inferiority trial.

BACKGROUND: WHO recommends gametocytocidal, single low-dose primaquine for blocking the transmission of Plasmodium falciparum; however, safety concerns have hampered the implementation of this strategy in sub-Saharan Africa. We aimed to investigate the safety of age-dosed, single low-dose primaquine in children from Uganda and the Democratic Republic of the Congo. METHODS: We conducted this randomised, double-blind, placebo-controlled, non-inferiority trial at the Mbale Regional Referral Hospital, Mbale, Uganda, and the Kinshasa Mahidol Oxford Research Unit, Kinshasa, Democratic Republic of the Congo. Children aged between 6 months and 11 years with acute uncomplicated P falciparum infection and haemoglobin concentrations of at least 6 g/dL were enrolled. Patients were excluded if they had a comorbid illness requiring inpatient treatment, were taking haemolysing drugs for glucose-6-phosphate dehydrogenase (G6PD) deficiency, were allergic to the study drugs, or were enrolled in another clinical trial. G6PD status was defined by genotyping for the G6PD c.202T allele, the cause of the G6PD-deficient A- variant. Participants were randomly assigned (1:1) to receive single low-dose primaquine combined with either artemether-lumefantrine or dihydroartemisinin-piperaquine, dosed by bodyweight. Randomisation was stratified by age and G6PD status. The primary endpoint was the development of profound (haemoglobin <4 g/dL) or severe (haemoglobin <5 g/dL) anaemia with severity features, within 21 days of treatment. Analysis was by intention to treat. The sample size assumed an incidence of 1·5% in the placebo group and a 3% non-inferiority margin. The trial is registered at ISRCTN, 11594437, and is closed to new participants. FINDINGS: Participants were recruited at the Mbale Regional Referral Hospital between Dec 18, 2017, and Oct 7, 2019, and at the Kinshasa Mahidol Oxford Research Unit between July 17, 2017, and Oct 5, 2019. 4620 patients were assessed for eligibility. 3483 participants were excluded, most owing to negative rapid diagnostic test or negative malaria slide (n=2982). 1137 children with a median age of 5 years were enrolled and randomly assigned (286 to the artemether-lumefantrine plus single low-dose primaquine group, 286 to the artemether-lumefantrine plus placebo group, 283 to the dihydroartemisinin-piperaquine plus single low-dose primaquine group, and 282 to the dihydroartemisinin-piperaquine plus placebo group). Genotyping of G6PD identified 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (defining the G6PD-deficient group), 119 heterozygous females, 418 G6PD-c.202C normal males and 299 G6PD-c.202C normal females (defining the non-G6PD-deficient group), and 17 children of unknown status. 67 patients were lost to follow-up and four patients withdrew during the study-these numbers were similar between groups. No participants developed profound anaemia and three developed severe anaemia: from the G6PD-deficient group, none (0%) of 133 patients who received placebo and one (0·66%) of 151 patients who received primaquine (difference -0·66%, 95% CI -1·96 to 0·63; p=0·35); and from the non-G6PD-deficient group, one (0·23%) of 430 patients who received placebo and one (0·25%) of 407 patients who received primaquine (-0·014%, -0·68 to 0·65; p=0·97). INTERPRETATION: Gametocytocidal, age-dosed, single low-dose primaquine was well tolerated in children from Uganda and the Democratic Republic of the Congo who were infected with P falciparum, and the safety profile of this treatment was similar to that of the placebo. These data support the wider implementation of single low-dose primaquine in Africa. FUNDING: UK Government Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust Joint Global Health Trials Scheme.

Prevalence of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency among Malaria Patients in Southern Thailand: 8 Years Retrospective Study.

Erythrocytes deficient in glucose-6-phosphate dehydrogenase (G6PD) is more susceptible to oxidative damage from free radical derived compounds. The hemolysis triggered by oxidative agents such as primaquine (PQ) is used for the radical treatment of hypnozoites of P. vivax. Testing of G6PD screening before malaria treatment is not a common practice in Thailand, which poses patients at risk of hemolysis. This retrospective study aimed to investigate the prevalence of G6PD in malaria patients who live in Southern Thailand. Eight hundred eighty-one malaria patients were collected for 8-year from 2012 to 2019, including 785 (89.1%) of P. vivax, 61 (6.9%) of P. falciparum, 27 (3.1%) of P. knowlesi, and 8 (0.9%) of mixed infections. The DiaPlexC genotyping kit (Asian type) and PCR-RFLP were employed to determine the G6PD variants. The result showed that 5 different types of G6PD variants were identified in 26 cases (2.9%); 12/26 (46.2%) had Mahidol (487G>A) and 11/26 (42.3%) had Viangchan (871G>A) variants, while the rest had Kaiping (1388G>A), Union (1360C>T), and Mediterranean (563C>T) variants. G6PD Songklanagarind (196T>A) variant was not found in the study. Our result did not show a significant difference in the malaria parasite densities in patients between G6PD-deficient and G6PD-normal groups. According to our findings, testing G6PD deficiency and monitoring the potential PQ toxicity in patients who receive PQ are highly recommended.

Prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency and Gametocytemia in a Pre-Elimination, Low Malaria Transmission Setting in Southern Zambia.

The WHO recommends single low-dose (SLD) primaquine as a gametocytocide to reduce Plasmodium falciparum transmission in areas of low transmission. Despite this recommendation, uptake of SLD primaquine has been low because of concerns of glucose-6-phosphate dehydrogenase (G6PD) deficiency. Individuals with G6PD deficiency can experience hemolysis when exposed to primaquine. In Southern Province, Zambia, malaria transmission has declined significantly over the past decade. Single low-dose primaquine may be an effective tool, but there is limited information on G6PD deficiency. We screened 137 residents in Macha, Southern Province, Zambia, and the prevalence of G6PD (A-) was 15%. We also revisited data collected from 2008 to 2013 in the same area and found the highest gametocyte burden among those aged 5-15 years. The findings from this study suggest that SLD primaquine targeted to school-aged children may be an effective tool to help achieve malaria elimination in southern Zambia.

Naphthalene Toxicity in Clinical Practice.

BACKGROUND: Naphthalene ingestion and skin or inhalational exposure (accidental or deliberate) is an under-recognized cause of a severe toxidrome in regions where it is commonly used (e.g., mothballs in households). METHODS: This review is an update for the clinicians to understand the pharmacology, clinical features, laboratory evaluation, and treatment for naphthalene toxicity. High-quality literature for the past eight decades was collected and reviewed in this article. Several landmark articles were reviewed using PubMed, EMBASE Ovid, and the Cochrane Library, which have essential implications in the current toxicology practice. RESULTS AND CONCLUSION: Naphthalene toxicity usually occurs abruptly and leads to acute hemolysis, methemoglobinemia, renal failure, respiratory depression, and acute brain dysfunction that are difficult to manage. The toxicity is more marked in patients with G6PD deficiency and associated with high morbidity and mortality. The management should mainly focus on high-quality supportive care; however, severe methemoglobinemia (>20-30%) requires specific therapy with intravenous methylene blue. Methylene blue is a highly effective agent but contraindicated in severe G6PD deficiency.

Prevalence of glucose-6-phosphate dehydrogenase deficiency, U.S. Armed Forces, May 2004-September 2018.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited genetic disorder most commonly associated with hemolytic anemia. Among those with G6PD deficiency, hemolytic anemia may be triggered by bacterial or viral infections and by certain foods and drugs, including the 8-aminoquinoline (8-AQ) class of antimalarials. Because 8-AQ drugs remain the only drugs approved by the U.S. Food and Drug Administration for malaria relapse prevention, the Department of Defense (DoD) requires testing of all service members' G6PD status. To estimate prevalence of G6PD deficiency among DoD service members, Composite Health Care System-generated, Health Level 7-formatted laboratory records for all service members (n=2,311,223) dated between May 2004 and September 2018 were queried for G6PD testing. Corresponding demographic data were obtained from the Defense Enrollment Eligibility Reporting System. Overall prevalence of G6PD deficiency among this cohort was low, at 2.2%. Demographic trends mirrored U.S. statistics; the cohort prevalence among males (2.3%) was higher than among females (1.5%), and the prevalence among non-Hispanic blacks (9.5%) was higher than among those in any other race/ethnicity group.

Drug-induced Hemolysis in G6PD Deficiency: an Unusual Presentation of a Common Clinical Condition.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency can present a diagnostic dilemma owing to the varying degrees of disease severity and the wide range of precipitating factors. Here, we report a case of a 56-year-old man who presented with signs and symptoms of heart failure and, during the course of treatment, developed intravascular hemolysis. On investigation, he was found to be G6PD deficient. Following discontinuation of the fixed-dose combination of isosorbide dinitrate and hydralazine, the clinical condition of the patient improved, and there were no further episodes of hemolysis. The case highlights the need for a high degree of suspicion of G6PD deficiency in patients with unexplained signs and symptoms of intravascular hemolysis.

Maternal consumption of quinine-containing sodas may induce G6PD crises in breastfed children.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect often presenting with neonatal jaundice and/or hemolytic anemia. G6PD hemolytic events are linked with exposure to a pro-oxidant agent. We here report three cases of initial G6PD crises in breastfed children secondary to maternal consumption of a tonic drink which contains quinine. Quinine was found in breast milk of one of the mothers after she consumed tonic water. CONCLUSION: The amount of quinine that is transmitted through breast milk appears to be sufficient to induce G6PD crises in breastfed children. We hence recommend that consumption of quinine-containing sodas during breastfeeding should be avoided in populations with a high prevalence of G6PD deficiency. What is Known: • G6PD hemolytic events are linked with exposure to a pro-oxidant agent. • Ingestion of fava beans by a mother who was breastfeeding has been reported to induce a neonatal G6PD crisis. What is New: • Maternal consumption of tonic drink which contains quinine appears to be sufficient to induce G6PD crises in breastfed children. • Maternal consumption of quinine-containing sodas during breastfeeding should be avoided in populations with a high prevalence of G6PD deficiency.

Safe fluoroquinolones prophylaxis in blood cancer patients with chemotherapy-induced neutropenia and Glucose-6-Phosphate-Dehydrogenase deficiency.

WHAT IS KNOWN AND OBJECTIVE: Bacterial infections are the leading causes of morbidity and mortality in haematologic patients with chemotherapy-induced neutropenia. The only strategy shown to be effective in reducing febrile neutropenia incidence is fluoroquinolone prophylaxis, but the safety of this class of drugs in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD-), the most common human enzyme defect, is still controversial because of the claimed association with acute haemolytic anaemia. METHODS: We retrospectively analysed 242 patients treated with 628 intensive chemotherapy courses. Of these, 59 patients were with G6PD-. All patients underwent fluoroquinolone prophylaxis and were transfused according to our single-unit transfusion policy. The principal endpoint was the incidence of acute haemolytic anaemia. Secondary endpoints included the incidence of febrile neutropenia, microbiologically and clinically documented infection (MDI and CDI) and the incidence of Gram-positive or Gram-negative infections. RESULTS AND DISCUSSIONS: No episode of acute haemolytic anaemia was observed in the entire cohort. The incidence of MDI and CDI was similar, but the incidence of invasive fungal disease (IFD; P<.0001, HR 11.4, 95%CI 3.5-37.05) and Candida sepsis (P=.008, HR 37, 95%CI 2.01-680.9) was higher in patients with G6PD-. Interestingly, we observed a reduced incidence of febrile neutropenia in patients with G6PD- (P=.01, HR 0.46, 95%CI 0.25-0.8). WHAT IS NEW AND CONCLUSIONS: Our data suggest that fluoroquinolone prophylaxis in patients with G6PD-, treated with intensive chemotherapy, is feasible and safe. Our findings on the incidence of IFD and febrile neutropenia suggest that G6PD may be important in susceptibility to opportunistic pathogens and host response in neutropenic patients.

Glucose-6-Phosphate Dehydrogenase Deficiency and Haemoglobin Drop after Sulphadoxine-Pyrimethamine Use for Intermittent Preventive Treatment of Malaria during Pregnancy in Ghana - A Cohort Study.

BACKGROUND: Sulphadoxine-Pyrimethamine (SP) is still the only recommended antimalarial for use in intermittent preventive treatment of malaria during pregnancy (IPTp) in some malaria endemic countries including Ghana. SP has the potential to cause acute haemolysis in G6PD deficient people resulting in significant haemoglobin (Hb) drop but there is limited data on post SP-IPTp Hb drop. This study determined the difference, if any in proportions of women with significant acute haemoglobin drop between G6PD normal, partial deficient and full deficient women after SP-IPTp. METHODS AND FINDINGS: Prospectively, 1518 pregnant women who received SP for IPTp as part of their normal antenatal care were enrolled. Their G6PD status were determined at enrollment followed by assessments on days 3, 7,14 and 28 to document any adverse effects and changes in post-IPTp haemoglobin (Hb) levels. The three groups were comparable at baseline except for their mean Hb (10.3 g/dL for G6PD normal, 10.8 g/dL for G6PD partial deficient and 10.8 g/dL for G6PD full defect women).The prevalence of G6PD full defect was 2.3% and 17.0% for G6PD partial defect. There was no difference in the proportions with fractional Hb drop ≥ 20% as compared to their baseline value post SP-IPTp among the 3 groups on days 3, 7, 14. The G6PD full defect group had the highest median fractional drop at day 7. There was a weak negative correlation between G6PD activity and fractional Hb drop. There was no statistical difference between the three groups in the proportions of those who started the study with Hb ≥ 8g/dl whose Hb level subsequently fell below 8g/dl post-SP IPTp. No study participant required transfusion or hospitalization for severe anaemia. CONCLUSIONS: There was no significant difference between G6PD normal and deficient women in proportions with significant acute haemoglobin drop post SP-IPTp and lower G6PD enzyme activity was not strongly associated with significant acute drug-induced haemoglobin drop post SP-IPTp but a larger study is required to confirm consistency of findings.

Glucose-6-phosphate dehydrogenase deficiency: an unusual cause of acute jaundice after paracetamol overdose.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest human enzyme defect causing haemolytic anaemia after exposure to specific triggers. Paracetamol-induced haemolysis in G6PD deficiency is a rare complication and mostly reported in children. We report the first case (to the best of our knowledge) of acute jaundice without overt clinical features of a haemolytic crisis, in an otherwise healthy adult female following paracetamol overdose, due to previously undiagnosed G6PD deficiency. It is important that clinicians consider this condition when a patient presents following a paracetamol overdose with significant and disproportionate jaundice, without transaminitis or coagulopathy.

G6PD deficiency: global distribution, genetic variants and primaquine therapy.

Glucose-6-phosphate dehydrogenase (G6PD) is a potentially pathogenic inherited enzyme abnormality and, similar to other human red blood cell polymorphisms, is particularly prevalent in historically malaria endemic countries. The spatial extent of Plasmodium vivax malaria overlaps widely with that of G6PD deficiency; unfortunately the only drug licensed for the radical cure and relapse prevention of P. vivax, primaquine, can trigger severe haemolytic anaemia in G6PD deficient individuals. This chapter reviews the past and current data on this unique pharmacogenetic association, which is becoming increasingly important as several nations now consider strategies to eliminate malaria transmission rather than control its clinical burden. G6PD deficiency is a highly variable disorder, in terms of spatial heterogeneity in prevalence and molecular variants, as well as its interactions with P. vivax and primaquine. Consideration of factors including aspects of basic physiology, diagnosis, and clinical triggers of primaquine-induced haemolysis is required to assess the risks and benefits of applying primaquine in various geographic and demographic settings. Given that haemolytically toxic antirelapse drugs will likely be the only therapeutic options for the coming decade, it is clear that we need to understand in depth G6PD deficiency and primaquine-induced haemolysis to determine safe and effective therapeutic strategies to overcome this hurdle and achieve malaria elimination.

[Studies on influence of Siwu decoction and its composite drugs on chemical-induced blood-deficiency model mice].

OBJECTIVE: To investigate Siwu decoction and its composite drugs on the blood-deficiency model mice induced by acetylphenyhydrazine and cyclophosphamide. METHOD: Acetylphenyhydrazine and cyclophosphamide were used to copy the blood-deficiency model mice. Automatic hematology analyzer was used to test the peripheral hemogram. Weighting method was used to test the liver index and spleen index; Kits for ATPase test was used to test the activities of Na+ - K+ - ATPase/Ca2+ - Mg2+ - ATPase in erythrocyte membrane. Flow cytometry was used to test the bone marrow cells' cell cycle. RESULT: Angelicar Sinensis Radix and Paeoniae Radix Alba had the most effective activity on the peripheral hemogram. Paeoniae Radix Alba, the drug pair including Angelicar Sinensis Radix and the drug- group including Paeoniae Radix Alba had the most effective activity on the liver index. All the drugs, drug-pairs, drug-groups and the formula had effect on the spleen index. To the activity of Na+ - K+ - ATPase in erythrocyte membrane, Rehmanniae Radix Praeparata, the drug-pairs and drug-groups including Angelicar Sinensis Radix exhibited the most effective activity. All the drugs, drug-pairs, drug-groups and the formula had the protective effect on the damaged bone marrow cells. CONCLUSION: Siwu decoction and its composite drugs all had effect on the blood-deficiency model mice, but the action intensity was different. Angelicar Sinensis Radix and Paeoniae Radix Alba exhibited the most effective activity to the protection of the blood-deficiency model mice.