Enzymatic Deficiency in Primaquine-Sensitive Erythrocytes

Carson, Paul E.; Flanagan, C. Larkin; Ickes, C. E.; Alving, Alf S.

doi:10.1126/science.124.3220.484.b

Cited by 152 publications

(31 citation statements)

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“…The other triggers of acute hemolytic anemia include certain medications such as anti-malarials, and to a lesser extent, bacterial or viral infection. Incidentally, it was the investigation into primaquine-sensitive RBCs that led to the discovery of G6PD deficiency ( 53 ). Primaquine and Pamaquine are antimalarial drugs known to induce hemolysis in G6PD-deficient patients.…”

Section: Clinical Manifestationmentioning

confidence: 99%

Glucose-6-Phosphate Dehydrogenase Deficiency and Neonatal Hyperbilirubinemia: Insights on Pathophysiology, Diagnosis, and Gene Variants in Disease Heterogeneity

et al. 2022

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a prevalent condition worldwide and is caused by loss-of-function mutations in the G6PD gene. Individuals with deficiency are more susceptible to oxidative stress which leads to the classical, acute hemolytic anemia (favism). However, G6PD deficiency in newborn infants presents with an increased risk of hyperbilirubinemia, that may rapidly escalate to result in bilirubin induced neurologic dysfunction (BIND). Often with no overt signs of hemolysis, G6PD deficiency in the neonatal period appears to be different in the pathophysiology from favism. This review discusses and compares the mechanistic pathways involved in these two clinical presentations of this enzyme disorder. In contrast to the membrane disruption of red blood cells and Heinz bodies formation in favism, G6PD deficiency causing jaundice is perhaps attributed to the disruption of oxidant-antioxidant balance, impaired recycling of peroxiredoxin 2, thus affecting bilirubin clearance. Screening for G6PD deficiency and close monitoring of affected infants are important aspects in neonatal care to prevent kernicterus, a permanent and devastating neurological damage. WHO recommends screening for G6PD activity of all infants in countries with high prevalence of this deficiency. The traditional fluorescent spot test as a screening tool, although low in cost, misses a significant proportion of cases with moderate deficiency or the partially deficient, heterozygote females. Some newer and emerging laboratory tests and diagnostic methods will be discussed while developments in genomics and proteomics contribute to increasing studies that spatially profile genetic mutations within the protein structure that could predict their functional and structural effects. In this review, several known variants of G6PD are highlighted based on the location of the mutation and amino acid replacement. These could provide insights on why some variants may cause a higher degree of phenotypic severity compared to others. Further studies are needed to elucidate the predisposition of some variants toward certain clinical manifestations, particularly neonatal hyperbilirubinemia, and how some variants increase in severity when co-inherited with other blood- or bilirubin-related genetic disorders.

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Section: Clinical Manifestationmentioning

confidence: 99%

Glucose-6-Phosphate Dehydrogenase Deficiency and Neonatal Hyperbilirubinemia: Insights on Pathophysiology, Diagnosis, and Gene Variants in Disease Heterogeneity

et al. 2022

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“…The current global situation with respect to malaria indicates that about two billion people are exposed to the disease. Each year between 100 and 200 million new cases of infection are reported, and approximately 1−2 million people die due to malaria. , The situation is rapidly worsening, mainly due to the nonavailability of effective drugs and development of drug resistance to the existing first-line drugs, such as chloroquine and pyrimethamine. − In addition to the drug resistance of the first-line antimalarial drugs, the usefulness of many newer antimalarial drugs was impaired by their side effects. Multiple drug resistance in Plasmodium falciparum malaria continues to pose special problems for targeting the blood stages of malaria.…”

Section: Introductionmentioning

confidence: 99%

Unambiguous Synthesis and Prophylactic Antimalarial Activities of Imidazolidinedione Derivatives

et al. 2005

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The public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing the burden, to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. WR 182393, a guanidinoimidazolidiondione derivative with potent causal prophylactic antimalarial activity by intramuscular injection, was previously prepared by treatment of chloro-proguanil and diethyl oxalate, yielding a mixture of two closely related isomers. Poor solubility of the mixture made the separation and purification impossible. To overcome the separation problem, new and facile unamgibuous syntheses of the two active components were reported. The new synthetic methods facilitate the synthesis of not only the active components, but also their derivatives. To search for compounds with good oral efficacy, a series of carbamate derivatives of the active components were prepared by the new procedure, many of which showed profound causal prophylactic antimalarial activity against Plasmodium yoelii in mouse by oral administration. PLEASE DO NOT AND ADDRESS(ES).Enter the name and address of the thesis, progress, quarterly, research, special, group organization(s) financially responsible for and study, etc.orazaonsfiacalrepniefrad monitoring the work. DATESCOVERED. Indicate the time during which the work was performed and the report was 10. SPONSOR/MONITOR'S ACRONYM(S). Enter, if written, e.g., Jun 1997 -Jun 1998; 1-10 Jun 1996;;;' available, e.g. BRL, ARDEC, NADC.May -Nov 1998; Nov 1998. with; translation of; report supersedes; old edition number, etc. 5d. PROJECT NUMBER. Enter all project numbers as they appear in the report, e.g. 1F665702D1257; SPONSOR/MONITOR'S REPORT NUMBER(S14. ABSTRACT. A brief (approximately 200 words) ILIR. factual summary of the most significant information.5e. TASK NUMBER. Enter all task numbers as they 15. SUBJECT TERMS. Key words or phrases * appear in the report, e.g. 05; RF0330201; T4112.• identifying major concepts in the report.5f. WORK UNIT NUMBER. Enter all work unit numbers as they appear in the report, e.g. 001; 16. SECURITY CLASSIFICATION. Enter security AFAPL30480105.classification in accordance with security classification regulations, e.g. U, C, S, etc. If this form contains 6. AUTHOR(S). Enter name(s) of person(s) classified information, stamp classification level on the responsible for writing the report, performing...

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“…The earliest example of pharmacogenetics was in 1956 when it was discovered that a deficiency in glucose-6-phosphate dehydrogenase (G6PD) predisposes patients to hemolysis when taking several medications. 805 Transformative studies in the fields of pharmacogenetics involved studies of antipyrine (a pain reliever) metabolism in identical and fraternal twins. 806 Vesell and Page showed that the metabolism of antipyrine is consistent in identical twins but not as consistent in fraternal twins, implying that responses to drugs could be inherited.…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Section: Pharmacogeneticsmentioning

confidence: 99%

Using Genome Sequence to Enable the Design of Medicines and Chemical Probes

et al. 2018

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Rapid progress in genome sequencing technology has put us firmly into a postgenomic era. A key challenge in biomedical research is harnessing genome sequence to fulfill the promise of personalized medicine. This Review describes how genome sequencing has enabled the identification of disease-causing biomolecules and how these data have been converted into chemical probes of function, preclinical lead modalities, and ultimately U.S. Food and Drug Administration (FDA)-approved drugs. In particular, we focus on the use of oligonucleotide-based modalities to target disease-causing RNAs; small molecules that target DNA, RNA, or protein; the rational repurposing of known therapeutic modalities; and the advantages of pharmacogenetics. Lastly, we discuss the remaining challenges and opportunities in the direct utilization of genome sequence to enable design of medicines.

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Enzymatic Deficiency in Primaquine-Sensitive Erythrocytes

Cited by 152 publications

References 1 publication

Glucose-6-Phosphate Dehydrogenase Deficiency and Neonatal Hyperbilirubinemia: Insights on Pathophysiology, Diagnosis, and Gene Variants in Disease Heterogeneity

Glucose-6-Phosphate Dehydrogenase Deficiency and Neonatal Hyperbilirubinemia: Insights on Pathophysiology, Diagnosis, and Gene Variants in Disease Heterogeneity

Unambiguous Synthesis and Prophylactic Antimalarial Activities of Imidazolidinedione Derivatives

Using Genome Sequence to Enable the Design of Medicines and Chemical Probes

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