Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole

Metamizole is a pain-killer drug that has been banned in some countries because of its toxicity, but it is still used in many countries due to its effective analgesic and antispasmodic properties. Although large variability in the biodisposition and adverse effects of metamizole are known, factors underlying this variability are poorly understood. We analyzed the urinary recovery of metabolites, as well as the association of these profiles with genetic and non-genetic factors, in a group of 362 healthy individuals. Gender and functional polymorphisms are strongly related to metabolic profiles. N-demethylation of the active metabolite MAA is diminished in carriers of the CYP2C19*2 allele and in NAT2-slow acetylators. Acetylation of the secondary metabolite AA is decreased in men, in drinkers and in NAT2-slow acetylators with a differential effect of NAT2*5 and NAT2*6 alleles. The formylation of MAA is diminished in older subjects and in carriers of defect CYP2C9 and CYP2C19 alleles. Two novel arachidonoyl metabolites were identified for the first time in humans. Women and NAT2-slow acetylators show higher concentrations, whereas the presence of the rapid CYP2C19*17 allele is associated with lower concentrations of these metabolites. All genetic associations show a gene-dose effect. We identified for the first time genetic and non-genetic factors related to the oxidative metabolism of analgesic drug metamizole, as well as new active metabolites in humans. The phenotypic and genetic factors identified in this study have a potential application as biomarkers of metamizole biotransformation and toxicity.We are grateful to Prof. James McCue for assistance in language editing. Financed by grants PS09/00943, PS09/00469, PI12/00241, PI12/00324 and RETICS RD07/0064/0016 and RD12/0013/0002 and RD12/0013/0009 from Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, Madrid, Spain; GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Union. I.A. is supported by a Servet Contract CP11/00154.Martínez, C.; Andreu Ros, MI.; Amo, G.; Miranda Alonso, MÁ.; Esguevillas, G.; Torres, MJ.; Blanca López, N.... (2014). Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole. Biochemical Pharmacology. 92(3):457-466. https://doi.org/10.1016/j.bcp.2014.09.005S45746692

Allergic Reactions to Metamizole: Immediate and Delayed Responses

[EN] Background: Pyrazolones are the most common causes of selective nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. We studied a large group of patients with immediate and delayed selective responses to metamizole. Methods: Patients with suspicion of hypersensitivity to metamizole were evaluated. We verified acetylsalicylic acid tolerance and classified patients as immediate or delayed responders if they showed symptoms less or more than 24 h after metamizole administration. Skin tests were performed and if negative, a basophil activation test (BAT) was performed on immediate responders. If it was negative, we performed a drug provocation test (DPT) with metamizole. Results: A total of 137 patients were included: 132 reacted within 24 h (single NSAID-induced urticaria/angioedema/ anaphylaxis; SNIUAA) and 5 after 24 h (single NSAID-induced delayed hypersensitivity reaction; SNIDHR). Most SNIUAA patients developed anaphylaxis (60.60%); for SNIDHR, maculopapular exanthema was the most frequent entity (60%). Skin testing was positive in 62.04% of all cases and BAT in 28% of the SNIUAA patients with negative skin tests. In 5.1% of the cases, DPT with metamizole was needed to establish the diagnosis. In 22.62% of the cases, diagnosis was established by consistent and unequivocal history of repeated allergic episodes in spite of a negative skin test and BAT. Conclusions: SNIUAA to metamizole is the most frequent type of selective NSAID hypersensitivity, with anaphylaxis being the most common clinical entity. It may occur within 1 h after drug intake. SNIDHR occurs in a very low percentage of cases. The low sensitivity of diagnostic tests may be due to incomplete characterization of the chemical structures of metamizole and its metabolites.The present study has been supported by the Institute of Health ‘Carlos III’ of the Ministry of Economy and Competitiveness [grants cofounded by European Regional Development Fund (ERDF), Red de Reacciones Adversas a Alergenos y Farmacos (RD12/0013/0001 and PI15/01317)] and by Consejeria de Salud de la Junta de Andalucía (PI-0463-2013).Blanca-López, N.; Pérez-Sanchez, N.; Agúndez, JA.; García-Martín, E.; Torres, MJ.; Cornejo-Garcia, JA.; Perkins, JR.... (2016). Allergic Reactions to Metamizole: Immediate and Delayed Responses. International Archives of Allergy and Immunology. 169(4):223-230. https://doi.org/10.1159/000444798S223230169

Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting

This manuscript provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward

The Relationship Between Parkinson's Disease and Essential Tremor: Review of Clinical, Epidemiologic, Genetic, Neuroimaging and Neuropathological Data, and Data on the Presence of Cardinal Signs of Parkinsonism in Essential Tremor

Background:&nbsp;The possible relationship between essential tremor (ET) and Parkinson&rsquo;s disease (PD) remains controversial since the first description of PD. However, there is increasing evidence suggesting the overlap between these two disorders. The aim of this review is to examine the relationship between PD and ET, focusing on clinical, epidemiologic, genetic, neuroimaging and neuropathological data, and the presence of cardinal symptoms of parkinsonism in ET.Methods:&nbsp;We conducted a PubMed search from 1966 until November 2011 on the relationship between ET and PD and the presence of postural tremor in PD patients, and the presence of rest tremor, rigidity and slowed movements in ET patients are reviewed.Results:&nbsp;Clinical series, follow-up studies of ET patients, and case-control and genetic epidemiological studies indicate that ET is associated with increased risk for PD. Some neuroimaging studies and neuropathological reports suggest association between the two diseases. ET patients have shown a high prevalence of rest tremor and at least 7 studies showed slowed movements (possibly related with cerebellar dysfunction and/or bradykinesia) in patients with ET.Conclusions:&nbsp;There is reasonable epidemiological and clinical evidence to support a link between ET and PD, although it is not clear what factors could predict the risk of developing PD in ET patients (or more rarely, of developing ET in PD patients). Future multicentric and multidisciplinary studies including epidemiological, clinical, neuroimaging, genetic and neuropathological assessment would be required to understand these associations.&nbsp;&nbsp;</p

Data from: Association between restless legs syndrome and other movement disorders

Objectives. The present review focuses on the possible association between restless legs syndrome and movement disorders, including Parkinson’s disease, other parkinsonian syndromes, essential tremor, choreic and dystonic syndromes, Tourette’s syndrome and heredodegenerative ataxias. Methods. Review of PubMed Database from 1966 to September 2018 and identification of references of interest for the topic. Meta-analysis of eligible studies on the frequency of RLS in Parkinson’s disease patients and controls using the Meta-DiSc1.1.1 software and using the PRISMA guidelines. Results and conclusions. Although there are substantial clinical, neuroimaging, neuropathological and genetic differences between RLS and Parkinson’s disease, many reports describe a higher than expected prevalence of RLS in patients with Parkinson’s disease, when compared both with the general population or with matched control groups; several studies have also suggested that RLS could be an early clinical feature of Parkinson’s disease. RLS symptoms are very frequent in multiple system atrophy, essential tremor, Tourette’s syndrome, Friedreich ataxia, and spinocerebellar ataxia type 3 (SCA3) as well. Finally, possible genetic links between Parkinson’s disease and RLS (the presence of allele 2 of the complex microsatellite repeat Rep1 within the alpha-synuclein gene promoter) and between Tourette’s syndrome and RLS (several variants in the BTBD9 gene) have been reported in two case-control association studies, although these data, based on preliminary data with small sample sizes, need to be replicated in further studies

<i>NAT2</i> polymorphisms and risk for Parkinson’s disease: a systematic review and meta-analysis

<p><b>Introduction</b>: Several studies suggested a possible association between certain polymorphisms in the <i>N-acetyl-transferase 2</i> (<i>NAT2</i>) gene (which encodes a very important enzyme involved in xenobiotic metabolism) and the risk for Parkinson’s disease (PD). As the results of studies on this issue are controversial, we conducted a systematic review and a meta-analysis of eligible studies on this putative association.</p> <p><b>Areas covered</b>: The authors revised the relationship between <i>NAT2</i> polymorphisms and the risk of developing PD using several databases, and performed a meta-analysis using the software <i>Meta-Disc1.1.1</i>. In addition heterogeneity between studies was analyzed. A description of studies regarding gene-gene interactions and gene-environmental interactions involving <i>NAT2</i> polymorphisms is also made.</p> <p><b>Expert opinion</b>: Despite several recent meta-analyses showing an association between several polymorphisms in genes related with detoxification mechanisms such <i>as cytochrome</i> P4502D6 (<i>CYP2D6</i>), and <i>glutathione transferases M1</i> and <i>T1</i> (<i>GSTM1</i>, and <i>GSTT1</i>), data on <i>NAT2</i> gene polymorphisms obtained from the current meta-analysis do not support a major association with PD risk, except in Asian populations. However, data from many studies are incomplete and therefore insufficient data exists to draw definitive conclusions. Several studies suggesting gene-gene and gene-environmental factors involving <i>NAT2</i> gene in PD risk await confirmation.</p

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for and Nonsteroidal Anti‐Inflammatory Drugs

Theken KN, Lee CR, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for and Nonsteroidal Anti‐Inflammatory Drugs. Clinical Pharmacology &amp; Therapeutics. 2020;108(2):191-200.Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used analgesics due to their lack of addictive potential. However, NSAIDs have the potential to cause serious gastrointestinal, renal, and cardiovascular adverse events. CYP2C9 polymorphisms influence metabolism and clearance of several drugs in this class, thereby affecting drug exposure and potentially safety. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for NSAIDs based on CYP2C9 genotype (updates at www.cpicpgx.org)

Genetic Variants in Cytosolic Phospholipase A2 Associated With Nonsteroidal Anti-Inflammatory Drug-Induced Acute Urticaria/Angioedema

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main triggers of drug hypersensitivity reactions, probably due to their high consumption worldwide. The most frequent type of NSAID hypersensitivity is NSAID cross-hypersensitivity, in which patients react to NSAIDs from different chemical groups in the absence of a specific immunological response. The underlying mechanism of NSAID cross-hypersensitivity has been linked to cyclooxygenase (COX)-1 inhibition causing an imbalance in the arachidonic acid pathway. Despite NSAID-induced acute urticaria/angioedema (NIUA) being the most frequent clinical phenotype, most studies have focused on NSAID-exacerbated respiratory disease. As NSAID cross-hypersensitivity reactions are idiosyncratic, only appearing in some subjects, it is believed that individual susceptibility is under the influence of genetic factors. Although associations with polymorphisms in genes from the AA pathway have been described, no previous study has evaluated the potential role of cytosolic phospholipase A2 (cPLA2) variants. This enzyme catalyzes the initial hydrolysis of membrane phospholipids to release AA, which can be subsequently metabolized into eicosanoids. Here, we analyzed for the first time the overall genetic variation in the cPLA2 gene (PLA2G4A) in NIUA patients. For this purpose, a set of tagging single nucleotide polymorphisms (tagSNPs) in PLA2G4A were selected using data from Europeans subjects in the 1,000 Genomes Project, and genotyped with the iPlex Sequenom MassArray technology. Two independent populations, each comprising NIUA patients and NSAID-tolerant controls, were recruited in Spain, for the purposes of discovery and replication, comprising a total of 1,128 individuals. Fifty-eight tagSNPs were successfully genotyped in the discovery cohort, of which four were significantly associated with NIUA after Bonferroni correction (rs2049963, rs2064471, rs12088010, and rs12746200). These polymorphisms were then genotyped in the replication cohort: rs2049963 was associated with increased risk for NIUA after Bonferroni correction under the dominant and additive models, whereas rs12088010 and rs12746200 were protective under these two inheritance models. Our results suggest a role for PLA2G4A polymorphisms in NIUA. However, further studies are required to replicate our findings, elucidate the mechanistic role, and evaluate the participation of PLA2G4A variants in other phenotypes induced by NSAID cross-hypersensitivity.This work was supported by Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Science and Innovation), co-founded by Fondo Europeo de Desarrollo Regional-FEDER for Research Projects (PI17/ 01593, PI18/00540, and PI20/01540), GR18145 from Junta de Extremadura, the Thematic Networks and Co-operative ResearchYe

Association study among candidate genetic polymorphisms and chemotherapy-related severe toxicity in testicular cancer patients

Testicular cancer is one of the most commonly occurring malignant tumors in young men with fourfold higher rate of incidence and threefold higher mortality rates in Chile than the average global rates. Surgery is the initial line of treatment for testicular cancers, and is generally followed by chemotherapy, usually with combinations of bleomycin, etoposide, and cisplatin (BEP). However, the adverse effects of chemotherapy vary significantly among individuals; therefore, the present study explored the association of functionally significant allelic variations in genes related to the pharmacokinetics/pharmacodynamics of BEP and DNA repair enzymes with chemotherapy-induced toxicity in BEP-treated testicular cancer patients. We prospectively recruited 119 patients diagnosed with testicular cancer from 2010 to 2017. Genetic polymorphisms were analyzed using PCR and/or qPCR with TaqMan®probes. Toxicity was evaluated based on the Common Terminology Criteria for Adverse Events, v4.03. After univariate analyses to define more relevant genetic variants (p &lt; 0.2) and clinical conditions in relation to severe (III-IV) adverse drug reactions (ADRs), stepwise forward multivariate logistic regression analyses were performed. As expected, the main severe ADRs associated with the non-genetic variables were hematological (neutropenia and leukopenia). Univariate statistical analyses revealed that patients with ERCC2 rs13181 T/G and/or CYP3A4 rs2740574 A/G genotypes are more likely to develop alopecia; patients with ERCC2 rs238406 C/C genotype may develop leukopenia, and patients with GSTT1-null genotype could develop lymphocytopenia (III-IV). Patients with ERCC2 rs1799793 A/A were at risk of developing severe anemia. The BLMH rs1050565 G/G genotype was found to be associated with pain, and the GSTP1 G/G genotype was linked infection (p &lt; 0.05). Multivariate analysis showed an association between specific ERCC1/2 genotypes and cumulative dose of BEP drugs with the appearance of severe leukopenia and/or febrile neutropenia. Grades III-IV vomiting, nausea, and alopecia could be partly explained by the presence of specific ERCC1/2, MDR1, GSTP1, and BLMH genotypes (p &lt; 0.05). Hence, we provide evidence for the usefulness of pharmacogenetics as a tool for predicting severe ADRs in testicular cancer patients treated with BEP chemotherapy