Metamizole-associated neutropenia: Comparison of patients with neutropenia and metamizole-tolerant patients

Rudin, Deborah; Spoendlin, Julia; Cismaru, Anca Liliana; Liakoni, Evangelia; Bonadies, Nicolas; Amstutz, Ursula; Meier, Christoph; Krähenbühl, Stephan; Haschke, Manuel

doi:10.1016/j.ejim.2019.07.029

Cited by 14 publications

(17 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This study was approved by the local ethics committees ("Ethikkommission Nordwest-und Zentralschweiz" and "Kantonale Ethikkommission Bern, " BASEC protocol number 2015-00231). Clinical data was collected as described previously (Rudin et al, 2019c).…”

Section: Participants and Settingmentioning

confidence: 99%

High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis

et al. 2020

Self Cite

View full text Add to dashboard Cite

Cismaru et al. HLA and Pharmacogenetics of Metamizole-Agranulocytosis Results: Eight candidate alleles (p < 0.05) were identified in the discovery subset, of which HLA-C * 04:01 was associated with MIA in the full Swiss cohort (p < 0.01) restricted to agranulocytosis (ANC < 0.5 × 10 9 /L) cases. However, no candidate allele showed a consistent association in the Swiss, German and Spanish cohorts. Analysis of individual sequence variants in class I genes produced consistent results with HLA typing but did not reveal additional small nucleotide variants associated with MIA. Conclusion: Our results do not support an HLA-restricted T cell-mediated immune mechanism for MIA. However, we established an efficient high-resolution (threefield) eight-locus HTS HLA resequencing method to interrogate the HLA region and demonstrated the feasibility of its application to pharmacogenetic studies.

show abstract

Section: Participants and Settingmentioning

confidence: 99%

High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Since erythrocytes have no mitochondria, they have to rely solely on glycolysis for ATP generation [ 45 ] and could therefore be a target for MAA/hemin toxicity. In support of this assumption, anemia possibly associated with the use of metamizole has been reported in patients with metamizole-induced neutropenia [ 12 , 22 ]. However, anemia is not as frequent as would be expected in patients with metamizole-induced neutropenia, when ATP generation by glycolysis is considered to be an important risk factor for metamizole-induced cytotoxicity.…”

Section: Discussionmentioning

confidence: 89%

“…An allergic mechanism is supported by the fact that metamizole can cause skin eruptions [ 9 , 17 ] and liver injury [ 18 , 19 ] by a delayed type of drug allergy and by the finding that myelotoxicity may be related to a certain HLA constellation [ 20 ]. However, allergic features such as exanthema, eosinophilia, or lymphadenopathy are usually lacking in patients with metamizole-induced myelotoxicity [ 21 , 22 ], rendering an allergic mechanism less probable. MAA can react with the iron contained in heme and form reactive electrophilic metabolites [ 6 , 23 ], which suggests another mechanism for the observed myelotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Reactive Metamizole Metabolites Enhance the Toxicity of Hemin on the ATP Pool in HL60 Cells by Inhibition of Glycolysis

et al. 2020

Self Cite

View full text Add to dashboard Cite

Metamizole is an analgesic, whose pharmacological and toxicological properties are attributed to N-methyl-aminoantipyrine (MAA), its major metabolite. In the presence of heme iron, MAA forms reactive metabolites, which are toxic for granulocyte precursors. Since decreased cellular ATP is characteristic for MAA-associated toxicity, we studied the effect of MAA with and without hemin on energy metabolism of HL60 cells, a granulocyte precursor cell line. The combination MAA/hemin depleted the cellular ATP stronger than hemin alone, whereas MAA alone was not toxic. This decrease in cellular ATP was observed before plasma membrane integrity impairment. MAA/hemin and hemin did not affect the proton leak but increased the maximal oxygen consumption by HL60 cells. This effect was reversed by addition of the radical scavenger N-acetylcysteine. The mitochondrial copy number was not affected by MAA/hemin or hemin. Hemin increased mitochondrial superoxide generation, which was not accentuated by MAA. MAA decreased cellular ROS accumulation in the presence of hemin. In cells cultured in galactose (favoring mitochondrial ATP generation), MAA/hemin had less effect on the cellular ATP and plasma membrane integrity than in glucose. MAA/hemin impaired glycolysis more than hemin or MAA alone, and N-acetylcysteine blunted this effect of MAA/hemin. MAA/hemin decreased protein expression of pyruvate kinase more than hemin or MAA alone. In conclusion, cellular ATP depletion appears to be an important mechanism of MAA/hemin toxicity on HL60 cells. MAA itself is not toxic on HL60 cells up to 100 µM but boosts the inhibitory effect of hemin on glycolysis through the formation of reactive metabolites.

show abstract

“…Tolerant controls included in the study had received at least 500 mg metamizole per day for a minimum of twenty-eight consecutive days, a treatment duration encompassing the latency time observed for a majority of cases for the occurrence of MIA based on a previous report [6]. Clinical drug tolerability during metamizole therapy was assessed by the absence of symptoms including fever, sore throat, or mucositis [23]. EDTA blood samples for genetic analyses were collected and coded at the time of recruitment.…”

Section: Study Design and Participantsmentioning

confidence: 99%

“…Clinical data, including patient characteristics and concomitant drug therapy (such as antibiotics, analgesics and β-lactam antibiotics) were retrieved from medical charts. A more detailed description of participants recruited for this study has been previously published [23]. In addition, participants genotyped as part of a project of the EuDAC were assigned to two independent replication cohorts based on their recruitment site: Germany (EuDAC-DE) and Spain (EuDAC-ES).…”

Section: Study Design and Participantsmentioning

confidence: 99%

Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations

Cismaru

Rudin

Ibáñez

et al. 2020

Genes

Self Cite

View full text Add to dashboard Cite

Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 × 10−7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41–6.68, p = 1.01 × 10−7) and rs4427239 (OR = 5.47, 95%CI: 2.81–10.65, p = 5.75 × 10−7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.

show abstract

Metamizole-associated neutropenia: Comparison of patients with neutropenia and metamizole-tolerant patients

Cited by 14 publications

References 22 publications

High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis

High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis

Reactive Metamizole Metabolites Enhance the Toxicity of Hemin on the ATP Pool in HL60 Cells by Inhibition of Glycolysis

Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations

Contact Info

Product

Resources

About