{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T20:06:38Z","timestamp":1760817998613,"version":"3.43.0"},"reference-count":20,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:p>Metamizole is a widely prescribed NSAID with excellent analgesic and antipyretic properties. Although very effective, it is banned in some countries because of the risk for severe agranulocytosis. We here describe three patients with metamizole-associated agranulocytosis. Patient #1 suffered from agranulocytosis and tonsillitis followed by severe sepsis by <jats:italic toggle=\"yes\">Streptococcus pneumoniae<\/jats:italic> and Epstein\u2013Barr virus reactivation. Her dizygotic twin sister (patient #2) also suffered from agranulocytosis after a surgical intervention. Patient #3 initially had a tonsillitis and also developed neutropenia after metamizole intake. For all patients, pharmacogenetic diagnostic for the genes <jats:italic toggle=\"yes\">CYP2C9<\/jats:italic>, <jats:italic toggle=\"yes\">CYP2C19<\/jats:italic> and <jats:italic toggle=\"yes\">NAT2<\/jats:italic>, which are involved in metamizole metabolism and degradation of toxic metabolites, was initiated. Pharmacogenetic analysis revealed NAT2 slow acetylator phenotype in all three patients. Additionally, patient #2 is an intermediate metabolizer for <jats:italic toggle=\"yes\">CYP2C19<\/jats:italic> and patient #3 is a poor metabolizer for <jats:italic toggle=\"yes\">CYP2C9<\/jats:italic>. Impairment of these enzymes causes a reduced degradation of toxic metabolites, for example, 4-methylaminoantipyrine (4-MAA) or 4-aminoantipyrine. The metabolite 4-MAA can complex with hemin, which is an early breakdown product during hemolysis. Hemolysis is often observed during invasive infections or after surgical procedures. It is known that the 4-MAA\/hemin complex can induce cytotoxicity in the bone marrow and interrupt granulocyte maturation. In conclusion, metamizole-induced agranulocytosis most likely was a consequence of the underlying genetical predisposition, that is, polymorphisms in the genes <jats:italic toggle=\"yes\">NAT2<\/jats:italic>, <jats:italic toggle=\"yes\">CYP2C9<\/jats:italic> and <jats:italic toggle=\"yes\">CYP2C19<\/jats:italic>. Hemolysis may have increased the toxicity of metamizole metabolites.<\/jats:p>","DOI":"10.1097\/fpc.0000000000000432","type":"journal-article","created":{"date-parts":[[2021,3,6]],"date-time":"2021-03-06T11:01:55Z","timestamp":1615028515000},"page":"140-143","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":9,"title":["NAT2 polymorphisms as a cause of metamizole-induced agranulocytosis"],"prefix":"10.1097","volume":"31","author":[{"given":"Ivana","family":"Radulovic","sequence":"first","affiliation":[{"name":"Department of Pediatrics III, Pediatric Hematology and Oncology, Cardiology, Pulmonology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Burcin","family":"Dogan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics I, Neonatology, Pediatric Intensive Care, Pediatric Neurology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Dohna-Schwake","sequence":"additional","affiliation":[{"name":"Department of Pediatrics I, Neonatology, Pediatric Intensive Care, Pediatric Neurology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael M.","family":"Sch\u00fcndeln","sequence":"additional","affiliation":[{"name":"Department of Pediatrics III, Pediatric Hematology and Oncology, Cardiology, Pulmonology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Winfried","family":"Siffert","sequence":"additional","affiliation":[{"name":"Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birte","family":"M\u00f6hlendick","sequence":"additional","affiliation":[{"name":"Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2021,3,5]]},"reference":[{"key":"R1-20250808","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1007\/s00228-015-1895-y","article-title":"Metamizole (dipyrone)-associated agranulocytosis. 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