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Mechanisms and Genetics of Metamizole-induced Agranulocytosis

English title Mechanisms and Genetics of Metamizole-induced Agranulocytosis
Applicant Haschke Manuel
Number 160206
Funding scheme Project funding
Research institution Klinische Pharmakologie und Toxikologie Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Clinical Pharmacology
Start/End 01.03.2016 - 29.02.2020
Approved amount 429'000.00
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Keywords (5)

genome-wide association; metamizole; metabolic toxicity; drug-induced agranulocytosis; immune-mediated toxicity

Lay Summary (German)

Lead
Metamizol ist ein gut wirksames Schmerzmedikament. Bei bestimmten Patienten kann es aber einen lebensbedrohlichen Mangel an weissen Blutzellen (Neutropenie) verursachen. In diesem Projekt werden die zugrundeliegenden Mechanismen sowie genetische Merkmale untersucht, welche das Risiko für diese gefährliche Toxizität erhöhen.
Lay summary

Hintergrund und Ziele des Forschungsprojektes

Metamizol wird aufgrund seiner guten schmerzlindernden und fiebersenkenden Wirkung immer häufiger eingesetzt. Während viele Patienten Metamizol auch über längere Zeit problemlos vertragen,  können andere Patienten unter Metamizol eine lebensbedrohliche Neutropenie entwickeln. Der Mangel an weissen Blutzellen erhöht das Risiko von bakteriellen Infektionen. Für Patienten, die wegen Magen-Darmerkrankungen oder Nierenfunktions-störungen nicht mit üblichen Schmerzmedikamenten wie z.B. NSAR behandelt werden können, ist Metamizol abgesehen von Opiate jedoch praktisch die einzige gut wirksame Alternative. Die genauen Ursachen für die Toxizität von Metamizol sind bis heute nicht geklärt. Auch ist zurzeit nicht möglich, gefährdete Patienten vor Beginn einer Therapie zu identifizieren.

Ziel dieses Projektes ist es, die Ursachen und Risikofaktoren für die Metamizol-induzierte Neutropenie zu klären, um die Patientensicherheit unter Metamizol-Therapie zu erhöhen. Dazu werden direkte Toxizitätsmechanismen von Metamizol und seinen Abbauprodukten auf die weissen Blutzellen und deren Vorläuferzellen untersucht. Parallel wird untersucht, ob es zu einer Aktivierung des körpereigenen Immunsystems kommt, welches weisse Blutzellen oder deren Vorläuferzellen im Knochenmark zerstören kann. Zusätzlich wird nach einer genetischen Veranlagung gesucht, welche das Risiko für eine Neutropenie erhöht.

Bedeutung des Forschungsprojektes

Das Projekt wird zu einem besseren Verständnis über Mechanismen und Risikofaktoren der Metamizol-induzierten Neutropenie beitragen. Im Rahmen der personalisierten Medizin wird dies eine verbesserte individuelle Risikostratifizierung ermöglichen. Entsprechend kann Metamizol bei Patienten, welche andere Schmerzmittel schlecht vertragen mit minimalem Risiko eingesetzt werden, während es bei gefährdeten Patienten vermieden wird. So werden weniger Patienten gefährdet und es können Kosten für die Behandlung von betroffenen Patienten eingespart werden.

Direct link to Lay Summary Last update: 04.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Development and validation of an LC–MS/MS method for the bioanalysis of the major metamizole metabolites in human plasma
Bachmann Fabio, Blaser Lea, Haschke Manuel, Krähenbühl Stephan, Duthaler Urs (2020), Development and validation of an LC–MS/MS method for the bioanalysis of the major metamizole metabolites in human plasma, in Bioanalysis, 12(3), 175-189.
Metamizole-associated neutropenia: Comparison of patients with neutropenia and metamizole-tolerant patients
Rudin Deborah, Spoendlin Julia, Cismaru Anca L., Liakoni Evangelia, Bonadies Nicolas, Amstutz Ursula, Meier Christoph R., Krähenbühl Stephan, Haschke Manuel (2019), Metamizole-associated neutropenia: Comparison of patients with neutropenia and metamizole-tolerant patients, in European Journal of Internal Medicine, 68, 36-43.
Toxicity of metamizole on differentiating HL60 cells and human neutrophil granulocytes
Rudin Deborah, Roos Noëmi Johanna, Duthaler Urs, Krähenbühl Stephan (2019), Toxicity of metamizole on differentiating HL60 cells and human neutrophil granulocytes, in Toxicology, 426, 152254-152254.
Non-immunological toxicological mechanisms of metamizole-associated neutropenia in HL60 cells.
Rudin Deborah, Lanzilotto Angelo, Bachmann Fabio, Housecroft Catherine E, Constable Edwin C, Drewe Jürgen, Haschke Manuel, Krähenbühl Stephan (2019), Non-immunological toxicological mechanisms of metamizole-associated neutropenia in HL60 cells., in Biochemical pharmacology, 163, 345-356.
N -demethylation of N -methyl-4-aminoantipyrine, the main metabolite of metamizole
Bachmann Fabio, Duthaler Urs, Rudin Deborah, Krähenbühl Stephan, Haschke Manuel (2018), N -demethylation of N -methyl-4-aminoantipyrine, the main metabolite of metamizole, in European Journal of Pharmaceutical Sciences, 120, 172-180.

Collaboration

Group / person Country
Types of collaboration
Dr. Mariam Molokhia, Department of Population Health Sciences, King’s College London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Reinhold Kreutz, Institute of Clinical Pharmacology and Toxicology, Charité Berlin Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Sinuhe HahnDepartment of Biomedicine University Hospital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Werner J. Pichler, ADR-AC GmbH Switzerland (Europe)
- Industry/business/other use-inspired collaboration
Prof. J. Passweg, Hematology and stem cell transplantation, University Hospital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Luisa Ibañez, Vall d’Hebron University Hospital and Autonomous University of Barcelona Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Colin J. Ross, Depts. of Pediatrics and Medical Genetics, University of British Columbia Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Rémy Bruggman, Dr. Irene Keller, University of Bern Bioinformatics Group Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dr. Mia Wadelius, Dr. Pär Hallberg; Department of Medical Genetics, Uppsala University Sweden (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
14th International Summer School on Immunogenetics and Histocompatibility Talk given at a conference Genetics of metamizole-induced agranulocytosis 14.07.2019 Montreal, Canada Cismaru Anca Liliana; Amstutz Ursula;
EAACI 8th Drug Hypersensitivity Meeting Poster Involvement of the Adaptive Immune System in Metamizole-induced Agranulocytosis 20.04.2018 Amsterdam, Netherlands Dina Dolores; Yerly Daniel;


Awards

Title Year
Poster award (3rd place) Schweizerische Gesellschaft für Klinische Chemie Jahrestagung, Bern, CH, 15-16.11.2018 2018

Associated projects

Number Title Start Funding scheme
179346 Efficacy of Metamizole or Ibuprofen With or Without a Short Educational Intervention Compared to Standard Care in Acute and Subacute Low Back Pain (the EMISI trial): A Multicenter, Randomized, Factorial Trial 01.03.2019 Project funding

Abstract

Metamizole is an analgesic and antipyretic drug widely used in many parts of the world, including European countries such as Germany, France and Switzerland. Although metamizole has a favorable overall safety profile, susceptible patients can experience agranulocytosis, a severe and potentially fatal loss of neutrophil granulocytes. This serious adverse drug reaction has led to the withdrawal of metamizole from the market in some countries. However, drug withdrawal is not an optimal solution, as metamizole, due to its favorable gastrointestinal and renal tolerability is a valuable treatment option for patients intolerant to conventional non-steroidal antiinflammatory drugs. This has led to a continuous rise in metamizole prescriptions in recent years, paralleled by a growing number of safety reports on metamizole-induced hematologic toxicity, including multiple cases with fatal outcome. Despite the use of broad-spectrum antibiotics and granulocyte growth factors, the fatality rate of metamizole-induced agranulocytosis is approximately 10%. The increasing use of metamizole and the severity of its hematologic toxicity highlight the need to improve the safety of metamizole treatment.To date, the mechanisms underlying metamizole-induced agranulocytosis are poorly understood. Whilesome evidence points to immune-mediated mechanisms, other observations, such as the rapid onset of the adverse reaction in some patients and the observation that bi-and pancytopenia can occur, favor a direct toxic mechanism on hematopoiesis. Since hematotoxicity of metamizole is an idiosyncratic adverse reaction (i.e. rare manifestation at therapeutic dose), affected patients must have susceptibility factors. Regardless of the mechanism of toxicity, individual susceptibility risk may be determined by genetic factors.To improve the safety of the growing number of patients treated with metamizole, a better understanding of such susceptibility factors is needed. We therefore propose a project for the comprehensive investigation of the mechanisms and genetics of metamizole-induced agranulocytosis, with the goal of identifying susceptibility factors that would allow efficient pre-treatment risk stratification. Similar approaches have already successfully been implemented for other drugs (e.g. abacavir, carbamazepine, azathioprine), resulting in a major improvement of their benefit-risk profile and preventing their removal from the market.In our project, we plan to investigate in the first part, whether A) direct metabolic toxicity or B) immune-mediatedmechanisms can lead to metamizole-induced agranulocytosis. In the second part, we will conduct a case-control association study to identify genetic risk factors. To this aim, we will compare a unique case cohort of patients who suffered metamizole-induced agranulocytosis with metamizole-tolerant and matched population controls. Using recent genotyping and sequencing technology, we plan to use a complementary approach of a targeted, comprehensive investigation of HLA genomic regions often implicated in immunemediated drug reactions, and a genome-wide analysis of genetic variation to investigate novel pathways potentially involved in metamizole-induced agranulocytosis.By comprehensively investigating underlying mechanisms and the potential genetic basis of metamizoleinduced agranulocytosis, this project is expected to generate important new knowledge regarding factors associated with susceptibility to this serious adverse drug reaction. The results of the project will facilitate informed clinical decision-making and have direct implications for patient safety and the healthcare system, both by preventing exposure of at-risk patients and by saving expenses for the treatment of affected patients.
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