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- Cismaru, Anca Liliana, et al.
(författare)
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Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations
- 2020
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Ingår i: Genes. - : MDPI AG. - 2073-4425 .- 2073-4425. ; 11:11
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Duthaler, Urs, et al.
(författare)
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The effect of food on the pharmacokinetics of oral ivermectin
- 2020
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Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 75:2, s. 438-440
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Tidskriftsartikel (refereegranskat)abstract
- Background: Ivermectin is an older anthelminthic agent that is being studied more intensely given its potential for mass drug administration against scabies, malaria and other neglected tropical diseases. Its pharmacokinetics (PK) remain poorly characterized. Furthermore, the majority of PK trials are performed under fasted-state dosing conditions, and the effect of food is therefore not well known. To better plan and design field trials with ivermectin, a model that can account for both conditions would be valuable.Objectives: To develop a PK model and characterize the food effect with single oral doses of ivermectin.Patients and methods: We performed a population-based PK analysis of data pooled from two previous trials of a single dose of 12mg ivermectin, one with dosing after a high-fat breakfast (n=12) and one with fasted-state dosing (n=3).Results: The final model described concentration-time profiles after fed and fasted dosing accurately, and estimated the food effect associated with relative bioavailability to 1.18 (95% CI 1.10-1.67).Conclusions: In this analysis, the effect of a high-fat breakfast compared with a fasted-state administration of a single oral dose of 12mg ivermectin was minimal.
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