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- Konte, B, et al.
(författare)
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HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry
- 2021
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1, s. 214-
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Tidskriftsartikel (refereegranskat)abstract
- The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E−06) and agranulocytosis (OR = 10.49, P = 1.83E−06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E−08; agranulocytosis: OR = 16.31, P = 1.39E−06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.
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- Puehringer, F. K., et al.
(författare)
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Sugammadex rapidly reverses moderate rocuronium- or vecuronium-induced neuromuscular block during sevoflurane anaesthesia: a dose-response relationship
- 2010
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Ingår i: British Journal of Anaesthesia. - : Elsevier BV. - 1471-6771 .- 0007-0912. ; 105:5, s. 610-619
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Tidskriftsartikel (refereegranskat)abstract
- Sugammadex shows a dose-response relationship for reversal of neuromuscular block (NMB) during propofol anaesthesia. Sevoflurane, unlike propofol, can prolong the effect of neuromuscular blocking agents (NMBAs), increasing recovery time. This open-label, randomized, dose-finding trial explored sugammadex dose-response relationships, safety, and pharmacokinetics when administered for reversal of moderate rocuronium- or vecuronium-induced NMB during sevoflurane maintenance anaesthesia. After anaesthesia induction with propofol, adult patients were randomized to receive single-dose rocuronium 0.9 mg kg(-1) or vecuronium 0.1 mg kg(-1), with maintenance doses as needed. Anaesthesia was maintained with sevoflurane. NMB was monitored using acceleromyography. After the last dose of NMBA, at reappearance of T-2, single-dose sugammadex 0.5, 1.0, 2.0, or 4.0 mg kg(-1) or placebo was administered. The primary efficacy variable was time from the start of sugammadex administration to recovery of T-4/T-1 ratio to 0.9. Safety assessments were performed throughout. The per-protocol population comprised 93 patients (rocuronium, n=46; vecuronium, n=47). A statistically significant dose-response relationship was demonstrated for mean recovery times of T-4/T-1 ratio to 0.9 with increasing sugammadex dose with both NMBAs: rocuronium, 96.3 min (placebo) to 1.5 min (sugammadex 4.0 mg kg(-1)); vecuronium, 79.0 min (placebo) to 3.0 min (sugammadex 4.0 mg kg(-1)). Plasma sugammadex concentrations indicated linear pharmacokinetics, independent of NMBA administered. No study drug-related serious adverse events occurred. Evidence of reoccurrence of block was reported in seven patients [sugammadex 0.5 mg kg(-1) (suboptimal dose), n=6; 2.0 mg kg(-1), n=1]. During sevoflurane maintenance anaesthesia, sugammadex provides well-tolerated, effective, dose-dependent reversal of moderate rocuronium- and vecuronium-induced NMB.
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- Zindovic, Igor, et al.
(författare)
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The Coagulopathy of Acute Type A Aortic Dissection : A Prospective, Observational Study
- 2019
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Ingår i: Journal of Cardiothoracic and Vascular Anesthesia. - : Elsevier BV. - 1053-0770. ; 33:10, s. 2746-2754
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate the hemostatic system in patients undergoing surgery for acute type A aortic dissection (ATAAD) compared with those undergoing elective aortic procedures. Design: This was a prospective, observational study. Setting: The study was performed at a single university hospital. Participants: Twenty-five patients with ATAAD were compared with 20 control patients undergoing elective surgery of the ascending aorta or the aortic root. Interventions: No interventions were performed. Measurements and Main Results: Platelet count and levels of fibrinogen, D-dimer, prothrombin time/international normalized ratio, activated partial thromboplastin time, and antithrombin were analyzed perioperatively and compared between the 2 groups. Patients with ATAAD had lower preoperative levels of platelets (188 [156-217] × 10 9 /L v 221 [196-240] × 10 9 /L; p = 0.018), fibrinogen (1.9 [1.6-2.4] g/L v 2.8 [2.2-3.0] g/L; p = 0.003), and antithrombin (0.81 [0.73-0.94] kIU/L v 0.96 [0.92-1.00] kIU/L; p = 0.003) and significantly higher levels of D-dimer (2.9 [1.7-9.7] mg/L v 0.1 [0.1-0.2] mg/L; p < 0.001) and prothrombin time/international normalized ratio (1.15 [1.1-1.2] v 1.0 [0.93-1.0]; p = 0.001). Surgery caused significant changes of the coagulation system in both groups. Intraoperative bleeding volumes were larger in the ATAAD group (2,407 [1,804-3,209] mL v 1,212 [917-1,920] mL; p < 0.001), and patients undergoing ATAAD surgery received significantly more transfusions of red blood cells (2.5 [0.25-4.75] U v 0 [0-2.75] U; p = 0.022), platelets (4 [3.25-6] U v 2 [2-4] U; p = 0.002), and plasma (2 [0-4] U v 0 [0-0] U; p = 0.004) compared with the elective group. Conclusions: This study demonstrates that ATAAD is associated with a coagulopathic state. Surgery causes additional damage to the hemostatic system in ATAAD patients, but also in patients undergoing elective surgery of the ascending aorta or the aortic root.
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