Metoprolol is a selective β-1 adrenergic receptor blocker that undergoes extensive metabolism by the polymorphic enzyme, CYP2D6. Our objective was to investigate the influence of CYP2D6 polymorphisms on efficacy and tolerability of metoprolol tartrate. 281 study participants with uncomplicated hypertension received 50 mg of metoprolol twice daily followed by response guided titration to 100 mg twice daily. Phenotypes were assigned based on results of CYP2D6 genotyping and copy number variation assays. Clinical response to metoprolol and adverse effect rates were analyzed in relation to CYP2D6 phenotypes by using appropriate statistical tests. Heart rate response differed significantly by CYP2D6 phenotype (p-value <0.0001) with poor metabolizers & intermediate metabolizers showing greater HR reduction. However, blood pressure response and adverse effect rates were not significantly different by CYP2D6 phenotype. Other than a significant difference in heart rate response, CYP2D6 polymorphisms were not a determinant of the variability in response or tolerability to metoprolol.

Cardiotoxicity has been extensively reported in venlafaxine (VEN) overdoses. Asthenia is also among the common side effects described for this antidepressant. VEN is metabolized mainly by CYP2D6 and to a minor extent by CYP2C19 to the major active metabolite O-desmethylvenlafaxine (ODV). Altered pharmacokinetic parameters in patients with polymorphisms in the CYP2D6 and CYP2C19 genes that result in decreased enzymatic activity have been documented. Here we describe a patient case of VEN associated palpitations and asthenia. The patient takes VEN extended release 150 mg twice daily. Genotyping confirmed the patient is a poor metabolizer for CYP2D6 and an intermediate metabolizer for CYP2C19. We propose that the palpitations and asthenia are related to sustained VEN exposure due to reduced metabolism.

Background:The advent of medical alternatives to splenectomy, particularly the thrombopoietin receptor agonists (TPO‐RA) has seen reduction in its use for ITP. It is now generally reserved in the UK for patients who fail multiple lines of therapy.Aims:We aimed to evaluate practices around splenectomy in the UK and long term response rates using data from the UK ITP registry, a large national database of primary ITP cases set up in 2007.Methods:We analysed all splenectomy cases from the UK ITP registry entered to December 2018. Data was studied on demographics, response rates, relapse rates and influence on response to medical therapies. Statistical analysis was performed using STATA. To identify the influence of medical therapies, we divided patients into treatment time brackets: 1989–1998, 1999–2008 and 2009–2018. The following response criteria were used:Complete response (CR platelets>100 x 109/l),partial response (PR platelets>30 but <100x109/l or doubling from baseline),overall response (OR = PR+CR).Results:Of 3236 registered patients(ITP diagnosis date ranging 1951 – 2018), 321(9.92%)(62%F/38%M) had undergone splenectomy with a total of 4611patient‐years follow‐up(Median 13.2 years, IQR 6.68,23.6). Median age at splenectomy was 40 years(y)(IQR27.0, 55.5).86.2%(268 patients) were <65y old and 13.8%(43 patients) 65y or older.72 patients were excluded from subsequent analysis due to incomplete data(including patients who had splenectomy <1989).Number of patients undergoing splenectomy decreased over time:1989–1998 34.1%;1999–2008 14.8%;2009–2018 4.8%. Median time from ITP diagnosis to splenectomy was 1.46y(IQR 0,20.3) increasing from 1.51y(IQR0,9.23.) in 1989–1998 to 1.69y(IQR0.14,18.5) in 2009–2018. This was associated with an increase in median number of treatment modalities from 2(IQR1,3) in 1989–1998 to 3 (IQR1,7) in 2009–2018 and median number of treatment episodes from 1(IQR1,2) in 1989–1998 to 3 (IQR1,11) in 2009–2018 pre‐splenectomy. The most common treatment modalities pre‐splenectomy were prednisolone(92%),IV immunoglobulin(50%),Azathioprine(27%),Rituximab(21%),Dexamethasone(12%),Mycophenolate(10%) and Romiplostim(10%).CR/PR and OR rates post‐splenectomy were 63.1%/24.3%/87.4% at 1month and 52.2%/15.3%/67.5% at 6months.67.2% of patients who had OR to splenectomy at 1month still had OR at latest follow‐up(median follow‐up 10.5y,IQR4.37,14.4).OR in patients <65y old were 86.8% at 1month and 51.8% at 6months post‐splenectomy.OR in those 65y and older were 73.9% at 1month and 46.2% at 6months post‐splenectomy.Beyond 6 months there is a trend towards reducing response in >65y group, but currently further analysis is limited by missing data.Overall median duration of response(DOR) was 2.5y(IQR0.51,7.01).The median DOR fell over time from 7.35y(1989–1998) to 0.52y(2009–2018).Median DOR was 3.02y in <65y old(IQR0.60,7.70) and 0.76y in 65y or older(IQR0.17,4.2.93).In patients who relapsed post‐splenectomy, median time to treatment was 2.56y(IQR0.09,35.48).59patients(18.4%) had complications post splenectomy.42patients(13.1%) had infections of which 32cases(76.2%) were attributed to splenectomy.53patients(11.2%) had an arterial or venous thrombotic event post‐splenectomy. Of 4deaths(1.25%),1 was listed as being attributed to splenectomy.Summary/Conclusion:Splenectomy rates for ITP in the UK have fallen since 1989, associated with increased medical treatment. There appears to be a trend to reduced response rates and shortened remission duration when this is used later in the treatment pathway.

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