A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study.

BACKGROUND: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. METHODS: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. FINDINGS: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54-0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61-0·79]; p <0·0001). INTERPRETATION: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. FUNDING: European Union Horizon 2020.

Being precise with anticoagulation to reduce adverse drug reactions: are we there yet?

Anticoagulants are potent therapeutics widely used in medical and surgical settings, and the amount spent on anticoagulation is rising. Although warfarin remains a widely prescribed oral anticoagulant, prescriptions of direct oral anticoagulants (DOACs) have increased rapidly. Heparin-based parenteral anticoagulants include both unfractionated and low molecular weight heparins (LMWHs). In clinical practice, anticoagulants are generally well tolerated, although interindividual variability in response is apparent. This variability in anticoagulant response can lead to serious incident thrombosis, haemorrhage and off-target adverse reactions such as heparin-induced thrombocytopaenia (HIT). This review seeks to highlight the genetic, environmental and clinical factors associated with variability in anticoagulant response, and review the current evidence base for tailoring the drug, dose, and/or monitoring decisions to identified patient subgroups to improve anticoagulant safety. Areas that would benefit from further research are also identified. Validated variants in VKORC1, CYP2C9 and CYP4F2 constitute biomarkers for differential warfarin response and genotype-informed warfarin dosing has been shown to reduce adverse clinical events. Polymorphisms in CES1 appear relevant to dabigatran exposure but the genetic studies focusing on clinical outcomes such as bleeding are sparse. The influence of body weight on LMWH response merits further attention, as does the relationship between anti-Xa levels and clinical outcomes. Ultimately, safe and effective anticoagulation requires both a deeper parsing of factors contributing to variable response, and further prospective studies to determine optimal therapeutic strategies in identified higher risk subgroups.

Cardiovascular drugs and COVID-19 clinical outcomes: a systematic review and meta-analysis of randomized controlled trials.

AIMS: To update our previously reported systematic review and meta-analysis of observational studies on cardiovascular drug exposure and COVID-19 clinical outcomes by focusing on newly published randomized controlled trials (RCTs). METHODS: More than 500 databases were searched between 1 November 2020 and 2 October 2021 to identify RCTs that were published after our baseline review. One reviewer extracted data with other reviewers verifying the extracted data for accuracy and completeness. RESULTS: After screening 22 414 records, we included 24 and 21 RCTs in the qualitative and quantitative syntheses, respectively. The most investigated drug classes were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARBs) and anticoagulants, investigated by 10 and 11 studies respectively. In meta-analyses, ACEI/ARBs did not affect hospitalization length (mean difference -0.42, 95% confidence interval [CI] -1.83; 0.98 d, n = 1183), COVID-19 severity (risk ratio/RR 0.90, 95% CI 0.71; 1.15, n = 1661) or mortality (risk ratio [RR] 0.92, 95% CI 0.58; 1.47, n = 1646). Therapeutic anticoagulation also had no effect (hospitalization length mean difference -0.29, 95% CI -1.13 to 0.56 d, n = 1449; severity RR 0.86, 95% CI 0.70; 1.04, n = 2696; and, mortality RR 0.93, 95% CI 0.77; 1.13, n = 5689). Other investigated drug classes were antiplatelets (aspirin, 2 trials), antithrombotics (sulodexide, 1 trial), calcium channel blockers (amlodipine, 1 trial) and lipid-modifying drugs (atorvastatin, 1 trial). CONCLUSION: Moderate- to high-certainty RCT evidence suggests that cardiovascular drugs such as ACEIs/ARBs are not associated with poor COVID-19 outcomes, and should therefore not be discontinued. These cardiovascular drugs should also not be initiated to treat or prevent COVID-19 unless they are needed for an underlying currently approved therapeutic indication.

A European cross-sectional survey to investigate how involved doctors training in clinical pharmacology are in drug concentration monitoring.

PURPOSE: Therapeutic drug monitoring (TDM) is widely recognised as a key attribute of clinical pharmacologists; yet, the extent to which physicians undertaking postgraduate training in clinical pharmacology (hereafter trainees) are involved in TDM is poorly characterised. Our own experience suggests wide variation in trainee exposure to TDM. METHOD: We performed a Europe-wide cross-sectional internet-based survey of trainees to determine the nature and extent of trainee involvement in TDM. RESULTS: There were 43 responses from eight countries analysed. Of the 21 respondents from the UK, all were also training in general internal medicine (GIM), while all of the respondents who were solely training in clinical pharmacology were from outside the UK. Overall, 86.0% of respondents reported access to drug monitoring for clinical care at their affiliated institution, of which 81.0% were personally involved in TDM in some capacity. On average, trainees reported that drug monitoring was available for 16 of the 33 (48%) of the drug/drug classes surveyed. UK-based respondents were involved in requesting drug-level investigations and interpreting the results for patients under their care in 76.2% and 85.7% of cases, respectively, while non-UK respondents supported other healthcare professionals to interpret results in 45.4% of cases. Trainees felt TDM training was generally either insufficient or very inadequate. CONCLUSION: While access to TDM is relatively available at institutions where trainees are based, the role of trainees is variable and affected by a variety of factors including country and training programme. Universally, trainees feel they need more education in TDM.

Pharmacogenomics of anticancer drugs: Personalising the choice and dose to manage drug response.

The field of pharmacogenomics has made great strides in oncology over the last 20 years and indeed a significant number of pre-emptive genetic tests are now routinely undertaken prior to anticancer drug administration. Many of these gene-drug interactions are the fruits of candidate gene and genome-wide association studies, which have largely focused on common genetic variants (allele frequency>1%). Examples where there is clinical utility include genotyping or phenotyping for G6PD to prevent rasburicase-induced RBC haemolysis, and TPMT to prevent thiopurine-induced bone marrow suppression. Other associations such as CYP2D6 status in determining the efficacy of tamoxifen are more controversial because of contradictory evidence from different sources, which has led to variability in the implementation of testing. As genomic technology becomes ever cheaper and more accessible, we must look to the additional data our genome can provide to explain interindividual variability in anticancer drug response. Clearly genes do not act on their own and it is therefore important to investigate genetic factors in conjunction with clinical factors, interacting concomitant drug therapies and other factors such as the microbiome, which can all affect drug disposition. Taking account of all of these factors, in conjunction with the somatic genome, is more likely to provide better predictive accuracy in determining anticancer drug response, both efficacy and safety. This review summarises the existing knowledge related to the pharmacogenomics of anticancer drugs and discusses areas of opportunity for further advances in personalisation of therapy in order to improve both drug safety and efficacy.

Cardiovascular drugs and COVID-19 clinical outcomes: A living systematic review and meta-analysis.

AIMS: The aim of this study was to continually evaluate the association between cardiovascular drug exposure and COVID-19 clinical outcomes (susceptibility to infection, disease severity, hospitalization, hospitalization length, and all-cause mortality) in patients at risk of/with confirmed COVID-19. METHODS: Eligible publications were identified from more than 500 databases on 1 November 2020. One reviewer extracted data with 20% of the records independently extracted/evaluated by a second reviewer. RESULTS: Of 52 735 screened records, 429 and 390 studies were included in the qualitative and quantitative syntheses, respectively. The most-reported drugs were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) with ACEI/ARB exposure having borderline association with confirmed COVID-19 infection (OR 1.14, 95% CI 1.00-1.31). Among COVID-19 patients, unadjusted estimates showed that ACEI/ARB exposure was associated with hospitalization (OR 1.76, 95% CI 1.34-2.32), disease severity (OR 1.40, 95% CI 1.26-1.55) and all-cause mortality (OR 1.22, 95% CI 1.12-1.33) but not hospitalization length (mean difference -0.27, 95% CI -1.36-0.82 days). After adjustment, ACEI/ARB exposure was not associated with confirmed COVID-19 infection (OR 0.92, 95% CI 0.71-1.19), hospitalization (OR 0.93, 95% CI 0.70-1.24), disease severity (OR 1.05, 95% CI 0.81-1.38) or all-cause mortality (OR 0.84, 95% CI 0.70-1.00). Similarly, subgroup analyses involving only hypertensive patients revealed that ACEI/ARB exposure was not associated with confirmed COVID-19 infection (OR 0.93, 95% CI 0.79-1.09), hospitalization (OR 0.84, 95% CI 0.58-1.22), hospitalization length (mean difference -0.14, 95% CI -1.65-1.36 days), disease severity (OR 0.92, 95% CI 0.76-1.11) while it decreased the odds of dying (OR 0.76, 95% CI 0.65-0.88). A similar trend was observed for other cardiovascular drugs. However, the validity of these findings is limited by a high level of heterogeneity and serious risk of bias. CONCLUSION: Cardiovascular drugs are not associated with poor COVID-19 outcomes in adjusted analyses. Patients should continue taking these drugs as prescribed.

Generating evidence for precision medicine: considerations made by the Ubiquitous Pharmacogenomics Consortium when designing and operationalizing the PREPARE study.

OBJECTIVES: Pharmacogenetic panel-based testing represents a new model for precision medicine. A sufficiently powered prospective study assessing the (cost-)effectiveness of a panel-based pharmacogenomics approach to guide pharmacotherapy is lacking. Therefore, the Ubiquitous Pharmacogenomics Consortium initiated the PREemptive Pharmacogenomic testing for prevention of Adverse drug Reactions (PREPARE) study. Here, we provide an overview of considerations made to mitigate multiple methodological challenges that emerged during the design. METHODS: An evaluation of considerations made when designing the PREPARE study across six domains: study aims and design, primary endpoint definition and collection of adverse drug events, inclusion and exclusion criteria, target population, pharmacogenomics intervention strategy, and statistical analyses. RESULTS: Challenges and respective solutions included: (1) defining and operationalizing a composite primary endpoint enabling measurement of the anticipated effect, by including only severe, causal, and drug genotype-associated adverse drug reactions; (2) avoiding overrepresentation of frequently prescribed drugs within the patient sample while maintaining external validity, by capping drugs of enrolment; (3) designing the pharmacogenomics intervention strategy to be applicable across ethnicities and healthcare settings; and (4) designing a statistical analysis plan to avoid dilution of effect by initially excluding patients without a gene-drug interaction in a gatekeeping analysis. CONCLUSION: Our design considerations will enable quantification of the collective clinical utility of a panel of pharmacogenomics-markers within one trial as a proof-of-concept for pharmacogenomics-guided pharmacotherapy across multiple actionable gene-drug interactions. These considerations may prove useful to other investigators aiming to generate evidence for precision medicine.

Investigating the clinical factors and comedications associated with circulating levels of atorvastatin and its major metabolites in secondary prevention.

Aims The lipid-lowering drug, atorvastatin (ATV), is 1 of the most commonly prescribed medications worldwide. The aim of this study was to comprehensively investigate and characterise the clinical factors and comedications associated with circulating levels of ATV and its metabolites in secondary prevention clinical practice. Methods The plasma concentrations of ATV, 2-hydroxy (2-OH) ATV, ATV lactone (ATV L) and 2-OH ATV L were determined in patients 1 month after hospitalisation for a non-ST elevation acute coronary syndrome. Factors were identified using all subsets multivariable regression and model averaging with the Bayesian information criterion. Exploratory genotype-stratified analyses were conducted using ABCG2 rs2231142 (Q141K) and CYP2C19 metaboliser status to further investigate novel associations. Results A total of 571 patients were included; 534 and 37 were taking ATV 80 mg and 40 mg daily, respectively. Clinical factors associated with ATV and/or its metabolite levels included age, sex, body mass index and CYP3A inhibiting comedications. Smoking was newly associated with increased ATV lactonisation and reduced hydroxylation. Proton pump inhibitors (PPIs) and loop diuretics were newly associated with modestly increased levels of ATV (14% and 38%, respectively) and its metabolites. An interaction between PPIs and CYP2C19 metaboliser status on exposure to specific ATV analytes (e.g. interaction P = .0071 for 2-OH ATV L) was observed. Overall model R2 values were 0.14-0.24.ConclusionMultiple factors were associated with circulating ATV and metabolite levels, including novel associations with smoking and drug-drug(-gene) interactions involving PPIs and loop diuretics. Further investigations are needed to identify additional factors that influence ATV exposure.

Callipeltosides A, B and C: Total Syntheses and Structural Confirmation.

Since their isolation almost 20 years ago, the callipeltosides have been of long standing interest to the synthetic community owing to their unique structural features and inherent biological activity. Herein we present our full research effort that has led to the synthesis of these molecules. Key aspects of our final strategy include 1) synthesis of the C1-C9 pyran core (5) using an AuCl3 -catalysed cyclisation; 2) formation of C10-C22 vinyl iodide (55) by sequential bidirectional Stille reactions and 3) diastereoselective union of these advanced fragments by means of an alkenylzinc addition (d.r.=91:9 at C9). The common callipeltoside aglycon (4) was completed in a further five steps. Following this, all three sugar fragments were appended to provide the entire callipeltoside family. In addition to this, D-configured callipeltose B was synthesised and appended to the callipeltoside aglycon. The (1) H NMR spectrum of this molecule was found to be significantly different to the natural isolate, further supporting our assignment of callipeltoside B (2).

Flow chemistry meets advanced functional materials.

Flow chemistry and continuous processing techniques are beginning to have a profound impact on the production of functional materials ranging from quantum dots, nanoparticles and metal organic frameworks to polymers and dyes. These techniques provide robust procedures which not only enable accurate control of the product material's properties but they are also ideally suited to conducting experiments on scale. The modular nature of flow and continuous processing equipment rapidly facilitates reaction optimisation and variation in function of the products.

Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis.

AIMS: To determine whether thiazolidinedione use is associated with a risk of bladder cancer. METHODS: We searched MEDLINE and EMBASE in June 2012 (with PubMed update to July 2013) and conducted meta-analysis on the overall risks of bladder cancer with pioglitazone or rosiglitazone and the risk with different categories of cumulative dose or duration of drug use. RESULTS: We screened 230 citations and included 18 studies, comprising five randomized controlled trials (RCTs) and 13 observational studies. Meta-analysis showed a significantly higher overall risk of bladder cancer with pioglitazone in RCTs [7878 participants; odds ratio (OR) 2.51, 95% confidence interval (CI) 1.09-5.80] and observational studies (>2.6 million patients; OR for 'ever' users vs. non-users 1.21, 95% CI 1.09-1.35). Subgroup analysis of observational studies by cumulative dose showed the risk of bladder cancer to be greatest with >28.0 g of pioglitazone (OR 1.64, 95% CI 1.28-2.12). A significantly increased risk was found with both 12-24 months (OR 1.41, 95% CI 1.16-1.71) and >24 months (OR 1.51, 95% CI 1.26-1.81) cumulative durations of pioglitazone exposure. No significant risk was seen with rosiglitazone in RCTs (OR 0.84, 95% CI 0.35-2.04) or 'ever' users vs. non-users in observational studies (OR 1.03, 95% CI 0.94-1.12); the evidence for any relationship between bladder cancer risk and rosiglitazone cumulative duration is limited and inconsistent. Direct comparison of pioglitazone to rosiglitazone 'ever' users yielded an OR of 1.25 (95% CI 0.91-1.72). CONCLUSIONS: A modest but clinically significant increase in the risk of bladder cancer with pioglitazone was found, which appears to be related to cumulative dose and duration of exposure. We recommend that prescribers limit pioglitazone use to shorter durations.

A self-organizing chemical assembly line.

Chemical syntheses generally involve a series of discrete transformations whereby a simple set of starting materials are progressively rendered more complex. In contrast, living systems accomplish their syntheses within complex chemical mixtures, wherein the self-organization of biomolecules allows them to form "assembly lines" that transform simple starting materials into more complex products. Here we demonstrate the functioning of an abiological chemical system whose simple parts self-organize into a complex system capable of directing the multistep transformation of the small molecules furan, dioxygen, and nitromethane into a more complex and information-rich product. The novel use of a self-assembling container molecule to catalytically transform a high-energy intermediate is central to the system's functioning.

Continuous flow reaction monitoring using an on-line miniature mass spectrometer.

RATIONALE: A recently developed miniature electrospray ionisation mass spectrometer has been coupled to a preparative flow chemistry system in order to monitor reactive intermediates and competing reaction paths, screen starting materials, and optimise reaction conditions. Although ideally suited to the application, mass spectrometers have rarely been used in this way, as traditional instruments are too bulky to be conveniently coupled to flow chemistry platforms. METHODS: A six-port switching valve fitted with a 5 µL loop was used to periodically sample the flow stream leaving the reactor coil. Mass spectra corresponding to the sample loop contents were observed approximately 10 s after activating the valve. High fluidic pressure was maintained throughout to ensure that gaseous products remained in solution. As an illustrative example of how this apparatus can be employed, the generation of benzyne and its subsequent reaction with furan were investigated. Benzyne was prepared via diazotisation of anthranilic acid using tert-butyl nitrite. RESULTS: Unexpectedly, the explosive diazotised intermediate was detected by the mass spectrometer at low coil temperatures or short residence times. The optimum reactor temperature and residence time for production of the desired Diels-Alder product are 50 °C and 3-5 min, respectively. There are competing reaction pathways leading to the formation of acridone and several other by-products. CONCLUSIONS: On-line mass spectrometry allowed the flow conditions to be quickly tuned for safe operation and optimal generation of the desired product. The validity of this approach was corroborated by off-line liquid chromatography/mass spectrometry (LC/MS) analysis of flow samples.

Statins and associated risk of pneumonia: a systematic review and meta-analysis of observational studies.

PURPOSE: Statins have potential anti-inflammatory effects, but the association between statin use and lower incidence of pneumonia is unclear. We have therefore performed a systematic review on the risk of pneumonia in statin users versus non-users. METHODS: MEDLINE and EMBASE were searched in December 2010 for controlled observational studies that reported on the risk of pneumonia in statin users. We performed a random effects meta-analysis and assessed heterogeneity using the I² statistic. RESULTS: A total of 451 citations were screened, and ultimately nine studies (4 case-control, 4 retrospective cohort, 1 prospective cohort) with more than 3 million participants were included in the meta-analysis. Pooled analysis of seven studies that reported unadjusted data failed to show a significantly reduced risk of pneumonia [odds ratio (OR) 0.94, 95% confidence interval (CI) 0.84-1.06, p = 0.33, I² = 79%] in statin users as compared to non-users. However, a significant reduction in the likelihood of pneumonia associated with statin use (n = 8 studies, OR 0.85, 95% CI 0.75-0.97, p = 0.02, I² = 81%) was found in the meta-analysis of adjusted data. Both analyses were limited by substantial statistical heterogeneity. Sensitivity analysis failed to fully clarify the source of heterogeneity, but cohort studies seemed to be less heterogenous (n = 5 studies, OR 0.92, 95% CI 0.84-1.01, I² = 43%). CONCLUSION: Our findings indicate that the purported benefit of statins in preventing pneumonia is inconsistent, and of low magnitude, with upper bounds of the confidence interval being close to null. In view of the substantial statistical and clinical heterogeneity in the dataset, there is no convincing evidence to support the therapeutic application of statins for reducing the risk of pneumonia.

Pharmacogenomics decision support in the U-PGx project: Results and advice from clinical implementation across seven European countries.

BACKGROUND: The clinical implementation of pharmacogenomics (PGx) could be one of the first milestones towards realizing personalized medicine in routine care. However, its widespread adoption requires the availability of suitable clinical decision support (CDS) systems, which is often impeded by the fragmentation or absence of adequate health IT infrastructures. We report results of CDS implementation in the large-scale European research project Ubiquitous Pharmacogenomics (U-PGx), in which PGx CDS was rolled out and evaluated across more than 15 clinical sites in the Netherlands, Spain, Slovenia, Italy, Greece, United Kingdom and Austria, covering a wide variety of healthcare settings. METHODS: We evaluated the CDS implementation process through qualitative and quantitative process indicators. Quantitative indicators included statistics on generated PGx reports, median time from sampled upload until report delivery and statistics on report retrievals via the mobile-based CDS tool. Adoption of different CDS tools, uptake and usability were further investigated through a user survey among healthcare providers. Results of a risk assessment conducted prior to the implementation process were retrospectively analyzed and compared to actual encountered difficulties and their impact. RESULTS: As of March 2021, personalized PGx reports were produced from 6884 genotyped samples with a median delivery time of twenty minutes. Out of 131 invited healthcare providers, 65 completed the questionnaire (response rate: 49.6%). Overall satisfaction rates with the different CDS tools varied between 63.6% and 85.2% per tool. Delays in implementation were caused by challenges including institutional factors and complexities in the development of required tools and reference data resources, such as genotype-phenotype mappings. CONCLUSIONS: We demonstrated the feasibility of implementing a standardized PGx decision support solution in a multinational, multi-language and multi-center setting. Remaining challenges for future wide-scale roll-out include the harmonization of existing PGx information in guidelines and drug labels, the need for strategies to lower the barrier of PGx CDS adoption for healthcare institutions and providers, and easier compliance with regulatory and legal frameworks.

The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms.

Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin-associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long-term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP-C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1, ABCG2, and CYP2C9 genotype with the goal of improving the overall safety, adherence, and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin-induced myopathy.

The role of pharmacogenomics in contemporary cardiovascular therapy: a position statement from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.

There is a strong and ever-growing body of evidence regarding the use of pharmacogenomics to inform cardiovascular pharmacology. However, there is no common position taken by international cardiovascular societies to unite diverse availability, interpretation, and application of such data, nor is there recognition of the challenges of variation in clinical practice between countries within Europe. Aside from the considerable barriers to implementing pharmacogenomic testing and the complexities of clinically actioning results, there are differences in the availability of resources and expertise internationally within Europe. Diverse legal and ethical approaches to genomic testing and clinical therapeutic application also require serious thought. As direct-to-consumer genomic testing becomes more common, it can be anticipated that data may be brought in by patients themselves, which will require critical assessment by the clinical cardiovascular prescriber. In a modern, pluralistic and multi-ethnic Europe, self-identified race/ethnicity may not be concordant with genetically detected ancestry and thus may not accurately convey polymorphism prevalence. Given the broad relevance of pharmacogenomics to areas, such as thrombosis and coagulation, interventional cardiology, heart failure, arrhythmias, clinical trials, and policy/regulatory activity within cardiovascular medicine, as well as to genomic and pharmacology subspecialists, this position statement attempts to address these issues at a wide-ranging level.

Challenges in cardiovascular pharmacogenomics implementation: a viewpoint from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.

Pharmacogenomics promises to advance cardiovascular therapy, but there remain pragmatic barriers to implementation. These are particularly important to explore within Europe, as there are differences in the populations, availability of resources, and expertise, as well as in ethico-legal frameworks. Differences in healthcare delivery across Europe present a challenge, but also opportunities to collaborate on pharmacogenomics implementation. Clinical workforce upskilling is already in progress but will require substantial input. Digital infrastructure and clinical support tools are likely to prove crucial. It is important that widespread implementation serves to narrow rather than widen any existing gaps in health equality between populations. This viewpoint supplements the working group position paper on cardiovascular pharmacogenomics to address these important themes.

Total synthesis of chloptosin: a dimeric cyclohexapeptide.

Here we describe in full our investigations into the synthesis of the dimeric cyclohexapeptide chloptosin in 17 linear steps. Particularly, this work features an organocatalytic tandem process for the synthesis of the embedded piperazic acids, in which a differentially protected azodicarboxylate is used together with pyrrolidinyl tetrazole as the catalyst. The central biaryl bond is being formed by Stille coupling of two sterically demanding ortho-chloropyrroloindole fragments. The inherent flexibility of the synthetic strategy proved beneficial as the route could be adjusted smoothly during the progression of the synthesis programme.