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Tacrolimus, as one of cytochrome P450 (CYP) 4/5 substrates is known to have many drug–drug interactions. Metabolism of tacrolimus is inhibited by many drugs, such as the azole antifungal agents due to their effects on CYP 3A4/5. Implementation of therapeutic drug monitoring is commended during tacrolimus treatment for maintaining optimal plasma concentration levels, and to avoid its toxicity. We herein report a case of a 58-year-old female patient with lupus nephritis whose plasma concentration of orally ministered tacrolimus increased after a single administration of 300 mg voriconazole for suspected Aspergillus infection. Our observations were the result of therapeutic drug monitoring before the second administration of voriconazole. Although tacrolimus dose did not vary, the plasma tacrolimus concentration was markedly increased and concentration dose ratio was 2.1 fold more than prior to voriconazole treatment. This case suggests that even after a single intravenous administration of voriconazole, the plasma concentration of tacrolimus may increase. Dose optimization of tacrolimus by therapeutic drug monitoring soon after the first dose of voriconazole is therefore warranted to minimize the risk of tacrolimus toxicity.

Substantial interindividual variability exists in drug response. This variability often means differences in drug concentrations in the body between individuals receiving the same dose. Insufficient drug concentrations can cause poor efficacy whereas too high concentrations can predispose to adverse drug reactions. Genetic variants in pharmacokinetic genes, which encode drug-metabolizing enzymes and drug transporters, can affect drug concentrations, and thus, drug pharmacokinetics in the body. Knowledge of the effects of genetic variants in these genes can enable dose adjustments and more safe and efficient drug treatments. This doctoral thesis investigated the associations of genetic variants in pharmacokinetic genes with the pharmacokinetics of four drugs: montelukast, fluvastatin, telmisartan, and celiprolol. For this purpose, full pharmacokinetic profiles of the drugs were determined in 188-200 healthy volunteers after a single dose of each drug and 379 pharmacokinetic genes were fully sequenced using targeted massive parallel sequencing. Statistical analyses were performed using stepwise linear regression analysis with log-additive modelling. The analyses were done with all 379 genes applying Bonferroni-correction and with selected candidate genes without correction for multiple testing. The linear regression models of the candidate gene analyses were used to generate multigenic genotype scores, which predict the fold differences in areas under the plasma concentration-time curves (AUC0-∞) between carriers of different genetic variants and non-carriers. As a mechanistic validation, in vitro experiments were performed to further confirm the role of the identified metabolizing enzymes on the metabolism of montelukast and fluvastatin enantiomers, and the role of the identified transporter on the transport of fluvastatin enantiomers. Furthermore, the thesis investigated the associations of genetic variants, which were found to be associated with montelukast pharmacokinetics, with messenger ribonucleic acid (mRNA) expression of the respective genes in human liver samples. The increased-function UGT1A3*2 allele was associated with significantly decreased plasma concentrations of montelukast and with increased glucuronidation. The AUC0-∞ of montelukast was 18% smaller per copy of the UGT1A3*2 allele (P = 2.75 × 10-10). UGT1A3 variants have not previously been associated with montelukast pharmacokinetics. The gene encodes the uridine diphospho glucuronosyltransferase (UGT) 1A3 drug-metabolizing enzyme. In addition to UGT1A3, single nucleotide variations (SNV) in CYP2C8 (encoding cytochrome P450 (CYP) 2C8 enzyme) and ABCC9 (encoding sulfonylurea receptor 2) genes were associated with montelukast pharmacokinetics in the candidate gene analysis. In vitro, montelukast was highly metabolized by UGT1A3. Furthermore, variants in ABCC9 and UGT1A3 were associated with mRNA expression in human liver samples. The no function CYP2C9*3 allele was associated with significantly increased plasma concentrations of fluvastatin enantiomers. The AUC0-∞ of active 3R,5S-fluvastatin was increased by 67% (P = 3.77 × 10-9) and that of inactive 3S,5R-fluvastain by 94% (P = 3.19 × 10-12) per copy of the allele. CYP2C9 encodes the CYP2C9 drug-metabolizing enzyme. The no function c.521T>C SNV in SLCO1B1 gene, which encodes organic anion transporting polypeptide (OATP) 1B1 transporter, was associated with increased AUC0-∞ of 3R,5S-fluvastatin but not with that of 3S,5R-fluvastatin. Thus, the effect of this genetic variant appears to be enantiospecific although both enantiomers were transported similarly by OATP1B1 in vitro. On the other hand, SLCO2B1 transporter gene (encoding OATP2B1) SNVs were associated only with 3S,5R-fluvastatin AUC0-∞ in the candidate gene analysis. The decreased-function CYP2C9*2 allele was associated with increased AUC0-∞ of both fluvastatin enantiomers in the candidate gene analysis. The increased-function UGT1A3*2 allele was associated with significantly decreased plasma concentrations of telmisartan and increased plasma concentrations of telmisartan acyl-glucuronide. In addition, the telmisartan plasma concentrations were lower in men than in women. The AUC0-∞ of telmisartan in men heterozygous and homozygous for UGT1A3*2 was decreased by 64% (P = 1.21 × 10-16) and 63% (P = 5.21 × 10-8), respectively. In heterozygous and homozygous women, the decreases were 57% (P = 1.54 × 10-11) and 72% (P = 3.31 × 10-15), respectively. An SLCO1B3 SNV was associated with increased telmisartan AUC0-∞ in the candidate gene analysis. SLCO1B3 encodes the OATP1B3 transporter. No variants were associated with celiprolol pharmacokinetics in the analysis with the 379 pharmacokinetic genes. In the candidate gene analysis, variants in transporter genes SLCO1A2 and ABCB1, which encode OATP1A2 and P-glycoprotein, respectively, were associated with reduced celiprolol AUC0-∞. This thesis showed that genetic variants explain a significant proportion of interindividual variability in the pharmacokinetics of montelukast, fluvastatin, telmisartan, and celiprolol. The multigenic genotype scores combined the effects of the significantly associated variants. In the case of montelukast, telmisartan, and celiprolol, individuals with low genotype score values may have an increased risk of poor efficacy. In the case of fluvastatin, individuals with high genotype score for the active 3R,5S-fluvastatin may have an increased risk of adverse reactions. Furthermore, the studies found associations of genetic variants that have not previously been associated with drug pharmacokinetics. Yksilöiden väliset erot lääkeaineiden farmakokinetiikassa eli lääkeaineiden vaiheissa ja pitoisuuksissa elimistössä voivat aiheuttaa merkittävää vaihtelua lääkkeiden tehossa tai haittavaikutusriskissä. Liian suuret lääkeainepitoisuudet lisäävät haittavaikutusten riskiä, kun taas liian pienet pitoisuudet huonon tehon riskiä. Keskeisiä farmakokineettisiä geenejä ovat lääkeaineiden aineenvaihduntaentsyymejä ja kuljetusproteiineja koodaavat geenit, joissa esiintyvät geenimuunnokset voivat vaikuttaa lääkeaineiden pitoisuuksiin. Farmakokineettisissä geeneissä esiintyvien geenimuunnosten vaikutusten ymmärtäminen voi mahdollistaa lääkeannosten yksilöllisen valinnan sekä tehokkaamman ja turvallisemman lääkehoidon. Tämän tutkimuksen tavoitteena oli tutkia, miten farmakokineettisten geenien geenimuunnokset vaikuttavat montelukastin, fluvastatiinin, telmisartaanin ja seliprololin farmakokinetiikkaan. Tutkimukseen osallistui 200 tervettä vapaaehtoista tutkittavaa, joille annettiin kerta-annos kutakin tutkimuslääkettä ja lääkeaineiden pitoisuudet määritettiin verinäytteistä. Lisäksi tutkittavilta sekvensoitiin kohdennetusti 379 farmakokineettistä geeniä. Geenimuunnosten yhteyttä pitoisuuksista laskettuihin farmakokineettisiin muuttujiin tutkittiin 379 geenin analyysissa ja kandidaattigeenianalyysissa. Sekä montelukastin että telmisartaanin farmakokinetiikkaan vaikutti merkitsevimmin UGT1A3 geenin ilmentymistä lisäävä UGT1A3*2 alleeli, joka pienensi molempien lääkeaineiden pitoisuuksia plasmassa. Toimimatonta CYP2C9-entsyymiä tuottava CYP2C9*3 alleeli lisäsi merkitsevästi kummankin fluvastatiinin enantiomeerin pitoisuuksia plasmassa, mutta SLCO1B1-kuljetusproteiinigeenin toimimaton c.521T>C muunnos lisäsi vain aktiiviseen 3R,5S-fluvastatiiniin pitoisuuksia. Kandidaattigeenianalyyseissa löytyi lisäksi useita merkitseviä geenimuunnoksia kaikille neljälle lääkeaineelle. Kullekin lääkeaineelle muodostettiin tulosten perusteella genotyyppikerroin, joka kuvaa eri geenimuunnosten yhdistelmien vaikutusta lääkeainealtistukseen. Tämän tutkimuksen tulokset osoittavat, että geneettinen vaihtelu selittää ison osan tutkittujen lääkeaineiden farmakokinetiikan vaihtelusta. Tutkimuksessa tunnistettiin myös muunnoksia, joita ei ole aiemmin yhdistetty lääkeaineiden farmakokineettisiin muuttujiin. Muodostetuista genotyyppikertoimista voi olla hyötyä lääkehoitojen yksilöllistämisessä.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9∗2 (rs1799853), CYP2C9∗3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in extreme-dosage patients. The predictability of the pharmacogenetic algorithm did not vary significantly between diseases., This study was funded by a grant from the Spanish Ministry of Health and Social Policy (Instituto de Salud Carlos III, PI07/0710) and the Andalusian Regional Ministry of Health (Progress and Health Foundation, PI-0717-2013)

The blood-brain barrier significantly limits effective drug delivery to central nervous system (CNS) targets. The recently characterized glymphatic system offers a perivascular highway for intrathecally (i.t.) administered drugs to reach deep brain structures. Although periarterial cerebrospinal fluid (CSF) influx and concomitant brain drug delivery can be enhanced by pharmacological or hyperosmotic interventions, their effects on drug delivery to the spinal cord, an important target for many drugs, have not been addressed. Hence, we studied in rats whether enhancement of periarterial flow by systemic hypertonic solution might be utilized to enhance spinal delivery and efficacy of i.t. morphine. We also studied whether the hyperosmolar intervention affects brain or cerebrospinal fluid drug concentrations after systemic administration. Periarterial CSF influx was enhanced by intraperitoneal injection of hypertonic saline (HTS, 5.8%, 20 ml/kg, 40 mOsm/kg). The antinociceptive effects of morphine were characterized, using tail flick, hot plate and paw pressure tests. Drug concentrations in serum, tissue and microdialysis samples were determined by liquid chromatography-tandem mass spectrometry. Compared with isotonic solution, HTS increased concentrations of spinal i.t. administered morphine by 240% at the administration level (T13-L1) at 60 min and increased the antinociceptive effect of morphine in tail flick, hot plate, and paw pressure tests. HTS also independently increased hot plate and paw pressure latencies but had no effect in the tail flick test. HTS transiently increased the penetration of intravenous morphine into the lateral ventricle, but not into the hippocampus. In conclusion, acute systemic hyperosmolality is a promising intervention for enhanced spinal delivery of i.t. administered morphine. The relevance of this intervention should be expanded to other i.t. drugs and brought to clinical trials.

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.

Inflammation; Neuroprotection; Stroke Inflamació; Neuroprotecció; Ictus Inflamación; Neuroprotección; Ictus In the reperfusion era, a new paradigm of treating patients with endovascular treatment (EVT) and neuroprotective drugs is emerging as a promising therapeutic option for patients with acute ischemic stroke (AIS). In this context, ApTOLL, a Toll-like receptor 4 (TLR4) antagonist with proven neuroprotective effect in preclinical models of stroke and a very good pharmacokinetic and safety profile in healthy volunteers, is a promising first-in-class aptamer with the potential to address this huge unmet need. This protocol establishes the clinical trial procedures to conduct a Phase Ib/IIa clinical study (APRIL) to assess ApTOLL tolerability, safety, pharmacokinetics, and biological effect in patients with AIS who are eligible for EVT. This will be a multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to evaluate the administration of ApTOLL together with EVT in patients with AIS. The study population will be composed of men and non-pregnant women with confirmed AIS with a

Background Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. Objective This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail. Methods In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim(R). The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (C-max), and trough concentrations for multiple dosings (C-trough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens. Results The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregateC(max)ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregateC(max)ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2 mg/L to

Drug-drug interactions (DDIs) are a major concern for the safe use of medications. Breast cancer resistance protein (BCRP) is a clinically relevant ATP-binding cassette (ABC) transporter for drug disposition. Inhibition of BCRP increases the plasma concentrations of BCRP substrate drugs, which potentially could lead to adverse drug reactions. The aim of the present study was to identify BCRP inhibitors amongst a library of 232 commonly used drugs and anticancer drugs approved by the United States Food and Drug Administration (FDA). BCRP inhibition studies were carried out using the vesicular transport assay. We found 75 drugs that reduced the relative transport activity of BCRP to less than 25% of the vehicle control and were categorized as strong inhibitors. The concentration required for 50% inhibition (IC50) was determined for 13 strong inhibitors that were previously poorly characterized for BCRP inhibition. The IC50 ranged from 1.1 to 11 mu M, with vemurafenib, dabigatran etexilate and everolimus being the strongest inhibitors. According to the drug interaction guidance documents from the FDA and the European Medicines Agency (EMA), in vivo DDI studies are warranted if the theoretical intestinal luminal concentration of a drug exceeds its IC50 by tenfold. Here, the IC50 values for eight of the drugs were 100-fold lower than their theoretical intestinal luminal concentration. Moreover, a mechanistic static model suggested that vemurafenib, bexarotene, dabigatran etexilate, rifapentine, aprepitant, and ivacaftor could almost fully inhibit intestinal BCRP, increasing the exposure of concomitantly administered rosuvastatin over 90%. Therefore, clinical studies are warranted to investigate whether these drugs cause BCRP-mediated DDIs in humans.

Pathogen-focused, randomized, controlled trials (PF-RCT) are important in the fight against carbapenem-resistant (CR) Gram-negative infections. Some recently approved antibiotics and older generic antibiotics with activity against CR Gram-negative bacteria were investigated in PF-RCTs in a variety of infections. We searched Pubmed, Cochrane database and international clinical trial databases for PF-RCTs for the period between 2005 and 2020 and compared the study designs, patient populations, infection types, pathogens, and Day-28 all-cause mortality (ACM). PF-RCTs are particularly challenging to quantitatively assess and compare due to the heterogeneity in infection types, pathogens, CR mechanism, inclusion/exclusion criteria, and endpoints. Data interpretation is further complicated by lack of formal statistical analysis plans and/or non-inferiority design, and limited power across most PF-RCTs. The studies with new antibiotics (i.e. plazomicin, meropenem/vaborbactam, cefiderocol) ranked lower regarding feasibility, with relatively small sample sizes (analyzed: 37–118) versus the comparative effectiveness studies of older generic drugs (analyzed: 94–406). ACM ranged between 11.8% and 40% for CR Enterobacterales, 17.7% and 57.4% for CR Acinetobacter spp., and 20.0% and 30.8% for CR Pseudomonas aeruginosa. The information gathered must be considered carefully alongside the study limitations and caution should be exercised when making direct comparisons across trials. PLAIN LANGUAGE SUMMARY New antibiotics to treat multidrug-resistant Gram-negative bacterial infections are needed because antimicrobial resistance has become a global threat. In recent years, several pathogen-focused, randomized, controlled clinical trials were conducted to test new antibiotics or combinations of older generic antibiotics in the fight against resistant bacteria. However, these trials were exceptionally challenging and most of them enrolled relatively few patients. These studies were highly heterogeneous in terms of species, antibiotics, infection site, mechanism of resistance, endpoints and patient factors. In these trials, all-cause mortality at Day 28 or Day 30 were numerically lower with the new antibiotics in infections caused by carbapenem-resistant (CR) Enterobacterales. However, in the trials which investigated CR Acinetobacter spp. infections, there was no reduction in all-cause mortality at Day 28 or Day 30 with combinations of older generic antibiotics compared with colistin monotherapy. Limited information was available for CR Pseudomonas aeruginosa. More pathogen-focused, randomized, controlled clinical trials with more feasible design and higher patient numbers are needed to demonstrate clinical benefit in drug-resistant infections.

Coronavirus; Operacions quirúrgiques; Epidemiologia Coronavirus; Intervenciones quirúrgicas; Epidemiología Coronavirus; Surgical procedures; Epidemiology Background: Surgical failure-to-rescue (FTR, death rate following complications) is a reliable cross-sectional quality of care marker, but has not been evaluated dynamically. We aimed to study changes in FTR following emergency surgery during the COVID-19 pandemic. Material and methods: Matched cohort study including all COVID-19-non-infected adult patients undergoing emergency general surgery in 25 Spanish hospitals during COVID-19 pandemic peak (March-April 2020), non-peak (May-June 2020), and 2019 control periods. A propensity score-matched comparative analysis was conducted using a logistic regression model, in which period was regressed on observed baseline characteristics. Subsequently, a mixed effects logistic regression model was constructed for each variable of interest. Main variable was FTR. Secondary variables were post-operative complications, readmissions, reinterventions, and length of stay. Results: 5003 patients were included (948, 1108, and 2947 in the pandemic peak, non-peak, and control periods), with comparable clinical characteristics, prognostic scores, complications, reintervention, rehospitalization rates, and length of stay across periods. FTR was greater during the pandemic peak than during non-peak and pre-pandemic periods (22.5% vs. 17.2% and 12.7%), being this difference confirmed in adjusted analysis (odds ratio [OR] 2.13, 95% confidence interval [95% CI] 1.27-3.66). There was sensible inter-hospital variability in FTR changes during the pandemic peak (median FTR change +8.77%, IQR 0-29.17%) not observed during the pandemic non-peak period (median FTR change 0%, IQR -6.01-6.72%). Greater FTR increase was associated with higher COVID-19 incidence (OR 2.31, 95% CI 1.31-4.16) and some hospital characteristics, including tertiary level (OR 3.07, 95% CI 1.27-8.00), medium-volume (OR 2.79, 95% CI 1.14-7.34), and high basal-adjusted complication risk (OR 2.21, 95% CI 1.07-4.72). Conclusion: FTR following emergency surgery experienced a heterogeneous increase during different periods of the COVID-19 pandemic, suggesting it to behave as an indicator of hospital resilience. FTR monitoring could facilitate identification of centres in special needs during ongoing health care challenges.

We investigated genetic determinants of single-dose simvastatin pharmacokinetics in a prospective study of 170 subjects and a retrospective cohort of 59 healthy volunteers. In a microarray-based genomewide association study with the prospective data, the SLCO1B1 c.521T>C (p.Val174Ala, rs4149056) single nucleotide variation showed the strongest, genomewide significant association with the area under the plasma simvastatin acid concentration-time curve (AUC; P = 6.0 x 10(-10)). Meta-analysis with the retrospective cohort strengthened the association (P = 1.6 x 10(-17)). In a stepwise linear regression candidate gene analysis among all 229 participants, SLCO1B1 c.521T>C (P = 1.9 x 10(-13)) and CYP3A4 c.664T>C (p.Ser222Pro, rs55785340, CYP3A4*2, P = 0.023) were associated with increased simvastatin acid AUC. Moreover, the SLCO1B1 c.463C>A (p.Pro155Thr, rs11045819, P = 7.2 x 10(-6)) and c.1929A>C (p.Leu643Phe, rs34671512, P = 5.3 x 10(-4)) variants associated with decreased simvastatin acid AUC. Based on these results and the literature, we classified the volunteers into genotype-predicted OATP1B1 and CYP3A4 phenotype groups. Compared with the normal OATP1B1 function group, simvastatin acid AUC was 273% larger in the poor (90% confidence interval (CI), 137%, 488%; P = 3.1 x 10(-6)), 40% larger in the decreased (90% CI, 8%, 83%; P = 0.036), and 67% smaller in the highly increased function group (90% CI, 46%, 80%; P = 2.4 x 10(-4)). Intermediate CYP3A4 metabolizers (i.e., heterozygous carriers of either CYP3A4*2 or CYP3A4*22 (rs35599367)), had 87% (90% CI, 39%, 152%, P = 6.4 x 10(-4)) larger simvastatin acid AUC than normal metabolizers. These data suggest that in addition to no function SLCO1B1 variants, increased function SLCO1B1 variants and reduced function CYP3A4 variants may affect the pharmacokinetics, efficacy, and safety of simvastatin. Care is warranted if simvastatin is prescribed to patients carrying decreased function SLCO1B1 or CYP3A4 alleles.

ObjectivesMental health conditions (MHCs) have been associated with undertreatment of unrelated medical conditions, but whether patients with MHCs face disparities in receiving rhythm control therapies for atrial fibrillation (AF) is currently unknown. We assessed the hypothesis that MHCs are associated with a lower use of antiarrhythmic therapies (AATs).DesignA nationwide retrospective registry-based cohort study.SettingThe Finnish AntiCoagulation in Atrial Fibrillation cohort included records on all patients with AF in Finland during 2007–2018 identified from nationwide registries covering all levels of care as well as drug purchases. MHCs of interest were diagnosed depression, bipolar disorder, anxiety disorder, schizophrenia and any MHC.ParticipantsWe identified 239 222 patients (mean age 72.6±13.2 years; 49.8% women) with incident AF, in whom the prevalence of any MHC was 19.9%.OutcomesPrimary outcome was use of any AAT, including cardioversion, catheter ablation, and fulfilled antiarrhythmic drug (AAD) prescription.ResultsLower overall use of any AAT emerged in patients with any MHC than in those without MHC (16.9% vs 22.9%, pConclusionsAmong patients with AF, a clear disparity exists in AAT use between those with and without MHCs.Trial registration numberClinicalTrials Identifier:NCT04645537; ENCePP Identifier: EUPAS29845.

BACKGROUND: Low socioeconomic status has been associated with higher risk of ischemic stroke and death in patients with atrial fibrillation (AF). However, whether socioeconomic status affects risk of bleeding events is unknown. We assessed the hypothesis that low income and educational attainment are associated with higher risk of bleeding in patients with AF. METHODS: The registry-based FinACAF study covers all patients with AF in Finland during 2007-2018. Patients were divided into income quartiles and three categories based on their educational attainment. Outcomes of interest were the first-ever gastrointestinal (GI), intracranial (IC) and any bleeding. RESULTS: We identified 205 019 patients (50.9 % female; mean age 72.3 (SD 13.4) years) with incident AF without prior bleeding. Mean follow-up time was 4.0 (SD 3.2) years, during which 25 013 (12.2 %) patients experienced first-ever any bleeding (incidence rate 3.07 (95 % CI 3.03-3.10) /100 patient-years). Low income was independently associated with hazard of any bleeding as well as GI and IC bleeding (adjusted hazard ratios (HRs) comparing lowest vs highest income quartile: 1.13 (1.08-1.17), 1.32 (1.23-1.41) and 1.15 (1.06-1.24), respectively). Income-related bleeding disparities were larger among younger patients under 65 years and among men. Education-related bleeding disparities were smaller than income related-disparities (adjusted HRs comparing lowest vs highest educational category: any bleeding 1.06 (1.02-1.11), GI bleeding 1.16 (1.08-1.24), IC bleeding 1.10 (0.93-1.09)). CONCLUSIONS: Patients with AF and low income are at higher risk of bleeding, especially GI bleeding. publishedVersion

Medical associations and other societies have announced their theses on protection of the climate and environmental aspects in medicine. The challenges with climate change and sustainability are complex, and no quick solutions are to be found. However, basic knowledge on these issues should be available to everyone, and environmental aspects of drugs are important to all healthcare professionals. We present here a study with medical students who were introduced for the first time to environmental aspects of medicines. The results confirmed the suitability and feasibility of the approach to introduce this subject to students, and we propose that the same method can be used also when explaining the issue to medical professionals. We would like to encourage particularly clinical pharmacologists, pharmacologists and pharmacists to take a more apparent position in this field and to participate in the discussions where the strategies for the choice of medicines are considered.

Purpose To study if second-generation antipsychotic (S-GA) use during the first trimester of pregnancy is associated with an increased risk of major congenital malformations (MCM). Methods A population-based birth cohort study using national register data extracted from the Drugs and Pregnancy database in Finland, years 1996–2017. The sampling frame included 1,273,987 pregnant women. We included singleton pregnancies ending in live or stillbirth or termination of pregnancy due to severe malformation. Pregnancies with exposure to known teratogens were excluded. Women were categorized into three groups: exposed to S-GAs (n = 3478), exposed to first-generation antipsychotics (F-GAs) (n = 1030), and unexposed (no purchases of S-GAs or F-GAs during pregnancy, n = 22,540). We excluded genetic conditions and compared the prevalence of MCMs in S-GA users to the two comparison groups using multiple logistic regression models. Results Use of S-GAs during early pregnancy was not associated with an increased risk of overall MCMs compared to unexposed (adjusted odds ratio, OR 0.92; 95% CI 0.72–1.19) or to F-GA users (OR 0.82; 95% CI 0.56–1.20). Of individual S-GAs, olanzapine use was associated with an increased risk of overall MCMs (OR 2.12; 95% CI 1.19–3.76), and specifically, an increased risk of musculoskeletal malformations (OR 3.71; 95% CI 1.35–10.1) when compared to unexposed, while comparisons to F-GA users did not show significant results. Conclusions Olanzapine use is associated with an increased risk of major congenital malformations and specifically, musculoskeletal malformations. Use during pregnancy should be restricted to situations where no safer alternatives exist.

Deletions covering the entire or partial JARID2 gene as well as pathogenic single nucleotide variants leading to haploinsufficiency of JARID2 have recently been shown to cause a clinically distinct neurodevelopmental syndrome phenotype. Here, we present a previously undescribed partial de novo duplication of the JARID2 gene in a patient displaying a phenotype associated with known JARID2 loss-of-function variant carriers. The phenotype of the index patient included coordination problems, clumsiness, language delay, unclear speech, problems with behavior and attention as well as difficulties with social contacts and daily activities. The patient has markedly dark infraorbital circles and slightly prominent supraorbital ridges. The phenotype shares a notable resemblance to previously characterized JARID2 deletion patients. Genetic analyses from the samples of the index patient and the parents were performed. Whole-genome sequencing and array comparative genomic hybridization revealed a novel disease-causing variant type, a partial tandem duplication of JARID2, covering the exons 1-7. Furthermore, RNA sequencing validated increased expression of these exons. Expression alterations were also detected in the target genes of PRC2 complex, in which JARID2 acts as an essential member. Our data adds to the variety of different pathogenic variants causing the JARID2 specific neurodevelopmental syndrome phenotype.

Intragenic segmental duplication regions are potential hotspots for recurrent copy number variation and possible pathogenic aberrations. Two large sarcomeric genes, nebulin and titin, both contain such segmental duplication regions. Using our custom Comparative Genomic Hybridisation array, we have previously shown that a gain or loss of more than one copy of the repeated block of the nebulin triplicate region constitutes a recessive pathogenic mutation. Using targeted array-CGH, similar copy number variants can be detected in the segmental duplication region of titin. Due to the limitations of the array-CGH methodology and the repetitiveness of the region, the exact copy numbers of the blocks could not be determined. Therefore, we developed complementary custom Droplet Digital PCR assays for the titin segmental duplication region to confirm true variation. Our combined methods show that the titin segmental duplication region is subject to recurrent copy number variation. Gains and losses were detected in samples from healthy individuals as well as in samples from patients with different muscle disorders. The copy number variation observed in our cohort is likely benign, but pathogenic copy number variants in the segmental duplication region of titin cannot be excluded. Further investigations are needed, however, this region should no longer be neglected in genetic analyses.

Atrial fibrillation; Oral anticoagulants; Adherence; Persistence; Electronic health records Fibrilación auricular; Tratamiento anticoagulante oral; Adherencia; Persistencia; Registros electrónicos de salud Fibril·lació auricular; Tractament anticoagulant oral; Adherència; Persistència; Registres electrònics de salut Objective: We aimed to describe sociodemographic, comorbidities, co-medication and risk of thromboembolic events and bleeding in patients with NVAF initiating oral anticoagulants (OAC) for stroke prevention, and to estimate adherence and persistence to OAC. Setting: Primary Health Care (PHC) in the Catalan Health Institute (ICS), Catalunya, Spain. Participants: All NVAF adult patients initiating OAC for stroke prevention in August 2013---December 2015. Methods: Population-based cohort study. Persistence was measured in patients initiating OAC in August 2013---December 2014. Data source: SIDIAP, which captures electronic health records from PHC in the (ICS), covering approximately 5.8 million people. Results: 51,690 NVAF patients initiated OAC; 47,197 (91.3%) were naive to OAC and 32,404 (62.7%) initiated acenocoumarol. Mean age was 72.8 years (SD 12.3) and 49.4% were women. Platelet-aggregation inhibitors were taken by 9105 (17.6%) of the patients. Persistence and adherence were estimated up to the end of follow-up. For 22,075 patients, persistence was higher among the non-naive patients [n = 258 (61.7%)] than among the naive [n = 11,502 (53.1%)]. Adherence was estimated for patients initiating DOAC and it was similar in naive and non-naive patients. Among the naive to DOAC treatment, those starting rivaroxaban showed a highest proportion [(n = 360 (80.1%)] of good adherence at implementation (MPR > 80%) while patients starting dabigatran were less adherent [n = 203 (47.8%)]. Conclusions: Acenocoumarol was the most frequently prescribed OAC as first therapy in NVAF patients. Non-naive to DOAC showed better persistence than naive. Rivaroxaban showed higher proportion of adherent patients during the implementation phase than apixaban and dabigatran the lowest. Objetivo: Describir datos sociodemográficos, comorbilidades, comedicaciones y riesgo de eventos tromboembólicos y hemorrágicos de los pacientes con fibrilación auricular no valvular (FANV) que inician tratamiento anticoagulante por vía oral (TAO) para prevención del ictus. Estimar adherencia y persistencia al TAO. Emplazamiento: Atención primaria (AP) del Instituto Catalán de Salud (ICS), Cataluña, España. Participantes: Adultos con FANV que inician TAO para prevención de ictus entre agosto del 2013 y diciembre del 2015. Métodos: Estudio de cohortes de base poblacional. Adherencia y persistencia se midieron en pacientes que iniciaban TAO entre agosto del 2013 y diciembre del 2014. Fuente de datos: SIDIAP, base de datos procedentes de registros electrónicos de AP del ICS, que cubre aproximadamente una población de 5,8 millones de personas. Resultados: Cincuenta y un mil seiscientos noventa pacientes con FANV iniciaron TAO, 47.197 (91,3%) eran naïve al TAO y 32.404 (62,7%) iniciaron acenocumarol. Su edad media era 72,8 años (DE 12,3) y el 49,4% eran mujeres; 90105 (17,6%) recibían tratamiento antiagregante plaquetario. Persistencia y adherencia se estimaron hasta el final del seguimiento. La persistencia a anticoagulantes orales directos (ACOD) fue mayor en no naïve que en naïve (61,7% vs. 53,1%). La adherencia a ACOD fue similar en los 2 grupos. Entre los naïve, los pacientes que iniciaban rivaroxabán (80,1%) mostraron mayor adherencia en la implementación (MPR > 80%), mientras que los que iniciaban dabigatrán fueron menos adherentes (47,8%). Conclusiones: Acenocumarol fue el anticoagulante más prescrito. Los pacientes no naïve mostraron mejor persistencia al tratamiento que los naïve. Rivaroxabán mostró mayores tasas de adherencia que apixabán y dabigatrán, las menores.

Descending facilitatory circuitry that involves the rostroventromedial medulla (RVM) exerts a significant role in the development of antinociceptive tolerance and hyperalgesia following chronic morphine treatment. The role of the RVM in the development of antinociceptive tolerance to oxycodone, another clinically used strong opioid. is not yet known. Ketamine, an N-methyl-o-aspartate (NMDA) receptor antagonist, attenuates opioid antinociceptive tolerance, but its effect on RVM cell discharge in opioid-tolerant animals is not known. Here, we compared chronic effects of morphine and oxycodone on the discharge properties of RVM cells and attempted to attenuate chronic treatment-induced changes with ketamine. Parallel recordings of RVM cell discharge and limb withdrawal response were performed under light pentobarbital anesthesia in male rats following sustained systemic treatment with morphine or oxycodone at equianalgesic doses. Ongoing activity and the response to noxious heat and pinch were determined in pronociceptive RVM ON-cells and antinociceptive OFF-cells on the sixth treatment day. Proportions of RVM cell types were not changed. Chronic oxycodone induced antinociceptive tolerance both in limb withdrawal and RVM cell activity. Chronic morphine induced antinociceptive tolerance in limb withdrawal that was accompanied by pronociceptive heat response changes in RVM ON- and OFF-cells. A behaviorally subantinociceptive dose of acute ketamine reversed antinociceptive tolerance both to morphine and oxycodone in limb withdrawal and reversed the chronic morphine-induced pronociceptive discharge changes in RVM cells. The results indicate that an NMDA receptor-dependent descending pronociceptive circuitry involving the RVM has an important role in behavioral antinociceptive tolerance to morphine but not oxycodone. NEW & NOTEWORTHY Morphine and oxycodone are two clinically used strong opioids. Chronic treatment with oxycodone as well as morphine can lead to analgesic tolerance and paradoxical hyperalgesia. Here we show that an N-methyl-n-aspartate receptor-dependent pronociceptive change in discharge properties of rostroventromedial medullary neurons controlling spinal nociception has an important role in antinociceptive tolerance to morphine but not oxycodone. Interestingly, chronic oxycodone did not induce pronociceptive changes in the rostroventromedial medulla.

Oxycodone is a strong opioid frequently used as an analgesic. Although proven efficacious in the management of moderate to severe acute pain and cancer pain, use of oxycodone imposes a risk of adverse effects such as addiction, overdose, and death. Fast and accurate determination of oxycodone blood concentration would enable personalized dosing and monitoring of the analgesic as well as quick diagnostics of possible overdose in emergency care. However, in addition to the parent drug, several metabolites are always present in the blood after a dose of oxycodone, and to date, there is no electrochemical data available on any of these metabolites. In this paper, a single-walled carbon nanotube (SWCNT) electrode and a Nafion-coated SWCNT electrode were used, for the first time, to study the electrochemical behavior of oxycodone and its two main metabolites, noroxycodone and oxymorphone. Both electrode types could selectively detect oxycodone in the presence of noroxycodone and oxymorphone. However, we have previously shown that addition of a Nafion coating on top of the SWCNT electrode is essential for direct measurements in complex biological matrices. Thus, the Nafion/SWCNT electrode was further characterized and used for measuring clinically relevant concentrations of oxycodone in buffer solution. The limit of detection for oxycodone with the Nafion/SWCNT sensor was 85 nM, and the linear range was 0.5-10 mu M in buffer solution. This study shows that the fabricated Nafion/SWCNT sensor has potential to be applied in clinical concentration measurements.

The oral bioavailability of ibrutinib is low and variable, mainly due to extensive first-pass metabolism by cytochrome P450 (CYP) 3A4. The unpredictable exposure can compromise its safe and effective dosing. We examined the impact of itraconazole on ibrutinib pharmacokinetics. In a randomized crossover study, 11 healthy subjects were administered itraconazole 200 mg or placebo twice on day 1, and once on days 2-4. On day 3, 1 hour after itraconazole (placebo) and breakfast, ibrutinib (140 mg during placebo; 15 mg during itraconazole) was administered. Itraconazole increased the dose-adjusted geometric mean area under the concentration-time curve from zero to infinity (AUC(0-infinity)) of ibrutinib 10.0-fold (90% confidence interval (CI) 7.2-13.9; P

Low socioeconomic status has been associated with poor outcomes in patients with atrial fibrillation (AF). However, little is known about socioeconomic disparities in adherence to stroke prevention with direct oral anticoagulants (DOACs). We assessed the hypothesis that AF patients with higher income or educational levels have better adherence to DOACs in terms of treatment implementation and persistence. The used nationwide registry-based FinACAF cohort covers all patients with incident AF starting DOACs in Finland during 2011-2018. The implementation analyses included 74 222 (mean age 72.7 +/- 10.5 years, 50.8% female) patients, and persistence analyses included 67 503 (mean age 75.3 +/- 8.9 years, 53.6% female) patients with indication for permanent anticoagulation (CHA(2)DS(2)-VASc score >1 in men and >2 in women). Patients were divided into income quartiles and into three categories based on their educational attainment. Therapy implementation was measured using the medication possession ratio (MPR), and patients with MPR >= 0.90 were defined adherent. Persistence was measured as the incidence of therapy discontinuation, defined as the first 135-day period without DOAC purchases after drug initiation. Patients with higher income or education were consistently more likely adherent to DOACs in the implementation phase (comparing the highest income or educational category to the lowest adjusted odds ratios 1.18 (1.12-1.25) and 1.21(1.15-1.27), respectively). No association with income or educational levels was observed on the incidence of therapy discontinuation. In conclusion, we observed that income and educational levels both have independent positive association on the implementation of DOAC therapy but no association on therapy persistence in patients with AF.

The aim of this study was to estimate healthcare costs and mortality associated with serious fluoroquinolone-related adverse reactions in Finland from 2008 to 2019. Serious adverse reaction types were identified from the Finnish Pharmaceutical Insurance Pool's pharmaceutical injury claims and the Finnish Medicines Agency's Adverse Reaction Register. A decision tree model was built to predict costs and mortality associated with serious adverse drug reactions (ADR). Severe clostridioides difficile infections, severe cutaneous adverse reactions, tendon ruptures, aortic ruptures, and liver injuries were included as serious adverse drug reactions in the model. Direct healthcare costs of a serious ADR were based on the number of reimbursed fluoroquinolone prescriptions from the Social Insurance Institution of Finland's database. Sensitivity analyses were conducted to address parameter uncertainty. A total of 1 831 537 fluoroquinolone prescriptions were filled between 2008 and 2019 in Finland, with prescription numbers declining 40% in recent years. Serious ADRs associated with fluoroquinolones lead to estimated direct healthcare costs of 501 938 402 (sic), including 11 405 ADRs and 3,884 deaths between 2008 and 2019. The average mortality risk associated with the use of fluoroquinolones was 0.21%. Severe clostridioides difficile infections were the most frequent, fatal, and costly serious ADRs associated with the use of fluoroquinolones. Although fluoroquinolones continue to be generally well-tolerated antimicrobials, serious adverse reactions cause long-term impairment to patients and high healthcare costs. Therefore, the risks and benefits should be weighed carefully in antibiotic prescription policies, as well as with individual patients.

Background Mental health conditions (MHCs) are associated with poor outcomes in patients with atrial fibrillation. However, persistence of oral anticoagulation therapy in patients with atrial fibrillation and MHCs is unknown. We aimed to evaluate the effect of MHCs on the persistence of direct oral anticoagulant (DOAC) use in patients with atrial fibrillation based on a nationwide cohort. Methods and Results The nationwide registry‐based FinACAF (Finnish Anticoagulation in Atrial Fibrillation) cohort included 67 503 patients with incident atrial fibrillation and indication for permanent oral anticoagulation (CHA 2 DS 2 ‐VASc score >1 in men and >2 in women) starting DOAC therapy between 2011 and 2018. MHCs of interest were depression, bipolar disorder, anxiety disorder, schizophrenia, and composite of any MHC. The main outcome was nonpersistence of DOAC use, defined as the first 120‐day period without DOAC purchases after drug initiation. The mean age of the patients was 75.3±8.9 years, 53.6% were women, and the prevalence of any MHC was 17.8%. Persistence after 1 year from DOAC initiation was 79.3% in patients without MHCs and 77.2% in patients with any MHC, and after 2 years were 64.4% and 60.6%, respectively ( P Conclusions MHCs are associated with nonpersistence of DOAC use. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04645537.

Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences.

BACKGROUND: Pharmacometabolomics uses large-scale data capturing methods to uncover drug-induced shifts in the metabolic profile. The specific effects of anaesthetics on the human metabolome are largely unknown. OBJECTIVE: We aimed to discover whether exposure to routinely used anaesthetics have an acute effect on the human metabolic profile. DESIGN: Randomised, open-label, controlled, parallel group, phase IV clinical drug trial. SETTING: The study was conducted at Turku PET Centre, University of Turku, Finland, 2016 to 2017. PARTICIPANTS: One hundred and sixty healthy male volunteers were recruited. The metabolomic data of 159 were evaluable. INTERVENTIONS: Volunteers were randomised to receive a 1-h exposure to equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml-1; n = 40), propofol (1.7 μg ml-1; n = 40), sevoflurane (0.9% end-tidal; n = 39), S-ketamine (0.75 μg ml-1; n = 20) or placebo (n = 20). MAIN OUTCOME MEASURES: Metabolite subgroups of apolipoproteins and lipoproteins, cholesterol, glycerides and phospholipids, fatty acids, glycolysis, amino acids, ketone bodies, creatinine and albumin and the inflammatory marker GlycA, were analysed with nuclear magnetic resonance spectroscopy from arterial blood samples collected at baseline, after anaesthetic administration and 70 min postanaesthesia. RESULTS: All metabolite subgroups were affected. Statistically significant changes vs. placebo were observed in 11.0, 41.3, 0.65 and 3.9% of the 155 analytes in the dexmedetomidine, propofol, sevoflurane and S-ketamine groups, respectively. Dexmedetomidine increased glucose, decreased ketone bodies and affected lipoproteins and apolipoproteins. Propofol altered lipoproteins, fatty acids, glycerides and phospholipids and slightly increased inflammatory marker glycoprotein acetylation. Sevoflurane was relatively inert. S-ketamine increased glucose and lactate, whereas branched chain amino acids and tyrosine decreased. CONCLUSION: A 1-h exposure to moderate doses of routinely used anaesthetics led to significant and characteristic alterations in the metabolic profile. Dexmedetomidine-induced alterations mirror α2-adrenoceptor agonism. Propofol emulsion altered the lipid profile. The inertness of sevoflurane might prove useful in vulnerable patients. S-ketamine induced amino acid alterations might be linked to its suggested antidepressive properties. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02624401. URL: https://clinicaltrials.gov/ct2/show/NCT02624401. CC BY 4.0September 15, 2021Correspondence to Aleksi J. Nummela, Department of Internal Medicine, Turku University Hospital, 20521 Turku, Finland E-mail: aljunu@utu.fiFinancial support and sponsorship: this work was supported by Academy of Finland, Helsinki, Finland (grant numbers 266467, 266434); Jane and Aatos Erkko Foundation, Helsinki, Finland; The Finnish Medical Foundation, Helsinki, Finland (JWL); The Emil Aaltonen Foundation, Tampere, Finland (JWL); and The Paulo Foundation, Espoo, Finland (LTL) and Orion Research Foundation, Espoo, Finland (LTL); Signe and Ane Gyllenberg Foundation, Helsinki, Finland (KJV); The Finnish Medical Foundation, Eero Matti Raninen Fund, Helsinki, Finland (AJN) and University of Turku, Finland (AJN).

Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in their use. The role of peripheral opioid receptors in analgesia has been discussed especially under inflammatory conditions. The results from pharmacological and conditional knockout studies together do not provide a clear picture of the contribution of peripheral opioid receptors on antinociceptive tolerance and this needs to be evaluated. Therefore, we studied whether the peripherally restricted opioid receptor antagonist, methylnaltrexone (MNTX), could prevent morphine tolerance without attenuating the antinociceptive effect of morphine. Male Sprague-Dawley rats were treated for 7 days with increasing subcutaneous doses of morphine (5-30 mg/kg) and were coadministered saline, MNTX (0.5 or 2 mg/kg), or naltrexone (NTX; 2 mg/kg). Nociception was assessed with tail-flick, hotplate, and von Frey tests. Morphine, MNTX, and NTX concentrations in the plasma, brain, and spinal cord were measured by liquid chromatography-tandem mass spectrometry. In acute coadministration, NTX, but not MNTX, abolished the acute antinociceptive effects of morphine in all nociceptive tests. The antinociceptive tolerance after repeated morphine administration was also prevented by NTX but not by MNTX. MNTX penetrated to the spinal cord and the brain to some extent after repeated administration. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.

Funding Information: This work was supported by the Aarne Koskelo Foundation , The Finnish Foundation for Cardiovascular Research , and Helsinki and Uusimaa Hospital District research fund. Funding Information: Konsta Teppo: none. Jussi Jaakkola: none. Fausto Biancari: none Olli Halminen: none. Jukka Putaala: Dr. Putaala reports personal fees from Boehringer-Ingelheim, personal fees and other from Bayer, grants and personal fees from BMS-Pfizer, personal fees from Portola, other from Amgen, personal fees from Herantis Pharma, personal fees from Terve Media, other from Vital Signum, personal fees from Abbott, outside the submitted work. Pirjo Mustonen: Consultant: Roche, BMS-Pfizer-alliance, Novartis Finland, Boehringer Ingelheim, MSD Finland. Miika Linna: Speaker: BMSPfizer-alliance, Bayer, Boehringer-Ingelheim. Juha Hartikainen: Research grants: The Finnish Foundation for Cardiovascular Research, EU Horizon 2020, EU FP7. Advisory Board Member: BMS-Pfizer-alliance, Novo Nordisk, Amgen. Speaker: Cardiome, Bayer. K.E. Juhani Airaksinen: Research grants: The Finnish Foundation for Cardiovascular Research; Speaker: Bayer, Pfizer and Boehringer-Ingelheim. Member in the advisory boards: Bayer, Pfizer and AstraZeneca. Mika Lehto: Consultant: BMS-Pfizer-alliance, Bayer, Boehringer-Ingelheim, and MSD; Speaker: BMS-Pfizer-alliance, Bayer, Boehringer Ingelheim, MSD, Terve Media and Orion Pharma. Research grants: Aarne Koskelo Foundation, The Finnish Foundation for Cardiovascular Research, and Helsinki and Uusimaa Hospital District research fund, Boehringer-Ingelheim. Publisher Copyright: © 2022 Objective: We assessed the hypothesis that mental health conditions (MHCs) are associated with higher risk of bleeding in patients with atrial fibrillation (AF). Methods: The registry-based FinACAF study covers all patients with AF diagnosed during 2007–2018 in Finland. MHCs of interest were depression, bipolar disorder, anxiety disorder, schizophrenia, and any MHC. The outcomes were first-ever gastrointestinal, intracranial, and any bleeding event. Results: We identified 205,019 patients (50.9% female; mean age 72.3 [standard deviation 13.4] years) with incident AF without prior bleeding, and the prevalence of any MHC was 6.1%. Any MHC, depression, and anxiety disorder were associated with the risk of any bleeding (adjusted hazard ratios (HRs) 1.19 [1.12–1.27], 1.21 [1.13–1.30], and 1.21 [1.08–1.35], respectively). Additionally, any MHC and depression were associated with the risk of gastrointestinal and intracranial bleeding and anxiety disorder with gastrointestinal bleeding. Bipolar disorder and schizophrenia were not associated with risk of bleeding. Use of oral anticoagulants was associated with the risk of any bleeding (adjusted HR 1.24 [95% CI 1.21–1.28)]), and this association was similar in patients with and without MHCs. Serotonin reuptake inhibitors were not associated with bleeding risk. Conclusions: MHCs are associated with a higher risk of bleeding in patients with AF.

Multimorbidity, polypharmacotherapy and drug interactions are increasingly common in the ageing population. Many drug-drug interactions (DDIs) are caused by perpetrator drugs inhibiting or inducing cytochrome P450 (CYP) enzymes, resulting in alterations of the plasma concentrations of a victim drug. DDIs can have a major negative health impact, and in the past, unrecognized DDIs have resulted in drug withdrawals from the market. Signals to investigate DDIs may emerge from a variety of sources. Nowadays, standard methods are widely available to identify and characterize the mechanisms of CYP-mediated DDIs in vitro. Clinical pharmacokinetic studies, in turn, provide experimental data on pharmacokinetic outcomes of DDIs. Physiologically based pharmacokinetic (PBPK) modelling utilizing both in vitro and in vivo data is a powerful tool to predict different DDI scenarios. Finally, epidemiological studies can provide estimates on the health outcomes of DDIs. Thus, to fully characterize the mechanisms, clinical effects and implications of CYP-mediated DDIs, translational research approaches are required. This minireview provides an overview of translational approaches to study CYP-mediated DDIs, going beyond regulatory DDI guidelines, and an illustrative case study of how the DDI potential of clopidogrel was unveiled by combining these different methods.