Small-Molecule Ebselen Binds to YTHDF Proteins Interfering with the Recognition of N 6-Methyladenosine-Modified RNAs.

YTHDF proteins bind the N 6-methyladenosine (m6A)-modified mRNAs, influencing their processing, stability, and translation. Therefore, the members of this protein family play crucial roles in gene regulation and several physiological and pathophysiological conditions. YTHDF proteins contain a hydrophobic pocket that accommodates the m6A embedded in the RRACH consensus sequence on mRNAs. We exploited the presence of this cage to set up an m6A-competitive assay and performed a high-throughput screen aimed at identifying ligands binding in the m6A pocket. We report the organoselenium compound ebselen as the first-in-class inhibitor of the YTHDF m6A-binding domain. Ebselen, whose interaction with YTHDF proteins was validated via orthogonal assays, cannot discriminate between the binding domains of the three YTHDF paralogs but can disrupt the interaction of the YTHDF m6A domain with the m6A-decorated mRNA targets. X-ray, mass spectrometry, and NMR studies indicate that in YTHDF1 ebselen binds close to the m6A cage, covalently to the Cys412 cysteine, or interacts reversibly depending on the reducing environment. We also showed that ebselen engages YTHDF proteins within cells, interfering with their mRNA binding. Finally, we produced a series of ebselen structural analogs that can interact with the YTHDF m6A domain, proving that ebselen expansion is amenable for developing new inhibitors. Our work demonstrates the feasibility of drugging the YTH domain in YTHDF proteins and opens new avenues for the development of disruptors of m6A recognition.

A Landscape Analysis of Post-Marketing Studies Registered in the EU PAS Register and ClinicalTrials.gov Focusing on Pregnancy Outcomes or Breastfeeding Effects: A Contribution from the ConcePTION Project.

INTRODUCTION: A large proportion of medicine product labels lack information on safety in pregnancy and breastfeeding. To address this gap, pharmaceutical companies are requested to develop post-approval studies regarding the use of drugs by pregnant and breastfeeding women. OBJECTIVE: Our study aims to review key features of observational studies in pregnancy and breastfeeding and their impact on the respective medicine product labels. METHODS: Observational studies focusing on the safety evaluation of medicines used during pregnancy and breastfeeding were selected from the European Union Register of Post-Authorization Studies (EU PAS register) and ClinicalTrials.gov. We extracted information on the variables of interest and performed an impact assessment on the respective label. RESULTS: A total of 141 observational studies were eligible. Of these, 63 studies (45%) were based on primary data collection and 55 studies (39%) on secondary use of health data. A small number of studies (8%) aimed to evaluate drug safety during breastfeeding. Studies using secondary data collection lasted around 2.9 years as opposed to 7.5 years' duration for studies using primary data collection. Only two product labels were updated based on the study results. CONCLUSION: The duration is significantly longer for studies based on primary data collection, and these are also smaller in size (less power), whereas outcomes of interest are similar. For completed studies, the impact on the label was very low. Given the gap in adequate pregnancy information on product labels, the current process of generating evidence in pregnancy and breastfeeding seems neither efficient nor impactful. To support evidence-based decision making by prescribers, this current process might be redesigned.

Overview of the European post-authorisation study register post-authorization studies performed in Europe from September 2010 to December 2018.

BACKGROUND: The European post-authorisation study (EU PAS) register is a repository launched in 2010 by the European Medicines Agency (EMA). All EMA-requested PAS, commonly observational studies, must be recorded in this register. Multi-database studies (MDS) leveraging secondary data have become an important strategy to conduct PAS in recent years, as reflected by the type of studies registered in the EU PAS register. OBJECTIVES: To analyse and describe PAS in the EU PAS register, with focus on MDS. METHODS: Studies in the EU PAS register from inception to 31st December 2018 were described concerning transparency, regulatory obligations, scope, study type (e.g., observational study, clinical trial, survey, systematic review/meta-analysis), study design, type of data collection and target population. MDS were defined as studies conducted through secondary use of >1 data source not linked at patient-level. Data extraction was carried out independently by 14 centres with expertise in pharmacoepidemiology, using publicly available information in the EU PAS register including study protocol, whenever available, using a standardised data collection form. For validation purposes, a second revision of key fields for a 15% random sample of studies was carried out by a different centre. The inter-rater reliability (IRR) was then calculated. Finally, to identify predictors of primary data collection-based studies/versus those based on secondary use of healthcare databases) or MDS (vs. non-MDS), odds ratios (OR) and 95% confidence intervals (CI) were calculated fitting univariate logistic regression models. RESULTS: Overall, 1426 studies were identified. Clinical trials (N = 30; 2%), systematic reviews/meta-analyses (N = 16; 1%) and miscellaneous study designs (N = 46; 3%) were much less common than observational studies (N = 1227; 86%). The protocol was available for 63% (N = 360) of 572 observational studies requested by a competent authority. Overall, 36% (N = 446) of observational studies were based fully or partially on primary data collection. Of 757 observational studies based on secondary use of data alone, 282 (37%) were MDS. Drug utilisation was significantly more common as a study scope in MDS compared to non-MDS studies. The overall percentage agreement among collaborating centres that collected the data concerning study variables was highest for study type (93.5%) and lowest for type of secondary data (67.8%). CONCLUSIONS: Observational studies were the most common type of studies in the EU PAS register, but 30% used primary data, which is more resource-intensive. Almost half of observational studies using secondary data were MDS. Data recording in the EU PAS register may be improved further, including more widespread availability of study protocols to improve transparency.

Community Attitudes and Habits Toward Over-The-Counter Drugs: Results of a Study Conducted in Thessaloniki, Greece.

OBJECTIVES: To determine the frequency of use, sources of information, and selection criteria of Greek residents regarding over-the-counter (OTC) drugs, as well as their opinion about their dispensing in nonpharmacy settings. METHODS: This was a survey study in which an anonymous cross-sectional questionnaire was used to assess the knowledge, habits, and attitudes about OTC drugs. Data were collected from March 2017 to July 2017 in Thessaloniki, the second largest city in Greece. Logistic regression was used to investigate significant factors that affect the participants' behavior. RESULTS: A total of 782 participants completed the questionnaire. The population had a mean (SD) age of 46 (17) years and 55.1% were females. About one-third (32.5%) of the participants used nonsteroidal anti-inflammatory drugs more than once per week. OTC drugs acting on the gastrointestinal tract were used to a lower extent (13.2%). The majority (84%) of the respondents consult a healthcare professional about the information on OTC drugs. Furthermore, when not sure about which OTC drug to use, 510 participants (65.6%) valued their physician's advice, whereas 480 participants (60.2%) valued their pharmacist's advice. Most participants (61.2%) were negatively inclined toward the purchase of OTC drugs in nonpharmacy settings, with younger participants being more receptive to out-of-pharmacy OTC drug purchase than older ones (odds ratio 2.20; 95% confidence interval 1.37-3.54). CONCLUSIONS: Healthcare professionals play an important role in providing people information on their selection of OTC drugs. This could be the main reason why participants prefer to buy OTC drugs from community pharmacies rather than retail shops.

Investigating Potential Drug-Drug Interactions from Greek e-Prescription Data.

BACKGROUND: The prevalence of potential drug-drug interactions (pDDIs) is indicative of the prevalence of actual drug-drug interactions and prescription quality. However, they are significantly understudied in Greece. OBJECTIVE: The objective of the study was to determine the prevalence of pDDIs among outpatients and identify factors associated with their occurrence. METHODS: Anonymous e-prescription data between 2012 and 2017 were obtained from community pharmacies in Thessaloniki, Greece. Patients taking more than one medication for at least three months were included. pDDIs were identified and categorized depending on their clinical significance using Drug Interactions Checker. Crude and adjusted odds ratios (ORs) with accompanying 95% confidence intervals (CIs) of risk factors of pDDIs occurrence were identified using multivariable logistic regression. RESULTS: During the study period, 6,000 anonymous e-prescriptions (1,000 per year) satisfying the inclusion criteria were collected. The overall prevalence of major pDDIs was 17.4% (63.0% for moderate pDDIs). The most common major pDDIs were between amlodipine and simvastatin (22.8% of major interactions), followed by clopidogrel and omeprazole (6.4% of major interactions). Polypharmacy (≥5 concomitantly received medications) was associated with an increased risk of major pDDIs (adjusted OR, 5.72; 95% CI, 4.87-6.72); no associations were observed regarding age, sex, and number of prescribing physicians. CONCLUSION: The prevalence of pDDIs in this study was higher than previously reported in other European countries, with polypharmacy being a potential risk factor. Those results argue for a need for improvement in the area of prescribing in Greece.

Potential drug-drug interaction between sodium-glucose co-transporter 2 inhibitors and statins: pharmacological and clinical evidence.

INTRODUCTION: Recent case reports suggested that concomitant use of sodium-glucose co-transporter 2 (SGLT2) inhibitors with statins could lead to increased statin toxicity. We provide a comprehensive overview of the available pharmacological and clinical evidence on this potential drug-drug interaction (DDI). AREAS COVERED: We searched MEDLINE PubMed until November 2020 for (i) pharmacokinetic studies on SGLT2 inhibitors, statins, and their potential interaction, and (ii) case reports and clinical studies assessing the safety of concomitant use of SGLT2 inhibitors and statins. We also searched regulatory documents submitted to the United States Food and Drug Administration for unpublished data on this potential DDI. EXPERT OPINION: SGLT2 inhibitors are increasingly used for type 2 diabetes, chronic heart failure, and chronic kidney disease, and concomitant use with statins is common given the comorbidity of indications. While pharmacokinetic studies in healthy subjects showed no clinically relevant changes in statin levels during SGLT2 inhibitor co-administration, the published case reports and pharmacologic reasoning support the possibility of an interaction. Underlying mechanisms could be pharmacokinetic or pharmacodynamic, and canagliflozin appears to be the SGLT2 inhibitor with the highest interaction potential. Further research including 'real-world' pharmacoepidemiologic studies is needed to better understand the clinical significance of this DDI.