OBJECTIVE: To characterise the exposure to valproate within a cohort of pregnant women using electronic health records (EHRs) from Catalonia (System for the Development of Research in Primary Care, SIDIAP).
METHODS: Drug-utilisation cohort study covering the period from January 2011 to June 2020. The study included pregnancy episodes of women from Catalonia identified by the algorithm.
METHODS: Data were sourced from SIDIAP, a comprehensive EHR repository that includes information from various data sources: recorded prescriptions (both hospital and primary care), diagnoses and sociodemographic characteristics identified by primary care physicians, and sexual and reproductive health data from ASSIR (used by gynaecologists and midwives).
METHODS: Women aged 12-50 with at least one pregnancy episode occurred during January 2011-June 2020 and at least a prescription of valproate during pregnancy.
METHODS: Primary outcomes included valproate exposure, measured through prevalence and cumulative incidence in pregnancy episodes and by trimester. The impact of regulatory measures (risk mitigation measures, RMMs) was assessed, and prescriptions over time were analysed using interrupted time series analysis. Secondary outcomes included health issues, pregnancy outcomes, smoking habits and socioeconomic characteristics.
RESULTS: A total of 99 605 pregnancies were identified, with at least 3.03‰ (95% CI 2.69‰ to 3.39‰) exposed to valproate at some point (302 pregnancies, 276 women). The median pregnancy duration was 38.30 weeks (IQR 12.6-40.1), and the median age at pregnancy was 32.37 years (IQR 27.20-36.56). Epilepsy was the most frequent health issue. The prevalence and cumulative incidence of valproate prescriptions decreased during pregnancy and increased postpregnancy. The RMMs implemented in 2014 led to a reduction in monthly valproate prescriptions during pregnancy in this cohort.
CONCLUSIONS: The study highlights the decline in valproate prescriptions during pregnancy due to RMMs and underscores the need for standardised methodologies in future studies to ensure the safety of pregnant patients and optimise scientific evidence.

UNASSIGNED: Assessment of drug-related adverse events is essential to fully understand the benefit-risk balance of any drug exposure, weighing efficacy versus safety. This is needed for both drug labeling and clinical decision-making. Assessment is based on seriousness, severity and causality, be it more difficult to apply in neonates. Adverse event detection or prevention in the neonatal clinical setting is also more complicated because of polypharmacy, and off-label or unlicensed pharmacotherapy.
UNASSIGNED: Tools became available to assess severity and causality of adverse events in neonates recruited in clinical trials. The first version of the Neonatal Adverse Event severity score (NAESS) reduced the inter-observer variability. Causality tools like the Naranjo score were also tailored to neonates. These tools are also instrumental to support proactive pharmacovigilance in clinical care, while multidisciplinary care teams and computerized pharmacovigilance using advanced data analysis, like machine learning are emerging approaches to develop effective decision strategies.
UNASSIGNED: All stakeholders involved in development of medicines or its clinical use should be aware of the limitations of the currently available assessment tools. Extension and optimization of these tools, advanced data analysis approaches, and capturing the variability in time-dependent physiology are warranted to improve pharmacovigilance in neonates.

OBJECTIVE: This study aims to quantitatively analyse nortriptyline\'s analgesic potency, safety and tolerability.
METHODS: Systematic review and meta-analysis.
METHODS: The systematic search was conducted in Scopus, Web of Science and PubMed in February 2023.
METHODS: Clinical trials evaluating the efficacy of nortriptyline in reducing pain scores (open-label studies and comparisons of nortriptyline with placebo or other analgesics) in different pain types were included.
METHODS: The data extraction procedure and the screening phases were carried out based on predetermined eligibility criteria. To pool the data, the standardised mean difference (SMD) and standardised mean change (SMC) methods, along with random-effect and fixed-effect meta-analysis, were used. The risk of bias was assessed using the Cochrane Collaboration method, and the Grading of Recommendations Assessment, Development and Evaluation criteria were used to measure the certainty of the results.
RESULTS: 14 of the initial 648 studies were eventually imported. Nortriptyline was reported to significantly reduce pain severity in chronic low back pain, painful symptoms in major depressive disorder, neuropathy, chronic pelvic pain and neuropathic corneal pain. However, it was not superior to placebo in fibromyalgia and knee osteoarthritis. In comparison to placebo and various alternative analgesics, the pooled SMD for lowering pain scores was 0.43 (0.23-0.64) and -0.18 (-0.39 to 0.03), respectively. In the pretreatment and post-treatment analyses, the pooled SMC was -1.20 (-1.48 to -0.93). Although constipation and xerostomia were the most commonly reported side effects, all references indicated that the adverse events were well tolerated at the administered dosages.
CONCLUSIONS: While nortriptyline is effective in some chronic pains, such as neuropathies, it lacks efficacy in some other chronic pains, such as fibromyalgia and osteoarthritis. Nortriptyline is well tolerated when administered in doses intended for its analgesic effects. Moreover, several studies suggested that the analgesic effects of nortriptyline are comparable to those of amitriptyline and gabapentin.

OBJECTIVE: To evaluate whether the effectiveness and safety of low (81 mg daily) versus high-dose (325 mg daily) aspirin is consistent across races among patients with established atherosclerotic cardiovascular disease (ASCVD).
METHODS: A secondary analysis of the randomised controlled trial ADAPTABLE was performed.
METHODS: The study was conducted in 40 centres and one health plan participating in the National Patient-Centred Clinical Research Network (PCORnet) in the USA.
METHODS: Among 15 076 participants with established ASCVD, 14 096 had self-reported race available and were included in the analysis. Participants were divided according to self-reported race as Black (n=1311, 9.3%), White (n=11 990, 85.1%) or other race (n=795, 5.6%).
METHODS: Participants were randomised to open-label daily aspirin doses of 81 mg versus 325 mg in a 1:1 ratio for a median of 26.2 months.
METHODS: The primary effectiveness endpoint was a composite of death from any cause, hospitalisation for myocardial infarction or hospitalisation for stroke. The primary safety endpoint was hospitalisation for bleeding requiring blood product transfusion.
RESULTS: Estimated cumulative incidence of the primary effectiveness endpoint at median follow-up with the 81 mg and the 325 mg daily doses were 6.70% and 7.12% in White participants (adjusted HR: 1.00 [95% CI: 0.88 to 1.15]); 12.27% and 10.69% in Black participants (adjusted HR: 1.40 [95% CI: 1.02 to 1.93]); and 6.88% and 7.69% in other participants (adjusted HR: 0.86 [95% CI: 0.54 to 1.39]) (p-interaction=0.12), respectively. There was no significant interaction between self-reported race and assigned aspirin dose regarding the secondary effectiveness and the primary safety endpoints.
CONCLUSIONS: Race is not an effect modifier on the impact of aspirin dosing on effectiveness and safety in patients with established ASCVD. In clinical practice, treatment decisions regarding aspirin dose in secondary prevention of ASCVD should not be influenced by race.
BACKGROUND: NCT02697916.

BACKGROUND: Psychiatric medications are not efficacious for treating borderline personality disorder (BPD), yet many patients with BPD are prescribed multiple psychiatric medications. This study aimed to (1) characterize psychiatric medication prescribing practices in adolescents with BPD and (2) assess whether demographic features are associated with prescribing practices.
METHODS: This sample was N = 2950 pediatric patients with BPD (ages 10-19) across the U.S. Data came from the NeuroBlu database, which includes data from 30 U.S. healthcare systems and hundreds of hospitals. Poisson regressions and chi-squared tests determined whether gender, race, and ethnicity were associated with (1) number of unique psychiatric medications prescribed and (2) number of unique medication classes prescribed.
RESULTS: Roughly two-thirds (64.85%) of youth were prescribed any medications. Of these youth, 79.40% were prescribed ≥ 2 unique medications and 72.66% were prescribed ≥ 2 unique medications classes. The mean number of unique medications was 3.50 (SD = 2.50). The mean number of unique medication classes was 2.35 (SD = 1.15). The most commonly prescribed medication classes were antidepressants and antipsychotics, which were often prescribed in combination. Poisson regressions showed that boys were prescribed more unique medications (M = 3.67) than girls (M = 3.47). Non-Latinx youth were prescribed significantly more unique medications (M = 44.12) than Latinx youth (M = 3.60, p = .01).
CONCLUSIONS: Results characterize psychiatric medication prescribing practices in youth with BPD. Prescribing practices vary by demographics, such that boys and non-Latinx youth are prescribed more medications than girls and Latinx youth, respectively. These demographic differences suggest that prescribers may treat BPD differently based on patient demographic characteristics.

OBJECTIVE: To assess antibiotics prescribing and use patterns for inpatients at Benjamin Mkapa Zonal Referral Hospital (BMH) using the WHO-Point Prevalence Survey (WHO-PPS).
METHODS: A cross-sectional survey.
METHODS: The Benjamin Mkapa Zonal Referral Hospital, Dodoma, Tanzania.
METHODS: Inpatient prescriptions, regardless of whether antibiotics were prescribed (n=286) on the day of PPS.
METHODS: Our study analysed the prevalence of antibiotic use at BMH for inpatients, the type of antibiotics used, the indications for use and the proportion of oral and parenteral antibiotics. We also assessed prescription-prescribed antibiotics after a positive antimicrobial susceptibility testing (AST) result.
RESULTS: A survey was conducted on 286 prescriptions, which revealed that 30.07% of them included antibiotics. On average, each prescription contained at least 1.6 antibiotics. All prescriptions that included antibiotics were written in generic names, and 77.91% (67/86) of them followed the Standard Treatment Guidelines. Of the prescriptions that included antibiotics, 58.14% (50/86) had a single antibiotic, 20.93% (18/86) had parenteral antibiotics and 79.07% (68/86) had oral antibiotics. Based on AWaRe\'s (Access, Watch and Reserve) categorisation of antibiotics, 50% (8/16) were in the Access group, 31.25% (5/16) were in the Watch group, 12.50% (2/16) were in the Reserve group and 6.25% (1/16) were not recommended antimicrobial combinations. Out of 86 prescriptions included antibiotics, only 4.65% showed positive culture growth. However, antibiotics were still prescribed in 29.07% of prescriptions where there was no growth of bacteria, and in 66.28% of prescriptions, antibiotics were prescribed empirically without any requesting of bacteria culture and AST.
CONCLUSIONS: BMH has reduced inpatient Antibiotic Use by half compared with the 2019 WHO-PPS. Adherence to National Treatment Guidelines is suboptimal. Clinicians should use AST results to guide antibiotic prescribing.

Warfarin, with its narrow therapeutic range, requires the understanding of various influencing factors for personalized medication. Vascular senescence, marked by vascular stiffening and endothelial dysfunction, has an unclear effect on the efficacy and safety of warfarin. Based on previous studies, we hypothesized that vascular senescence increases the risk of bleeding during warfarin therapy. This study aimed to explore these effects using animal models and clinical cohorts. We established rat models of vascular senescence and calcification using d-galactose (D-Gal), vitamin D and nicotine (VDN). After validating the models, we examined changes in the International Normalized Ratio (INR) at fixed warfarin doses (0.20 and 0.35 mg/kg). We found that vascular senescence caused significantly elevated INR values and increasd bleeding risk. In the prospective clinical cohort study(NCT06428110), hospitalized warfarin patients with standard dose adjustments were divided into vascular senescence and control groups based on ultrasound and Computed Tomography (CT) diagnosis. Using propensity score matching (PSM) to exclude the influence of confounding factors, we found that the vascular senescence group had lower steady-state warfarin doses and larger dose adjustments, with a higher probability of INR exceeding the therapeutic range. The vascular senescence group tended to experience more bleeding or thromboembolic/ischemic events during one year of follow-up, while there was no statistical difference. In conclusion, vascular senescence leads to unstable INR values and increases higher bleeding risk during warfarin therapy, highlighting the importance of considering vascular senescence in future precision warfarin therapies. Significance Statement Many factors influence warfarin efficacy, however, the effect of vascular senescence remains unclear. This study aimed to investigate the effects of vascular senescence on the efficacy and safety of warfarin. Through both rat models and clinical cohort studies, our findings indicated that vascular senescence may compromise the stability of warfarin, presenting challenges in maintaining its efficacy and safety.

As the population continues to age, the occurrence of chronic illnesses and comorbidities that often necessitate the use of polypharmacy has been on the rise. Polypharmacy, among other factors that tend to coincide with chronic diseases, such as obesity, impaired kidney and liver function, and older age, can increase the risk of medication errors (MEs). Our study aims to evaluate the prevalence of MEs in the Internal medicine, Cardiology, and Neurology departments at the secondary-level university hospital. We conducted a prospective observational study of 145 patients\' electronic or paper-based data of inpatient prescriptions and patients\' pharmacokinetic risk factors, such as an impairment of renal and/or hepatic function, weight, and age. All included patients collectively received 1252 prescribed drugs. The median (Q1; Q3) number of drugs per patient was 8 (7;10). At least one ME was identified in 133 out of the 145 patients, indicating a significantly higher prevalence than hypothesized (91.7% vs. 50%; p < .001). There was moderate, positive correlation between the quantity of prescribed drugs and the number of MEs, meaning that the more drugs are prescribed, the higher the number of identified MEs (Spearman\'s ρ = 0.428; p < .001). These findings suggest that there is a need for continuous medication education activity for prescribing physicians, continuous evaluation of prescription appropriateness to objectively identify the MEs and to contribute to more rational patient treatment.

Clinical pharmacology is often the nexus in any cross-disciplinary team that is seeking solutions for human healthcare issues. The use and application of real-world data and artificial intelligence to better understand our ecosystem has influenced our view at the world and how we do things. This has resulted in remarkable advancements in the healthcare space and development of personalized medicines with great attributes from the application of models and simulations, contributing to a more efficient healthcare development process. A cross-disciplinary symposium was held in December 2023, whereby experts from different scientific disciplines engaged in a high-level discussion on the opportunities and challenges of mathematical models in different fields, possible future developments and decision making. A strong interlink amongst the disciplines represented was apparent, with clinical pharmacology identified as the one which integrates various scientific disciplines. Deliberate and strategic cross-disciplinary dialogues are required to break out of the silos and implement integration for efficiency and cost-effectiveness of novel interventions.

With the continuous development of genetics in healthcare, there has been a significant contribution to the development of precision medicine, which is ultimately aimed at improving the care of patients. Generally, drug treatments used in Oncology are characterized by a narrow therapeutic range and by their potential toxicity. Knowledge of pharmacogenomics and pharmacogenetics can be very useful in the area of Oncology, as they constitute additional tools that can help to individualize patients\' treatment. This work includes a description of some genes that have been revealed to be useful in the field of Oncology, as they play a role in drug prescription and in the prediction of treatment response.