This is just an editorial and does not include an abstract

Objective: Taking the practice of clinical pharmacists participating in enhanced recovery after surgery (ERAS) protocol of gastric cancer patients undergoing radical gastrectomy as an example, to explore the value of pharmacists in hospitalization cost control. Methods: 160 gastric cancer patients who underwent radical gastrectomy in Jiangsu Cancer Hospital from February 2023 to October 2023 were divided into control group and research group, with 80 cases in each group. The control group implemented the conventional ERAS protocol without the involvement of the clinical pharmacist. The research group was managed by a professional clinical pharmacist on the base of the conventional ERAS protocol. Results: (1) There were no significant differences in age, gender, site of surgical resection, and TNM stage between the two groups. (2) Compared with the control group, patients in the research group had shorter length of stay (LOS) (P < 0.001) and first postoperative ventilation time (P < 0.001), as well as fewer hospitalization cost (P = 0.005). (3) Albumin on postoperative day (POD) 30 and prealbumin on POD7 were significantly different between two groups (P = 0.029, P = 0.046). (4) The irrational prescription rate of antimicrobials (P < 0.001) and total nutrient admixture (P = 0.001) in the research group were significantly lower than those in the control group. Conclusion: This study shows that clinical pharmacists participating in perioperative ERAS program for gastric cancer can improve the nutritional status, promote the rehabilitation postoperative, shorten LOS, and increase the rate of rational drug use, thus reducing medical expenses

Aim: This study aims to refine the anticholinergic burden (AB) scale developed in our previous research by incorporating additional drug properties, such as Lipophilicity and Molecular Weight, and implementing a new weighting approach to address the varying influence of each drug property on anticholinergic burden. The objective is to improve the scale’s predictive accuracy and compare its performance against established scales. Methods: The scale, which covers 87 drugs, was expanded to include seven drug properties, combining new properties, Lipophilicity and Molecular Weight, with previously utilised experimental and in silico ADME, physicochemical, and pharmacological properties. A weighting approach was introduced to the hierarchical clustering process to account for the differential impact of each drug property on AB. The performance of this revised scale was evaluated through 10-fold cross-validation against the clinical Anticholinergic Cognitive Burden (ACB) scale and the non-clinical Anticholinergic Toxicity Scores (ATS) scale. Results: The scale showed improved alignment with the ACB and ATS scales, agreeing with the rankings of 54 out of 87 drugs and 16 out of 25 drugs respectively. The Area Under the Receiver Operating Characteristic Curve (AUROC) indicated strong performance. The ML-ACB and ACB has an AUC of 0.99 and 0.81 respectively, whilst the ML-ACB and ATS had an AUC of 0.96 and 0.62. Conclusion: The ML-ACB scale offers improved alignment with the established ACB scale. This highlights the potential of the ML-ACB scale as a valuable tool for clinical and research applications, providing a data-driven alternative that closely correlates with existing validated scales.

Aims CYP2D6 is a key enzyme for metabolizing tamoxifen into active metabolites, but polymorphisms in this enzyme lead to varying metabolic capacities. Increasing the tamoxifen dose in patients with deficient CYP2D6 metabolism can elevate endoxifen levels to those of patients with normal phenotypes. This study examines the impact of increasing the dose of tamoxifen on toxicity in poor metabolizers of the CYP2D6 enzyme. Methods Eighty-six breast cancer patients treated with tamoxifen were classified by CYP2D6 metabolizer phenotype according to Clinical Pharmacogenetics Implementation Consortium guidelines. All patients started with a 20 mg/day dose of tamoxifen, with poor metabolizers having their doses increased to 60 mg/day. Side effects, including osteoarticular pain, hot flashes, asthenia, and uterine changes, were analyzed using Kaplan-Meier analysis and the Cox proportional hazards regression model to assess the relationship between CYP2D6 metabolizer type and these side effects. Results Significant differences were found only in uterine changes among CYP2D6 metabolizer types in both the overall cohort and a subgroup selected via Propensity Score Matching (PSM). Rapid metabolizers exhibited a lower incidence of uterine changes (p < 0.001 in Kaplan-Meier analysis; HR 0.195, 95% CI: 0.07 - 0.52, p = 0.001) in the complete cohort. In the PSM cohort, Kaplan-Meier analysis showed a p-value of 0.001 with an HR of 0.07 (95% CI: 0.01 - 0.54, p = 0.011). Conclusion Tamoxifen dose scalation in patients with poor CYP2D6 metabolism may increase the occurrence of uterine changes but does not significantly affect the incidence of osteoarticular pain, hot flashes, or asthenia.

Aim: To assess the risk of major congenital malformations following first-trimester PSE exposure. Methods: A population-based retrospective cohort study was conducted on pregnancies of women aged 15-49 years, insured by Clalit Health Services in southern Israel, who gave birth or had elective pregnancy terminations due to suspected fetal malformation at Soroka Medical Center (1999-2017). The study focused on the drug Clarinase (120 mg PSE, 5 mg loratadine). Multivariate negative binomial regression models were used to evaluate the risk for major congenital malformations, adjusting for potential confounders. Results: Of 251,543 pregnancies, 313 (0.12%) were exposed to Clarinase in the first trimester. PSE exposure was not associated with major congenital malformations overall (adjusted Relative Risk [aRR] = 0.90, 95% CI 0.558-1.45; p=0.66) or by organ system (cardiovascular: aRR = 0.938, p=0.841; central nervous: aRR = 0.618, p=0.633; musculoskeletal: aRR = 1.800, p=0.155; gastrointestinal: aRR = 1.013, p=0.990; genitourinary: aRR = 0.704, p=0.547). Conclusion: First-trimester PSE exposure was not associated with major congenital malformations, either overall or by organ system.

Introduction: Suboptimal adherence to antipsychotics leads to poorer outcomes and relapse. The adherence behaviour of people may be influenced by several factors including the number of antipsychotics used and their formulation. This study aimed to identify longitudinal adherence patterns to oral and long-acting injectable (LAI) antipsychotics in monotherapy or polypharmacy through group-based trajectory modelling (GBTM). Methods: This was a retrospective cohort study that linked prescription and dispensing data of adult patients with a new antipsychotic prescribed between 2015-2019 in Catalonia (Spain). GBTM was used to classify patients following a similar longitudinal pattern of adherence. The response variable was adherence, estimated through the continuous medication availability measure (CMA), in each 30-day period during 12 months of follow-up. Baseline and treatment characteristics were used to characterize the trajectories identified. Results: Among the 7,730 patients included in the study, we identified seven clinically distinct trajectory groups of adherence to antipsychotics: “non-adherent” (19%), “low adherent” (9%), “early-decline” (6%), “mid-decline” (5%), “late-decline” (5%), “high adherent” (21%), and “fully adherent” (35%). Trajectories with better adherence were more likely to receive the prescription from a psychiatrist, receive LAIs and have previous exposure to other antipsychotics. Intermittent medication use patterns and high levels of polypharmacy were characteristics of the “low” and “high adherent” groups. Conclusions: The trajectories reflect three adherence behaviours: stable over time; patients who discontinue treatment and; patients with an intermittent refill pattern. Patients on polypharmacy should have more regular adherence monitoring and LAIs should be considered, as they appear to be associated with better adherence.

Background Use of medications to treat attention-deficit/hyperactivity disorder (ADHD) is increasingly prevalent among women of reproductive age, but little is understood about their potential cardiometabolic effects in pregnancy. We aimed to examine associations between ADHD medication use and cardiometabolic conditions during pregnancy (gestational hypertension, preeclampsia, and gestational diabetes) and the pharmacological treatment thereof. Methods Linking statewide hospital and dispensing data, we conducted a population-based matched cohort study of women who gave birth between January 2014 and June 2021 in New South Wales, Australia (n=312,697). We compared the incidence of cardiometabolic conditions and cardiometabolic medication use during pregnancy among women who used ADHD medications during pregnancy (n=336) with a 1:10 matched cohort of unexposed women, and with women who used ADHD medications in the 12 months before pregnancy (n=252). We used Poisson regression models to calculate risk ratios (RR) and 95% confidence intervals (CI), adjusting for sociodemographic and pregnancy-related factors. Results Compared with unexposed women, women who used ADHD medications during pregnancy had an increased risk of gestational hypertension (adjusted RR:1.76, 95% CI:1.20-2.57) and gestational diabetes (aRR:1.41, 95% CI:1.09-1.82), with slightly elevated risk estimates for preeclampsia (aRR:1.30, 95% CI:0.82-2.05) and cardiometabolic medication use (aRR:1.40, 95% CI:0.97-2.01). Compared with women who used ADHD medications before pregnancy only, risk estimates attenuated for all outcomes except gestational diabetes (aRR:1.76, 95% CI:1.06-2.93). Conclusions Women using ADHD medications had an elevated incidence of cardiometabolic conditions during pregnancy, but it remains unclear to what extent this is attributable to medications rather than the underlying ADHD.

Aims: Adavosertib, a WEE1 inhibitor, has been studied for safety and efficacy as monotherapy and in combination therapy. The phase 2b ADAGIO trial evaluated adavosertib monotherapy for uterine serous carcinoma with a recommended dose of 300 mg dosing on days 1 to 5 and days 8 to 12 of 21‑day cycle. However, reports of severe neutropaenia and dose reduction in approximately half of patients at 300 mg suggested potential tolerability concerns. Methods: We conducted a model-based benefit-risk analysis, including an exposure-safety analysis, pooling data from all AstraZeneca-sponsored monotherapy studies. The analysis focused on the relationship between adavosertib exposure and incidence of adverse events such as haematological and gastrointestinal toxicities. A preliminary exposure-efficacy analysis was conducted based on available efficacy data from the ADAGIO study. Results: A strong correlation is observed between adavosertib exposure and predicted probability of developing neutropenia. Also, baseline creatinine clearance (bCLCr) was identified as an independent factor for severe neutropaenia development. Patients with bCLCr ≥50 mL/min were less likely to experience severe neutropaenia than those with bCLCr <50 ml/min. The model shows that a dose reduction from 300 to 250 mg reduces the predicted probability of neutropaenia by 55% when compared at the 95th percentile exposure range at these doses. Contrary to exposure safety, exposure-efficacy relationship was similar across doses. Conclusion: The model-based approach identifies risk factors, aiding in the decision to use a 250 mg monotherapy dose. This regimen may manage hematological toxicities across studies. Reducing adavosertib doses minimizes risks, underscoring the need for dose adjustment

Statin prescription intensity, defined by statin type and dose required to achieve a targeted decrease in plasma low-density lipoprotein-cholesterol (LDL-C), has been involved in statin-associated muscle symptoms (SAMS) development. This study aimed to assess whether muscle function improved differentially according to treatment intensity after two months of statin withdrawal in patients self-reporting SAMS. Patients (53.0±8.4 years [Mean±SD]) undergoing primary cardiovascular prevention were divided in two groups: low to moderate (n=49, targeted plasma LDL-C reduction <50%) and high (n=12, ≥50%). Strength, endurance, and power in extension and flexion of the dominant leg, and handgrip strength were measured using dynamometers. SAMS intensity was assessed using a 0-10 visual analog scale. After withdrawal, repeated-measures analyses showed improvements for 7/8 performance variables (+7.2 to +13.3%, all p<0.05), concomitant with a decrease in SAMS intensity (5.09 to 1.85, p<0.01), with no between-group difference. The improvement of muscle function following withdrawal was not differentiated according to treatment intensity.

Structured Medication Reviews (SMRs) were introduced into the National Health Service (NHS) Primary Care to support the delivery of the NHS Long-Term Plan for medicines optimisation. SMRs improve the quality of care, reduce harm, and offer value for money. However, evidence to support SMRs for patients with chronic kidney disease (CKD) stage G4-5D with elevated risk of cardiovascular disease and premature mortality is unknown. This scoping review aimed to assess the extent and nature of SMR research in the population of patients with CKD stage G4-5D. Electronic databases were searched on 20 October 2023. Studies were eligible if they described an SMR in adults with CKD stage G4-5D, regardless of the study design. Data detailing the global patterns, population and intervention descriptions, professionals performing SMR, and reported areas for future research were extracted. The extracted outcome data were categorised as clinically important, patient-important, medication-related, and experience-related. A narrative synthesis was completed. Seventeen studies (81%) were conducted in nephrology outpatient setting, three (14%) during acute hospital admissions, and one (5%) within the community pharmacy. Eighteen studies (86%) were quantitative, to include five randomised controlled trials. Ten (48%) studies were undertaken in the United States of America and Canada, and two in Europe (France and Norway). No such studies have been conducted in the United Kingdom. Our review revealed that there is a lack of evidence for SMR as a strategy to reduce polypharmacy and harms from medication for adults with CKD stage G4-5D. Therefore, further research is required in this area.

Aims: Endostatin is a type of human vascular endostatin with more stable and higher activity. This study sought to evaluate pharmacokinetics (PK), safety and preliminary efficacy between treatment with endostatin 4 hours intravenous infusion and 72 hours or 168 hours intravenous pump infusion in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 24 patients with advanced NSCLC were randomly assigned to group A and B. All patients received a standard 21 days treatment cycle of platinum-based doublet chemotherapy (paclitaxel or pemetrexed) and endostatin. Endostatin was administered at 7.5 mg/m2/day for 4 hours from day 1 to day 14 of cycle 1. Starting from day 1 of cycle 2, endostatin was administered at 105 mg/m2/cycle for 72 hours (group A) or 168 hours (group B), respectively. The total treatment duration was 4 cycles, with the option to extend up to 6 cycles. Results: The PK exposure per cycle of endostatin 4 hours infusion and 72 hours or 168 hours pump infusion were comparable between group A and group B. The majority of adverse events during pump infusion were consistent with those observed during infusion and no endostatin-related serious adverse events were reported. The overall objective response rate (ORR) was 37.5%. Conclusion: The PK exposure between intravenous infusion and intravenous pump infusion at the same total cycle dose is similar. Both 72 hours and 168 hours intravenous pump infusion endostatin were well tolerated, and no new unexpected safety signals were observed.

Aim Recording the indication for a medicine in the prescription supports communication. In May 2023 our district hospitals made the free-text indication field in prescriptions compulsory for all medicines in the inpatient prescribing system. This study aimed to evaluate the effect of introducing a compulsory indication field in an inpatient prescribing system. Methods Text in the indication field was manually classified as an indication, ‘other text’, ‘rubbish text’, ‘to be determined’, and ‘blank’. Prescribing data were extracted from the district data warehouse. The change in proportion of prescriptions with an indication was compared for eight-weeks after introduction of a compulsory indication field to an equivalent eight-weeks in 2022. Secondary outcomes included patient outcomes, medication cessation, and indication recording before discharge. Results We analysed 81,634 prescriptions before and 82,726 after indications were made compulsory. The proportion of prescriptions with an indication increased from 29.2% to 75.6%. ‘Rubbish text’ increased from 0% to 2.3%, ‘other text’ from 2.5% to 14.7%, and ‘to be determined’ from 0.0% to 6.6%. Of 5,557 prescriptions with ‘to be determined’ initially, 18.1% were ceased and 2.7% had an indication before discharge. There was minimal change in patient outcomes. Conclusion Introducing a compulsory indication field increased the proportion of medicines with an indication from 29% to 76%, with only a small increase in ‘rubbish text’. The carefully selected compulsory field improved information quality but did not alter medicine use or patient outcomes. Compulsory fields should be combined with improvements in other components of care to improve medicine use.

The use of tramadol and other opioids for pain management has been accompanied by a multitude of challenges and concerns worldwide. The use of tramadol saw a decline in Denmark during 2017-2019 accompanied by a slight increase in the use of morphine and oxycodone. Using the Danish National Prescription Registry and utilizing data until and including 2023, we aimed to provide updated data on the utilization patterns of tramadol and other opioids in Denmark. We found a 35% decline in the use of tramadol from 2017-2023 most likely due to media attention, regulatory actions, health campaigns, and targeted education of physicians and patients by the Danish health authorities. This decline was accompanied by an increase in the number of new (+90%) and current users of morphine (+57%) which surpassed those of tramadol, oxycodone, and other opioids in 2023.

Aim: Coagulation factor XI (FXI) plays a crucial role in the intrinsic coagulation pathway, and inhibitors targeting it may mitigate the risk of hemorrhage compared to anticoagulants currently on the market. SKB336, a novel selective inhibitor of FXI/FXIa, has been shown to prolong the activated partial thromboplastin time (APTT) in in-vitro and in-vivo studies. This study aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of SKB336 in healthy subjects. Methods: In this randomized, single-blinded, placebo-controlled, and dose-escalation phase I study, 60 healthy subjects were allocated to six cohorts (0.1 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.25 mg/kg, 2.5 mg/kg, and 4 mg/kg) and received SKB336 injection or placebo in a 4:1 ratio. The safety, tolerability, pharmacokinetics, and immunogenicity were measured up to 85 days post-dose. Exploratory analysis consisted of FXI activity and APTT. Results: SKB336 was well tolerated in all six cohorts, without any hemorrhagic events, reported deaths, or serious adverse events. No significant dose-dependent correlation was observed with the incidence of adverse events. Dose-dependent increases in the Cmax and AUC were observed. The mean t1/2 was 21.3–33.5 days, indicating a potential monthly dosing frequency. The maximum inhibition rate of FXI activity for all six cohorts reached 0, 17%, 28%, 48%, 54%, and 59%, respectively. The maximum APTT ratio to baseline reached 1.09-, 1.26-, 1.47-, 1.77, 1.91-, and 2.00-fold, respectively. Conclusion: SKB336 was generally tolerated, without any bleeding events in healthy volunteers. Besides, SKB336 presented a persistent dose-dependent prolongation of APTT and duration of FXI inhibition.

Early approval mechanisms, such as conditional approval in the EU, have been used extensively to provide timely access to therapeutic innovations to cancer patients with unmet medical needs. While based on promising early evidence, such approvals are challenging from many perspectives due to the lack of comprehensive data. The limitation typically relates to data that demonstrates clinical benefit via particular endpoints and is only acceptable when the early evidence is particularly convincing to assume that the benefits of early access are greater than the potential harms. This paper describes the requirements for conditional approval and reviews common pitfalls in oncology, such as misunderstandings about the strength of evidence from exploratory trials and secondary analyses, lack of planning, and opportunities to improve communication. Thereafter, we present a framework (“EDGE”) on how to improve the submission and evaluation of drug applications for conditional approval in the EU.

Background Study on the effect of hydroxychloroquine (HCQ) in treating children with chronic immune thrombocytopenia (ITP) is limited. The association between ANA positivity and its efficacy is not clear. Methods This was a retrospective cohort study on chronic ITP children. We compared the clinical characteristics of patients who received HCQ with those who didn’t, as well as patients who responded to HCQ at 3 months with those who didn’t. Mixed-effects models were performed to assess the effect of HCQ on platelet counts and the association between ANA and its efficacy. Records of side effects associated with HCQ were reviewed. Results A total of 191 children with chronic ITP were included in this study, involved 42 patients who received HCQ. In patients who received HCQ, 69.0% of patients achieved complete response /response at the last follow-up, with a higher frequency than in patients who didn’t (69.0% vs. 48.3%). The overall response rate was 56.8% at 3 months and 40.5% at 1 year. Our results showed no difference in ANA positivity between patients with response to HCQ and those without. HCQ was effective for increasing platelet counts (mean difference: 23.82×109/L; 95% CI: 7.44 ~ 40.21), but the association between ANA positivity and its efficacy was not found. Side effects were recorded in 6 of 42 patients (14.3%). Conclusions HCQ was associated with increased platelet counts in chronic ITP children. The baseline ANA level was not found to have an interaction effect on this efficacy. Side effects of HCQ should be concerned.

The prescription of medications should be a constant concern in the daily practice of doctors, focusing not only on potential interactions with other prescription drugs, but also with herbal medicines, natural remedies, substances of misuse, and even certain foods. Minimizing the risks of interactions between these substances is the duty of all doctors.

Background & Aims: The potential of mechanistic biomarkers to improve prediction of drug-induced liver injury (DILI) and hepatic regeneration is widely acknowledged. We sought to determine reference intervals for new biomarkers of DILI and regeneration, as well as to characterize their natural variability and impact of diurnal variation. Methods: Serum samples from 227 healthy volunteers were recruited as part of a cross-sectional study; of these, 25 subjects had weekly serial sampling over 3 weeks, while 23 had intensive blood sampling over a 24h period. Alanine aminotransferase (ALT), MicroRNA-122 (miR-122), High Mobility Group Box-1 (HMGB1), total Keratin-18 (K18), caspase-cleaved Keratin-18 (ccK18), Glutamate Dehydrogenase (GLDH) and Macrophage Colony-Stimulating Factor-1 (CSF-1) were assayed. Results: Reference intervals were established for each biomarker based on the 97.5% quantile (90% CI) following the assessment of fixed effects in univariate and multivariable models. Intra-individual variability was found to be non-significant, and there was no significant impact of diurnal variation. Conclusions: Reference intervals for novel DILI biomarkers have been described. An upper limit of a reference range might represent the most appropriate mechanism to utilize these data. These data can now be used to interpret data from exploratory clinical DILI studies and to assist their further qualification as required by regulatory authorities.