Artificial intelligence-powered chatbots in search engines: a cross-sectional study on the quality and risks of drug information for patients.

BACKGROUND: Search engines often serve as a primary resource for patients to obtain drug information. However, the search engine market is rapidly changing due to the introduction of artificial intelligence (AI)-powered chatbots. The consequences for medication safety when patients interact with chatbots remain largely unexplored. OBJECTIVE: To explore the quality and potential safety concerns of answers provided by an AI-powered chatbot integrated within a search engine. METHODOLOGY: Bing copilot was queried on 10 frequently asked patient questions regarding the 50 most prescribed drugs in the US outpatient market. Patient questions covered drug indications, mechanisms of action, instructions for use, adverse drug reactions and contraindications. Readability of chatbot answers was assessed using the Flesch Reading Ease Score. Completeness and accuracy were evaluated based on corresponding patient drug information in the pharmaceutical encyclopaedia drugs.com. On a preselected subset of inaccurate chatbot answers, healthcare professionals evaluated likelihood and extent of possible harm if patients follow the chatbot's given recommendations. RESULTS: Of 500 generated chatbot answers, overall readability implied that responses were difficult to read according to the Flesch Reading Ease Score. Overall median completeness and accuracy of chatbot answers were 100.0% (IQR 50.0-100.0%) and 100.0% (IQR 88.1-100.0%), respectively. Of the subset of 20 chatbot answers, experts found 66% (95% CI 50% to 85%) to be potentially harmful. 42% (95% CI 25% to 60%) of these 20 chatbot answers were found to potentially cause moderate to mild harm, and 22% (95% CI 10% to 40%) to cause severe harm or even death if patients follow the chatbot's advice. CONCLUSIONS: AI-powered chatbots are capable of providing overall complete and accurate patient drug information. Yet, experts deemed a considerable number of answers incorrect or potentially harmful. Furthermore, complexity of chatbot answers may limit patient understanding. Hence, healthcare professionals should be cautious in recommending AI-powered search engines until more precise and reliable alternatives are available.

Assessment of the influence of body fat indices on antihypertensive drug responses.

AIMS: Less than 50% of patients treated for hypertension reach a target office systolic blood pressure (SBP). We aimed to evaluate the role of adiposity on antihypertensive drug responses in newly diagnosed hypertensive patients. METHODS: Estimated glomerular filtration rates, body mass index (BMI), skinfold thickness (SFT), body surface areas and waist circumferences of 150 hypertensive patients naïve to treatment were measured. Treatment protocols were started as combination of angiotensin converting enzyme inhibitor (ACE-I) plus calcium channel blocker (CCB), angiotensin receptor blocker plus CCB or ACE-I plus diuretic. Pre-treatment and change in blood pressure (ΔBP) after 4 weeks treatment were determined. Multiple linear regression analysis was used to find independent predictors of Δblood pressure changes, and multivariable binary logistic regression analysis to find independent predictors of target SBP < 140 mmHg at 4 weeks. RESULTS: A total of 104 patients reached the target systolic pressure of <140 mmHg at 4 weeks. Triceps, mid-abdomen and subscapular SFT were significantly thicker in the uncontrolled blood pressure group (P = .011, P = .006 and P = .016, respectively). Pretreatment SBP (r = 0.644), pretreatment diastolic blood pressure (DBP) (r = 0.188), subscapular SFT (r = -0.318), suprailiac SFT (r = -0.211) and ΔDBP (r = 0.433) were correlated with ΔSBP in correlation analysis. Pretreatment SBP (ß = 0.644, 95% CI = 0.697-0.993, P < .001), subscapular SFT (ß = -0.253, 95% CI = -0.886--0.329, P < .001), pretreatment DBP (ß = -0.380, 95% CI = -0.1001- -0.453, P = .001) and ΔDBP (ß = 0.401, 95% CI = 0.377-0.796, P < .001) were independent predictors of ΔSBP in multivariable linear regression analysis. Subscapular SFT was an independent predictor of target SBP < 140 mmHg in multivariable logistic regression analysis (OR = 0.895, 95% CI = 0.832-0.963, P = .003). CONCLUSIONS: Subscapular SFT may be a valuable marker for prediction of response to antihypertensive drugs.

Clinical Pharmacology of Pemafibrate Extended-release Formulation in Patients with Hypertriglyceridemia-A Phase 2, Multicenter, Active-controlled, Randomized, Single-blind, Crossover study.

AIMS: Efficacy, safety, and pharmacokinetics of the selective PPARα modulator pemafibrate as once-daily extended-release (XR) tablets were compared with those of twice-daily immediate-release (IR) tablets in patients with hypertriglyceridemia. METHODS: A multicenter, randomized, single-blind, active-controlled crossover, phase 2 clinical pharmacology study was performed in patients with hypertriglyceridemia. Patients were randomly assigned to IR 0.2 mg/day, XR 0.4 mg/day, or XR 0.8 mg/day before/after meals (fasted/fed) and treated for a total of eight weeks. The primary endpoint was percentage change in fasting serum triglycerides (TG). RESULTS: Of 63 randomized patients, 60 received the study drug. Patients were 78.3% male, mean age (±SD) 57.5±9.8 years, BMI 25.5±3.7 kg/m2, and fasting TG 221.3±68.1 mg/dL. Fasting serum TG decreased significantly from baseline in all groups (LS mean [95% CI];-43.6 [-47.7, -39.5] % for IR 0.2 mg/day, -41.1 [-45.1, -37.0] % for XR 0.4mg/day, -39.7 [-43.8, -35.6] % for XR 0.8 mg/day), indicating that XR 0.4 and XR 0.8 mg/day were not inferior to IR 0.2 mg/day. TG-lowering effects tended to be stronger for fed than fasted administration. MRTss, tmax, and t1/2 were longer for XR than for IR. Adverse events showed no major inter-group differences: 12.5% (5/40 patients) for IR 0.2, 17.5% (7/40) for XR 0.4, and 20.0% (8/40) for XR 0.8 mg/day. CONCLUSIONS: In patients with hypertriglyceridemia, XR substantially lowered TG at all doses, with maximum effectiveness at 0.4 mg/day, the dose approved in Japan, to a level comparable to IR 0.2 mg/day. There were no safety concerns up to 0.8 mg/day.

Evaluation of a short-structured learner-centric training program on rational drug prescribing for medical interns: A quasi-experimental study.

Introduction: Rational drug prescribing skills of interns remain bleak despite clinical pharmacology training during their second year, warranting the need for further training. This study was designed to evaluate the effectiveness of a short-structured learner-centric training program using the World Health Organization (WHO) guide to good prescribing in improving interns' knowledge of rational drug use and their rational drug prescribing skills. Methods: This quasi-experimental study was implemented at a tertiary care teaching hospital in South India. We conducted a short-structured learner-centric training program on rational drug prescribing for interns in September 2022, using the WHO guide to good prescribing. The medical interns who consented to participate were included in the study. A pre-test was administered at the start of the training, followed by a post-test and feedback questions at the end of the program. Statistical tests used for quantitative data were the Wilcoxon signed-ranks test and McNemar's Chi-square test. Qualitative data were analyzed using manual content analysis. Results: Of the 77 interns who attended the training program, 73 provided consent and completed both the pre-test and the post-test. Their mean age was 22 years, with a slight preponderance of female participants (53.4%). Overall, there was a statistically significant increase in the median (interquartile range) total scores from 52 (44.6 - 60) to 84 (70 - 88) after the training (P = 0.001), out of a maximum score of 93. Also, a significantly greater number of them wrote legible prescriptions (grade 4/excellent - 44 in pre-test vs 52 in post-test; P = 0.001) after the training. Conclusion: The short-structured learner-centric training program based on the WHO guide to good prescribing significantly improved the knowledge of rational drug use and rational drug prescribing skills among medical interns.

Apixaban anti-Xa levels in clinical practice: A case report.

Apixaban is a widely used direct oral anticoagulant that is recommended over warfarin therapy for many clinical indications. In patients with atrial fibrillation, dose reductions are recommended for patients with advanced age (≥80 years), low weight (≤60 kg) or elevated serum creatinine (≥1.5 mg/dL), but there is no routine laboratory monitoring necessary for long term-use. Furthermore, apixaban dose reductions due to renal dysfunction are not recommended when treating acute venous thromboembolism. Apixaban-calibrated anti-Xa assays are readily available at some medical centres, and they may be of clinical utility in certain circumstances such as in patients with renal insufficiency, medication adherence assessment, periprocedural planning, extremes in body weight and advanced age. Here, we describe the case of an elderly patient with chronic kidney disease taking apixaban for acute pulmonary embolism. The patient had an unanticipated prolonged apixaban half-life, with detectable apixaban-calibrated anti-Xa levels for >10 days after the last administered dose, which delayed a necessary surgical intervention by >1 week. This case is an example of appropriately using apixaban-calibrated anti-Xa levels to guide therapeutic decision making in perioperative planning.

The effect of down-titration and discontinuation of heart failure pharmacotherapy in older people: A systematic review and meta-analysis.

The aim of this study was to investigate whether interventions to discontinue or down-titrate heart failure (HF) pharmacotherapy are feasible and associated with risks in older people. A systematic review and meta-analysis were conducted according to PRISMA 2020 guidelines. Electronic databases were searched from inception to 8 March 2023. Randomized controlled trials (RCTs) and observational studies included people with HF, aged ≥50 years and who discontinued or down-titrated HF pharmacotherapy. Outcomes were feasibility (whether discontinuation or down-titration of HF pharmacotherapy was sustained at follow-up) and associated risks (mortality, hospitalization, adverse drug withdrawal effects [ADWE]). Random-effects meta-analysis was performed when heterogeneity was not substantial (Higgins I2 < 70%). Sub-analysis by frailty status was conducted. Six RCTs (536 participants) and 27 observational studies (810 499 participants) across six therapeutic classes were included, for 3-260 weeks follow-up. RCTs were conducted in patients presenting with stable chronic HF. Down-titrating a renin-angiotensin system inhibitor (RASI) in patients with chronic kidney disease was 76% more likely than continuation (risk ratio [RR] 1.76, 95% confidence interval [CI] 1.14-2.73), with no difference in mortality (RR 0.64, 95% CI 0.30-1.64). Discontinuation of beta-blockers were feasible compared to continuation in preserved ejection fraction (RR 1.00, 95% CI 0.68-1.47). Participants were 25% more likely to re-initiate discontinued diuretics (RR 0.75, 95% CI 0.66-0.86). Digoxin discontinuation was associated with 5.5-fold risk of hospitalization compared to continuation. Worsening HF was the most common ADWE. One observational study measured frailty but did not report outcomes by frailty status. The appropriateness and associated risks of down-titrating or discontinuing HF pharmacotherapy in people aged ≥75 years is uncertain. Evaluation of outcomes by frailty status necessitates investigation.

Steady-state trumps accuracy: target-controlled infusion as a gain switch.

Target-controlled infusion (TCI) is a mature technology that enables the delivery of intravenous anaesthetics in the concentration domain. The accuracy of the pharmacologic models used by TCI systems is imperfect, especially regarding pharmacodynamic predictions. This shortcoming of TCI devices is not critical. That TCI systems produce steady-state effect-site concentrations at or near a specified target is a more important attribute than a high level of accuracy because anaesthesiologists titrate to a stable level of drug effect whatever the actual concentration is. In this sense, TCI functions as a 'gain switch'. Achieving a steady state is more important than perfect accuracy.

A comprehensive review of artificial intelligence for pharmacology research.

With the innovation and advancement of artificial intelligence, more and more artificial intelligence techniques are employed in drug research, biomedical frontier research, and clinical medicine practice, especially, in the field of pharmacology research. Thus, this review focuses on the applications of artificial intelligence in drug discovery, compound pharmacokinetic prediction, and clinical pharmacology. We briefly introduced the basic knowledge and development of artificial intelligence, presented a comprehensive review, and then summarized the latest studies and discussed the strengths and limitations of artificial intelligence models. Additionally, we highlighted several important studies and pointed out possible research directions.

Infliximab in Inflammatory Bowel Disease: Leveraging Physiologically Based Pharmacokinetic Modeling in the Clinical Context.

In this study, a physiologically based pharmacokinetic (PBPK) modeling framework was employed to explore infliximab exposure following intravenous (5 mg/kg) and subcutaneous administration (encompassing the approved 120 mg flat-fixed dose as a switching option) in virtual adult and pediatric patients with inflammatory bowel disease (IBD). The PBPK model and corresponding simulations were conducted using the PK-Sim® software platform. The PBPK simulation indicated that a 120 mg subcutaneous flat-fixed dose might not be optimal for heavier adults with IBD, suggesting the need for infliximab dose escalation. For an older virtual pediatric patient (14 years old), subcutaneous administration of a 120 mg flat-fixed dose appears to be a feasible IBD treatment option. In the final exploration scenario, the model was extended to predict hypothetical subcutaneous infliximab doses in a virtual pediatric population (6-18 years old), stratified into three weight bands (20-30 kg, 30-45 kg, and 45-70 kg), that would yield post-switch trough concentrations of infliximab comparable to those seen in adults with the 120 mg flat-fixed subcutaneous dose. The PBPK-model-informed dose suggestions were 40 mg for the 20-30 kg band, 80 mg for the 30-45 kg band, and 120 mg for the 45-70 kg band. As demonstrated in this paper, the PBPK modeling framework can serve as a versatile tool in clinical pharmacology to investigate various clinical scenarios, such as exploring alternative dosing regimens and routes of administration, ultimately advancing IBD treatment across diverse (sub)populations of clinical interest.

Characterization of Ganciclovir Dosing for the Management of Cytomegalovirus in Solid Organ Transplant Recipients Receiving Sustained Low-Efficiency Dialysis.

BACKGROUND: The optimal dosing of intravenous ganciclovir in patients receiving sustained low-efficiency dialysis (SLED) remains unclear. OBJECTIVE: The primary objective is to characterize the dosing of ganciclovir for treating and preventing cytomegalovirus (CMV) in Solid Organ Transplant Recipients receiving SLED. The secondary objective is to evaluate the safety and efficacy of the dosing practices described in this study. METHODS: Retrospective review of electronic medical records from solid organ transplant recipients (SOTRs) admitted to the Medical Surgical Intensive Care Unit at the Toronto General Hospital (TGH) between November 28, 2016, and September 1, 2021, was conducted. Patients concurrently receiving ganciclovir and SLED were included. RESULTS: Among the 27 encounters for CMV prevention, 18 patients underwent 8-hour SLED, 6 underwent 24-hour SLED, and 3 received other SLED durations. Most patients (80%) on 8-hour SLED began ganciclovir at 2.5 mg/kg/d, whereas 80% of those on 24-hour SLED started at 5 mg/kg/d. No breakthrough viremia occurred at 5 mg/kg/d, with 1 instance at 2.5 mg/kg/d. Cytopenia rates were higher at 5 mg/kg/d (33% vs 20%). For treatment (n = 20), 16 patients underwent 8-hour SLED, 2 underwent 24-hour SLED, and 2 underwent 12-hour SLED. Most (75%) on 8-hour SLED started at 2.5 mg/kg/d, whereas all on 24-hour SLED began at 5 mg/kg/d. Viral eradication rates were 75% and 60% at 2.5 and 5 mg/kg/d, respectively, with higher cytopenia rates at 5 mg/kg/d (37.5% vs 0%). Dose adjustments were primarily in response to refractory disease or cytopenia. CONCLUSION AND RELEVANCE: At our institution, ganciclovir dosing patterns suggest that for patients requiring 8-hour SLED, there is clinician comfort in using 2.5 mg/kg/d for prevention and 5 mg/kg/d for treatment. In 24-hour SLED, 5 mg/kg/d may be considered for prevention. Higher doses may be considered for CMV treatment; however, we found greater variability in the dosing practices for these patients. Further research with larger sample sizes and ganciclovir drug-level assessments is needed to optimize dosing strategies for CMV treatment.

High prevalence of medication errors in a secondary-level Lithuanian hospital: A prospective cross-sectional observational study.

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.

Characterizing psychopharmacological prescribing practices in a large cohort of adolescents with borderline personality disorder.

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. METHOD: 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.

Drug related adverse event assessment in neonates in clinical trials and clinical care.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Evaluation of Obesity-Related Physiological Changes on Pantoprazole Clearance in Children Using a Population Pharmacokinetic Approach.

Pediatric obesity is a growing health concern, affecting millions of children worldwide. While pharmacokinetic (PK) changes in numerous commonly prescribed medications have been linked to obesity, the physiological mechanisms driving these alterations and their implications for drug dosing remain poorly understood. The objective of this study was to evaluate previously reported observations of reduced pantoprazole clearance (CL) in children with obesity, investigate obesity-related characteristics in liver physiology as explanatory causes for these observations, and evaluate the clinical relevance of obesity on drug dosing. A prospective, comparative PK study, enrolling participants 6-21 years of age, with and without obesity, was conducted to evaluate the association between obesity-related characteristics and pantoprazole CL. A nonlinear mixed-effects modeling approach was used to identify sources of interindividual variability in pantoprazole PK. Monte Carlo simulations were performed to assess pantoprazole exposure in children and evaluate the association between obesity and pantoprazole exposure. The study population consisted of 39 pediatric participants: 31% without obesity and 69% with obesity. A two-compartment PK model with covariate effects of total body weight (TBW), CYP2C19 metabolizer phenotype, and obesity status adequately described the PK data. After accounting for differences due to TBW and CYP2C19 metabolizer phenotype, obesity was associated with an estimated 18% reduction in pantoprazole CL (comparable to the reduction estimated for a CYP2C19 loss of function allele). Further research is warranted to evaluate the physiological mechanisms associated with reduced drug CL in children with increased body size and the implications for drug dosing.

Impact of aspirin dose according to race in secondary prevention of atherosclerotic cardiovascular disease: a secondary analysis of the ADAPTABLE randomised controlled trial.

OBJECTIVES: 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). DESIGN: A secondary analysis of the randomised controlled trial ADAPTABLE was performed. SETTING: The study was conducted in 40 centres and one health plan participating in the National Patient-Centred Clinical Research Network (PCORnet) in the USA. PARTICIPANTS: 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%). INTERVENTIONS: 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. PRIMARY AND SECONDARY OUTCOMES MEASURES: 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. CONCLUSION: 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. TRIAL REGISTRATION NUMBER: NCT02697916.

Pharmacokinetics and Safety of Cilofexor and Firsocostat in Healthy Japanese and Non-Japanese Participants.

Cilofexor, an oral farnesoid X receptor agonist, and firsocostat, an oral, liver-targeted inhibitor of acetyl-coenzyme A carboxylase, are being investigated in combination with semaglutide for the treatment of metabolic dysfunction-associated steatohepatitis (previously known as nonalcoholic steatohepatitis; NCT04971785). The pharmacokinetics and safety profiles of cilofexor (100 mg) and firsocostat (20 mg) were separately investigated in two phase 1 studies, each of which included healthy Japanese participants (n = 20 in the cilofexor study and n = 21 in the firsocostat study) and non-Japanese participants (n = 20 in the cilofexor study and n = 21 in the firsocostat study). Intensive pharmacokinetic sampling was performed over 96 h following a single-dose administration of the study drug. Safety was monitored throughout the study. In total, 39 participants completed each study. The plasma exposures of cilofexor and firsocostat (area under the concentration-time curve [AUC] calculated from time 0 to infinity [AUCinf]) in Japanese participants were 1.24-fold and 1.98-fold, respectively, of those in non-Japanese participants. Both study drugs were well tolerated with no clear differences in adverse events or laboratory abnormalities between Japanese and non-Japanese participants. The approximate 2-fold exposure difference of firsocostat between Japanese and non-Japanese participants at the 20 mg dose does not warrant dose reduction given the previously established safety and tolerability of once-daily doses of firsocostat up to 200 mg.

Sabatolimab in combination with spartalizumab in patients with non-small cell lung cancer or melanoma who received prior treatment with anti-PD-1/PD-L1 therapy: a phase 2 multicentre study.

OBJECTIVE: This study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC). DESIGN, SETTING AND PARTICIPANTS: This is a phase 1-1b/2, open-label, multinational, multicentre study of patients with advanced/metastatic melanoma or NSCLC with ≥1 measurable lesion. INTERVENTIONS: Patients were given sabatolimab 800 mg every 4 weeks plus spartalizumab 400 mg every 4 weeks until unacceptable toxicity, disease progression and/or treatment discontinuation. OUTCOME MEASURES: The phase 2 primary outcome measure was overall response rate and secondary objectives included evaluation of the safety, tolerability, efficacy and pharmacokinetics of sabatolimab in combination with spartalizumab. RESULTS: 33 patients (melanoma n=16, NSCLC n=17) received sabatolimab plus spartalizumab. 31 (94%) experienced ≥1 adverse event (AE); 15 (46%) experienced grade 3/4 events. The most frequent grade ≥3 AEs for NSCLC were anaemia, dyspnoea and pneumonia (each n=2, 12%); for patients with melanoma, the most frequent grade ≥3 AEs were physical health deterioration, hypokalaemia, hypophosphataemia, pathological fracture and tumour invasion (each n=1; 6%). One (3%) patient discontinued treatment due to AE. Stable disease was seen in three patients with melanoma (19%) and six patients with NSCLC (35%). Median progression-free survival was 1.8 (90% CI 1.7 to 1.9) and 1.7 (90% CI 1.1 to 3.4) months for patients with melanoma and NSCLC, respectively. Patients with stable disease had higher expression levels of CD8, LAG3, programmed death-ligand 1 and anti-T-cell immunoglobulin and mucin-domain containing-3 at baseline. The pharmacokinetics profile of sabatolimab was consistent with the phase 1 study. CONCLUSIONS: Sabatolimab plus spartalizumab was well tolerated in patients with advanced/metastatic melanoma or NSCLC who had progressed following antiprogrammed death-1/antiprogrammed death-ligand 1 treatment. Limited antitumour activity was observed. The tolerability of sabatolimab administration supports the potential to explore treatment with sabatolimab in various combination regimens and across a spectrum of tumour types. TRIAL REGISTRATION NUMBER: NCT02608268.

Impact of Probiotics on the Glycemic Control of Pediatric and Adolescent Individuals with Type 1 Diabetes: A Systematic Review and Meta-Analysis.

AIMS: Human recombinant insulin is currently the only therapy for children and adolescents with type 1 diabetes (T1D), although not always efficient for the glycemic control of these individuals. The interrelation between the gut microbiome and the glycemic control of apparently healthy populations, as well as various populations with diabetes, is undeniable. Probiotics are biotherapeutics that deliver active components to various targets, primarily the gastrointestinal tract. This systematic review and meta-analysis examined the effect of the administration of probiotics on the glycemic control of pediatric and adolescent individuals with T1D. MATERIALS AND METHODS: Randomized controlled trials employing the administration of probiotics in children and adolescents with T1D (with ≥10 individuals per treatment arm), written in English, providing parameters of glycemic control, such as mean glucose concentrations and glycosylated hemoglobin (HbA1c), were deemed eligible. RESULTS: The search strategy resulted in six papers with contradictory findings. Ultimately, five studies of acceptable quality, comprising 388 children and adolescents with T1D, were included in the meta-analysis. Employing a random and fixed effects model revealed statistically significant negative effect sizes of probiotics on the glycemic control of those individuals, i.e., higher concentrations of glucose and HbA1c than controls. CONCLUSIONS: Children and adolescents with T1D who received probiotics demonstrated worse glycemic control than controls after the intervention. Adequately powered studies, with extended follow-up periods, along with monitoring of compliance and employing the proper strains, are required to unravel the mechanisms of action and the relative effects of probiotics, particularly concerning diabetes-related complications and metabolic outcomes.

Precision medicine for Defence?

Proteins control individual patient's response to pharmaceutical medication, be they receptors, transporters or enzymes. These proteins are under the control of genes. The study of these genes and the interplay between multiple genes is pharmacogenomics, with individual genes being termed pharmacogenes. The greatest understanding of pharmacogenetics is of the drug metabolising enzymes, the cytochrome P450s. Almost the entire UK population is likely to have at least one genetic variant that controls these P450s and thus the phenotype for metabolic competence. This means two patients receiving the same medication and dose may have very different responses, from adverse reaction to being ineffective. An individual military person's response to medications can be predicted from their pharmacogenetics, as an example; the response to the commonly prescribed 'pain killers', codeine, tramadol, hydrocodone or oxycodone. These opioids are metabolised into their active forms by the cytochrome 2D6. Four phenotypes classify an individual's metabolic competency: ultra-rapid, extensive, intermediate or poor. A poor metaboliser is at risk of ineffective pain relief from one of the opioids listed, whereas an ultra-rapid metaboliser is at risk of overexposure and subsequent dependency or abuse. In white European populations, the prevalence of the phenotypes is well known and may be used to guide prescribing; however, in other populations such as Nepalese or Pacific Islander the distribution of these phenotypes is unknown. Genotyping provides a framework for the precise treatment of patients and cost-effective use of medication for the UK Armed Forces, as well as potentially providing equity for minority groups.