Objective: To analyze the medication discrepancies (MD) in prescriptions of patients during a medication reconciliation (MR) service at admission to the Medical Unit. Methods: Cross-sectional study, carried out from March 2021 to February 2022, in a medium-sized hospital. Patients aged 18 years or older and in continuous use of at least one medication at the time of hospitalization were included. The first interview at the MR service was preferably carried out within 24 hours to collect sociodemographic data, health indicators, detailed information on home pharmacotherapy. Data were analyzed using Stata 13.0 software. Pearson’s chi-square test was performed for statistical analysis. The study was approved by CEP/UFOP under number 4,845,642. Results: Of the 215 patients included, 115 were female, with a mean age of 68 ± 18 years. The mean number of medications in use at the time of admission was 6±3. Polypharmacy was identified in 128 patients. The variables age group (p=0.005), polypharmacy (p<0.001), having Hypertension and/or Diabetes Mellitus (p=0.001), hospitalization for infectious and parasitic diseases (p<0.001) and diseases of the circulatory system (p=0.040) are significantly related to the occurrence of at least one DM. Medications used in Diabetes Mellitus (p<0.001), Agents that act on the Renin-Angiotensin System (p=0.028), Lipid Modifying Agents (p=0.026), Medications for Obstructive Airway Diseases (p=0.001), general nutrients (p=0.005) and thyroid hormone medications (p=0.002) were associated with unintentional DM Conclusion: It was possible to identify a significant percentage of MD in the prescription evaluated. Polypharmacy and age group were related to the occurrence of MD

Aim: The influence of human factors on safety in healthcare settings is well established, with targeted interventions reducing risk and enhancing team performance. In experimental and early phase clinical research participant safety is paramount and safeguarded by guidelines, protocolised care and staff training, however the real-world interaction and implementation of these risk-mitigating measures has never been subjected to formal system-based assessment. Methods: Independent structured observations, systematic review of study documents, and interviews and focus groups were used to collate data on three key tasks undertaken in a Clinical Research Facilty (CRF) during a SARS CoV-2 controlled human infection model (CHIM) study. The Systems Engineering Initiative for Patient Safety (SEIPS) was employed to analyse and categorise findings, and develop recommendations for safety interventions. Results: High levels of team functioning and a clear focus on participant safety were evident throughout the study. Despite this, latent risks in both study-specific and CRF work systems were identified in all four SEIPS domains (people, environment, tasks and tools). 14 actionable recommendations were generated collaboratively. These included inter-organisation and inter-study standardisation, optimised checklists for safety critical tasks, and use of simulation for team training and exploration of work systems. Conclusion: This pioneering application of human factors techniques to analyse work systems during the conduct of research in a CRF revealed risks unidentified by routine review and appraisal, and despite international guideline adherence. SEIPS may aid categorisation of system problems and the formulation of recommendations that reduce risk and mitigate potential harm applicable across a trials portfolio

Abstract Aims This study aims to assess the safety of medication that can affect blood pressure in patients with hypertension and provide practical recommendations for healthcare professionals. Methods For the development of recommendations for the drug-disease interaction (DDSI) hypertension, a six-step plan that combined literature selection and multidisciplinary expert opinion was used. The process involved (1) defining the scope of the DDSI and selecting relevant drugs, (2) collecting evidence, (3) data-extraction, (4) reaching of expert consensus, (5) publication and implementation of the recommendations in healthcare systems and (6) updating of the information. Results An increase of 10 mmHg in systolic blood pressure and 5 mmHg in diastolic blood pressure was defined as clinically relevant. Corticosteroids, danazol, and yohimbine caused a clinically relevant DDSI with hypertension. Several other drugs with warnings for hypertension in the official product information, were assessed to have no clinically relevant DDSI due to minor influence or lack of data on blood pressure. Drugs with evidence for a relevant change in blood pressure which are prescribed under close monitoring of blood pressure according to clinical guidelines, were deemed to be not clinically relevant for signalling. Conclusions This study provides specific recommendations that can be implemented directly in clinical practice, potentially resulting in safer drug use in patients with hypertension and better healthcare by reducing alert fatigue. Future research should focus on evaluating the effectiveness of implementation strategies and their impact on reducing unsafe use of medication in patients with hypertension.

A sixty-year-old male presented with three-day history of a widespread erythematous rash with associated chills, paraesthesia, and haematuria. On review of medications, he had recently been commenced on Vimovo (Naproxen/Esomeprazole) 500mg/20mg twice daily for a week for back pain. Bloods showed hypereosinophilia and a moderate acute kidney injury. Histology revealed parakeratosis, mild spongiosis with eosinophils. His admission was complicated by the acute onset of rapid atrial fibrillation with acute coronary syndrome. Coronary angiogram was non-obstructive. Cardiac MRI revealed acute myocarditis. This was felt to be a complication secondary to Drug reaction with eosinophilia and systemic symptoms (DRESS). In addition to his cardiac management, he was treated with oral corticosteroids and supportive care. Naproxen/Esomeprazole was stopped. On repeat cardiac MRI 3 months later his myocarditis had resolved, and his skin remains clear. DRESS is a rare drug induced hypersensitivity reaction that includes skin eruption, haematological abnormalities, lymphadenopathy, and internal organ involvement which has morality rate of up to 10%. The objective of this case report is to highlight the significant cardiac complications that can ensue. Naproxen/Esomeprazole was the culprit drug which is rare. There has been one previous case of DRESS secondary to NSAID with myocarditis. However, it presented as cardiogenic shock. This case was complicated by arrythmia and acute coronary syndrome. DRESS warrants prompt recognition with identification of causative drug and withdrawal. Multiorgan complications can be severe, and treatment should not be delayed. DRESS should always be considered with a new onset rash in the context of a new medication.

A document by Raoudha Slim. Click on the document to view its contents.

AIM Levetiracetam is a widely used anti-epileptic in the critical care setting that is almost exclusively (>90%) renally excreted. A significant number of critically unwell patients develop renal failure requiring haemofiltration. This paper investigates the pharmacokinetics of levetiracetam in such patients and the implications on dosing strategies. METHODS A systematic review of the available literature from 2000 was conducted. 7 articles were identified for inclusion from 54 records. A novel hybrid model was used to evaluate the quality of pharmacokinetic and haemofiltration data. Simulations were performed using pooled pharmacokinetic data to evaluate various dosing strategies. RESULTS Total clearance was 3.49 – 4.63L/hr (mean 3.55, S.D. 0.52). Elimination half-life was 5.66 – 12.88 hours (mean 9.41, S.D. 2.86). Volume of distribution was 0.45 – 0.73 L/kg. Levetiracetam clearance from CRRT was 52 – 73% (mean 54.7%, S.D. 13.5). At 72 hours, a significant proportion of simulated patients who received the recommended dose of levetiracetam demonstrated sub-therapeutic drug concentrations. Conversely, the majority who received a standard loading dose (60mg/kg) and twice daily doses in excess of 750mg demonstrated more consistent therapeutic drug concentrations. CONCLUSION Levetiracetam clearance in haemofiltration is similar to healthy adults with normal renal function. The current recommendation to dose as in CKD Stage 3b is likely to result in sub-therapeutic drug concentrations in a high number of patients. A twice daily dosing of 500 – 1,000 mg with an initial loading dose of 60mg/kg should be considered in such patients alongside therapeutic drug monitoring.

Aims: Despite their overall favourable safety profile, the intraocular pressure increases after any routes of triamcinolone acetonide application are not rare. We designed a systematic review and network meta-analysis to compare risk of IOP elevation among TA for different routes of administration used by patients diagnosed with macular edema. Methods: We obtained data from the PubMed, MEDLINE, Embase, and Cochrane Library. We performed random-effects model and consistency model network meta-analyses to summarize the evidence. The Bayesian approach was used for direct and indirect comparisons, and the treatments were ranked by the surface under the cumulative ranking curve. The study was registered with PROSPERO, CRD42022366513 Results: Sixteen studies were included in the network meta-analysis. There was a significant difference in IOP between IVTA and STiTA (MD, 1.67 [95% CrI, 0.25, 3.15]) at the 12th week. At the 24th week, compared with the placebo group, IVTA, SCTA and STiTA had statistically significant effect on IOP (MD, 1.35 [95% CrI, 0.23, 2.30], 2.42 [95% CrI, 4.53, 0.19], and 1.31 [95% CrI, 2.49, 0.02]). The probabilities of rankings and SUCRA showed that IVTA and SCTA were generally considered the higher risk of IOP elevation than the other routes of injection therapy. In addition, RITA was shown to be safer. Conclusion: IVTA and SCTA appeared as the least safe routes of injection therapy for ME, which being more prone to increase the risk of IOP elevation. RITA demonstrated a safer profile. However, more high-quality randomized controlled trials will be necessary to further confirm this.

Background: Older adults often have polypharmacy and multiple comorbidities. Cardiovascular diseases (CVDs) are the most common morbidities in older adults and are linked to many adverse drug effects and drug-related issues. Several patient settings use the medication appropriateness index (MAI) to assess older adults’ Potentially Inappropriate Medication (PIM) prescribing. Aim: This study estimated CVDs outpatient clinic PIM prescribing. It also tested the MAI’s ability to detect and quantify PIMs in CVD outpatient clinics. Methods: It is a cross-sectional, single-center, cardiovascular outpatient clinic study. Demographic, medical, and drug data from 65 years or older patients were retrospectively reviewed. Two clinical pharmacists randomly selected 70 patients and assessed medication appropriateness using the MAI. Statistical Package for the Social Sciences (SPSS) descriptive and logistic regression analyses calculated the number of potentially inappropriate medications, the percentage of patients with inappropriate medication prescribing, and factors associated with inappropriate medication prescribing. Results: Total of 87.14% of participants had PIMs. Two clinical pharmacists evaluated 539 prescriptions, and 59.9% had an MAI weighted score of zero (no prescription error). Drug-drug interaction, duplication, and drug-disease interaction almost perfectly agreed among raters. The two raters’ MAI criteria kappa coefficient was 0.44, indicating moderate agreement. The results showed that only some medications significantly affected MAI-defined inappropriate prescribing. Conclusion: The MAI is a reliable and valid tool in CVD outpatient clinics. A relatively high prevalence of PIMs was found in the studied population. It mandates implementing specific measures to reduce PIMs.

Critically ill patients with infections present with considerable challenges in antimicrobial use due to multiple reasons such as pathophysiological alterations, comorbidities, supportive treatment and the pathogenicity of implicated organism. Fluid shifts, hyperdynamic state, altered renal clearance are the rapid changes which are often not considered while administering antimicrobials. Vital organ dysfunction with or without Multi–Organ Dysfunction Syndrome (MODS) often necessitates use of supportive management in the form of Ventilatory Support or Renal Replacement Therapy (RRT) to Extracorpeal Membrane Oxygenation (ECMO) to name a few. These supportive measures may have implication on PK-PD of administered antimicrobials. Certain patient parameters such as age, weight, comorbid illnesses like cystic fibrosis, burns or immunocompromised state can be important determinants of pharmacokinetics and pharmacodynamics (PK-PD) of antimicrobials. Issues such as bioavailability of the antimicrobial at the primary focus of infection need to be taken into consideration while making choice of antimicrobial(s) and deciding a dose. The critical pharmacodynamic parameters that need to be taken into account consider are disease state, altered bacterial susceptibility, pathogenicity and localization of the organism and host immunity while making decisions about optimized antimicrobial treatment in a critically ill patient with infection. The current review delves on these nuances with a focus on PK-PD for optimized use of antimicrobials in a critically ill patient.

The aim of the study was to describe the use of two Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis (RA) recorded at Vall d’Hebron University Hospital (VHUH) between September 2017-November 2019. The data was extracted from the register of Patients and Treatments and medical records. Out of the thirty-nine patients included 90.0% were women, median age 56 years (IQR 29-72) and disease duration 15 years (IQR 8-20). Tofacitinib was the most used (28 patients). All patients had been previously treated with conventional synthetic disease modifying antirheumatic drugs (csDMARDs), and 79.5% with at least one biological DMARD (bDMARD). In 16 patients (41.0%) disease activity category improved. Treatment was withdrawn in 9 patients, mainly due to lack of efficacy (5). Five patients treated with tofacitinib reported gastrointestinal and/or skin disorders. This study shows the usefulness of registries of treated patients to study the use of the new and expensive drugs.

Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) is considered a toxemic disorder in which early intervention with neutralizing antibodies may have therapeutic benefits. INM004, composed of F(ab’)2 fragments from equine immunoglobulins, neutralizes Stx1/Stx2, potentially preventing the onset of HUS. A single-center, randomized, Phase 1, single-blind, placebo-controlled clinical trial to evaluate INM004 safety, tolerance, and pharmacokinetics (PK) in healthy adult volunteers, was conducted; In Stage I, eight subjects were divided in two cohorts (n=4) to receive a single INM004 dose of 2 or 4 mg.kg-1, or placebo (INM004:placebo rate 3:1). In Stage II six subjects received either three INM004 doses of 4 mg.kg-1 repeated every 24 h, or placebo (INM004:placebo rate of 5:1). Hospital discharged was 24 hours after the last infusion. INM004 was quantified by ELISA in serum samples obtained at predefined times. Safety and tolerability were assessed in both Stages by monitoring adverse events (AEs), laboratory test values, and vital signs. Eight subjects (57.1%) experienced treatment-emergent AEs (TEAEs), that resolved within 24 hours without requiring changes in treatment or additional intervention. No serious AEs were reported. Most TEAEs were of mild or moderate intensity, and four were possibly drug-related. Peak concentrations (Cmax) of INM004 were 45.1 µg.mL-1 and 77.7 µg.mL-1 for different doses, within two hours after infusion. The serum concentration declined in a biphasic manner (t1/2 range 30.7-52.9 hours). Systemic exposures showed accumulation in the repeated dose regimen (Cmax Day1 85.7 vs.149 µg.mL-1 Day3). These results supporting progression into the phase 2 trial in children with HUS

Aim: Elamipretide is a mitochondrial-targeting agent being developed for the treatment of mitochondrial dysfunction-associated diseases. While prior studies have shown that subcutaneous elamipretide is generally safe/well tolerated, injection site reactions (ISRs) were reported in most subjects. We evaluated the efficacy of interventions to mitigate ISRs, identify underlying ISR mechanisms, and evaluate the pharmacokinetic and safety profile of subcutaneous elamipretide. Methods: Subcutaneous elamipretide 60 mg was administered to healthy subjects (N=10) on six separate occasions with/without potential ISR interventions (mometasone furoate, ice application, tacrolimus ointment, doxepin cream, and oral diphenhydramine). ISR clinical/self-assessments, blood samples, and safety data were collected at predetermined intervals. Preclinical studies investigated mast cell-specific receptor MRGPRX2 mediation of ISRs. Results: Mometasone significantly reduced the incidence of induration/swelling and pruritus. Diphenhydramine significantly decreased the incidence of induration; 50% reported somnolence. Ice application significantly reduced the incidence of pain, although it reduced elamipretide’s maximum plasma concentration and area-under-the-curve from time 0-6hrs versus elamipretide alone. Preclinical data suggest that SQ-elamipretide induced ISRs by activating MRGPRX2 in humans and its ortholog Mrgprb2 in mice. Conclusion: Elamipretide activated MRGPRX2 and Mrgprb2 receptors, resulting in activation of mast cells and inflammation in mouse models, suggesting that targeting mast-cell activation may ameliorate elamipretide ISRs. Topical mometasone prior to subcutaneous elamipretide demonstrated significant reductions in ISR signs and symptoms and did not cause significant changes in elamipretide plasma exposure or additional adverse events. Therefore, mometasone prior to subcutaneous injection of elamipretide warrants further investigation in clinical studies for alleviating ISRs.

Background: In clinical experience, the adverse events of alprostadil are widely acknowledged; However, there remain adverse reactions that go unnoticed. Methods: In order to evaluate the imbalance of adverse events associated with alprostadil in real-world data, four algorithms (ROR, PRR, BCPNN, and EBGM) were utilized as metrics to identify signals of adverse events linked to alprostadil. Results: In this study, a total of 13,703,053 reported cases were collected from the FAERS database during the study period (from the third quarter of 2014 to the second quarter of 2023). 2393 case reports were analyzed after the exclusion of duplicates and identified using four algorithms. Among these cases, 725 AEs were identified, of which 119 were found to be ADRs related to alprostadil as the primary suspect drug. The observed adverse effects of alprostadil, including hypokalemia and pain, were discovered. Additionally, other noted adverse effects were identified, indicating a condition that is not mentioned in the package insert. Conclusion: This study has discovered previously unknown indicators of adverse drug reactions linked to alprostadil, offering valuable understanding into the correlation between adverse drug reactions and the usage of alprostadil. The results emphasize the potential negative effects arising from alprostadil usage, as well as the potential harm resulting from incorrect administration operation, ultimately enhancing patient safety throughout alprostadil treatment.

Objective: Pharmacists are health care professionals who are actively involved in identifying and solving drug-related problems (DRPs) in patients with hepatitis C virus (HCV) infection. However, the effectiveness of pharmaceutical services at outpatient clinic for patients with HCV infection have not been reported in China. This study aims to describe and investigate the impacts of pharmacists-managed outpatient clinic in patients with HCV infection. Methods: We conducted a descriptive and retrospective study between May 2020 and April 2022. In order to give full play to the efficacy of direct-acting antivirals (DAAs), we established a referral process for HCV patients with DAAs. Doctors prescribed DAAs for HCV-infected outpatients, and then transferred them to the outpatient clinic managed by pharmacists. Pharmacists cooperated to complete the pharmaceutical monitoring of DAAs treatment for patients. The pharmacist conducted a comprehensive evaluation of the patient’s medication and developed planned intervention measures based on identified DRPs. Results: A total of 473 eligible patients participated in 851 pharmaceutical care. A total of 518 DRPs were identified (an average of 1.1 per patient). Treatment effectiveness (48.8%) was the most common DRP. The most commonly recommended intervention was changing the drug (18.3%). There were 97.1% patients accepting the interventions and 93.05% patients completely implemented. The overall sustained virologic response at week 12 posttreatment (SVR12) rate was 98.5% (466/473). Conclusions: We confirmed that pharmacists had a valuable role to perform pharmacy services for HCV-infected outpatients. The intervention of pharmacists is effective in solving the DRPs and saving drug costs

Letter to Editor:Title:Potentially inappropriate prescribing in middle-aged adults: A significant problem with a lack of action and evidence to address it.Authors: Dr Michael Naughton1, Frank Moriarty2, Professor Patrick Redmond3Author Affiliation:1 The Clinical Effectiveness Group, Wolfson Institute of Population Health, Queen Mary University of London2 School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine & Health Sciences3 Department of General Practice, RCSI University of Medicine & Health SciencesWord Count: 652Key words: Potentially inappropriate prescribing, middle-aged adults, intervention, medicines optimisationDear Dr Serge Cremers,Potentially inappropriate prescribing (PIP), prescribing where the potential harms outweigh the potential benefits, or where a medication that a patient would benefit from is not prescribed, is an important healthcare challenge. PIP has been well characterised among older adults and is linked to adverse drug reactions (ADRs), hospitalisations, and increased healthcare costs [1]. While studies have been conducted to address PIP in older adults, middle-aged adults remain overlooked despite also being vulnerable to PIP due to age-related chronic conditions [2].Our recently published systematic review showed that PIP is common in middle-aged adults, with an estimated 38% being exposed to PIP annually [3]. PIP in middle-aged adults is known to occur in higher risk and disadvantaged groups those with multimorbidity, polypharmacy, and those from deprived areas [4]. It has been shown to be associated with ADRs [5], and may be associated with increased healthcare utilisation [6]. A further study by our team, examined the cost of PIP in 1.2 million middle-aged adults in South London, finding that the total cost of PIP in this age group across six years was £2.8 million. The cost of adequate alternative prescribing would be £2.2 million, a cost-saving of approximately £553,874 compared with PIP [7].Following on from these studies, we conducted a further systematic search (unpublished) to examine interventions to reduce this prescribing. Searches were conducted in MEDLINE, EMBASE, CINAHL, Cochrane library, ProQuest, Web of Science, OpenGrey, Clinicaltrials.gov, and the WHO Clinical Trials Registry Platform. All English language studies that included adults aged 45-64 years, applied explicit PIP criteria, and implemented an intervention to reduce PIP and were published by June 2022, were eligible. In total, 12,384 studies underwent title and abstract screening with 248 articles identified for full text screening, however ultimately none met our inclusion criteria.Our search has revealed a literature gap, with no studies having been conducted with interventions aiming to reduce PIP in middle-aged adults. Conversely, there are numerous interventional studies to reduce PIP in older adults [8, 9]. PIP in older adults has a similar prevalence[10], but in absolute terms the largest burden of PIP exists in middle-aged adults due to the larger population size. Intervening earlier in middle age may allow patients’ medicines to be optimised and avoid adverse outcomes as they age.Furthermore, the benefits of targeting high risk prescribing independent of age, rather than concentrating only on older adults, have been demonstrated by multiple studies. Concentrating on high-risk prescribing across all age groups, these studies have shown interventions can reduce high risk prescribing, and associated adverse outcomes such as GI-bleeds, heart failure, and hospital admissions [11]. The PINCER intervention has also shown that interventions to reduce high risk prescribing can be highly cost effective [12]. The current, extremely welcome, deprescribing initiatives (https://deprescribing.org/) are applicable beyond older adults and could also be used to benefit the middle-aged in particular. Therefore, as well as extending interventions to middle-aged people specifically, it is also worth considering a whole population approach to high risk prescribing or PIP, given the demonstrated successes and cost effectiveness of these approaches previously.As practising clinical academics, we are concerned about the lack of policy and research activity to develop interventions to reduce PIP in middle-aged adults. This is an issue effecting a significant proportion of the middle-aged population and it is vital to understand how to reduce this prescribing to avoid preventable harms and unnecessary cost to the health service. I urge the British Journal of Clinical Pharmacology to prioritise the issue of appropriate prescribing outside of the narrow focus on older adults by encouraging submissions and facilitating discourse among researchers, practitioners, and policymakers. This would contribute to our understanding of PIP in other age groups, including middle-aged adults, and help to develop interventions to address the issue in wider patient groups. I hope this letter serves as a catalyst for discussion and research on this pressing issue.Yours sincerely,References:1. O’Connor MN, Gallagher P, O’Mahony D. Inappropriate Prescribing Criteria, Detection and Prevention. Drugs Aging 2012; 29: 437-52.2. Gallagher PF, O’Connor MN, O’Mahony D. Prevention of Potentially Inappropriate Prescribing for Elderly Patients: A Randomized Controlled Trial Using STOPP/START Criteria. Clin Pharmacol Ther 2011; 89: 845-54.3. Naughton M, Moriarty F, Bailey J, Bowen L, Redmond P, Molokhia M. A systematic review of the prevalence, determinants, and impact of potentially inappropriate prescribing in middle-aged adults. Drugs & Therapy Perspectives 2022; 38: 21-32.4. Khatter A, Moriarty F, Ashworth M, Durbaba S, Redmond P. Prevalence and Predictors of Potentially Inappropriate Prescribing in Middle-Aged Adults: Repeated Cross-Sectional Study. British Journal of General Practice 2021: BJGP.2020.1048.5. Smeaton T, McElwaine P, Cullen J, Santos-Martinez MJ, Deasy E, Widdowson M, Grimes TC. A prospective observational pilot study of adverse drug reactions contributing to hospitalization in a cohort of middle-aged adults aged 45-64 years. Drugs and Therapy Perspectives 2020; 36: 123-30.6. Moriarty F, Cahir C, Bennett K, Hughes CM, Kenny RA, Fahey T. Potentially inappropriate prescribing and its association with health outcomes in middle-aged people: a prospective cohort study in Ireland. Bmj Open 2017; 7: 11.7. Jayesinghe R, Moriarty F, Khatter A, Durbaba S, Ashworth M, Redmond P. Cost outcomes of potentially inappropriate prescribing in middle-aged adults: A Delphi consensus and cross-sectional study. British Journal of Clinical Pharmacology 2022; 88: 3404-20.8. Spinewine A, Schmader KE, Barber N, Hughes C, Lapane KL, Swine C, Hanlon JT. Prescribing in elderly people 1 - Appropriate prescribing in elderly people: how well can it be measured and optimised? Lancet 2007; 370: 173-84.9. Clyne B, Fitzgerald C, Quinlan A, Hardy C, Galvin R, Fahey T, Smith SM. Interventions to Address Potentially Inappropriate Prescribing in Community-Dwelling Older Adults: A Systematic Review of Randomized Controlled Trials. J Am Geriatr Soc 2016; 64: 1210-22.10. Liew TM, Lee CS, Goh SKL, Chang ZY. The prevalence and impact of potentially inappropriate prescribing among older persons in primary care settings: multilevel meta-analysis. Age Ageing 2020; 49: 570-79.11. Dreischulte T, Donnan P, Grant A, Hapca A, McCowan C, Guthrie B. Safer Prescribing — A Trial of Education, Informatics, and Financial Incentives. New England Journal of Medicine 2016; 374: 1053-64.12. Avery AJ, Rodgers S, Cantrill JA, Armstrong S, Cresswell K, Eden M, Elliott RA, Howard R, Kendrick D, Morris CJ, Prescott RJ, Swanwick G, Franklin M, Putman K, Boyd M, Sheikh A. A pharmacist-led information technology intervention for medication errors (PINCER): a multicentre, cluster randomised, controlled trial and cost-effectiveness analysis. Lancet 2012; 379: 1310-19.

Background: Vancomycin is a glycopeptide antibiotic used for gram-positive infections. Several vancomycin population pharmacokinetic models have been introduced in the last decades. Thus, a systematic review was performed to compare published pharmacokinetics models and (ii) to summarise and explore identified covariates influencing the vancomycin pharmacokinetics models. Methods: A search of publications for population pharmacokinetic analyses of vancomycin in critically ill obese patients from inception to October 2022 was conducted in PubMed and SCOPUS databases. Reviews, methodology articles, in vitro and animal studies, and noncompartmental analyses were excluded. Data on study characteristics, patient demographics, clinical parameters, pharmacokinetic parameters, and outcomes were collected. Results: Six studies were included in this review. Vancomycin pharmacokinetics was described as one-compartment in most of the studies. Significant interindividual variations of vancomycin pharmacokinetic parameters were found in most of the included studies. Age, sex, body weight, fibrinogen, aspartate aminotransferase, blood urea nitrogen, cystatin, and concomitant nephrotoxic drugs were the most commonly identified covariates affecting these parameters. External validation was only performed in one study to determine the predictive performance of the models. Conclusions. Large pharmacokinetic variability remains despite the inclusion of several covariates. This can be improved by including other potential factors, such as metabolic factors and significant drug-drug interactions in a well-designed population pharmacokinetic model in the future, taking into account the incorporation of a larger sample size and a more stringent sampling strategy. External validation should also be performed to the previously published models to compare their predictive performances.

Significant shortages of key medicines are a global health issue. Drugs recommended as a first-line treatment are often unavailable raising concerns in patients, prescribers, and pharmacists. Among the main factors affecting the periodical drug shortages production shortages, and poor or temporary shortcomings in distribution are the most frequent. Drug replacement, when possible, can result in medication errors, and adverse reactions. National and international efforts by drug agencies, pharmaceutical companies, and political authorities are need to prevent these delays and guarantee the right to health for all.

Clinical drug trials have traditionally focused on younger, healthier participants with less comorbidities and excluded frail older adults due to concerns regarding their ability to tolerate and respond to treatments. However, with population ageing, drug trials are increasingly turning their attention to older, frailer people. The aim of this review is to provide an overview of how frailty was assessed in published studies related to clinical pharmacological trials, and on the interaction of frailty on the safety and efficacy of the treatments. We searched MEDLINE, EMBASE and Cochrane for studies published in English that focused on clinical drug trials in older people. The review showed that frailty has been increasingly and successfully applied into clinical drug trials, especially trials in patients with cardiovascular disease and cancer. In most of the studies in the review, frailty was assessed retrospectively. How frailty was treated in statistical regression models was not consistent among the studies. Frailty was treated as an ordinal variable (with different levels of frailty) or binary variable (frail/non-frail) using cut-offs in some studies, and as a continuous in some other studies. There was heterogeneity in the effect of frailty, depending on the disease and treatment type. The results of this review suggest that frailty should not be assumed to always attenuate treatment effects, and routine measurement of frailty in participants in clinical drug trials would improve our knowledge of the effect of treatment in the frail and identify those who have more or least to gain from treatment.

Introduction: This study aimed to assess the frequency of dosing inconsistencies in prescription data and the effect of four dosing assumption strategies on adherence estimates for antipsychotic treatment. Methods: A retrospective cohort, which linked prescription and dispensing data of adult patients with ≥ 1 antipsychotic prescription between 2015-2016 and followed up until 2019, in Catalonia (Spain). Four strategies were proposed for selecting the recommended dosing in overlapping prescription periods for the same patient and antipsychotic drug: 1) the minimum dosing prescribed; 2) the dose corresponding to the latest prescription issued, 3) the highest dosing prescribed, and 4) all doses included in the overlapped period. For each strategy, one treatment episode per patient was selected and the Continuous Medication Availability measure was used to assess adherence. Descriptive statistics were used to describe results by strategy. Results: Of 277,324 prescriptions included, 76% overlapped with other prescriptions (40% with different recommended dosing instructions). The number and characteristics of patients and treatment episodes (18,292, 18,303, 18,339, and 18,536, respectively per strategy) were similar across strategies. Mean adherence was similar between strategies, ranging from 57-60%. However, the proportion of patients with adherence ≥ 90% was lower when selecting all doses (28%) compared to the other strategies (35%). Conclusions: Despite the high prevalence of overlapping prescriptions, the strategies proposed did not show a major effect on the adherence estimates for antipsychotic treatment. Taking into consideration the particularities of antipsychotic prescription practices, selecting the highest dose in the overlapped period provided a more accurate adherence estimate.

Aims: There is no clinical evidence of differences in drugs associated with long-term survival in patients with pulmonary arterial hypertension (PAH) due to a small population and the lack of information on death in the Japanese medical database systems. This study evaluated whether patient data from a spontaneous reporting database could be used for comparing the effects of pulmonary vasodilators on long-term survival in PAH patients. Methods: PAH patient data reported in the Japanese Adverse Drug Event Report (JADER) database from April 2004 to July 2022 were extracted. Kaplan-Meier curves were used to compare survival times. Adjusted hazard ratios (aHRs) for all-cause mortality were determined using Cox proportional hazards models. Results: Of 1969 PAH patients reported in the JADER database, 1208 patients were included in the survival analyses. The patient demographics were similar to those of the PAH population reported in the Japan Pulmonary Hypertension Registry. Among drugs targeting the prostacyclin pathway, epoprostenol was most associated with long-term survival (aHR: 0.38; 95% confidence interval [CI], 0.23–0.64). The PAH patients treated with endothelin receptor antagonists had improved survival, especially in the macitentan users (aHR: 0.30; 95% CI, 0.22–0.42). Sildenafil was associated with a poor prognosis in the PAH patients (aHR: 1.56; 95% CI, 1.19–2.04). Conclusion: Although our results must be interpreted with caution due to several limitations inherent to spontaneous reporting databases, our approach using the JADER database for survival analysis may provide useful information in limited situations such as the treatment of rare diseases including PAH.

Fosfomycin is an antibiotic often used to treat urinary tract infections (UTIs) with only rare transient hepatotoxicity. We present a case of fosfomycin-induced liver injury and describe the histopathologic findings on biopsy. A 64 year-old female patient with no prior liver disease or risk factors was started on fosfomycin as prophylaxis for recurrent UTIs. Within a week of her first dose she presented with fatigue, jaundice, and mixed liver enzyme elevation. Clinical workup for acute liver injury was unremarkable, and biopsy showed panacinar and portal necroinflammation with predominantly lymphocytic infiltrate and cholestasis. This was thought to be likely related to fosfomycin exposure. While liver enzymes trended down, bilirubin initially remained elevated. However, within three months the patient achieved clinical and biochemical recovery. Only two other reports of fosfomycin-induced liver injury requiring biopsy were found. Both developed acute cholestatic hepatitis within days of exposure, and subsequent biopsy similarly showed lymphocytic necroinflammation. Although one patient initially developed acute liver failure, both recovered fully within few months. Overall, these cases suggest likely an idiosyncratic or immune-mediated liver toxicity of fosfomycin which is typically self-limited with rapid recovery. Liver biopsy may be useful in confirming the diagnosis.

Space medicine has developed controlled terrestrial models to investigate the impacts on human health and performance, and their application should be expanded to encompass disease conditions involving hypoxia and other factors, in order to make valuable contributions to clinical drug development. Hypoxia, a condition in which the body is deprived of adequate oxygen supply, profoundly affects human physiology at multiple levels and contributes to the pathogenesis of various diseases. Experimental exposure to hypoxic conditions has gained recognition as a valuable model for studying diseases like pulmonary hypertension, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA), migraine, and kidney disease. The approach may be particularly useful in mechanism-oriented early-stage clinical studies. This review will discuss the ability to mimic or induce these conditions in a controlled laboratory setting using hypoxia, making it a valuable tool for testing the efficacy and safety of new pharmaceutical interventions.

Aim: This systematic review and meta-analysis assessed the effects of pharmacist interventions in Asian health care environments on hospitalization, mortality, and quality of life (QoL) among older people in Asia. Methods: A comprehensive search was conducted across 5 databases, encompassing studies from inception until December 2021. Only studies involving pharmacist interventions for people aged 65 years or older, residing in Asian countries, were considered. Studies without evidence of pharmacist involvement or conducted outside of Asia were excluded. Data extraction was independently performed by two reviewers, capturing key study characteristics, pharmacist intervention types, and outcome measures for subsequent meta-analyses. Forest plots were generated using a random effects model to obtain risk ratios or pooled standardized mean differences (SMD). Results: A total of 142 articles underwent thorough review, and ultimately, eight studies meeting the inclusion criteria were included in the meta-analyses. These studies encompassed diverse healthcare settings such as outpatient, inpatient, and nursing homes, with sample sizes ranging from 32 to 306 older adults. Pharmacist interventions were found to significantly reduce hospitalization rates (n=4, risk ratio: 0.64, 95% CI: 0.42-0.98) and mortality rates (n=4, risk ratio: 0.59, 95% CI: 0.38-0.92) among older people. However, the analysis did not reveal a significant improvement in QoL compared to usual care (n=5, SMD: 0.37, P = 0.208). Conclusions: These findings highlight the crucial role of pharmacists within healthcare teams in Asian countries. Pharmacist interventions have an impact on reducing hospitalization and mortality rates among the elderly, underscoring the importance of optimizing patient outcomes in Asia.

Aims: To analyze and compare the adverse events (AEs) and adverse drug reaction (ADRs) associated with pirfenidone and nintedanib, two antifibrotic drugs commonly used in the treatment of idiopathic pulmonary fibrosis (IPF), based on real-world data. Methods: We collected reports from the FD Adverse Event Reporting System (FAERS) and VigiAccess databases. Two main disproportional analysis, including reporting odds ratio (ROR) and proportional reporting ratio (PRR), were conducted to determine the association of these drugs with signals at both the preferred term (PT) and system organ class (SOC) levels. Results: A total of 55,949 reports for pirfenidone and 35,884 reports for nintedanib were obtained from the FAERS database. Correspondingly, the VigiAccess database provided 37,187 reports for pirfenidone and 23,134 reports for nintedanib. Male patients and individuals over the age of 65 were more likely to report AEs for both drugs. Gastrointestinal disorders emerged as the most significant signal at SOC level for both pirfenidone and nintedanib. Additionally, signals such as nausea, diarrhoea and decreased appetite were notable at PT level. Furthermore, we also identified signals, including hemiplegic migraine for pirfenidone and asthenia, constipation, as well as flatulence for nintedanib, which were previously unknown or underestimated risks. Conclusion: This study identified AEs and ADRs of pirfenidone and nintedanib in the treatment of IPF, confirming the most of the corresponding label information is relatively safe. However, some unexpected risk signals should be taken seriously, and further research is needed to manage the safety profiles of these drugs in IPF patients.