OBJECTIVES: There is a need for early identification and intervention of Adverse Drug Reaction (ADR) to alleviate unacceptably growing burden, morbidity and mortality associated in People With Epilepsy (PWE). This study is aimed at identifying factors associated with ADR and medication adherence among patients in PWE. METHODS: It is a cross-sectional questionnaire-based study consisting of 940 consenting participants aged 16 years and above attending epilepsy clinics for period of 5years with diagnosis confirmed by International League against Epilepsy (ILAE) criteria and supported by Electroencephalography (EEG). 21-item Liverpool Adverse Effect Profile (LEAP) and 8-item. Morinsky Medication Adherence Scale (MMAS) were used to assess ADR and adherence respectively. RESULTS: The highest reported ADR in PWE were nervousness (34.3%), aggression (33.6%) and weight gain (32.3%). Specifically, (20.1%) of the participant complained of memory problem, while the lowest were hair loss (7.2%), trouble with mouth (8.9%) and problem with skin (9.3%). Using the MMAS, 545(90.2%), 28(4.6%) and 31(5.1%) of PWE in this study were classified as having high, medium, and low adherence, respectively. Duration of AEDs use and duration of epilepsy were the major determinant of ADR in PWE on regression model. CONCLUSION: Duration of AEDs use and duration of epilepsy are the major determinant of ADR in PWE. Effective strategies to identify and reduce ADR should be incorporated to management of PWE by Health Care Providers to improve their quality of life. Furthermore, physician should aim towards reducing the duration of AED use and the epilepsy.

INTRODUCTION: Paroxetine is an antidepressant belonging to the class of SSRI. It is used in multiple psychiatric disorders including depression, anxiety and obsessive-compulsive disorder. Apart from being very efficacious, it causes some adverse effects too and hyponatremia is one of them. The association between the two is not well established, which makes this case worth of attention. CASE PRESENTATION: A 52 years old male hypertensive patient was brought to the ER after having an episode of seizure. Hyponatremia due to an unknown cause was made a provisional diagnosis. He was then referred to the psychiatric department for further assessment, where his detailed history was taken and mental state examination was performed. The patient was found to be suffering from chronic depression. The patient has been taking a combination of antipsychotics and antidepressants for this condition. Paroxetine, Olanzapine and Quetiapine were prescribed to him by his psychiatrist 10 years back, and since then he was taking it daily. His current medication was then immediately altered and paroxetine was replaced by mirtazapine. DISCUSSION/ CONCLUSION: Numerous studies have been done on the effects of SSRIs, but very few of them mentioned their association with hyponatremia. Electrolyte imbalances are common with many medications including antiepileptic and antidepressant drugs as well. Although some literature has shown the link between the two, drug induced hyponatremia remained one of the rarest adverse effect. In summary, paroxetine is very effective in the management of depression but its long-term use could result in an electrolyte imbalance in hypertensive patients

Background: Interleukin-23 (IL-23) inhibitors are widely used in clinical practice for Psoriasis , but multiple adverse events (AEs) have been reported. We aimed to describe the distribution of AEs related IL-23 inhibitors including Guselkumab, Tildrakizumab, Risankizumab, Ustekinumab. Methods: Data from January 1, 2014, to September 30, 2022 were extracted from the FDA Adverse Event Reporting System (FAERS). Disproportionality analysis including reporting odds ratio (ROR) and information component (IC) was performed to access potential signals. It was defined a signal when the lower limit of 95% confidence interval (CI) of ROR (ROR025) more than one or IC(IC025) exceeding zero, with the number of cases greater than or equal to three at the same time. Results: A total of 41,408,408 drug-AE reports were extracted from the FAERS database involving 13271168 people. 704, 13164, 62853, 11399 patients have used Tildrakizumab, Guselkumab, Ustekinumab, Risankizumab and 8, 20, 107 and 115 signals were found respectively. The “infections and infestations” has the highest incidence of SOC in Tildrakizumab(6/8), Guselkumab(5/20), Ustekinumab(50/107), Risankizumab(25/115). Conclusion: Our pharmacovigilance analysis showed that a high frequency was reported for AEs triggered by IL-23 inhibitors. IL-23 inhibitors had the potential to impair immune function resulting in a risk of infections or cancers. We need to pay special attention to Risankizumab because the drug has more AE occurrences than Ustekinumab despite Risankizumab has few reports than Ustekinumab and launched later than Ustekinumab.

Background & purpose Morphine is important for treatment of acute and chronic pain. However, there is high interpatient variability and often inadequate pain relief and adverse effects. To better understand variability in the dose effect relationships of morphine, we investigated the impact of its nonlinear blood-brain-barrier (BBB) transport on mu-opioid receptor (μ-OR) occupancy in different CNS locations, in conjunction with its main metabolites that bind to the same receptor. Methods CNS exposure profiles for morphine, M3G and M6G for clinically relevant dosing regimens based on intravenous, oral immediate- and extended-release formulations were generated using a CNS PBPK model which incorporated nonlinear BBB transport of morphine. The simulated CNS exposure profiles were then used to derive corresponding μ-OR occupancies at multiple CNS pain matrix locations. Results The simulated CNS exposure profiles for morphine, M3G and M6G, associated with nonlinear BBB transport of morphine resulted in varying μ-OR occupancies between the different dose regimens, formulations, and CNS locations. We find that at lower doses, the μ-OR occupancy of morphine was relatively higher than at higher doses of morphine, due to the relative contribution of M3G and M6G. At such higher doses, M6G showed higher occupancy than morphine, whereas M3G occupancy was low throughout the dose ranges. Conclusion and implications Nonlinear BBB transport of morphine influences the μ-OR occupancy ratios of morphine and its metabolites, depending on dose and route of administration, and CNS location. This may impact the clinical effects of morphine treatment for pain relief.

Off-label drug use which could be defined as the practice of prescribing a drug for a different purpose than what is permissible by the regulation is a common practice among clinicians, nevertheless, it is often subject to ethical and legal uncertainties. In general, clinicians must balance the need to provide patients with the best possible care while complying with the regulatory requirements governing drug use. This paper will review the current literature on off-label drug use, including its prevalence, the regulatory landscape, and the ethical issues involved with the aim of formulating an ethical and legal framework that could guide clinicians in using off-label drugs in clinical practice in Malaysia. The framework will include ethical considerations that are centred on the principles of beneficence, non-maleficence, and autonomy, which require clinicians to balance the benefits and risks of using off-label drugs while respecting patients’ autonomy. The legal framework consists of federal and state regulations governing drug use, including the Control of Drugs and Cosmetics Regulations (CDCR) 1984 and other regulations published by the National Pharmaceutical Regulatory Agency (NPRA). The aim of this paper is to provide guidance on how clinicians can navigate the ethical and legal terrain of off-label drug use by understanding the regulatory requirements, being obliged to the requirements of obtaining informed consent from patients and documenting the rationale for off-label use. Ultimately, by understanding the ethical and legal framework, clinicians can provide patients with the best possible care while complying with the regulatory requirements governing drug use.

Anemia is a public health problem affecting about a third of the world's population, the major cause of it being iron deficiency. The many oral iron preparations available at present, are inadequate due to intolerance, or contraindications. IV iron preparations are painful, require patient monitoring and carry the risk of anaphylaxis. Iron salts like Iron pyrophosphate are covered with liposome, a spherical structure of a phospholipidic nature that is similar to those human cell membranes. The bioavailability of liposomal pyrophosphate iron is 3.5 times greater than the free pyrophosphate iron, 2.7 times higher than iron sulfate, and 4.1 times higher compared with iron gluconate. Clinical studies showed that oral liposomal iron is a safe and efficacious alternative to correct anaemia, as also it is a viable treatment option for iron deficiency anaemia in pregnant women.

Abstract Introduction One of the most often used OTC antipyretic and analgesic is paracetamol or acetaminophen. Though widely used, the mechanism by which it reduces fever and pain remains unknown. Although paracetamol is available in a variety of formulations, there are no set guidelines for the various formulations of paracetamol alone or in combination. Materials and Methods In Department of Pharmacology at Government Doon Medical College, the study was planned as an observational cross-sectional study. Data regarding different paracetamol dosages and dosages of paracetamol in fixed dose combinations (FDCs) with various ingredients were gathered and evaluated from the editions of Drug Today, Current Index Of Medical Specialties (CIMS), Monthly Index Of Medical Specialties (MIMS), and India 2021/2022. Results Analysing Drug Today, CIMS and MIMS, it was found, 810 formulations of paracetamol tablets are available in the Indian market, of which, 77 formulations contain only paracetamol, rest being fixed dose combinations (FDCs). Among all the available FDCs with paracetamol having 2or 3 drug formulation, among the 2 constituent FDCs group containing paracetamol, 47% drugs have paracetamol in 325 mg or less dose, whereas, 53% drugs are in clear violation of the notice by CDSCO, by containing more than 325 mg paracetamol. Conclusion In spite of widespread use there is ambiguity in paracetamol doses, as well as absence of data for few constituents in the FDCs. Thus, further research into paracetamol dosing, as well as strict regulation is the need of the hour for one of the most widely used drug.

Abstract: Background: Sotrovimab, a monoclonal antibody, is among the approved therapies for coronavirus disease – 2019 (COVID-19). Sotrovimab binds to the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and inhibits virus attachment to human cells. Real-life experience about the effectiveness of Sotrovimab is limited. We aimed to evaluate the efficacy of Sotrovimab in preventing COVID-19 hospitalizations and other patient-related outcomes as well as the appropriateness of use in an academic hospital in Lebanon. Methodology: In this retrospective observational study, we included adult patients with positive test results for SARS-CoV-2 who received intravenous (IV) Sotrovimab at the American University of Beirut Medical Center (AUBMC) from November 2021 through March 2022. The data collected included patient demographics and comorbidities. Primary outcomes were hospitalization, deterioration after 24 hours, and death due to any cause up to 60 days after the Sotrovimab infusion. Secondary outcomes were progression to critical illness and adverse events. Results: A total of 62 subjects received Sotrovimab infusion at our hospital. More than 50% of the patients had a malignancy. About 77% of the cohort belonged to Tier 1 of the National Institutes of Health (NIH) criteria for Sotrovimab use, and 21% of the patients had clinical deterioration 24 hours after Sotrovimab infusion. The percentage of progression to critical disease was 9.7% and the mortality 6.5 %. Conclusion: Sotrovimab is effective against COVID-19 infection and prevents mortality in high-risk patients.

The dose selections for phase 1 assessments which aim to investigate intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a central and challenging question in long drug development programs. The dose of an investigational product are selected with respect to regulatory guidances, stage of program, feasibility and maximization of information for later regulatory submission. This review selected 37 development programs of drugs recently approved in the EMA- and FDA-covered regions to explore the doses selected in these trials and also supporting modeling activities with focus on drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment. This survey found that most sponsors followed regulatory guidance documents, with some interesting deviations. Particular oncology drugs programs but also some cardiovascular programs which have a drug associated safety risks were not able to test supratherapeutic dose levels. Drugs using a titration scheme in development or label were often tested using a dose range. Drugs from combination treatments incorporated the expected exposure increase through interactions or tested the combination in patients. Sponsors included multiple food effect studies due to ongoing formulation developments. Incomplete programs were subject of post market commitments. In this retrospective review, the discrepancies from conventional approaches may give interesting insights into strategic consideration and regulatory acceptability for drug development programs.

Aims: Over the years, Indian regulations have undergone numerous amendments including stringent reporting deadlines, relatedness requirements, and compensation obligations for Serious Adverse Event (SAE). A historic change, New drugs and trial rules- 2019 was proposed on 19th March 2019. Study aimed to ascertain whether various stakeholders were reporting in accordance with the evolving SAE criteria. Methods: Data was retrieved after Ethics approval between August 2014 and December 2021. Data gathered before 19th March 2019, was categorised as “BEFORE” data while remaining data was categorised as “AFTER”. Utilising causality, on-site SAE reporting, and the ethics committee review procedure, we evaluated the compliance. The data was evaluated using descriptive statistics, appropriate statistical tests were used to compare the “BEFORE” and “AFTER” groups. Results: A total of 163 (6.9%) of 2361 studies were drug trials. 26 clinical trials with 77 SAE, 92.3% of which were in Phase-III. Endocrine projects made up 9/26 (34.61%). In the cardiology studies, the greatest SAE distribution was 21 SAEs/ 89 participants (23.59%) with approximately 48% of these being vascular. The “AFTER” group noticed a decrease in the total number and length of SAE sub-committee meetings. In the “AFTER” group, there was significantly higher median number of agenda items/ meetings [8 (4.5 – 10.75)] (p<0.0001). The median interval between the onset of SAE and the first reporting date, however, was just 1 day [IQR: 1-5 days]. In non-death SAEs, there was no significant difference in the compensation paid. Conclusion: There is acceptable adherence to SAE reporting criteria.

Background: Although Two first-generation tropomyosin receptor kinase (TRK) inhibitors larotrectinib and entrectinib have been approved by the Food and Drug Administration (FDA), The current adverse effect profile in the real world remains unknown. Objective: The purpose of this study was to retrospectively examine the adverse effects of two typical first-generation TRK inhibitors by spontaneously mining the data from FDA Adverse Event Reporting System (FAERS) database. Methods: Four general data mining algorithms were used to conduct a disproportionate analysis of TRK inhibitors, and the time of adverse events of drugs was counted. The definition relied on the system organ class (SOC) and preferred terms (PT) by the MedDRA. Results: A total of 326 cases of ‘larotrectinib’ and 450 cases of ‘entrectinib’ as the ‘primary suspect’ drug were collected in this study. A total of 86 adverse drug reaction (ADR) signals involving 18 SOCs were mined. ‘Dizziness’ was the most common ADR, with ‘glioma’ as the strongest signal. The SOC with the highest number of occurrences was ‘Nervous system disorders’.The median time of onset of larotinib and entertinib-related ADR was 41 days and 18 days, respectively. Most cases occurred within one month after treatment. Conclusion: The main ADRs found in this study were ‘Neurotoxicity’, ‘Pain’, ‘Hepatotoxicity’, ‘Drug resistance’, ‘Nephrotoxicity’ and ‘Weight increased’, which provide important support for clinical monitoring and risk identification of TRK inhibitors.

Background: Major Depressive Disorder (MDD) is a heterologous disease in respect to clinical symptoms, severity and responsiveness to treatment, and is often accompanied by somatic comorbidities. The objective of this study was to identify and characterize subgroups of patients with a first-time MDD diagnosis based on somatic drug utilization, including socio-demographic and clinical characteristics, and psychiatric healthcare-related outcomes. Methods: The nationwide register-based study included all Danish patients with an incident MDD diagnosis between 2011 and 2015. Using Latent Class Analysis (LCA), the population was sub-grouped according to somatic drug use (drug profiles). Sociodemographic and clinical characteristics at baseline and odds/hazards of shift in antidepressant treatment and psychiatric hospitalization one year after index were compared between the drug profiles. Trajectories of drug profile membership over time was also analyzed. Results: Of 37,080 MDD patients (mean age 41.5 years, 62% women), the LCA identified five unique somatic drug profiles: 1) limited drug use (74.3%), 2) drugs for pain management (7.6%), 3) cardiovascular drugs (10.7%), 4) drugs for obstructive airway diseases (2.3%) and 5) high drug burden (5.1%). There were large differences in age between the drug profiles, and limited drug use profile and high drug burden profile had lower rates of psychiatric hospitalization than the cardiovascular drug profile. When analyzing the trajectories, we found that the majority of the population continued in the same drug profile during all time intervals. Conclusion: The identified five somatic drug profiles were comparable in respect to the course of the depression during one year following diagnosis.

Paraquat is an extremely corrosive and lethal herbicide. After intentional or unintentional ingestion, paraquat causes extensive mucosal damages extending through the upper gastrointestinal tract which are characterized by pain, inflammation, ulceration, bleeding, and sloughing of the associated mucosa. The aim of this systematic review is to compile and evaluate evidence based studies in relation to the effectiveness of different methods of management of oral mucositis induced by paraquat in terms of reduction of associated pain and duration of symptoms.We undertook computerized electronic searches through both English and Chinese databases so as to identify all published articles in the subject. We also searched reference lists from relevant articles for any related articles. This review is not registered.A total of 10 relevant randomized controlled trials (RCTS) were selected after the electronic searches after satisfying our inclusion criteria. They were published between the 2000s and 2020. The primary outcome measurement assessed an improvement in the healing time/recovery time or adequate pain management. Interventions from all the studies highlighted the use of multi-agent management that included either oral care by the use of bland and multi-agent mouth rinses, corticosteroids, Chinese herbal remedies, growth factors, smectites or anti-oxidant therapy. The main findings were that the main method of management was the implementation of a multi-drug regimen, through the use of compounded preparations or a polydrug system. In addition, herbal and natural remedies, if used appropriately, can play a beneficial role in the management of paraquat induced oral mucositis.

Purpose: To evaluate the drug-induced liver injury (DILI) adverse events related to antidepressants. Method: Post-marketing cases were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS). Disproportionality analyses were conducted by estimating the reporting odds ratio (ROR) and the information component (IC). Result: There were a total of 10,355 reported cases of DILI out of a total of 324,588 cases reported from January 2004 to December 2021. Among the 42 antidepressants assessed, nefazodone (n = 47, ROR = 7.79, IC=2.91), fluvoxamine (n = 29, ROR = 4.69, IC=2.20), and clomipramine (n = 24, ROR = 3.97, IC=1.96), were the top three compounds ranked with the highest reporting odds of cholestatic injury. Mianserin (n = 3, ROR = 21.46, IC=3.99), nefazodone (n = 264, ROR = 18.67, IC=3.84), and maprotiline (n = 15, ROR = 5.65, IC=2.39), were the top three compounds ranked with the highest reporting odds of hepatocellular injury. Nefazodone (n = 187, ROR = 12.71, IC=0.48), clomipramine (n = 35, ROR = 2.07, IC=0.26), and mirtazapine (n = 483, ROR = 1.96, IC=0.94) were the top three on drug related severe hepatic disorders. Only nefazodone detected the signals (n = 48, ROR = 18.64, IC=4.16) in the study of hepatic faliure. Conclusion: The data mining of FAERS suggested significant association between DILI and nefazodone. Duloxetine and clomipramine detected the signals on three categories of DILI besaides hepatic failure. Moreover, DILI risk on the new generation of antidepressants should also be taken into consideration.

We are reporting a case of toxic epidermal necrosis induced by herbal medicine in a 54-year-old woman who had been diagnosed with primary Sjogren’s syndrome for nine years and had discontinued all conventional therapies for at least one year. Approximately two weeks prior to her current admission, she developed crops of petechiae and purpuric macules on her lower extremities, which are typical symptoms of hypergammaglobulinemic purpura of Waldenström, and began taking herbal medicine. The following day, she presented to us with a high fever and new, generalized erythematous rashes over her face and trunk. She was ultimately diagnosed with toxic epidermal necrosis induced by the herbal medicine.

Aims Venous thromboembolism (VTE) is a rare but serious adverse drug reaction could be caused by antipsychotic drugs. However, the specific correlation of VTE caused by antipsychotic drugs is still controversial. This study explored the potential association between antipsychotics and VTE. Method All VTE cases of antipsychotic drugs as primary suspected medicines were extracted from the US Food and Drug Administration adverse event reporting system (FAERS) from 2004 to 2021.Disproportionality analyses were conducted by estimating the reporting odds ratio (ROR) and the information component (IC). Results 4, 455 VTE cases with antipsychotics as primary suspected drugs were identified. The VTE signal was detected in haloperidol, olanzapine, quetiapine and paliperidone. The RORs and the 95% confidence intervals (95% CI) of t haloperidol, olanzapine, quetiapine and paliperidone were (ROR=2.17, 95% CI(2.17-1.91), IC=1.1, 95%CI(1.52-0.66)), (ROR 2.53 95% CI 2.69–2.38 IC 1.31 95%CI 1.52-1.1), (ROR 1.37, 95% CI 1.47–1.28 IC 0.45 95%CI 0.67-0.23) and (ROR 1.6 95% CI 1.83–1.4 IC 0.67 95%CI 1.11-0.22), respectively. Pulmonary embolism occurred in more than 50% of VTE events (2760 cases, 52.84%). The outcome indicated that venous thrombosis caused by antipsychotics is usually a serious consequence. Conclusion The current data mining of FAERS suggested an association between VTE and antipsychotic drugs including olanzapine, haloperidol, paliperidone and quetiapine, which reminds health professionals to pay attention to the serious adverse drug effects of antipsychotic drugs leading to venous thromboembolism.

Aim The prevalence of undocumented medical treatments among children is a significant issue, as well as many EU countries lack access to newly developed children friendly medicines. Consequently, there is a pressing need for supplementary resources that can facilitate informed decision-making regarding children’s medication. We therefore aim to describe the process of establishing a children’s Drug and Therapeutics Committee (cDTC), as well as the preparing and implementation of recommendations for children in the Capital region of Denmark Method Following the guidelines outlined by the World Health Organization a cDTC was established. Recommendations for pediatric medication practice were constructed from assessments of medication use patterns among children in the Capital Region between 2019 and 2021. The recommendations were meticulously crafted based on evaluation of the current marketing authorization landscape and existing best available evidence. Results In 2019, the Capital Region established the first cDTC supported by expert councils and an editorial board. A total of 2.429 purchase item numbers covering 1.222.846 defined daily doses and 592.088 purchased packages covering 10.200.000 defined daily doses were identified in the secondary and primary sectors, respectively. Three comprehensive lists covering recommendations for newborns and children were published between 2021 and 2020 totaling 331 recommended pharmaceutical products. The recommendations primarily intended for use in the secondary healthcare sector were implemented through the revision of 38 pediatric- and 6 neonatal product ranges throughout Capital region. Conclusion Recommendation lists for children governed by a cDTC provide a rational auxiliary tool that can be immediately implemented in the clinic.

Background Metformin has been frequently used off-label for childhood obesity besides diabetes. Studies have demonstrated the thyroid-stimulating hormone (TSH) suppressive effect of metformin in patients with a diagnosis of primary hypothyroidism. This study aimed to evaluate free T4 (fT4) and free T3 (fT3) tests and influencing factors in adolescents (TSH) who were on metformin therapy for obesity and insulin resistance and had no diagnosed thyroid disease. Material and Methods A total of 54 patients aged 10-18 years who presented to the Pediatric Endocrinology Outpatient Clinic for overweight between 2017 and 2020 and who were diagnosed with exogenous obesity and insulin resistance based on examinations by excluding hypothyroidism were retrospectively evaluated. Baseline and post-treatment 6-month thyroid function tests, HOMA-IR, and anthropometric measurements were evaluated. Results Of the 54 patients included in the study, 38 (70.4%) were female and 16 (29.6%) were male. the mean time from admission to follow-up was 6.5±2.7 months. There was a moderate negative (inverse) correlation between the change in weight SDS (∆weight SDS) and the change in fT4 (∆fT4) of the patients (r=-0.319), and a moderate positive correlation between ∆weight SDS and the change in fT3 value (∆fT3) (r=0.534) (p=0.035; p=0.027, respectively). A moderate significant positive correlation was found between the change in HOMA-IR (∆HOMA-IR) and the change in TSH (∆TSH) (r=0.376; p=0.009).

Background and Purpose: Chinese materia medica is an important part in China’s medical system, and the authority has issued a series of regulations and guiding principles to improve the quality of research and development (R&D) of new Chinese drugs. Approach: Investigational new drug (IND) and new drug application (NDA) applications of new Chinese medicines and approval condition were analyzed in 4 categories including number of applications, review conclusions, registration classification and therapeutic area from 2007 to 2022. Key Results：The overall number of IND and NDA acceptance and approval of Chinese materia medica is far less than that of chemical drugs and biological preparations. The 6th classification of traditional Chinese medicine was the most in the INDs and NDAs accepted by drug evaluation authority, with a total number of 889 cases, accounting for 76.6% of all the accepted cases, indicating that the difficulties and risks of R&D of this type were relatively low. Conclusions & Implications: China is still left behind in the aspect of drug R&D by developed countries. The problems about relevant regulations, trial quality, selection of efficacy and safety evaluation indicators and review evidence system should be paid great attention to in the future research on Chinese materia medica.

Abstract Aims Bruton’s tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib, and zanubrutinib may have certain mechanisms of action (MOAs) related to adverse effects (AEs) on the cardiovascular system. We aimed to evaluate the cardiac AEs of BTKIs reported to the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and to compare the differences in cardiovascular toxicity of ibrutinib, acalabrutinib, and zanubrutinib. Methods Only primary suspect drugs from the FAERS database were extracted from January 2013 to December 2022 across all indications of FDA-approved BTKIs. Disproportionality was measured by reporting odds ratios (RORs) and information components (ICs). An additional disproportionality analysis was also performed from January 2020 to December 2022. Results A total of 10,353 cases involving ibrutinib, acalabrutinib and zanubrutinib were included. Ibrutinib was significantly associated with the incidence of cerebrovascular accidents, myocardial infarction and other thrombotic events. Acalabrutinib was associated with new signals, including cardiac failure, ventricular extrasystoles, pulmonary edema and angina pectoris, and hypertension and myocardial infarction were found in additional analyses. Furthermore, acalabrutinib was characterized by a much earlier onset of cardiovascular events. Only atrial fibrillation was associated with zanubrutinib use. Acalabrutinib and zanubrutinib had lower ROR values for cardiac AEs, and fewer signals for these two drugs compared with ibrutinib. Conclusion This study indicated that new AEs were not clearly noted on the label for acalabrutinib. It is suggested that the cardiovascular risks of BTKIs remain a concern and worth attention as next-generation BTKIs are discovered and developed.

Objectives: Inappropriate dose of vancomycin can cause nephrotoxicity, which should be avoided in clinical, particularly in patients with renal insufficiency. We aim to use machine learning techniques to explore important variables influencing vancomycin dose in patients with renal insufficiency and establish an individualized medication model to benefit these patients. Methods: Vancomycin administration cases in patients with renal insufficiency were collected at Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine from May 2018 to March 2022. Sequential Forward Selection was used for feature selection. Eight machine learning algorithms were compared the predictive performance, including XGBoost, LightGBM, CatBoost, GBDT, RF, SVC, KNN, and Logistic Regression. The one with the best predictive performance was chosen to calculate the importance score of modeling variables and establish the individualized medication model. Dose subgroups were divided into 500 mg, 1000 mg, 1500 mg and 2000 mg. Subgroup analysis based on the modeling variables were conducted. Results: This study included 237 eligible patients with 351 vancomycin cases. Six important variables were screened out, including gender, weight, AUC, uric acid, creatinine and total protein. CatBoost was chosen with the best prediction performance (accuracy=0.59) for modeling. The individualized medication model had precision over 53% and recall rate over 50% among all dose subgroups. The prediction of 1500 mg vancomycin had the best precision (65%), recall rate (71%) and F1-score (0.68). Conclusion: The individualized medication model of vancomycin for patients with renal insufficiency has good predictive performance, which can help clinicians make better decision of vancomycin use.

Introduction: A key reason for the failure of anti-tuberculosis (TB) treatment is missed doses (instances where medication is not taken). Adverse drug reactions (ADRs) are one cause of missed doses, but the global evidence for this, their relative contribution to missed doses versus other causes, the patterns of missed doses due to ADRs, and the specific ADRs associated with missed doses have not been appraised. We sought to address these questions through a scoping review. Methods: MEDLINE, Embase and Web of Science were searched on 3 November 2021 using terms around active TB, missed doses and treatment challenges. Studies reporting both ADR and missed dose data were examined. (PROSPERO: CRD42022295209). Results: Searches identified 108 eligible studies. 88/108 (81%) studies associated ADRs with an increase in missed doses. 33/61 (54%) studies documenting the reasons for missed doses gave ADRs as a primary reason. No studies examined patterns of missed doses due to ADRs. 41/108 (38%) studies examined associations between 68 types of ADR (across 15 organ systems) and missed doses. Nuance around ADR-missed doses relations regarding drug susceptibility testing profile and missed dose originator was found. Conclusions: There is extensive evidence that ADRs are a key driver for missed doses of anti-TB treatment. Some papers examined specific ADRs, none evaluated the patterns of missed doses due to ADRs, demonstrating a knowledge deficit. Knowing why doses both are and are not missed due to ADRs is essential in providing targeted interventions to improve treatment outcomes.

Aims: A phase I open-label study assessed the effect of multiple oral doses of a potent CYP3A4 inducer (rifampicin) on the pharmacokinetic profile of SHR2554, a novel enhancer of zeste homolog 2 inhibitor (EZH2) and CYP3A4 substrate. Methods: Eighteen adult Chinese healthy subjects were enrolled in this study. All participants received a single oral dose of SHR2554 (300 mg) on day 1, rifampin (600 mg) from day 4 to day 10 and day 12, the same dose was coadministered with SHR2554 (300 mg) and rifampicin (600 mg) on day 11. The primary endpoints were SHR2554 exposure parameters. Lack of drug–drug interaction was concluded if 90% confidence intervals (CIs) for the ratio of area under the plasma concentration–time curve (AUC) or maximum concentration (Cmax), with/without oral rifampicin, were within a pre-specified interval (0.80–1.25). Results: The Cmax, AUC0-t, and AUC0-∞ of administration alone and coadministration with rifampin were 177.265 ±127.9889 ng/mL, 17.001 ± 8.4759 ng/mL; 672.12 ± 507.390 h*ng/mL, 38.58 ± 19.495 h*ng/mL; and 721.50 ±514.386 h*ng/mL, 46.30 ± 20.750 h*ng/mL, respectively. Coadministration with rifampin decreased the least-squares geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ by 89%, 93%, and 93%, respectively. Well tolerance and acceptable safety profile showed during the trial. Conclusion: The exposure of SHR2554 was significantly decreased when coadministered with rifampicin. It is recommended to avoid concomitant use of SHR2554 and strong inducers of CYP3A4.

Medically qualified clinical pharmacologists specialise in drugs and their usage. Thus, a clinical pharmacologist should be involved in patient education, drug development, access and utilisation research, policy and procedure development, and safer medicine use. India has 5.2 million medication errors yearly, which are just a fraction of healthcare system incidents. Clinical pharmacological reconciliation, review, and feedback (CPRRF) is essential to reduce medication-related tragedies. Clinical pharmacologists can employ CPRRF principles to improve patient safety and efficacy.To improve patient safety, the World Health Organisation wants to integrate Clinical Pharmacology into the health care system. However, this is taking time. Policymakers should design and execute novel strategies to speed up this process.