Purpose: Anti-seizure medications (ASMs) are associated with a variety of adverse events (AEs) that have a significant detrimental impact on quality of life and treatment adherence. The aim of the study was to identify and quantify the AEs of ASMs in persons with epilepsy (PWE) using Liverpool Adverse Events Profile (LAEP), and to determine the feasibility of LAEP for predicting depression in PWE. Methods: After ethical clearance, 309 PWE above 18 years of age, on ASMs, attending epilepsy clinic in neurology outpatient department of All India Institute of Medical Sciences, New Delhi, India, were recruited and evaluated for depression using different assessment tools, and LAEP screening tool was used for adverse event profiling. Results: The mean LAEP scores in PWE were 28.2±6.2 and ranged from 19 to 49. Only 16 PWE had LAEP score ≥45 i.e. had high toxicity. Phenytoin had the highest LEAP score, followed by carbamazepine, levetiracetam, and sodium valproate. As compared to monotherapy, PWE on polytherapy had higher LAEP score (26.7±5.9 vs. 29.03±6.3; p=0.0013). Subjects positive for depression had significantly higher LAEP score than PWE without depression (33.5±6.2 vs. 24.7±3.1; p<0.0001). A strong positive correlation of the LAEP score was observed with depression scores as assessed by different assessment tools, and a LAEP score of ≥28 was recommended to screen PWE for depression. Conclusion: The systematic use of LAEP in epilepsy outpatient settings will allow for better detection and management of ASM’s adverse effects, as well as the identification of PWE at risk of depression.

Severe Acute Respiratory Coronavirus Syndrome 2 (SARS-CoV-2) is a new human coronavirus family discovered during the highly communicable respiratory disease outbreak in Wuhan, China, in 2019. Various COVID-19 vaccines are up to 95% effective against symptomatic infections caused by the COVID-19. Whether people with PD or PS have an increased risk of COVID-19 and are associated with a higher risk of death is still uncertain. In this study, we report eleven cases of PD patients who died whitin 24 hours after vaccination with the Sinopharm. All patients were over 79 years old (84.64 ± 5.08). All patients were SARS-CoV2 PCR negative and took their first dose of the Sinopharm. All patients had a duration of more than 5 years with PD. All patients presented to the hospital less than 12 hours after vaccination. All patients died less than 24 hours after vaccination. In this study, All the patients were elderly and hypertension and diabetes were seen in 11 (100%) and 7 (63.6%) patients which could reinforce the hypothesis that older patients with PD should be vaccinated more cautiously and these patients should be discussed the vaccine with their physician especially in patients who have other comorbidities. Because our report was a case series study, we only identified patients, and the causality could not be assumed or proven.

Background: Hypertensive disorder of pregnancy (HDP), a common obstetric complication that seriously threatens maternal and infant health. The current clinical treatment drugs include methyldopa, calcium channel blockers, etc. In order to provide evidence-based medicine for the treatment and medication of gestational hypertension, this study compared the efficacy and safety of different drugs in the treatment of gestational hypertension through network meta-analysis. Methods: Search and select relevant articles in the published and unpublished available data from Controlled Trials, PsycINFO, CINAHL,, etc. To assess the efficacy and safety of HDP treatment, 4 primary outcomes [SBP, DBP, perinatal fetal deaths, and NICU cases] and 9 secondary outcomes were selected. Results: 50 articles with 8212 participants were included. Low molecular weight heparin (LMH), Labetalol + LMH and Labetalol + Methyldopa can reduce DBP, and Ambrisentan + Methyldopa can prevent the occurrence of severe hypertension. Methyldopa and Atenolol were associated with lower rates of preterm birth, and Nifedipine, Methyldopa as well as Labetalol reduced the incidence of placental abruption. Ambrisentan + Nifedipine, Methyldopa, Labetalol + Nimodipine, Labetalol + LMH, Labetalol and LMH significantly reduced the incidence of postpartum complications. Magnesium sulfate (SM) and SM+ LMH can prolong the mean gestational age, LMH and Kethyldopa can reduce perinatal fetal death. Conclusions: LMH, labetalol, Methyldopa, labetalol in combination with LMH, and labetalol in combination with Methyldopa have better efficacy and safety.

Nowadays, the clinical application of antitumor drugs tends towards precision and individualization. Numerous efforts have been put in exploiting technologies to precisely discern the features of tumors and discover the possible response of every cancer patient to antitumor drugs at multiple dimensions from genes, proteins, tissues to whole organism, including Genomic data, histological information, functional drug profiling and drug metabolism of cancer patients can be obtained through polymerase chain reaction, sanger sequencing, next-generation sequencing, fluorescence in situ hybridization, immunohistochemistry staining, patient-derived tumor xenograft models, patient-derived organoid models and therapeutic drug monitoring. The application of various detection technologies in clinical practice has enabled ‘individualized treatment’ to be realized, but the ideal accuracy effect has not yet been achieved. More novel technologies or technology combinations are needed to predict the correlation between detection information and therapeutic effect, and to put forward more accurate and effective therapeutic strategies for every patient. Here, we briefly summarize the conventional and state-of-the-art technologies contributing to the clinical individualized medication and their application in clinical practice, attempting to seek therapy options that may ultimately improve clinical outcomes.

Abstract Objective To compare the Liverpool Causality Assessment Tool versus Naranjo Scale for screening suspected adverse drug reaction (ADR) cases. Methods We retrospectively reviewed patient charts with a history of suspected ADR, scored using both instruments and determined how each correlates with laboratory and other investigations. 924 charts from the Clinical Pharmacology Clinic at the London Health Sciences Centre were reviewed and 529 charts contained objective findings to support or against the diagnosis of ADR. The participant age ranged from 1 month old to 93 years. We determined the sensitivity and specificity of Liverpool and Naranjo tools for predicting ADRs with scores ranging from “Possible” to “Definite” were considered positive and “Unlikely/Doubtful” as negative for ADR. These results were confirmed by laboratory or clinical (re-challenge) testing in 529 cases. Results Liverpool causality tool had sensitivity (SN) of 97.2% ± 2.4% and specificity (SP) of 2.3% ± 1.57%. The positive (PPV) and negative predictive values (NPV) were 34.1% and 61.5%, respectively. The Naranjo scale had SN of 81.2% ± 5.69% and SP of 13.2% ± 3.56%. PPV and NPV were 32.7% and 57.5%, respectively. Conclusions The Liverpool Causality Assessment Tool is a more sensitive tool than the Naranjo Scale in the assessment of possible ADRs but both tools have poor specificity. The Liverpool Tool can be a useful screening tool in settings where other tests may not be readily available. However the low PPV and NPV of both instruments suggests pursue further testing is needed to confirm or deny an ADR.

Aim: To identify older patients’ risk factors for drug-related readmissions and assess the preventability of older patients’ drug-related revisits. Methods: Post-hoc analysis of a randomised clinical trial with patients aged ≥ 65 years at eight wards within four hospitals in Sweden. The primary outcome used to identify risk factors was drug-related readmission within 12 months post-discharge. A Cox proportional hazards model was made with sociodemographic and clinical baseline characteristics. Four hundred trial participants were randomly selected and their revisits (admissions and emergency department visits) were assessed to identify potentially preventable drug-related revisits, related diseases and causes. Results: Among 2,637 patients (median age (interquartile range) 81 (74–87) years), 582 (22%) experienced a drug-related readmission within 12 months. Sixteen risk factors (hazard ratio > 1, p < 0.05) related to age, previous hospital visits, medication use, multimorbidity and cardiovascular, liver, lung and peptic ulcer disease were identified. The 400 patients experienced a total of 522 hospital revisits, of which 85 (16%) were potentially preventable drug-related revisits. The two most prevalent diseases and causes related to preventable revisits were heart failure (n=24, 28%) and chronic obstructive pulmonary disease (n=13, 15%), and inadequate treatment (n=23, 27%) and insufficient or no follow-up (n=22, 26%). Conclusion: Risk factors for drug-related readmissions in older hospitalised patients were age, previous hospital visits, medication use and multiple diseases. Potentially preventable drug-related hospital revisits are common and might be prevented through adequate medication use and follow-up in older patients with cardiovascular or lung disease.

The recent introduction of the European Medical Device Regulation poses stricter legislation for manufacturers developing medical devices in the EU. Many devices have been placed into a higher risk category, thus requiring more data before market approval, and a much larger focus has also been placed on safety. For implantable and Class III devices, the highest risk class, clinical evidence is a necessity. However, the requirements of clinical study design and developmental outcomes are only described in general terms due to the diversity of devices. A structured approach to determining the requirements for the clinical development of high-risk medical devices is introduced, utilising the question-based development framework, which is already used for pharmaceutical drug development. An example of a novel implantable device for haemodialysis demonstrates how to set up a relevant target product profile defining the device requirements and criteria. This can then be used to define specific questions to be answered during clinical development, based upon 5 general questions as specified by the question-based framework. The result is a clear and evaluable overview of requirements and methodologies to verify and track these requirements in the clinical development phase. Development organisations will be guided to the optimal route, also to abandon projects destined for failure in an early stage to minimise development risks. Moreover, the framework facilitates communication with funding agencies, regulators and clinicians, while highlighting remaining “known unknowns” that are to be answered in the post-market phase after sufficient benefit has been established relative to the risks.

Aim Antidepressants are well-established fall-risk increasing drugs(FRIDs) and therefore falls should be considered an important adverse drug event(ADE) of antidepressants. However, not all antidepressant users experience fall incidents and factors associated with increased fall risk among antidepressant users are incompletely understood. Our objective was to explore whether antidepressant plasma concentrations are associated with falls in older antidepressant users. Methods For this study, we included antidepressant users of the multicenter B-PROOF study. Fall incidents were recorded prospectively using fall calendars. Antidepressant plasma concentrations were analyzed by Liquid chromatography-mass spectrometry(LC-MS) at baseline and at 2 years follow-up. The associations between the observed antidepressant concentration, or concentration change over time (delta) and fall risk were assessed using Cox proportional hazard and logistic regression models and adjusted for potential confounders. Results In total 93 selective serotonin reuptake inhibitor(SSRI) and 41 antidepressant(TCA) users were identified. There was a significant association between baseline TCA plasma concentration and fall risk within users (HR 2.50, 95% CI 1.07-5.87, crude model). Adjusted there were no significant associations between concentrations of SSRIs and fall risk. Also, for delta concentrations there was no association with fall risk in users. Conclusion There might be an association between plasma concentrations of TCAs and the risk of falling in older users. However, these results needs to be interpreted with caution considering the small sample size and accompanying limitation of confinement to crude analyses. Therefore, replication in a larger cohort, preferably including adjustment for potential confounders and more frequent measures of plasma concentrations is needed.

A common approach to assess the efficacy of piperacillin is to firstly measure the total concentration, and to afterwards apply a theoretical unbound fraction of 70% to obtain the unbound concentration. However, hypoalbuminemia is a common phenomenon in critically ill patients, resulting in variations in unbound fraction. Therefore, we aimed to simulate the impact of piperacillin unbound fraction fluctuations on the predictive performance of a population pharmacokinetic model and on dosing recommendations of piperacillin. Unbound factors of 70, 75, 80 and 85% were applied to total concentrations of piperacillin administered by continuous infusion from an external dataset. A validated model was used for assessment of predictive performance and to estimate patient clearance. Dosing simulations were performed to evaluate target attainment. Variation in unbound fraction caused minimal impact on piperacillin clearance and target attainment but revealed to influence model evaluation.

The management of Borderline Personality Disorder (BPD) is limited to psychological intervention along with pharmacotherapy. It is now evident that chronodegeneration is one of clinical phenotype in BPD individuals, therefore, the use of chronotherapeutics in BPD is developing day by day. Therefore, we assess the chronotherapeutics either individually or in combination with conventional therapeutic interventions to conclude the best possible therapy for improvement of the BPD symptomatology. A systematic electronic literature search of PubMed, Google Scholar, Cochrane Central Register of Control Trials, Clinical Trials Registry (ClinicalTrials.gov), APA PsycNET and BMJ evidence-Based Medicine was conducted between 2000-2022. In these data bases, search terms describing borderline personality disorder, and circadian rhythm restoration were combined with the term of treatment. From five selected studies, there are three types of chronotherapeutic interventions that were practiced, as bright light therapy, physical exercise and triple chronotherapy. Our included 4 out of 5 studies concluded chronotherapy as a successful adjunctive therapy with pharmacotherapy and/or psychotherapy in amelioration of BPD traits especially depression (Mean Hamilton depression rating scale score decreases from 19.5 to 7.2) and suicidal ideation (Mean Columbia suicide severity rating scale score decreases from 19.5 to 7.2). One of our selected study on physical exercise proved no significant effect on BPD when compared with control group. According to our explored literature, chronotherapy particularly bright light therapy might be a safe and effective addition to conventional therapeutic interventions. It is principally effective for patients in which depression is present as a co-morbidity or as a sign of BPD.

Introduction Pharmaceutical treatment in the neonatal intensive care unit (NICU) is challenging, and newborns are often exposed to numerous different medicines during their hospitalization There is currently insufficient knowledge of gestational age dependent medicine disposition, and accordingly the use of off-label medicines, i.e., use of medicines outside its approved marketing authorization, is high. This study aims to estimate the off-label medicine use in Danish neonatal departments. Methods By using data from the Danish National Pharmaceutical Hospital Purchase Database, we identified the most commonly occurring medicines and calculated the on/off-label ratios for premature and term neonates. Data was extracted on ATC level 5 and based on defined daily doses as per WHO. Results Data included was covering the 4 high-level NICUs and 10 of 13 of the intermediate/standard level neonatal departments in Denmark. Of the identified medicines, 87% and 70% did not have approved marketing authorization for use in premature and full-term neonates, respectively. Furthermore one-fifth of the top 100 medicines did not have a (Danish) marketing license. Overall, the presence of off-label medicines was widespread covering virtually all ATC groups and no ATC group had an off-label level lower than 50%. Finally, in 21% of the identified medicines, additives from 8 different chemical groups with potential deleterious effects for neonates were identified. Conclusion Off-label medication in the Danish neonatal departments is widespread, and the current state of neonatal official regulatory drug approval leaves both patients and neonatologists in a limbo between legal pharmaco-regulation and clinical need for pharmacotherapy in neonatology.

Rosuvastatin is a lipid-lowering medication that is routinely used to reduce blood cholesterol levels. It acts by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol production, preventing de novo cholesterol synthesis and increasing the amount of low-density lipoprotein (LDL) receptors on the liver surface, resulting in lower blood LDL levels. Rosuvastatin has some adverse effects, including moderate ones like headache, stomach discomfort, nausea, and weakness, as well as major ones like muscle, liver, and renal issues including severe muscular pain, decreased appetite, dark-colored urine, and continuous nausea/vomiting. According to recent research, rosuvastatin medication can produce renal tubular toxicity in persons who have no prior history of kidney disease. Rosuvastatin has been linked to myalgia, rhabdomyolysis, and elevated creatine phosphokinase levels. If patients on rosuvastatin have muscular or renal difficulties, they should seek emergency medical assistance. Nonetheless, Rosuvastatin’s lipid-lowering effects exceed the danger of adverse effects. Strong adherence to these safety precautions can enhance Rosuvastatin’s safety profile and allow it to be given safely for hypercholesterolemia.

The sarcoid-like reaction is a rare autoinflammatory disease that can affect lymph nodes or organs but does not meet the diagnostic criteria for systemic sarcoidosis. Several drug classes have been associated with the development of a systemic sarcoid-like reaction, which defines drug-induced sarcoidosis-like reactions and can affect a single organ. Anti-CD20 antibodies (rituximab) have rarely been reported as responsible for this reaction and this adverse effect has mainly been described during the treatment of Hodgkin’s lymphoma. We report a unique case of a sarcoid-like reaction complicating rituximab following the treatment of a mantle cell lymphoma and interesting only the kidney. The 60-year-old patient presented with severe acute renal failure six months after the end of his r-CHOP protocol and the urgent renal biopsy revealed acute interstitial nephritis rich in granulomas without caseous necrosis. After ruling out other causes of granulomatous nephritis, a sarcoid-like reaction was retained since infiltration was limited to the kidney. The temporal relationship between rituximab administration and the sarcoid-like reaction onset in our patient supported the diagnosis of a rituximab-induced sarcoidosis-like reaction. Oral corticosteroid treatment led to rapid and lasting improvement in renal function. Clinicians should be warned of this adverse effect and regular and prolonged monitoring of renal function should be recommended during the follow-up of patients after the end of treatment with rituximab.

Aims: The serratus anterior plane block (SAPB) has commonly been utilized as a regional anesthesia technique for pain management in various upper chest surgical procedures. The purpose of this study was to investigate the analgesic effect and pharmacokinetics of ropivacaine in continuous SAPB undergoing VATS. Methods: This prospective randomized study included patients scheduled for elective VATS. Patients first received a bolus of 20 ml of 0.2% (Group L) or 0.375% (Group H) ropivacaine that was administered beneath the serratus anterior muscle. The pump was connected to the catheter for continuous administration within 48 hours postoperatively, in which a background infusion at a rate of 7 ml·h−1 of low-dose at 0.2% (Group L) or high-dose at 0.375% (Group H) of ropivacaine was administered. The main results were to compare the analgesic effects and analyze the pharmacokinetics of different concentrations of ropivacaine. Results: Eighty-eight patients agreed to participate in the trial and were recruited. The VAS scores in Group H at 12, 24, and 48 hours postoperatively at rest and on coughing were significantly lower than those in Group L. The peak values of total ropivacaine plasma concentrations were observed at 48 hours (2.01 μg·mL−1 for Group L and 2.93 μg·mL−1 for Group H), which were far below the theoretical toxicity threshold. Postoperative rescue analgesia, complications, and other outcomes did not differ significantly. Conclusions: In VATS patients, the analgesic effect of 0.2% ropivacaine for continuous SAPB was not inferior to that of 0.375% ropivacaine, and the blood concentration of 0.2% ropivacaine was

We report a case of TEN probably related to Pristinamycin

Guidelines for the approval or licensing of biosimilars have evolved over the past 18 years since the first introduction of biosimilars. Amendments to these guidelines are constrained in the US by legislation and in the EU and WHO due to collaborative consent requirements. The MHRA has recently joined ICH and brought its guideline that is most rational and scientific; it removes animal and clinical efficacy testing, as evidenced by hundreds of studies, billions of doses administered, and a better understanding of recombinant therapeutic proteins. However, there remains a need to bring a neutral jurisdiction guideline that all countries can adopt; while the EU, FDA, Japan, and now the UK are the deciding countries, they all realize the shortcomings and will be willing to support an ICH guideline, as proposed here. Compliance with a unified ICH guideline will promote the entry of safer biosimilars and cross-country registrations. This review is based on identifying the shortcomings of the current regulatory guidelines and scientific data to support the amendments proposed. These recommendations have been submitted to the ICH and are under consideration in the pre-Stage 1 consensus-building evaluation that will require comments of scientists and regulatory authorities. A new ICH guideline for the approval of biosimilars will bring global harmony and enhanced accessibility of safer biosimilars.

Background Total Intravenous Anaesthesia (TIVA) with propofol infusion is done by manual co’ntrolled infusion (MCI) or by target-controlled infusion (TCI) devices. This is a comparative study of MCI/TCI administration. Method In this randomized controlled trial, Anaesthesia was induced with propofol 1%, using a target blood concentration of 5 Meg/ml in the TCI group or at a dose of 1.5 mg/kg at an infusion rate of 1200 ml/h in the MCI group. Subsequently, a step-down maintenance regimen (10, 8 and 6 mg/kg/h at 10-min interval) was commenced for the MCI group. Primary outcome was the time to induction of anaesthesia in both groups. Data was analysed using Statistical Package for Social Sciences (SPSS) version 20.0. Results 52 patients were recruited into the study. The duration of induction of anaesthesia in the TCI group compared to the MCI group was (94.62 ± 11.34 sec vs. 79.50 ±16.23 sec, p = 0.001). The induction dose of propofol TCI against MCI was (118.00 ± 22.33 mg vs.133.04 ± 20.58 mg, p = 0.015). Both groups were comparable in terms of total dose of propofol (I 152.92 ± 234.47 mg vs. 1014.97 ± 264.18 mg, p = 0.052), recovery time (8.45 ± 2.13 min vs. 7.86 ± 2.05 min, p = 0.314), haemodynamic parameters and incidence of adverse events. Conclusion Manual controlled infusion was comparable to target controlled infusion for the induction and maintenance of general anaesthesia using propofol; providing similar quality and ease of anaesthesia as a viable option in resource challenged settings.

Aim: Advanced age is an important risk factor for adverse events during procedural sedation. Remimazolam is safe and effective in adults’ gastroscopy sedation. The ideal dose and availability for elderly patients are not well known. We aim to investigate its 95% effective dose (ED95) for elderly patients undergoing gastroscopy, and to assess its safety and efficacy, with propofol as the comparison. Methods: The trial consists of two parts, patients who are over 65 and scheduled for elective outpatient painless gastroscopy were enrolled. In the first part, Dixon’s up-and-down methodology was used to determine the ED95 of remimazolam and propofol for inhibiting body movement during gastroscopic insertion, in combination with 0.2μg/kg remifentanil. In the second part, patients in each group received 0.2μg/kg remifentanil and the ED95 dose of the study drug for sedation induction, adding supplemental doses to maintain sedation depth when necessary. The primary outcome was the incidence of adverse events. The secondary outcome was the recovery time. Results: The ED95 of remimazolam and propofol induction dose were 0.204mg/kg [95% CI (0.175–0.390) mg/kg] and 1.994 mg/kg [95% CI (1. 739–5.955) mg/kg] respectively in gastroscopy. Adverse events were reported in 40.6% of patients in the remimazolam group and 83.1% in the propofol group (p<0.001), whereas the remimazolam group showed a higher incidence of hiccup(p=0.017). A shorter time to awakening (p<0.05) in the remimazolam group was observed. Conclusion: For elderly patients undergoing gastroscopy, the ED95 dose of remimazolam is a safer alternative than propofol when inducing the same sedation depth.

Aims. To provide an overview of the types of interventions performed by community pharmacists and describe their effects on patients with type 2 diabetes mellitus (T2DM) in low- and middle-income countries (LMICs). Methods. This review was conducted according to the PRISMA-Scr guidelines. PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for (non-) randomized controlled, before-after, and interrupted time series design. There was no restriction in the publication language. Included interventions had to be delivered by community pharmacists in primary care and community settings. The study quality was assessed using the National Institute of Health tools. Results were analyzed descriptively. Results. Twenty-eight studies were included representing 4,434 patients (mean age from 47.4 to 59.5 years, 55.4% female). Four studies were single- and the remaining studies were multiple-component interventions. Face-to-face counseling of patients was the most common intervention, often combined with providing printed materials, remote consultations, or conducting medication reviews. Generally, studies showed improved outcomes in the intervention group, including clinical, patient-reported and medication safety outcomes. In most studies at least one domain was judged to be of poor quality, with heterogeneity among studies. Conclusions. Community pharmacist-led interventions among T2DM patients showed positive effects in LMICs, but the quality of the evidence was poor. Face-to-face counseling of varying intensity, often combined with other strategies, was the most common type of intervention. Although these findings support the expansion of the role of the community pharmacist in diabetes care in LMICs, better quality studies are needed to evaluate further impact.

Repurposing non-oncology drugs to improve cancer therapy has been increasingly attracting drug developers due to potentially lower costs and shorter timelines. Propranolol, a non-cardiac selective, lipophilic β-adrenergic receptor blocker used to treat hypertension, arrhythmia, and anxiety, has successfully been repurposed as first-line therapy for infantile hemangioma. Thereafter, accumulating preclinical and clinical studies have demonstrated the safe and promising antitumor activity of propranolol to treat different types of human cancers. In this review, we have focused on summarizing the therapeutic potential of propranolol in both solid and hematologic malignancies. We have also discussed the current bottleneck of repurposing propranolol in cancer therapy. Taken together, these inspiring findings help to shed light on propranolol repurposing and future drug discovery.

Aims Protein kinase inhibitors (PKI) have revolutionized the prognosis of several types of cancer, justifying the acceleration of their clinical evaluation before they obtain marketing authorization. Pharmacovigilance signals of heart failure (HF) following exposure to PKIs have been detected in recent years. Our objective was to identify the PKIs most frequently associated with the development of HF. Methods Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalisation diagnosis and long-term disease codes related to HF were used to identify HF patients. HF Incidence Rate Ratios (IRR) were measured and adjusted Hazard Ratios (aHR) were estimated using a Cox model. Results Thirteen PKIs were studied. Among the 49,714 new PKI users during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for 6 drugs: pazopanib (aHR= 2.42, 95% CI: 1.67-3.52), dasatinib (aHR= 2.22, 95% CI: 1.42-3.44), ruxolitinib (aHR= 2.11, 95% CI: 1.69-2.64), crizotinib (aHR= 1.71, 95% CI: 1.07-2.72), everolimus (aHR= 1.45, 95% CI: 1.26-1.67) and vemurafenib (aHR= 1.37, 95% CI: 1.01-1.86). Conclusions Our study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two drugs with results slightly above the significance threshold, crizotinib and vemurafenib in our sensitivity analyses.

The impetus of this review is to provide an overview of Neurodevelopmental disorder i.e., ADHD (attention deficit hyperactivity disorder), its complications, and information on ADHD-affected regions in the brain. An attempt was made to understand the hereditary cause of ADHD. Many reviews and research articles were compared and analyzed throughout the study. The concepts include (a) ADHD and its symptoms (b) complexities involved in brain regions for ADHD-affected patients (c) linkage analysis for studying the genetics of ADHD. Results derived from review analysis show that there will be a change in the structure, growth, and function of the brain. Prefrontal and frontal lobes, parietal lobes, and cerebellum are the principal brain regions involved. From the study it is observed that there will be a decrease in the volume of the cerebellum and the front striatal region is majorly affected. There is no strong evidence that ADHD is caused to hereditary however few researchers explain that there is a linkage between genes and the cause of ADHD in siblings. Many more research works need to be done for a clear understanding of the disease. The analysis of this review explains the genetic interaction taking place in ADHD patients, and the effect of ADHD on the brain and its structural and functional changes.

Letter to the Editor- Suboptimal Dosing of EsomeprazoleI read the informative research article “Night-time gastric acid suppression by tegoprazan compared to vonoprazan or esomeprazole” by Yang E et al., with great interest.There are a few points that I would like to highlight regarding the methodology of the study. The dosing schedule used in the study for esomeprazole is likely to produce suboptimal effects. The optimal effect of esomeprazole depends on two factors i.e. timing of dosing and the cumulative effect.• Esomeprazole which is a proton pump inhibitor (PPI) inhibits gastric acid secretion by non-competitively inhibiting the enzyme H+, K+ ATPase in parietal cells. After the meal, parietal cells are maximally stimulated which results in the activation of proton pumps, thus, it is the best time for the antisecretory effect of PPI. PPIs are recommended to be taken 30 minutes before the first meal.1Therefore, timing administration of PPI with meals may be critical for optimal effect.1, 2 Plasma half-life of esomeprazole is approximately 1-1.5 hours.3 Only the expressed acid-secreting proton pumps on the luminal membrane of parietal cells are inhibited by esomeprazole. Administering esomeprazole at night will inhibit only very few proton pumps during the brief period when the PPI is available for therapeutic action. Furthermore, bedtime PPI administration will not contribute to nocturnal acid breakthrough inhibition because the drug will have disappeared by the time night-time acid secretion is perceptible. As per the dosing schedule followed in the study, by the time patient had the maximum expression of the H+K+ ATPase, esomeprazole was already eliminated from plasma. Tegoprazan and vonoprazan, being reversible and competitive inhibitors of H+K+ ATPase are devoid of such effects. • The antisecretory action of esomeprazole increases with repeated dosing to reach a plateau phase after 3-4 days to produce 80-98 % suppression of 24-hour acid output.4 Even when given 30-60 minutes before meals, PPIs are unable to block all proton pumps with oral formulations and single dosing because all pumps are not active during 1.5 hr half-life of PPIs. Because of this short t1/2, only 70% of pumps are inhibited.5 Thus, approximately 20% of pumps are newly synthesized over 24 hours. As the once optimized amount of drug is reached, increasing the dose has almost no effect. An increase in the frequency of administration seems to have some effect, a morning and evening dose before food results in approximately 80% inhibition of maximal acid output.6,7The drug metabolism by CYP3A4 (30.9%) is more common than CYP2C19 (6.8%).8 As tegoprazan and vonoprazan are metabolized by CYP3A4,9 and it makes them more susceptible to drug-drug interactions in the case of polypharmacy.Tegoprazan and vonoprazan belong to the novel class of drugs which offers reversible and competitive inhibition of H+K+ ATPase. For their comparison with esomeprazole, the dosing schedule should be designed so that its optimal effect can be considered for comparison.Conflict of interest: NoneDr. Ajay Kumar Shukla1, Dr. Sameer Khasbege1*1 Department of Pharmacology, All India Institute of Medical Sciences, Bhopal,M.P., India*Corresponding author

Aims: Posaconazole is often used for the prophylaxis and treatment of invasive fungal infections (IFI). However, intra- and inter-individual differences and drug interactions affect the efficacy and safety of posaconazole. Precision dosing of posaconazole based on the population pharmacokinetic (PopPK) model may assist in making significant clinical decisions. This review aimed to comprehensively summarize the published PopPK models of posaconazole and analyze covariates that significantly influence posaconazole exposure. Methods: Articles published until May 2022 for PopPK analysis of posaconazole were searched in PubMed and EMBASE databases. Demographic characteristics, model characteristics, and results of PopPK analysis were extracted from the selected articles. In addition, the steady-state pharmacokinetic profiles of posaconazole were simulated at different covariate levels and dosing regimens. Results： Out of the 13 studies included in our review, nine studies included adults, three included children, and one included both adults and children. All oral administration models were one-compartment models, and all intravenous administration models were two-compartment models. Body weight, proton pump inhibitors, and incidence of diarrhea were found to be important covariates. In addition, age, sex, total protein, rifampin, phenytoin, intake of nutritional supplements, levels of bilirubin and gamma-glutamyl transferase, and administration of chemotherapy also appeared as covariates in several PopPK models. Conclusion: Posaconazole exposure was found to be influenced by various factors such as the type of formulation, the incidence of diarrhea, body weight, and use of concomitant medications. It was concluded that routine therapeutic drug monitoring was required for dose adjustment and in promoting individualized dosing.