Pharmacology Research & Perspectives最新文献

This study assessed whether the completeness of spontaneously reported adverse drug reaction (ADR) reports differs between consumers and healthcare professionals when submitted directly to regulators, and how this compares to reports from pharmaceutical companies. ADR reports (2014-2023) were obtained from public databases in Canada and the United Kingdom (UK), focusing on the medicine classes sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and dipeptidyl peptidase-4 inhibitors. ADR report completeness was assessed using vigiGrade tool variables. Descriptive statistics and chi-square tests were used for analysis. A total of 17 897 reports were analyzed-13 613 from the UK Yellow Card Scheme and 4284 from Canada. Most Canadian reports were submitted by pharmaceutical companies (55%), while in the UK, healthcare professionals submitted the majority (69%). Few reports were submitted directly by consumers in either Canada (4%) or the UK (7%). In Canada, the average completeness was 82% for consumer and healthcare professional reports and 57% for pharmaceutical companies. In the UK, completeness was 80% (consumers), 82% (healthcare professionals), and 69% (pharmaceutical companies). Canadian pharmaceutical company reports were significantly less complete for age, sex, outcome, dose, indication, and route of administration (all p < 0.001). In the UK, they were less complete for age, sex, and route of administration (all p < 0.001). In conclusion, reports submitted directly to regulators by consumers and healthcare professionals were more complete than those from pharmaceutical companies. The low consumer reporting rate, yet high completeness rate, highlights the need to encourage direct reporting to regulators to improve medicine safety monitoring.

Pharmacology is an integrative discipline that plays an integral part in the development of new medicines with improved safety and efficacy profiles. Sustained growth of this important discipline within the UK is made possible through training of the next generation of pharmacologists. In order to ensure that interest in pharmacology continues to grow, endeavors aimed at exposing students to pharmacology from earlier stages of their educational journeys have to be put in place. To this end, the current study aimed at capturing the perception of further education students on pharmacology in the East London area. This survey-based study, which took place between 2020 and 2021, consisted of multiple choice questions. The study revealed that over 80% of the surveyed biology and chemistry students have previously heard about pharmacology. However, when assessing their basic knowledge of pharmacology, it emerged that students had a somewhat distorted perception of pharmacology, as only 9.8% of the students associated pharmacology with biology. Additionally, students confused pharmacology with pharmacy. Students also had a somewhat limited understanding of what pharmacologists do. Finally, 23.5% of the students stated that they would consider studying pharmacology at university if they received sufficient introduction, with 92.2% of the students stating that they would like to see pharmacology added to their further education curriculum. In order to ensure the growth of pharmacology in the UK and given the misconceptions that students have, as highlighted in this study, we recommend that basic pharmacology education be introduced to the further education curriculum.

Risk and cost of transportation and other unforeseen circumstances can hamper in-person pharmacology lectures with students. Hence, the study is aimed at identifying the advantages and disadvantages of pharmacology lectures via Zoom. A crossover design was adopted for the study that involved a total of 151 students of veterinary medicine, which comprised students of 400 level (52), 500 level (52) and 600 level (47) who participated six times in the study for one semester. All the lectures were delivered online. The levels and average numbers of online lecture participants were 400 level (22.3), 500 level (22.8) and 600 level (21.3) for Principles of Pharmacology, Applied Pharmacology, and Therapeutics, respectively. The findings showed no significant difference in online connection (p > 0.05) between 400, 500, and 600 level students. The numbers of students that passed Principles of Pharmacology (15), Applied Pharmacology (13) and Therapeutics (14) showed that the level of study and performance on the tests were connected with lecture attendance. Fourty-four percent attended the lectures, whereas 56% were absent. However, 27.8% of all the students passed the tests, whereas 72.2% failed the tests, respectively. The highest number of feedbacks (p < 0.05) was received from 500 level students (32), as compared to 400 level students (24) and 600 level students (17), respectively. The study has shown that online pharmacology lectures can serve as an alternative to in-person lectures, though associated with technical problems. However, many students showed much enthusiasm and praised the lecturer for his frantic effort in delivering the lectures, cordial lecturer/student relationship, and his objectivity toward class. The failure of power supply, problems of coordinating courses, zoom meeting network issues, insufficient laptops and phones, as well as the problem of connection with the course lecturer for the online lectures are disadvantages. Online lecturer/student relationship, objectivity of the lecturer, and lecturing methods can boost students' morale and interest in online lectures.

Tropomyosin receptor kinase (Trk) inhibitors are an essential class of anticancer drugs treating NTRK gene fusions-positive cancer. However, the potential for the emergence of on-target resistance suggests newer Trk inhibitors with low drug resistance risk are needed. LPM4870108 is a novel Trk inhibitor with robust anticancer efficacy in preclinical studies. To support future clinical development, this study systematically evaluated the acute and subacute (4-week) toxicity, toxicokinetic, genotoxic, and safety pharmacology of LPM4870108. The acute toxicity study revealed the maximum tolerated dose of LPM4870108 was 300 mg/kg, whereas subacute studies determined its STD₁₀ in rats was 10 mg/kg/day. The toxicological effects of LPM4870108 were consistent with its pharmacodynamic efficacies as a Trk inhibitor, including corneal inflammation, splenic lymphocytopenia, hepatocyte vacuolar degeneration, scab formation, and increased food consumption and body weight. These changes were partially or fully recovered after 4 weeks of recovery. In rats treated with 10 or 20 mg/kg/day, 2/30, or 6/30 rats died or were moribund, and the primary organs affected by treatment-related toxicity included the eyes, liver, and skin. Rat toxicokinetic findings were consistent with a dose-dependent effect of LPM4870108. There was no evidence of LPM4870108-related genotoxicity, nor did it affect respiratory function or neurobehavioral activity in rats or blood pressure or electrocardiogram results in rhesus monkeys. The IC₅₀ of LPM4870108 for hERG current inhibition was 18.2 μM. Together, these results demonstrate that LPM4870108 exhibits a satisfactory safety profile which is appropriate for further clinical development.

Ceftazidime-avibactam is a novel cephalosporin/beta-lactamase inhibitor combination developed to address increasing antimicrobial resistance. This report presents a comparative study of the pharmacokinetics of ceftazidime and avibactam, utilizing in vitro data derived from two experiments with continuous venovenous hemodiafiltration (CVVHDF) simulation and a comparison with a previously published in vivo case report. The results highlight the importance of therapeutic drug monitoring and the need for higher dosing or continuous infusion of ceftazidime-avibactam in critically ill children under crontinuous renal replacement therapy (CRRT).

Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is a heterogenous disorder that may lead to severe hemolytic events with the ingestion of fava beans and exposure to certain drugs. We report the first case of a 65-year-old male with Crohn's disease who developed a hemolytic crisis leading to hospitalization shortly after commencement of upadacitinib. An autoimmune condition was excluded but, as his family history was a positive for G6PD deficiency, very low levels of erythrocyte G6PD were detected. Upadacitinib was immediately discontinued with subsequent resolution of hemolysis. This case highlights the importance of rigorous pharmacological surveillance and suggests the need for further studies to clarify the pathogenetic mechanisms underlying this adverse reaction.

We investigated the influence of CYP2B6, GSTP1, and SLCO1B1 star allele-predicted phenotypes and CBR1 variants on clinical outcomes in patients with HCC receiving DOX via TACE. A prospective cohort of patients with HCC underwent DOX therapy via TACE. Selected genes were genotyped in germline DNA samples from the final cohort (82 patients) via Axiom Precision Medicine Diversity (PMD) Research Array technology. The Kaplan-Meier (KM) method and Cox proportional hazards (CPH) model were employed to find independent clinical and genetic predictors of overall survival (OS) and progression-free survival (PFS) after TACE. Based on univariate and combined association analyses of genetic factors, the star alleles predicting the phenotypic status of three genes (CYP2B6, GSTP1, and SLCO1B1) did not significantly modify the response potential of DOX via TACE, as indicated by OS or PFS. Conversely, we found a novel association between two CBR1 polymorphisms (rs3787728 and rs1005695) and interindividual differences in OS and PFS. The presence of a heterozygous genotype (TC or CG at either locus, which were highly frequent in our cohort), probably with greater CBR metabolic activity, appeared to have an expressive influence by negatively modulating the consequences of DOX locoregional therapy on HCC by shortening the median OS (KM p = 0.02 and 0.04, respectively) and median PFS (KM p = 0.05 and 0.023, respectively) in comparison to those with other haplotypes. Exploratory PGx studies involving a wider HCC cohort and targeting more DOX-related genes are needed to replicate our findings. Trial Registration: NCT06313047 (Study Details | Pharmacogenetic of Doxorubicin in HCC. | clinicaltrials.gov).

Recapitulating in vivo conditions of metabolism remains a challenging subject in biomedical research such as ADME-Tox assays (absorption, distribution, metabolism, excretion, and toxicity). The advanced technologies using 3D co-culture methods enabled researchers to develop cell-cell and cell-extracellular matrix (ECM) interactions similar to the natural liver, resulting in the improvement of the metabolic performance of ex vivo cultured primary hepatocytes (PHs). Although PHs are the best candidates in cell-based drug screening methods, access to these cells is limited. The application of stem cell-derived hepatocyte-like cells (HLCs) could overcome these limitations in high-throughput assessments. However, the functional capacity of HLCs is not enough. Hepatoma cells could be reliable substitutes for PHs and HLCs; however, compared to PHs, their metabolic performance is low. Mimicking the complexity of the liver microenvironment using hepatoma cells and liver-specific stromal cells in a 3D culture condition represents an innovative, accessible, and scalable platform to accelerate drug development if the metabolic capacity of hepatoma cells is enhanced. This can reduce time, costs, and address the ethical concerns related to animal models and pluripotent stem cells. In this manuscript, we showed that mimicking the complexity of the liver microenvironment in a 3D co-culture condition with non-parenchymal cells and improving the metabolic performance of hepatoma cells represents an innovative and accessible platform to accelerate drug discovery and development.

Multiple signaling pathways have been implicated in the pathogenesis of ulcerative colitis (UC), including Sphingosine Kinase 1 (SPHK)/Sphingosine-1-Phosphate (S1P), AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/NLR family pyrin domain-containing 3 (NLRP3), zonula occludens-1 (ZO-1), and signal transducer and activator of transcription 3 (STAT3). We aimed to investigate the Colo protective and anti-ulcerative effects of pentoxifylline (PTX) in a rat model of UC. Colitis was induced by intracolonic administration of 2 mL of 3% (v/v) acetic acid (AA). Thirty-five rats were randomly assigned to five groups (n = 7 each): normal control, colitis, mesalamine, PTX, and a combination of PTX plus mesalamine. Disease activity was assessed using the disease activity index, colon weight and length measurements, histological examination, and immunohistochemical detection of caspase-3. Colonic tissue homogenates were analyzed for interleukin-6 (IL-6), S1P, SPHK, mTOR, heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2), AMPK, and STAT3 levels. Gene expression of ZO-1 and NLRP3 was also evaluated. Intracolonic AA induced marked functional, biochemical, and inflammatory damage to colonic tissue. Treatment with PTX, mesalamine, or their combination significantly attenuated these effects. Specifically, all treatments reduced levels of IL-6, S1P, SPHK, mTOR, STAT3, NLRP3, and caspase-3, while increasing levels of ZO-1, HO-1, Nrf2, and AMPK. The combination treatment group exhibited near-complete restoration of normal colonic architecture, characterized by intact crypt morphology and minimal fibrosis in the lamina propria. PTX attenuated inflammation, apoptosis, and oxidative stress in colitis, supporting its potential as an adjuvant therapy in UC management.

Clesrovimab, an extended half-life monoclonal antibody, aims to protect infants for an entire RSV season. The pandemic impacted RSV epidemiology and strategies were implemented to support clesrovimab trials. Near real-time monitoring of data showed minimal RSV activity in 2020. In 2021, RSV resurged early in some countries and was delayed in others, resulting in a change in trial enrollment strategy.