Pharmacology Research & Perspectives最新文献

{"title":"The endocannabinoid system in appetite regulation and treatment of obesity.","authors":"Marija Kurtov,Igor Rubinić,Robert Likić","doi":"10.1002/prp2.70009","DOIUrl":"https://doi.org/10.1002/prp2.70009","url":null,"abstract":"The endocannabinoid system (ECS) is a complex cell-signaling system that is responsible for maintaining homeostasis by modulating various regulatory reactions in response to internal and environmental changes. The influence of ECS on appetite regulation has been a subject of much recent research, however, the full extent of its impact remains unknown. Current evidence links human obesity to ECS activation, increased endocannabinoid levels in both central and peripheral tissues, along with cannabinoid receptor type 1 (CBR1) up-regulation. These findings imply the potential pharmacological use of the ECS in the treatment of obesity. Here, we present various pathophysiological processes in obesity involving the ECS, highlighting different pharmacological options for modulating endocannabinoid activity to treat obesity. However, the potential of those pharmacological possibilities remains under investigation and requires further research.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142265086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risks of oral anticoagulants: Analysis of adverse drug reactions reported to the Portuguese National Pharmacovigilance System","authors":"Ana Sofia Martins, Cristina Monteiro, Ana Paula Duarte","doi":"10.1002/prp2.1235","DOIUrl":"https://doi.org/10.1002/prp2.1235","url":null,"abstract":"Cardiovascular diseases are the leading cause of death globally, making the use of oral anticoagulants for prevention increasingly important. Historically, warfarin has played a significant role in this context. In recent years, introduction of new oral anticoagulants, such as rivaroxaban, apixaban, dabigatran, and edoxaban, has been seen. This study evaluates the risk associated with the use of oral anticoagulants by analyzing spontaneous adverse drug reactions reported to the Portuguese Pharmacovigilance System from 2012 to 2021. The study includes 951 adverse drug reactions reports, with the majority (<jats:italic>n</jats:italic> = 770; 80.97%) classified as serious. Of the 770 serious adverse drug reactions reports, the most commonly reported seriousness criterion was “Clinically Important” (<jats:italic>n</jats:italic> = 350; 45.45%). In terms of demographics, there was a higher reporting rate among the elderly population, with a greater prevalence of females. The System Organ Class group with the highest number of adverse drug reactions was “Gastrointestinal disorders,” with the most commonly reported Preferred Term being “Gastrointestinal hemorrhage,” and dabigatran was the most frequently reported drug. In summary, oral anticoagulants have adverse drug reactions that require continuous monitoring. Accurate identification and monitorization of adverse drug reactions is an important starting point to improve drug safety in population.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142265085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the quality of multiple‐choice question pilot database: A global educator‐created tool for concept‐based pharmacology learning","authors":"Adeladlew Kassie Netere, Tony Hughes, Anna‐Marie Babey, Martin Hawes, Janet Mifsud, John P. Kelly, Willmann Liang, Mark Hernandez, Kelly Karpa, Hesham Al‐Sallami, Lynette B. Fernandes, Patrik Aronsson, Carolina Restini, Fabiana Caetano Crowley, Elvan Djouma, Tina Hinton, Johnson J. Liu, Fatima Mraiche, Paul J. White","doi":"10.1002/prp2.70004","DOIUrl":"https://doi.org/10.1002/prp2.70004","url":null,"abstract":"The Core Concepts of Pharmacology (CCP) initiative is developing educational resources to transform pharmacology education into a concept‐based approach. This study evaluated the quality of global educator‐created MCQs in generating items for the pharmacology concept inventory (PCI) instrument and developed as a resource for learning pharmacology fundamental concepts. A panel of 22 global pharmacology experts recruited from the CCP initiative research team participated in the MCQ pilot database design and evaluation. The quality analysis framework of the MCQs in the pilot database included four assessment tools: item writing guidelines (IWGs), Bloom's taxonomy, the CCP, and the MCQ design format. A two‐phase evaluation process was involved, including inter‐rater agreement on item quality, followed by resolving conflicts that occurred in quality assessment. The chi‐square (<jats:italic>χ</jats:italic><jats:sup>2</jats:sup>) test of independence and Cramer's V correlation tests were utilized to measure the relationship among quality assessment attributes. About 200 MCQs were gathered and 98% underwent expert evaluation. Nearly 80% addressed one or more CCP, with 52% designed using a context‐dependent format. However, only 40% addressed higher levels of Bloom's cognitive domain and 10% adhered to all IWGs. A strong positive correlation was observed between the context‐based item format and its effectiveness in assessing the higher cognitive domain, the main CCP and improved IWGs adherence. Context‐based item construction can assess the higher cognitive skills and fundamental pharmacology concepts, showing potential for rigorous PCI development. The pilot database will store items to create the PCI, aiding the development of a concept‐based pharmacology curriculum.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142265087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An improvement of the safety profile of SARS‐CoV‐2 vaccines is desirable","authors":"Josef Finsterer","doi":"10.1002/prp2.70008","DOIUrl":"https://doi.org/10.1002/prp2.70008","url":null,"abstract":"","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics, disposition, and biotransformation of the cardiac myosin inhibitor aficamten in humans","authors":"Donghong Xu, Punag Divanji, Adrienne Griffith, Rajaa Sukhun, Kathleen Cheplo, Jianlin Li, Polina German","doi":"10.1002/prp2.70006","DOIUrl":"https://doi.org/10.1002/prp2.70006","url":null,"abstract":"Aficamten, a cardiac myosin inhibitor, is being developed for the treatment of patients with symptomatic hypertrophic cardiomyopathy (HCM). The purpose of this study was to determine the absorption, metabolism, and excretion of aficamten. Eight healthy male participants received a single oral dose of 20 mg aficamten (containing approximately 100 μCi of radiocarbon). Blood, urine, and feces samples were collected up to a maximum of Day 26. The pharmacokinetics of aficamten were characterized by moderate absorption, with a median t<jats:sub>max</jats:sub> of 2.0 h postdose. The median t<jats:sub>1/2</jats:sub> of aficamten was 99.6 h with similar t<jats:sub>1/2</jats:sub> observed for metabolites and total radioactivity in plasma and whole blood. The overall total recovery of administered total radioactivity was 89.7% with 57.7% of the dose recovered in feces and 32.0% in urine. The main circulating metabolites in plasma included monohydroxylated metabolites M1a (CK‐3834282) and M1b (CK‐3834283) accounting for 10.5% and 36.4% of the total radioactivity AUC both with a median t<jats:sub>max</jats:sub> of 5 h. The other major plasma metabolite was M5 (an oxygen‐linked glucuronide conjugate of M1a), which accounted for 10.3% of the total plasma radioactivity exposure, with a t<jats:sub>max</jats:sub> of 24 h. In urine, M5 was the most abundant metabolite with 8.02% total radioactive dose (TRD), followed by M1a and M1b with 6.16% and 2.85% TRD, respectively; however, there were no metabolites in urine observed at &gt;10% of dose. The major metabolite in feces was M18 representing 44.1% of the radioactive dose. These findings indicated that aficamten was eliminated by metabolism, and to a minor extent, by fecal excretion of unchanged aficamten with renal excretion playing a minor role. Feces were the principal route of excretion of the radioactive dose.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142208532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An open-label study to explore the optimal design of CYP3A drug-drug interaction clinical trials in healthy Chinese people.","authors":"Jingcheng Chen, Jiangshuo Li, Jingxuan Wu, Yuqin Song, Lijun Li, Jianxiong Zhang, Ruihua Dong","doi":"10.1002/prp2.1252","DOIUrl":"10.1002/prp2.1252","url":null,"abstract":"<p><p>A drug-drug interaction (DDI) trial of cytochrome P450 3A (CYP3A) is a necessary part of early-phase trials of drugs mainly metabolized by this enzyme, but CYP3A DDI clinical trials do not have a standard design, especially for Chinese people. We aimed to offer specific recommendations for CYP3A DDI clinical trial design. This was an open, three-cycle, self-controlled study. Healthy subjects were given different administration strategies of CYP3A4 perpetrators. In each cycle, blood samples were collected before and within 24 h after the administration of midazolam, the CYP3A indicator substrate. The plasma concentrations of midazolam and 1-hydroxymidazolam was obtained using liquid chromatography tandem mass spectrometry assay. For CYP3A inhibition, itraconazole exposure with a loading dose could increase the exposure of midazolam by 3.21-fold based on maximum plasma concentration (C_max), 8.37-fold based on area under the curve Pharmacology Research & Perspectives for review only from zero to the time point (AUC_0-t), and 11.22-fold based on area under the curve from zero to infinity (AUC_0-∞). The data were similar for itraconazole pretreatment without a loading dose. For CYP3A induction, the exposure of rifampin for 7 days decreased the plasma concentration of midazolam ~0.27-fold based on C_max, ~0.18-fold based on AUC_0-t, and ~0.18-fold based on AUC_0-∞. Midazolam exposure did not significantly change when the pretreatment of rifampin increased to 14 days. This study showed that itraconazole pretreatment for 3 days without a loading dose was enough for CYP3A inhibition, and pretreatment with rifampin for 7 days could induce near-maximal CYP3A levels.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrase inhibitor drugs during pregnancy and congenital anomalies: A case/non-case study from the global pharmacovigilance database VigiBase®.","authors":"Laura Saint-Lary, Isabelle Lacroix, Valériane Leroy, Agnès Sommet","doi":"10.1002/prp2.1247","DOIUrl":"10.1002/prp2.1247","url":null,"abstract":"<p><p>In 2018, a significant neural tube defects (NTD) signal was reported after pre-conceptional exposure to dolutegravir, but was not confirmed in further analysis. Since 2019, dolutegravir-based regimen, an integrase inhibitor (INI), is recommended by WHO as the most-effective first-line therapy in all patients living with HIV. To explore the potential INI-related teratogenic effect, we searched disproportionate signals between exposure to INI-class drugs and congenital anomalies, compared to non-INI drugs, using the international pharmacovigilance database, VigiBase®. We selected all the reports registered in VigiBase® between 01/01/2007 and 30/03/2021 on any antiretroviral drug-related fetal or neonatal adverse drug reactions, declared either in children (<2 years) exposed in utero or in pregnant women (12-50 years). A case/non-case study was conducted to detected signals between congenital anomalies and prenatal exposure to any INI-class drug, compared to non-INI drugs, by estimating adjusted reporting odds ratios (aROR) with 95% confidence intervals (95%CI). We identified 2521 unique reports, among which 664 (26.3%) were related to INI-class use. Overall, 520 congenital anomalies were cited from 327 unique reports, of whom 31.0% were INI-related. Compared to non-INI drugs, no significant disproportionate reporting signal between prenatal exposure to INI-class drugs and congenital anomalies was found (aROR 1.13; 95% CI:0.85-1.51). However, specific significant signals were reported for raltegravir/elvitegravir/dolutegravir drug exposure and urinary malformations (aROR 2.43; 95%CI:1.08-5.43), digestive malformations (aROR 3.09; 95%CI:1.22-7.84), and NTDs (aROR 3.02; 95%CI:1.09-8.37). Although specific congenital anomalies signals associated with raltegravir/elvitegravir/dolutegravir exposure were notified, causal relationship needs to be further investigated in prospective studies.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"No dose adjustment of metformin or substrates of organic cation transporters (OCT)1 and OCT2 and multidrug and toxin extrusion protein (MATE)1/2K with fostemsavir coadministration based on modeling approaches.","authors":"Dung Nguyen, Xiusheng Miao, Kunal Taskar, Mindy Magee, Pete Gorycki, Katy Moore, Guoying Tai","doi":"10.1002/prp2.1238","DOIUrl":"10.1002/prp2.1238","url":null,"abstract":"<p><p>Fostemsavir is an approved gp120-directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment-experienced adults with multi-drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug-drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co-administered with fostemsavir.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11237172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of intra- and inter-individual variations in plasma belimumab concentrations in adult patients with systemic lupus erythematosus.","authors":"Chisato Yoshijima, Yosuke Suzuki, Ryota Tanaka, Hiroyuki Ono, Ayako Oda, Takashi Ozaki, Hirotaka Shibata, Hiroki Itoh, Keiko Ohno","doi":"10.1002/prp2.1255","DOIUrl":"10.1002/prp2.1255","url":null,"abstract":"<p><p>In this study, plasma belimumab concentrations were measured over the course of treatment in systemic lupus erythematosus (SLE) patients on belimumab therapy, and intra- and interindividual variations in plasma belimumab concentration were evaluated. A single-center prospective study was conducted at Oita University Hospital to evaluate trough plasma concentrations over the course of treatment in 13 SLE patients treated with intravenous belimumab. Plasma belimumab concentrations were measured by a validated ultra-high performance liquid chromatography with tandem mass spectrometry method. The median age of the patients was 40 (interquartile range: 35-51) years and the median weight was 51.8 (47.0-58.1) kg. A mean of 9.4 (range: 1-13) blood samples was collected per patient at routine visits. The mean (± SD) plasma belimumab concentration was 33.4 ± 11.9 μg/mL in the patient with the lowest concentration and 170.0 ± 16.6 μg/mL in the patient with the highest concentration, indicating a 5-fold difference between patients. On the other hand, the within-patient coefficient of variation ranged from 7.1% to 35.7%, showing no large variations. No significant correlation was observed between plasma belimumab concentration and belimumab dose (mg/kg) (Spearman's rank correlation coefficient = 0.22, p = .54). Examinations of trough plasma belimumab concentrations over the course of treatment in patients with SLE showed small intraindividual variation but large interindividual variation. Plasma belimumab trough concentration varied widely among patients administered the approved dose.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miRNA and leptin signaling in metabolic diseases and at extreme environments.","authors":"Samrita Mondal, Richa Rathor, Som Nath Singh, Geetha Suryakumar","doi":"10.1002/prp2.1248","DOIUrl":"10.1002/prp2.1248","url":null,"abstract":"<p><p>The burden of growing concern about the dysregulation of metabolic processes arises due to complex interplay between environment and nutrition that has great impact on genetics and epigenetics of an individual. Thereby, any abnormality at the level of food intake regulating hormones may contribute to the development of metabolic diseases in any age group due to malnutrition, overweight, changing lifestyle, and exposure to extreme environments such as heat stress (HS), cold stress, or high altitude (HA). Hormones such as leptin, adiponectin, ghrelin, and cholecystokinin regulate appetite and satiety to maintain energy homeostasis. Leptin, an adipokine and a pleiotropic hormone, play major role in regulating the food intake, energy gain and energy expenditure. Using in silico approach, we have identified the major genes (LEP, LEPR, JAK2, STAT3, NPY, POMC, IRS1, SOCS3) that play crucial role in leptin signaling pathway. Further, eight miRNAs (hsa-miR-204-5p, hsa-miR-211-5p, hsa-miR-30, hsa-miR-3163, hsa-miR-33a-3p, hsa-miR-548, hsa-miR-561-3p, hsa-miR-7856-5p) from TargetScan 8.0 database were screened out that commonly target these genes. The role of these miRNAs should be explored as they might play vital role in regulating the appetite, energy metabolism, metabolic diseases (obesity, type 2 diabetes, cardiovascular diseases, inflammation), and to combat extreme environments. The miRNAs regulating leptin signaling and appetite may be useful for developing novel therapeutics for metabolic diseases.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11253706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141627339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}