Pharmacological Reviews最新文献

{"title":"Beyond the stomach stall: Current and emerging pharmacotherapeutics for gastroparesis.","authors":"Ali H Eid","doi":"10.1016/j.pharmr.2024.100021","DOIUrl":"https://doi.org/10.1016/j.pharmr.2024.100021","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 2","pages":"100021"},"PeriodicalIF":19.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shared molecular, cellular, and environmental hallmarks in cardiovascular disease and cancer: Any place for drug repurposing?","authors":"Elisa Avolio, Barbara Bassani, Marzia Campanile, Khaled Ak Mohammed, Paola Muti, Antonino Bruno, Gaia Spinetti, Paolo Madeddu","doi":"10.1016/j.pharmr.2024.100033","DOIUrl":"https://doi.org/10.1016/j.pharmr.2024.100033","url":null,"abstract":"<p><p>Cancer and cardiovascular disease (CVD) are the 2 biggest killers worldwide. Specific treatments have been developed for the 2 diseases. However, mutual therapeutic targets should be considered because of the overlap of cellular and molecular mechanisms. Cancer research has grown at a fast pace, leading to an increasing number of new mechanistic treatments. Some of these drugs could prove useful for treating CVD, which realizes the concept of cancer drug repurposing. This review provides a comprehensive outline of the shared hallmarks of cancer and CVD, primarily ischemic heart disease and heart failure. We focus on chronic inflammation, altered immune response, stromal and vascular cell activation, and underlying signaling pathways causing pathological tissue remodeling. There is an obvious scope for targeting those shared mechanisms, thereby achieving reciprocal preventive and therapeutic benefits. Major attention is devoted to illustrating the logic, advantages, challenges, and viable examples of drug repurposing and discussing the potential influence of sex, gender, age, and ethnicity in realizing this approach. Artificial intelligence will help to refine the personalized application of drug repurposing for patients with CVD. SIGNIFICANCE STATEMENT: Cancer and cardiovascular disease (CVD), the 2 biggest killers worldwide, share several underlying cellular and molecular mechanisms. So far, specific therapies have been developed to tackle the 2 diseases. However, the development of new cardiovascular drugs has been slow compared with cancer drugs. Understanding the intersection between pathological mechanisms of the 2 diseases provides the basis for repurposing cancer therapeutics for CVD treatment. This approach could allow the rapid development of new drugs for patients with CVDs.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 2","pages":"100033"},"PeriodicalIF":19.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analyzing lognormal data: A nonmathematical practical guide.","authors":"Harvey J Motulsky, Trajen Head, Paul B S Clarke","doi":"10.1016/j.pharmr.2025.100049","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100049","url":null,"abstract":"<p><p>Lognormal distributions are pervasive in pharmacology and elsewhere in biomedical science, arising naturally when biological effects multiply rather than add. Despite their ubiquity in pharmacological parameters (eg, EC50, IC50, Kd, and Km), lognormal distributions are often overlooked or misunderstood, leading to flawed data analysis. This largely nonmathematical review explains why lognormal distributions are common, how to recognize them, and how to analyze them appropriately. We show that many measured variables are lognormal. So are many derived parameters, particularly those defined as ratios of lognormal variables. Through examples and simulations accessible to working scientists, we demonstrate how misidentifying lognormal distributions as normal leads to reduced statistical power, unnecessarily large sample sizes, false identification of outliers, and inappropriate reporting of effects as differences rather than ratios. We challenge the common practice of using normality tests to decide how to analyze data, showing that many data sets pass both normality and lognormality tests, especially with small sample sizes. Instead, we advocate for assuming lognormality based on the nature of the variable. This review provides practical guidance on recognizing and presenting lognormal data, and comparing data sets sampled from lognormal distributions. Based on Monte Carlo simulations, we recommend the lognormal Welch's t test or nonparametric Brunner-Munzel test for comparing 2 unpaired groups, the lognormal ratio paired t test for paired comparisons, and lognormal ANOVA for ≥3 groups. By recognizing and properly handling lognormal distributions, pharmacologists can design more efficient experiments, obtain more reliable statistical inferences, and communicate their results more effectively. SIGNIFICANCE STATEMENT: Lognormal distributions are common in pharmacology and many scientific fields, but they are often misunderstood or overlooked. This review provides a detailed guide to recognizing and analyzing lognormal data, aiming to help pharmacologists perform more appropriate and more powerful statistical analyses, draw more meaningful conclusions from their data, and communicate their results more effectively.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100049"},"PeriodicalIF":19.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"International Union of Basic and Clinical Pharmacology: Fundamental insights and clinical relevance regarding the carnitine palmitoyltransferase family of enzymes.","authors":"Rosalía Rodríguez-Rodríguez, Miguel Baena, Sebastián Zagmutt, West Kristian Paraiso, Ana Cristina Reguera, Rut Fadó, Núria Casals","doi":"10.1016/j.pharmr.2025.100051","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100051","url":null,"abstract":"<p><p>The carnitine palmitoyltransferases (CPTs) play a key role in controlling the oxidation of long-chain fatty acids and are potential therapeutic targets for diseases with a strong metabolic component, such as obesity, diabetes, and cancer. Four distinct proteins are CPT1A, CPT1B, CPT1C, and CPT2, differing in tissue expression and catalytic activity. CPT1s are finely regulated by malonyl-CoA, a metabolite whose intracellular levels reflect the cell's nutritional state. Although CPT1C does not exhibit significant catalytic activity, it is capable of modulating the functioning of other neuronal proteins. Structurally, all CPTs share a Y-shaped catalytic tunnel that allows the entry of 2 substrates and accommodation of the acyl group in a hydrophobic pocket. Several molecules targeting these enzymes have been described, some showing potential in normalizing blood glucose levels in diabetic patients, and others that, through a central mechanism, are anorexigenic and enhance energy expenditure. However, given the critical roles that CPTs play in certain tissues, such as the heart, liver, and brain, it is essential to fully understand the differences between the various isoforms. We analyze in detail the structure of these proteins, their cellular and physiological functions, and their potential as therapeutic targets in diseases such as obesity, diabetes, and cancer. We also describe drugs identified to date as having inhibitory or activating capabilities for these proteins. This knowledge will support the design of new drugs specific to each isoform, and the development of nanomedicines that can selectively target particular tissues or cells. SIGNIFICANCE STATEMENT: Carnitine palmitoyltransferase (CPT) proteins, as gatekeepers of fatty acid oxidation, have great potential as pharmacological targets to treat metabolic diseases like obesity, diabetes, and cancer. In recent years, significant progress has been made in understanding the 3-dimensional structure of CPTs and their pathophysiological functions. A deeper understanding of the differences between the various CPT family members will enable the design of selective drugs and therapeutic approaches with fewer side effects.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100051"},"PeriodicalIF":19.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety in treatment: Classical pharmacotherapeutics and new avenues for addressing maternal depression and anxiety during pregnancy.","authors":"Merel Dagher, Catherine M Cahill, Anne M Andrews","doi":"10.1016/j.pharmr.2025.100046","DOIUrl":"10.1016/j.pharmr.2025.100046","url":null,"abstract":"<p><p>We aimed to review clinical research on the safety profiles of antidepressant drugs and associations with maternal depression and neonatal outcomes. We focused on neuroendocrine changes during pregnancy and their effects on antidepressant pharmacokinetics. Pregnancy-induced alterations in drug disposition and metabolism impacting mothers and their fetuses are discussed. We considered evidence for the risks of antidepressant use during pregnancy. Teratogenicity associated with ongoing treatment, new prescriptions during pregnancy, or pausing medication while pregnant was examined. The Food and Drug Administration advises caution regarding prenatal exposure to most drugs, including antidepressants, largely owing to a dearth of safety studies caused by the common exclusion of pregnant individuals in clinical trials. We contrasted findings on antidepressant use with the lack of treatment where detrimental effects to mothers and children are well researched. Overall, drug classes such as selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors appear to have limited adverse effects on fetal health and child development. In the face of an increasing prevalence of major mood and anxiety disorders, we assert that individuals should be counseled before and during pregnancy about the risks and benefits of antidepressant treatment given that withholding treatment has possible negative outcomes. Moreover, newer therapeutics, such as ketamine and κ-opioid receptor antagonists, warrant further investigation for use during pregnancy. SIGNIFICANCE STATEMENT: The safety of antidepressant use during pregnancy remains controversial owing to an incomplete understanding of how drug exposure affects fetal development, brain maturation, and behavior in offspring. This leaves pregnant people especially vulnerable, as pregnancy can be a highly stressful experience for many individuals, with stress being the biggest known risk factor for developing a mood or anxiety disorder. This review focuses on perinatal pharmacotherapy for treating mood and anxiety disorders, highlighting the current knowledge and gaps in our understanding of consequences of treatment.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100046"},"PeriodicalIF":19.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heme-thiolate monooxygenase cytochrome P450 1B1, an old dog with many new tricks.","authors":"Jong-Won Kim, Hung-Chun Tung, Bin Yang, Rajat Pant, Xiuchen Guan, Ye Feng, Wen Xie","doi":"10.1016/j.pharmr.2025.100045","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100045","url":null,"abstract":"<p><p>Cytochrome P450 CYP1B1 is a heme-thiolate monooxygenase traditionally recognized for its xenobiotic functions and extrahepatic expressions. Recent studies have suggested that CYP1B1 is also expressed in hepatic stellate cells, immune cells, endothelial cells, and fibroblasts within the tumor microenvironment, as well as tumor cells themselves. CYP1B1 is responsible for the metabolism of a wide range of substrates, including xenobiotics such as drugs, environmental chemicals, and endobiotics such as steroids, retinol, and fatty acids. Consequently, CYP1B1 and its associated exogenous and endogenous metabolites have been critically implicated in the pathogenesis of many diseases. Understanding the mode of action of CYP1B1 in different pathophysiological conditions and developing pharmacological inhibitors that allow for systemic or cell type-specific modulation of CYP1B1 may pave the way for novel therapeutic opportunities. This review highlights the significant role of CYP1B1 in maintaining physiological homeostasis and provides a comprehensive discussion of recent advancements in our understanding of CYP1B1's involvement in the pathogenesis of diseases such as fibrosis, cancer, glaucoma, and metabolic disorders. Finally, the review emphasizes the therapeutic potential of targeting CYP1B1 for drug development, particularly in the treatment and prevention of cancers and liver fibrosis. SIGNIFICANCE STATEMENT: CYP1B1 plays a critical role in various physiological processes. Dysregulation or genetic mutations of the gene encoding this enzyme can lead to health complications and may increase the risk of diseases such as cancer and liver fibrosis. In this review, we summarize recent preclinical and clinical evidence that underscores the potential of CYP1B1 as a therapeutic target.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100045"},"PeriodicalIF":19.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclic nucleotide phosphodiesterases as drug targets.","authors":"Michy P Kelly, Viacheslav O Nikolaev, Leila Gobejishvili, Claire Lugnier, Christian Hesslinger, Peter Nickolaus, David A Kass, Walma Pereira de Vasconcelos, Rodolphe Fischmeister, Stefan Brocke, Paul M Epstein, Gary A Piazza, Adam B Keeton, Gang Zhou, Mohammad Abdel-Halim, Ashraf H Abadi, George S Baillie, Mark A Giembycz, Graeme Bolger, Gretchen Snyder, Kjetil Tasken, Nathaniel E B Saidu, Martina Schmidt, Manuela Zaccolo, Ralph T Schermuly, Hengming Ke, Rick H Cote, Soroush Mohammadi Jouabadi, Anton J M Roks","doi":"10.1016/j.pharmr.2025.100042","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100042","url":null,"abstract":"<p><p>Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze cyclic nucleotides. PDEs control cyclic adenosine-3',5'monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) intracellular levels by mediating their quick return to the basal steady state levels. This often takes place in subcellular nanodomains. Thus, PDEs govern short-term protein phosphorylation, long-term protein expression, and even epigenetic mechanisms by modulating cyclic nucleotide levels. Consequently, their involvement in both health and disease is extensively investigated. PDE inhibition has emerged as a promising clinical intervention method, with ongoing developments aiming to enhance its efficacy and applicability. In this comprehensive review, we extensively look into the intricate landscape of PDEs biochemistry, exploring their diverse roles in various tissues. Furthermore, we outline the underlying mechanisms of PDEs in different pathophysiological conditions. Additionally, we review the application of PDE inhibition in related diseases, shedding light on current advancements and future prospects for clinical intervention. SIGNIFICANCE STATEMENT: Regulating PDEs is a critical checkpoint for numerous (patho)physiological conditions. However, despite the development of several PDE inhibitors aimed at controlling overactivated PDEs, their applicability in clinical settings poses challenges. In this context, our focus is on pharmacodynamics and the structure activity of PDEs, aiming to illustrate how selectivity and efficacy can be optimized. Additionally, this review points to current preclinical and clinical evidence that depicts various optimization efforts and indications.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100042"},"PeriodicalIF":19.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carbonic anhydrase inhibitors: \"Old\" drugs with new potential in unexpected areas.","authors":"Ali H Eid","doi":"10.1016/j.pharmr.2024.100007","DOIUrl":"https://doi.org/10.1016/j.pharmr.2024.100007","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 1","pages":"100007"},"PeriodicalIF":19.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioactives from marine resources as natural health products: A review.","authors":"Sarusha Santhiravel, Deepika Dave, Fereidoon Shahidi","doi":"10.1124/pharmrev.123.001227","DOIUrl":"https://doi.org/10.1124/pharmrev.123.001227","url":null,"abstract":"<p><p>The oceans are a rich source of a myriad of structurally different and unique natural products that are mainly found in invertebrates, with potential applications in different disciplines. Microbial infection and cancer are the leading causes of death worldwide. The discovery of new sources of therapy for microbial infections is an urgent requirement owing to the emergence of pathogenic microorganisms that are resistant to existing therapies. Marine bioactives have been demonstrated to be promising sources for the discovery and development of novel antimicrobial and anticancer compounds. Several marine compounds are confirmed to have antibacterial effects, and most marine-based antifungal compounds are cytotoxic. Numerous antitumor marine natural products, derived mainly from not only sponges or molluscs but also bryozoans and cyanobacteria, exhibit potent antimitotic activity. In addition, marine biodiversity offers some possible leads or new drugs to treat human immunodeficiency virus. A majority of marine-derived drugs are currently in clinical trials or under preclinical evaluation. Furthermore, marine-based drugs approved by the US Food and Drug Administration are available in the market. This review summarizes the sources, mechanisms of action, and potential utilization of marine natural products such as peptides, alkaloids, polyketides, polyphenols, terpenoids, and sterols as antifungal, antibacterial, antiviral, and anticancer compounds. SIGNIFICANCE STATEMENT: Utilization of natural bioactive compounds from marine resources is a crucial advancement in the field of health care and wellness. A valuable source of potent compounds with therapeutic potential exists in marine organisms. These bioactives offer promising medicinal value for disease prevention, promoting overall wellbeing, and advancing pharmaceutical and nutraceutical industries. Their sustainable extraction and utilization not only benefit human health but also contribute to the conservation of marine ecosystems. This transformative approach enhances global health outcomes and sustainability.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 1","pages":"100006"},"PeriodicalIF":19.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drugs from the ocean floor.","authors":"Maha Khachab, Amirhossein Sahebkar, Ali H Eid","doi":"10.1016/j.pharmr.2024.100009","DOIUrl":"https://doi.org/10.1016/j.pharmr.2024.100009","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 1","pages":"100009"},"PeriodicalIF":19.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}