Pharmacological Reviews最新文献

{"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":"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":"2025-05-01","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":"Application of Kirchhoff's Laws to pharmacologic and pharmacokinetic analyses.","authors":"Leslie Z Benet, Jasleen K Sodhi, Markus Ville Tiitto, Yue Xiang","doi":"10.1016/j.pharmr.2025.100050","DOIUrl":"10.1016/j.pharmr.2025.100050","url":null,"abstract":"<p><p>Recently, we introduced a straightforward approach to derive clearance and rate constant equations, without relying on differential equations, utilizing Kirchhoff's Laws, a well known physics methodology used to describe rate-defining processes either in series or parallel. Manuscripts from our laboratory have re-examined published experimental data, demonstrating that the Kirchhoff's Laws methodology can explain data previously considered anomalous, such as the following: (1) all experimental perfused liver clearance data conforming to the equation once thought to represent the unphysiological well stirred model, (2) instances where linear pharmacokinetic systemic bioavailability determinations exceed unity, (3) renal clearance being influenced by drug input processes, (4) statistically significant differences in bioavailability measures between urinary excretion and systemic concentration measurements, and (5) how the long-accepted steady-state clearance approach used in pharmacokinetics for the past half-century leads to unrealistic conclusions about the relationship between liver-to-blood Kp_uu and hepatic availability F_H. These findings demonstrate the potential for errors in pharmacokinetic evaluations that rely on differential equations. The Kirchhoff's Laws approach is applicable to all pharmacokinetic analyses of quality experimental data, both those that align with present pharmacokinetic theory, and those that do not. Although 3 publications have attempted to rebut our position, they fail to address unexplained experimental data, and we detail here why these analyses are invalid. Our discoveries are ongoing. Additionally, we briefly discuss the application of Kirchoff's Laws to saturable nonlinear kinetics, explaining increased pharmacodynamic response for extended vs immediate release dosage forms, as well as the advantages of successfully formulating high hepatic extraction drugs. SIGNIFICANCE STATEMENT: The Kirchhoff's Laws approach to deriving clearance equations for linear systems in parallel or in series, independent of differential equations, successfully describes anomalous published pharmacokinetic data that have previously been unexplained. We review 9 experimental outcomes in humans that are newly explained using the Kirchhoff's Laws approach, including the extension to deriving nonlinear saturable clearance relationships.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100050"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693087","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":"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":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163497/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Toward a paradigm shift: Oral agents and injectable drugs in the future of obesity management\" [Pharmacological Reviews 77 (2025) 100008].","authors":"Amirhossein Sahebkar, Ali H Eid","doi":"10.1016/j.pharmr.2025.100047","DOIUrl":"10.1016/j.pharmr.2025.100047","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100047"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582355","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":"Activating autophagy to eliminate toxic protein aggregates with small molecules in neurodegenerative diseases.","authors":"Yuqi Fu, Jin Zhang, Rui Qin, Yueting Ren, Tingting Zhou, Bo Han, Bo Liu","doi":"10.1016/j.pharmr.2025.100053","DOIUrl":"10.1016/j.pharmr.2025.100053","url":null,"abstract":"<p><p>Neurodegenerative diseases (NDs), such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are well known to pose formidable challenges for their treatment due to their intricate pathogenesis and substantial variability among patients, including differences in environmental exposures and genetic predispositions. One of the defining characteristics of NDs is widely reported to be the buildup of misfolded proteins. For example, Alzheimer disease is marked by amyloid beta and hyperphosphorylated Tau aggregates, whereas Parkinson disease exhibits α-synuclein aggregates. Amyotrophic lateral sclerosis and frontotemporal dementia exhibit TAR DNA-binding protein 43, superoxide dismutase 1, and fused-in sarcoma protein aggregates, and Huntington disease involves mutant huntingtin and polyglutamine aggregates. These misfolded proteins are the key biomarkers of NDs and also serve as potential therapeutic targets, as they can be addressed through autophagy, a process that removes excess cellular inclusions to maintain homeostasis. Various forms of autophagy, including macroautophagy, chaperone-mediated autophagy, and microautophagy, hold a promise in eliminating toxic proteins implicated in NDs. In this review, we focus on elucidating the regulatory connections between autophagy and toxic proteins in NDs, summarizing the cause of the aggregates, exploring their impact on autophagy mechanisms, and discussing how autophagy can regulate toxic protein aggregation. Moreover, we underscore the activation of autophagy as a potential therapeutic strategy across different NDs and small molecules capable of activating autophagy pathways, such as rapamycin targeting the mTOR pathway to clear α-synuclein and Sertraline targeting the AMPK/mTOR/RPS6KB1 pathway to clear Tau, to further illustrate their potential in NDs' therapeutic intervention. Together, these findings would provide new insights into current research trends and propose small-molecule drugs targeting autophagy as promising potential strategies for the future ND therapies. SIGNIFICANCE STATEMENT: This review provides an in-depth overview of the potential of activating autophagy to eliminate toxic protein aggregates in the treatment of neurodegenerative diseases. It also elucidates the fascinating interrelationships between toxic proteins and the process of autophagy of \"chasing and escaping\" phenomenon. Moreover, the review further discusses the progress utilizing small molecules to activate autophagy to improve the efficacy of therapies for neurodegenerative diseases by removing toxic protein aggregates.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100053"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788590","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":"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":"2025-05-01","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":"International Union of Basic and Clinical Pharmacology. CXIX. 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":"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":"2025-05-01","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":"Corrigendum to \"International Union of Basic and Clinical Pharmacology. CXIX. Fundamental insights and clinical relevance regarding the carnitine palmitoyltransferase family of enzymes\" [Pharmacological Reviews 77 (2025) 100051].","authors":"Rosalía Rodríguez-Rodríguez,Miguel Baena,Sebastián Zagmutt,West Kristian Paraiso,Ana Cristina Reguera,Rut Fadó,Núria Casals","doi":"10.1016/j.pharmr.2025.100057","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100057","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"7 1","pages":"100057"},"PeriodicalIF":21.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872101","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":"Reversing the odds: Advanced and emerging therapeutic strategies for male infertility.","authors":"Ali H Eid","doi":"10.1016/j.pharmr.2024.100020","DOIUrl":"https://doi.org/10.1016/j.pharmr.2024.100020","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 2","pages":"100020"},"PeriodicalIF":19.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731114","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":"The Hippo pathway: Organ size control and beyond.","authors":"Pengfei Guo, Sicheng Wan, Kun-Liang Guan","doi":"10.1016/j.pharmr.2024.100031","DOIUrl":"10.1016/j.pharmr.2024.100031","url":null,"abstract":"<p><p>The Hippo signaling pathway is a highly conserved signaling network for controlling organ size, tissue homeostasis, and regeneration. It integrates a wide range of intracellular and extracellular signals, such as cellular energy status, cell density, hormonal signals, and mechanical cues, to modulate the activity of YAP/TAZ transcriptional coactivators. A key aspect of Hippo pathway regulation involves its spatial organization at the plasma membrane, where upstream regulators localize to specific membrane subdomains to regulate the assembly and activation of the pathway components. This spatial organization is critical for the precise control of Hippo signaling, as it dictates the dynamic interactions between pathway components and their regulators. Recent studies have also uncovered the role of biomolecular condensation in regulating Hippo signaling, adding complexity to its control mechanisms. Dysregulation of the Hippo pathway is implicated in various pathological conditions, particularly cancer, where alterations in YAP/TAZ activity contribute to tumorigenesis and drug resistance. Therapeutic strategies targeting the Hippo pathway have shown promise in both cancer treatment, by inhibiting YAP/TAZ signaling, and regenerative medicine, by enhancing YAP/TAZ activity to promote tissue repair. The development of small molecule inhibitors targeting the YAP-TEAD interaction and other upstream regulators offers new avenues for therapeutic intervention. SIGNIFICANCE STATEMENT: The Hippo signaling pathway is a key regulator of organ size, tissue homeostasis, and regeneration, with its dysregulation linked to diseases such as cancer. Understanding this pathway opens new possibilities for therapeutic approaches in regenerative medicine and oncology, with the potential to translate basic research into improved clinical outcomes.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 2","pages":"100031"},"PeriodicalIF":19.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731134","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}