Pharmacological Reviews最新文献

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Intestinal Lymphatic Biology, Drug Delivery, and Therapeutics: Current Status and Future Directions. 肠道淋巴生物学、给药和治疗:现状与未来方向。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.123.001159
Sanjeevini Babu Reddiar, Yining Xie, Mohammad Abdallah, Sifei Han, Luojuan Hu, Orlagh M Feeney, Gracia Gracia, Abel Anshabo, Zijun Lu, Muhammad Asim Farooq, Ian K Styles, Anthony R J Phillips, John A Windsor, Christopher J H Porter, Enyuan Cao, Natalie L Trevaskis
{"title":"Intestinal Lymphatic Biology, Drug Delivery, and Therapeutics: Current Status and Future Directions.","authors":"Sanjeevini Babu Reddiar, Yining Xie, Mohammad Abdallah, Sifei Han, Luojuan Hu, Orlagh M Feeney, Gracia Gracia, Abel Anshabo, Zijun Lu, Muhammad Asim Farooq, Ian K Styles, Anthony R J Phillips, John A Windsor, Christopher J H Porter, Enyuan Cao, Natalie L Trevaskis","doi":"10.1124/pharmrev.123.001159","DOIUrl":"10.1124/pharmrev.123.001159","url":null,"abstract":"<p><p>Historically, the intestinal lymphatics were considered passive conduits for fluids, immune cells, dietary lipids, lipid soluble vitamins, and lipophilic drugs. Studies of intestinal lymphatic drug delivery in the late 20th century focused primarily on the drugs' physicochemical properties, especially high lipophilicity, that resulted in intestinal lymphatic transport. More recent discoveries have changed our traditional view by demonstrating that the lymphatics are active, plastic, and tissue-specific players in a range of biological and pathological processes, including within the intestine. These findings have, in turn, inspired exploration of lymph-specific therapies for a range of diseases, as well as the development of more sophisticated strategies to actively deliver drugs or vaccines to the intestinal lymph, including a range of nanotechnologies, lipid prodrugs, and lipid-conjugated materials that \"hitchhike\" onto lymphatic transport pathways. With the increasing development of novel therapeutics such as biologics, there has been interest in whether these therapeutics are absorbed and transported through intestinal lymph after oral administration. Here we review the current state of understanding of the anatomy and physiology of the gastrointestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. We summarize the current state-of-the-art approaches to deliver drugs and quantify their uptake into the intestinal lymphatic system. Finally, and excitingly, we discuss recent examples of significant pharmacokinetic and therapeutic benefits achieved via intestinal lymphatic drug delivery. We also propose approaches to advance the development and clinical application of intestinal lymphatic delivery strategies in the future. SIGNIFICANCE STATEMENT: This comprehensive review details the understanding of the anatomy and physiology of the intestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. It highlights current state-of-the-art approaches to deliver drugs to the intestinal lymphatics and the shift toward the use of these strategies to achieve pharmacokinetic and therapeutic benefits for patients.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"1326-1398"},"PeriodicalIF":19.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047017","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}
引用次数: 0
Nitric Oxide Signaling and Regulation in the Cardiovascular System: Recent Advances. 一氧化氮在心血管系统中的信号传递和调节:最新进展。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.001060
Mattias Carlström, Eddie Weitzberg, Jon O Lundberg
{"title":"Nitric Oxide Signaling and Regulation in the Cardiovascular System: Recent Advances.","authors":"Mattias Carlström, Eddie Weitzberg, Jon O Lundberg","doi":"10.1124/pharmrev.124.001060","DOIUrl":"10.1124/pharmrev.124.001060","url":null,"abstract":"<p><p>Nitric oxide (NO) from endothelial NO synthase importantly contributes to vascular homeostasis. Reduced NO production or increased scavenging during disease conditions with oxidative stress contribute to endothelial dysfunction and NO deficiency. In addition to the classical enzymatic NO synthases (NOS) system, NO can also be generated via the nitrate-nitrite-NO pathway. Dietary and pharmacological approaches aimed at increasing NO bioactivity, especially in the cardiovascular system, have been the focus of much research since the discovery of this small gaseous signaling molecule. Despite wide appreciation of the biological role of NOS/NO signaling, questions still remain about the chemical nature of NOS-derived bioactivity. Recent studies show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase, and directly activate the soluble guanylyl cyclase-cGMP-protein kinase G pathway without intermediacy of free NO. Moreover, interaction between red blood cells and the endothelium in the regulation of vascular NO homeostasis have gained much attention, especially in conditions with cardiometabolic disease. In this review we discuss both classical and nonclassical pathways for NO generation in the cardiovascular system and how these can be modulated for therapeutic purposes. SIGNIFICANCE STATEMENT: After four decades of intensive research, questions persist about the transduction and control of nitric oxide (NO) synthase bioactivity. Here we discuss NO signaling in cardiovascular health and disease, highlighting new findings, such as the important role of red blood cells in cardiovascular NO homeostasis. Nonclassical signaling modes, like the nitrate-nitrite-NO pathway, and therapeutic opportunities related to the NO system are discussed. Existing and potential pharmacological treatments/strategies, as well as dietary components influencing NO generation and signaling are covered.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"1038-1062"},"PeriodicalIF":19.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311273","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}
引用次数: 0
Roles of Individual Human Cytochrome P450 Enzymes in Drug Metabolism. 人类细胞色素 P450 酶在药物代谢中的作用。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.001173
F Peter Guengerich
{"title":"Roles of Individual Human Cytochrome P450 Enzymes in Drug Metabolism.","authors":"F Peter Guengerich","doi":"10.1124/pharmrev.124.001173","DOIUrl":"10.1124/pharmrev.124.001173","url":null,"abstract":"<p><p>Our knowledge of the roles of individual cytochrome P450 (P450) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for \"phenotyping\" metabolism reactions with new drug candidates. Endogenous biomarkers are being used for noninvasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining \"orphan\" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating interspecies differences in drug metabolism, particularly in the context of \"metabolism in safety testing\" regulatory issues [\"disproportionate (human) metabolites\"]. SIGNIFICANCE STATEMENT: Cytochrome P450 enzymes are the major catalysts involved in drug metabolism. The characterization of their individual roles has major implications in drug development and clinical practice.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"1104-1132"},"PeriodicalIF":19.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760253","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}
引用次数: 0
Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. 代谢性疾病、炎症性疾病和药物开发中的胆汁酸信号转导。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.000978
Tiangang Li, John Y L Chiang
{"title":"Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development.","authors":"Tiangang Li, John Y L Chiang","doi":"10.1124/pharmrev.124.000978","DOIUrl":"10.1124/pharmrev.124.000978","url":null,"abstract":"<p><p>Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"1221-1253"},"PeriodicalIF":19.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559459","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}
引用次数: 0
Somatostatin: Linking Cognition and Alzheimer Disease to Therapeutic Targeting. 生长抑素:将认知和阿尔茨海默病与治疗目标联系起来。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.001117
Karin E Sandoval, Ken A Witt
{"title":"Somatostatin: Linking Cognition and Alzheimer Disease to Therapeutic Targeting.","authors":"Karin E Sandoval, Ken A Witt","doi":"10.1124/pharmrev.124.001117","DOIUrl":"10.1124/pharmrev.124.001117","url":null,"abstract":"<p><p>Over 4 decades of research support the link between Alzheimer disease (AD) and somatostatin [somatotropin-releasing inhibitory factor (SRIF)]. SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid-<i>β</i> peptide (A<i>β</i>), culminating in cognitive decline and dementia. The connection between the SRIF and AD further extends to the neuropsychiatric symptoms, seizure activity, and inflammation, whereas preclinical AD investigations show SRIF or SRIF receptor agonist administration capable of enhancing cognition. SRIF receptor subtype-4 activation in particular presents unique attributes, with the potential to mitigate learning and memory decline, reduce comorbid symptoms, and enhance enzymatic degradation of A<i>β</i> in the brain. Here, we review the links between SRIF and AD along with the therapeutic implications. SIGNIFICANCE STATEMENT: Somatostatin and somatostatin-expressing neurons in the brain are extensively involved in cognition. Loss of somatostatin and somatostatin-expressing neurons in Alzheimer disease rests at the center of a series of interdependent pathological events contributing to cognitive decline and dementia. Targeting somatostatin-mediated processes has significant therapeutic potential for the treatment of Alzheimer disease.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"1291-1325"},"PeriodicalIF":19.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141627303","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}
引用次数: 0
International Union of Basic and Clinical Pharmacology CXV: The Class F of G Protein-Coupled Receptors. 国际基础与临床药理学联合会。CXV:G 蛋白偶联受体 F 类。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.001062
Gunnar Schulte
{"title":"International Union of Basic and Clinical Pharmacology CXV: The Class F of G Protein-Coupled Receptors.","authors":"Gunnar Schulte","doi":"10.1124/pharmrev.124.001062","DOIUrl":"10.1124/pharmrev.124.001062","url":null,"abstract":"<p><p>The class F of G protein-coupled receptors (GPCRs) consists of 10 Frizzleds (FZD<sub>1-10</sub>) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched. The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first-class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation, and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to the rapid development of our knowledge about structure-function relationships, providing a great starting point for drug development. Despite the progress, questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems. SIGNIFICANCE STATEMENT: The recent years of research have brought about substantial functional and structural insight into mechanisms of activation of Frizzleds and Smoothened. While the advance furthers our mechanistic understanding of ligand recognition, receptor activation, signal specification, and initiation, broader opportunities emerge that allow targeting class F GPCRs for therapy and regenerative medicine employing both biologics and small molecule compounds.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"1009-1037"},"PeriodicalIF":19.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492969","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}
引用次数: 0
Posttranslational Modifications of α-Synuclein, Their Therapeutic Potential, and Crosstalk in Health and Neurodegenerative Diseases. α-突触核蛋白的翻译后修饰、其治疗潜力以及在健康和神经退行性疾病中的相互影响。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.123.001111
Kambiz Hassanzadeh, Jun Liu, Santhosh Maddila, M Maral Mouradian
{"title":"Posttranslational Modifications of <b>α</b>-Synuclein, Their Therapeutic Potential, and Crosstalk in Health and Neurodegenerative Diseases.","authors":"Kambiz Hassanzadeh, Jun Liu, Santhosh Maddila, M Maral Mouradian","doi":"10.1124/pharmrev.123.001111","DOIUrl":"10.1124/pharmrev.123.001111","url":null,"abstract":"<p><p><i>α</i>-Synuclein (<i>α</i>-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of <i>α</i>-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. <i>α</i>-Syn undergoes various posttranslational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the cooccurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between <i>α</i>-Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of <i>α</i>-Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in <i>α</i>-Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential. SIGNIFICANCE STATEMENT: <i>α</i>-Synuclein is a key pathogenic protein in Parkinson's disease and other synucleinopathies, making it a leading therapeutic target for disease modification. Multiple posttranslational modifications occur at various sites in <i>α</i>-Synuclein and alter its biophysical and pathological properties, some interacting with one another to add to the complexity of the pathogenicity of this protein. This review details these modifications, their implications in disease, and potential therapeutic opportunities.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"1254-1290"},"PeriodicalIF":19.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009195","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}
引用次数: 0
Pharmacological Approaches to Hearing Loss. 听力损失的药物治疗方法。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.001195
Christopher R Cederroth, Jonas Dyhrfjeld-Johnsen, Barbara Canlon
{"title":"Pharmacological Approaches to Hearing Loss.","authors":"Christopher R Cederroth, Jonas Dyhrfjeld-Johnsen, Barbara Canlon","doi":"10.1124/pharmrev.124.001195","DOIUrl":"10.1124/pharmrev.124.001195","url":null,"abstract":"<p><p>Hearing disorders pose significant challenges to individuals experiencing them and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches to address these conditions. Current treatment options often focus on amplification devices, cochlear implants, or other rehabilitative therapies, leaving a substantial gap regarding effective pharmacological interventions. Advancements in our understanding of the molecular and cellular mechanisms involved in hearing disorders induced by noise, aging, and ototoxicity have opened new avenues for drug development, some of which have led to numerous clinical trials, with promising results. The development of optimal drug delivery solutions in animals and humans can also enhance the targeted delivery of medications to the ear. Moreover, large genome studies contributing to a genetic understanding of hearing loss in humans combined with advanced molecular technologies in animal studies have shown a great potential to increase our understanding of the etiologies of hearing loss. The auditory system exhibits circadian rhythms and temporal variations in its physiology, its vulnerability to auditory insults, and its responsiveness to drug treatments. The cochlear clock rhythms are under the control of the glucocorticoid system, and preclinical evidence suggests that the risk/benefit profile of hearing disorder treatments using chronopharmacological approaches would be beneficial. If translatable to the bedside, such approaches may improve the outcome of clinical trials. Ongoing research into the molecular and genetic basis of auditory disorders, coupled with advancements in drug formulation and delivery as well as optimized timing of drug administration, holds great promise of more effective treatments. SIGNIFICANCE STATEMENT: Hearing disorders pose significant challenges to individuals and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches to address these conditions. Ongoing research into the molecular and genetic basis of auditory disorders, coupled with advancements in drug delivery procedures and optimized timing of drug administration, holds the promise of more effective treatments.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"1063-1088"},"PeriodicalIF":19.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009196","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}
引用次数: 0
Drug-Drug Interactions and Synergy: From Pharmacological Models to Clinical Application. 药物之间的相互作用和协同作用:从药理学模型到临床应用。
IF 19.3 1区 医学
Pharmacological Reviews Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.000951
Luigino Calzetta, Clive Page, Maria Gabriella Matera, Mario Cazzola, Paola Rogliani
{"title":"Drug-Drug Interactions and Synergy: From Pharmacological Models to Clinical Application.","authors":"Luigino Calzetta, Clive Page, Maria Gabriella Matera, Mario Cazzola, Paola Rogliani","doi":"10.1124/pharmrev.124.000951","DOIUrl":"10.1124/pharmrev.124.000951","url":null,"abstract":"<p><p>This review explores the concept of synergy in pharmacology, emphasizing its importance in optimizing treatment outcomes through the combination of drugs with different mechanisms of action. Synergy, defined as an effect greater than the expected additive effect elicited by individual agents according to specific predictive models, offers a promising approach to enhance therapeutic efficacy while minimizing adverse events. The historical evolution of synergy research, from ancient civilizations to modern pharmacology, highlights the ongoing quest to understand and harness synergistic interactions. Key concepts, such as concentration-response curves, additive effects, and predictive models, are discussed in detail, emphasizing the need for accurate assessment methods throughout translational drug development. Although various mathematical models exist for synergy analysis, selecting the appropriate model and software tools remains a challenge, necessitating careful consideration of experimental design and data interpretation. Furthermore, this review addresses practical considerations in synergy assessment, including preclinical and clinical approaches, mechanism of action, and statistical analysis. Optimizing synergy requires attention to concentration/dose ratios, target site localization, and timing of drug administration, ensuring that the benefits of combination therapy detected bench-side are translatable into clinical practice. Overall, the review advocates for a systematic approach to synergy assessment, incorporating robust statistical analysis, effective and simplified predictive models, and collaborative efforts across pivotal sectors, such as academic institutions, pharmaceutical companies, and regulatory agencies. By overcoming critical challenges and maximizing therapeutic potential, effective synergy assessment in drug development holds promise for advancing patient care. SIGNIFICANCE STATEMENT: Combining drugs with different mechanisms of action for synergistic interactions optimizes treatment efficacy and safety. Accurate interpretation of synergy requires the identification of the expected additive effect. Despite innovative models to predict the additive effect, consensus in drug-drug interactions research is lacking, hindering the bench-to-bedside development of combination therapies. Collaboration among science, industry, and regulation is crucial for advancing combination therapy development, ensuring rigorous application of predictive models in clinical settings.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"1159-1220"},"PeriodicalIF":19.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620614","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}
引用次数: 0
Biochemistry, pharmacology and in vivo function of arginases. 精氨酸酶的生物化学、药理学和体内功能。
IF 21.1 1区 医学
Pharmacological Reviews Pub Date : 2024-10-15 DOI: 10.1124/pharmrev.124.001271
Sophia K Heuser,Junjie Li,Silke Pudewell,Anthea LoBue,Zhixin Li,Miriam M Cortese-Krott
{"title":"Biochemistry, pharmacology and in vivo function of arginases.","authors":"Sophia K Heuser,Junjie Li,Silke Pudewell,Anthea LoBue,Zhixin Li,Miriam M Cortese-Krott","doi":"10.1124/pharmrev.124.001271","DOIUrl":"https://doi.org/10.1124/pharmrev.124.001271","url":null,"abstract":"Arginase catalyzes the hydrolysis of L-arginine into L-ornithine and urea. The two existing isoforms Arg1 and Arg2 show different cellular localizations and metabolic functions. Arginase activity is crucial for nitrogen detoxification in the urea cycle, synthesis of polyamines, and control of l-arginine bioavailability and nitric oxide production. Despite significant progress in the understanding of the biochemistry and function of arginases, several open questions remain. Recent studies have revealed that the regulation and function of Arg1 and Arg2 are cell-type-specific, species-specific, and profoundly different in mice and humans. The main differences were found in the distribution and function of Arg1 and Arg2 in immune and erythroid cells. Contrary to what was previously thought, Arg1 activity appears to be only partially related to vascular NO signaling under homeostatic conditions in the vascular wall, but its expression is increased under disease conditions and may be targeted by treatment with arginase inhibitors. Arg2 appears to be mainly a catabolic enzyme involved in the synthesis of L-ornithine, polyamine, and proline but may play a putative role in blood pressure control, at least in mice. The immunosuppressive role of arginase-mediated arginine depletion is a promising target for cancer treatment. This review critically revises and discusses the biochemistry, pharmacology, and in vivo function of arginase, focusing on the insights gained from the analysis of cell-specific Arg1 and Arg2 knockout mice and human studies using arginase inhibitors or pegylated recombinant arginase. Significance Statement The review emphasizes the need for further research to deepen our understanding of the regulation of Arg1 and Arg 2 in different cell types under consideration of their localization, species-specificity, and multiple biochemical and physiological roles. This could lead to better pharmacological strategies to target arginase activity in liver, cardiovascular, hematological, immune/infection diseases and cancer.","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"89 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443713","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}
引用次数: 0
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