Pharmacological Reviews最新文献

{"title":"Pharmacology and therapeutics of bile acid synthesis and modification enzymes in metabolic diseases.","authors":"Lili Ding, Lihua Jin, Wendong Huang","doi":"10.1016/j.pharmr.2026.100115","DOIUrl":"10.1016/j.pharmr.2026.100115","url":null,"abstract":"<p><p>Bile acids (BAs) are mainly synthesized in the liver as end products of cholesterol catabolism through the classic (neutral) and alternative (acidic) pathways. BA synthesis requires a coordinated series of enzymes, in which CYP7A1 catalyzes the rate-limiting step, whereas CYP8B1 determines the proportion of the 2 primary BAs-cholic acid and chenodeoxycholic acid. Enterohepatic circulation of BAs is essential not only for nutrient absorption but also for maintaining systemic metabolic homeostasis. The expanding catalog of BA-responsive receptors throughout the gastrointestinal tract and peripheral metabolic tissues underscores the hormone-like nature of BAs in metabolic regulation. Moreover, dynamic and bidirectional interactions between BAs and the gut microbiota introduce an additional layer of complexity that shapes physiological and pathological metabolic processes. Targeting BA synthesis and microbial modification offers substantial therapeutic potential for a wide spectrum of metabolism-related diseases. SIGNIFICANCE STATEMENT: Bile acids (BAs) comprise a large family of endogenous steroid metabolites with diverse chemical structures. They can activate or inhibit a panel of BA-responsive receptors to elicit distinct cellular signaling programs integral to metabolic regulation. Their reciprocal interactions with gut microbiota further amplify the complexity of host metabolic control. Therapeutic strategies that modulate BA synthesis and microbial BA transformation, leveraging both BA synthesis enzymes and microbial partners, hold great promise for treating metabolic disorders.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100115"},"PeriodicalIF":20.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13084608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195279","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":"Pharmacological modulation of the blood-brain barrier: Mechanisms, therapeutic strategies, and emerging technologies.","authors":"Iosif Pediaditakis, Serena Tsakali, Maddie R Lemieux, Matthew Brennan, William H Robinson, Spyridon Papapetropoulos, Andreas Papapetropoulos","doi":"10.1016/j.pharmr.2026.100118","DOIUrl":"10.1016/j.pharmr.2026.100118","url":null,"abstract":"<p><p>The blood-brain barrier (BBB) is a specialized vascular interface that safeguards central nervous system homeostasis by tightly regulating molecular exchange between blood and the brain. While essential for neuroprotection, its restrictive permeability limits therapeutic access, and its dysfunction is increasingly recognized as a driver of pathology across neurodegenerative, inflammatory, cerebrovascular, traumatic, and rare genetic disorders. In this review, we provide a comprehensive overview of pharmacological strategies to modulate BBB function, linking mechanistic insights into tight junction dynamics, transporter networks, endothelial-pericyte interactions, and immune crosstalk to emerging therapeutic approaches. We discuss interventions ranging from small molecules, peptides, and biologics to nanocarriers, noninvasive technologies, gene therapy, and stem cell-based strategies, highlighting their applications in 2 key translational contexts: transient enhancement of drug delivery and restoration of barrier integrity in disease. Ongoing challenges include ensuring safety, accounting for patient heterogeneity, and addressing the limitations of current experimental models. Finally, we consider how advances in BBB-on-chip systems, patient-specific induced pluripotent stem cell-derived models, and novel molecular targets are accelerating translation. Collectively, pharmacological modulation of the BBB, whether by reversible opening to enhance delivery or by reinforcing its protective function, represents a transformative frontier in central nervous system therapy. SIGNIFICANCE STATEMENT: The blood-brain barrier (BBB) is both a vital safeguard of neural homeostasis and a central obstacle to drug development in the central nervous system. This review integrates mechanistic insights into BBB regulation with translational advances in pharmacology and biotechnology, highlighting strategies that restore barrier integrity in disease and enhance therapeutic delivery. Emerging approaches, including gene therapy, nanotechnology, stem cell-based interventions, and next-generation human-relevant BBB models, illustrate how pharmacological innovation can overcome longstanding challenges and expand therapeutic access to the brain.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 2","pages":"100118"},"PeriodicalIF":20.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158062","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":"Metformin-mechanisms of its glycemia-reducing effect.","authors":"Jürgen Drewe, Marc Foretz, Stephan Krähenbühl","doi":"10.1016/j.pharmr.2025.100106","DOIUrl":"10.1016/j.pharmr.2025.100106","url":null,"abstract":"<p><p>Metformin currently serves as the basis of oral treatment for patients with type 2 diabetes. While metformin's effect on glycemia is well established, its mode of action remains unclear. In clinical studies, long-term metformin treatment improved glucose disposal and reduced hepatic gluconeogenesis. The effects on gluconeogenesis have been confirmed in experimental animals and cell preparations, but mostly at higher doses than those used in humans. Proposed hepatic mechanisms can be grouped into those with and without AMP-activated protein kinase (AMPK) activation; the latter include inhibition of mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase. Experimental studies on the effects of metformin on skeletal muscles suggest that AMPK activation and anti-inflammatory activities are possible mechanisms for increasing glucose disposal. Inhibition of renal gluconeogenesis may contribute to the extraintestinal glycemia-lowering effects of metformin. Following the observation that short-term intravenous metformin lacks glycemia-lowering effects in humans, intestinal mechanisms have been investigated. Suggested mechanisms include inhibition of intestinal glucose absorption owing to increased glycolysis driven by complex I inhibition in the mitochondria of enterocytes, stimulation of glucose transport into the colon, and stimulation of glucagon-like peptide-1 (GLP-1) secretion. Intestinal GLP-1 activates the gut-brain-liver axis, which impairs hepatic gluconeogenesis through vagal stimulation. Metformin can enhance intestinal GLP-1 secretion by L-cells directly through AMPK activation via complex I inhibition or indirectly by increasing the availability of glucose, bile acids, and/or metabolites produced by intestinal bacteria. Thus, metformin improves muscle glucose disposal, reduces gluconeogenesis, and has several intestinal effects that impact glycemia. Inhibition of mitochondrial complex I in different organs appears to be an important mechanism of metformin's glucose-lowering effect. SIGNIFICANCE STATEMENT: Most previous studies on the mechanism of metformin's glycemia-reducing effect focused on inhibition of hepatic gluconeogenesis. However, clinical studies show that increased glucose transport into skeletal muscle is at least as important. Furthermore, recent studies suggest that intestinal effects, including inhibition of glucose absorption, stimulation of the gut-liver and gut-brain-liver axes, and changes in the intestinal microbiota, contribute to metformin's glycemia-lowering effect. Thus, metformin's glycemia-reducing effect is multifactorial, affecting glucose metabolism in the gut, liver, and skeletal muscle.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 1","pages":"100106"},"PeriodicalIF":17.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752031","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":"Edaravone: Advances on cytoprotective effects, pharmacological properties, and mechanisms of action.","authors":"Fatima Dakroub, Bassel Awada, Samar Abdelhady, Abdullah A Shaito, Ali H Eid, Joseph Walker, Stefania Mondello, Corina O Bondi, Federico Moro, Bahaa Elgendy, Kevin K Wang, Elisa R Zanier, Yehia Mechref, Firas Kobeissy","doi":"10.1016/j.pharmr.2025.100101","DOIUrl":"10.1016/j.pharmr.2025.100101","url":null,"abstract":"<p><p>Neurological diseases often lead to life-altering consequences, underscoring the urgent need for therapies that can reverse or mitigate their effects. Effective management of neurological disorders necessitates a thorough understanding of the common pathological mechanisms driving their onset and progression. Mitochondrial dysfunction and oxidative stress stand out as critical contributors to neuronal damage, implicated in traumatic brain injury, stroke, and amyotrophic lateral sclerosis. Disruptions in energy metabolism lead to the accumulation of reactive oxygen species and elevate the level of neural injury. Moreover, these imbalances disrupt cellular homeostasis and activate apoptotic pathways, further exacerbating neuronal loss and ultimately worsening the clinical prognosis. In this context, edaravone (Eda), a Food and Drug Administration-approved free radical scavenger, has emerged as a compelling candidate for the treatment of neuropathologies. This review provides a comprehensive overview of Eda, detailing its chemical structure and pharmacokinetic profile, with a focus on strategies to enhance its delivery to the central nervous system by modulating blood-brain barrier permeability or employing delivery systems that facilitate central nervous system penetration. Moreover, the review examines Eda's pharmacodynamic properties, including the signaling pathways it influences. The neurotherapeutic potential of Eda is further examined through in vitro and in vivo models of neurological disease. Insights from clinical trials are discussed to bridge the gap between preclinical findings and patient outcomes. Finally, the review highlights the synergistic effects of combining Eda with other pharmacological agents or therapeutic interventions, underscoring its promise as a versatile and indispensable treatment for neurological disorders. SIGNIFICANCE STATEMENT: Edaravone, a Food and Drug Administration-approved free radical scavenger, shows broad neuroprotective potential by mitigating oxidative stress and mitochondrial dysfunction across diverse neurological disorders, including stroke, amyotrophic lateral sclerosis, and traumatic brain injury. By synthesizing preclinical and clinical evidence, this review highlights edaravone's pleiotropic therapeutic actions, identifies translational challenges, and underscores its promise as a versatile treatment strategy for neurodegenerative and acute and chronic brain conditions.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 1","pages":"100101"},"PeriodicalIF":20.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605401","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":"Genetic therapies for neurological diseases.","authors":"Ahad A Rahim, Manju A Kurian, Haiyan Zhou, Ross Ferguson, Sarah J Tabrizi, Gabriele Lignani, Kristian Aquilina, Simon N Waddington","doi":"10.1016/j.pharmr.2025.100093","DOIUrl":"10.1016/j.pharmr.2025.100093","url":null,"abstract":"<p><p>Often, gene therapy reviews concentrate upon specific therapeutic modalities-particularly either viral vector-mediated or a nonviral approach. Here, we draw together a comprehensive array of knowledge across the field of genetic therapy for genetic neurological disease. The sections on preclinical and clinical application of viral vectors are followed by sections on RNA-based therapies and then by antisense oligonucleotide approaches also in preclinical and clinical settings. We present a separate section on gene editing strategies and conclude with a section elaborating on the neurosurgical techniques and the expertise required for clinical application of many of these technologies. SIGNIFICANCE STATEMENT: Genetic therapies have significant potential to treat life-limiting neurological diseases. This review examines the different approaches, clinical successes, and considerations on how to deploy them.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 1","pages":"100093"},"PeriodicalIF":17.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12881687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752018","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":"Leading artificial intelligence-driven drug discovery platforms: 2025 landscape and global outlook.","authors":"Mahendiran Dharmasivam, Busra Kaya, Adedoyin Akinware, Mahan Gholam Azad, Des R Richardson","doi":"10.1016/j.pharmr.2025.100102","DOIUrl":"10.1016/j.pharmr.2025.100102","url":null,"abstract":"<p><p>Artificial intelligence (AI) has progressed from experimental curiosity to clinical utility, with AI-designed therapeutics now in human trials across diverse therapeutic areas. This review critically compares 5 leading AI-driven discovery platforms: generative chemistry, phenomics-first systems, integrated target-to-design pipelines, knowledge-graph repurposing, and physics-plus-machine learning design. Key developments since 2024 include positive phase IIa results for Insilico Medicine's Traf2- and Nck-interacting kinase inhibitor, ISM001-055, in idiopathic pulmonary fibrosis. Another key development was the Recursion-Exscientia merger, which integrated phenomic screening with automated precision chemistry into a full end-to-end platform. In addition, advancement of the Nimbus-originated tyrosine kinase 2 inhibitor, zasocitinib (TAK-279), into phase III clinical trials exemplifies Schrödinger's physics-enabled design strategy reaching late-stage clinical testing. Emerging platforms such as Insitro, Isomorphic Labs, Atomwise, and XtalPi illustrate the field's expanding geographic and technical footprint. SIGNIFICANCE STATEMENT: Artificial intelligence (AI) is reshaping pharmacology by shortening discovery timelines, potentially reducing attrition, and expanding the design space of therapeutic candidates. Alongside technical milestones, regulatory and ethical frameworks from the US Food and Drug Administration and European Medicines Agency are beginning to address transparency, bias, accountability, intellectual property, and data privacy. Robotics tightly integrated with AI now enables self-driving laboratories that accelerate design-make-test-learn cycles and improve reproducibility. Together, these advances chart a forward-looking roadmap in which multimodal foundation models, robotics-led platforms, and hybrid physics-AI strategies are poised to accelerate translation, derisk development, and establish trustworthy AI as a cornerstone of modern drug discovery.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 1","pages":"100102"},"PeriodicalIF":17.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752013","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":"Modeling lung transporters and their influence on inhaled drug disposition.","authors":"Shekhar Yeshwante, Ramya Mahadevan, Olagoke Sule, Jacqueline B Tiley, Courtney L Luterbach, Sean McCann, John K Fallon, Philip C Smith, Ming-Liang Tan, Ross Walenga, Bryan Newman, Liang Zhao, Martina Gentzsch, Charles R Esther, Gauri G Rao","doi":"10.1016/j.pharmr.2025.100100","DOIUrl":"10.1016/j.pharmr.2025.100100","url":null,"abstract":"<p><p>Administering drugs via inhalational routes is an attractive approach for treating respiratory diseases. Effective lung delivery provides a rapid therapeutic effect, minimizes systemic toxicities, and enhances overall public health responses, particularly for orally inhaled products during pandemics. However, assessing the pharmacokinetic (PK) properties of inhaled agents within the airway is challenging. In silico modeling, especially using physiologically based pharmacokinetic (PBPK) models, has emerged as a crucial clinical translational tool that integrates in vitro, in vivo, and ex vivo lung model data to improve predictions of lung exposure for inhaled drugs. Developing effective PBPK models requires a deeper understanding of the factors influencing drug disposition. Membrane transporters can significantly impact airway PKs, but there is a knowledge gap regarding their role and expression within the human airways. This review explores the following: (1) preclinical and clinical studies on lung transporter localization, expression, and their potential impact on the PKs of inhaled drugs; (2) conflicting data on transporter expression and localization; and (3) factors influencing transporter expression, such as inflammatory processes and diseases. We summarize the transporters involved in inhaled drug disposition, drug-specific parameters, and current PBPK models and approaches that account for transporter involvement. Only a few studies quantify transporter protein levels in the lung, particularly for respiratory diseases, limiting the ability to incorporate lung expression levels to inform the development of enhanced PBPK models. Overall, a comprehensive understanding of lung transporters and their impact on drug disposition is crucial for estimating and optimizing model-informed dosing of inhaled therapeutics. SIGNIFICANCE STATEMENT: Inhaled drugs are ideal for treating respiratory diseases because they increase drug exposure in the lungs and minimize off-target effects. Speeding up their approval, development, and dosing relies on accurate computational models. This review examines improving these models by integrating knowledge about lung transporters, focusing on understanding, characterizing, and quantifying these transporters and their influence on drug disposition.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 1","pages":"100100"},"PeriodicalIF":17.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145637260","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":"Platelet activation, aspirin, and cancer: From basic science to clinical trials.","authors":"Carlo Patrono, John Burn, Paola Patrignani, Ruth E Langley","doi":"10.1016/j.pharmr.2025.100109","DOIUrl":"10.1016/j.pharmr.2025.100109","url":null,"abstract":"<p><p>There is extensive evidence that aspirin prevents cancer, but the mechanism of action is uncertain. Once-daily low-dose aspirin (75-100 mg) completely and permanently inactivates the cyclooxygenase (COX) activity of prostaglandin G/H synthase-1 (COX-1) in platelets, suppressing thromboxane (TX)A₂-dependent platelet activation. In this article, we review the mechanistic links between platelet activation, inflammation, cancer development, and progression and summarize recent clinical trial results and associated biomarker studies. We hypothesize that persistently enhanced platelet activation has 2 distinct tumorigenic consequences mediated by the release of TXA₂: (1) at sites of gastrointestinal mucosal lesions, it promotes a local inflammatory response with COX-2 induction and enhanced prostaglandin E₂ biosynthesis, contributing to early events in carcinogenesis; (2) it inhibits T-cell immunity to cancer by the activation of TXA₂ receptors in lymphocytes, promoting cancer progression and metastasis dissemination. Supporting these hypotheses, abnormal and persistent platelet activation has been demonstrated in patients recently diagnosed with cancer and in those with adenomatous colonic polyps. To date, most clinical trials evaluating aspirin have focused on either primary cancer prevention, metastasis prevention (adjuvant treatment), or cardiovascular prevention. For an individual, benefits may accrue from one (or all) of these areas, and they collectively need to be balanced against bleeding risk. Collating large clinical datasets for meta-analysis alongside mechanistic studies will inform the interpretation of clinical trials, with the aim of identifying individuals most likely to benefit from aspirin. SIGNIFICANCE STATEMENT: We reviewed the experimental and clinical evidence supporting a previously unrecognized role of platelet activation in both the early stage of colorectal carcinogenesis and in cancer progression and metastasis. The findings support the use of low-dose aspirin in cancer prevention and treatment. Data from large randomized clinical trials support the use of aspirin for the prevention of Lynch syndrome cancers and in the adjuvant setting for patients with colorectal cancer whose tumors have a mutation in the phosphatidylinositol 3-kinase pathway genes. Although thromboxane A₂-dependent platelet activation is the most thoroughly investigated mechanism and the established drug target of the antiplatelet effect of low-dose aspirin, it seems biologically plausible that other pathways of platelet activation, such as the ADP-P2Y₁₂ pathway, may play a similar and possibly complementary role.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 1","pages":"100109"},"PeriodicalIF":20.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7619208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146065916","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":"Waking up to the evidence of pharmacological treatments used to manage sleep disorders in people with dementia and mild cognitive impairment-A scoping review.","authors":"Bandana Saini, Shawn D X Kong, Zoe Menczel Schrire, Laura H Jacobson, Ron Grunstein, Sharon L Naismith","doi":"10.1016/j.pharmr.2025.100094","DOIUrl":"10.1016/j.pharmr.2025.100094","url":null,"abstract":"<p><p>Sleep disturbance is increasingly recognized as a viable prevention target that could lower dementia risk. While a wide range of pharmacological options exist to manage sleep disturbance in people living with dementia, their use often does not adherent to the quality use of medicine. The complex nature of dementia as a syndrome often requires drugs that target multiple complaints (eg, sleep, cognition, and mood) and thus could produce psychological and physiological side effects that have the potential to do more harm than confer benefits. Therefore, this review first provides an expert narration of the pharmacology of sleep and the mechanisms of agents used to treat sleep disturbance. Then, a systematic scoping review was conducted to analyze evidence from studies over the past 10 years, which examined various pharmacological agents used for sleep disturbance in people living with dementia. SIGNIFICANCE STATEMENT: Sleep disturbances are a common consequence of the neurodegenerative changes occurring in dementia syndromes. They may also be etiologically linked to its development and progression. This review summarizes the pharmacological basis of sleep and collates the impact of medications used for dementia or sedatives on sleep and cognition outcomes. The review highlights gaps in research and will provide clinicians with key information required to make decisions about the quality use of medications to improve sleep health in those with dementia.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 1","pages":"100094"},"PeriodicalIF":17.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145605443","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":"Synergistic combinations of antimicrobial peptides and conventional antibiotics: A strategy to delay resistance emergence in World Health Organization priority bacteria.","authors":"Cesar Augusto Roque-Borda, Qi Zhang, Thi Phuong Truc Nguyen, Thi Thu Hoai Nguyen, Himadri Medhi, Heitor Leocádio de Souza Rodrigues, Christian S Canales Carnero, Darcy Sutherland, Naiera M Helmy, Prasanna Babu Araveti, Beatriz G de la Torre, Fernando Albericio, Fernando Rogério Pavan","doi":"10.1016/j.pharmr.2025.100104","DOIUrl":"10.1016/j.pharmr.2025.100104","url":null,"abstract":"<p><p>Antimicrobial resistance represents one of the most pressing global health challenges of the 21st century, significantly compromising the efficacy of conventional antibiotics. In response to this crisis, the World Health Organization has updated its 2024 list of priority bacterial pathogens-classified into critical-, high-, and medium-risk groups-based on their resistance mechanisms, clinical impact, and global dissemination. This comprehensive review explores the emerging therapeutic potential of antimicrobial peptides (AMPs) when used in synergistic combinations with conventional antibiotics. By dissecting the mechanistic interplay-ranging from membrane disruption and efflux pump inhibition to biofilm penetration and intracellular antibiotic delivery-we provide a structured analysis of how these dual strategies overcome specific resistance barriers. Special emphasis is given to the World Health Organization-designated pathogens such as Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus (methicillin-resistant/vancomycin-resistant), Enterococcus faecium, Salmonella spp., Shigella spp., and Mycobacterium tuberculosis. Supported by extensive in vitro and in vivo data, this review catalogs dozens of successful AMP-antibiotic pairings, highlighting their fractional inhibitory concentration indices, clinical relevance, and implications for translational development. The evidence presented demonstrates that AMPs not only potentiate antibiotic action but also extend the useful lifespan of existing drugs while reducing toxicity. These findings support the advancement of AMP-based combination therapies as a next-generation strategy to contain resistance and restore the effectiveness of the antimicrobial arsenal. SIGNIFICANCE STATEMENT: Antimicrobial resistance remains a global health emergency, especially among World Health Organization 2024 priority pathogens. This review highlights the therapeutic promise of synergistic combinations between antimicrobial peptides and conventional antibiotics, offering a rational strategy to restore efficacy, overcome resistance mechanisms, and extend the clinical utility of existing drugs. By bridging microbiology, pharmacology, and translational medicine, this work provides timely insights for researchers and policymakers seeking innovative solutions to combat multidrug-resistant infections.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"78 1","pages":"100104"},"PeriodicalIF":17.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752004","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}