Pharmacological Reviews最新文献

The therapeutic value of placebo analgesia to treat conditions of chronic pain is both underappreciated and understudied. It is now abundantly clear that chronic pain is caused by a complex array of biological adaptations, including changes to neural, endocrine, and immune function, which undoubtedly explains why it is so difficult to treat. Paradoxically, however, this also presents a unique opportunity for placebo interventions by offering several biological targets that could lead to analgesic relief for chronic pain patients. In this review, we first outline the problem of chronic pain, highlighting the similarities and differences between acute and chronic pain mechanisms. Next, we comprehensively review studies investigating the neurobiological and neuropharmacological mechanisms underlying placebo analgesia in acute and chronic pain contexts. We conclude that the neural mechanisms and neuropharmacology of placebo analgesia in the context of chronic pain are currently poorly understood and deserve specific focus for future research. Finally, we discuss the range of therapeutic possibilities for placebo interventions to provide clinically relevant and meaningful pain relief to chronic pain patients, many of which could be quickly, easily, and ethically implemented into clinical practice today. SIGNIFICANCE STATEMENT: Chronic pain remains a significant global health challenge as it is often resistant to conventional treatments. This review synthesizes our current knowledge of the neurobiology of acute and chronic pain and highlights key overlaps in the mechanisms of placebo analgesia. We highlight how placebo-based strategies, including expectancy modulation, pharmacological conditioning, and open-label placebos, could be ethically integrated into clinical practice to enhance pain management. These approaches offer a promising avenue to activate endogenous pain relief systems, reduce opioid reliance, and personalize treatment for both placebo responders and nonresponders. Harnessing placebo mechanisms presents a largely underused yet promising approach to chronic pain management, with the potential to refine existing treatment strategies and address the global burden of chronic pain.

Familial hypercholesterolemia (FH) is a hereditary disorder with a semidominant inheritance pattern, characterized by elevated levels of low-density lipoprotein cholesterol, which significantly increases the risk of early atherosclerosis-related cardiovascular disease. This review discusses the genetics, epidemiology, diagnosis, and novel therapeutic approaches for FH. Mutations in the LDL receptor gene are the primary cause of FH. Less common causes include mutations in proprotein convertase subtilisin/kexin type 9 and apolipoprotein B-100. In extremely rare cases, LDLR adaptor protein 1 mutations can also cause FH. Epidemiological data indicate that FH is frequently underdiagnosed, particularly within certain ethnic populations. Diagnostic criteria often rely on clinical manifestations and family history, although genetic testing is increasingly advocated for confirmation. Recent advancements in pharmacotherapy offer substantial opportunities for effective low-density lipoprotein cholesterol control and management of FH, providing new hope for affected patients. This includes established drugs such as proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, lomitapide, and bempedoic acid. Emerging therapies include evinacumab, lerodalcibep, antisense oligonucleotide-based drugs, certain cholesteryl ester transfer protein inhibitors like obicetrapib, AZD8233, gemcabene, diacylglycerol O-acyltransferase-2 inhibitors, acyl-CoA:cholesterol acyltransferase-2 inhibitors, vupanorsen, volanesorsen, olezarsen, pelacarsen (TQJ230), olpasiran (AMG890), zerlasiran (SLN360), lepodisiran (LY3819469), and muvalaplin. However, some of these newer agents are specifically designed to lower elevated Lp(a), which often occurs in patients with FH, and triglycerides. Furthermore, gene-editing approaches, such as clustered regularly interspaced short palindromic repeats -Cas9 and meganuclease, as well as vaccines targeting key components of cholesterol metabolism, represent promising future directions for FH treatment. SIGNIFICANCE STATEMENT: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol levels, which increase the risk of atherosclerotic cardiovascular disease. Conventional therapies, such as statins, often have limited efficacy in patients with FH. Recent pharmacological advancements provide significant opportunities for successful low-density lipoprotein cholesterol management and control of FH. Although some of these agents are already used, several highly effective compounds are in development, heralding a promising future for FH treatment.

Carbon dots (CDs), a remarkable class of novel nanomaterials, have attracted significant attention in the biomedical field owing to their extraordinary chemical, physical, and biological properties. Among their diverse applications, CDs stand out as highly promising nanocarriers for drug delivery owing to their ability to cross cell membranes efficiently and deliver therapeutic agents directly to damaged cells or tissues. What makes CDs truly unique is their intrinsic photoluminescence and the abundance of reactive groups on their surface, allowing for extensive multifunctionalization. This versatility enables the conjugation of various functional groups, therapeutic molecules, biomolecules, and targeting ligands, paving the way for an integrated approach to diagnosis and therapy. This review highlights the latest advancements in the application of CDs for drug delivery, focusing on their use in anticancer and antiviral therapies, as well as in the treatment of osteoarticular diseases and neurological disorders. Particular attention is given to the critical aspects of biocompatibility and toxicity, which remain key challenges for their translation into clinical practice. These promising developments position CDs as cutting-edge tools in nanopharmacology, offering exciting opportunities for future therapeutic innovations. SIGNIFICANCE STATEMENT: Carbon dots represent a transformative class of nanomaterials whose tunable chemistry, intrinsic photoluminescence, and high biocompatibility make them highly promising for next-generation drug delivery. By enabling targeted, multifunctional, and trackable therapeutic strategies across cancer, viral infections, osteoarticular, and neurological diseases, carbon dots offer a unique platform that bridges diagnostics and therapy, with the potential to significantly advance precision medicine while addressing current limitations of conventional drug carriers.

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.

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.

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.

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.

In 2015, we coined the term "Resolution Pharmacology" to indicate how the biology of the resolution of inflammation could, and should, be harnessed to produce novel therapeutics. Here we update these concepts and discuss the most recent developments in this innovative field of pharmacology. We begin by discussing how the inflammatory response is lifesaving through the engagement, expression, and function of several mediators, which have been labeled as proinflammatory or proresolving mediators. In reality, they act in concert and regulate each other in a fully integrated fashion, so that the notion between inflammation onset and inflammation resolution, as 2 distinct phases, is mainly didactic and temporal. Moreover, the observation that the inflammatory reaction that our body mounts always, or nearly always, resolves indicate that inflammation resolution is a robust process. What remain to be addressed, though, is how to harness the biology of acute resolving inflammation so that innovative therapeutic options can be offered for the clinical management of chronic nonresolving inflammation. The holistic view of physiological inflammation, and its disruption in pathology, comes with implications in relation to the application of Resolution Pharmacology. We predict resolution-based drugs will work better in presence of a florid inflammatory status, which would augment expression of resolution targets. We conclude by proposing a renovated focus on endogenous tissue-protective regenerative pathways by specific targets for drug development programs: Resolution Pharmacology remains an untapped opportunity for the pharmaceutical industry. SIGNIFICANCE STATEMENT: The process of the resolution of inflammation represents an integral part of the whole acute inflammatory response. A florid inflammatory reaction ensures proper engagement of resolution mechanisms. Dysregulation in resolution mechanisms can lead to disease. Conversely, harnessing resolution can offer therapeutic guidance to develop medicines that are disease independent, broadening their potential. There is ongoing intensive clinical development in this area. Proresolving drugs will be patient centric in their pharmacology and would promote natural processes of healing and repair.

Transient receptor potential (TRP) channels represent an extensive and diverse protein family fulfilling salient roles as versatile cellular sensors and effectors. The pivotal role of TRP and related ion channels in sensory processes has been well documented. Over the last few years, a new concept has emerged that TRP proteins control an exceptionally broad spectrum of homeostatic physiological functions such as maintenance of body temperature, blood pressure, transmitter release from neurons, mineral and energy homeostasis, and reproduction. This notion is further supported by more than 20 hereditary human diseases in areas as diverse as neurology, cardiology, hematology, pulmonology, nephrology, dermatology, and urology. Most TRP channel-related human disorders impinge on development, metabolism, and other homeostatic functions. The remarkable diversity of pathologies caused by TRP channel dysfunction underscores these proteins' broad spectrum of roles in vivo. Here, we provide a comprehensive overview of our progress in the identification, characterization, and clinical relevance of pharmacological agents targeting mammalian TRP channels. SIGNIFICANCE STATEMENT: Accumulating evidence links transient receptor potential (TRP) channels to various human diseases and highlights TRPs as the most appealing pharmacological targets. The review provides an overview of this quickly developing research area, focusing on identified pharmacological modulators of mammalian TRP channels.