Current Opinion in Pharmacology最新文献

{"title":"Novel treatments for dry eye syndrome","authors":"Esther Roucaute ,&nbsp;Marcela Huertas-Bello ,&nbsp;Alfonso L. Sabater","doi":"10.1016/j.coph.2024.102431","DOIUrl":"10.1016/j.coph.2024.102431","url":null,"abstract":"<div><p>Dry eye syndrome (DES) is a prevalent and multifactorial disease that leads to a self-perpetuating cycle of inflammation and damage to the ocular surface. This results in symptoms such as redness, burning, and blurred vision, which can negatively affect a patient's quality of life. While treatments are available to manage DES, they only temporarily relieve symptoms. Furthermore, long-term use of certain medications can cause harm to the ocular surface. Therefore, there is a need for safer and effective treatments for DES. This review highlights the latest advancements in DES therapy, providing valuable insights into ongoing efforts to improve patient outcomes.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"75 ","pages":"Article 102431"},"PeriodicalIF":4.0,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139567295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analgesic potential of voltage gated sodium channel modulators for the management of pain","authors":"Jason J. McDougall,&nbsp;Melissa S. O'Brien","doi":"10.1016/j.coph.2024.102433","DOIUrl":"10.1016/j.coph.2024.102433","url":null,"abstract":"<div><p>Neuronal electrochemical signals involve the flux of sodium ions through voltage-gated sodium channels (Na_V) located in the neurolemma. Of the nine sodium channel subtypes, Na_V-1.7, 1.8, and 1.9 are predominantly located on nociceptors, making them prime targets to control pain. This review highlights some of the latest discoveries targeting Na_V channel activity, including: (1) charged local anaesthetic derivatives; (2) Na_V channel toxins and associated small peptide blockers; (3) regulation of Na_V channel accessory proteins; and (4) genetic manipulation of Na_V channel function. While the translation of preclinical findings to a viable treatment in humans has remained a challenge, a greater understanding of Na_V channel physiology could lead to the development of a new stream of therapies aimed at alleviating chronic pain.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"75 ","pages":"Article 102433"},"PeriodicalIF":4.0,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1471489224000031/pdfft?md5=c9504924cde4ad710a2f60d171f937bb&pid=1-s2.0-S1471489224000031-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139554837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting ferroptosis in the maintenance of mitochondrial homeostasis in the realm of septic cardiomyopathy","authors":"Hua Ye ,&nbsp;Huantao Hu ,&nbsp;Xiaoliang Zhou ,&nbsp;Maolong Dong ,&nbsp;Jun Ren","doi":"10.1016/j.coph.2023.102430","DOIUrl":"https://doi.org/10.1016/j.coph.2023.102430","url":null,"abstract":"<div><p><span>Septic cardiomyopathy is one of the predominant culprit factors contributing to the rising mortality in patients with severe </span>sepsis<span><span><span>. Among various mechanisms responsible for the etiology of septic heart anomalies<span>, disruption of mitochondrial homeostasis has gained much recent attention, resulting in myocardial inflammation and even cell death. </span></span>Ferroptosis is a novel category of regulated cell death (RCD) provoked by iron-dependent </span>phospholipid peroxidation through iron-mediated phospholipid (PL) peroxidation, enroute to the rupture of plasma membranes and eventually cell death. This review summarizes the recent progress of ferroptosis in mitochondrial homeostasis during septic cardiomyopathy. We will emphasize the role of mitochondrial iron transport channels and the antioxidant system in ferroptosis. Finally, we will summarize and discuss future research, which should help guide disease treatment.</span></p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"74 ","pages":"Article 102430"},"PeriodicalIF":4.0,"publicationDate":"2024-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139487681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-driven GPCR analysis, engineering, and targeting","authors":"João P.L. Velloso ,&nbsp;Aaron S. Kovacs ,&nbsp;Douglas E.V. Pires ,&nbsp;David B. Ascher","doi":"10.1016/j.coph.2023.102427","DOIUrl":"https://doi.org/10.1016/j.coph.2023.102427","url":null,"abstract":"<div><p>This article investigates the role of recent advances in Artificial Intelligence (AI) to revolutionise the study of G protein-coupled receptors (GPCRs). AI has been applied to many areas of GPCR research, including the application of machine learning (ML) in GPCR classification, prediction of GPCR activation levels, modelling GPCR 3D structures and interactions, understanding G-protein selectivity, aiding elucidation of GPCRs structures, and drug design. Despite progress, challenges in predicting GPCR structures and addressing the complex nature of GPCRs remain, providing avenues for future research and development.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"74 ","pages":"Article 102427"},"PeriodicalIF":4.0,"publicationDate":"2024-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139434599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating network pharmacology: The next-generation approach in ocular drug discovery","authors":"Francesca Lazzara ,&nbsp;Federica Conti ,&nbsp;Erika Giuffrida ,&nbsp;Chiara Maria Eandi ,&nbsp;Filippo Drago ,&nbsp;Chiara Bianca Maria Platania ,&nbsp;Claudio Bucolo","doi":"10.1016/j.coph.2023.102425","DOIUrl":"https://doi.org/10.1016/j.coph.2023.102425","url":null,"abstract":"<div><p>With the spread of the “omics” sciences, the approaches of systems biology can be considered as new paradigms of pharmacological research for discovery of novel targets and/or treatments for complex multifactorial diseases. Data from omics sciences can be used for the design of biologic networks, that in turn can be quantitatively analyzed to identify new pharmacological targets. In this review, we will introduce the concept of network pharmacology, particularly the application of this innovative approach in the field of ocular pharmacology, with a focus on retinal diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD) and glaucoma.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"74 ","pages":"Article 102425"},"PeriodicalIF":4.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1471489223000802/pdfft?md5=337890bbaef8e8510e189b6a155a1a30&pid=1-s2.0-S1471489223000802-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139107512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optic nerve regeneration: Potential treatment approaches","authors":"Jessica Lee ,&nbsp;Sherilyn Nguyen ,&nbsp;Sanjoy Bhattacharya","doi":"10.1016/j.coph.2023.102428","DOIUrl":"10.1016/j.coph.2023.102428","url":null,"abstract":"<div><p><span><span>The optic nerve, predominantly constituted by the axons of retinal ganglion cells (RGCs), lacks the ability to regenerate and re-establish function after injury. RGCs are crucial for visual function, and thus, RGC death contributes to the development of numerous progressive neurodegenerative optic neuropathies including glaucoma, ischemic optic neuropathy, and </span>optic neuritis<span><span>. Regenerating optic nerve axons poses numerous challenges due to factors such as the intricate and inhibitory conditions that exist within their environment, intrinsic breaks to regeneration, and the geometric tortuosity that offers physical hindrance to axon growth. However, recent research advancements offer hope for clinically meaningful regeneration for those who suffer from </span>optic nerve damage. In this review, we highlight the current treatment approaches for optic nerve </span></span>axon regeneration.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"74 ","pages":"Article 102428"},"PeriodicalIF":4.0,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139077611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the NRF2 pathway: A promising approach for corneal endothelial dysfunction","authors":"Keith W. Ward","doi":"10.1016/j.coph.2023.102429","DOIUrl":"10.1016/j.coph.2023.102429","url":null,"abstract":"<div><p><span><span>Maintaining corneal endothelial function is required for vision, and corneal endothelial dysfunction is a major cause of visual deficits and blindness worldwide. To date there has been a dearth of innovation for therapeutics targeting the </span>corneal endothelium<span>. However, recent advances in understanding the role of oxidative stress and mitochondrial dysfunction have revealed potential avenues for the development of new therapies. This review summarizes recent developments in elucidating the role of the NRF2 pathway in corneal endothelial health and disease, focusing specifically on Fuchs’ endothelial </span></span>corneal dystrophy and the loss of corneal endothelial cells associated with cataract surgery. The pro-mitochondrial and antioxidant phenotype elicited by NRF2 activation offers a promising opportunity for new therapeutics for the diseased corneal endothelium.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"74 ","pages":"Article 102429"},"PeriodicalIF":4.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139077559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human experience and efficacy of omidenepag isopropyl (Eybelis®; Omlonti®): Discovery to approval of the novel non-prostaglandin EP2-receptor-selective agonist ocular hypotensive drug","authors":"Najam A. Sharif","doi":"10.1016/j.coph.2023.102426","DOIUrl":"10.1016/j.coph.2023.102426","url":null,"abstract":"<div><p><span><span>More than 75 million people worldwide suffer from ocular hypertension<span> (OHT)-associated retinal and optic nerve degenerative diseases that cause </span></span>visual impairment and can lead to blindness. In an effort to find novel pharmaceutical therapeutics to combat OHT with reduced side-effect potential, several emerging drug candidates have advanced to human proof-of-concept in recent years. One such compound is a nonprostaglandin (non-PG) EP2-receptor-selective agonist (omidenepag isopropyl ester). Omidenepag (OMD; free acid form) is a novel non-PG that selectively binds to and activates the human EP2-prostglandin receptor (EP2R) with a high affinity (K</span>_i = 3.6 nM) and which potently generates intracellular cAMP in living cells (EC₅₀ = 3.9–8.3 nM). OMD significantly downregulated <em>COL12A1</em> and <em>COL13A1</em><span><span><span> mRNAs in human trabecular meshwork (TM) cells, a tissue involved in the pathogenesis of OHT. Omidenepag isopropyl (OMDI) potently and efficaciously lowered </span>intraocular pressure<span> (IOP) in ocular normotensive rabbits, dogs, and monkeys, and also in ocular hypertension (OHT) Cynomolgus monkeys, after a single topical ocular (t.o.) instillation at doses of 0.0001–0.01%. No reduction in IOP-lowering response to OMDI was observed after repeated t.o. dosing with OMDI in dogs and monkeys. Additive IOP reduction to OMDI was noted with brinzolamide, </span></span>timolol<span><span><span><span>, and brimonidine<span> in rabbits and monkeys. OMDI 0.002% t.o. decreased IOP by stimulating the conventional (TM) and uveoscleral (UVSC) outflow of aqueous humor (AQH) in OHT monkeys. In a Phase-III clinical investigation, 0.002% OMDI (once daily t.o.) reduced IOP by 5–6 mmHg in OHT/primary open-angle glaucoma (POAG) patients (22–34 mmHg baseline IOPs) that was maintained over 12-months. In an additional month-long clinical study, 0.002% OMDI induced IOP-lowering equivalent to that of latanoprost (0.005%), a </span></span>prostanoid FP-receptor agonist, thus OMDI was noninferior to latanoprost. Additive IOPreduction was also noted in OHT/OAG patients when OMDI (0.002%, once daily t.o.) and timolol (0.05%, twice daily t.o.) were administered. Patients with OHT/POAG who were low responders or nonresponders to latanoprost (0.005%, q.d.; t.o.) experienced significant IOP-lowering (additional approximately 3 mmHg) when they were switched over to OMDI 0.002% (q.d.; t.o.). No systemic or ocular adverse reactions (e.g. iris color changes/deepening of the </span>upper eyelid sulcus/abnormal </span>eyelash<span> growth) were noted after a year-long, once-daily t.o. dosing with 0.002 % OMDI in OHT/POAG patients. However, OMDI caused transient conjunctival hyperemia. These characteristics of OMDI render it a suitable new medication for treating OHT and various types of glaucoma, especially where elevated IOP is implicated.</span></span></span></p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"74 ","pages":"Article 102426"},"PeriodicalIF":4.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139069129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Currently available prostanoids for the treatment of glaucoma and ocular hypertension: A review","authors":"Betsy Benitez ,&nbsp;Abdelrahman M. Anter ,&nbsp;Jennifer Arcuri ,&nbsp;Sanjoy K. Bhattacharya","doi":"10.1016/j.coph.2023.102424","DOIUrl":"10.1016/j.coph.2023.102424","url":null,"abstract":"<div><p><span><span><span><span>Recent advancements in prostaglandin analogs (PGAs) have reinforced their role in managing </span>intraocular pressure (IOP). </span>Latanoprost<span> excels in 24-h IOP control, while various PGAs offer similar effectiveness and side effects, generic PGAs perform as well as branded ones, and a notable IOP rise observed upon PGA discontinuation. Formulations with or without preservatives show comparable IOP reduction and adherence, often surpassing benzalkonium chloride (BAK)-preserved options. Emergent PGAs, such as latanoprostene bunod, fixed-dose </span></span>netarsudil combined with latanoprost, and </span>omidenepag Isopropyl<span>, offer enhanced or non-inferior IOP reduction. The bimatoprost<span> implant introduces a novel administration method with effective IOP reduction. These developments underscore ongoing progress in PGA-focused ophthalmological research. This article offers a comprehensive review of available prostanoid analogs and explores new developments.</span></span></p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"74 ","pages":"Article 102424"},"PeriodicalIF":4.0,"publicationDate":"2023-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139069704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiotensin II type 2 receptor signalling as a pain target: Bench, bedside and back-translation","authors":"Andrew J. Shepherd ,&nbsp;Andrew SC. Rice ,&nbsp;Maree T. Smith","doi":"10.1016/j.coph.2023.102415","DOIUrl":"https://doi.org/10.1016/j.coph.2023.102415","url":null,"abstract":"<div><p>Translating promising preclinical pain relief data for novel molecules from drug discovery to positive clinical trial outcomes is challenging. The angiotensin II type 2 (AT₂) receptor is a clinically-validated target based upon positive proof-of-concept clinical trial data in patients with post-herpetic neuralgia. This trial was conducted because AT₂ receptor antagonists evoked pain relief in rodent models of neuropathic pain. EMA401 was selected as the drug candidate based upon its suitable preclinical toxicity and safety profile and good pharmacokinetics. Herein, we provide an overview of the discovery, preclinical and clinical development of EMA401, for the alleviation of peripheral neuropathic pain.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"73 ","pages":"Article 102415"},"PeriodicalIF":4.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S147148922300070X/pdfft?md5=dfede4c59e8d01336a83f135213edc06&pid=1-s2.0-S147148922300070X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138472672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}