Current Opinion in Pharmacology最新文献

{"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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}

{"title":"Interventional functional diagnostics in gastrointestinal endoscopy: Combining diagnostic and therapeutic tools in the endoscopy suite with the functional lumen imaging probe","authors":"Zuzana Vackova ,&nbsp;Ian Levenfus ,&nbsp;Daniel Pohl","doi":"10.1016/j.coph.2023.102414","DOIUrl":"https://doi.org/10.1016/j.coph.2023.102414","url":null,"abstract":"<div><p>With technical progress of gastrointestinal functional testing, there has been a demand for more comprehensive examination of esophageal physiology and pathophysiology beyond high-resolution manometry. A new interventional technology based on impedance planimetry, the functional lumen imaging probe (FLIP), enables intraluminal measurement of distensibility and compliance of hollow organs. EndoFLIP uses balloon catheters to measure diameter and distension pressure to calculate cross-sectional area and distensibility in different organs (mostly esophagus, stomach, anorectal region) and can be used in wide variety of indications (diagnostics, pre- and post-treatment evaluation) and currently serves as a helpful adjunctive tool in ambiguous clinical cases. EsoFLIP is a therapeutic variation that uses a stiffer balloon catheter allowing for dilation. The trend to simplify the clinical process from diagnosis to treatment tends to a one-session procedure combining diagnostics and therapeutic interventions. In specified conditions like e.g. achalasia or gastroparesis, a combination of EndoFLIP and EsoFLIP procedures may therefore be useful. The aim of this narrative review is to introduce the clinical use of FLIP and its potential benefit in combined diagnostic-therapeutic procedures.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1471489223000693/pdfft?md5=a85fbc9fb6d7221a1db26a1995fcc341&pid=1-s2.0-S1471489223000693-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138453586","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":"Illuminating GPCR signaling mechanisms by NMR spectroscopy with stable-isotope labeled receptors","authors":"Beining Jin,&nbsp;Naveen Thakur,&nbsp;Anuradha V. Wijesekara,&nbsp;Matthew T. Eddy","doi":"10.1016/j.coph.2023.102364","DOIUrl":"10.1016/j.coph.2023.102364","url":null,"abstract":"<div><p>G protein-coupled receptors (GPCRs) exhibit remarkable structural plasticity, which underlies their capacity to recognize a wide range of extracellular molecules and interact with intracellular partner proteins. Nuclear magnetic resonance (NMR) spectroscopy is uniquely well-suited to investigate GPCR structural plasticity, enabled by stable-isotope “probes” incorporated into receptors that inform on structure and dynamics. Progress with stable-isotope labeling methods in Eukaryotic expression systems has enabled production of native or nearly-native human receptors with varied and complementary distributions of NMR probes. These advances have opened up new avenues for investigating the roles of conformational dynamics in signaling processes, including by mapping allosteric communication networks, understanding the specificity of GPCR interactions with partner proteins and exploring the impact of membrane environments on GPCR function.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219246","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":"Pharmacologic treatment of gastroparesis: What is (still) on the horizon?","authors":"D. Schweckendiek,&nbsp;D. Pohl","doi":"10.1016/j.coph.2023.102395","DOIUrl":"10.1016/j.coph.2023.102395","url":null,"abstract":"<div><p>Gastroparesis is a neuromuscular disorder of the upper gastrointestinal tract. Patients typically complain about early satiety, postprandial fullness, nausea and vomiting. Etiology is multifactorial. Treatment strategies include nutritional support, pharmacologic agents or surgery for refractory cases. Metoclopramide is the first and only FDA approved pharmacologic agent for (diabetic) Gastroparesis. A couple of compounds are currently in clinical testing. Some beacons of hope have failed recently, however. Here we present an update on possible future treatment options.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219257","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":"Discerning conformational dynamics and binding kinetics of GPCRs by 19F NMR","authors":"R.S. Prosser ,&nbsp;Nicholas A. Alonzi","doi":"10.1016/j.coph.2023.102377","DOIUrl":"https://doi.org/10.1016/j.coph.2023.102377","url":null,"abstract":"<div><p>¹⁹F NMR provides a way of monitoring conformational dynamics of G-protein coupled receptors (GPCRs) from the perspective of an ensemble. While X-ray crystallography provides exquisitely resolved high-resolution structures of specific states, it generally does not recapitulate the true ensemble of functional states. Fluorine (¹⁹F) NMR provides a highly sensitive spectroscopic window into the conformational ensemble, generally permitting the direct quantification of resolvable states. Moreover, straightforward T₁- and T₂<span>-based relaxation experiments allow for the study of fluctuations within a given state and exchange between states, on timescales spanning nanoseconds to seconds. Conveniently, most biological systems are free of fluorine. Thus, via fluorinated amino acid analogues or thiol-reactive fluorinated tags, F or CF</span>₃ reporters can be site specifically incorporated into proteins of interest. In this review, fluorine labeling protocols and ¹⁹F NMR experiments will be presented, from the perspective of small molecule NMR (i.e. drug or small molecule interactions with receptors) or macromolecular NMR (i.e. conformational dynamics of receptors and receptor–G-protein complexes).</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50172845","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":"The role of Pannexin-1 channels, ATP, and purinergic receptors in the pathogenesis of HIV and SARS-CoV-2","authors":"Cristian A. Hernandez,&nbsp;Eliseo A. Eugenin","doi":"10.1016/j.coph.2023.102404","DOIUrl":"10.1016/j.coph.2023.102404","url":null,"abstract":"<div><p>Infectious agents such as human immune deficiency virus-1 (HIV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) use host proteins to infect, replicate, and induce inflammation within the host. A critical component of these diseases is the axis between pannexin-1 channels, extracellular ATP, and purinergic receptors. Here, we describe the potential therapeutic role of Pannexin-1/purinergic approaches to prevent or reduce the devastating consequences of these pathogens.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41177349","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}