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Integrating network pharmacology: The next-generation approach in ocular drug discovery 整合网络药理学:眼科药物发现的新一代方法
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-05 DOI: 10.1016/j.coph.2023.102425
Francesca Lazzara , Federica Conti , Erika Giuffrida , Chiara Maria Eandi , Filippo Drago , Chiara Bianca Maria Platania , Claudio Bucolo

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.

随着 "全方位 "科学的普及,系统生物学方法可被视为药理学研究的新范例,用于发现新的靶点和/或治疗复杂的多因素疾病。全方位科学的数据可用于生物网络的设计,而生物网络又可通过定量分析来确定新的药理靶点。在这篇综述中,我们将介绍网络药理学的概念,特别是这一创新方法在眼科药理学领域的应用,重点是糖尿病视网膜病变(DR)、老年性黄斑变性(AMD)和青光眼等视网膜疾病。
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引用次数: 0
Optic nerve regeneration: Potential treatment approaches 视神经再生:潜在的治疗方法
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-03 DOI: 10.1016/j.coph.2023.102428
Jessica Lee , Sherilyn Nguyen , Sanjoy Bhattacharya

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 optic neuritis. 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 optic nerve damage. In this review, we highlight the current treatment approaches for optic nerve axon regeneration.

视神经主要由视网膜神经节细胞(RGC)的轴突构成,损伤后缺乏再生和重建功能的能力。RGC 对视觉功能至关重要,因此,RGC 的死亡会导致青光眼、缺血性视神经病变和视神经炎等多种进行性神经退行性视神经病变的发生。由于视神经轴突所处环境的复杂性和抑制性、再生的内在障碍以及阻碍轴突生长的几何迂回等因素,视神经轴突的再生面临着诸多挑战。然而,最近的研究进展为视神经损伤患者带来了具有临床意义的再生希望。在这篇综述中,我们将重点介绍目前视神经轴突再生的治疗方法。
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引用次数: 0
Targeting the NRF2 pathway: A promising approach for corneal endothelial dysfunction 靶向 NRF2 通路:治疗角膜内皮功能障碍的有效方法
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-02 DOI: 10.1016/j.coph.2023.102429
Keith W. Ward

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 corneal endothelium. 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 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.

维持角膜内皮功能是视力的必要条件,而角膜内皮功能障碍是全球视力障碍和失明的主要原因。迄今为止,针对角膜内皮的治疗方法一直缺乏创新。然而,最近在了解氧化应激和线粒体功能障碍的作用方面取得的进展揭示了开发新疗法的潜在途径。本综述总结了在阐明 NRF2 通路在角膜内皮健康和疾病中的作用方面的最新进展,尤其侧重于福氏角膜内皮营养不良症和与白内障手术相关的角膜内皮细胞丧失。NRF2 激活所引发的促线粒体和抗氧化表型为针对患病角膜内皮的新疗法提供了大好机会。
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引用次数: 0
Human experience and efficacy of omidenepag isopropyl (Eybelis®; Omlonti®): Discovery to approval of the novel non-prostaglandin EP2-receptor-selective agonist ocular hypotensive drug omidenepag isopropyl(Eybelis®;Omlonti®)的人体体验和疗效:新型非前列腺素 EP2 受体选择性激动剂降眼压药物从发现到获批的过程
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-01-01 DOI: 10.1016/j.coph.2023.102426
Najam A. Sharif

More than 75 million people worldwide suffer from ocular hypertension (OHT)-associated retinal and optic nerve degenerative diseases that cause 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 (Ki = 3.6 nM) and which potently generates intracellular cAMP in living cells (EC50 = 3.9–8.3 nM). OMD significantly downregulated COL12A1 and COL13A1 mRNAs in human trabecular meshwork (TM) cells, a tissue involved in the pathogenesis of OHT. Omidenepag isopropyl (OMDI) potently and efficaciously lowered intraocular pressure (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, timolol, and brimonidine 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 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 upper eyelid sulcus/abnormal eyelash 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.

全世界有超过 7500 万人患有与眼压过高(OHT)相关的视网膜和视神经退行性疾病,这些疾病会造成视力损伤,甚至导致失明。近年来,为了寻找新型药物疗法来防治眼压过高症并降低副作用,一些新出现的候选药物已进入人体概念验证阶段。其中一种化合物是非前列腺素(non-prostaglandin,non-PG)EP2受体选择性激动剂(omidenepag isopropyl ester)。Omidenepag(OMD;游离酸形式)是一种新型非前列腺素,能以高亲和力(Ki = 3.6 nM)选择性地结合并激活人类前列腺素受体(EP2R),并能在活细胞中有效地产生细胞内 cAMP(EC50 = 3.9-8.3 nM)。OMD 能明显下调人小梁网(TM)细胞中的 COL12A1 和 COL13A1 mRNA,而小梁网是一种与 OHT 发病机制有关的组织。在眼压正常的兔子、狗和猴子身上,以及在眼压过高(OHT)的赛诺摩格斯猴(Cynomolgus Monkeys)身上,奥米地尼帕异丙酯(OMDI)以 0.0001-0.01% 的剂量单次局部眼部(t.o.)灌注后,能有效降低眼压(IOP)。在狗和猴中重复眼局部注射 OMDI 后,未观察到降低眼压的反应。在兔子和猴子身上发现,布林佐胺、噻吗洛尔和溴莫尼定对 OMDI 的降眼压作用具有相加作用。OMDI 0.002% t.o.通过刺激 OHT 猴的常规(TM)和葡萄膜巩膜(UVSC)流出房水(AQH)来降低眼压。在一项第三阶段临床研究中,0.002% OMDI(每天一次,每次口服)可将 OHT/原发性开角型青光眼(POAG)患者(基线眼压为 22-34 mmHg)的眼压降低 5-6 mmHg,并可维持 12 个月。在另一项为期一个月的临床研究中,0.002% OMDI 的降眼压效果与前列腺素 FP 受体激动剂拉坦前列素(0.005%)的降眼压效果相当,因此 OMDI 的效果不优于拉坦前列素。OHT/OAG 患者在使用 OMDI(0.002%,每天两次,每次点滴)和噻吗洛尔(0.05%,每天两次,每次点滴)时,眼压降低的效果也是相加的。对拉坦前列素(0.005%,口服,每日一次)反应较低或无反应的 OHT/POAG 患者在改用 OMDI 0.002%(口服,每日一次)后,眼压显著降低(额外降低约 3 mmHg)。在 OHT/POAG 患者使用 0.002 % OMDI 一年、每天一次口服后,未发现全身或眼部不良反应(如虹膜颜色变化/上眼睑沟加深/睫毛生长异常)。不过,OMDI 会引起短暂的结膜充血。OMDI 的这些特性使其成为治疗 OHT 和各种类型青光眼的合适新药,尤其是在涉及眼压升高的情况下。
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引用次数: 0
Currently available prostanoids for the treatment of glaucoma and ocular hypertension: A review 目前可用于治疗青光眼和眼压过高的前列腺素:综述
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-30 DOI: 10.1016/j.coph.2023.102424
Betsy Benitez , Abdelrahman M. Anter , Jennifer Arcuri , Sanjoy K. Bhattacharya

Recent advancements in prostaglandin analogs (PGAs) have reinforced their role in managing intraocular pressure (IOP). Latanoprost 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 netarsudil combined with latanoprost, and omidenepag Isopropyl, offer enhanced or non-inferior IOP reduction. The bimatoprost 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.

前列腺素类似物(PGA)的最新进展加强了其在控制眼压(IOP)方面的作用。拉坦前列素在 24 小时眼压控制方面表现出色,而各种前列腺素类似物具有相似的疗效和副作用,非专利前列腺素类似物的表现不亚于品牌前列腺素类似物,但停用前列腺素类似物后眼压会明显升高。含防腐剂或不含防腐剂的制剂在降低眼压和依从性方面的表现不相上下,通常超过含苯扎氯铵(BAK)防腐剂的制剂。新出现的 PGA,如拉坦前列腺素布诺、固定剂量的奈达昔洛联合拉坦前列腺素和奥美替尼帕格异丙戊等,可提高或降低眼压。比马前列素植入剂引入了一种新的给药方法,可有效降低眼压。这些发展凸显了以 PGA 为重点的眼科研究的不断进步。本文全面回顾了现有的类前列腺素类似物,并探讨了新的发展。
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引用次数: 0
Angiotensin II type 2 receptor signalling as a pain target: Bench, bedside and back-translation 血管紧张素II型2受体信号作为疼痛靶点:实验、临床和反向翻译
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-12-01 DOI: 10.1016/j.coph.2023.102415
Andrew J. Shepherd , Andrew SC. Rice , Maree T. Smith

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.

将新分子的临床前疼痛缓解数据从药物发现转化为积极的临床试验结果是具有挑战性的。血管紧张素II 2型(AT2)受体是基于疱疹后神经痛患者积极的概念验证临床试验数据的临床验证靶点。进行这项试验是因为AT2受体拮抗剂在啮齿动物神经性疼痛模型中引起疼痛缓解。EMA401因其适宜的临床前毒性和安全性以及良好的药代动力学而被选为候选药物。在此,我们概述了EMA401的发现,临床前和临床开发,以减轻周围神经性疼痛。
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引用次数: 0
Interventional functional diagnostics in gastrointestinal endoscopy: Combining diagnostic and therapeutic tools in the endoscopy suite with the functional lumen imaging probe 胃肠内窥镜介入功能诊断:将内窥镜套件中的诊断和治疗工具与功能性管腔成像探头相结合
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-11-28 DOI: 10.1016/j.coph.2023.102414
Zuzana Vackova , Ian Levenfus , Daniel Pohl

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.

随着胃肠功能检测技术的进步,人们要求在高分辨率测压法之外,对食管生理和病理生理进行更全面的检查。一种基于阻抗平面测量的新型介入技术——功能性管腔成像探针(FLIP),可以在腔内测量中空器官的扩张性和顺应性。EndoFLIP使用球囊导管测量直径和扩张压力,计算不同器官(主要是食道、胃、肛肠区域)的横截面积和扩张率,可用于各种适应症(诊断、治疗前和治疗后评估),目前是临床上模棱两可病例的辅助工具。EsoFLIP是一种治疗性的变体,使用更硬的球囊导管进行扩张。简化从诊断到治疗的临床过程的趋势趋向于将诊断和治疗干预相结合的一次会议程序。在特定的情况下,如贲门失弛缓症或胃轻瘫,EndoFLIP和EsoFLIP手术的组合可能是有用的。这篇叙述性综述的目的是介绍FLIP的临床应用及其在联合诊断和治疗过程中的潜在益处。
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引用次数: 0
Illuminating GPCR signaling mechanisms by NMR spectroscopy with stable-isotope labeled receptors 用稳定同位素标记的受体通过NMR光谱阐明GPCR信号机制。
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1016/j.coph.2023.102364
Beining Jin, Naveen Thakur, Anuradha V. Wijesekara, Matthew T. Eddy

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.

G蛋白偶联受体(GPCR)表现出显著的结构可塑性,这是其识别多种细胞外分子并与细胞内伴侣蛋白相互作用的能力的基础。核磁共振(NMR)光谱特别适合研究GPCR的结构可塑性,这是由结合到受体中的稳定同位素“探针”实现的,这些探针可以提供结构和动力学信息。在真核表达系统中稳定同位素标记方法的进展使得能够产生具有不同和互补分布的NMR探针的天然或几乎天然的人类受体。这些进展为研究构象动力学在信号传导过程中的作用开辟了新的途径,包括绘制变构通信网络,了解GPCR与伴侣蛋白相互作用的特异性,以及探索膜环境对GPCR功能的影响。
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引用次数: 1
Pharmacologic treatment of gastroparesis: What is (still) on the horizon? 胃轻瘫的药物治疗:什么(仍然)在地平线上?
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1016/j.coph.2023.102395
D. Schweckendiek, D. Pohl

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.

胃轻瘫是上消化道的一种神经肌肉疾病。患者通常会抱怨早期饱腹、餐后饱腹、恶心和呕吐。病因是多因素的。治疗策略包括营养支持、药物或手术治疗难治性病例。甲氧氯普胺是美国食品药品监督管理局批准的第一种也是唯一一种治疗(糖尿病)胃轻瘫的药物。一些化合物目前正在进行临床试验。然而,一些希望的灯塔最近失败了。在这里,我们介绍了未来可能的治疗方案的最新情况。
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引用次数: 0
Discerning conformational dynamics and binding kinetics of GPCRs by 19F NMR 用19F NMR鉴别GPCR的构象动力学和结合动力学
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-01 DOI: 10.1016/j.coph.2023.102377
R.S. Prosser , Nicholas A. Alonzi

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-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 CF3 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).

19F NMR提供了一种从集合的角度监测G蛋白偶联受体(GPCR)构象动力学的方法。虽然X射线晶体学提供了特定状态的精细解析的高分辨率结构,但它通常不能概括功能状态的真正集合。氟(19F)NMR为构象系综提供了一个高度灵敏的光谱窗口,通常允许直接定量可分辨状态。此外,基于T1和T2的直接弛豫实验允许在纳秒到秒的时间尺度上研究给定状态内的波动和状态之间的交换。方便的是,大多数生物系统都不含氟。因此,通过氟化氨基酸类似物或硫醇反应性氟化标签,F或CF3报告子可以位点特异性地结合到感兴趣的蛋白质中。在这篇综述中,将从小分子NMR(即药物或小分子与受体的相互作用)或大分子NMR(如受体和受体-G蛋白复合物的构象动力学)的角度介绍氟标记方案和19F NMR实验。
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引用次数: 0
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Current Opinion in Pharmacology
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