Adenosine receptors as promising targets for the management of ocular diseases

Baldassarri, Cecilia; Acquaticci, Laura; Bello, Fabio Del; Grifantini, Mario; Cappellacci, Loredana; Petrelli, Riccardo

doi:10.1007/s00044-021-02704-x

Cited by 19 publications

(13 citation statements)

References 124 publications

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“…On the negative side of adenosine-mediated inflammation suppression, many solid tumors escape immune response by increasing the concentration of adenosine in the tumor microenvironment. Both animal studies and clinical trials have shown that blocking A 2A AR can induce tumor regression (Sun et al, 2022).…”

Section: A 2a Ar Allosteric Modulatorsmentioning

confidence: 99%

“…In addition to the several physiological effects of adenosine, its receptor-mediated signaling has many documented effects on the progression of countless pathological states ( Karmouty-Quintana et al, 2013 ). Among the main ones, modulation of adenosine receptors has been indicated as a promising therapeutic strategy in pathological states such as cancer ( Vijayan et al, 2017 ; Allard et al, 2020 ), cardiovascular diseases ( Reiss et al, 2019 ), pain ( Vincenzi et al, 2020a ), neurological/neurodegenerative diseases ( Blum et al, 2018 ; Sebastião et al, 2018 ; Jenner et al, 2021 ; Merighi et al, 2021 ), neuropsychiatric disorders ( Pasquini et al, 2022 ), inflammatory diseases ( Pasquini et al, 2021 ; Antonioli et al, 2022 ), respiratory diseases ( Caruso et al, 2013 ), ocular diseases ( Spinozzi et al, 2021 ), diabetes, and other metabolic disorders ( Antonioli et al, 2015 ; Sanni and Terre’Blanche, 2021 ). Despite this encouraging profusion of experimental evidence, relatively few adenosinergic system-based drugs have so far achieved clinical approval.…”

Section: Introductionmentioning

confidence: 99%

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Update on the recent development of allosteric modulators for adenosine receptors and their therapeutic applications

et al. 2022

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Adenosine receptors (ARs) have been identified as promising therapeutic targets for countless pathological conditions, spanning from inflammatory diseases to central nervous system disorders, from cancer to metabolic diseases, from cardiovascular pathologies to respiratory diseases, and beyond. This extraordinary therapeutic potential is mainly due to the plurality of pathophysiological actions of adenosine and the ubiquitous expression of its receptors. This is, however, a double-edged sword that makes the clinical development of effective ligands with tolerable side effects difficult. Evidence of this is the low number of AR agonists or antagonists that have reached the market. An alternative approach is to target allosteric sites via allosteric modulators, compounds endowed with several advantages over orthosteric ligands. In addition to the typical advantages of allosteric modulators, those acting on ARs could benefit from the fact that adenosine levels are elevated in pathological tissues, thus potentially having negligible effects on normal tissues where adenosine levels are maintained low. Several A1 and various A3AR allosteric modulators have been identified so far, and some of them have been validated in different preclinical settings, achieving promising results. Less fruitful, instead, has been the discovery of A2A and A2BAR allosteric modulators, although the results obtained up to now are encouraging. Collectively, data in the literature suggests that allosteric modulators of ARs could represent valuable pharmacological tools, potentially able to overcome the limitations of orthosteric ligands.

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Section: A 2a Ar Allosteric Modulatorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Update on the recent development of allosteric modulators for adenosine receptors and their therapeutic applications

et al. 2022

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“…Adenosine receptors are numerous in ocular tissue, such as the ciliary body, the trabecular meshwork, the sclera, and the retina (61). We identified nine clinical trials that evaluated compounds acting on an adenosine receptor, but to date none of the compounds have succeeded in progressing to FDA approval (62)(63)(64). A single phase I/IIA trials is currently underway [NCT04585100].…”

Section: Adenosine Receptor Agonistsmentioning

confidence: 99%

Glaucoma Clinical Research: Trends in Treatment Strategies and Drug Development

et al. 2021

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Purpose: To investigate the trends and progresses in glaucoma research by searching two major clinical trial registries; clinicaltrials.gov, and Australianclinicaltrials.gov.au.Methods: All clinical trials with glaucoma covered by Clinicaltrials.gov, and Australianclinicaltrials.gov.au starting the study before 1 January 2021 were included. Trials evaluating glaucoma treatment were separated from non-treatment trials and divided into three major categories: “laser treatment,” “surgical treatment,” and “medical treatment.” In the category of “medical treatment,” new compounds and their individual targets were identified and subcategorized according to treatment strategy; intraocular pressure (IOP)-lowering, neuroprotective or vascular. The phase transition success rates were calculated.Results: One-thousand five hundred and thirty-seven trials were identified. Sixty-three percent (n = 971) evaluated glaucoma treatment, of which medical treatment accounted for the largest proportion (53%). The majority of medical trials evaluated IOP-lowering compounds, while trials with neuroprotective or vascular compounds accounted for only 5 and 3%, respectively. Eighty-eight new compounds were identified. Phase I, II, and III transition success rates were 63, 26, and 47%, respectively.Conclusion: The number of clinical trials in glaucoma research has increased significantly over the last 30 years. Among the most recently evaluated compounds, all three main treatment strategies were represented, but clinical trials in neuroprotection and vascular modalities are still sparse. In addition to traditional medicines, dietary supplements and growth factors are assessed for a potential anti-glaucomatous effect. Phase II and III success rates were below previously reported success rates for all diseases and ophthalmology in general. A stricter phenotyping of patients can improve the success rates in glaucoma and ophthalmological research and gain a better understanding of responders and non-responders.

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“…Approved therapeutics for treatment of ocular diseases include steroids such as hydrocortisone, triamcinolone acetonide, fluocinolone, and dexamethasone; antibiotics such as fluoroquinolones, tetracyclines, and aminoglycosides; and biological pharmaceuticals such as anti-VEGFs. Experimental therapeutics currently being investigated include antioxidants such as glutathione and ascorbic acid, complement factor inhibitors such as avacincaptad pegol and APL-2, and novel therapeutic mechanisms such as mesenchymal stem cell extracellular vesicles, miotic based eye drops, viral vectors for gene therapy, and adenosine receptors (13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Considerations for Polymers Used in Ocular Drug Delivery

et al. 2022

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PurposeAge-related eye diseases are becoming more prevalent. A notable increase has been seen in the most common causes including glaucoma, age-related macular degeneration (AMD), and cataract. Current clinical treatments vary from tissue replacement with polymers to topical eye drops and intravitreal injections. Research and development efforts have increased using polymers for sustained release to the eye to overcome treatment challenges, showing promise in improving drug release and delivery, patient experience, and treatment compliance. Polymers provide unique properties that allow for specific engineered devices to provide improved treatment options. Recent work has shown the utilization of synthetic and biopolymer derived biomaterials in various forms, with this review containing a focus on polymers Food and Drug Administration (FDA) approved for ocular use.MethodsThis provides an overview of some prevalent synthetic polymers and biopolymers used in ocular delivery and their benefits, brief discussion of the various types and synthesis methods used, and administration techniques. Polymers approved by the FDA for different applications in the eye are listed and compared to new polymers being explored in the literature. This article summarizes research findings using polymers for ocular drug delivery from various stages: laboratory, preclinical studies, clinical trials, and currently approved. This review also focuses on some of the challenges to bringing these new innovations to the clinic, including limited selection of approved polymers.ResultsPolymers help improve drug delivery by increasing solubility, controlling pharmacokinetics, and extending release. Several polymer classes including synthetic, biopolymer, and combinations were discussed along with the benefits and challenges of each class. The ways both polymer synthesis and processing techniques can influence drug release in the eye were discussed.ConclusionThe use of biomaterials, specifically polymers, is a well-studied field for drug delivery, and polymers have been used as implants in the eye for over 75 years. Promising new ocular drug delivery systems are emerging using polymers an innovative option for treating ocular diseases because of their tunable properties. This review touches on important considerations and challenges of using polymers for sustained ocular drug delivery with the goal translating research to the clinic.

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Adenosine receptors as promising targets for the management of ocular diseases

Cited by 19 publications

References 124 publications

Update on the recent development of allosteric modulators for adenosine receptors and their therapeutic applications

Update on the recent development of allosteric modulators for adenosine receptors and their therapeutic applications

Glaucoma Clinical Research: Trends in Treatment Strategies and Drug Development

Considerations for Polymers Used in Ocular Drug Delivery

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