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Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma.

ABSTRACT: In patients with ocular hypertension or glaucoma, all treatments aim to lower intraocular pressure (IOP) by modulating aqueous humour (AH) production and/or uveoscleral and trabecular meshwork/Schlemm's canal AH drainage. PG analogues are considered to be the 'gold standard' treatment and are the most frequently used IOP-lowering agents. Recent data support an important role for NO in regulating IOP. Thus, novel PG analogues carrying a NO-donating moiety were recently advanced. Latanoprostene bunod (LBN) and NCX 470, NO-donating derivatives of latanoprost and bimatoprost, respectively, are examples of such compounds. LBN ophthalmic solution, 0.024% (Vyzulta™), showed greater IOP-lowering efficacy compared with that of Xalatan® (latanoprost ophthalmic solution, 0.005%) or 0.5% timolol maleate in clinical settings. NCX 470 was found to be more effective than bimatoprost in animal models of ocular hypertension and glaucoma. Selective EP2 receptor agonists (i.e. taprenepag isopropyl, omidenepag isopropyl and aganepag isopropyl) and non-selective prostanoid receptor agonists (i.e. ONO-9054, sepetaprost isopropyl) that concomitantly stimulate FP and EP3 receptors have also been shown to hold promise as effective IOP-lowering agents. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.

SUBMITTER: Impagnatiello F

PROVIDER: S-EPMC6451067 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma.

Impagnatiello Francesco F Bastia Elena E Almirante Nicoletta N Brambilla Stefania S Duquesroix Brigitte B Kothe Angela C AC Bergamini Michael V W MVW

British journal of pharmacology 20180524 8

In patients with ocular hypertension or glaucoma, all treatments aim to lower intraocular pressure (IOP) by modulating aqueous humour (AH) production and/or uveoscleral and trabecular meshwork/Schlemm's canal AH drainage. PG analogues are considered to be the 'gold standard' treatment and are the most frequently used IOP-lowering agents. Recent data support an important role for NO in regulating IOP. Thus, novel PG analogues carrying a NO-donating moiety were recently advanced. Latanoprostene bu ...[more]

PMID: 29669171

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Project description:Analysis of the genotype that predicts the phenotypic characteristics of a cohort of glaucoma and ocular hypertension patients, and the correlation with their personal pharmacological response to beta-blockers (BB) and prostaglandin analogues (PGA). Prospective study that included 139 eyes from 72 patients under BB and/or PGA treatment, and in some cases other types of ocular hypotensive treatments. Five single-nucleotide polymorphisms were genotyped by real-time PCR assays: prostaglandin-F2α receptor (rs3766355, rs3753380); cytochrome-P450 2D6 (rs16947, rs769258); and beta-2-adrenergic receptor (rs1042714). Other studied variables were mean deviation (MD) of visual field, previous ocular interventions, medical treatment, baseline (bIOP), and treated intraocular pressure (tIOP). From a total of 139 eyes, 71 (51.1%) were left eyes. The main diagnosis was primary open angle glaucoma (66.2%). A total of 57 (41%) eyes were under three or more medications (PGA + BB + other) and, additionally, 57 eyes (41%) had had some kind of glaucoma surgery. The mean bIOP and tIOP were 26.55 ± 8.19 and 21.01 ± 5.54 mmHg, respectively. Significant differences in tIOP were found between heterozygous (HT) (21.07 ± 0.607 mmHg) and homozygous (HM) (20.98 ± 0.639 mmHg) rs3766355 with respect to wildtype individuals (16 ± 1.08 mmHg) (p = 0.031). The MD values presented significant differences between wildtype rs3766355 (-2 ± 2.2 dB), HT (-3.87 ± 4 dB), and HM carriers (-9.37 ± 9.51 dB) (p = 0.009). Significant differences were also observed between the MD in wildtype rs3753380 (-6.1 ± 8.67 dB), HT (-9.02 ± 8.63 dB), and HM carriers (-9.51 ± 7.44 dB) (p = 0.017). Patients carrying the variant rs3766355 in HM or HT presented clinically-significantly higher tIOP than wildtype patients. Additionally, some differences in MD were found in rs3766355 and rs3753380 carriers, and the more alleles that were affected, the worse the MD value, meaning greater severity of the glaucoma. Poor response to treatment and more visual field damage may be associated with being a carrier of these mutated alleles.

Project description:PurposePrimary open-angle glaucoma (POAG) is a major cause of blindness and visual disability. Several genetic risk factors for POAG and optic nerve features have been identified. We measured the relative risk for glaucoma that these factors contribute to participants in the Ocular Hypertension Treatment Study (OHTS).DesignComparative series.ParticipantsOne thousand fifty-seven of 1636 participants (65%) of the OHTS were enrolled in this genetics ancillary study.MethodsSamples of DNA were available from 1057 OHTS participants. Of these, 209 developed POAG (cases) and 848 did not develop glaucoma (controls) between 1994 and 2009. The frequencies of 13 risk alleles previously associated with POAG or with optic disc features in other cohorts were compared between POAG cases and controls in the OHTS cohort using analyses of variance. The 2 largest subgroups, non-Hispanic whites (n = 752; 70.7%) and blacks (n = 249, 23.7%), also were analyzed separately. The probability of glaucoma developing over the course of the OHTS was compared between participants stratified for transmembrane and coiled-coil domains 1 (TMCO1) risk alleles using Kaplan-Meier and Cox proportional hazards analyses.Main outcome measuresAssociation of POAG with known genetic factors.ResultsNo association was detected between the known POAG risk alleles when the OHTS cohort was examined as a whole. However, in the subgroup of non-Hispanic whites, allele frequencies at the TMCO1 locus were statistically different between cases and controls (P = 0.00028). By 13 years, non-Hispanic white participants with TMCO1 risk alleles had a 12% higher cumulative frequency of glaucoma developing than participants with no TMCO1 risk alleles. Moreover, the Cox proportional hazard analysis demonstrated that TMCO1 alleles increased relative risk comparable with that of some previously analyzed clinical measures (i.e., intraocular pressure).ConclusionsThe size of the OHTS cohort and its composition of 2 large racial subgroups may limit its power to detect some glaucoma risk factors. However, TMCO1 genotype was found to increase the risk of glaucoma developing among non-Hispanic whites, the largest racial subgroup in the OHTS cohort, at a magnitude similar to clinical predictors of disease that long have been associated with glaucoma.

Project description:Background: Brinzolamide as a carbonic anhydrase inhibitor could be combined with other intraocular pressure (IOP) lowering drugs for glaucoma and ocular hypertension (OHT), but the efficacy was controversial. So, this study was used to assess the efficacy and safety of brinzolamide as add-on to prostaglandin analogues (PGAs) or ?-blocker in treating patients with glaucoma or OHT who fail to adequately control IOP. Methods: We searched PubMed, Embase, MEDLINE, Cochrane Library, and clinicaltrials.gov from inception to October 4, 2018. Randomized controlled trials of brinzolamide as add-on to PGAs or ?-blocker for glaucoma and OHT were included. Meta-analysis was conducted by RevMan 5.3 software. Results: A total of 26 trials including 5,583 patients were analyzed. Brinzolamide produced absolute reductions of IOP as an adjunctive therapy for patients with glaucoma or OHT. Brinzolamide and timolol were not significantly different in lowering IOP as add-on to PGAs (9 am: P = 0.07; 12 am: P = 0.66; 4 pm: P = 0.66). Likewise, brinzolamide was as effective as dorzolamide in depressing IOP (9 am: P = 0.59; 12 am: P = 0.94; 4 pm: P = 0.95). For the mean diurnal IOP at the end of treatment duration, there were no statistical differences in above comparisons (P > 0.05). Compared with brimonidine (b.i.d.), there was a significant reduction of IOP in brinzolamide (b.i.d.) at 9 am (P < 0.0001); however, the difference was cloudy in thrice daily subgroup (P = 0.44); at 12 am, brinzolamide (b.i.d.) was similar to brimonidine (b.i.d.) in IOP-lowering effect (P = 0.23), whereas brimonidine (t.i.d.) led to a greater effect than brinzolamide (t.i.d.) (P = 0.02). At 4 pm, brinzolamide (b.i.d.) was superior IOP-lowering effect compared with brimonidine (b.i.d.) (P = 0.0003); conversely, the effect in brinzolamide (t.i.d.) was lower than brimonidine (t.i.d.) (P < 0.0001). For the mean diurnal IOP, brinzolamide was lower in twice daily subgroup (P < 0.00001); brimonidine was lower in thrice daily subgroup (P < 0.00001). With regard to the safety, brinzolamide and dorzolamide had a higher incidence of taste abnormality; moreover, brinzolamide resulted in more frequent blurred vision; dorzolamide resulted in more frequent ocular discomfort and eye pain. Timolol resulted in more frequent blurred vision and less conjunctival hyperemia. Brimonidine resulted in more frequent ocular hyperemia. As to other adverse events (AEs) (conjunctivitis, eye pruritus, foreign body sensation in eyes, and treatment-related AEs), brinzolamide was similar to other three active comparators. Conclusions: Brinzolamide, as add-on to PGAs or ?-blocker, significantly decreased IOP of patients with refractory glaucoma or OHT and the AEs were tolerable.

Project description:Glaucoma is a progressive optic neuropathy characterized by axonal degeneration and retinal ganglion cells loss. Several factors have been postulated to play a role in glaucoma, elevated intraocular pressure (IOP) being the best well-known causative factor. The mechanisms leading to ocular hypertension and glaucoma are still not fully understood. An increasing number of evidence indicates a role of autophagy in the pathophysiological process of ocular hypertension and glaucoma. However, while all of the studies agree that autophagy is induced in RGCs in response to injury, autophagy was found to either protect or promote cell death depending on the experimental model used. In order to gain more insight into both, the role of autophagy in the pathogenesis of glaucoma and the effect of chronic IOP elevation in the autophagy pathway, we have investigated here for the first time autophagy in the iridocorneal angle region, retinal ganglion cell bodies, and ON axons in the spontaneous ocular hypertensive DBA/2J mouse glaucoma model and in the transgenic DBA/2J::GFP-LC3 mice, generated in our laboratory. Our results indicate decreased autophagic flux in the outflow pathway cells in the DBA/2J mice, characterized by increased levels of LC3-II and p62 together with a decrease in the lysosomal marker LAMP1, evaluated by western blot and immunofluorescence. Elevated presence of autophagic vacuoles in the DBA/2J and, in particular, in the DBA/2J::GFP-LC3 mice was also observed. Expression of the GFP-LC3 transgene was associated to higher cumulative IOP in the DBA/2J background. In addition to higher elevation in IOP, DBA/2J::GFP-LC3 were characterized by further RGCs and exacerbated axonal degeneration compared to DBA/2J. This was accompanied by the notable high presence of autophagic figures within degenerating axons. These results strongly suggest overactivation of autophagy as a potential cellular mechanism leading to ON degeneration in the chronic hypertensive DBA/2J mice.

Project description:In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the cytoskeleton. Ultimately, a search for Rho kinase inhibitors led to the discovery of several molecules of therapeutic interest, leaving us today with 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP in patients with glaucoma and ocular hypertension represents a triumph in translational research. Rho kinase inhibitors are effective alone or when combined with other known ocular hypotensive medications. They also offer the possibility of neuroprotective activity, a favorable impact on ocular blood flow, and even an antifibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages, and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower IOP and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors, as well as the antifibrotic properties, of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma.

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Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma.

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Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma.

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