The predominant risk factor for the progression of glaucoma is an increase in IOP, mediated via a reduction in aqueous outflow through the conventional (trabecular meshwork and Schlemm's canal) outflow pathway. Current IOP lowering pharmacological strategies target the uveoscleral (nonconventional) outflow pathway or aqueous humor production; however, to date no therapy that primarily targets the conventional pathway exists. Nitric oxide (NO) is an intracellular signaling molecule produced by endogenous NO synthases, well-known for its key role in vasodilation, through its action on smooth muscle cells. Under physiological conditions, NO mediates a multitude of diverse ocular effects, including maintenance of IOP. Nitric oxide donors have been shown to mediate IOP-lowering effects in both preclinical models and clinical studies, primarily through cell volume and contractility changes in the conventional outflow tissues. This review is focused on evaluating the current knowledge of the role and mechanism of action of endogenous NO and NO donors in IOP regulation. Data on key additional functions of NO in glaucoma pathology (i.e., ocular blood flow and effects on optic neuropathy) are also summarized. The potential for future therapeutic application of NO in the treatment of glaucoma is then discussed.
AimTo assess the efficacy and safety of latanoprostene bunod (LBN) compared with latanoprost 0.005%, and to determine the optimum drug concentration(s) of LBN in reducing intraocular pressure (IOP) in subjects with open angle glaucoma or ocular hypertension.MethodsRandomised, investigator-masked, parallel-group, dose-ranging study. Subjects instilled one drop of study medication in the study eye once daily each evening for 28 days and completed five study visits. The primary efficacy endpoint was the reduction in mean diurnal IOP at Day 28.ResultsOf the 413 subjects randomised (LBN 0.006%, n=82; LBN 0.012%, n=85; LBN 0.024%, n=83; LBN 0.040%, n=81; latanoprost, n=82), 396 subjects completed the study. Efficacy for LBN was dose-dependent reaching a plateau at 0.024%–0.040%. LBN 0.024% led to significantly greater reductions in diurnal IOP compared with latanoprost at the primary endpoint, Day 28 (p=0.005), as well as Days 7 (p=0.033) and 14 (p=0.015). The incidence of adverse events, mostly mild and transient, was numerically higher in the LBN treatment groups compared with the latanoprost group. Hyperaemia was similar across treatments.ConclusionsLBN 0.024% dosed once daily was the lower of the two most effective concentrations evaluated, with significantly greater IOP lowering and comparable side effects relative to latanoprost 0.005%. LBN dosed once daily for 28 days was well tolerated.Clinical trial numberNCT01223378.
In this phase 3 study, LBN 0.024% qpm demonstrated significantly greater IOP lowering than timolol 0.5% BID throughout the day over 3 months of treatment. Latanoprostene bunod 0.024% was effective and safe in these adults with OAG or OHT.
Physiological pressure inside the eye is maintained by a resistance mechanism provided by the trabecular meshwork tissue. In most cases, prolonged, elevated pressure leads to an eye pathology characterized by retinal ganglion cell (RGC) degeneration, optic nerve damage, and non-remedial blindness. We are investigating the regulation of trabecular meshwork genes in response to elevated pressure. Using perfused organ cultures from postmortem human donors, we have previously demonstrated the presence of a homeostatic mechanism at 2-4 days of pressure insult (Borrás et al. 2002, Invest Ophthalmol Vis Sci 43:33-40). Here, we sought to identify trabecular meshwork genes whose expression was altered during this homeostatic period. By macroarray hybridization, we compared the expression profiles of high-pressure (HP) and normal-pressure (NP) treated eyes from the same individual (n = 3 pairs). Our results identified 40 upregulated and 14 downregulated genes. The highest proportion of upregulated genes encoded proteins involved in signal transduction (32%). Among the potentially relevant genes, PIP 5K1C, VIP, tropomodulin, and MMP2 encoded mediators known to influence outflow resistance. Others encoded functions which are new for the trabecular meshwork, but which are intrinsic to unrelated tissues. These new mechanisms appear as they could be of benefit for trabecular meshwork function. Matrix Gla protein (MGP), perlecan, osteomodulin, and osteoblast-specific factor are essential in cartilage and bone physiology whereas spectrin and ICAM4 are specific for blood cells and crucial in maintaining their shape and adhesion. In addition, MGP transcripts were stimulated by extracellular calcium and downregulated by TGF-beta1. We propose that MGP might be an important player in the adaptive homeostatic mechanism by contributing to maintain a softer trabecular meshwork tissue and facilitate aqueous humor outflow.
LBN 0.024% QD in the evening was noninferior to timolol 0.5% BID over 3 months of treatment, with significantly greater IOP lowering in subjects with OAG or OHT at all but the earliest time point evaluated, and demonstrated a good safety profile.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.