COPHAR-1105; NO. OF PAGES 6 Please cite this article in press as: Bucolo C, et al.: Pharmacological management of ocular hypertension: current approaches and future prospective, Curr Opin Pharmacol (2012), http://dx.doi.org/ 10.1016/j.coph.2012.09.012 Pharmacological management of ocular hypertension: current approaches and future prospective Claudio Bucolo 1 , Salvatore Salomone 1 , Filippo Drago 1 , Michele Reibaldi 2 , Antonio Longo 2 and Maurizio Giacinto Uva 2 Elevated eye pressure is the main risk factor for glaucoma, and intraocular pressure rises when the balance between aqueous humor formation and outflow resistance is compromised. In a normal eye there is a precise tune of aqueous outflow under the fine control of ciliary body and trabecular meshwork. Current pharmacological therapies for lowering the intraocular pressure in glaucoma include increasing aqueous humor outflow and suppression of aqueous humor production. However, most of antiglaucoma drugs currently on the market do not target the trabecular meshwork that represents the site of the pathology. This review focuses on pharmacological management of ocular hypertension with a particular attention to the future pharmacotherapy scenario. Addresses 1 Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania University, Catania, Italy 2 Department of Ophthalmology, Catania University, Catania, Italy Corresponding author: Bucolo, Claudio (claudio.bucolo@unict.it, bucocla@unict.it) Current Opinion in Pharmacology 2012, 13:xx–yy This review comes from a themed issue on Neurosciences Edited by Carlo Nucci, Nicholas G Strouthidis and Peng Tee Khaw 1471-4892/$ – see front matter, Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.coph.2012.09.012 Introduction Ocular hypertension is the main risk factor for glaucoma, a progressive optic neuropathy, which is the leading cause of blindness in industrialized countries. Epidemiological studies have shown that the risk of glaucoma increases by 12% with every 1 mmHg increase in intraocular pressure (IOP) [1]. When treatment is initiated for primary open- angle glaucoma (POAG), topical medications are the first choice therapy. There are five main classes of these topical drugs, and they include, beta-blockers, carbonic anhydrase inhibitors, prostaglandin derivatives, sym- pathomimetics and miotics. The molecules of the first two classes are ‘‘inflow’’ drugs, the other three are ‘‘out- flow’’ drugs. All these medications are licensed to treat glaucoma by reducing IOP. Currently, prostaglandin analogues and beta blockers are licensed for both first and second line uses, whereas the remainder are only licensed for second line use, according to the National Institute for Health and Clinical Excellence (NICE, http://guidance.nice.org.uk/CG85/Guidance) glaucoma guidelines. Pharmacological management of ocular hy- pertension is one of the most interesting and challenging endeavors facing the ocular pharmacology scientist. Further, there is a real need for ophthalmologists to have more potent medications available for this disease. This review focuses on pharmacological management of ocular hypertension with a particular attention to the novel molecules classified in two major classes: inflow and outflow drugs (Table 1). Inflow drugs b-Adrenoceptors and siRNA Beta-blockers are inflow suppressants, they lower IOP by decreasing aqueous humor production via b 2 receptor. This class of drugs is used since 30 years to treat glau- coma, but the b 2 receptor still represents a very interest- ing target. Currently, the innovative pharmacological approach consists in developing small interfering RNA (siRNA) to silence b 2 receptor. RNA interference (RNAi)-based drugs appear to be promising for glaucoma treatment, even though they possess several limitations, such as targeted delivery and safety. Ocular delivery represents one of the most challenging issues for this kind of molecules. Effects can be short-lived, as endo- nucleases and exonucleases and RNases that are present in many tissue microenvironments quickly degrade unmodified, naked siRNAs [2]. SYL040012 is a small siRNA that triggers RNAi, an endogenous cellular pro- cess in which double-stranded RNA can cause physio- logical gene silencing in organisms [3]. SYL040012 may potentially reduce IOP by knockdown of b 2 adrenergic receptors. This new pharmacological approach appears to be promising for glaucoma treatment, though delivery of siRNA into the retina represents a significant challenge. Melatonin receptors ligands Melatonin receptors, a class of G protein-coupled recep- tors (GPCRs), have been detected in ciliary body [4] and melatonin, an endogenous neuro-hormone, and some melatonin analogues are able to reduce the IOP in several species [5,6,7  ,8  ]. Recently, Alcantara-Contreras et al. [9  ] demonstrated that administration of melatonin in wild-type mice significantly reduced IOP, on the contrary IOP did not change in melatonin receptor type 1 (MT 1 ) knockout mice after drug administration. The signal Available online at www.sciencedirect.com www.sciencedirect.com Current Opinion in Pharmacology 2012, 13:1–6