Circadian rhythm and the molecules involved in it, such as melanopsin and melatonin, play an important role in the eye to regulate the homeostasis and even to treat some ocular conditions. As a result, many ocular pathologies like dry eye, corneal wound healing, cataracts, myopia, retinal diseases, and glaucoma are affected by this cycle. This review will summarize the current scientific literature about the influence of circadian patterns on the eye, focusing on its relationship with increased intraocular pressure (IOP) fluctuations and glaucoma. Regarding treatments, two ways should be studied: the first one, to analyze if some treatments could improve their effect on the ocular disease when their posology is established in function of circadian patterns, and the second one, to evaluate new drugs to treat eye pathologies related to the circadian rhythm, as it has been stated with melatonin or its analogs, that not only could be used as the main treatment but as coadjutant, improving the circadian pattern or its antioxidant and antiangiogenic properties.

Melatonin is a neurohormone which is not only produced by the pineal gland but also by several ocular structures. One of the main physiological roles of melatonin is the reduction of intraocular pressure (IOP). Using both control C57BL/6J and glaucomatous DBA/2J mice and by means of Tono-lab tonometry it has been studied the effect of melatonin and 5-Methoxycarbonylamino-N-Acetyltryptamine, 5-MCA-NAT, when the glaucomatous pathology is fully established, and the pharmacological behavior compared to the control mice. In addition, 5-MCA-NAT has been tested in its effect ameliorating the rise of IOP in the glaucoma model. The results have demonstrated that melatonin and 5-MCA-NAT, can reduce IOP in a concentration manner. The EC50 values for melatonin in control and glaucomatous animals were 34 µM and 50 µM respectively. Interestingly, melatonin decreased IOP in 19.4 ± 3.7 % and 32.6 ± 6.0 % in the control and glaucomatous mice respectively, when the animals were studied at 12 months of age. 5-MCA-NAT reduced IOP in the same manner and was able to stop the IOP progression in the glaucomatous mice. The use of melatonin receptor antagonists showed that the hypotensive effects were blocked by the MT2 receptor antagonists luzindole and 4-PPDOT in the case of melatonin and only by 4-PPDOT in the case of 5-MCA-NAT. In conclusion, melatonin and 5-MCA-NAT can effectively reduce IOP in a model of glaucoma, their hypotensive effects being more profound in the glaucoma model than in the control animals.

Melatonin and its analog 5-MCA-NAT (5-methylcarboxyamino-N-acetyl tryptamine) are active compounds reducing intraocular pressure (IOP). This action is mediated through MT2 and the putative MT3 melatonin receptor, producing a transient reduction of IOP that lasts for a few hours and has not yet been characterized. The use of melatonin and its analog are causing a decrease in chloride efflux from rabbit nonpigmented epithelial cells (NPE), possibly explaining the decrease in IOP. Melatonin and 5-MCA-NAT inhibited rabbit NPE chloride release in a concentration-dependent manner, whereas the pD2 values were between 4.5 ± 1.2 and 4.4 ± 1.0, respectively. Melatonin hypotensive action was enhanced by the presence of MT2 antagonists, such as DH97 (N-pentanoyl-2-benzyltryptamine) and 4-P-P-DOT (4-phenyl-2-propionamidotetralin) and by the nonselective melatonin receptor antagonist luzindole. Prazosin (1.5 µM) partially reverses the melatonin action by acting as a selective MT3 antagonist. However, at 15 nM it acts as an α-adrenergic receptor antagonist, enhancing the melatonin effect. Regarding the intracellular pathways triggered by melatonin receptors, neither phospholipase C/protein kinase C pathway nor the canonical reduction of intracellular cAMP was responsible for melatonin or 5-MCA-NAT actions. On the contrary, the application of these substances produced a concentration-dependent increase of cAMP, with pD2 values of 4.6 ± 0.2 and 4.9 ± 0.7 for melatonin and 5-MCA-NAT, respectively. In summary, melatonin reduces the release of chloride concomitantly to cAMP generation. The reduction of Cl(-) secretion accounts for a decrease in the water outflow and therefore a decrease in aqueous humor production. This could be one of the main mechanisms responsible for the reduction of IOP after application of melatonin and 5-MCA-NAT.

Glaucoma is an optical neuropathy associated to a progressive degeneration of retinal ganglion cells with visual field loss and is the main cause of irreversible blindness in the world. The treatment has the aim to reduce intraocular pressure. The first therapy option is to instill drugs on the ocular surface. The main limitation of this is the reduced time of the drug staying on the cornea. This means that high doses are required to ensure its therapeutic effect. A drug-loaded contact lens can diffuse into the post lens tear film in a constant and prolonged flow, resulting in an increased retention of the drug on the surface of the cornea for up to 30 min and thus providing a higher drug bioavailability, increasing the therapeutic efficacy, reducing the amount of administered drug, and thereby provoking fewer adverse events. Several different systems of drug delivery have been studied in recent decades; ranging from more simple methods of impregnating the lenses, such as soaking, to more complex ones, such as molecular imprinting have been proposed. Moreover, different drugs, from those already commercially available to new substances such as melatonin have been studied to improve the glaucoma treatment efficacy. This review describes the role of contact lenses as an innovative drug delivery system to treat glaucoma.

Dry eye disease affects a substantial segment of the word population with increasing frequency. It is a multifactorial disease of the ocular surface and tear film, which causes ocular discomfort, visual disturbances, and tear instability with potential damage to the cornea and conjunctiva. Because of its multifactorial etiology, the use of different pharmacological treatment for dry eye treatment has been proposed, which include anti-inflammatory molecules, lubricants or comfort agents, and secretagogues. However, in some cases these pharmacological approaches only relieve symptoms temporarily, and consequently, eye care professionals continue to have difficulties managing dry eye. To improve pharmacological therapy that allows a more efficient and long-term action, effective ocular drug delivery of the currently available drugs for dry eye treatment is required. Contact lenses are emerging as alternative ophthalmic drugs delivery systems that provide an increased residence time of the drug at the eye, thus leading to enhanced bioavailability and more convenient and efficacious therapy. In this article, we reviewed the different techniques used to prepare contact lens-based drug delivery systems and focused on articles that describe the delivery of compounds for dry eye treatment through contact lenses.