The management of glaucoma and macular degeneration

Abstract

Glaucoma [1–8] and macular degeneration [9–11] are among the ophthalmologic diseases increasingly affecting the aging population worldwide. It is estimated that around 76 million patients will suffer of glaucoma in 2020, whereas the prevalence in the population between 40 and 80 years old is expected to increase to 111.8 million in 2040 [2]. Both conditions are neuropathies and are associated with vision loss, eventually leading to blindness. Glaucoma is a multifactorial disease, with the most salient feature being an elevated intraocular pressure (IOP), which still is nowadays the only clinically modifiable risk factor for its development and progression [3–6]. Macular degeneration, also denominated agerelated macular degeneration (AMD) is characterized by the loss of vision in the central part of the visual field, involving the central part of the retina where the macula is found [9–11]. Blurred vision and/or visual hallucinations may also occur in AMD patients. These conditions, together with glaucoma, represent the leading causes of blindness in the industrialized countries [1–6,9]. AMD is classified in two main types, the dry or non-neovascular AMD, with a prevalence of 90% among the affected patients [11], and the wet, or neovascular AMD, which involves abnormal neo-vascularization under or nearby the macula [12,13]. The pathogenesis of AMD is poorly understood, but the prevalent hypothesis is nowadays that metabolic and more precisely mitochondrial dysfunctions are the main triggering factors of the disease [14]. On the other hand, glaucoma pathogenesis is much better understood, compared to that of AMD. There are two main categories of this condition: open-angle glaucoma (OAG) and closed-angle glaucoma [1,2]. OAG is the most common form, with a prevalence of about 2% in adults older than 40 years and develops progressively, leading to an elevated IOP of more than 18 mm Hg. In contrast, closed-angle glaucoma occurs unexpectedly showing signs and symptoms such as blurred vision, eye pain, red eyes and similar vision problems [1,2]. IOP is the result of the balance between the production in the ciliary body of aqueous humor (AH), a fluid rich in bicarbonate but containing many other ion and molecules, and its outflow [1–3,6]. Trabecular meshwork (TM) and Shlemm’s canal (SC) are responsible for the drainage of up to 80% of the total AH within the eye, being considered as the conventional outflow pathway, whereas ciliary muscle, supraciliary and suprachoroidal spaces constitute an alternative or unconventional outflow pathway [1–3,6]. Drugs used for the treatment of glaucoma are as a consequence molecules which can interact with the production or the outflow of the AH. Nowadays there are six classes of pharmacological agents clinically used for the management of glaucoma: the β-adrenergic blockers [15], the systemically or topically acting carbonic anhydrase inhibitors (CAIs) [16–19], the α-adrenergic agonists [20], the cholinergic agonists [21], the prostaglandin analogs [22], and the recently introduced in clinical practice Rho kinase inhibitors [8]. It should be mentioned that other targets, such as the melatonin receptors [23], the fatty acid amide hydrolase (FAAH) [3,23]; the adenosine receptors [3,4,21], or nitric oxide, alone [5] or combined with other pharmacologic agents [24,25] were also explored and led to interesting experimental approaches for the management of glaucoma, which however were not yet translated to the clinic. Considering the wealth of new data in glaucoma and macular degeneration research/management, the current special issue of Expert Opinion on Therapeutic Patents presents a collection of review articles and several patent evaluations which discuss the latest aspects of literature and patent literature in the field. The adrenergic agonists and antagonists, which are among the most used but rather outdated anti-glaucoma drugs, are reviewed by Nocentini and Supuran [26], which present a state of the art review of the field. The carbonic anhydrase (CA) inhibitors (CAIs) are also a rather old class of anti-glaucoma agents [7,27,28]. However, as shown in the review of Supuran et al. [29], the many exciting developments in this field were made possible by a significant number of relevant findings on the various new classes of CAIs reported in the last decade, which differ significantly from the classical sulfonamide inhibitors [30]. The next review articles present the Rho-kinase inhibitors [31], the newest class of anti-glaucoma agents that arrived in clinics in 2017 (ripasudil) and 2019 (netarsudil), respectively (Figure 1), with their particular pharmacologic and chemical features. The prostaglandin (PG) analogs, a highly successful class of anti-glaucoma agents, with many representatives widely used clinically, alone or in combination with other agents, were reviewed by Angeli and Supuran [32]. Some new drug targets