Neuroprotection and Other Investigational Antiglaucoma Drugs

The primary goal of glaucoma therapy is to stop the loss of retinal ganglion cells (RGCs) by rescuing injured cells or regenerating new, functional cells to replace those that are lost. The classes of drugs discussed in the preceding chapters are used to reduce intraocular pressure (IOP), arguably the most important known risk factor for glaucomatous optic neuropathy. Although reducing IOP is often efficacious, in many cases achieving an appropriate target IOP for an individual patient may not halt progression. Over the past decades, our knowledge of neuronal function has greatly increased—and, along with it, the broader therapeutic concept of “neuroprotection.” Medically speaking, this notion includes many classes of agents whose principal function is to protect RGCs utilizing approaches in addition to modulating IOP. In this chapter, the following topics are covered: investigational antiglaucoma drugs, immunomodulation, gene- and cell-based treatments, and drug delivery.

INVESTIGATIONAL ANTIGLAUCOMA DRUGS

In the late 1970s, neuroprotection was introduced as a concept that surrounding neurons are vulnerable to secondary neuronal degeneration adjacent to the area of ischemic stroke (1). Although some clinical and experimental evidence provided proof of concept for pharmacologic intervention to protect the brain tissue from ischemic insults, the use of calcium channel antagonists and agents that decrease the impact of excitatory amino acids in acute stroke has not been systematically evaluated in clinical studies (2,3).

In glaucoma, lowering the IOP has been validated by clinical trials as a neuroprotective approach to slow progression of glaucomatous optic neuropathy (see Chapter 29). Non–IOP-based approaches have also been described earlier, such as diphenylhydantoin (4). Currently, no glaucoma treatments approved by the U.S. Food and Drug Administration (FDA) are non-IOP (or neuroprotective) based, in part because the end points for efficacy in the past were based on pressure lowering. However, an interdisciplinary dialogue has been initiated to establish evidence-based guidelines for evaluating clinical trial end points for non–IOP-based treatment interventions (5).

In this section, the discussion is focused on IOP-based and non–IOP-based drugs that are being tested in registered clinical trials (www.clinicaltrials.gov/ct2/home) with the exception of cannabinoids. These include anecortave, cannabinoids, cellular cytoskeleton modulators, cellular signaling pathways, memantine, nitric oxide synthase (NOS) inhibitors, prostanoid agents, and rho kinase inhibitors.

Anecortave

Anecortave, an angiostatic steroid without glucocorticoid activity, has been evaluated for its therapeutic potential for glaucoma and age-related macular degeneration (6–8). Although there was promising IOP-lowering effect for the anterior justascleral depot injection of anecortave acetate in phase II and early phase III clinical trials (6–9), it is no longer being pursued for glaucoma treatment indications.

Cannabinoids

The role of marijuana for medical purposes continues to be controversial and complex. In the United States, marijuana is a Schedule I-controlled substance and is illegal under federal law. There is growing public support for its medicinal use and 14 U.S. states have legalized medical marijuana. Containing more than 460 active chemicals and over 60 unique cannabinoids, marijuana has the purported use for severe nausea and vomiting from chemotherapy, weight loss associated with debilitating illnesses like HIV infection and cancer, spasticity secondary to neurologic diseases, pain syndromes, and glaucoma (10). In addition, there are endogenous bioactive lipid compounds, called endocannabinoids, which have been implicated in physiologic functions, both in the central and peripheral nervous systems and in peripheral organs (11). The pharmacology of the cannabinoids includes the cannabinoid (CB) receptors type 1 and type 2, or CB1 and CB2, respectively, transporters, and enzymes that break down these molecules (12). The CB1 receptor is present in the ciliary body of rat and human (13,14).

The evidence for its use for glaucoma is based on the observation that smoking marijuana lowers IOP (15). The primary active ingredient in marijuana, tetrahydrocannabinol (THC), effectively lowered IOP when given orally or intravenously, but appeared to have no effect on topical application in humans (16–18). However in a monkey model of glaucoma, topical application of WIN 55212-2, a cannabinoid selective agonist for the cannabinoid type 1 receptor (CB1), lowered IOP by decreasing aqueous humor flow (19). Marijuana has also been shown to decrease aqueous humor flow in humans (20). In a rat model of glaucoma, weekly injections of THC lowered IOP in the episcleral vessel cauterized eye, but not the contralateral untreated eye, and attenuated the loss of ganglion cell death (21).

The acute systemic side effects include tachycardia, hypotension, and euphoria, and long-term adverse effects include pulmonary fibrosis and impaired neurologic behavior and performance (10). Ocular side effects associated with marijuana inhalation include conjunctival hyperemia, a slight miosis, and reduced tear production (22). In particular, the most disturbing adverse reaction is systemic hypotension, which may be associated with reduced perfusion of the optic nerve head and could be detrimental in protecting against progressive glaucomatous optic atrophy (23). These side effects of the cannabinoids thus far tested in humans seriously limit their usefulness in the treatment of glaucoma.

Cellular Cytoskeletal Modulators

Ethacrynic acid is a prototype agent in this drug class. It is a sulfhydryl-reactive diuretic that has been shown to markedly change actin, alpha-actinin, vinculin, and vimentin in cultured trabecular meshwork cells (24), which is thought to alter trabecular meshwork shape as the main mechanism of action for lowering IOP. In monkeys, intracameral injection of this agent increased aqueous outflow (25) and lowered IOP but it also caused corneal edema (26). However, in human clinical trials, although there was IOP reduction, there were concerns of corneal toxicity and trabecular meshwork toxicity (27–29). These latter limitations precluded the clinical application of ethacrynic acid in the management of glaucoma.

Latrunculins are part of a family of natural toxins produced by a marine sponge Latrunculia and have been investigated for their potential therapeutic use due to disrupting the actin cytoskeleton (30). Topical application of latrunculin B lowers IOP in monkeys by increasing outflow facility and does not adversely affect the cornea (31). Histologic features of the treated monkey eye showed the following changes: loss of microfilament integrity in trabecular meshwork cells on the collagen beams; changes in cytoplasmic projections; reorganization of intermediate filaments in Schlemm canal inner wall cells; and massive “ballooning” of the juxtacanalicular region (32). There were no other apparent effects in the trabecular meshwork, and the corneal endothelium was unchanged. Based on these apparently selective effects on the trabecular meshwork, the compound INS115644 is now in clinical trials.

Other Cellular Signaling Pathways

Among this broad category, there is a clinical trial of an angiotensin II receptor antagonist, olmesartan (DE-092), currently being tested in Japan to determine safety and efficacy for lowering IOP. Components of the renin–angiotensin system are expressed in the eye (33), which is the rationale for testing the efficacy of such agents to lower IOP.

Another agent in clinical trials in Japan is lomerizine (DE-090), which is a calcium channel blocker that is currently approved for treating migraines. There has been long-standing interest in the potential use of calcium channel blockers for glaucoma based on the physiologic role of these channels in cardiovascular physiology (34). Several older studies have shown a favorable effect of calcium channel blockers in slight improvement or lack of progression in visual fields over various times of follow-up from patients with normal-tension glaucoma compared with similar groups not receiving such medication (35,36). In a recent randomized study of nilvadipine (2 mg twice daily) treatment versus placebo, nilvadipine-treated patients with normal-tension glaucoma showed a slightly slow visual field progression compared with placebo-treated patients over 3 years (37). Of interest, the posterior choroidal circulation increased in treated patients, which supports the potential to improve vascular perfusion to the optic nerve head. Also, there was no significant change from baseline or intergroup difference was seen in blood pressure or pulse rate. Currently, however, the level of evidence at this time, as well as the potential serious systemic side effects of calcium channel blockers, does not support the use of this class of drugs for the routine management of glaucoma.

Neurotrophins are peptides that have an important role in the development and maintenance of various neuronal populations (38). In the adult human retina, there are neural progenitor cells that can be induced to differentiate into neuronal phenotypes with basic fibroblast growth factor (39). In models of glaucoma, obstruction to retrograde transport of neurotrophins at the optic nerve head results in the deprivation of neurotrophic support to RGCs, which contributes to apoptotic cell death (40). There was a recent report of beneficial effects of nerve growth factor eye drops with reduced RGC death in a rat model of glaucoma treated for 7 weeks and “long lasting improvements” in psychofunctional and electrofunctional tests in humans with glaucoma treated for 3 months (41). The results of this study should be interpreted with caution since the number of participants was small and follow-up testing was performed only 6 months after baseline testing. Other clinical trials have shown that visual field performance can fluctuate considerably and individual test locations exhibit both short- and long-term sensitivity variations (42). Additional guarded enthusiasm is based on a previous study showing that nerve growth factor was not effective in delaying RGC death because the protective effect is mediated through only one of the receptors, the prosurvival TrkA receptor, and not proapoptotic p75 receptor (43). In other retinal diseases, nerve growth factor was not very effective compared with ciliary neurotrophic factor, brain-derived neurotrophic factor, glia-derived neurotrophic factor, and others with development in gene-modulated protein therapy or gene transfer (44).

Memantine

Memantine is an N-methyl-d-aspartate (NMDA) receptor antagonist (45); it is used for the treatment of Parkinson disease, vascular dementia, and Alzheimer disease (46

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