At present, the only effective approach available to treat glaucoma is to reduce IOP. Hypotension medications used clinically include aqueous humor secretory inhibitors (e.g., beta-adrenergic receptor antagonists, alfa2-adrenergic agonists, and carbonic anhydrase inhibitors), uveoscleral-outflow enhancers (e.g., prostaglandin analogues), cholinergic drugs that affect trabecular outflow indirectly by contracting the ciliary muscle and deforming the TM, and epinephrine drugs that work on both the TM (inducing changes in cell shape through a beta-adrenergic receptor-cAMP/PKA-mediated cellular relaxation) and the uveoscleral (mediating endogenously synthesized prostaglandins) outflow routes. Secretory suppression may affect supplies of oxygen and nutrients to the non-vascularized cornea, lens and TM. Prostaglandin analogues do not substantially improve trabecular outflow. Cholinergic drug effects on the pupil and accommodation limit their clinical use. Epinephrine-like drugs are no longer used clinically because of their local and systemic side effects. Thus, there are no TM-selective outflow enhancers in current clinical use.
Numerous studies indicate that dynamics of the TM cytoskeleton may be involved in the regulation of aqueous humor outflow. Reduction of outflow resistance induced by cytoskeletal agents acting directly on the TM/Schlemm’s canal of glaucomatous eyes may mimic the normal physiological function. However, cytoskeletal drugs could, in principle, have detrimental effects on other anterior segment tissues, especially the cornea. Lower drug concentrations in larger volumes could minimize corneal toxicity without significantly sacrificing the drug’s effect on the TM following topical administration. This speculation is supported by several studies: intracameral doses of ECA reduce IOP in glaucoma patients without inducing corneal or anterior segment side effects (Melamed et al., 1992
); a maximal resistance-reducing intracameral dose of H-7 produces general relaxation and expansion in the TM/Schlemm’s canal but no visible changes in the corneal endothelium or ciliary epithelium (Sabanay et al. 2000
; Tian et al., 2001
); and multiple doses of 0.01% topical LAT-B, which decreases IOP similar to a single dose of 0.02% LAT-B, did not increase corneal thickness as did the latter (Okka et al., 2004
; Peterson et al., 2000
). However, the potential cornea toxicity is still an obstacle to the use of higher concentrations of the drugs topically for a greater outflow facility increase.
To overcome this problem, novel methods of drug delivery need to be developed. Receptors might be different in different cell types or ECM, so understanding better the bio-molecular differences between cornea and TM, the different molecular targets or mechanisms for different actin-disrupting agents, and a pro-drug, gene therapy or other site-activated approach, could facilitate development of TM-selective “drugs” that reduce outflow resistance without affecting other ocular tissues.