MMPs, Hyaluronidases, Chondroitinases AL-3037A, t-BHQ

AL-6598, BW245C, Sulprostone AGN192093

Inhibit AH formation and promote AH efflux via TM and CM-associated uveoscleral outflow pathway

Inflow inhibition

Alteration in signal transducer

Outflow via multiple mechanisms

Inflow and outflow promotion; confusing literature

Most increase retinal blood flow to provide protection in normal-tension glaucoma patients

Mostly via outflow, but mechanism needs to be defined

Undefined mechanism

Apparently promotes outflow, especially when combined with PGF2a

Degrade ECM to promote outflow. May upregulate ECM-degrading enzymes such as MMPs

Multiple mechanisms of action involving cAMP production; Ca2 + mobilization leading to relaxation/contraction of ciliary muscles/TM

to locally produced neurotoxic agents (e.g., glutamate, oxidants, nitric oxide (NO), cytokines, and vasogenic/neurotoxic peptides like endothelin). Consequently, there is now a heightened search for drugs that are neuroprotective. Obviously, agents that possess both ocular hypotensive and neuroprotective activities will be extremely useful in the future. Even though much preclinical data support such dual pharmacophoric claims for brimonidine83 and betaxolol,84 the clinical endpoints for neuroprotection afforded by these drugs are not yet fully realized. In the meantime, numerous classes of drugs have been studied as potential neuroprotectants for the treatment of glaucoma (Figure 8), including caspase inhibitors, nitric oxide inhibitors (e.g., aminoguanidine), calcium channel blockers (e.g., nimodipine and betaxolol),82 endothelin, and tumor necrosis factor receptor antagonists. Furthermore, glutamate receptor subtype antagonists (e.g., eliprodil, memantine, and CP101-606), flupirtine, HU-211, anti-apoptotic agents, and certain neurotrophins/growth factors have exhibited neuroprotective activity in experimental models of glaucoma.2,3 Memantine is currently in clinical trials as a retinoprotectant,85 but its clinical efficacy and utility remains undefined. Age-Related Macular Degeneration

New research areas for the treatment of AMD will be guided by a combination of biochemical reasoning, results from in vitro and animal models, and retrospective and prospective epidemiological studies of disease-associated risk factors in humans. This last method represents an especially relevant source that will likely increasingly inform therapeutic research, as evidenced for example by the CFH mutation-AMD genetic linkage discovery. Table 3 summarizes some potential new AMD research areas and therapeutic targets.

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