NEW TREATMENT MODALITY IN GLAUCOMA

1. Newer treatment modalities of glaucoma
Dr. ATIF RAHMAN RAINI

2. Glaucoma
 Glaucoma is a chronic optic neuropathy involving damage to the retinal
ganglion cells and their axons.
 Hypothesised that the retinal ganglion cells and their axons become damaged
through various, specific insults.
 However, the pathogenesis of glaucoma is still largely unknown.
 IOP is a major risk factor

3. Increased intraocular pressure risk
factors and therapies
 Lowering intraocular pressure remains the only currently approved medical
course of treatment.
 Conventional therapy has focused on affecting the balance of aqueous humor
production and outflow, as a decrease in net aqueous humor volume results in
decreased intraocular pressure.

4. Current therapies to reduce IOP
 includes medication eye drops, laser treatment to the trabecular meshwork,
or surgery.
 Six classes of drug currently approved for lowering IOP
 miotics,
 beta-blockers
 alpha-agonists
 epinephrine derivatives
 carbonic anhydrase inhibitors
 prostaglandin analogues

5.  Although reducing IOP is often efficacious, in many cases
achieving an appropriate target IOP for an individual
patients may not halt the progression.

6.  Primary goal of glaucoma therapy is to stop
the loss of retinal ganglionic cells by
rescuing injured cells or regenerating new,
functional cells to replace those that are
lost.

7.  A number of mechanisms have been proposed to explain
retinal ganglion cell death in glaucoma, including
ischemia, oxidative stress, excitotoxicity, defective axonal
transport, trophic factor withdrawal, and
neuroinflammation.

8.  Broader therapeutic concept – NEUROPROTECTION

9. Novel medical therapy
 Includes
 Anecortave
 Cannabinoids
 Cellular cytoskeletal modulators
 Memantine
 Rho kinase inhibitors

10. Anecortave
 Angiostatic steroid without glucocorticoid activity
 Evaluated for therapeutic potential in glaucoma and ARMD
 No longer being persued for glaucoma treatment studies
(Robin AL, Clark AF, Covert DW et al. anterior juxtascleral delievery of
anecortave acetate in eyes with POAG: a pilot investigation. Am J
Ophthalmology. 2009;147(1):45-50.)

11. Cannabinoids
 Marijuana
 Acts on cannabinoid receptors – CB1 and CB2
 CB1 – present in the ciliary body of human
 Evidence for its use in glaucoma came from the observation – smoking
marijuana decreases IOP.
 Primary active ingredient- tetrahydrocannabinol (THC)
 THC effectively lower IOP when given orally or I.V. but not effective
topically

12.  Ocular side effect – conjunctival hyperemia, slight miosis, reduced tear production
 Systemic side effect- tachycardia, hypotension, euphoria
 Long term side effect- pulmonary fibrosis, impaired neurological behaviour
 SYSTEMIC HYPOTENSION may leads to reduced optic nerve
perfusion, limit their usefulness in Glaucoma

13. Cellular cytoskeletal Modulators
 Ethacrynic Acid- diuretic
 Change actin, alpha- actinin,vinculin and vimentin in cultured trabecular
meshwork
 Altering trabecular meshwork shape – main mechanism to decrease IOP
 Human clinical trial – though there is IOP reduction but corneal toxicity and
trabecular toxicity precluded its clinical application
(Tingey DP, Ozment RR, Schoeder A et al. the effect of intracameral ethacrynic acid
on IOP in patients with glaucoma. Am J Ophthalmology. 1992;113(6):706-711.)
( Jhonson Dh, Tschumper RC. Ethacrynic acid:outflow effects and toxicity in human
trabecular meshwork in perfusion organ culture. Curr Eye Res. 1993:12(5):385-396.)

14.  Latrunculins
 Disrupt the actin cytoskeleton
 Selective effects on trabecular meshwork
 Compound INS115644- now in clinical trials
(Sabanay I, Tian B, Gabelt BT et al. latrunculin B effect on trabecular meshwork
and cornel endothelial morphology in monkeys. Exp Eye Res.2006;82(2):236-246.)

15. memantine
 N-methyl-D-aspartate receptor antagonist
 Used for treatment of Parkinson disease, vascular dementia, Alzheimer
disease
 NMDA an ion channel is activated by glutamate and coagonist glycine leads to
extracellular calcium to enter cells.
 Excess activation of NMDA signaling cascade leads to “ EXCITOTOXICITY” leads
to overloads of intracellular ions in neuron causes apoptosis.
 The concept of excitotoxicity is based on the observation that subcutaneous
glutamate injection causes inner retinal damage.
(Lucas Dr, Newhouse JP. The toxic effect of Sodium l- glutamate on the inner
layers of retina. AMA Arch Ophthalmol.1957;58(2):193-201)

16.  After completing phase 3 clinical trial in United States, memantine did meet
glaucoma end points of efficacy.
(danesh- Mayer HV, Levin LA.neuroprotection :extrapolating from neurologic
diseases to eye. Am J Ophthalmol. 1996;114(3):299-305.)

17. Rho kinase inhibitors
 Two types of rho kinases- ROCK1 and ROCK2
 Serine – threonine kinases downstream effectors of Rho GTPase
 Regulate smooth muscle contraction in a calcium independent manner
 By selectively inhibiting ROCK activity, aqueous humor drainage through the
trabecular meshwork can be increased
 INS117548, DE-104, RKI983 in clinical trials
( RaoVP, Epstein DL. Rho GTPase/Rhokinase inhibition as a novel target for the
treatment for glaucoma. BioDrugs.2007;21(3):239-348.)

18. Thank You…….