Ophthalmological Research

• •Global Burden: It is estimated to affect over 80 million people worldwide, with this number projected to rise to over 111 million by 2040 due to an aging population.

• •Leading Cause of Blindness: It is the second leading cause of blindness globally (after cataracts), but it is the leading cause of irreversible blindness.

• •Age-Related: Prevalence increases dramatically with age. It is rare before age 40 but becomes significantly more common in older populations, affecting around 2-3% of people aged 40-80.

• •Geographical and Racial Variation:
• • ◦ Primary Open-Angle Glaucoma (POAG) is the most common form, accounting for about 90% of cases in the United States and Europe. It is up to 4-6 times more prevalent in individuals of African and Hispanic descent compared to those of European descent, and it often presents earlier and is more severe.
• • ◦ Primary Angle-Closure Glaucoma (PACG) is more common in East Asian populations and in people with anatomically shallower anterior chambers of the eye.

The two main types, POAG and PACG, have distinct mechanisms:

• •A. Primary Open-Angle Glaucoma (POAG)

• •Core Mechanism: Increased Resistance to Aqueous Humor Outflow through the trabecular meshwork.
• • ◦ Aqueous humor, produced by the ciliary body, normally drains out of the eye primarily via the trabecular meshwork and Schlemm's canal (the conventional pathway).
• • ◦ In POAG, this drainage system becomes less efficient, akin to a clogged filter. The exact cause is multifactorial but involves:
• • ▪ Increased rigidity and loss of cells in the trabecular meshwork.
• • ▪ Accumulation of extracellular material in the drainage pathways.
• • ◦ This leads to a gradual, painless increase in IOP.

• •Optic Neuropathy: The elevated IOP is the primary risk factor for optic nerve damage, but the exact mechanism of RGC death is complex and involves:
• • ◦ Mechanical Stress: Direct compression of the optic nerve head lamina cribrosa, damaging the RGC axons.
• • ◦ Ischemia: Compression of the blood vessels supplying the optic nerve head, reducing blood flow and causing ischemic damage.
• • ◦ Excitotoxicity & Neuroinflammation: Elevated IOP can trigger the release of glutamate and other neurotoxic substances, leading to inflammatory processes that further damage RGCs.

• •Normal-Tension Glaucoma (NTG): A significant subset of POAG patients have optic nerve damage and visual field loss despite having IOP within the normal statistical range. This highlights that factors beyond IOP are critical, including vascular dysregulation (e.g., migraines, Raynaud's phenomenon), low cerebrospinal fluid pressure, and increased susceptibility of the optic nerve to even normal pressure levels.

• •B. Primary Angle-Closure Glaucoma (PACG)

• •Core Mechanism: Physical Blockage of the Drainage Angle by the iris.
• • ◦ The drainage angle between the iris and the cornea is anatomically narrow.
• • ◦ When the pupil dilates or the lens thickens with age, the iris can be pushed forward, obstructing the trabecular meshwork (appositional closure) or adhering to it (synechial closure).

• •Clinical Presentation:
• • ◦ Acute Angle-Closure: A sudden, complete blockage causes a rapid, dramatic rise in IOP. This is an ophthalmic emergency presenting with severe eye pain, headache, blurred vision, halos around lights, nausea, and vomiting.
• • ◦ Chronic Angle-Closure: The angle closes gradually over time, causing a slower rise in IOP and damage similar to POAG, often without acute symptoms.

• •A. Pharmacological (Medications)
• •First-line treatment, especially for POAG. Eye drops work by either reducing aqueous production or increasing its outflow.

• •Prostaglandin Analogs (e.g., Latanoprost, Bimatoprost, Travoprost):
• • ◦ Mechanism: Increase uveoscleral outflow (an alternative drainage pathway).
• • ◦ Role: First-line therapy due to their high efficacy, once-daily dosing, and minimal systemic side effects.

• •Beta-Blockers (e.g., Timolol):
• • ◦ Mechanism: Reduce aqueous humor production by the ciliary body.
• • ◦ Role: Former first-line, now often used as an adjunct. Can have systemic side effects (e.g., bradycardia, bronchospasm, fatigue).

• •Alpha-2 Adrenergic Agonists (e.g., Brimonidine):
• • ◦ Mechanism: Reduces aqueous production and may increase uveoscleral outflow.
• • ◦ Role: Adjunctive therapy. Can cause allergic conjunctivitis.

• •Carbonic Anhydrase Inhibitors (e.g., Dorzolamide - drop; Acetazolamide - oral):
• • ◦ Mechanism: Reduces aqueous production.
• • ◦ Role: Adjunctive therapy. Oral form is used for acute emergencies.

• •Rho Kinase Inhibitors (e.g., Netarsudil):
• • ◦ Mechanism: A newer class that both increases outflow through the trabecular meshwork and reduces episcleral venous pressure.
• • ◦ Role: Used when other medications are insufficient or not tolerated.

• •For Open-Angle Glaucoma:
• • ◦ Selective Laser Trabeculoplasty (SLT): Uses a low-energy laser to selectively target pigmented cells in the trabecular meshwork, improving drainage facility. It is increasingly used as a first-line treatment alternative to drops due to its excellent safety profile and ability to improve medication adherence.

• •For Angle-Closure Glaucoma:
• • ◦ Laser Peripheral Iridotomy (LPI): A small hole is created in the peripheral iris to allow aqueous humor to flow from the posterior to the anterior chamber, bypassing the pupil block. This deepens the anterior chamber and opens the drainage angle. It is the definitive preventive and treatment procedure for PACG.

• •Minimally Invasive Glaucoma Surgery (MIGS): A newer class of procedures that are safer than traditional surgery but offer more modest IOP reduction. They are often performed concurrently with cataract surgery. Examples include the iStent, Hydrus Microstent, and Kahook Dual Blade goniotomy.

• •Trabeculectomy: The traditional gold standard surgery. A new drainage channel is created surgically, allowing aqueous to flow out of the eye and form a controlled blister (a "bleb") under the conjunctiva, from where it is absorbed.

• •Glaucoma Drainage Devices (e.g., Ahmed, Baerveldt tubes): A small tube is inserted into the anterior chamber to shunt aqueous humor to an equatorial plate attached to the eye, where the fluid is absorbed. Used in complex or refractory cases where trabeculectomy has failed or is likely to fail.

• •At Panaceutics, our research and intervention are of three folds; first, we seek to reverse the loss of cells within the trabecular meshwork (TM) by specially-formulated Breviflorex which contain botanicals which specifically modulate oxidative stress, prevent cell death via apoptosis, and thus, maintain resident stem cell population. While the other botanicals in Breviflorex activate largeconductance Ca²⁺-activated K⁺ (BKca) Channels within the trabecular meshwork (TM) which in turn increases aqueous humor outflow, and decreases intraocular pressure (IOP). The main carbonic anhydrase (CA) isoforms in the eye (CA-II and CA-IV) are also inhibited by Breviflorex. Secondly, within the RGCs, other synergistic botanicals within Breviflorex modulate excitotoxicity and neuroinflammation associated with optic nerve damage by regulating glutamate and Ca²⁺- activated processes. Breviflorex increases the expression of BDNF (brain-derived neurotrophic factor) which promotes the regeneration RGCs.