Pathogenic treatment of Open-angle glaucoma with normatin and bestoxol

Despite wide array of pharmaceutical medications, modern laser and surgical methods glaucoma still stays one of the most causes of irreversible blindness in Asia, Europe and Africa equally. According to the latest data only in U.S there are 4 million people with glaucoma (every 25 of American) 62 000 of them are practically blind (1).

In pathogenesis of primary glaucoma main importance is in destructive processes in aqueous humor drainage system (2), eye hemodynamic (3), normal consistency of aqueous humor (4), transmembrane potential (5) changes and others. Among these main factors functional state of adrenergic receptors in eye biostructures is also played high attention. Particularly many authors (6, 7) consider that development of glaucoma is linked to b-adrenergic receptors and process delay to a-adrenergic receptor activation.

b-adrenergic receptors are genetically determined protein structures embedded in cellular plasma membrane with very labile conformation (8). Even minor pathologic process causes derangement of their normal function.

In the eye ‘a’ and ‘b’ adrenergic receptors are situated in the tissue structures of  ciliary body and drainage system. They are in such biostructures that determine aqueous humor production and drainage. In particular a- receptor stimulation causes intraocular pressure (IOP) decrease as well as production rate per/min of aqueous humor, inhibition of ciliary body hemodynamic and increase in aqueous humor “ejection ease coefficient”.

b- receptor stimulation causes decrease in ophthalmic tonus, but increases aqueous humor production rate and its ejection ease coefficient. b receptor blockage decrease aqueous humor production rate and its total volume.

In the process of glaucoma development membrane lipid peroxidation processes  (LPO) (9) is also very important.

In normal physiologic situations lipid peroxidation processes always take place in cellular membranes to renew membrane lipid composition, influence permeability and membrane associated enzyme actions. Membrane is universal regulating cooperative structure. Its structural change acts like a trigger that drives the cell from one metabolic state into another (10). This is why lipid peroxidation is important in metabolic regulation process. Level of lipid peroxidation is very low in healthy environment because it is under very sensitive regulatory system.

Today lipid peroxidation in biomembranes is considered under many pathologic disorders as a universal mechanism of damaging membranes (11).

Intensification of the role of lipid peroxidation in glaucoma development that is discussed in various points by many authors pointed us to pay special attention to connection between LPO and adrenergic receptors.

Particularly many authors note that during LPO processes binding affinity of agonists and antagonists to their receptors is markedly decreased. This is proved by observing in vitro interaction of: etorphin (opiate agonist) (12), dihydroergocryptan (a- adrenergic antagonist) (13), Clonidine a-agonist (14), anticholinergic quinoclinidyl benzilate (15) and Serotonin (16) to their appropriate receptors.

Heikkila (17) notes, that LPO intensification causes lessening of dihydroalprenol (b- adrenergic blocker) binding affinity toward its receptor. The author noted that lessening of this binding grade by 83% coincides with intensification of LPO at a maximal rate, so there is negative proportional relationship between. So we see clearly that in primary glaucoma intensification in LPO causes adrenergic receptor damage, reduces binding affinity with their agonists and antagonists, which by itself decrease efficiency of intraocular pressure lowering medications. LPO also reduce antioxidant system activity (18). In the eye main substances of antioxidant system are ascorbic  acid (Vitamin C), a-tocopherol, taurine, cysteine, glutamine, methionine and else.

In accordance with everything discussed above we consider reasonable for pathogenic treatment of glaucoma with combination of b-adrenergic blockers and antioxidants.

There are two main b-blockers used as a first line therapy in glaucoma: Timolol and Betaxolol. We stopped our choice at the first one as the most effective pressure lowering agent today (19, 20).

Timolol is remarkable with its high binding capacity for b-receptors. Timolol equally blocks b1 receptors (present on synaptic nerve endings and reacting with released norepinephrine) and b2 receptors present outside of synaptic clefts and mainly bind catecholamines that are released into the blood (21).

Among antioxidants we gave priority to taurine, this substance was first taken from ox bile in 1827, as implies its name “Taurus” in Latin means an ox. Taurine is often  called sulfur containing amino acid which is misnomer according to general chemical structure, it lacks carboxylic group. Some consider taurine as vitamin like substance.  In organism it is synthesized by enzymatic oxidation of cysteine and methionine with SH group.

Apart from typical amino acids which are used in protein synthesis taurine stays in free form in the organism. Especially high concentrations are found in myocardium, CNS and retina exceeding 100-400 times its plasma concentration. Taurine activates reparative processes in eye during degenerative changes as well as in metabolic derangements.

Its property to contribute to normal membrane functioning is related to its antioxidant actions.

For the purpose of observation 46 patients were chosen (46 eyes). By traditional ophthalmologic examinations (visometry, tonometry, refractometry, bio-microscopy, ophthalmoscopy, gonioscopy, perimetry) diagnosis of primary open-angled glaucoma was established stages II-III (this form seen in 90% of glaucoma patients). Average  age of the patients examined was 50,2 years (from ages 42 to 70 years). 59% of the patients were women, 41% men; 42% had initial stages of cataract, 17% were diabetic and 37% with systemic hypertension.

Each patient filled 15 min duration questionnaires concerning their personal passport information, present and past medical history and genetic predisposition.

Before start of our study 2-3 days before all antihypertensive medications were stopped.

After this patients were prescribed Normatin 0.5% (Timolol) 1-2 drops in the morning and before bedtime with 12 hour interval, with tonometry recheck in 10 days, 1 and 3 months after. With this initial treatment regimen average intraocular pressure dropped by 4-6 mm Hg (by 20-35%). At the next stage of the study, 30 minutes before Normatin instillation patients were given Bestoxol (taurine) eye-drops 1-2 drops 2 times/day. Eye pressure rechecks were taken with the same intervals as it was during first stage of our study. According to the results received pressure drop was 1-3mm Hg (by 7-15%) increased compared to first stage of the study. During the whole study period (6-7 months) in addition to pressure stabilization remarkable improvements was seen in peripheral and central vision in every participating patient. Side effect like mild bradycardia was seen only in 2 patients and at the initial period of the study, it improved and soon therapy was continued.

From the results obtained we can make following conclusions:

• Monotherapy with 0.5% Normatin eye-drops (2 times/day ) reduces intraocular pressure by 4-6 mm Hg in primary open-angle
• Bestoxol instillation 30 minutes before Normatin increases pressure lowering capacity of the later by 1-3 mm

These conclusions mentioned above give us opportunity to consider Normatin and Bestoxol combination as rational, effective and pathogenically approved mode of treatment of primary open-angle glaucoma, as well as recommend it for widespread  use in clinical practice.

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NANA GAPRINDASHVILI

Ophthalmology, MD