1. Field of the Invention
This invention is in the field of pharmacology, and relates specifically to the pharmacological treatment of the chronic glaucomas of the eye.
2. Description of the Prior Art
Pertinent Anatomy of the Eye
The eye is a closed, fluid-filled environment divided into two segments separated by the crystalline lens. The anterior segment is bordered anteriorly by the arching, clear cornea and posteriorly by the anterior surface of the lens and the iris. The posterior segment is bordered in the front by the back surface of the lens and iris and posteriorly by the concave surface of the retinal lining of the globe. The only significant opening in this otherwise closed globe is through the retina in the distal back; the exit point of approximately 1 million bundled axonal nerves gathered from all points of the retina carrying their electrically digitized images for manipulation and display by the brain--our impression of this electrical activity is called vision. This opening for the bundled coaxial cable of nerves is called the optic nerve head and represents the weakest point in an otherwise very strong, inelastic globe. A locally dense, layered network of blood vessels supplies the optic nerve head and its health is almost totally dependent upon the oxygen delivered to it by this labyrinth of small vessels. These fine vessels are derived, in the main, from the short posterior ciliary arteries that arise from the ophthalmic artery. This particular vascular source for the eye is important when consideration is given to vascular reactions to vasoconstrictors and vasodilators such as endothelin-1 and nitric oxide (vide infra).
At the peripheral circumference of the posterior surface of the iris is a fringe of secretory cells (ciliary processes) which secrete a thin, watery fluid (aqueous fluid) at a relatively constant, though variable rate. This fluid passes through an intervening meshwork (trabecular meshwork) and then exits the eye through tiny openings into a collection channel that circles the interior periphery of the cornea concentric with the outer edge of the anterior iris (Schlemm's canal). The flow of aqueous fluid, therefore, originates in the periphery of the posterior chamber, washes forward around the crystalline lens through the pupil and exits through Schlemm's canal in the periphery of the anterior chamber.
Pertinent Physiology of the Eye
The eye is maintained in a homeostatic shape by a relatively stable intraocular pressure (IOP) which varies within a reasonably narrow range. This is true so long as the production of aqueous fluid by the ciliary processes remains equal to its exit through Schlemm's canal. However, should aqueous production outstrip aqueous outflow, the IOP increases. Because the eye is a closed, fluid-filled, minimally expansile organ, any hydraulic pressure increase in one part of the eye is transmitted equally throughout the eye.
So long as the availability of oxygen from the posterior ciliary arteries and the small optic nerve head arterioles remains adequate, the nerve head itself can tolerate relatively high levels of IOP. However, it is perhaps intuitively obvious that the ability of arterially-delivered oxygen to move efficiently from the red blood cells of terminal arterioles, through the arteriolar wall and into the oxygen-dependent tissues of the optic nerve head, is at least partially dependent upon the difference between the intravascular oxygen pressure and the extravascular pressure countering its diffusion. Thus, if the intraocular pressure of the globe which compresses the outside of the arterioles is higher than the oxygen diffusion pressure driving oxygen through the arteriole into the surrounding tissues, decreasing amounts of oxygen will reach the optic nerve head and nerve disability will result. Over a variable period of time this chronic, local vascular disability results in atrophy, progressive functional death of the nerve, visual field defects and blindness.
Similarly, if the vessels which carry blood to the nerve head are unable to provide sufficient volumes of blood, and thus oxygen, to the optic nerve or have structural barriers to oxygen diffusion, then even in an environment of normal or "low" intraocular or extravascular pressure (&lt;21 mm Hg.), local tissues will be oxygen deprived and optic nerve dysfunction or atrophy will follow. These arteriolar deficiencies may occur because of vasoconstriction secondary to generalized or localized microvascular dysregulation, or in conjunction with arteriolar muscular hypertrophy (perhaps as a result of chronic spasm), atherosclerotic luminal reduction, changes in the viscosity or laminar flow patterns of the arterial blood, or in either essential or iatrogenic systemic hypotension. Interestingly, there is significant evidence that "low" or normotensive glaucoma patients do indeed have reduced optic nerve head blood flow
Clearly if the intraocular pressure is elevated and the vascular ability to provide sufficient volumes of blood is compromised, the danger of optic nerve head failure is greatly increased.
Chronic Glaucoma--The Disease
Glaucoma in various guises affects a large segment of the public. It is estimated that 2% to 2.5% of the population over the age of 40 has chronic open angle glaucoma (COAG), sometimes, synonymously, referred to as Primary Open Angle Glaucoma (POAG). In this disease, there is no major structural obstruction to aqueous access to the outflow trabeculum, but there is increased resistance to aqueous transit through the trabeculum to Schlemm's canal. This is the most common form of glaucoma.
Smaller but additive segments of the population suffer from other types of chronic glaucoma: pigmentary glaucoma, angle recession glaucoma, pseudoexfoliative glaucoma and combined (mixed) mechanism glaucoma.
Although, as noted, there are several forms of the disease, all incorporate a limited number of common features, the most disastrous of which is an ultimate failure of the optic nerve leading to complete blindness. Except for some less common varieties of glaucoma, this failure usually involves asymptomatic, slowly progressive visual field loss over a very long period of years and, as a result, the patient is frequently unaware of the disease. All too often the diagnosis is made after much damage to the optic nerve has occurred and some irreversible loss of vision has taken place.
Normal IOP is given as 18 mm. Hg. Elevated IOP is classically defined as pressure over 21 to 24 mm. Hg.
Because optic nerve damage is known to occur in patients with chronically elevated or, less frequently, acutely elevated IOP, present treatment methods concentrate on reducing this easy-to-measure, objective clinical finding by the application of a variety of modalities: topical eyedrops, oral medications, intravenous medications, surgical procedures, laser phototherapy, etc. While each of these treatment approaches may function differently, they are all focused upon the reduction of pressure inside the eye and rely upon this pressure fall to prevent optic nerve damage. In some cases the therapy attempts to reduce the production of aqueous fluid by the ciliary processes, in other cases therapy attempts to increase the outflow of aqueous fluid through Schlemm's canal.
For some patients this approach is adequate and effective. However, the effectiveness of each of these treatments has a place on a treatment continuum which runs from total ineffectiveness and progressive optic atrophy and eventual blindness, to an arrest of the disease, complete cessation or prevention of further optic nerve failure and preservation of vision.
This treatment solution, however, is complicated by two facts:
a. Some patients develop progressive and seemingly irreversible optic nerve failure and visual loss in the face of normal IOP or lower than normal IOP (sometimes very much lower). These states are referred to as "normotensive glaucoma" or "low tension glaucoma". PA1 b. Although optic nerve failure does in fact occur in patients with elevated IOP, not everyone who has IOP elevation develops optic nerve failure; in fact, most patients with higher than normal IOP do not develop optic nerve failure or visual field loss and by definition, do not suffer from glaucoma. In spite of this, many of them receive pressure-lowering medications as treatment for their "glaucoma". PA1 a. The microglial ganglion cells which are necessary for the functional health of the retinal axons traversing the optic disc; and PA1 b. the transiting axonic neurons themselves and their dependency upon a healthy oxygen environment and adequate axoplasmic flow. PA1 As one example: LDL3, the densest of the three LDL subfractions, shows statistically significant lower levels of CoQ10, a condition which is associated with higher hydroperoxide levels when compared with the lighter counterparts. After CoQ10 supplementation, although all three LDL subfractions increase their CoQ10 levels, LDL3 responds with the greatest and is associated with a significant decrease in hydroperoxide level. These results support the hypothesis that the CoQ10 endowment in subfractions of LDL lessens their oxidizability. PA1 a. Arg is the amino acid L-arginine or bis-L,arginine; PA1 b. M is a metal ion taken from, Mg.sup.+2, Cu.sup.+2 or Zn.sup.+2 ; PA1 c. X is an anion taken from the group including hydroxides, halides, sulfates, acetates, ascorbates or bis-ascorbic acid salts. PA1 a. A is cysteine, acetylcysteine, NAC, MPG or OTC; PA1 b. M is a metal ion taken from the metallic cations contemplated by this invention: PA1 c. X is an anion taken from the group including hydroxides, halides, sulfates, phosphates, acetates, ascorbates or bis-ascorbic acid salts. PA1 a. A is LA or TA; PA1 b. M is a metal ion taken from, Mg.sup.+2, Cu.sup.+2, Zn.sup.+2 or Se.sup.+2 ; PA1 c. X is an anion taken from the group including hydroxides, halides, sulfates, phosphates, acetates, ascorbates or bis-ascorbic acid salts. PA1 a. A is LA or TA, PA1 b. M is a metal ion taken from Mg.sup.+2, Cu.sup.+2, Zn.sup.+2 or Se.sup.+2 ; PA1 c. X is an anion taken from the group including hydroxides, halides, sulfates, phosphates, acetates or ascorbates or bis-ascorbic acid salts. PA1 a. A is 2,N-thioctylarginine (2NTA), 2,N-thioctylcysteine (2NTCy), 2,N-thioctyllysine (2NTL), 2,N-thioctyltaurine (2NTT); PA1 b. M is a metal ion taken from Mg.sup.+2, Cu.sup.+2, Zn.sup.+2 or Se.sup.+2 ; PA1 c. X is an anion taken from the group including hydroxides, halides, sulfates, phosphates, acetates or ascorbates or bis-ascorbic acid salts, PA1 a. A is 2,N-thioctylarginine (2NTA), 2,N-thioctylcysteine (2NTCy), 2,N-thioctyllysine (2NTL), 2,N-thioctyltaurine (2NTT); PA1 b. M is a metal ion taken from Mg.sup.+2, Cu.sup.+2, Zn.sup.+2 or Se.sup.+2 ; PA1 c. X is an anion taken from the group including hydroxides, halides, sulfates, phosphates, acetates or ascorbates or bis-ascorbic acid salts.
Clearly, factors other than IOP level influence the clinical outcome for a large group of individuals. Currently attention is focusing upon a primary alternative: hypovascularity of the optic nerve head and loss of the vascular integrity of the optic nerve resulting in glial collapse, ganglion cell apoptosis and progressive neural atrophy with visual loss. Unfortunately, local optic nerve vascular inadequacy in the face of low IOP ("low tension" glaucoma) may result in clinical results just as damaging as those which appear in the presence of "high tension" glaucoma. Conversely, a recognizably large majority of patients with adequate optic nerve vascular integrity, even in the face of an elevated IOP, do not have progressive optic nerve damage.
A second potential variable, which may influence the clinical outcome, is hypoxic interference with retrograde axoplasmic flow within the neural axons from retinal ganglion cells to the occipital cortex. The variable ability of these axonal fibrils to continue adequate axoplasmic flow in the face of reduced oxygen availability also helps explain the variable survivability of the nerve head independent of IOP levels. It also highlights an additional functional activity of the optic nerve that is potentially sensitive to local oxygen saturation levels.
Ocular Microvascular Regulation
A balanced biochemistry of nitric oxide (NO) and endothelin-1 (ET-1) mediate local ocular blood flow and many facets of systemic vascular autoregulation.
NO is a highly soluble gas formed within endothelial cells by the action of the constitutive enzyme nitric oxide synthetase (eNOS). NO activates guanylate cyclase and increases guanosine monophosphate (cGMP) within the vascular musculature. cGMP produces relaxation and dilatation of the vessel. NO is the most powerful vascular dilator known, excepting histamine. It also may have powerful, less vascular specific and more generalized smooth muscle relaxing abilities; in this regard it would participate in the relaxation of the contractile trabecular elements of the eye and increase of aqueous outflow. An increase of aqueous outflow results in a decrease in IOP. However, levels of NO in the trabecular region of eyes of glaucoma patients are lower than in the eyes of non-glaucoma patients; this may be the effect of an inappropriate variation in the promoter region of the eNOS gene which has been found in glaucoma patients. Additionally, aging and atherosclerosis of the vascular endothelium reduce the latter's ability to produce NO because of reduced local levels of eNOS.
ET-1 is also formed within and secreted by endothelial cells. ET-1 reacts with local receptors on smooth muscle cells to produce a powerful and long-lasting vasoconstriction. ET-1 is particularly released by aged or unhealthy endothelial cells, e.g., in the presence of atherosclerosis or in the presence of locally-bound, collections of endothelial leukocytes or platelets, etc. The smooth muscle contraction produced by ET-1 strongly opposes the relaxation properties of NO and, as a result, trabecular contraction is stimulated, resistance to aqueous outflow is increased and IOP increases. At the same time this pressure increase is occurring, vasoconstriction of the small vessels of the optic nerve occurs, local hypoxia ensues and a course is set for optic nerve atrophy. Aqueous levels of ET-1 are elevated in glaucomatous eyes. Induced elevations of aqueous ET-1 levels produce optic nerve collapse.
This balance between NO and ET-1 mediates the autoregulation of blood flow within the optic nerve and the peripheral circulation. Interestingly, the vascular reactivity of the peripheral circulation to ET-1 is much more pronounced in glaucoma patients than in non-glaucomatous subjects and is particularly elevated in low tension glaucoma patients.
Exposure of patients to vasodilating stimuli or to calcium channel blockers has resulted in an improvement of the glaucomatous visual field. This is understandable since vascular endothelial production of ET-1 is dependent upon cytosolic calcium influx via transmembrane calcium channels. Calcium channel blockade reduces this calcium influx and reduces the production of ET-1. A reduction of IOP has been observed as a side effect in glaucoma patients using calcium channel blockers for systemic hypertension. However, prescribing therapeutic doses of calcium channel blockers to non-hypertensive glaucoma patients subjects the optic nerve to a risk of hypoxia secondary to iatrogenic hypotension and produces gross, unstable perturbations of cellular calcium fluxes (vide infra, Calcium Wave Modulation).
Ocular Vascular Disease
Ocular vascular diseases can exist in a variety of forms and result in a variety of pathological clinical conditions. All are associated with a reduction of oxygen delivery to surrounding, dependent tissues. In the optic nerve there are two tissues particularly vulnerable to hypoxia:
A reduction in optic nerve oxygen delivery may follow acute or chronic, segmental or widespread, vascular spasm or prolonged vasoconstriction secondary to a physical, or functional, reduction in the vascular lumen. This luminal reduction may be caused by or associated with hypertrophy of the vascular muscle wall (the media), the accumulation of atherosclerotic plaque, platelet agglutination, disturbed laminar flow or local inflammatory swelling and leukocytic accumulation. Any and all of these findings often occur with simple aging or in association with other systemic disease: diabetes, hypertension, dyslipogenesis, hyperinsulinemia, arteriosclerosis, thyroid disease, etc. Although vascular insufficiency at specific tissue sites is widely variable and not predictable with certainty, the fact that most COAG patients are over 50 years old makes the frequency of these risk factors and the frequency of vascular insufficiency, high in this clinical group. Any proposed therapy should attempt to reduce the negative influences of the above risk factors and reduce local optic nerve head vascular insufficiency, in addition to lowering the IOP. For example: A therapeutic reduction of those endothelial abnormalities which contribute to specific or generalized risk factors which compromise local vascular integrity, will reduce the potential for glaucomatous optic nerve failure where microvascular dysregulation is significant. If this reduction of vascular risk factors is united with a reduction in aqueous production or outflow resistance, the combined effects of a well-oxygenated, more pressure-resistant nerve head and reduced IOP will further decrease the potential for optic atrophy and blindness.
Glaucoma--Biochemistry of Present Treatment
Current non-surgical treatments of COAG are based upon a limited number of biochemical approaches and focus exclusively upon reducing IOP:
a. Enzyme poisons--representatives of this group are most frequently carbonic anhydrase inhibitors. Carbonic anhydrase is an enzyme found in the ciliary processes and is required by them in their production of aqueous humor from blood. The members of this group are usually administered in tablet dosage forms. Besides the development of renal stones, potassium loss is a constant concern, especially in patients using digitalis derivatives. New, topical forms of this group have appeared as eyedrops. However, carbonic anhydrase activity is also present in the cytoplasm of corneal endothelial cells. The long-term corneal effects of this form of these medications are unknown. To avoid systemic reactions, patients with sulfonamide allergies should not use these drugs.
b. Parasympathomimetics--pilocarpine-containing compounds are particularly widely prescribed and act by causing pupillary constriction. As the pupil constricts, the relational anatomy of the peripheral iris and the filtering trabeculum causes the openings in the trabeculum to enlarge; thus, mechanical resistance to the outflow of aqueous is reduced as the summed area of the openings is increased. These agents are delivered in eyedrop dosage forms. Frequent side effects include headache from iris spasm, decreased night vision from miosis and blurred vision in myopes especially.
c. Beta-blocking agents--this very widely used group of drugs block the beta-adrenergic sympathetic rete responsible for increased vascular flow to the ciliary processes and, thus, indirectly reduce the production of aqueous humor. They also increase aqueous outflow through the trabeculum by methods that are less clearly defined. These agents are delivered in eyedrop dosage forms but must be used with great caution in patients with low blood pressure (orthostatic hypotension), sinus bradycardia or second/third degree heart block (severe bradycardia), obstructive pulmonary disease or bronchial asthma (acute bronchospasm) and diabetes (masking of hypoglycemia). They result in impotency in a significant number of men. There is contested evidence that ocular beta-blocking agents generally reduce blood flow to the posterior segment of the eye; some products are stated to have less significant bronchospastic side effects than others.
d. Topical prostaglandin analogs--this very new group of anti-inflammatory eyedrops presumably reduces IOP by increasing the outflow of aqueous through the trabeculum by widening the intra-trabecular space and, perhaps, by reducing platelet aggregation. Their use is associated with progressive and possibly permanent change in iris color to brown and some embryocidal outcomes in laboratory animals. Women of reproductive age and nursing women should avoid their use.
All of these treatment modes have significant and unavoidable, potential or demonstrable, local or systemic side effects or toxicities that directly contraindicate their use, reduce patient compliance or are worrisomely interactive with other systemic pharmaceuticals. These side effects may be serious even with conjunctival delivery by eyedrop dosage forms. Nevertheless, these medicaments represent today's entire medical armamentarium for the treatment of glaucoma.