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Life Extension Magazine June 2011


New paradigms in the mechanisms and management of glaucoma.

During the last 30 years, the definition of glaucoma as been revised to eliminate the inclusion of intraocular pressure. Open angle glaucoma is the second leading cause of blindness in the world, but the proportion of those with the disease who become blind is low. Diagnostic methods for glaucoma need improvement. The pathogenetic steps to loss of neurons in glaucoma are increasingly understood and non-pressure lowering therapies are on the horizon.

Eye (Lond). 2005 Dec;19(12):1241-8

Effects of Mirtogenol on ocular blood flow and intraocular hypertension in asymptomatic subjects.

PURPOSE: The most important variable risk factor for developing glaucoma is intraocular hypertension. Timely lowering of high intraocular pressure (IOP) significantly lowers the likelihood of developing glaucoma. The aim of this study was to evaluate the effects of the food supplement Mirtogenol (Mirtoselect and Pycnogenol on IOP and ocular blood flow in a product evaluation study. METHODS: Thirty-eight asymptomatic subjects with intraocular hypertension were either given Mirtogenol (20 subjects) or were not treated (18 subjects). The visual acuity, IOP, and ocular blood flow were measured at two, three, and six months. RESULTS: After two months of supplementation with Mirtogenol, the mean IOP decreased from a baseline of 25.2 mmHg to 22.2 mmHg. After three months of treatment with Mirtogenol, the IOP was significantly lowered compared to that of untreated controls (p<0.05) to 22.0 mmHg. No further improvement was found after six months. Nineteen of the twenty patients taking Mirtogenol had a decreased IOP after three months. Only marginal effects on the IOP were found in the 18 control subjects. No side effects were observed. Ocular blood flow (central retinal, ophthalmic, and posterior ciliary arteries) improved both in the systolic and diastolic components as measured by Color Doppler imaging. After three months of treatment, the improvement of ocular blood flow was significant as compared to both baseline and control group (p<0.05). CONCLUSIONS: An improved ocular blood flow may contribute to the prevention of glaucoma. The results of this study indicate that Mirtogenol may represent a safe preventative intervention for lowering the risk for developing symptomatic glaucoma by controlling IOP and improving ocular blood flow.

Mol Vis. 2008 Jul 10;14:1288-92

Mirtogenol potentiates latanoprost in lowering intraocular pressure and improves ocular blood flow in asymptomatic subjects.

PURPOSE: The dietary supplement Mirtogenol((R)) was previously shown to lower elevated intraocular pressure (IOP). We here present the effects of this supplement on IOP in comparison as well as in combination with latanoprost eye drops. METHODS: Seventy-nine patients with asymptomatic ocular hypertension were randomly assigned to three groups receiving either the supplement, or latanoprost eye drops, or both in combination. Intraocular pressure and retinal blood flow were investigated in monthly intervals over 24 weeks. RESULTS: Mirtogenol alone lowered IOP from baseline 38.1 to 29.0 mmHg after 16 weeks, with little further improvement during the following eight weeks. Latanoprost rapidly lowered IOP from baseline 37.7 to 27.2 mmHg within four weeks, without further effects thereafter. The combination of the supplement and latanoprost lowered IOP from 38.0 to 27.3 mmHg after four weeks, and further decreased IOP to 24.2 mmHg after six weeks. After 24 weeks IOP with the combination treatment (23.0 mmHg) was significantly lower than with latanoprost alone (27.2 mmHg). Mirtogenol and latanoprost individually showed comparable effects for gradually increasing central artery blood flow with treatment duration. Combination treatment showed higher systolic blood flow velocity throughout the trial period. The diastolic blood flow velocity gradually increased with treatment duration in all three groups. From twelve weeks onwards, the diastolic component with combination treatment was higher than with individual treatments. CONCLUSIONS: Mirtogenol lowered elevated IOP in patients almost as effectively as latanoprost, however, it takes much longer (24 vs 4 weeks). The combination of both was more effective for lowering IOP and the combination yielded better retinal blood flow. No serious side effects occurred during the study, apart from standard side effects in patients related to Latanoprost. These promising results warrant further research of Mirtogenol with a larger patient group.

Clin Ophthalmol. 2010 May 14;4:471-6

Current management of glaucoma and the need for complete therapy.

Glaucoma is a long-term ocular neuropathy defined by optic disc or retinal nerve fiber structural abnormalities and visual field abnormality. Primary open-angle glaucoma is the most common type of glaucoma. Currently available treatments, initiated in a stepwise process, focus on intraocular pressure (IOP) reduction, and initially include topical drug therapy (single then multidrug combinations), followed by laser then surgical treatment. Topical prostaglandin analogues or beta-adrenergic receptor blockers are first used, followed by alpha-agonists or topical carbonic anhydrase inhibitors, and infrequently, cholinergic agonists and oral therapy. Limitations to existing topical IOP-reducing medications include continued disease progression in glaucoma patients with normal IOP, treatment failure, and low rates of compliance and persistence. Therapeutic agents under investigation include neuroprotectants, which target the disease process manifested by death of retinal ganglion cells, axonal loss, and irreversible loss of vision. Neuroprotectants may be used alone or in combination with IOPreducing therapy (a treatment strategy called complete therapy). Memantine, an N-methyl-D-aspartate receptor blocker currently approved for dementia, is the neuroprotectant farthest along in the process seeking regulatory approval for glaucoma treatment and has a favorable safety profile because of its selective mechanism of action. Several other neuroprotectants are in early stage investigation. Complete therapy provides hope for improved outcomes by reducing the significant morbidity and economic consequences that occur as a result of neurodegeneration and disease progression.

Am J Manag Care. 2008 Feb;14(1 Suppl):S20-7

Neuroprotection in glaucoma - Is there a future role?

In glaucoma, the major cause of global irreversible blindness, there is an urgent need for treatment modalities that directly target the RGCs. The discovery of an alternative therapeutic approach, independent of IOP reduction, is highly sought after, due to the indirect nature and limited effectiveness of IOP lowering therapy in preventing RGC loss. Several mechanisms have been implicated in initiating the apoptotic cascade in glaucomatous retinopathy and numerous drugs have been shown to be neuroprotective in animal models of glaucoma. These mechanisms and their potential treatment include excitotoxicity, protein misfolding, mitochondrial dysfunction, oxidative stress, inflammation and neurotrophin deprivation. All of these mechanisms ultimately lead to programmed cell death with loss of RGCs. In this article we summarize the mechanisms involved in glaucomatous disease, highlight the rationale for neuroprotection in glaucoma management and review current potential neuroprotective strategies targeting RGCs from the laboratory to the clinic.

Exp Eye Res. 2010 Nov;91(5):554-66

Disease progression and the need for neuroprotection in glaucoma management.

Glaucoma, the second leading cause of worldwide blindness, is a progressive optic neuropathy characterized by a loss of retinal ganglion cells and their axons beyond typical age-related baseline loss. Diagnosis is defined by optic disc and visual field changes, and the primary goal of glaucoma treatment is to preserve vision. Proven existing therapies (ie, pharmacotherapy, laser, and surgical) focus on reduction of intraocular pressure (IOP), although elevated IOP is no longer a diagnostic feature of glaucoma. New neuroprotectant drugs are being investigated, with the goal of reducing retinal ganglion cell loss, either prophylactically or after the insult has occurred. Various treatment strategies are being evaluated, and include a neuroprotectant only, or a complete therapy approach comprised of both a neuroprotectant supplemented by an IOP-lowering therapy. Dually targeted complete therapy may directly preserve the optic nerve, decrease the risk factors that cause glaucoma damage, and reduce glaucoma-related morbidities. Neuroprotectant therapy outcomes should include functional and structural effects of disease progression and neuroprotectant therapies, as well as patient functioning and economic impact.

Am J Manag Care. 2008 Feb;14(1 Suppl):S15-9

Management of glaucoma: focus on pharmacological therapy.

Glaucoma represents a major cause of vision loss throughout the world. Primary open-angle glaucoma, the most common form of glaucoma, is a chronic, progressive disease often, though not always, accompanied by elevated intraocular pressure (IOP). In this disorder, retinal ganglion cell loss and excavation of the optic nerve head produce characteristic peripheral visual field deficits. Patients with normal-tension glaucoma present with typical visual field and optic nerve head changes, without a documented history of elevated IOP. A variety of secondary causes, such as pigment dispersion syndrome and ocular trauma, can result in glaucoma as well. Treatment of all forms of glaucoma consists of reducing IOP. With proper treatment, progression of this disease can often be delayed or prevented. Treatment options for glaucoma include medications, laser therapy and incisional surgery. Laser techniques for the reduction of IOP include argon laser trabeculoplasty and selective laser trabeculoplasty. Both techniques work by increasing outflow of aqueous humour through the trabecular meshwork. Surgical options for glaucoma treatment include trabeculectomy, glaucoma drainage tube implantation and ciliary body cyclodestruction. While each of these types of procedures is effective at lowering IOP, therapy usually begins with medications. Medications lower IOP either by reducing the production or by increasing the rate of outflow of aqueous humour within the eye. Currently, there are five major classes of drugs used for the treatment of glaucoma: (i) cholinergics (acetylcholine receptor agonists); (ii) adrenoceptor agonists; (iii) carbonic anhydrase inhibitors (CAIs); (iv) beta-adrenoceptor antagonists; and (v) prostaglandin analogues (PGAs). Treatment typically begins with the selection of an agent for IOP reduction. Although beta-adrenoceptor antagonists are still commonly used by many clinicians, the PGAs are playing an increasingly important role in the first-line therapy of glaucoma. Adjunctive agents, such as alpha-adrenoceptor agonists and CAIs are often effective at providing additional reduction in IOP for patients not controlled on monotherapy. As with any chronic disease, effective treatment depends on minimising the adverse effects of therapy and maximising patient compliance. The introduction of a variety of well tolerated and potent medications over the past few years now allows the clinician to choose a treatment regimen on an individual patient basis and thereby treat this disorder more effectively.

Drugs Aging. 2005;22(1):1-21

Current and emerging medical therapies in the treatment of glaucoma.

Introduction: Glaucoma is a disease of the eye in which the optic nerve and retinal ganglion cells (RGCs) are injured, leading to the loss of the peripheral visual field and eventually to profound vision loss and blindness. Glaucoma is usually characterized by an increase in intraocular pressure (IOP), which is treated with ocular hypotensive drugs. However, both RGC apoptosis and optic nerve atrophy, due to glaucoma, can occur independently of IOP. Areas covered: This review discusses several current and emerging treatments for glaucoma. Current research is updating the known properties of a number of drugs now used to treat glaucoma. Some drugs may offer neuroprotection, not only reducing vision loss, but restoring injured or compromised RGCs and optic nerve cells. Several molecules now under development aim to lower IOP primarily by enhancing aqueous drainage through conventional pathways of the trabecular meshwork and Schlemm’s canal. Gene transfer models are being investigated, and a murine-derived neurotrophic growth factor (NGF) seems to offer the promise of actually restoring visual function in some patients. Drugs that are already widely used are being re-branded in preservative-free formulations. Expert opinion: The ultimate goal in glaucoma research is to find new compounds that will not only normalize IOP, but also arrest or even reverse apoptotic damage to the optic nerve and RGCs to slow the rate of progression of the disease so that it will not interfere with the patient’s ability to see and his/her quality of life. This should be obtained with affordable costs, minimal side effects and a reasonable schedule.

Expert Opin Emerg Drugs. 2011 Apr 7

Resveratrol prevents the expression of glaucoma markers induced by chronic oxidative stress in trabecular meshwork cells.

Elevated intraocular pressure (IOP) constitutes the best characterized risk for primary open-angle glaucoma (POAG). Elevated IOP is believed to result from an increase in aqueous humor outflow resistance at the level of the trabecular meshwork (TM)/Schlemm’s canal. Malfunction of the TM in POAG is associated with the expression of markers for inflammation, cellular senescence, oxidative damage, and decreased cellularity. Current POAG treatments rely on lowering IOP, but there is no therapeutic approach available to delay the loss of function of the TM in POAG patients. We evaluated the effects of chronic administration of the dietary supplement resveratrol on the expression of markers for inflammation, oxidative damage, and cellular senescence in primary TM cells subjected to chronic oxidative stress (40% O2). Resveratrol treatment effectively prevented increased production of intracellular reactive oxygen species (iROS) and inflammatory markers (IL1alpha, IL6, IL8, and ELAM-1), and reduced expression of the senescence markers sa-beta-gal, lipofuscin, and accumulation of carbonylated proteins. Furthermore, resveratrol exerted antiapoptotic effects that were not associated with a decrease in cell proliferation. These results suggest that resveratrol could potentially have a role in preventing the TM tissue abnormalities observed in POAG.

Food Chem Toxicol. 2009 Jan;47(1):198-204

Protective effects of bilberry (Vaccinium myrtillus L.) extract against endotoxin-induced uveitis in mice.

Endotoxin-induced uveitis (EIU), a useful animal model of ocular inflammation, is induced by injection of lipopolysacharide (LPS). These experiments showed that the nitric oxide (NO) level significantly increased in the whole eye homogenate of BALB/C mice 24 h after footpad injection of LPS at a dosage of 100 mg/mouse. However, the elevated NO level was significantly reduced by oral administration of bilberry extract (containing 42.04% anthocyanins) at dosages of 50, 100, and 200 mg/kg/day for 5 days before the LPS injection. In addition, bilberry extract decreased malondialdehyde (MDA) level and increased oxygen radical absorbance capacity (ORAC) level, glutathione (GSH) level, vitamin C level, and total superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Moreover, bilberry extract increased expression of copper/zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), and GPx mRNA. Taken together, bilberry extract showed protective effects against EIU, whereas the effects of bilberry extract (100 and 200 mg/kg/day, 5 days) were dose-dependent. In conclusion, these results provide new evidence to elucidate the beneficial effects of bilberry extract on eye health.

J Agric Food Chem. 2010 Apr 28;58(8):4731-6