Revival of the Lens Transparency with N-Acetylcarnosine

Mark   A.   Babizhayev; Anatoly   I.   Deyev; Valentina   N.   Yermakova; Valerii   V.   Remenshchikov; Johan      Bours

Abstract

The risk, cost and social requirement factors drive the investigation of pharmaceutical approaches to the management of cataracts. The role of free-radical-induced lipid oxidation (LPO) in the development of cataracts has been identified. Initial stages of cataract are characterized by the accumulation of primary (diene conjugates, cetodienes) LPO products,while in later stages there is a prevalence of LPO fluorescent end products. Reliable increase in oxiproducts of fatty acyl content of lenticular lipids was shown by a direct gas chromatography technique producing fatty acid fluorinesubstituted derivatives. The lens opacity degree correlates with the level of the LPO fluorescent end product accumulation in its tissue, accompanied by SH group oxidation of lens proteins due to a decrease of reduced glutathione concentration in the lens. The injection of LPO products into the vitreous was shown to induce cataract. Peroxide damage of the lens fiber membranes may be the initial cause of cataract formation. The authors developed N-Acetylcarnosine ophthalmic drug with lubricant carboxymethylcellulose in eye drops (NAC, Can-C™, Nu-Eyes™) suitable for the non-surgical prevention and treatment of age-related cataracts. The NAC ophthalmic drug protects the crystalline lens from oxidative stress-induced damages and in a recent clinical trial it was shown to produce an effective, safe and long-term improvement in sight. When administered topically to the eye, NAC drug functions as a time-release prodrug form of Lcarnosine resistant to hydrolysis with carnosinase and significantly increases the intraocular uptake of L-carnosine in the aqueous humor. The mechanisms of prevention and reversal of cataracts with NAC ophthalmic drug are considered which include prevention by the intraocular released carnosine of free-radical-induced inactivation of proprietary lens antioxidant enzymes (superoxide dismutase), prevention of carbohydrate and metal-catalysed autooxidation of ascorbic acid -induced cross-linking glycation reactions to the lens proteins, universal antioxidant and scavenging activity towards lipid hydroperoxides, aldehydes and oxygen radicals, activation with L-carnosine ingredient of proteasome activity in the lens. In this study the clinical effects of a topical solution of NAC ophthalmic drug on lens opacities were examined in patients with cataracts and canines with age-related cataracts. The positive effect on lens clarity and clarifying modification of opacification zones is demonstrated. The data suggest a potential and show the efficacy of developed NAC ophthalmic drug for a positive effect of treatment (both reversal and prevention) of age-related cataracts. Innovative Vision Products, Inc. is a holder of the worldwide patent (including PCT International Publication Number WO 2004/028536 A1) for the application of N-acetylcarnosine for the treatment of ophthalmic disorders including cataracts.

Keywords: Age-related cataracts, crystalline lens, epidemiology, lipid peroxidation, active oxygen species, universal antioxidant, L-carnosine, ophthalmic prodrug, N-acetylcarnosine, eye drops