State of the art clinical efficacy and safety evaluation of N-acetylcarnosine dipeptide ophthalmic prodrug. Principles for the delivery, self-bioactivation, molecular targets and interaction with a highly evolved histidyl-hydrazide structure in the treatment and therapeutic management of a group of sight-threatening eye diseases

Abstract

Objective: The exact biological functions of the aminoacyl-histidine dipeptides in ophthalmology are still unknown but they are the subject of intensive research activities at Innovative Vision Products, Inc. (IVP). Numerous studies have demonstrated, both at the tissue and organelle levels, that naturally occuring imidazole containing peptidomimetics possess strong and specific antioxidant properties, by preventing and reducing the accumulation of oxidised products derived from the lipid peroxidation (LPO) of biological membranes. Carnosine has been shown to act as a competitive inhibitor of the non-enzymatic glycosylation of proteins.Thus, carnosine may prevent and reverse (de-link) the formation of the advanced glycation end-products (AGEs), whose accumulation in the ocular tissues has been proposed to play a direct role in the etiology and pathogenesis of cataract and diabetic ocular complications (DOC). Besides, histidine-containing dipeptides are believed to act as cytosolic buffering agents.

Aims: To compare the efficacy of L-carnosine and derivatives in inhibiting/reversing oxidative stress-induced reactions relevant for cataract pathogenesis. To assess the transglycation activity of carnosine versus representatives of a new group of synthetic carnosine histidyl-hydrazide analogs. To test the clinical efficacy of N-acetylcarnosine prodrug eye drops, developed by IVP's scientists, in decreasing the symptoms of age-related cataract.

Main methods: Antioxidant activity of L-carnosine and N-acetylcarnosine was studied in liposomes, a model of lipid membranes. Iron/ascorbate was used for induction of LPO and peroxidation products were measured. Second-generation carnosine analogs were synthesized and tested vs. L-carnosine for their ability to reverse the glycation process, ultimately resulting in the formation of the AGEs. Visual acuity and glare sensitivity was measured before and after 9-month of topical administration of N-acetylcarnosine eye drops in a randomized placebo-controlled cohort of patients presenting age-related uncomplicated cataract and non-cataract subjects of the same age range.

Key findings: L-carnosine operates as aldehyde and reactive oxygen species (ROS) scavenger in aqueous and lipid environments, preventing ROS-induced damage to biomolecules. L-carnosine and histidyl-hydrazide analogs present transglycation properties which could be used to decrease the occurrence of long term complications of AGE formation in DOC and age-related cataracts. In the patented ophthalmic formulations, the designed leucyl-histidylhydrazide (not hydrolizable by carnosinase substrate) is endowed with a highly evolved structure optimized for the bioactivation of a N-acetylcarnosine dipeptide prodrug, targeting therapeutics of the main DOC: cataract, diabetic retinopathy, central retinal vein occlusion, central retinal artery occlusion and neovascular glaucoma. Besides, the data support the clinical application of N-acetylcarnosine lubricant eye drops to compensate corneal acidosis. Nine-month treatment with N-acetylcarnosine resulted in improved visual acuity in subjects with cataract. Glare sensitivity was improved in subjects with cataract and in non-cataract older subjects. The results from the matched studies indicate that the N-acetylcarnosine-laden therapeutic contact lenses increasing the intraocular and systemic absorption of the active dipeptide carnosine ingredient, are an effective and well-tolerated bandage lens for anterior segment disease and for post-operative management of LASEK patients.This allows practitioners to prescribe extended wear of therapeutic contact lenses loaded with N-acetylcarnosine during medical treatment of cataracts, ocular complications of diabetes, primary open-angle glaucoma and potentially creates a healthier eye and body environment during healing. A number of clinically developed with alliance groups famous International brands of patented by IVP N-acetylcarnosine lubricant eye drops (Can-C, IVP C and D-Smile) are described with a quick reference guide for completing a vendor official registration in EC countries, U.A.E., Indonesia, Japan for human and veterinary use. In a separate development series of data Carcinine (beta-alanylhistamine) significantly protected photoreceptors against light-induced apoptosis, suggesting that this compound is sufficiently resistant to degradation with enzymatic hydrolysis and can be used in vivo representing new strategies in the anti-apoptotic ophthalmic therapy.

Significance: Cataract is a major disease both in terms of number of people involved and economic impact. The research into causative factors and mechanisms to prevent the development of cataract is essential, particularly in developing countries where cataract surgery is often inaccessible. The results of this study provide a substantial basis for further evaluation of N-acetylcarnosine eye drops patented by IVP in the treatment and prevention of visual impairment in the temporal cross-sections of an older population several years apart. In the number of promotion studies this ophthalmic drug showed experimental and clinical potential for the non-surgical treatment of age-related cataracts. Comprehensive studies that investigate clinical, economic, and humanistic outcomes for the patient and society are conducted and will be described with different types of identified pharmacoeconomic evaluations to adequately assess the comparative value of current N-acetylcarnosine eye drops therapeutics for medical care and its place in future ophthalmic practices. Patients and the public expect that safe and cost-effective cataract medical care with N-acetylcarnosine therapeutic platform should be commissioned for them.