title: The natural histidine-containing dipeptide Nalpha-acetylcarnosine as an antioxidant for ophthalmic use.
abstract: The naturally occurring compound Nalpha-acetylcarnosine is proposed as a prodrug of L-carnosine that is resistant to enzymatic hydrolysis by carnosinase. Eyes of rabbits were treated with 1% Nalpha-acetylcarnosine, L-carnosine, or placebo and extracts of the aqueous humor from the anterior eye chamber were analyzed for imidazole content by reverse-phase analytical high performance liquid chromatography (HPLC) and thin-layer (TLC) and ion-exchange chromatographic techniques. Topical administration of pure L-carnosine to the rabbit eye did not lead to accumulation of this compound in the aqueous humor over 30 min in concentration exceeding that in the placebo-treated matched eye. Nalpha-Acetylcarnosine showed dose-dependent hydrolysis in its passage from the cornea to the aqueous humor, releasing L-carnosine after l5-30 min of ocular administration of the prodrug in a series of therapeutic modalities: instillation < or = subconjunctival injection < or = ultrasound-induced phoresis. Different treatment techniques showed excellent toleration of 1%Nalpha-acetylcarnosine by the eye. Once in the aqueous humor, L-carnosine might act as an antioxidant and enter the lens tissue when present at effective concentrations (5-l5 mM). The advantage of the ophthalmic prodrug Nalpha-acetylcarnosine and its bioactivated principle L-carnosine as universal antioxidants relates to their ability to give efficient protection against oxidative stress both in the lipid phase of biological membranes and in aqueous environments. Nalpha-Acetylcarnosine is proposed for treatment of ocular disorders that have a component of oxidative stress in their genesis (cataracts, glaucoma, retinal degeneration, corneal disorders, ocular inflammation, complications of diabetes mellitus, and systemic diseases).
authors.affiliation: Innovative Vision Products Inc., County of New Castle, Delaware 19810, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Babizhayev
authors.forename: V N
authors.initials: VN
authors.lastname: Yermakova
authors.forename: Y A
authors.initials: YA
authors.lastname: Semiletov
authors.forename: A I
authors.initials: AI
authors.lastname: Deyev
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002336:Carnosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D002852:Chromatography, Ion Exchange; D006639:Histidine / Q000032:analysis*; D007908:Lens, Crystalline / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009883:Ophthalmic Solutions; D018384:Oxidative Stress; D011817:Rabbits
chemical_list: D000975:Antioxidants; D009883:Ophthalmic Solutions; C033681:N-acetylcarnosine; D006639:Histidine; D002336:Carnosine