Efficacy of N-acetylcarnosine in the treatment of cataracts.

Babizhayev MA, Deyev AI, Yermakova VN, Semiletov YA, Davydova NG, Doroshenko VS, Zhukotskii AV, Goldman IM.

Innovative Vision Products, Inc., County of Newcastle , Delaware , USA . markbabizhayev@yahoo.com

PURPOSE: To evaluate the effects of 1% N-acetylcarnosine (NAC) solution on lens clarity over 6 and 24 months in patients with cataracts. TRIAL DESIGN: Randomised, placebo-controlled study. PARTICIPANTS: 49 subjects (76 affected eyes) with an average age of 65.3 +/- 7.0 years with a diagnosis of senile cataract with minimum to advanced opacification in various lens layers. METHODS: 26 patients (41 eyes) were allocated to topical NAC 1% eyedrops twice daily. The control group consisted of 13 patients (21 eyes) who received placebo eyedrops and 10 patients (14 eyes) who did not receive eyedrops. MAIN OUTCOME MEASURES: All patients were evaluated at entry and followed up every 2 months for a 6-month period (trial 1), or at 6-month intervals for a 2-year period (trial 2), for best-corrected visual acuity and glare testing. In addition, cataract was measured using stereocinematographic slit-images and retro-illumination examination of the lens. Digital analysis of lens images displayed light scattering and absorbing centres in two- and three-dimensional scales. RESULTS: The overall intra-reader reproducibility of cataract measurements (image analysis) was 0.830, and glare testing 0.998. After 6 months, 90% of NAC-treated eyes showed improvement in best corrected visual acuity (7 to 100%) and 88.9% showed a 27 to 100% improvement in glare sensitivity. Topographic studies indicated fewer areas of posterior subcapsular lens opacity and 41.5% of treated eyes had improvement in image analysis characteristics. The overall ratios of image analysis characteristics at 6 months compared with baseline measures were 1.04 and 0.86 for the control and NAC-treated group, respectively (p < 0.001). The apparent benefits of treatment were sustained after 24 months' treatment. No treated eyes demonstrated worsening of vision. The overall visual outcome in the control group showed significant worsening after 24 months in comparison with both baseline and the 6-month follow-up examination. The overall clinical results observed in the NAC-treated group by the 24-month period of examination differed significantly (p < 0.001) from the control group in the eyes with cortical, posterior subcapsular, nuclear or combined lens opacities. Tolerability of NAC eyedrops was good in almost all patients, with no reports of ocular or systemic adverse effects. CONCLUSION: Topical NAC shows potential for the treatment and prevention of cataracts.

Publication Types:

·         Clinical Trial

·         Randomized Controlled Trial

PMID: 12001824 [PubMed - indexed for MEDLINE]

 2: unknown.

The Natural Histidine-Containing Dipeptide N^alpha-Acetylcarnosine as an Antioxidant for Ophthalmic Use

M. A. Babizhayev^1,2*, V. N. Yermakova², Yu. A. Semiletov¹, and A. I. Deyev¹

¹Innovative Vision Products, Inc., 3511 Silverside Road, Suite 105 , County of New Castle , Delaware , USA 19810

²Moscow Helmholtz Research Institute of Eye Diseases, ul. Sadovaya-Chernogryazskaya 14/19, Moscow , 103064 Russia ; fax: (7-095) 977-2387;

^* To whom correspondence should be addressed.

Received January 25, 1999 ; Revision received February 7, 2000

The naturally occurring compound N^alpha-acetylcarnosine is proposed as a prodrug of L-carnosine that is resistant to enzymatic hydrolysis by carnosinase. Eyes of rabbits were treated with 1% N^alpha-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. N^alpha-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 <= subconjunctival injection <= ultrasound-induced phoresis. Different treatment techniques showed excellent toleration of 1%N^alpha-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 N^alpha-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. N^alpha-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).

Erratum in:

·         Clin Chim Acta 1997 Mar 18;259(1-2):199-201.

 
N alpha-acetylcarnosine is a prodrug of L-carnosine in ophthalmic application as antioxidant.

Babizhayev MA, Yermakova VN, Sakina NL, Evstigneeva RP, Rozhkova EA, Zheltukhina GA.

Moscow Helmholtz Research Institute of Eye Diseases, Russian Federation .

The naturally occurring compound N alpha-acetylcarnosine (NAC) is proposed as the prodrug of L-carnosine (C) resistant to enzymatic hydrolysis by human serum carnosinase. Rabbit eyes were treated with 1% NAC, C 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), thin-layer (TLC) and ion-exchange chromatographic techniques. The topical administration of pure C 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. NAC showed dose-dependent hydrolysis in its passage from the cornea to the aqueous humor, releasing C after 15. 30 min of ocular administration of prodrug in a series of therapeutical modalities: instillation < or = subconjunctival injection < or = ultrasound induced phoresis. Different treatment techniques showed excellent toleration of 1% NAC by the eye. Once in the aqueous humor, C might act as an antioxidant and enter the lens tissue when present at effective concentrations (5-15 mmol/l). The advantage of the ophthalmic prodrug NAC and its bioactivated principle C as universal antioxidants relates to their ability to give efficient protection against oxidative stress both in the lipid phase of biological membranes and in an aqueous environment. NAC is proposed to treat ocular disorders which have the component of oxidative stress in their genesis (cataracts, glaucoma, retinal degeneration, corneal disorders, ocular inflammation, complications of diabetes mellitus, systemic diseases).

PMID: 8894306 [PubMed - indexed for MEDLINE]

 

4: Ann N Y Acad Sci. 2002 Apr;959:285-94.

 
Reaction of carnosine with aged proteins: another protective process?

Hipkiss AR, Brownson C, Bertani MF, Ruiz E, Ferro A.

GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London SE1 1UL, United Kingdom. alan.hipkiss@kcl.ac.uk

Cellular aging is often associated with an increase in protein carbonyl groups arising from oxidation- and glycation-related phenomena and suppressed proteasome activity. These "aged" polypeptides may either be degraded by 20S proteasomes or cross-link to form structures intractable to proteolysis and inhibitory to proteasome activity. Carnosine (beta-alanyl-l-histidine) is present at surprisingly high levels (up to 20 mM) in muscle and nervous tissues in many animals, especially long-lived species. Carnosine can delay senescence in cultured human fibroblasts and reverse the senescent phenotype, restoring a more juvenile appearance. As better antioxidants/free-radical scavengers than carnosine do not demonstrate these antisenescent effects, additional properties of carnosine must contribute to its antisenescent activity. Having shown that carnosine can react with protein carbonyls, thereby generating "carnosinylated" polypeptides using model systems, we propose that similar adducts are generated in senescent cells exposed to carnosine. Polypeptide-carnosine adducts have been recently detected in beef products that are relatively rich in carnosine, and carnosine's reaction with carbonyl functions generated during amino acid deamidation has also been described. Growth of cultured human fibroblasts with carnosine stimulated proteolysis of long-labeled proteins as the cells approached their "Hayflick limit," consistent with the idea that carnosine ameliorates the senescence-associated proteolytic decline. We also find that carnosine suppresses induction of heme-oxygenase-1 activity following exposure of human endothelial cells to a glycated protein. The antisenescent activity of the spin-trap agent alpha-phenyl-N-t-butylnitrone (PBN) towards cultured human fibroblasts resides in N-t-butyl-hydroxylamine, its hydrolysis product. As hydroxylamines are reactive towards aldehydes and ketones, the antisenescent activity of N-t-butyl-hydroxylamine and other hydroxylamines may be mediated, at least in part, by reactivity towards macromolecular carbonyls, analogous to that proposed for carnosine.

Publication Types:

• Review
• Review, Tutorial

PMID: 11976203 [PubMed - indexed for MEDLINE]

 

5: Mol Aspects Med. 1992;13(5):379-444.

Carnosine: its properties, functions and potential therapeutic applications.

Quinn PJ, Boldyrev AA, Formazuyk VE.

Biochemistry Department, King's College London, U.K.

Carnosine and related dipeptides such as anserine are naturally-occurring histidine-containing compounds. They are found in several tissues most notably in muscle where they represent an appreciable fraction of the total water-soluble nitrogen-containing compounds. The biological role of these dipeptides are conjectural but they are believed to act as cytosolic buffering agents. Numerous studies have demonstrated, both at the tissue and organelle level, that they possess strong and specific antioxidant properties. Carnosine and related dipeptides have been shown to prevent peroxidation of model membrane systems leading to the suggestion that they represent water-soluble counterparts to lipid-soluble antioxidants such as alpha-tocopherol in protecting cell membranes from oxidative damage. Other roles ascribed to these dipeptides include actions as neurotransmitters, modulation of enzymic activities and chelation of heavy metals. Many claims have been made in respect of therapeutic actions of carnosine and histidine-containing dipeptides. These include antihypertensive effects, actions as immunomodulating agents, wound healing and antineoplastic effects. Many of these claims have not been convincingly documented nor subject to rigorous clinical evaluation. Nevertheless, there are examples where studies have shown considerable promise. One is the treatment of senile cataract in dogs and another is in acceleration of healing of surface wounds and burns to the skin. It is clear from this review that many of the effects of these histidine-containing dipeptides, especially in regard to claims for their therapeutic effects, need to be subjected to critical experimental and clinical examination. Several applications do, however, show clear evidence of being useful therapeutic agents.

Publication Types:

• Review
• Review, Tutorial

PMID: 9765790 [PubMed - indexed for MEDLINE]

6: Nutrition 2003 Jan;19(1):21-4

Research Report : Lutein supplements improve visual function in patients with age-related cataracts

 
In the study published in January 2003 [Olmedilla B, Granado F, Blanco I, Vaquero M., Lutein, but not alpha-tocopherol, supplementation improves visual function in patients with age-related cataracts: a 2-y double-blind, placebo-controlled pilot study. Nutrition 2003 Jan;19(1):21-4.],

The authors reported the results from an investigation on the effect of long-term antioxidant supplementation (lutein and alpha-tocopherol) on serum levels and visual performance in patients with cataracts. Seventeen patients clinically diagnosed with age-related cataracts were randomized in a double-blind study involving dietary supplementation with lutein (15 mg; n = 5), alpha-tocopherol (100 mg; n = 6), or placebo (n = 6), three times a week for up to 2 years. Serum carotenoid and tocopherol concentrations were determined with quality-controlled high-performance liquid chromatography, and visual performance (visual acuity and glare sensitivity) and biochemical and hematologic indexes were monitored every 3 mo throughout the study. Changes in these parameters were assessed by General Linear Model (GLM) repeated measures analysis. Serum concentrations of lutein and alpha-tocopherol increased with supplementation, although statistical significance was reached only in the lutein group. 

Visual performance (visual acuity and glare sensitivity) improved in the lutein group, whereas there was a trend toward the maintenance of and decrease in visual acuity with alpha-tocopherol and placebo supplementation, respectively. No significant side effects or changes in biochemical or hematologic profiles were observed in any of the subjects during the study.

Visual function in patients with age-related cataracts who received the lutein supplements improved, suggesting that a higher intake of lutein, through lutein-rich fruit and vegetables or supplements, may have beneficial effects on the visual performance of people with age-related cataracts.

7: Nutrition 2003 June 1st 2003

Cataracts are responsible for about 30 to 50 million cases of blindness throughout the world. Cataract increases with age, reducing visual acuity and constituting a major cause of disability in the elderly, according to the researchers.

The team investigated the effect of long-term antioxidant supplementation, testing both lutein and alpha-tocopherol (or vitamin E), on serum levels and visual performance in seventeen patients with cataracts. They found that the patients' eyesight improved with both nutrients, although most significantly with lutein supplements.

The patients were randomised in a double-blind study. They took either 15mg of lutein, 100mg of alpha-tocopherol, or a placebo, three times a week for up to two years. Serum carotenoid and tocopherol concentrations were measured, and visual performance (visual acuity and glare sensitivity) was monitored every 3 months throughout the study.

The authors noted: “Serum concentrations of lutein and alpha-tocopherol increased with supplementation, although statistical significance was reached only in the lutein group." Visual performance (visual acuity and glare sensitivity) improved in the lutein group, but with vitamin E it remained at the same level and it decreased in those taking placebos. They reported no significant side effects in any of the subjects during the study.

The researchers say the results suggest that a higher intake of lutein, through lutein-rich fruit and vegetables or supplements, may have improve the visual performance of people with age-related cataracts.

8: Archives of Biochemistry and Biophysics 22nd March 2004

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