Clinical experience with N-acetylcarnosine use in patients with age-related cataract

CLINICAL EXPERIENCE OF USING N-ACETYLCARNOSINE IN PATIENTS WITH AGE-RELATED CATARACT

Malachkova N. V.¹, Prus Ye. L.², Radyoga K. M.²

¹ Vinnytsia National Pirogov Memorial Medical University, Vinnytsia, Ukraine

² Eye Center "Optimal", Vinnytsia, Ukraine

Abstract. Relevance. Worldwide, cataract remains one of the leading diseases causing blindness. Pathological conditions associated with the aging of the lens have long been known. These include presbyopia and age-related cataract. That is why WHO supports the feasibility of further large-scale studies of the effectiveness of drugs for preventing cataract development, especially with the use of antioxidants (WHO, 2018). The aim of the study was to evaluate the effect of N-acetylcarnosine in the preparation "Clarastil" on the condition of the lens during long-term use (6 months) in patients with cataract. Materials and methods. The study lasted 6 months in two groups. The first (control) group included 10 patients (18 eyes) aged 65.3 ± 3.0 years. The second group consisted of 20 patients (37 eyes) aged 63.4 ± 5.0 years with a diagnosis of senile cataract. The study was conducted in accordance with the Declaration of Helsinki 1964. Patients in the first group did not receive any drops and were only observed during the entire period. Patients in the second group received "Clarastil" twice a day (topical instillations into the conjunctival sac) for 6 months. Results. It was found that in the group of patients who used N-acetylcarnosine, improvement was observed in visual acuity, achromatic visocontrastometry, Norn test, Schirmer test, as well as lens condition according to the LOCS III system. Conclusions. "Clarastil", as a pharmaceutical product containing N-acetylcarnosine, influences the delay of cataract progression, and in some cases contributes to significant restoration of lens transparency at the initial (early) stages of cataract formation, and may potentially significantly delay surgical intervention.

Keywords: age-related cataract, achromatic visocontrastometry, lens, LOCS III system, antioxidants.

Introduction

Worldwide, cataract remains one of the leading causes of blindness. As is known, the transparency of the lens is ensured by the symmetrical organization of its structural elements, namely the orderly arrangement of lens fibers. During the differentiation of lens epithelial cells, the fibers that are formed are shifted to the center of the lens and are retained in the body throughout life. The aging processes of the lens epithelium are subject to the laws of aging of proliferating tissues. Pathological conditions associated with the aging processes of the lens have long been known. These include presbyopia and age-related cataracts. That is why WHO supports the feasibility of further large-scale studies of the effectiveness of drugs for the prevention of cataract development, especially with the use of antioxidants (WHO, 2018) [1].

According to modern views, the aging processes that occur in the lens and lead to its opacity are manifestations of protein conformational disorders due to peroxidation and the appearance of disulfide and other covalent bonds between them. Both cytoplasmic proteins and protein complexes of cell membranes undergo oxidation. In turn, membrane changes cause their increased permeability, hydration and swelling of lens fibers. Other authors support the idea of the primary role of photooxidation of lens cell membranes in the violation of its transparency. At the same time, ultraviolet radiation is considered the main cause. In addition to the direct effect of light on the protein and lipid components of lens cells, oxidation leads to a decrease in the concentration of natural antioxidants in the lens, namely glutaminyl-cysteinyl-glycine, ascorbic acid, etc. [2]. Oxidative stress is a pathological condition caused by the presence of an excess of free radical particles in the body or a reduced efficiency of the antioxidant system [3]. Increased formation of reactive oxygen species (prooxidants) and reduced antioxidant protection are the causes of chronic oxidative stress in the tissues of the eye, which creates conditions for the development of cataracts.

The search for drugs for non-surgical treatment of cataracts has been going on for decades. Treatment with intervention in the antioxidant system of the body is the most interesting and relevant. Humanity has a much longer average life expectancy. Disorders that arise as a result of oxidative stress in the body in general and in the eye in particular are one of the risk factors for the occurrence of pathological conditions that affect the formation of age-related changes in the organ of vision. Such factors include environmental factors, in particular, ultraviolet radiation, eye infections, dust, air conditioning, working with a computer, as well as various injuries [4]. The question of whether these changes can be prevented by medical measures and pharmaceutical achievements remains without a clear answer.

In view of this, for the prevention of lens opacification, it is advisable to use replacement therapy, which will ensure the entry into the cells of substances, the deficiency of which is associated with the development of cataracts, namely antioxidants. Antioxidants are divided into two main groups depending on their solubility in water: hydrophilic and lipophilic [5].

Known water-soluble antioxidants, thiol antioxidants and their chemical derivatives, which have recently been isolated as anti-cataract agents, are N-acetylcarnosine, N-acetylcysteine and N-acetylcysteine amide, glutathione, cysteine, prodrugs of cysteine L-2-oxothiazolidine-4-carboxylic acid. N-acetylcarnosine inhibits the peroxidation of membrane lipids and are prodrugs of carnosine [6].

The drug "Clarastil" has appeared on the pharmaceutical market of Ukraine (contains an aqueous sterile solution of 0.3% carboxymethylcellulose, methyl-p-hydroxybenzoate 0.03%, glycerin, disodium edetate, N-acetylcarnosine, sodium chloride, sodium tetraborate, potassium bicarbonate, water). In the medical device, the concentration of substances is selected to obtain hydrogel rheological characteristics identical to those of tear fluid, and good adhesion to the surface of the eye. Modern anti-cataract drugs have a wide range of reparative effects, which allows them to be successfully used for the prevention and treatment of cataracts and metabolic lesions of other structures of the eye - the cornea and, according to recent data, the retina.

Due to the antioxidant properties of the components of the drug "Clarastil" and the ability to counteract free radicals, this medical device protects the tissues of the eye (lens, cornea, conjunctiva) from the effects of oxidative stress, which occurs due to the adverse effects of environmental factors and is a trigger for the development of a number of eye diseases, including cataracts.

It is known that the protein L-carnosine has an antioxidant effect on the lens, so biochemically there is a clear logic for studying L-carnosine as a means for reversing the development of cataracts or even preventing its progression. When used in the form of eye drops, L-carnosine cannot penetrate the eye. However, when applied to the surface of the eye, N-acetylcarnosine penetrates through the cornea into the anterior chamber of the eye, where it is metabolized into L-carnosine. Therefore, it is quite likely that the use of eye drops with N-acetylcarnosine can reduce the risk of cataracts or even prevent their progression, improving vision and quality of life.

In the drug "Clarastil", as mentioned above, the concentration of carboxymethylcellulose (0.3%) is carefully selected to obtain hydrogel rheological characteristics identical to those of tear fluid, and good adhesiveness on the outer membrane of the eye, which provides protective, eutrophic, moisturizing and softening properties without the effect of blurring vision.

Taking into account the opinion of the authors on the feasibility of using the antioxidant N-acetylcarnosine in the prevention and stabilization of the process of lens opacification [7; 8], we considered it necessary to obtain our own experience of using this substance, which is part of the drug "Clarastil".

The purpose of our study is to evaluate the effect of the drug N-acetylcarnosine on the condition of the lens under the condition of its long-term use (6 months) in patients with cataracts.

Materials and Methods

The study lasted 6 months in two groups. The first (control) group included 10 patients (18 eyes) aged 65.3 ± 3.0 years. The second group included 20 patients (37 eyes) aged 63.4 ± 5.0 years with a diagnosis of senile cataract. The inclusion criteria were: the presence of cataract in at least one eye, the absence of the necessary urgent intervention for cataract, the possibility of performing complete and safe mydriasis.

As exclusion criteria, we defined other concomitant ophthalmological diseases, such as glaucoma, diabetic retinopathy, previous retinal laser coagulation and anterior segment surgery, as well as the presence of a history of injuries and degenerative processes in the eye. During the study period, the patients did not take any vitamins or nutraceuticals.

The study was conducted in accordance with the principles of the 1964 Declaration of Helsinki.

Patients in the first group did not receive any drops and were only observed throughout the entire period. Patients in the second group received the specified drug twice a day (local instillations into the conjunctival sac) for 6 months.

All patients were examined before the start of the study, 3 and 6 months after the start of treatment. During the study, the determination of the maximum corrected visual acuity (Golovin-Sivtsev tables), autorefractometry (Huvitz 3000, Korea), achromatic (black and white) visocontrastometry, Schirmer test, ophthalmoscopy, slit lamp photofixation and photo retroillumination image of the condition of the lens were performed. The results obtained during slit lamp photofixation (Huvitz, Korea) were analyzed using the LOCS III system (the Lens Opacities Classification System III) [6].

When determining the severity of disorders according to the LOCS III classification, the expert assesses the presence or absence of opacification, as well as the degree of its severity in three main areas of the lens: the cortex, the nucleus and the posterior subcapsular zone. Accordingly, NO – opalescence of the nucleus, NC – assessment of the color of the nucleus. The degree of changes, according to the photo scale proposed by the authors, is graded from 0 to 5. The doctor also assesses cortical (C) or subcapsular cataract (P) from 0 to 5 using standardized images on the film.

According to the results of the examination, the patients of the second group were divided into 3 subgroups. Thus, the first subgroup (NO3–NC3/C2–3/P0) included 18 eyes; the second subgroup (NO4–NC4/C3–4/P0) – 14 eyes; to the third (NО5–NC5/С4–5/Р0–1) – 5 eyes.

Results

For a comprehensive assessment of the functional state of the visual analyzer, in addition to checking visual acuity with maximum correction, spatial contrast sensitivity was determined. Contrast sensitivity of the eye is the ability to determine the minimum contrast in order to distinguish images of different sizes and contrast [9]. All examinations were performed under conditions of full ocular correction. It is worth noting that in the area of low spatial frequencies (0.1–1.4 cycles/degree) contrast sensitivity in all patients of both groups was within the acceptable norm and changes ranged from 5–7 dB. The decrease in contrast sensitivity in the range of medium frequencies (2.0–3.02 cycles/degree) varied from 10 to 15 dB below normal. However, the greatest deviations from normal were observed in the area of high frequencies (5.0–36.25 cycles/degree). The decrease in sensitivity indicators sometimes reached 35–40 dB below normal. No significant difference in the indicators between the first and second groups was observed during visocontrastometry at the beginning of the study.

Visocontrastometry was performed under the same conditions, at the same level of lighting, at the same time of day (Table 1).Table 1

Results of visocontrastometry at the first examination

Indicators	First (control) group	Second (study) group	Subgroup 1	Subgroup 2	Subgroup 3
Total number of patients	10	20	9	5	6
Number of eyes	18	37	18	14	5
Age	65.3 ± 3.0	63.4 ± 5.0	58.5 ± 5.0	63.0 ± 3.0	68.0 ± 3.0
Schirmer test	7.0 ± 2.0	7.5 ± 2.0	8.0 ± 1.0	7.5 ± 3.0	7.0 ± 2.0
Norn test	9.1 ± 2.0	9.3 ± 1.0	10.0 ± 1.0	10.0 ± 2.0	8.0 ± 2.0

Changes in the results of the visocontrastometry were noticeable in both groups after 3 months. This trend remained stable until the final examination after 6 months. Thus, according to the results of achromatic visocontrastometry, one of the patients in the control group was withdrawn from the study. He underwent surgery (FEC with IOL implantation), since the visual acuity and contrast sensitivity indicators significantly deteriorated, and the patient complained of symptoms that sharply reduced his social capabilities.

In the first group, according to the results of six-month observation, a gradual decrease in contrast sensitivity indicators in all ranges was recorded. At the same time, in the group of patients who received L-carnosine in the form of eye drops, an increase in sensitivity was observed at medium (changes reached an average of 15 dB) and high frequencies (changes from 15 to 25 dB). There were no significant changes at low frequencies. The best results were found in the subgroup NO3–NC3/С2–3/Р0, in the third subgroup (NO5–NC5/С4–5/Р0–1) the increase in contrast sensitivity occurred compared to the baseline level within 7–12 dB.

During the entire observation period, no adverse reactions and complaints were detected in patients receiving N-acetylcarnosine that could affect their health in general and the results of the study in particular. It is worth noting, however, that a side effect, and rather an unexpected effect, was a decrease in the feeling of “sand in the eyes”. Patients noticed the effect of moisturizing the eyes and subjectively noted an increase in visual acuity – improved image clarity after 1 month of regular use of the drops. We associate these phenomena with the improvement of the stability of the tear film on the surface of the eye, which is due to the content of carboxymethylcellulose in the drug “Clarastil”. Such phenomena were not observed in the control group.

After 6 months, the results of the Schirmer test and the Norn test in both groups differed, although they were not statistically significant (Table 2).

Table 2

Results of Schirmer and Norn tests in both groups after 6 months of observation

Indicators	First (control) group	Second (study) group	Subgroup 1	Subgroup 2	Subgroup 3
Total number of patients	10	19	9	5	5
Number of eyes	18	36	18	14	4
Age	65.3 ± 3.0	63.4 ± 5.0	58.5 ± 5.0	63.0 ± 3.0	68.0 ± 3.0
Schirmer test	6.6 ± 2.0	7.7 ± 2.0	8.5 ± 1.0	7.5 ± 3.0	7.0 ± 2.0
Norn test	9.3 ± 2.0	9.7 ± 1.0	10.5 ± 1.0	10.0 ± 2.0	8.5 ± 2.0

It should be noted that visual acuity, as well as contrast sensitivity, also differed in the control group and the observation group after 6 months, however, visual acuity was not an evaluation criterion in the dynamics of observation. In the study group, the greatest changes occurred in the 1st and 2nd subgroups, which indicated less pronounced changes in the condition of the lens. In the 3rd subgroup, in patients whose lens condition corresponded to NO5–NC5/C4–5/P0–1, visual acuity, and the results of visocontrastometry did not differ significantly from the initial ones.

Thus, at the beginning and end of the study, each patient from the study group also underwent photofixation of changes from the lens on an autorefractometer in the retroillumination mode. The individual photos below indicate that changes occurred in patients of the 1st and 2nd subgroups (an example of one of the patients before the start of treatment – Fig. 1, after treatment – Fig. 2).

Fig. 1. Retroillumination photo of the right and left eye before treatment

Fig. 2. Retroillumination photo of the right and left eye after treatment

Discussion

N-acetylcarnosine, a component of Klarastil drops, due to its antioxidant properties and ability to counteract free radicals, is an oxidase in itself and protects eye tissues (lens, cornea, conjunctiva) from damage by cellular lipid peroxidases, which is observed in cataracts. Numerous publications and studies confirm these data.

It is worth noting that visual acuity, although a subjective indicator, is extremely important for the patient himself, for preserving his social functions and working capacity. During the study, we used qualitative and quantitative methods, which allows us to formulate a general opinion about the effect of N-acetylcarnosine on the condition of the lens. However, in our opinion, visual acuity in some cases increased due to hydration, which reduced the symptoms of dry eye disease, including blurred vision. The results of the visocontrastometry are somewhat similar to those obtained during the studies conducted by a group of authors from Russia [10]. The tendency of the curve characteristics to change depending on the frequency characteristics of the pattern was identical. Photofixation of results in modern medicine is an important and integral component of independent monitoring of the state of disease progression, in particular cataract.

The changes that were detected during the study indicate that the use of the LOCS III system during the analysis of the stage of cataract is of great importance, since it is an objective quantitative characteristic that made it possible to establish: patients with initial changes in the lens (in subgroups 1 and 2) had better results during the study period, which indicates the need for earlier prescription of the drug, which includes N-acetylcarnosine. However, in advanced stages (NO5–NC5/C4–5/P0–1) (subgroup 3) there were no changes.

Improved contrast sensitivity, changes in the shape, size, and density of lens opacities – all of this is the result of biochemical changes that occurred due to the antioxidant properties of the drug.

Conclusions

"Clarastil", a pharmaceutical product containing N-acetylcarnosine, delays cataract progression, and in some cases contributes to significant restoration of lens transparency at the initial (early) stages of cataract formation, and may potentially significantly delay surgical intervention.

Conflict of interest. None declared.

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Source: "Archive of Ophthalmology of Ukraine". 2020. Vol. 8. No. 2. P. 29–34.