Клиническое исследование эффективности и безопасности препарата Визомитин®, глазные капли, у пациентов с возрастной катарактой

PURPOSE: The assessment of possibility to add a new indication for the registered pharmaceutical. Evaluation of safety and efficacy of Visomitin® compared to placebo in patients with age-related cataracts. METHODS: A randomized, double-blind, placebo-controlled clinical study of Visomitin® eye drops in patients with age-related cataracts was conducted in accordance with Good Clinical Practice guidance, the Declaration of Helsinki and the Russian regulatory requirements. The study included 80 patients (23 men and 57 women) aged 45 to 75 years with diagnosed age-related cataract. All subjects were randomized into two groups of 40 patients each. In the treatment group patients received Visomitin® eye drops and in the control group, patients were given placebo (vehicle, i.e. eye drops with the same composition as Visomitin® except for the active substance SkQ1) in the form of instillations of one drop per each eye three times daily for six months. The study comprised 7 monthly visits. The following standard ophthalmological examinations were used to evaluate the effectiveness of the therapy: visual acuity measurement, refractometry, biomicroscopy of the eye, ophthalmoscopy, tonometry, computer perimetry, densitometry. At certain visits lacrimal fluid was taken for evaluation of its antioxidant activity. Blood pressure and heart rate were measured as a part of safety evaluation which also included documentation of complaints and adverse events. Concomitant therapies were also documented. RESULTS: Analysis of safety parameters showed Visomitin® to be safe and well tolerated for patients with age-related cataract. Practically no adverse effects were documented during the study. In both groups a decrease of the number of patients with subjective complaints was observed. These complaints included: visual deterioration, dryness, grittiness, burning eyes, eye fatigue. The decrease of the number of complaints in the Visomitin® group was more pronounced than in the placebo group. During the first months of treatment an improvement of visual acuity was observed in both groups. This result can be explained by a protective effect of hypromellose contained in both Visomitin® and placebo. However, between the 4th and the 6th months, the improvement in visual acuity significantly slowed down in the placebo group, while positive dynamics remained the same in the Visomitin® group. At the end of the treatment visual acuity increased by more than 50% in Visomitin® group and remained at the level of 10-15% in the placebo group (statistically significant difference between placebo and Visomitin® groups, p<0.05). Even more pronounced difference was detected for older patients, where placebo did not cause any increase in visual acuity (p<0.001 at the end of the treatment). A tendency for decrease of the mean and maximum density of the lens was found in the group of patients treated with Visomitin®. On the contrary in the placebo group both mean and maximum density of the lens tended to increase. It is reasonable to suggest that these effects of Visomitin® resulted from an increase of antioxidant protection of eye that was verified by the measurement of the antioxidant activity of lacrimal fluid in the study. After 6 months of treatment antioxidant activity of lacrimal fluid significantly increased in the group of patients treated with Visomitin® compared to that in the placebo group. CONCLUSION: Study results support the use of Visomitin® as effective and safe treatment of age-related cataract. Such treatment can be aimed at deceleration of the disease progression in order to delay surgery. The study results allowed adding a new indication for the use of Visomitin® eye drops.

age-related cataract, oxidative stress, reactive oxygen species, mitochondria-targeted antioxidants, SkQ1

1. Rao G.N., Khanna R., Payal A. The global burden of cataract. Curr Opin Ophthalmol 2011; 22(1): 4-9. doi: 10.1097/icu.0b013e3283414fc8.

2. Benedek G.B. Cataract as a protein condensation disease: the Proctor Lecture. Invest Ophthalmol Vis Sci 1997; 38(10): 1911-1921. doi: 10.1016/s0002-9394(99)80119-6.

3. Asbell P.A., Dualan I., Mindel J., Brocks D., Ahmad M., Epstein S. Age-related cataract. The Lancet 2005; 365(9459): 599-609. doi: 10.1016/s0140-6736(05)17911-2.

4. Boscia F., Grattagliano I., Vendemiale G., Micelli-Ferrari T., Altomare E. Protein oxidation and lens opacity in humans. Invest Ophthalmol Vis Sci 2000; 41(9): 2461-2465. doi: 10.1016/00426989(95)90123-x.

5. Sunkireddy P., Jha S.N., Kanwar J.R., Yadav S.C. Natural antioxidant biomolecules promises future nanomedicine based therapy for cataract. Colloids Surf B: Biointerfaces 2013; 112: 554-562. doi: 10.1016/j.colsurfb.2013.07.068.

6. Mares J.A. High-dose antioxidant supplementation and cataract risk. Nutrition Reviews 2004; 62(1): 28-32. doi: 10.1111/j.17534887.2004.tb00003.x.

7. Selin J.Z., Rautiainen S., Lindblad B.E., Morgenstern R., Wolk A. High-dose supplements of vitamins C and E, low-dose multivitamins, and the risk of age-related cataract: a population-based prospective cohort study of men. Am J Epidemiol 2013; 177(6): 548-555. doi: 10.1093/aje/kws279.

8. Skulachev V.P. Functions of mitochondria: from intracellular power stations to mediators of a senescence program. Cel Molecul Life Sci 2009; 66(11-12): 1785-1793. doi: 10.1007/s00018-009-9183-6.

9. Korshunov S.S., Skulachev V.P., Starkov A.A. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS letters 1997; 416(1): 15-18. doi: 10.1016/s0014-5793(97)01159-9.

10. Babizhayev M.A. Mitochondria induce oxidative stress, generation of reactive oxygen species and redox state unbalance of the eye lens leading to human cataract formation: disruption of redox lens organization by phospholipid hydroperoxides as a common basis for cataract disease. Cell Biochemistry and Function 2011; 29(3): 183-206. doi: 10.1002/cbf.1737.

11. Kelso G.F., Porteous C.M., Coulter C.V., Hughes G., Porteous W.K., Ledgerwood E.C. et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and anti-apoptotic properties. J Biol Chemistry 2001; 276(7): 4588-4596. doi: 10.1074/jbc.m009093200.

12. Antonenko Y.N., Avetisyan A.V., Bakeeva L.E., Chernyak B.V., Chertkov V.A., Domnina L.V. et al. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: Synthesis and in vitro studies. J Biochemistry-Moscow 2008; 73(12): 1273-1287. doi: 10.1134/s0006297908120018.

13. Skulachev V.P., Anisimov V.N., Antonenko Y.N., Bakeeva L.E., Chernyak B.V., Erichev V.P. et al. An attempt to prevent senescence: a mitochondrial approach. Biochimica et Biophysica Acta (BBA)-Bioenergetics 2009; 1787(5): 437-461. doi: 10.1016/j.bbabio.2008.12.008.

14. Skulachev M.V., Antonenko Y.N., Anisimov V.N., Chernyak B.V., Cherepanov D. A., Chistyakov V.A. et al. Mitochondrial-targeted plastoquinone derivatives. Effect on senescence and acute age-related pathologies. Curr Drug Targets 2011; 12(6): 800-826. doi: 10.2174/138945011795528859.

15. Neroev V.V., Archipova M.M., Bakeeva L.E., Fursova A.Z., Grigorian E.N., Grishanova A.Y. et al. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 4. Age-related eye disease. SkQ1 returns vision to blind animals. Biochemistry (Moscow) 2008; 73(12): 1317-1328. doi: 10.1134/s0006297908120043.

16. Snytnikova O.A., Tsentalovich Y.P., Stefanova N.A., Fursova A.Z., Kaptein R., Sagdeev R.Z. et al. The therapeutic effect of mitochon-dria-targeted antioxidant SkQ1 and Cistanche deserticola is associated with increased levels of tryptophan and kynurenine in the rat lens. Doklady Biochemistry and Biophysics 2012; 447(1): 300-303. doi: 10.1134/s1607672912060087.

17. Rumyantseva Y.V., Ryabchikova E.I., Fursova A.Z., Kolosova N.G. Ameliorative effects of SkQ1 eye drops on cataractogenesis in senescence-accelerated OXYS rats. Graefe’s Arch Clin Exper Ophthalmol 2015; 253(2): 237-248. doi: 10.1007/s00417-014-2806-0.

18. Выгодин В., Гудкова Е., Скулачев М., Яни Е., Катаргина Л., Чеснокова Н. и др. Первый опыт использования препарата Визомитин® в терапии «сухого глаза». Практическая медицина 2012; 4(59): 134-137. .

19. Mancino R., Di Pierro D., Varesi C., Cerulli A., Feraco A., Cedrone C. et al. Lipid peroxidation and total antioxidant capacity in vitreous, aqueous humor, and blood samples from patients with diabetic retinopathy. Mol Vis 2011; 17: 1298-1304.

20. Grewal D.S., Brar G.S., Grewal S.P. Correlation of nuclear cataract lens density using Scheimpflug images with Lens Opacities Classification System III and visual function. Ophthalmology 2009; 116(8): 1436-1443. doi: 10.1016/j.ophtha.2009.03.002.

21. Аветисов С.Э., Полунин Г.С., Шеремет Н.Л., Муранов К.О., Макаров И.А., Федоров А.А. и др. Поиск шапероноподобных антикатарактальных препаратов - антиагрегантов кристаллинов хрусталика глаза. Сообщение 3. Возможности динамического наблюдения за процессами катарактогенеза на «пролонгированной» модели УФ-индуцированной катаракты у крыс. Вестник офтальмологии 2008; 124(2): 8-12.

22. Datiles M.B., Magno B.V., Freidlin V. Study of nuclear cataract progression using the National Eye Institute Scheimpflug system. Br J Ophthalmol 1995; 79(6): 527-534. doi: 10.1136/bjo.79.6.527.

23. Hockwin D., Dragomirescu V., Laser H. Measurements of lens transparency or its disturbance by densitometric image analysis of Scheimpflug photographs. Graefe’s Arch Clin Exper Ophthalmol 1982; 219(6): 255-262. doi: 10.1007/bf00231409.

24. Horwath-Winter J., Kirchengast S., Meinitzer A., Wachswender C., Faschinger C., Schmut O. Determination of uric acid concentrations in human tear fluid, aqueous humour and serum. Acta Ophthalmologica 2009; 87(2): 188-192. doi: 10.1111/j.1755-3768. 2008.01215.x.