References

glaucoma

Национальный журнал Глаукома

National Journal glaucoma

2078-41042311-6862

Federal State Budgetary Institution of Science “Krasnov Research Institute of Eye Diseases”

glaucoma-44

Research Article

ОБЗОР ЛИТЕРАТУРЫ

REVIEW OF LITERATURE

Ингибиторы Rho-киназы - новые препараты местной гипотензивной терапии глаукомы

Rho-kinase inhibitors - new topical hypotensive drugs in the glaucoma treatment

Петров

Сергей Юрьевич

Petrov

S. Yu.

post@glaucomajournal.ru

Сафонова

Д. М.

Safonova

D. M.

noemail@neicon.ru

ФГБУ «НИИ глазных болезней» РАМНРоссияThe Scientific Research Institute of Eye Diseases of the Russian Academy of Medical SciencesRussian Federation

2014

17012017

13492100

2017

Петров С.Ю., Сафонова Д.М.

Petrov S.Y., Safonova D.M.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.glaucomajournal.ru/jour/article/view/44

В литературном обзоре описывается новый класс гипотензивных препаратов, снижающих офтальмотонус путем прямого действия на трабекулярный отток - ингибиторов Rho-киназы. Упоминается важная роль актин-миозиновой системы и сократительной способности тканей дренажной системы в резистентности оттоку внутриглазной жидкости, а также влияние на него расслабления трабекулярной сети вследствие напрямую действующих на актин-миозиновую систему селективных ингибиторов Rho-киназы. Перечисляются представители ингибиторов Rho-киназы, находящиеся на стадии клинических исследований: Rhopressa™ (фаза III, «Aerie Pharmaceuticals», США), Roclatan™, AR-12286 (фаза II, «Aerie Pharmaceuticals», США), K-115 (фаза III, «Kowa Pharmaceutical», Япония), AMA0076 (фаза II, «Amakem Therapeutics», Бельгия). Представлены механизмы действия ингибиторов Rho-киназы, такие как расслабляющее действие на трабекулярную сеть, понижение эписклерального венозного давления, а также опосредованное ингибирование синтеза внутриглазной жидкости. Также в обзоре приводится описание преходящих умеренных побочных эффектов приведенных препаратов в виде конъюнктивальной гиперемии. Дан краткий обзор клинических исследований, проведенных на лабораторных животных и пациентах, в том числе сравнения эффективности с аналогами простагландинов.

This review presents ROCK inhibitors - a new family of hypotensive drugs that lower intraocular pressure by enhancing trabecular outflow. It mentions a crutial role of the actin- myosin contractile system in resisting the aqueous humor outflow, and describes the effect that selective Rho-kinase inhibitors have on trabecular system contraction, laxation and, consequently, on the outflow volume. The article also enumerates several Rho-kinase inhibitors that are currently in the pipeline, such as Rhopressa™ (Phase III, “Aerie Pharmaceuticals”, USA), Roclatan™, Ar-12286 (Phase II, “Aerie Pharmaceuticals”, USA), K-115 (Phase III, “Kowa Pharmaceutical”, Japan), AMA0076 (Phase II, “Amakem Therapeutics”, Belgium). The review provides a short description of their mechanisms of action, such as the relaxation of trabecular meshwork that leads to increased outflow, mediated decrease in fluid production and lowering of episcleral venous pressure. It also describes the transient moderate adverse reactions, and gives a brief recount of conducted clinical trials of the new drugs.

глаукомагипотензивная терапияингибиторы Rho-киназыRhopressaglaucomahypotensive therapyROCK inhibitorsRhopressa

References1

Нестеров А.П. Глаукома М.: Медицина, 1995. 256. [Nesterov A.P. Glaukoma [Glaucoma]. Moscow, Meditsina Publ., 1995. 256 p. (In Russ.)].

Авдеев Р.В., Александров А.С., Басинский А.С., Блюм Е.А., Брежнев А.Ю., Волков Е.Н. и др. Клинико-эпидемиологическое исследование факторов риска развития и прогрессирования глаукомы. Российский офтальмологический журнал 2013; 6(3):4-11. [Avdeev R.V., Alexandrov A.S., Basinsky A.S., Blum E.A., Brezhnev A.Yu., Volkov E.N., Gaponko O.V. et al. Clinical and epidemiological study of risk factors of glaucoma development and progression. Russian Ophthalmological J 2013; 6(3):4-11. (In Russ.)].

Золотарев А.В., Карлова Е.В., Николаева Г.А. Роль трабекулярного аппарата в осуществлении увеосклерального оттока. Клин. офтальмология 2006 (2):67-69. [Zolotarev A.V., Karlova E.V., Nikolaeva G.A. The role of trabecular meshwork in the uveoscleral outflow. Clin Ophthalmol 2006 (2): 67-69. (In Russ.)].

Wang S.K., Chang R.T. An emerging treatment option for glaucoma: Rho kinase inhibitors. Clin Ophthalmol 2014; 8:883-890.

Challa P., Arnold J.J. Rho-kinase inhibitors offer a new approach in the treatment of glaucoma. Expert Opin Invest Drugs 2014; 23(1):81-95.

Rao V.P., Epstein D.L. Rho GTPase/Rho kinase inhibition as a novel target for the treatment of glaucoma. Biodrugs 2007; 21(3):167-177.

Wang S.K., Chang R.T. An emerging treatment option for glaucoma: Rho kinase inhibitor. Clin Ophthalmol 2014; 8:883-890.

Zhang M., Maddala R., Rao P.V. Novel molecular insights into RhoA GTPase-induced resistance to aqueous humor outflow through the trabecular meshwork. Am J Physiol Cell Physiol 2008; 295(5):C1057-1070.

Pattabiraman P.P., Lih F.B., Tomer K.B., Rao P.V. The role of calcium-independent phospholipase A2y in modulation of aqueous humor drainage and Ca2+ sensitization of trabecular meshwork contraction. Am J Physiol Cell Physiol 2012; 302 (7):C979-991.

Ramachandran C., Patil R.V., Sharif N.A., Srinivas S.P. Effect of elevated intracellular cAMP levels on actomyosin contraction in bovine trabecular meshwork cells. Invest Ophthalmol Vis Sci 2011; 52(3):1474-1485.

Inoue T., Pecen P., Maddala R., Skiba N.P. Characterization of cytoskeleton-enriched protein fraction of the trabecular meshwork and ciliary muscle cells. Invest Ophthalmol Vis Sci 2010; 51(12):6461-6471.

Ko M.K., Tan J.C. Contractile markers distinguish structures of the mouse aqueous drainage tract. Mol Vis 2013; 19: 2561-2570.

Shimizu Y. et al. ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles. J Cell Biol 2005; 168:941-963.

Nakajima E., Nakajima T., Minagawa Y., Shearer T.R., Azu- ma M. Contribution of ROCK in contraction of trabecular meshwork: proposed mechanism for regulating aqueous outflow in monkey and human eyes. J Pharm Sci 2005; 94(4):701-708.

Lopez-Riquelme N., Villalba C., Tormo C., Belmonte A., Fernandez C., Torralba G. et al. Endothelin-1 levels and biomarkers of oxidative stress in glaucoma patients. Int Ophthalmol 2014 Jul 31. [Epub ahead of print]

Dismuke W.M., Liang J., Overby D.R., Stamer W.D. Concentration-related effects of nitric oxide and endothelin-1 on human trabecular meshwork cell contractility. Exp Eye Res 2014; 120:28-35.

Choritz L., Machert M., Thieme H. Correlation of endothelin-1 concentration in aqueous humor with intraocular pressure in primary open angle and pseudoexfoliation glaucoma. Invest Ophthalmol Vis Sci 2012; 53(11):7336-7342.

Павленко Т.А., Чеснокова Н.Б., Давыдова Х.Г., Охоцимс- кая Т.Д., Безнос О.В., Григорьев А.В. Уровень эндотелина-1 в слезной жидкости у пациентов с глаукомой и пролиферативной диабетической ретинопатией. Вестн. офтальмологии 2013. 129 (4):20-3. [Pavlenko T.A., Chesnokova N.B., Davydova H.G., Okhotsimskaia T.D., Beznos O.V., Grigor’ev A.V. Level of tear endothelin-1 and plasminogen in patients with glaucoma and proliferative diabetic retinopathy. Vestn Oftalmol 2013; 129(4):20-23. (In Russ.)].

Paulawcrnte-Baiktiene D., Baršauskaite R., Janulevičiene I. New insights into pathophysiological mechanisms regulating conventional aqueous humor outflow. Medicina (Kaunas) 2013; 49(4):165-169.

Stamer W.D., Braakman S.T., Zhou E.H., Ethier C.R., Fred- berg J.J., Overby D.R. et al. Biomechanics of Schlemm’s canal endothelium and intraocular pressure reduction. Prog Retin Eye Res 2014 Sep 16. pii: S1350-9462(14)00054-8. [Epub ahead of print].

Murphy K.C., Morgan J.T., Wood J.A., Sadeli A., Murphy C.J., Russell P. The formation of cortical actin arrays in human trabecular meshwork cells in response to cytoskeletal disruption. Exp Cell Res 2014; 328(1):164-171.

Fukiage C., Mizutani K., Kawamoto Y., Azuma M, Shearer T.R. Involvement of phosphorylation of myosin phosphatase by ROCK in trabecular meshwork and ciliary muscle contraction. Biochem Biophys Res Commun 2001; 288(2):296-300.

Tamm E.R. Functional morphology of the outflow pathways of aqueous humor and their changes in open angle glaucoma. Ophthalmologe 2013; 110 (11):1026-1035.

Ramachandran C., Patil R.V., Combrink K., Sharif N.A., Srini- vas S.P. Rho-Rho kinase pathway in the actomyosin contraction and cell-matrix adhesion in immortalized human trabecular meshwork cells. Mol Vis 2011; 17:1877-1890.

Koga T., Koga T., Awai M., Tsutsui J., Yue B.Y., Tanihara H. Rho-associated protein kinase inhibitor, Y-27632, induces alterations in adhesion, contraction and motility in cultured human trabecular meshwork cells. Exp Eye Res 2006; 82(3):362-370.

Wang J., Liu X., Zhong Y. Rho/Rho-associated kinase pathway in glaucoma (Review). Int J Oncol 2013; 43(5):1357-1367.

Шмырева В.Ф., Зиангирова Г.Г., Мазурова Ю.В., Петров С.Ю. Клинико-морфологическая характеристика дренажной зоны склеры при глаукоме нормального внутриглазного давления. Вестник офтальмологии 2007; 6:32-35. [Shmyreva V.F., Ziangirova G.G., Mazurova Yu.V., Petrov S.Yu. Clinical and morphological characteristics of the scleral drainage area in normotensive glaucoma. Vestn Oftalmol 2007; 6:32-35. (In Russ.)].

Boureux A., Vignal E., Faure S., Fort P. Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol Biol Evol 2007; 24(1):203-216.

Bustelo X.R., Sauzeau V., Berenjeno I.M. GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. Bioessays 2007; 29(4):356-370.

Leung T., Manser E., Tan L., Lim L. A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J Biol Chem 1995; 270(49):29051-29054.

Matsui T., Amano M., Yamamoto T., Chihara K., Nakafuku M., Ito M. et al. Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho. EMBO J 1996; 15:2208-2216.

Wang J., Liu X., Zhong Y. Rho/Rho-associated kinase pathway in glaucoma (Review). Int J Oncol 2013; 43(5):1357-1367.

Thieme H., Nuskovski M., Nass J.U., Pleyer U., Strauss O., Wiederholt M. Mediation of calcium-independent contraction in trabecular meshwork through protein kinase C and rho-A. Invest Ophthalmol Vis Sci 2000; 41 (13):4240-4246.

Inoue T., Tanihara H. Rho-associated kinase inhibitors: a novel glaucoma therapy. Prog Retin Eye Res 2013; 37:1-12.

Honjo M., Tanihara H., Inatani M., Kido N., Sawamura T., Yue B.Y. et al. Effects of rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility. Invest Ophthalmol Vis Sci 2001; 42(1):137-144.

Amano M., Fukata Y., Kaibuchi K. Regulation and function of Rho-associated kinase. Exp Cell Res 2000; 261:44-51.

Riento K., Ridley A. ROCKs: multifunctional kinases in cell behaviour. Nature Rev Mol Cell Bio 2003; 4: 446-456.

Tokushige H., Inatani M., Nemoto S. et al. Effects of topical- administration of Y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys. Invest Ophthalmol Vis Sci 2007; 48(7):3216-3222.

Tanihara H., Inatani M., Honjo M., Tokushige H., Azuma J., Araie M. Intraocular pressure-lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ- 1656, in healthy volunteers. Arch Ophthalmol 2008; 126(3): 309-315.

Chen J., Runyan S.A., Robinson M.R. Novel ocular antihypertensive compounds in clinical trials. Clin Ophthalmol 2011; 5:667-677.

Bain W.E.S. Variations in the episcleral venous pressure in relation to glaucoma. Br J Ophthalmol 1954; 38(3):129-135.

Zamora D.O., Kiel J.W. Episcleral venous pressure responses to topical nitroprusside and N-Nitro-l-arginine methyl ester. Invest Ophthalmol Vis Sci 2010; 51(3):1614-1620.

Шмырева В.Ф., Петров С.Ю., Антонов А.А., Стратонни- ков А.А., Савельева Т.А., Шевчик С.А. и др. Исследование метаболизма тканей переднего отрезка глаза по уровню оксигенации гемоглобина в венозном русле при первичной открытоугольной глаукоме. Глаукома 2008; 3:3-10. [Shmireva V.F., Petrov S.Yu., Antonov А.А., Stratonnikov A.A., Savelieva T.A., Shevchik S.S. et al. The study of the metabolism of the tissues in the anterior segment of the eye in relation to hemoglobin oxygenation in venous system at primary open- angle glaucoma. Glaucoma 2008; 3:3-10. (In Russ.)].

Leading Innovation in Glaucoma. The Next Generation. Aerie Pharmaceuticals Company Overview. EX-99.1 2 d707759dex 991.htm EX-99.1

Wang R.-F., Serle J.B., Kopczynski C. Effect of 0.04% AR-13324 on aqueous humor dynamics in normotensive monkey eyes. ARVO Meeting Abstracts. Invest Ophthalmol Vis Sci 53:E-Abstract 1994, 2012.

Weiss M., Levy B., Kopczynski C., van Haarlem T., Novack G. AR-13324-CS201 Study Group. Evaluation of AR-13324, a novel dual mechanism agent, in lowering of IOP in glaucoma and ocular hypertension. ARVO Meeting Abstracts. Invest Ophthalmol Vis Sci 54:E-Abstract 754, 2013.

Шмырева В.Ф., Петров С.Ю., Антонов А.А., Данилов С.С. Исследование суточных колебаний офтальмотонуса у пациентов с первичной открытоугольной глаукомой при монотерапии тимололом, латанопростом и травопростом. РМЖ. Клиническая офтальмология 2010; 11(4):125-127. [Shmi- reva V.F., Petrov S.Yu., Antonov A.A., Danilov S.S. Study of daily IOP fluctuations in patients with primary open-angle glaucoma as monotherapy with timolol, latanoprost and travoprost. RMJ Clinical Ophthalmology 2010; 11(4):125-127. (In Russ.)].

Kopczynski C., Novack G.D., Swearingen D., van Haarlem T. Ocular hypotensive efficacy, safety and systemic absorption of AR-12286 ophthalmic solution in normal volunteers. Br J Ophthalmol 2013; 97(5):567-572.

Williams R.D., Novack G.D., van Haarlem T., Kopczynski C.; AR-12286 Phase 2A Study Group. Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am J Ophthalmol 2011; 152(5):834-841.

Isobe T., Mizuno K., Kaneko Y., Ohta M., Koide T., Tanabe S. Effects of K-115, a rho-kinase inhibitor, on aqueous humor dynamics in rabbits. Curr Eye Res 2014; 39(8):813-822.

Tanihara H., Inoue T., Yamamoto T., Kuwayama Y., Abe H., Araie M. et al. K-115 Clinical Study Group. Phase 2 randomized clinical study of a Rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol 2013; 156(4):731-736.

Yamamoto K., Maruyama K., Himori N. et al. The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Invest Ophthalmol Vis Sci 2014 Oct 2. [Epub ahead of print].

Boland S., Defert O., Alen J., Bourin A., Castermans K., Kindt N. et al. 3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phe- nyl] benzoates as soft ROCK inhibitors. Bioorg Med Chem Lett 2013; 23(23):6442-6446.

Van de Velde S., Van Bergen T., Sijnave D., Hollanders K., Castermans K., Defert O. et al. AMA0076, a novel, locally acting Rho kinase inhibitor, potently lowers intraocular pressure in New Zealand white rabbits with minimal hyperemia. Invest Ophthalmol Vis Sci 2014; 55(2):1006-1016.

The authors declare that there are no conflicts of interest present.