Turkiye Klinikleri Journal of Ophthalmology

.: REVIEW
Glokom Tedavisinde Yeni İlaçlar
New Drugs in the Treatment of Glaucoma
İclal YÜCELa, Diğdem BEĞENDİa
aGöz Hastalıkları AD, Akdeniz Üniversitesi Tıp Fakültesi, Antalya, TÜRKİYE
Turkiye Klinikleri J Ophthalmol. 2019;28(3):189-97
doi: 10.5336/ophthal.2019-65668
Article Language: TR
Full Text
ÖZET
 Glokom, hem hastalar hem de doktorlar için tedavisi zor olan kronik, multifaktöriyel, nörodejeneratif bir hastalıktır. Günümüzde glokom tedavi modalitelerinin göz içi basıncını düşürmede her olguda yeterlilik sağlayamaması ve yan etkileri nedeni ile sıklıkla tedaviye uyum güçlüğü yaşanması, glokom patogenezindeki farklı etki mekanizmalarına ve uygulama yollarına yönelime yol açmıştır. Çıkış direncini azaltmak için doğrudan trabeküler ağ örgüsü (TM)/Schlemm kanalı/geleneksel çıkış yolunu hedef alan birkaç yeni topikal damla bileşiği geliştirilmiştir. Bunlar arasında Rho kinaz inhibitörleri, nitrik oksit veren bileşikler, adenozin reseptör agonistleri ve yeni prostaglandin analogları bulunur. Uzun süreli göz içi basıncını düşürücü ilaç dağıtım sistemi sunan alternatif tedaviler geliştirilmeye devam etmektedir. Bunlar gen terapisi ve kök hücre stratejileri ile birlikte kendi kendine uygulama yükünü kolaylaştırabilen veya birkaç yıl boyunca ortadan kaldırabilen topikal uygulamaları içerir. Gen tedavisinde; hücre içi fonksiyonları modifiye etmek için vektörler aracılığı ile gen taşınması ile defektif genin düzeltilmesi ve hücre içi var olan fonksiyonları değiştirmek amaçlanmaktadır. Ek olarak, terapötiklerin aylar boyunca kontrollü, sabit durumlu bir şekilde verilmesini amaçlayan çeşitli yeni formülasyonlar ve cihazlar da geliştirilmektedir. Ayrıca glokom tarafından uyarılan nörodejeneratif olayları engelleme potansiyeline sahip olan çeşitli moleküller tespit edilmiştir. Bunlar arasında memantin, koenzim Q ve sitikolin öne çıkanlardır. Glokomun patofizyolojisinde bilinmeyenler aydınlatıldıkça gelecekte bu multifaktöriyel hastalığın tedavisinde daha etkili moleküller, daha kolay ilaç uygulama yöntemleri ve daha kişisel tedavi stratejileri yer alacaktır.

Anahtar Kelimeler: Glokom; Rho ilişkili kinazlar; genetik tedavi; nörokoruma
ABSTRACT
 Glaucoma is a chronic, multifactorial, neurodegenerative disease that can be challenging to treat for both patients and physicians. A lack of deficient in reducing intraocular pressure and the difficulty in adapting to treatment due to side effects in every each case therefore current glaucoma treatment modalities have led to different mechanism of effects and administration routes in glaucoma pathogenesis. Several new topical drop compounds directly targeting the trabecular meshwork (TM)/Schlemm canal/conventional outflow pathway to reduce outflow resistance has been developed. These include Rho kinase inhibitors, nitric oxide donating compounds, adenosine receptor agonists and new prostaglandin analogues. Alternative therapies that offer longterm intraocular pressure lowering drug delivery system are moving forward in development. These include gene therapy and stem cell strategies, which could ease or eliminate the burden of topical drop self-administration for several years. In gene therapy, it is intended to modify the intracellular functions of the defective gene by gene transport via vectors to modify the intracellular functions. Additionally, a variety of novel formulations and devices are in development that aim for controlled, steady state delivery of therapeutics over periods of months. Besides this, several molecules have been identified which have the potential to inhibit neurodegenerative events induced by glaucoma. Memantine, coenzyme Q and citicolin are among the prominent ones. As the unknowns in the pathophysiology of glaucoma are elucidated, in the future, the treatment of this multifactorial disease will include more effective molecules, easier drug delivery methods and more personal treatment strategies.

Keywords: Glaucoma; Rho-associated kinases; genetic therapy; neuroprotection
REFERENCES:
  1. Kaufman PL, Mohr ME, Riccomini SP, Rasmussen CA. Glaucoma drugs in the pipeline. Asia Pac J Ophthalmol (Phila). 2018;7(5):345- 51.
  2. Fautsch MP, Johnson DH. Aqueous humor outflow: what do we know? Where will it lead us? Invest Ophthalmol Vis Sci. 2006;47(10): 4181-7. [Crossref]  [PubMed]  [PMC] 
  3. Clark AF, Brotchie D, Read AT, Hellberg P, English-Wright S, Pang IH, et al. Dexamethasone alters F-actin architecture and promotes cross-linked actin network formation in human trabecular meshwork tissue. Cell Motil Cytoskeleton. 2005;60(2):83-95. [Crossref]  [PubMed] 
  4. Filla MS, Schwinn MK, Sheibani N, Kaufman PL, Peters DM. Regulation of cross-linked actin network (CLAN) formation in human trabecular meshwork (HTM) cells by convergence of distinct β1 and β3 integrin pathways. Invest Ophthalmol Vis Sci. 2009;50(12):5723- 31. [Crossref]  [PubMed]  [PMC] 
  5. Prendes MA, Harris A, Wirostko BM, Gerber AL, Siesky B. The role of transforming growth factor β in glaucoma and the therapeutic implications. Br J Ophthalmol. 2013;97(6):680- 6. [Crossref]  [PubMed] 
  6. Shepard AR, Millar JC, Pang IH, Jacobson N, Wang WH, Clark AF. Adenoviral gene transfer of active human transforming growth factor-{beta}2 elevates intraocular pressure and reduces outflow facility in rodent eyes. Invest Ophthalmol Vis Sci. 2010;51(4):2067-76. [Crossref]  [PubMed] 
  7. Kaufman PL, Rasmussen CA. Advances in glaucoma treatment and management: outflow drugs. Invest Ophthalmol Vis Sci. 2012;53(5):2495-500. [Crossref]  [PubMed]  [PMC] 
  8. Bhattacharya SK, Gabelt BT, Ruiz J, Picciani R, Kaufman PL. Cochlin expression in anterior segment organ culture models after TGFβ2 treatment. Invest Ophthalmol Vis Sci. 2009;50(2):551-9. [Crossref]  [PubMed]  [PMC] 
  9. Mao W, Wordinger RJ, Clark AF. Focus on molecules: SFRP1. Exp Eye Res. 2010;91(5): 552-3. [Crossref]  [PubMed] 
  10. Stamer WD, Braakman ST, Zhou EH, Ethier CR, Fredberg JJ, Overby DR, et al. Biomechanics of Schlemm's canal endothelium and intraocular pressure reduction. Prog Retin Eye Res. 2015;44:86-98. [Crossref]  [PubMed]  [PMC] 
  11. Overby DR, Zhou EH, Vargas-Pinto R, Pedrigi RM, Fuchshofer R, Braakman ST, et al. Altered mechanobiology of Schlemm's canal endothelial cells in glaucoma. Proc Natl Acad Sci U S A. 2014;111(38):13876-81. [Crossref]  [PubMed]  [PMC] 
  12. Allingham RR, de Kater AW, Ethier CR, Anderson PJ, Hertzmark E, Epstein DL. The relationship between pore density and outflow facility in human eyes. Invest Ophthalmol Vis Sci. 1992;33(5):1661-9.
  13. Johnson M, Chan D, Read AT, Christensen C, Sit A, Ethier CR. The pore density in the inner wall endothelium of Schlemm's canal of glaucomatous eyes. Invest Ophthalmol Vis Sci. 2002;43(9):2950-5.
  14. Vargas-Pinto R, Gong H, Vahabikashi A, Johnson M. The effect of the endothelial cell cortex on atomic force microscopy measurements. Biophys J. 2013;105(2):300-9. [Crossref]  [PubMed]  [PMC] 
  15. Ethier CR, Read AT, Chan DW. Effects of latrunculin- B on outflow facility and trabecular meshwork structure in human eyes. Invest Ophthalmol Vis Sci. 2006;47(5):1991-8. [Crossref]  [PubMed] 
  16. Overby D, Stamer D, Johnson M. The changing paradigm of outflow resistance generation: towards synergistics models of the JCT and inner wall endothelium. Exp Eye Res. 2009;88(4):656-70. [Crossref]  [PubMed]  [PMC] 
  17. Dismuke WM, Mbadugha CC, Ellis DZ. NOinduced regulation of human trabecular meshwork cell volume and aqueous humor outflow facility involve the BKCa ion channel. Am J Physiol Cell Physiol. 2008;294(6):C1378-86. [Crossref]  [PubMed] 
  18. Wiederholt M, Sturm A, Lepple-Wienhues A. Relaxation of trabecular meshwork and ciliary muscle by release of nitric oxide. Invest Ophthalmol Vis Sci. 1994;35(5):2515-20.
  19. Ellis DZ, Sharif NA, Dismuke WM. Endogenous regulation of human Schlemm's canal cell volume by nitric oxide signaling. Invest Ophthalmol Vis Sci. 2010;51(11):5817-24. [Crossref]  [PubMed] 
  20. Borghi V, Bastia E, Guzzetta M, Chiroli V, Toris CB, Batugo MR, et al. A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma. J Ocul Pharmacol Ther. 2010;26(2):125-32. [Crossref]  [PubMed] 
  21. Nathanson JA. Nitrovasodilators as a new class of ocular hypotensive agents. J Pharmacol Exp Ther. 1992;260(3):956-65.
  22. Stamer WD, Lei Y, Boussommier-Calleja A, Overby DR, Ethier CR. eNOS, a pressure-dependent regulator of intraocular pressure. Invest Ophthalmol Vis Sci. 2011;52(13): 9438-44. [Crossref]  [PubMed]  [PMC] 
  23. Novack GD. RHO-kinase inhibitors for the treatment of glaucoma. Drugs Future. 2013;38 (2):107-13. [Crossref] 
  24. Inoue T, Tanihara H. Rho-associated kinase inhibitors: a novel glaucoma therapy. Prog Retin Eye Res. 2013:37:1-12. [Crossref]  [PubMed] 
  25. Kiel JW, Kopczynski CC. Effect of AR-13324 on episcleral venous pressure in Dutch belted rabbits. J Ocul Pharmacol Ther. 2015;31(3): 146-51. [Crossref]  [PubMed]  [PMC] 
  26. Levy B, Ramirez N, Novack GD, Kopczynski C. Ocular hypotensive safety and systemic absorption of AR-13324 ophthalmic solution in normal volunteers. Am J Opthalmol. 2015; 159(5):980-5. [Crossref]  [PubMed] 
  27. 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):309-15. [Crossref]  [PubMed] 
  28. Tanihara H, Inoue T, Yamamoto T, Kuwayama Y, Abe H, Araie M; 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):731-6. [Crossref]  [PubMed] 
  29. Tanihara H, Inoue T, Yamamoto T, Kuwayama Y, Abe H, Suganami H, et al; K- 115 Clinical Study Group. Additive intraocular pressurelowering effects of the Rho kinase inhibitor ripasudil (K-115) combined with timolol or latanoprost: A Report of 2 randomized clinical trials. JAMA Ophthalmol. 2015:133(7): 755-61. [Crossref]  [PubMed] 
  30. Aerie Pharmaceuticals initiates fourth phase 3 clinical trial of Rhopressa (NASDAQ: AERI). UW-Madison Libraries Web site. September 24, 2015. https://investors.aeriepharma.com/static-files/3e839af1-b0d0-4fa5-99fa-836e86334787
  31. Aerie Pharmaceuticals reports positive topline efficacy results of Rocket 4 phase 3 trial of RhopressaTM (Netarsudil Ophthalmic Solution) 0.02% (NASDAQ: AERI). Aerie Pharmaceuticals Web site. October 27, 2016. https://investors.aeriepharma.com/static-files/ee7b0ab6-5239-4a5a-86f3-df0630434032
  32. Aerie Pharmaceuticals reports positive Roclatan (netarsudil/latanoprost ophthalmic solution) 0.02%/0.005% phase 3 topline efficacy results. Aerie Pharmaceuticals Web site. May 24, 2017. https://www.marketwatch.com/press-release/aerie-pharmaceuticals-reports-positive-roclatantm-netarsudillatanoprost-ophthalmic-solution-0020005-phase-3-topline-efficacy-results-2017-05-24
  33. Cavet ME, Vittitow JL, Impagnatiello F, Ongini E, Bastia E. Nitric oxide (NO): an emerging target for the treatment of glaucoma. Invest Ophthalmol Vis Sci. 2014;55(8):5005-15. [Crossref]  [PubMed] 
  34. Impagnatiello F, Toris CB, Batugo M, Prasanna G, Borghi V, Bastia E, Ongini E,et al. Intraocular Pressure-Lowering Activity of NCX 470, a Novel Nitric Oxide-Donating Bimatoprost in Preclinical Models. Invest Ophthalmol Vis Sci. 2015;56(11):6558-64. [Crossref]  [PubMed] 
  35. Weinreb RN, Ong T, Scassellati Sforzolini B, Vittitow JL, Singh K, Kaufman PL; VOYAGER study group. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study. Br J Ophthalmol. 2015;99 (6):738-45. [Crossref]  [PubMed]  [PMC] 
  36. Medeiros FA, Martin KR, Peace J, Scassellati Sforzolini B, Vittitow JL, Weinreb RN. Comparison of latanoprostene bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma or ocular hypertension: the LUNAR study. Am J Opthalmol. 2016;168:250-9. [Crossref]  [PubMed] 
  37. Antipolis S. Nicox provides clinical and regulatory update for NCX 470 for IOP lowering. January 24, 2017. https://www.globenewswire.com/news-release/2017/01/24/910198/0/en/Nicox-provides-clinical-and-regulatory-update-for-NCX-470-for-IOP-lowering.html
  38. Agarwal R, Agarwal P. Newer targets for modulation of intraocular pressure: focus on adenosine receptor signaling pathways. Expert Opin Ther Targets. 2014;18(5):527-39. [Crossref]  [PubMed] 
  39. Zhong Y, Yang Z, Huang WC, Luo X. Adenosine, adenosine receptors and glaucoma: an updated overview. Biochim Biophys Acta. 2013;1830(4):2882-90. [Crossref]  [PubMed] 
  40. Myers JS, Sall KN, DuBiner H, Slomowitz N, McVicar W, Rich CC, et al. A dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of 2 and 4 weeks oftwice-daily ocular trabodenoson in adults with ocular hypertension or primary openangle glaucoma. J Ocular Pharmacol Ther. 2016;32(8):555-62. [Crossref]  [PubMed]  [PMC] 
  41. Prowse C. Inotek announces top-line results for MATrX-1, first phase 3 trial of trabodenosen for glaucoma. Intotek Pharma Web site. January 3, 2017 https://www.businesswire.com/news/home/20170103005518/en/Inotek-Announces-Top-line-Results-MATrX-1-Phase-3
  42. Harris A, Ward CL, Rowe-Rendleman CL, Ouchi T, Wood A, Fujii A, et al. Ocular hypotensive effectof ONO-9054, an EP3/FP receptor agonist: results of a randomized, placebo-controlled, dose escalation study. J Glaucoma. 2016;25(10):e826-33. [Crossref]  [PubMed] 
  43. Woodward DF, Nilsson SF, Toris CB, Kharlamb AB, Nieves AL, Krauss AH. Prostanoid EP4 receptor stimulation produces ocular hypotension by a mechanism that does notappear to involve uveoscleral outflow. Invest Ophthalmol Vis Sci. 2009;50(7):3320-8. [Crossref]  [PubMed] 
  44. Ihekoromadu N, Lu F, Iwamura R, Yoneda K, Kawabata-Odani N, Kamal Shams N. Safety and efficacy of DE-117, a selective EP2 agonist in a phase 2a study. Invest Opthalmol Vis Sci. 2015;56:5708.
  45. A phase IIb safety and efficacy study of DE- 126 ophthalmic solution in primary open-angle glaucoma or ocular hypertension-Angel Study. US National Library of Medicine Web site. July 13, 2017. https://clinicaltrials.gov/ct2/show/NCT03216902
  46. Rocha-Sousa A, Rodrigues-Araújo J, Gouveia P, Barbosa-Breda J, Azevedo-Pinto S, Pereira-Silva P, et al. New therapeutic targets for intraocular pressure lowering. ISRN Ophthalmol. 2013;2013:261386. [Crossref]  [PubMed]  [PMC] 
  47. Bettin P, Di Matteo F. Glaucoma: present challenges and future trends. Ophthalmic Res. 2013;50(4):197-208. [Crossref]  [PubMed] 
  48. Yüksel N, Cinik R. [Future perspectives of glaucoma medical treatment] Glokom- Katarakt. Özel sayı 2016;11(1):149-54.
  49. Brandt JD, Sall K, DuBiner H, Benza R, Alster Y, Walker G, et al; Collaborators. Six-month intraocular pressure reduction with a topical bimatoprost ocular insert: results of a phase II randomized controlled study. Ophthalmology. 2016;123(8):1685-94. [Crossref]  [PubMed] 
  50. Positive phase I/II interim data of bimatoprost sustained-release implant for IOP therapy in glaucoma. Allergan Web site. November 16, 2015. https://news.abbvie.com/index.cfm
  51. Safety and efficacy of ENV515 travoprost extended release (XR) in patients with bilateral ocular hypertension or primary open angle glaucoma. US National Library of Medicine Web site. February 26, 2015. https://clinicaltrials.gov/ct2/show/NCT02371746
  52. Glaukos will begin phase II clinical trial for iDose travoprost intraocular implant in glaucoma patients. Glaukos Web site. January 7, 2016 http://investors.glaukos.com/investors/press-releases/press-release-details/2016/Glaukos-Will-Begin-Phase-II-Clinical-Trial-for-iDose-Travoprost-Intraocular-Implant-in-Glaucoma-Patients/default.aspx
  53. U.S. National Institutes of Health Clinical Trials. A study of the L-PPDS with adjunctive Xalatan® Eye drops in subjects with OH or OAG. https://clinicaltrials.gov/ct2/show/NCT01037036
  54. Perera SA, Ting DS, Nongpiur ME, Chew PT, Aquino MC, Sng CC, et al. Feasibility study of sustainedrelease travoprost punctum plug for intraocular pressure reduction in an Asian population. Clin Ophthalmol. 2016;10:757-64. [Crossref]  [PubMed]  [PMC] 
  55. Product development. Amorphex Therapeutics LLC Web site. April 2, 2016. https://www.amorphexusa.com/
  56. Weinreb RN, Liebmann JM, Cioffi GA, Goldberg I, Brandt JD, Johnson CA, et al. Oral memantine for the treatment of glaucoma: design and results of 2 randomized, placebo-controlled, phase 3 studies. Ophthalmology. 2018;125(12):1874-85. [Crossref]  [PubMed] 
  57. Parisi V, Centofanti M, Gandolfi S, Marangoni D, Rossetti L,Tanga L, et al. Effects of coenzyme Q10 in conjunction with vitamin E on retinal-evoked and cortical-evoked responses in patients with open-angle glaucoma. J Glaucoma. 2014;23(6):391-404. [Crossref]  [PubMed] 
  58. Parisi V, Centofanti M, Ziccardi L, Tanga L, Michelessi M, Roberti G, et al. Treatment with citicoline eye drops enhances retinal function and neural conduction along the visual pathways in open angle glaucoma. Graefes Arch Clin Exp Ophthalmol. 2015;253(8):1327-40. [Crossref]  [PubMed] 
  59. Gerometta R, Kumar S, Shah S, Alvarez L, Candia O, Danias J. Reduction of steroid-induced intraocular pressure elevation in sheep by tissue plasminogen activator. Invest Ophthalmol Vis Sci. 2013;54(13):7903-9. [Crossref]  [PubMed]  [PMC] 
  60. He S, Park YH, Yorio T, Krishnamoorthy RR. Endothelin-mediated changes in gene expression in isolated purified rat retinal ganglion cells. Invest Ophthalmol Vis Sci. 2015;56(10): 6144-61. [Crossref]  [PubMed]  [PMC] 
  61. Stankowska DL, Minton AZ, Rutledge MA, Mueller BH 2nd, Phatak NR, He S, et al. Neuroprotective effects of transcription factor Brn3b in an ocular hypertension rat model of glaucoma. Invest Ophthalmol Vis Sci. 2015;56(2):893-907. [Crossref]  [PubMed]  [PMC] 
  62. Martínez T, González MV, Roehl I, Wright N, Pa-eda C, Jiménez AI. In vitro and in vivo efficacy of SYL040012, a novel siRNA compound for treatment of glaucoma. Mol Ther. 2014;22(1):81-91. [Crossref]  [PubMed]  [PMC] 
  63. Gonzalez V, Moreno-Montanes J, Oll M. Results of Phase IIB SYLTAG clinical trial with bamosiran in patients with glaucoma. Poster session presented at: Annual Meeting of The Association for Research in Vision and Ophthalmology (ARVO); 2016 May 1-5; Seattle, WA.
  64. Moreno-Monta-és J, Sádaba B, Ruz V, Gómez-Guiu A, Zarranz J, González MV, et al. Phase I clinical trial of SYL040012, a small interfering RNA targeting beta-adrenergic receptor 2, for lowering intraocular pressure. Mol Ther. 2014;22(1):226-32. [Crossref]  [PubMed]  [PMC] 
  65. Schehlein EM, Novack G, Robin AL. New pharmacotherapy for the treatment of glaucoma. Expert Opin Pharmacother. 2017;18(18):1939-46. [Crossref]  [PubMed] 
  66. Johnson TV, Bull ND, Hunt DP, Marina N, Tomarev SI, Martin KR. Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Invest Ophthalmol Vis Sci. 2010;51(4):2051-9. [Crossref]  [PubMed]  [PMC] 
  67. Emre E, Yüksel N, Duruksu G, Pirhan D, Subaşi C, Erman G, et al. Neuroprotective effects of intravitreally transplanted adipose tissue and bone marrow-derived mesenchymal stem cells in an experimental ocular hypertension model. Cytotherapy. 2015;17(5):543- 59. [Crossref]  [PubMed] 
  68. Du Y, Yun H, Yang E, Schuman JS. Stem cells from trabecular meshwork home to TM tissue in vivo. Invest Ophthalmol Vis Sci. 2013:54(2):1450-9. [Crossref]  [PubMed]  [PMC] 

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4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com