Topical Isopropyl Unoprostone for Retinitis Pigmentosa: Microperimetric Results of the Phase 2 Clinical Study

详细信息    查看全文

• 作者：Shuichi Yamamoto (1)
  Takeshi Sugawara (1)
  Akira Murakami (2)
  Mitsuru Nakazawa (3)
  Nobuhisa Nao-i (4)
  Shigeki Machida (5)
  Yuko Wada (6)
  Yukihiko Mashima (7) (8)
  Yozo Myake (9)
  
• 关键词：BK ; channel activator ; Central retinal sensitivity ; Clinical trial ; Isopropyl unoprostone ; MP ; 1 microperimetry ; Multiple topical instillations ; Neuroprotection ; Retinitis pigmentosa
• 刊名：Ophthalmology and Therapy
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：1
• 期：1
• 全文大小：697KB
• 参考文献：1. Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368:1795-09. CrossRef
  2. Welber RG, Gregory-Evans K. Retinitis pigmentosa and allied disorders. In: Hinton DR, editor. Retina. 4th ed. St Louis: Elsevier-Mosby; 2006. p. 395-98.
  3. Léveillard T, Mohand-Sa?d S, Lorentz O, et al. Identification and characterization of rod-derived cone viability factor. Nat Genet. 2004;36:755-. CrossRef
  4. Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111:761-2. CrossRef
  5. Pasantes-Morales H, Quiroz H, Quesada O. Treatment with taurine, diltiazem, and vitamin E retards the progressive visual field reduction in retinitis pigmentosa: a 3-year follow-up study. Metab Brain Dis. 2002;17:183-7. CrossRef
  6. Berson EL, Rosner B, Sandberg MA, et al. Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A. Arch Ophthalmol. 2010;128:403-1. CrossRef
  7. Clemson CM, Tzekov R, Krebs M, Checchi JM, Bigelow C, Kaushal S. Therapeutic potential of valproic acid for retinitis pigmentosa. Br J Ophthalmol. 2011;95:89-3. CrossRef
  8. Nakazawa M, Ohguro H, Takeuchi K, Miyagawa Y, Ito T, Metoki T. Effect of nilvadipine on central visual field in retinitis pigmentosa: a 30-month clinical trial. Ophthalmologica. 2011;225:120-. CrossRef
  9. Sieving PA, Caruso RC, Tao W, et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci USA. 2006;103:3896-01. CrossRef
  10. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008;358:2231-. CrossRef
  11. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008;358:2240-. CrossRef
  12. Hiramatsu A, Sugawara T, Ogata K, Mitamura Y, Yamamoto S. Improvement of central retinal sensitivity six months after topical isopropyl unoprostone in patients with retinitis pigmentosa. Indian J Ophthalmol. 2012 (in press).
  13. Haria M, Spencer CM. Unoprostone (isopropyl unoprostone). Drugs Aging. 1996;9:213-. CrossRef
  14. Makimoto Y, Sugiyama T, Kojima S, Azuma I. Long-term effect of topically applied isopropyl unoprostone on microcirculation in the human ocular fundus. Jpn J Ophthalmol. 2002;46:31-. CrossRef
  15. Kimura I, Shinoda K, Tanino T, Ohtake Y, Mashima Y. Effect of topical unoprostone isopropyl on optic nerve head circulation in controls and in normal-tension glaucoma patients. Jpn J Ophthalmol. 2005;49:287-3. CrossRef
  16. Thieme H, Stumpff F, Ottlecz A, Percicot CL, Lambrou GN, Wiederholt M. Mechanisms of action of unoprostone on trabecular meshwork contractility. Invest Ophthalmol Vis Sci. 2001;42:3193-01.
  17. Cuppoletti J, Malinowska DH, Tewari KP, Chakrabarti J, Ueno R. Cellular and molecular effects of unoprostone as a BK channel activator. Biochim Biophys Acta. 2007;1768:1083-2. CrossRef
  18. Tsuruma K, Tanaka Y, Shimazawa M, Mashima Y, Hara H. Unoprostone reduces oxidative stress- and light-induced retinal cell death, and phagocytotic dysfunction, by activating BK channels. Mol Vis. 2011;17:3556-5.
  19. Melamed S. Neuroprotective properties of a synthetic docosanoid, unoprostone isopropyl: clinical benefits in the treatment of glaucoma. Drugs Exp Clin Res. 2002;28:63-3.
  20. Hayami K, Unoki K. Photoreceptor protection against constant light-induced damage by isopropyl unoprostone, a prostaglandin F(2alpha) metabolite-related compound. Ophthalmic Res. 2001;33:203-. CrossRef
  21. Munemasa Y, Kitaoka Y, Hayashi Y, et al. Effects of unoprostone on phosphorylated extracellular signal-regulated kinase expression in endothelin-1-induced retinal and optic nerve damage. Visual Neuro Sci. 2008;25:197-08.
  22. Mukuno H, Nakamura M, Kanamori A, Nagai A, Negi A, Seigel G. Unoprostone isopropyl rescues retinal progenitor cells from apoptosis in vitro. Curr Eye Res. 2004;29:457-4. CrossRef
  23. Miyamura N, Uematsu K, Tsuiki E, et al. Effect of topical unoprostone on retinitis pigmentosa (in Japanese). Rinsho Ganka (Jpn J Clin Ophthalmol). 2007;64:541-.
  24. Nakamura M. A case with retinitis pigmentosa with improved subjective sign after topical use of isopropyl unoprostone (in Japanese). Ganka. 2009;51:1551-.
  25. de Arruda Mello PA, Yannoulis NC, Haque RM. Safety of unoprostone isopropyl as mono- or adjunctive therapy in patients with primary open-angle glaucoma or ocular hypertension. Drug Saf. 2002;25:583-7.
  26. Langham ME, Kramer T. Decreased choroidal blood flow associated with retinitis pigmentosa. Eye. 1990;4:374-1. CrossRef
  27. Schmidt KG, Pillunat LE, Kohler K, Flammer J. Ocular pulse amplitude is reduced in patients with advanced retinitis pigmentosa. Br J Ophthalmol. 2001;85:678-2. CrossRef
  28. Falsini B, Anselmi GM, Marangoni D, et al. Subfoveal choroidal blood flow and central retinal function in retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2011;22(52):1064-. CrossRef
  29. Tanito M, Kaidzu S, Anderson RE. Delayed loss of cone and remaining rod photoreceptor cells due to impairment of choroidal circulation after acute light exposure in rats. Invest Ophthalmol Vis Sci. 2007;48:1864-2. CrossRef
  30. Vingolo EM, Lupo S, Grenga PL, et al. Endothelin-1 plasma concentrations in patients with retinitis pigmentosa. Regul Pept. 2010;160:64-. CrossRef
  31. Cellini M, Strobbe E, Gizzi C, Campos EC. ET-1 plasma levels and ocular blood flow in retinitis pigmentosa. Can J Physiol Pharmacol. 2010;88:630-. CrossRef
  32. Polska E, Doelemeyer A, Luksch A, et al. Partial antagonism of endothelin 1-induced vasoconstriction in the human choroid by topical unoprostone isopropyl. Arch Ophthalmol. 2002;120:348-2. CrossRef
  33. Heckenlively JR. Clinical findings in retinitis pigmentosa. In: Heckenlively JR, editor. Retinitis pigmentosa. Philadelphia: JB Lippincott Company; 1988. p. 68-9.
  34. Applegate RA, Howland HC, Sharp RP, Cottingham AJ, Yee RW. Corneal aberrations and visual performance after radial keratotomy. J Refract Surg. 1998;14:397-07.
  35. Suzukamo Y, Oshika T, Yuzawa M, et al. Psychometric properties of the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25), Japanese version. Health Qual Life Outcomes. 2005;3:65-5. CrossRef
  36. Lupo S, Grenga PL, Vingolo EM. Fourier-domain optical coherence tomography and microperimetry findings in retinitis pigmentosa. Am J Ophthalmol. 2011;151:106-1. CrossRef
  37. Szlyk JP, Fishman GA, Alexander KR, Revelins BI, Derlacki DJ, Anderson RJ. Relationship between difficulty in performing daily activities and clinical measures of visual function in patients with retinitis pigmentosa. Arch Ophthalmol. 1997;115:53-. CrossRef
  38. Szlyk JP, Seiple W, Fishman GA, Alexander KR, Grover S, Mahler CL. Perceived and actual performance of daily tasks: relationship to visual function tests in individuals with retinitis pigmentosa. Ophthalmology. 2001;108:65-5. CrossRef
  39. Madreperla SA, Palmer RW, Massof RW, Finkelstein D. Visual acuity loss in retinitis pigmentosa. Relationship to visual field loss. Arch Ophthalmol. 1990;108:358-1. CrossRef
  40. Jacobson SG, Roman AJ, Aleman TS, et al. Normal central retinal function and structure preserved in retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2010;51:1079-5. CrossRef
  41. Hirakawa H, Iijima H, Gohdo T, Imai M, Tsukahara S. Progression of defects in the central 10-degree visual field of patients with retinitis pigmentosa and choroideremia. Am J Ophthalmol. 1999;127:436-2. CrossRef
  42. Iijima H. Correlation between visual sensitivity loss and affected years in eyes with retinitis pigmentosa. Jpn J Ophthalmol. 2012;56:224-. CrossRef
  43. Sugawara T, Sato E, Baba T, Hagiwara A, Tawada A, Yamamoto S. Relationship between vision-related quality of life and microperimetry-determined macular sensitivity in patients with retinitis pigmentosa. Jpn J Ophthalmol. 2011;55:643-. CrossRef
  44. Querques G, Prascina F, Iaculli C, Noci ND. Intravitreal pegaptanib sodium (Macugen) for refractory cystoid macular edema in pericentral retinitis pigmentosa. Int Ophthalmol. 2009;29:103-. CrossRef
  45. Rohrschneider K, Bültmann S, Springer C. Use of fundus perimetry (microperimetry) to quantify macular sensitivity. Prog Retin Eye Res. 2008;27:536-8. CrossRef
  46. Weingessel B, Sacu S, Vécsei-Marlovits PV, Weingessel A, Richter-Mueksch S, Schmidt-Erfurth U. Interexaminer and intraexaminer reliability of the microperimeter MP-1. Eye. 2009;23:1052-. CrossRef
  47. Cideciyan AV, Swider M, Aleman TS, et al. Macular function in macular degenerations: repeatability of microperimetry as a potential outcome measure for ABCA4-associated retinopathy trials. Invest Ophthalmol Vis Sci. 2012;53:841-2. CrossRef
  48. Midena E, Vujosevic S, Microperimetry Study Group. Normal values for fundus perimetry with the microperimeter MP1. Ophthalmology. 2010;117:1571-. CrossRef
  49. Midena E, Radin PP, Convento E, Cavarzeran F. Macular automatic fundus perimetry threshold versus standard perimetry threshold. Eur J Ophthalmol. 2007;17:63-.
  50. Mizuno K, Koide T, Shimada S, Mori J, Sawanobori K, Araie M. Route of penetration of topically instilled nipradilol into the ipsilateral posterior retina. Invest Ophthalmol Vis Sci. 2009;50:2839-7. CrossRef
  
• 作者单位：Shuichi Yamamoto (1)
  Takeshi Sugawara (1)
  Akira Murakami (2)
  Mitsuru Nakazawa (3)
  Nobuhisa Nao-i (4)
  Shigeki Machida (5)
  Yuko Wada (6)
  Yukihiko Mashima (7) (8)
  Yozo Myake (9)
  
  1. Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Chiba, Japan
  2. Department of Ophthalmology, Faculty of Medicine, Juntendo University, Tokyo, Japan
  3. Department of Ophthalmology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
  4. Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
  5. Department of Ophthalmology, Iwate Medical University, Morioka, Japan
  6. Yuko Wada Eye Clinic, Sendai, Japan
  7. R-tech Ueno Ltd., Tokyo, Japan
  8. Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
  9. Aichi Medical University, Nagakute, Japan
  

文摘

Introduction The purpose of this study was to determine whether topical 0.15% isopropyl unoprostone (IU), a BK-channel activator, could improve or maintain the central retinal sensitivity in patients with middle- to late-stage retinitis pigmentosa (RP). IU was approved for glaucoma and ocular hypertension in 1994. The drug re-profiling strategy is one of the effective ways to develop safe drugs for patients with RP. Methods A randomized, double-blind, and placebo-controlled phase II safety/efficacy trial was conducted. One hundred and nine patients with middle- to late-stage RP having a visual acuity of ?.5 were studied at six ophthalmological centers in Japan. The treatments of IU/day were divided into three groups: placebo group; two-drop group; and four-drop group for 24?weeks. The primary outcome measure was changes in the retinal sensitivity from baseline in the central 2° determined by MP-1 microperimetry (MP-1, Nidek, Japan). The secondary outcomes were changes in best-correct visual acuity, contrast sensitivity, retinal sensitivity of the central 10° by MP-1, mean deviation (MD) by a Humphrey field analyzer (HFA; Carl Zeiss Meditec, Dublin, CA, USA) 10-2, and the Visual Functioning Questionnaire 25 (VFQ-25) questionnaire scores. Results There was a tendency for a dose-dependent responsiveness in retinal sensitivity in the central 2°, MD, and total VFQ-25 score after 24?weeks of IU instillation by a simple linear regression analysis. A stratified analysis showed a significant dose-dependent responsiveness of the 2° central retinal sensitivity in more advanced patients (P?=?0.028). The number of patients having a ??dB decrease in the primary outcome measure was significantly fewer in the four-drop group than in the placebo group (P?=?0.02). No adverse reactions were observed. Conclusions A higher dose of IU can delay progression of the central retinal sensitivity decrease through an improvement of retinal sensitivity.