Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulator

Retina

Volumn 32, Issue 1, 2012, Pages 183-188

  Kubota, Ryo ^a   Boman, Nancy L ^a   David, Robert ^a   Mallikaarjun, Suresh ^c   Patil, Shiva ^c   Birch, David ^b  

^a Acucela Inc   (United States)

^b RETINA FOUNDATION OF THE SOUTHWEST   (United States)

^c OTSUKA PHARMACEUTICAL DEVELOPMENT AND COMMERCIALIZATION INC   (United States)

Author keywords

A2E; ACU 4429; dark adaptation; dry AMD; ERG; geographic atrophy; lipofuscin; retinal degeneration; visual cycle modulator

Indexed keywords

ACU 4429; AGENTS ACTING ON THE EYE; PLACEBO; SMALL MOLECULE TRANSPORT AGENT; UNCLASSIFIED DRUG;

ADULT; AGED; ARTICLE; BLEACHING; BLURRED VISION; CLINICAL ARTICLE; CLINICAL ASSESSMENT; COLOR VISION; COLOR VISION DEFECT; CONTROLLED STUDY; DARK ADAPTATION; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; ECCHYMOSIS; ELECTRORETINOGRAM; FEMALE; HEADACHE; HUMAN; HUMAN EXPERIMENT; MALE; MAXIMUM PLASMA CONCENTRATION; NAUSEA; NIGHT BLINDNESS; NORMAL HUMAN; PHOTOPHOBIA; RANDOMIZED CONTROLLED TRIAL; RETINA DEGENERATION; SIDE EFFECT; SINGLE DRUG DOSE; VISUAL DISORDER;

ADMINISTRATION, ORAL; AGED; AREA UNDER CURVE; DARK ADAPTATION; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; ELECTRORETINOGRAPHY; ENZYME INHIBITORS; FEMALE; HUMANS; MACULAR DEGENERATION; MALE; MIDDLE AGED; RETINAL ROD PHOTORECEPTOR CELLS; VISION, OCULAR;

EID: 84855205404     PISSN: 0275004X     EISSN: 15392864     Source Type: Journal    
DOI: 10.1097/IAE.0b013e318217369e     Document Type: Article

References (24)

1. VanNewkirk MR, Nanjan MB, Wang JJ, et al. The prevalence of age-related maculopathy: the visual impairment project. Ophthalmology 2000;107:1593-1600.
2. Seddon J. Epidemiology of age-related macular degeneration. In: Schachat A, Ryan S, eds. Retina. 3rd ed. St. Louis, MO: Mosby; 2001.
3. Travis GH, Golczak M, Moise AR, Palczewski K. Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents. Annu Rev Pharmacol Toxicol 2007;47: 469-512.
4. Dorey CK, Wu G, Ebenstein D, et al. Cell loss in the aging retina. Relationship to lipofuscin accumulation and macular degeneration. Invest Ophthalmol Vis Sci 1989;30:1691-1699. (Pubitemid 19214989)
5. Mata NL, Weng J, Travis GH. Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl Acad Sci USA 2000;97:7154-7159. (Pubitemid 30431433)
6. Mata NL, Tzekov RT, Liu X, et al. Delayed dark-adaptation and lipofuscin accumulation in abcr 6 mice: implications for involvement of ABCR in age-related macular degeneration. Invest Ophthalmol Vis Sci 2001;42:1685-1690. (Pubitemid 32652338)
7. Weng J, Mata NL, Azarian SM, et al. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell 1999; 98:13-23. (Pubitemid 29331192)
8. Bernstein PS, Tammur J, Singh N, et al. Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene. Invest Ophthalmol Vis Sci 2001;42:3331-3336. (Pubitemid 33740698)
9. Karan G, Lillo C, Yang Z, et al. Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration. Proc Natl Acad Sci USA 2005;102:4164-4169. (Pubitemid 40388573)
10. Zhang K, Kniazeva M, Han M, et al. A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet 2001;27:89-93. (Pubitemid 32044525)
11. Eldred GE. Lipofuscin fluorophore inhibits lysosomal protein degradation and may cause early stages of macular degeneration. Gerontology 1995;41:S15-S28.
12. Messias A, Zrenner E, Tzekov R, et al. Single doses of all-trans-N-retinylacetamide slow down the ERG amplitude recovery after bleaching in rats. Doc Ophthalmol 2010;120: 165-174.
13. Sieving PA, Chaudhry P, Kondo M, et al. Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc Natl Acad Sci USA 2001;98:1835-1840. (Pubitemid 32165584)
14. Radu RA, Mata NL, Nusinowitz S, et al. Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc Natl Acad Sci USA 2003;100:4742-4747. (Pubitemid 36457800)
15. Caruso RC, Zujewski J, Iwata F, et al. Effects of fenretinide (4-HPR) on dark adaptation. Arch Ophthalmol 1998;116: 759-763. (Pubitemid 28292729)
16. Conley B, O'Shaughnessy J, Prindiville S, et al. Pilot trial of the safety, tolerability, and retinoid levels of N-(4-hydrox-yphenyl) retinamide in combination with tamoxifen in patients at high risk for developing invasive breast cancer. J Clin Oncol 2000;18:275-283. (Pubitemid 30056415)
17. Denman S, Weleber R, Hanifin JM, et al. Abnormal night vision and altered dark adaptometry in patients treated with isotretinoin for acne. J Am Acad Dermatol 1986;14:692-693. (Pubitemid 16167360)
18. Kaiser-Kupfer MI, Peck GL, Caruso RC, et al. Abnormal retinal function associated with fenretinide, a synthetic retinoid. Arch Ophthalmol 1986;104:69-70. (Pubitemid 16172230)
19. Marmor MF, Jain A, Moshfeghi D. Total rod ERG suppression with high dose compassionate Fenretinide usage. Doc Ophthalmol 2008;117:257-261.
20. Modiano MR, Dalton WS, Lippman SM, et al. Ocular toxic effects of fenretinide. J Natl Cancer Inst 1990;82:1063. (Pubitemid 20204980)
21. Ribatti D, Alessandri G, Baronio M, et al. Inhibition of neuroblastoma-induced angiogenesis by fenretinide. Int J Cancer 2001;94:314-321. (Pubitemid 32906059)
22. Weleber RG, Denman ST, Hanifin JM, Cunningham WJ. Abnormal retinal function associated with isotretinoin therapy for acne. Arch Ophthalmol 1986;104:831-837. (Pubitemid 16114928)
23. Zujewski J, Pai L, Wakefield L, et al. Tamoxifen and fenretinide in women with metastatic breast cancer. Breast Cancer Res Treat 1999;57:277-283.
24. Camerini T, Mariani L, De PG, et al. Safety of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of contralateral breast cancer. J Clin Oncol 2001;19:1664-1670. (Pubitemid 32230866)