Intravitreal İnfliximab İnjeksiyonun Retinal Toksitesinin Değerlendirilmesi

Yıl 2023, , 25 - 29, 28.02.2023

Muhamet Kıvılcım

https://doi.org/10.54005/geneltip.1150171

Öz

Amaç : Tavşanlarda farklı dozlardaki intravitreal inflixamab injeksiyonun toksitesinin değerlendirilmesi.
İnfliximab romatoid artrit ve crohn hastalığı için FDA onaylı anti enflamatuar bir ilaçtır. Kronik dirençli üveitlerde özellikle behçet hastalığı, diyabetik retinopati ve PVR için alternatif veya yardımcı ilaç olabileceğini gösteren yayınlar bildirilmiştir.

Bulgular ve Gereçler : 20 beyaz Yeni Zelanda tavşanları 5 gruba (n=4) ayrılarak bu çalışmada kullanılmıştır. Hayvanlara uygulamalarda ARVO yönergeleri izlenmiştir. Tavşanların bir gözüne intravitreal olarak 0.125 mg , 0.250 mg, 0.500 mg, 1.25 mg ve 2.5 mg inflixmab 0.1 tuzlu solüsyon içinde , diğer kontrol gözüne ise 0.1 tuzlu solüsyon olarak uygulanmıştır. Tüm hayvanlar deneyden önce muayenesi ve deneyden sonraki 1., 7., ve 14. günde indirek oftalmoskopi ve yarık lamba biyomikroskopi muayeneleri yapılmıştır. ERG deneyden önce ve sonraki 14. günde yapılmıştır. Hayvanlara 14. günde ötonazi uygulanmıştır. Enükleasyon edilen gözlerin histolojik örnekleri retina toksidi açısından incelenmiştir.

BULGU : Biz 1.25 mg doza kadar olan grupta ERG ve histolojik olarak bir toksite bulmadık. 2.5 mg grubun 4 gözünden birinde ERG'sinde anlamlı azalma ve histoojik toksite bulguları saptadık.

SONUÇ : 1.5 mg doza kadar olan inflixmab injeksiyonu tavşan retinasında non toksiktir. İntravitreal inflixmab injeksiyonu üveitlerde özellikle de behçet hastalığında diyabetik retinopatide yaşa bağlı makula dejenerasyonunda ve proliratif vitreo retinopatide yararlı bir tedavi olabilir.

Anahtar Kelimeler

infliximab, retinal toksite, üveit, behçet hastalığı, diyabetik retinopati

The Evaluation Retinal Toxicity of Intravitreal Infliximab Injection

Öz

Objective
To evaluate toxicity of varying doses of Infliximab injecting intravitreally in rabbits. Infliximab, an FDA approved anti-inflammatory drug for Rheumatoid arthritis and Crohn’s disease. It has been reported as an alternative or adjunct drug to chronic recurrent uveitis especially Behcet’s disease, Diabetic retinopathy and PVR

Materials and Methods
Twenty New Zeland albino rabbits were used for this study and divided into five groups (n=4 each). ARVO guidelines were followed in treatment of animals. The rabbits were injected intravitreally with, 0.125mg 0.250mg, 0.500mg, 1.25mg or 2.5mg Infliximab in 0.1 ml in one eye and 0.1 ml saline solution was used in the contralateral eye. All the animals were examined using indirect ophthalmoscopy and slit-lamp biomicroscopic examination before intravitreal injection and at days 1,7 and 14. An ERG was performed before any treatment and at day 14. On day 14 the animals were euthanized. Histological preparations of the enucleated eyes were examined for retinal toxicity.

Results
We found no retinal toxicity up to 1.25mg groups according to ERG results and Histological signs. 1of 4 eyes in the 2.5mg group had some significant decrease in Electroretinogram and histological toxicity signs.

Conclusions
Infliximab injection up to 1.25 mg is nontoxic to the rabbit’s retina. Intravitreal injected Infliximab may be a useful treatment for Uveitis especially Behcet’s disease, Diabetic retinopathy, Age Related Macular Degeneration and Proliferative Vitreoretinopathy.

Anahtar Kelimeler

infliximab, retinal toxicity, intravitreal injection, uveitis, behcet’s, diabetic retinopathy

Kaynakça

• REFERENCES 1. -Suttorp-Schulten MS, Rothova A. The possible impact of uveitis in blindness: a literature survey. Br. J. Ophthalmology. 1996; 80:844-8
• 2. -Gurelik G, Coney JM, Zakov ZN. Binocular indirect panretinal laser photocoagulation for the treatment of proliferative diabetic retinopathy. Ophthalmology Surgery lasers&Imaging.2004;35:94-102
• 3. -Kramer M, Ehrlich R, Snir M, et al. Intravitreal injections of triamcinolone acetonide for severe vitritis in patients with incomplete Behcet’s disease. Am J Ophthalmology. 2004; 138:666-7
• 4. -Alan W Stitt , Timothy M Curtis , Mei Chen , Reinhold J Medina , Gareth J McKay ,Alicia Jenkins , Thomas A Gardiner , Timothy J Lyons , Hans-Peter Hammes ,Rafael Simó , Noemi Lois .The progress in understanding and treatment of diabetic retinopathy Affiliations expand PMID: 26297071 DOI: 10.1016/j.preteyeres.2015.08.001
• 5. -Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am. J Ophthalmology. 2000; 130:492-513
• 6. -Meredith TA., Kertes PJ, Conway MD. The diabetic retinopathy vitrectomy study. Clinical trials in ophthalmology. Williams&Wilkins.1998:37-48
• 7. -Murphy CC, Ayliffe WH, Booth A, Makanjuola D, Andrews PA, Jayne D. Tumor necrosis factor alpha blockade with infliximab for refractory uveitis and scleritis. Ophthalmology. 2004; 111:352-6
• 8. -Limb GA, Hollifield RD, Webster L, Charteris DG, Chignell AH. Soluble TNF receptors in vitreoretinal proliferative disease. Invest ophthalmology Vis Sci. 2001; 42:1586-91.
• 9. -Hawrami K, Hitman GA, Rema M, et al. An association in non-insulin-dependent diabetes mellitus subjects between susceptibility to retinopathy and tumor necrosis factor polymorphism. Hum. Immunol. 1996; 46:49-54
• 10. -Petros P Sficakis , Vlassis Grigoropoulos, Ioannis Emfietzoglou, George Theodossiadis, Nicholas Tentolouris, Evi Delicha, Christina Katsiari, Kleopatra Alexiadou, Erifili Hatziagelaki, Panayiotis G Theodossiadis Clinical Trial. Infliximab for diabetic macular edema refractory to laser photocoagulation: a randomized, double-blind, placebo-controlled, crossover, 32-week study.Diabetes Care2010 Jul;33(7):1523-8. doi: 10.2337/dc09-2372. Epub 2010 Apr 22.
• 11. -Ohno S, Nakamura S, Hori S, Shimakawa M, et al. Efficacy, safety, and pharmacokinetics of multiple administration of Infliximab in Behcet’s disease with refractory uveoretinitis. J. Rheumatol. 2004; 31:1362-8
• 12. -Falappone PC, Iannone F, Scioscia C, Grattagliano V, Covelli M, Lapadula G. The treatment of recurrent uveitis with TNF-alpha inhibitors. Reumatismo. 2004; 56:185-9
• 13. - Calvo-Río V, Blanco R, Beltrán E, et al. Anti-TNF-α therapy in patients with refractory uveitis due to Behçet’s disease: a 1-year follow-up study of 124 patients. Rheumatol Oxf Engl. 2014;53(12):2223–2231.doi:10.1093/rheumatology/keu266.
• 14. - R. Lejoyeux, E. Diwo, H. Vallet, D. Saadoun, S. Tezenas du Montcel, B. Bodaghi, P. LeHoang & C. Fardeau to cite this article: R. Lejoyeux, E. Diwo, H. Vallet, D. Saadoun, S. Tezenas du Montcel, B. Bodaghi, P. LeHoang & C. Fardeau (2018): Infliximab and Adalimumab in Uveitic Macular Edema, Ocular Immunology and Inflammation, DOI: 10.1080/09273948.2018.1498110.
• 15. - Sartani G, Silver BP, Rizzo LV et al. Anti-tumor necrosis factor alpha therapy suppresses the induction of experimental autoimmune uveoretinitis in mice by inhibiting antigen priming. Invest. Ophthalmol. Vis. Sci. 1996; 37:2211-8
• 16. - Fatma Savur, Orhan Aydemir & Nevin İlhan (2019): The effect of infliximab and octreotide on cytokine levels experimental proliferative vitreoretinopathy, Cutaneous and Ocular Toxicology, DOI: 10.1080/15569527.2019.1701000.
• 17. - Jeffrey L Olson , R Jackson Courtney, Naresh Mandava Intravitreal infliximab and choroidal neovascularization in an animal model Arch Ophthalmol. 2007 Sep;125(9):1221-4. doi: 10.1001/archopht.125.9.1221.
• 18. - Luiz Guilherme Azevedo de Freitas 1, David Leonardo Cruvinel Isaac, William Thomas Tannure, Luís Alexandre Rassi Gabriel, Ricardo Gomes dos Reis, Alan Ricardo Rassi, Clovis Arcoverde de Freitas, Marcos Pereira de Ávila Intravitreal bevacizumab combined with infliximab in the treatment of choroidal neovascularization secondary to age-related macular degeneration: case report series May-Jun 2013;76(3):180-4. doi: 10.1590/s0004- 27492013000300010.
• 19. Barouch FC, Miyamoto MK, Allport JR, et al. Integrin-mediated neutrophil adhesion and retinal leukocytosis in diabetes. Invest. Ophtlamol.Vis. Sci. 2000;41:1153-8
• 20. -Miyamoto MK, Khosrof S, Bursell SE, et al. Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc.Natl.Acad.Sci.USA. 1999; 96:10836-41
• 21. - Joussen AM, Murata T, Tsujikawa A, Kirchhof B, et al. Leuokocyte-mediated endothelial cell injury and death in diabetic retina. Am.J. Pathol. 2001; 158:147-52
• 22. - Kanagawa T, Matsuda S, et al. Role of ICAM-1 and LFA-1 in endotoxin-induced uveitis in mice. Jpn J Ophthalmol 1996; 40:174-180
• 23. -Whitcup SM, Hikita N, Shirao M, et al. Monoclonal antibodies against CD54(ICAM-1) and .CD11a(LFA-1) prevent and inhibit endotoxin induced uveitis. Exp Eye Res 1995; 60:597-601. 24. - Rosenbaum JT, Boney RS. Efficacy of antibodies to adhesion molecules, CD11a or CD18, in rabbit models of uveitis. Curr Eye Res 1993; 12:827-831
• 25. -Early treatment diabetic retinopathy study research group. Effects of aspirin treatment on diabetic retinopathy: ETDRS report number 8. Ophthalmology. 1991; 98:757-65
• 26. -Hamza MM, Macky TA, Sidky MK, Ragab G, Soliman MM. İntravitreal İnfliximab in refractory uveitis in Behcet’s disease : A Safety and Efficacy Clinical Study. Retina. 2016 Dec;36(12):2399-2408. doi: 10.1097/IAE.0000000000001109.PMID: 27870802
• 27. -intravitreal tumor necrosis factor inhibitors in the treatment of refractory diabetic macular edema: a pilot study from the Pan-American Collaborative Retina Study Group. Wu L, Hernandez-Bogantes E, Roca JA, Arevalo JF, Barraza K, Lasave AF. Retina. 2011 Feb;31(2):298-303. doi: 10.1097/IAE.0b013e3181eac7a6.PMID: 21099452
• 28. -Fabrizio Giansanti , Laura Papucci, Sergio Capaccioli, Daniela Bacherini, Lorenzo Vannozzi, Ewa Witort, Ugo Menchini. Ocular safety of infliximab in rabbit and cell culture models. PMID: 20148652 DOI: 10.1089/jop.2009.0035
• 29. - Fabrizio Giansanti , Matteo Ramazzotti, Lorenzo Vannozzi, Emilio Rapizzi, Tito Fiore, Barbara Iaccheri, Donatella Degl' Innocenti, Daniela Moncini, Ugo Menchini Affiliations expand PMID: 18326743 DOI: 10.1167/iovs.07-0932.
• 30. - Benitez Del Castillo Sanchez JM, Garcia Sanchez J. Intravitreal injection of triamcinolone acetonide in noninfectious uveitis. Arch. Soc. Esp. Oftalmol. 2001; 76:661-4
• 31. -Jonas JB, Hayler JK, Sofker A, et al. Intravitreal injection of crystalline cortisone as adjunctive treatment of proliferative diabetic retinopathy. Am.J. Ophthalmol. 2001; 131:468- 71
• 32. - Antcliff RJ, Spalton DJ, Stanford MR, et al. Intravitreal triamcinolone for uveitic cystoid macular edema: an optical coherence tomography study. Ophthalmology.2001;108:765-72
• 33. - Bakri SJ, et al. Pharmacokinetics of intravitreal ranibizumab (Lucentis ophthalmology. 2007; 114:2179-2182 (PubMed)