Резюме
Безкоровайна І.М. Використання анти-VEGF препаратів в лікуванні вторинної неоваскулярної глаукоми.
Виникнення вторинної неоваскулярної глаукоми пов’язано з ішемією внутрішніх шарів сітківки, внаслідок первинного захворювання і супроводжується рубеозом райдужки, значну роль в чому відіграє судинний ендотеліальний фактор росту (VEGF). Отже, для регресу фіброваскулярних мембран необхідно введення інгібиторів VEGF - бевацизумаб, пегаптаніб, ранібізумаб. Метою даного дослідження було уточнення можливості використання та біологічний ефект пегаптаніба в лікуванні вторинної неоваскулярної глаукоми. Спостерігалося 11 пацієнтів з вторинною неоваскулярною глаукомою на фоні проліферативної діабетичної ретинопатії з гостротою зору від 0,01 до 0,7. 1 доза «Макугена» (Pegaptanibum) вміщує 3,47 мг / мл. При інтравітреальному введенні пегаптанібу відмічено запустівання новоутворених судин в куті передньої камери. Зменшився ступінь макулярного набряку сітківки в центральній зоні. В 83% випадків відмічено об’єктивне покращення зорових функцій вже через 2 тижні від початку лікування, причому у 32% пацієнтів гострота зору підвищилась в середньому на 0,3±0,02. Внутрішньоочний тиск знижувався незначно і недостовірно, але з’являлась здатність до компенсації його місцевими гіпотензивними засобами. У 17% пацієнтів з тривалим протіканням первинного захворювання і вираженими симптомами НВГ при регулярному (кожні 6 тижнів) інтравітреальному введенні наступала стабілізація патологічного процесу та зорових функцій при спостереженні на протязі 1 року.
Ключові слова: вторинна неоваскулярна глаукома, неоваскулярізація, ендотеліальний фактор росту (VEGF).
Резюме
Безкоровайная И.Н. Использование анти-VEGF препаратов в лечении вторичной неоваскулярной глаукомы.
Возникновение вторичной неоваскулярной глаукомы связано с ишемией внутренних слоев сетчатки, вследствие первичного заболевания и сопровождается рубеозом радужки, в чем играет значительную роль сосудистый эндотелиальный фактор роста (VEGF). Следовательно, для регрессии фиброваскулярных мембран необходимо введение ингибиторов фактора роста эндотелия сосудов - бевацизумаб, пегаптаниб, ранибизумаб. Целью данного исследования было уточнение возможности использования и биологический эффект ингибитора VEGF пегаптаниба в лечении вторичной неоваскулярной глаукомы. Наблюдалось 11 пациентов с вторичной неоваскулярной глаукомой на фоне пролиферативной диабетической ретинопатии. Острота зрения 0,01 - 0,7. 1 доза «Макугена» (Pegaptanibum) содержит 3,47 мг / мл. При интравитреальном введении пегаптаниба отмечено запустевание новообразованых сосудов в углу передней камеры. Уменьшалась степень выраженности макулярного отека сетчатки в центральной зоне. В 83% случаев отмечено объективное улучшение зрительных функций уже через 2 недели от начала лечения, причем у 32% пациентов острота зрения увеличилась в среднем на 0,3±0,02. Внутриглазное давление снижалось незначительно и недостоверно, но появлялась способность к компенсации его местными гипотензивными средствами. У 17% пациентов с длительным течением первичного заболевания и выраженными симптомами НВГ при регулярном (каждые 6 недель интравитреальном введении) наступала стабилизация патологического процесса и зрительных функций при наблюдении в течение 1 года.
Ключевые слова: вторичная неоваскулярная глаукома, неоваскуляризация, эндотелиальный фактор роста (VEGF).
Summary
Bezkorovayna I. Anti-VEGF agents in the treatment of neovascular secondary glaucoma.
Secondary neovascular glaucoma (SNG) - the most severe form of glaucoma process. Its occurrence is associated with ischemia of the inner layers of the retina, resulting in the underlying cause, and accompanied rubeosis iris and anterior chamber angle. Vascular endothelial growth factor (VEGF) plays a significant role in the formation of newly formed blood vessels. Intravitreal administration of inhibitors of vascular endothelial growth factor - bevacizumab, pehaptanib, ranibizumab - should lead to a significant regression fibrovascular membranes. The aim of this study was to clarify the possibility of using and biological effect inhibitors VEGF pehaptaniba in the treatment of secondary neovascular glaucoma. 11 patients was observed with SNG on a background of proliferative diabetic retinopathy. Visual acuity ranged from 0.7 to 0.01. 1 dose «Macugen» (Pegaptanibum) contains 3.47 mg / ml. When we inject intravitreal pegaptanib, we observed desolation of the newly vessels in the anterior chamber angle, which nearly became invisible. Decreased the severity of macular edema in the affected area and the patient is usually immediately felt better view. In 83% of cases observed objective improvement of visual function after 2 weeks of treatment, and in 32% of patients, visual acuity increased by an average of 0,3±0,02. Intraocular pressure decreased slightly and unreliable, but appeared ability to compensate it by using antihypertensive drug . In 17% of patients with long course of the primary disease and symptomatic SNG with regular (every 6 weeks intravitreal administration) advancing stabilization of pathology and visual functions for observation for 1 year.
Key words: secondary neovascular glaucoma, neovascularization, vascular endoteal growth factor (VEGF).
Рецензент: д.мед.н., проф. А.М. Петруня

УДК 6 17.7 – 007.681 – 08:615

ВДНЗ України «Українська медична стоматологічна академія» (Полтава)

ВГУЗ "Украинская медицинская стоматологическая академия" (Полтава)

Higher medical educational institution of Ukraine "Ukrainian medical stomatological academy" (Poltava)

ibezkor@gmail.com

Secondary neovascular glaucoma (NVG) - the most heavy form of glaucoma process leading to the rapid development of blindness, disability and unbearable pain. Its occurrence is associated with ischemia of inner layers of the retina as a result of the primary disease and is accompanied with rubeoz of the iris and of the anterior chamber angle , which makes ineffective traditional glaucoma intervention [5]. The generally accepted method of preventing neovascularization of the anterior segment of the eye is timely panretynal laser coagulation in the presence of background disease. However, its adequate performance in the required amount is not always technically possible because of the dimness of media eye. In addition, the existing iris neovascularization and anterior angle laser coagulation effect is quite slow, and his expectation leads to the loss of visual function at high levels of intraocular pressure. 

Vascular endothelial growth factor (VEGF) plays a significant role in the formation of newly formed blood vessels and increased permeability of the vascular wall [7], and its levels increased relative stages of development of secondary neovascular glaucoma [1]. Therefore, the influence on it is an powerful treatment of NVG [2, 3] as well as diseases which result it has become. Intravitreal using of inhibitors of vascular endothelial growth factor (bevacizumab , pehaptanib , Ranibizumab ) leads to substantial regression of neovascular changes [7, 8]. However, widespread use of these drugs real only at different retinal pathologies : age-related macular degeneration, cystic macular edema [4], diabetic retinopathy, central retinal vein thrombosis . But the anti-angiogenic effect, which leads to the neglect of newly iris vessels and the corresponding inverse of fibrovaskular membranes suggests the appearence of a new method of treatment for patients with NVG. Bevacizumab - hiperhymer recombinant monoclonal antibody that selectively binds to different isoforms of biologically active vascular endothelial growth factor (VEGF) and neutralizes it. Ranibizumab selectively binds to vascular endothelial growth factor, VEGF-A (VEGF110, VEGF121, VEGF165). Pehaptanib is a pegylated modified oligonucleotide that binds selectively and has a high affinity to extracellular vascular endothelial growth factor (VEGF165), weakening its activity [6]. VEGF165 - isoform of VEGF, which primarily involved in the pathological process of ocular neovascularization [4]. Thus, the greatest influence selectivity characteristic pehaptaniba.

The aim of this study was to clarify the possibility of the using and learning of biological effect of inhibitor vazoproliferative`s pehaptanib factor in the treatment of secondary neovascular glaucoma.

Material and methods. We observed 11 patients with secondary NVG on a background of proliferative diabetic retinopathy. In patients were studied: visual acuity, static and kinetic perimetry of Humprey, Maklakova`s blood pressure monitor, digital blood pressure monitor of eye tonometr-tonohraf, honioskopy, optical coherence tomography of the anterior (OCT) segment of the eye on the machine 3D-OCT-1000 Mark II, ultrasound biomicroscopy (UBM) with Sonomed VuMAX II device using sensor 50 MHz to standard methods, fluorescent angiography in the anterior segment of the eye in slit lamp SL-20 Topcon company with a green filter and a digital camera, ophthalmoscopy.

Term course of diabetes in all patients exceeded 10 years. Visual acuity ranged from 0,01 to 0,7. 6 patients didn`t previously treat with an ophthalmologist, in 2 patients in one eye was performed vitrectomy, in 2nd patients over 4 years ago was performed laser coagulation of the retina, after which they were observed in the ophthalmologist , 1 patient had been previously made antyhlaukoma filtering operation. 1 dose pre-filled syringe " Makuhena » (Pegaptanibum) contains 3.47 mg/ml , corresponding to 0,3 mg pehaptaniba sodium in the form of free acid oligonucleotides, the nominal volume of 90 ml [6].

Results and discussion. Immediately it should be noted that all putted in monitoring patients belonged to the group of severe refractory glaucoma and or experienced in the previous treatment, which did not produce the desired effects of stabilization and compensation intraocular pressure or in the presence of diabetic encephalopathy is not evaluated by their health up rise to unbearable pain. Carrying out the proposed treatment was only possible in this situation. Significant anterior segment neovascularization was impeding the emergence of hemorrhagic complications during surgery.

Usual for antiangiogenic drug effect changes gradually advancing for the first three days after injection. After intravitreal using pehaptanib we observed a significant decrease in the number of newly formed vessels in the iris, the decrease of newly formed vessels in the anterior chamber angle, which became almost invisible. Thin-walled vessels completely disappeared and looked desolated. Those vessels that were larger became thin and sometimes their progress interrupted.

In the case of transparent media, was found reduced severity of macular edema, retina becamed thin in the affected area and the patient is usually immediately felt better view. According to optical coherence tomography height edema decreased from 411 ± 88,70 ± 57,15 to 232 microns.

Intraocular pressure decreased slightly and unreliable, but appeared ability to compensate for its local antihypertensive agents, which could not be achieved before the manipulation. Disappeared pain. In cases of high levels of intraocular pressure appeared the possibility of making to uncomplicated antyhlaukoma operations wich before of the intravitreal using was virtually impossible. Thus, the introduction of an inhibitor of vascular endothelial growth factor was performed as the first stage of the treatment of advanced stages of secondary neovascular glaucoma.

In 83 % of cases observed objective improvement of visual function after 2 weeks of treatment, and in 32 % of patients, visual acuity increased by an average of 0,3 ± 0,02. In the presence of small hemorrhages in the vitreous encouraging improvements to their dispersal ability. It should also be noted a slight improvement in visual acuity and stabilization of paired eyes ( an average of 0,06 ± 0,007), which was observed with the introduction of the drug in one eye.A number of patients with intravitreal administration conducted repeatedly (6 times).

It was observed that in 17 % of patients with a long course of primary disease and symptomatic NVG with regular (every 6 weeks intravitreal administration - according to instructions) advancing pathology and stabilization of visual function when observed for 1 year, and the subsequent re-introduction of a single, according to our observations , the term remission prolonged for another year. In the treatment within a year , according to optical coherence tomography retinal thickness (with the possibility of its study) decreased to an average of 226 ± 23 mm at its swing from 220 microns to 274 microns.

Analysis of our data of the study also showed that treatment by pehaptanib should be administered as soon as possible. Thus, when it intravitreal administration in patients with isolated small hemorrhages in the retina in diabetic retinopathy and neovascular membranes in the absence (ie NVG in prerubeotycal stage or stages of preglaukoma ) enough 1 - 2 injections to stabilize the process and of the prevention of the development or symptoms secondary neovascular glaucoma, 1-year follow-up. In the case of a long previous course of the disease and at high rates of intraocular pressure, treatment should be clearly by pehaptanib every 6 weeks and only in order to preserve visual function , as observed in the study of visual acuity improvement was unreliable - 0,08 ± 0,06. Thus, in patients with long-term complications of the disease leaking after 4 - 5 weeks after intravitreal injection of vascular tumor recurrence was observed, hifema, hemorrhages in the retina, flyuorests seepage through the vascular wall. This decreased visual acuity, intraocular pressure increased uncompensated. With repeated administration , from the 1st to the 4th day after administration clearly diagnosed disappearance of newly formed blood vessels in the anterior chamber angle, hifemy resorption and decreased intraocular pressure, which enables further antyhlaukoma of uncomplicated surgery if oftalmotonus, with a downward trend does not reach normal values even when using local antihypertensive drugs. There remains a need in the performance of hypotensive surgical intervention to normalize intraocular pressure.

When patients used pehaptanib we noted the following adverse reactions associated with the same drug and procedure administration: headache ( 28% of patients), short eye pain and transient increase in intraocular pressure in the range of 2 - 5 mm Hg (in 61 % of patients), brief appearance of " flies " to the eye (73%).

The downside of angiogenesis inhibitor monotherapy appeared the necessity of multiple intravitreal injections traumatic for the structures of the eye, as well as significant cost of treatment, which for this reason is sometimes available to patients.

Conclusions. Using the pehaptanib in the treatment of neovascular glaucoma can improve long-term prognosis, improve functional outcomes in patients with secondary neovascular glaucoma and reduce the percentage of its late stages.

Intravitreal administration of pehaptanib allows antyhlaukoma preoperative preparation before surgery , to lower the risk of intra-and postoperative complications.

Література

1. Безкоровайна І.М. Біохімічні алгоритми розвитку вторинної неоваскулярної глаукоми / І.М. Безкоровайна // Проблеми екологічної та медичної генетики і клінічної імунології: зб. наук. праць. – Київ; Луганськ, 2010. - Вип. 5 (101). - С. 174-179.
2. Кузьмин А.Г. Анти-VEGF препараты для лечения диабетической ретинопатии / А.Г. Кузьмин, Д.В. Липатов, О.М. Смирнова, М.В. Шестакова // Офтальмохирургия. - М., 2009. - № 3. - С. 20-24.
3. Кушнир В.Н. Авастин: оценка эффективности при неоваскулярной глаукоме / В.Н. Кушнир, А.А. Руссу, В.В. Кушнир // Материалы VIII Всерос. науч.–практ. конф. с междунар. участием «Федоровские чтения». - 2009. - С. 247–249.
4. Лихванцева В.Г. VEGF-зависимая антиангиогенная терапия в офтальмологии / В.Г. Лихванцева, О.В. Белоус, Е.В. Арутюнян // Офтальмохирургия. - 2011. - № 1.
5. Робустова О.В. Современные представления об этиологии и патогенезе неоваскулярной глаукомы / О.В. Робустова, А.М. Бессмертный // Глаукома. – 2003. - № 4. - С. 18-26.
6. Справочник «КОМПЕНДИУМ 2011 — лекарственные препараты» / Под редакцией В.Н. Коваленко, А.П. Викторова. – Киев: Морион, 2011. – 1500 с.
7. Тахчиди Х.П. Применение блокаторов VEGF в хирургии неоваскулярной глаукомы / Х.П. Тахчиди, С.А. Метаев, П.Ю. Чеглаков, С.С. Тилляходжаев // Материалы V Евро–Азиатской конф. по офтальмологии. - Екатеринбург, 2009. С. 154–155.
8. Macugen Diabetic Retinopathy Study Group. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals / A.P. Adamis, M. Altaweel, N.M. Bressler [et al.] //Ophthalmology. - 2006. - Vol. 113, № 1. - P. 23–28.