Pharmacologic Treatment of Wet Type Age-Related Macular Degeneration; Current and Evolving Therapies

H. Shams Najafabadi, N. Daftarian, H. Ahmadieh, et al. Review Article Pharmacologic Treatment of Wet Type Age-related Macular Degeneration; Current and Evolving Therapies Hoda Shams Najafabadi1, Narsis Daftarian2, Hamid Ahmadieh3, Zahra-Soheila SoheiliƔ1 Abstract $JHUHODWHGPDFXODUGHJHQHUDWLRQDVWKHPDMRUFDXVHRIEOLQGQHVVLQWKHHOGHUO\SRSXODWLRQKDVUHPDLQHGDWWKHHSLFHQWHURIFOLQLFDO UHVHDUFKLQRSKWKDOPRORJ\7KLVUHWLQDOGLVRUGHULVFKDUDFWHUL]HGE\WKHSKRWRUHFHSWRUDQGUHWLQDOSLJPHQWHSLWKHOLDOFHOOVORVVRFFXUULQJ ZLWKLQWKHPDFXOD 7KHGLVHDVHUHSUHVHQWVDVSHFWUXPRIFOLQLFDOPDQLIHVWDWLRQV,WLVDPXOWLIDFWRULDOGLVHDVHUHVXOWLQJIURPDFRPELQDWLRQRI JHQHWLFSUHGLVSRVLWLRQVDQGHQYLURQPHQWDOULVNIDFWRUV$0'LVFODVVL¿HGLQWRWZRGLIIHUHQWW\SHVGU\DQGZHW:HW$0'LVLQFORVHUHODWLRQ ZLWKDQJLRJHQHVLVDQGLQÀDPPDWRU\SURFHVVHV$YDULHW\RIDQWLDQJLRJHQHVLVDQGDQWLLQÀDPPDWRU\GUXJVKDYHEHHQSURSRVHGIRUWKH WUHDWPHQWRIWKHGLVHDVH7KHSXUSRVHRIWKLVSDSHULVWREULHÀ\UHYLHZWKHSKDUPDFRORJLFDOWKHUDSLHVRIWKHZHWIRUPRI$0'DQGIRFXVRQ QHZGUXJVWKDWDUHFXUUHQWO\LQGLIIHUHQWVWDJHVRIUHVHDUFKDQGGHYHORSPHQW Keywords: $JHUHODWHGPDFXODUGHJHQHUDWLRQDQJLRJHQHVLVDQWLDQJLRJHQHVLVGUXJVDQWLLQÀDPPDWRU\GUXJVLQÀDPPDWLRQ Cite this article as: Shams Najafabadi H, Daftarian N, Ahmadieh H, Soheili ZS, et al. Pharmacologic Treatment of Wet Type Age-related Macular Degeneration; Current and Evolving Therapies. Arch Iran Med. 2017; 20(8): 525 – 537. Introduction Anatomy of the eye The human eye has three main layers. The outermost layer of JHUHODWHG PDFXODU GHJHQHUDWLRQ ZDV ¿UVW LQWURGXFHG LQ the eye is called the sclera, which is composed of connective the medical literature in 1875 as a symmetrical central tissue that maintains the shape of the globe and offers resistance A chorioretinal disease occurring in the elderly.1 It was not to internal and external forces. studied until 1980 when macular degeneration was reported to be The choroid is the middle layer of the eye located between the a leading cause of blindness in the United States.2 According to sclera and the retina. The inner part of choroid is composed of World Health Organization estimates, AMD is the most common a capillary network and the outermost layer consists of larger- cause of blindness in people over the age of 50 in developed diameter blood vessels. The main function of the choroid is to countries (Figure 1).3 provide enough oxygen and nutrients to the retinal pigment About 35% of the U.S. population aged 75 years or more have epithelium10 and the outermost layers of the retina as well as to some signs of AMD and approximately 10% of these patients remove waste products from their environment. demonstrate late stages of the disease.4 Nowadays, more than 25 The retina is the inner part of the eye with two main layers: the to 30 million people are affected by AMD worldwide.5 According more posterior RPE layer consists of retinal pigment epithelial to the latest predictions, AMD is expected to undergo a nearly cells and the inner neurosensory layer which consists of a variety 2-fold increase in 2020.6 of different nerve cells and photoreceptors in a layered and Due to the progressive deterioration in the patients’ central FRPSOH[FRQ¿JXUDWLRQ vision, the ability to perform daily activities such as driving, RPE cells are separated from the choroid by a semi-permeable reading, ambulating, walking and recognizing people’s faces is matrix called Bruch’s membrane (BM) which facilitates the decreased.7 passage of nutrients and metabolites between the choroid and the Progression of AMD reduces the patient’s sense of well-being retina (Figure 2).11 and independence and increases the risk of depression. Patients with AMD in both eyes, especially if accompanied by hemorrhage Pathology of AMD in the macular area, are at high risk of falls and depression. AMD occurs when the photoreceptor cells in the macula are 2YHUDOO$0'OHDGVWRVLJQL¿FDQWUHGXFWLRQLQPHQWDOKHDOWKDQG slowly broken down or damaged. Macula is made up of the patient’s quality of life.8,9 highest density of cones photoreceptor cells responsible for a central, high resolution vision with precision detail. There are $XWKRUV¶ DI¿OLDWLRQV 1National institute Institute of Genetic Engineering and two main types of macular degeneration: dry, non-exudative or Biotechnology, Tehran, Iran. 2Ophthalmic Research Center, Shahid Beheshti atrophic AMD and exudative or wet AMD. Approximately 90% University of Medical Sciences, Tehran, Iran. 3Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. of cases of macular degeneration are the dry type. ƔCorresponding author and reprints: Zahra-Soheila Soheili, National Institute As with any disease, AMD exhibits a spectrum of clinical and of Genetic Engineering and Biotechnology, Shahrak-e Pajoohesh, km 15, Tehran- pathologic manifestations. In the case of dry AMD, the clinical Karaj Highway, Tehran 14965161, Iran. E-mail: [email protected]. Accepted for publication: 27 April 2017 signs can range from early pigmentary changes in the macula Archives of Iranian Medicine, Volume 20, Number 8, August 2017 525 Pharmacologic Treatment of Wet Type Age-related Macular Degeneration Figure 1. $FFRUGLQJWRWKH:RUOG+HDOWK2UJDQL]DWLRQHVWLPDWH$0'LV Figure 2.7KHKXPDQH\HLQWKHLQQHUOD\HULVFRPSRVHGRIWKHVFOHUD WKLUGPRVWFRPPRQZRUOGZLGHFDXVHRIEOLQGQHVVSourced: wwwunmc FKRURLGDQGUHWLQD$0'LVFDXVHGE\GDPDJHWRPDFXODRU\HOORZVSRW edueyeinternationalmissionhtm Source:ZZZHDVWRQH\HFRP to presence of Drusen (yellow deposits of extracellular material Studies have also demonstrated that smokers are three to four under the neural retina or RPE cells), of which the number times more likely to develop AMD.19 The general mechanisms and size can be increased distributing throughout the macula.12 by which smoking results in AMD include: impairment in the Gradually, the density of choroidal blood vessels is reduced and generation of antioxidants such as vitamin C, generation of RPE cells are atrophied. UHDFWLYHR[\JHQVSHFLHVDFWLYDWLRQRILQÀDPPDWRU\SDWKZD\VDQG The more advanced stage of dry macular degeneration is UHGXFWLRQRIFKRURLGDOEORRGÀRZ20 geographic atrophy, which appears as a circumscribed area of People with a family history of AMD are at a higher risk of RPE and photoreceptor cell loss. To compensate for this loss, developing AMD.21 peripheral RPE cells proliferate; therefore, hypertrophied RPE Obesity and high-fat diets containing cholesterol and saturated cells are observed in these areas.13 fats increase the risk of AMD22 while taking antioxidants in Exudative macular degeneration is marked by growth of aberrant the early stages of the disease may play a role in curbing its blood vessels under the retina, photoreceptor cells and Bruch’s progression.23 PHPEUDQHDORQJZLWKHSLWKHOLDOSUROLIHUDWLRQDQGLQÀDPPDWLRQ The AREDS (Age-Related Eye Disease Study) demonstrated This process is due to the release of vascular endothelial growth that a series of compounds such as vitamin C, vitamin E, beta- factor (VEGF) as angiogenic factor from RPE cells,14 which leads carotene, zinc oxide and copper oxide as dietary supplements in to formation of a choroidal neovascular membrane (CNVM). patients with intermediate and advanced AMD in one eye, lower CNVM can leak hemorrhage in the subretinal space that induces the risk of late stage AMD in the other eye.24 Taking beta-carotene EOXUU\ YLVLRQ DQG ¿QDOO\ FUHDWHV D GLVFLIRUP VFDU ZKLFK FDXVHV might put smokers at higher risk of lung cancer, so they should total central vision loss.15 take dietary supplements without beta-carotene Taking antioxidants such as lutein and zeaxanthin that are found Etiology of AMD in green leafy vegetables such as broccoli, corn, squash and AMD is a complex multifactorial disease resulting from RPHJDIDWW\DFLGVZKLFKDUHIRXQGLQ¿VKSOD\DYLWDOUROHLQ interactions between genetic variants and environmental factors. preventing intermediate or advanced AMD.10,25 These factors induce oxidative damage and structural changes Consumption of mono- and poly-unsaturated fatty acids and linoleic in the retina and RPE producing a cascade of events including acid was especially associated with an elevated risk for AMD.26 WKH LQÀDPPDWRU\ LQWHUPHGLDWHV WKDW LQWHUUXSW FHOOV DFWLYLW\ DQG destroy them. Treatment Strategies for Wet AMD Among environmental factors associated with AMD, only AMD is a complex, multifactorial disease associated with advanced age, cigarette smoking, diet, and race are the most environmental, dietary, and genetic factors. There is no known important factors.16 GH¿QLWH WUHDWPHQW IRU HLWKHU W\SH RI WKLV GLVHDVH $YDLODEOH Age-associated increase in AMD risk may be mediated by treatment methods can only reduce the risk of severe vision loss. gradual accumulation of daily oxidative stress in the retina and These methods include thermal laser photocoagulation, loss of normal physiological function in the aging RPE cells.17 transpupillary thermotherapy, radiotherapy, photodynamic Recent studies have demonstrated that white people are much therapy and pharmacologic treatment. This review article is more likely to lose vision from AMD than other races.18 devoted entirely to the last topic. 526 Archives of Iranian Medicine, Volume 20, Number 8, August 2017 H. Shams Najafabadi, N. Daftarian, H. Ahmadieh, et al. Figure 3. Strategies to inhibit the 9(*) signaling pathway include inhibition of 9(*)9(*)5 and tyrosine NLQDVH cascade Sourced: wwwDPGERRNorg Pharmacotherapy for wet AMD inhibition of VEGF, VEGFR, PDGF and tyrosine kinase activity Wet AMD occurs due to adventitious growth of blood vessels of VEGFR and decreasing VEGF

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