Recent Trends in the Treatment of Diabetic Retinopathy: a Review

Journal of Clinical Trials and Regulations Volume 1 Issue 2

Recent Trends in the Treatment of Diabetic Retinopathy: A Review

Munaf Jiwani1*, Priyanshi Patel1, Dipta Sarkar1, Sudarshan Patil1, Priyanka B. Patel2 M. Pharm Student1, Assistant Professor2 Department of Pharmaceutics, SSR College of Pharmacy, Sayli Road, Silvassa, Union Territory of Dadra and Nagar Haveli, India Email: *[email protected] DOI: http://doi.org/10.5281/zenodo.3364306

Abstract Treatments for diabetic retinopathy have had incredible advances but yet it remains most probable scenario for vision loss in diabetes. This review summarises various treatments for diabetic retinopathy including various drugs in clinical trials and also covers ongoing clinical trials in India, USA and Europe with the patents obtained for the same. The advances in pharmaceutical treatments have shown promising results yet they remain more damaging and less adequate for substantially stopping vision loss. Patient compliance and post treatment complication still occur in these widely used treatments.

Keywords: Clinical trials, diabetic retinopathy, patents, treatment, vitrectomy

INTRODUCTION damage in the retina are associated with Diabetes is now recognized as a global the loss of retinal capillary pericytes, epidemic, the incidence of retinopathy, a thickening of the vascular layers, and common micro vascular complication of breakdown of the blood retinal barrier, diabetes is expected to rise to alarming which will lead to retinal iscemia and levels. A Global meta-analysis study hypoxia. Proliferative growth of new reported that 1 in 3 (34.6%) had any form vessels and subsequent tractional retinal of Diabetic Retinopathy (DR) in the US, detachment will occur when NPDR Australia, Europe and Asia. It is also noted proceeds to PDR, and thus it finally led to that 1 in 10 (10.2%) had Vision severe vision loss [2]. Threatening DR (VTDR) i.e., Proliferative DR (PDR) and/or Diabetic Macular Edema A number of interconnecting biochemical (DME). DR remains a leading cause of pathways have been proposed as potential vision loss in working adult populations. links between hyperglycaemia and diabetic In India, diabetes shows a prevalence of retinopathy. These include increased 8.37% out of which 18% of diabetics are polyol pathway flux, increased advanced likely to develop DR. DR seriously glycation end-products (AGE) formation, decreases the quality of life in diabetic abnormal activation of signalling cascades patients, and it also brings heavy economic such as activation of protein kinase C burden to diabetic patients and country [1]. (PKC) pathway, increased oxidative stress, increased hexosamine pathway flux, and According to the development of DR, it peripheral nerve damage. All these has two distinct phases: an early non- pathways in one way or another end in proliferative phase (NPDR) characterized increased oxidative stress, inflammation by increased vascular permeability and and vascular occlusion causing up- intra-retinal haemorrhage; and a late regulation of factors such as insulin like proliferative phase (PDR) characterized by growth factor (IGF), stromal derived retinal neovascularization. During the factor1 (SDF-1), vascular endothelial process of NPDR, hyperglycaemia induced growth factor (VEGF), angiopoietins

Journal of Clinical Trials and Regulations Volume 1 Issue 2

(Ang-2), tumour necrosis factor (TNF), in 1960 [1, 2]. and basic fibroblast growth factor-2 (bFGF) that eventually contribute to the Laser treatment is one of the prototypical pathogenesis of diabetic retinopathy [2]. approaches for the treatment of diabetic retinopathy and focal and diffusive LASER TREATMENT FOR macular edema. Different approaches for DIABETIC RETINOPATHY laser photocoagulation are shown in Fig. 1. The introductory use of laser Laser photocoagulation when adopted photocoagulation was demonstrated by a properly can diminish the 5-year blindness German ophthalmologist Meyer- risk by 90% for proliferative diabetic Schwickerath who utilised a xenon arc retinopathy (PDR) and by 50% for photocoagulator along with Zeiss in macular edema. The mechanism of laser 1959. The utilisation of laser treatment photocoagulation is shown in Fig. 2 [2]. for diabetic retinopathy was initialised

Figure 1: Approaches for treatment of diabetic retinopathy using laser photocoagulation.

Figure 2: Mechanism of laser treatment for diabetic retinopathy.

Journal of Clinical Trials and Regulations Volume 1 Issue 2

Full Scatter Panretinal Laser Treatment are treated prior for operating panretinal for Diabetic Retinopathy laser treatment [2]. The scatter laser photocoagulation is the optimal approach to treat mild and Extensive scatter laser photocoagulation is moderate PDR considering that it operated promptly in the manifestation of extenuates the risk of severe vision loss high-risk characteristics PDR. A standard notably in type 2 diabetes. Although, full-scatter laser photocoagulation is macular edema and cystoid macular edema mentioned in the Table 1 [2].

Table 1: Criteria for standard pan retinal laser photocoagulation. Laser spot size 500 µm at retina Exposure 0.1–0.2 s Intensity Mild to moderate Number of burns 1,200–1,600 for standard, 2,000 for iris neovascularization 1 burn apart, 2-disc diameters temporal from macular centre, extended treatment in vascular arcades for retinal Placement neovascularization with a spot size of 200 µm and 1500 µm from foveal avascular zone. Number of sessions 2–5 Lesions treated directly NVE with overlapping burns Persistent or recurrent Follow-up treatment Neovascularization Sessions 2 or more Time 3-6 weeks Burns per session 500-600 Follow up visits 3 months Lenses Goldmann three-mirror laser lens and wide-angle lenses

The treatment is predominantly carried for Macular Laser Therapy for Diabetic outpatients with few exceptions pressing Retinopathy hospitalization. The treatment commences The treatment is predominantly carried for under local anaesthesia, patient relaxing outpatients. The therapy is performed decumbent. The ophthalmologist employs using a traditional ophthalmoscope with a a binocular indirect ophthalmoscope with a modification to secure laser fibreoptic wide-angle contact lens to grasp peripheral cable. The patient’s cornea is anesthetised retina [1]. The treatment utilizes excessive by use of Proxymetacaine or Benoxinate intense burns applied more briskly causing drops along with a therapeutic contact acute pain when applied over a nerve or lens. The eyes should remain still during previous laser burn. In such cases the the procedure of about 10 minutes in order treatment can be kept on hold until the to avoid the damage to fovea. The patient pain passes and can be resumed again. The experiences no pain and flashes of light. treatment takes about 30 minutes and it’s The patient should be instructed not to in mandatory to keep eye as still as speak as the movement of jaws might possible. The vison can be impaired for a interfere with the alignment of the laser causing damage to fovea. The spots may few days after the treatment which be observed by the patient after the recovers on their own and do not require treatment which may fade over days. The any post treatment remedies, however treatment does not require any post NSAIDs can be adopted to help with dull therapy eye drops or oral medicaments [3]. ache [3].

Journal of Clinical Trials and Regulations Volume 1 Issue 2

Modified Mild Macular Grid (MMG) SRI employs Nd:YLF (neodymium: Laser Technique for Diabetic yttrium lithium fluoride) laser at 527 nm Retinopathy with a pulse duration of 1.7 µs [5][6]. SRT MMG is a substitute and gentle technique chiefly prompts laser induced rejuvenation as compared to early treatment diabetic of chorioretinal junction by migration and retinopathy. This technique is based on the proliferation of RPE cells. SRT produces application of burns gently and wider high heat in confined areas without spaced, dodging the foveal region and all damaging the surrounding cells. In order to over the macula or placing them on the target area of 10 µ the SRT uses 30 laser thickened retinal region [4][5]. pulses of 1.7 µs of 100 Hz with a Pros: relaxation period of 0.1 ms [5].  The gentle and widely spaced burns have remote chances of producing thermal injuries. Patterned Scanned Laser (PASCAL)  Doesn’t break Bruch’s membrane. Technique for the treatment of diabetic  Improved Oxygenation. retinopathy.  Healthier Retinal Pigment Epithelium. PASCAL is an alternate method of  Forestalling edema recurrence. photocoagulation developed by  Helps to regain and stabilise the OptiMedica Corp. Santa Clara, CA. cellular changes in retina caused by PASCAL is comparatively less painful yet diabetes. equivalent in efficiency as compared to the traditional laser technique. PASCAL Selective Retina Therapy (SRT) For received its USFDA approval for Treatment of Diabetic Retinopathy ophthalmic use in 2005. PASCAL Traditional laser photocoagulation employs a 532 nm doubled frequency technique develops ophthalmoscopically Neodymium-doped Yttrium aluminium visible grey white lesions from coagulation garnet (Nd:YAG) solid state laser and due to thermal denaturation of retina and optically pumped semiconductor laser photoreceptors. (OPSL) coupled with multimode step index optical fibre wherein the exit surface Absorption of light by retinal pigment of the fibre is imaged by employing epithelium (RPE), choroid and inner scanning system onto the retina providing retinal produces heat which damages the variety of spot sizes [6]. cells. Traditional technique also causes pain, permanent scarring and rarely loss of PASCAL can deliver copious patterns night vision [6]. such as squares, arcs, full and subset grid

patterns synchronously which are single The SRT is based on the selective targeting of the RPE dodging thermal foot depression by the assistance of a coagulation to neural retina, microprocessor driven scanner. The pulse photoreceptors, choroid or other duration of laser is 10-20 ms that’s about neighbouring cells. The selective RPE 10 times shorter than traditional laser. cells are busted by micro-vaporization due PASCAL can deliver 26 laser spots of 20 to absorption of micro pulse (1.7 µs) ms pulse duration in 0.5 seconds which energy chiefly by melanosomes [7]. The reduces the overall time of the procedure micropulse also prevents the formation of [5][6][8]. microbubbles surrounding melanosomes. Subthreshold Micropulse Diode Laser The first reported SRT was performed on a Photocoagulation (SMDLP) for rabbit eye using 5 µs argon laser pulse at Treatment of Diabetic Retinopathy 514 nm with a repetition rate of 500 Hz. The use of laser photocoagulation for the

Journal of Clinical Trials and Regulations Volume 1 Issue 2

treatment of diabetic retinopathy and families of VEGF are: VGEF-A, VEGF-B, similar disorders have proven to be very VEGF-C, VEGF-D, VEGF-E, VEGF-F effective, but also have shown drawbacks and placental growth factor (PGIF). Out of like visible intraoperatively endpoints these VGEF-A has been reported to have causing iatrogenic chorioretinal damage. the most vital role in promoting hyper Hence, laser photocoagulation is only permeability and neovascularization [10]. advised based on severity and benefit to All members of the protein family bind to risk ratio. In traditional laser therapy the the VEGF receptor which work by signal laser energy is delivered in a single pulse transduction mechanism such as tyrosine of 0.1 - 0.5 s which causes the visible linked kinase receptor with the damage. While in SMDLP the laser energy intracellular tyrosine kinase domain and is delivered in form of a train of repetitive extracellular ligand binding domain [10, short pulses of 100-300 microseconds “on” 11]. and 1700-1900 microseconds “off” in an envelope of 200-300 milliseconds [9]. As these proteins bind to the receptors, the dimerization of the receptor takes place The use of SMDLP was first reported by and this leads to the phosphorylation of the Pankratov in 1990 after which Friberg in C terminal of the molecule and this causes 1997 developed iridex micropulsed laser. the initiation of the signalling cascade, The SMDLP employs an 810 nm and 577 which leads to the transcription of genes nm diode laser which minimizes the [11]. energy absorption and thermal diffusion by micropulsing and extending the “off” time The increase in the vascular permeability within the exposure envelope. Moreover, via multiple mechanism through VEGF the diode lasers are more compact, includes mechanisms such as: extracellular economic, easy to maintain, doesn’t need a injury, formation of fenestrate, leukocyte cooling system and also have prolonged mediated extracellular injury, dissolution operating time [5][9]. of tight junctions and transcellular bulk flow. ANTI- VEGF DRUGS The most promising factor extensively The VEGF is produced by multiple retinal related to the pathophysiology of diabetic cell type in response to ischemia and leads retinopathy and the destruction of the to the release of promoters that enhance blood retinal barrier is the Vascular vascular permeability and Endothelial Growth Factor (VEGF). neovascularization.

In comparison to the non-diabetic eye Monica Rodriguez-Fontal et al. suggested condition, the VEGF levels are elevated in the different mechanism for VEGF the vitreous of patients suffering from producing damage to the vascular macular oedema. endothelium: In the hyperglycaemic condition the pericyte located in the retina Vascular endothelial growth factor leads to death that causes the damage to (VEGF) is the single cytokine which plays the walls of the retinal vessels and this is a central role in the progression of DME. known as microaneurysm and this also VEGF is basically a glycoprotein, dimeric creates the damage to the retinal barrier. in structure, with a molecular weight of The diffusion through these damaged cells about 36 - 46 kDa. In comparison to does not influence any structural feature Histamine the vascular permeability of but the intense amount of the pro VEGF is 50,000 times more. The seven permeability factors ultimately leads to

Journal of Clinical Trials and Regulations Volume 1 Issue 2

damage of vascular endothelial membrane regression of the neovascularisation was and neovascularization [12]. observed with the down regulation of the angiogenic factors with the absence of Some of the anti-VEGF drugs recently pericyte and smooth muscle cell coating. used in the treatment of diabetic They also found that bevacizumab may retinopathy are: also inhibit infiltration of macrophages which is known to increase corneal Ranibizumab neovascularization [16]. Ranibizumab (Lucentis; Genentech USA, Inc., San Francisco, CA, USA/Novartis Pegaptanib Ophthalmics, Basel, Switzerland) is the Pegaptanib (Macugen, Eyetech Inc., Cedar fully humanized recombinant monoclonal Knolls, NJ, USA) is the aptamer that is antibody having anti-VEGF-A Fab pegylated modified oligonucleotide that fragment developed for intravitreal use. It specifically acts on VEGF164 isomer, a binds to all the isoforms of VEGF-A. prime factor responsible for pathological Ranibizumab has a half-life of about 3 neovascularisation [17]. It has a plasma days in all the ocular compartments [13]. half-life of about 2 - 4 days. Pegaptanib The binding site of the Ranibizumab is the also inhibited VEGF165-mediated VEGF receptor binding site. According to phosphorylation of VEGFR2 and the Monica Rodriguez-Fontal proposed phospholipase Cγ and inhibited VEGF165- mechanism for Ranibizumab, on binding induced calcium mobilization in human of the Ranibizumab with the VEGF umbilical vein endothelial cells. The receptor it disrupts the interaction with the binding of the Pegaptanib to the VEGF receptors located on the endothelial cells receptor results in the inhibition of specifically VEGF1 and VEGF2. Due to neovascularisation and decreased vascular this, blockage of the receptor takes place permeation [13]. and this leads to the reduction in the endothelial cell proliferation, vascular Aflibercept leakage and formation of new blood Aflibercept (Regeneron, Tarrytown, NY, vessels. USA) with trade name Eylea (also known as VEGF Trap-Eye), is a recombinant The special quality of the drug is that it fusion protein that possesses the key binds to all the VEGF isoforms, thus VEGF binding domains of human VEGF making it more powerful therapy in VEGF receptors 1 and 2. The binding capacity of inhibition [12]. Ranibizumab intravitreal Aflibercept to VEGF was found to be preparation has brought the revolution in greater than that of Bevacizumab or the treatment of Diabetic Retinopathy [14]. Ranibizumab. Aflibercept was approved

by FDA as a therapy for neovascular AMD Bevacizumab ® in 2011 [13]. Bevacizumab (Avastin , Genentech, San Francisco, CA) the full length humanized monoclonal IgG antibody derived from Its molecular weight is 115 kDa. It has an recombinant technology active against all extracellular VEGF receptor sequence that isoforms of VEGF-A [13][15]. Its is fused to the IgG backbone present in its molecular weight is 148 kDa and its half- structure and that resembles VEGF1 and 2 life is twice as that compared to present in human. It contains a soluble Ranibizumab [13]. Wei-Li Chen et.al. decoy receptor, the affinity for binding to proposed that Bevacizumab decreases the the VEGF-A is far greater than its natural neovascularization of cornea. The receptors.

Journal of Clinical Trials and Regulations Volume 1 Issue 2

As Christian Swinney et al. demonstrated, point: - 79°C) and liquid nitrogen (boiling the dissociation constant of Aflibercept is point: - 195.6°C). The safety and for VEGF165 was 0.49pM as compared to biological effect of various cryogens have native VEGF 1 and VEGF 2 which is 9.33 not yet been fully standardized and also and 88.80pM respectively. Due to this the storage of liquid nitrogen and other property, it resists the binding of the native cryogens further limit the scope of VEGFs, reducing VEGF activity that treatment [19]. subsequently leads to decrease in vascular permeability and angiogenesis. PIGF is The traditional cryotherapy treatment is also reported as one of the factors of progressed under anaesthesia where each angiogenesis and thus inhibition of PIGF session consists of 36 application of and VEGF-B can also be helpful in cryotherapy (- 60°C for 3, 4 seconds) that improving angiogenic condition. Since are applied 360° transconjunctivally with Aflibercept has an outstanding mechanism two applications applied at each clock of forming 1:1 inert complex by binding to hour between ora serrata and the equator both sides of VEGF dimer it is also known while one application at each clock half as VEGF trap and this is the only drug hour. The end point is determined by the available that target PIGF-2 [18]. formation of retinal whitening observed through an indirect ophthalmoscope CRYOTHERAPY FOR THE [19][20]. TREATMENT OF DIABETIC RETINOPATHY Mechanism of Cryotherapy: Cryotherapy is a relatively non-invasive  Ischemia through vascular stasis. surface technique which employs freezing  Destruction of smaller vessels. temperatures for the treatment of diabetic  Cell wall ruptures through formation of retinopathy and other eye diseases. ice crystals within the cell. Cryotherapy works on the principle of cell  Lipid-protein complex denaturation. death caused by necrosis and ischemia  Osmotic stress. caused by the formation of ice in smaller  Tissue necrosis. blood vessels and surrounding  Freezing injury leading to cellular extracellular fluid. The cryotherapy was apoptosis. initially utilised by Bietti to seal a retinal  Toxic concentrations build-up within hole by thermal chorioretinitis in 1933. cells. Bietti used a mixture of carbon dioxide  Dehydration due to the formation of and acetone to cool a metal probe applying ice crystals. it to the surface of the eye over the retinal  Supercooling. hole. The use of cryotherapy in ophthalmology began in 1961 and later The longer thaw cycles also contribute to Krwawiez developed a metal probe which the process by providing longer vascular can be dipped in a mixture of alcohol and stasis and increased exposure to the highly solid carbon dioxide wherein a new toxic concentrations leading to enhanced modification was brought forward by efficiency of the procedure. The cycle is repeated 2-3 times and increased freezing Amoils in form of a liquid nitrogen probe can be obtained by employing longer [19]. contact time [19].

Various cryogens used in cryotherapy Complications of the treatment: include freon (boiling point: - 29.8°C to -  Over-freezing: The contact time in the 40.8°C), nitrous oxide (boiling point: - cryotherapy is a critical parameter 88.5°C), solid carbon dioxide (boiling which should be controlled properly.

Journal of Clinical Trials and Regulations Volume 1 Issue 2

Extending the contact time can lead to in diabetic patients by preventing the the destruction of neighbouring cells increase in the macular thickness. by over-freezing. Dexamethasone can be a promising  Under-freezing: As stated earlier the treatment in DME [22]. contact time being a critical parameter the shorter contact time may lead to Fluocinolone Acetonide under-freezing. It is available as two extended release drug  The freezing of the non-target tissue. delivery system Retisert (Bausch & Lomb,  Tissue cracking: The probe when in Rochester, NY, USA) and Iluvien contact with tissue adheres to it due to (Alimera Sciences, Atlanta, GA, USA) extremely cold temperatures. [21]. Detaching the Probe from the tissue is very critical as complete defrosting Intravitreal Triamcinolone Acetonide shall be allowed or it would crack the (IVTA) for the Treatment of Diabetic tissue adhere to it while detaching the Retinopathy probe. Triamcinolone acetonide is a synthetic steroid belonging to the family of STEROIDS glucocorticoid with hydrogen atom Steroids may be a choice of treatment for substituted by fluorine at the ninth DME even when Anti-VEGF drug are position. Commercially it is available as considered to be the first line therapy in ester in the form of white powder, DME because of some of the limitations of insoluble in water but soluble in ethanol Anti- VEGF drugs and thus steroids are and chloroform. After intravitreal injection gaining high interest in treatment of DME. vitreous concentration is found to be 1.22 A study was carried out for determining ± 0.24 µg/ml [23]. the activity of steroid in DME using Dexamethasone injection and it was found The VEGF partially regulates the that it significantly decreases aqueous breakdown of blood retinal barrier which angiopoietin-2, hepatocyte growth factor causes edema. Corticosteroids when and endocrine gland-VEGF administered blocks VEGF, cytokines, concentrations. Apart from anti- prostaglandin and leukotriene resulting in inflammatory action of corticosteroids, it regulation of endothelial tight junctions, also causes alteration in the composition of decreasing inflammation and modulation endothelial basal membrane and thus of calcium channel which in turn reduces strengthen and tighten the junctions to the edema [24]. limit permeability and leakage. Neuroprotective effect on the retina is also A study by Yilmaz T et al., concluded that observed on its long-term usage [21]. IVTA proves to be effective in improving visual acuity in patients with refractory Burcu Nurözler Tabakcı, Nurten Ünlü diabetic edema. (Yilmaz T, 2009) Another demonstrated that steroids can be an study by Philip L et al., demonstrated that effective treatment and can reduce the exudation decreased and vision was retinopathic condition and can improve the improved in 87% of patients with type 1 vision also. But the steroid related side and 2 diabetes mellitus when treated with effects are mostly observed like increase in IVTA. However, the treatment yet remains the intra ocular pressure and cataract [21]. unproven [25].

Dexamethasone ISLET CELL TRANSPLANTATION Pilar Calvo conducted a study and he The improvisation and benefits in type 1 concluded that single Dexamethasone diabetic patients was observed by islet injection can avoid the increase in cataract

Journal of Clinical Trials and Regulations Volume 1 Issue 2

transplantation and the result found was 7.34% were lost due to severe with islet isolation, immunosuppression complications [26]. free of glucocorticoid and the provision of islet mass of more than 10000 islet RUBOXISTAURIN equivalent/kg of individual’s body weight. In hyperglycaemic condition protein This also includes the long-term secretion kinase C is activated by induction of de- of c peptide and reduction of novo synthesis of diglycerol which is a hypoglycaemic events and in addition to physiological factor for activation of PKC. this it also showed improved HbA1c Ahmed M. Abu El-Asrar demonstrated values and reduction in progression of that the β form of the same may be a retinopathy in comparison to another prominently responsible for diabetic microvascular complication. Retinal intensive medical therapies that need three vascular permeability and years follow up [26]. Clinical trials to neovascularization is observed with improve engraftment, the availability of increase in β isomer of PKC. The PKC β insulin-producing cell sources, as well as inhibitor was found to be subsequently alternative transplant sites are currently reducing visual loss, progression of under investigation to expand treatment. macular edema and also improve vision The current scenario shows that the islet specifically in case of non-proliferative transplantation is very exciting and diabetic retinopathy [26]. attractive therapy specifically in the treatment of type 1 diabetes mellitus with RENIN-ANGIOTENSIN SYSTEM aim of treatment for few to cure for many (RAS) FOR DIABETIC [27]. RETINOPATHY RAS has been gaining considerable VITRECTOMY SURGERY FOR attention for the treatment of diabetic DIABETIC RETINOPATHY retinopathy and current studies have The first vitrectomy surgery was provided evidence of its role in performed in 1970 by Robert Machemar, pathogenesis of diabetic retinopathy and on diabetic eye with persistent vitreous its blockade can reduce the progression of haemorrhage. In today’s era vitrectomy diabetic retinopathy. Angiotensin – II surgery allows the most important upregulates the VEGF causing the increase exudation and stimulation of new blood technique to omit the complex cases of vessels [28]. retinal detachment. The patient with non- clearing vitreous haemorrhage, Tasma Harindhanavudhi et al., vitreomacular traction syndrome demonstrated that RAS blockage can (epiretinal membranes, retinal reduce Diabetic retinopathy progression in detachments, and macular heterotopia), normoalbuminuric type 1 diabetic patients persistent neovascularization with [29]. However, Pradhan et al., suggested rubeosisiridis, persistent or tractional that small doses of ACE- I cannot macular edema are advised to undergo reportedly slow the progression of diabetic vitrectomy procedure. Brănişteanu Daniel retinopathy [30]. Constantin et. al. studied and reported that 88.71% of the population studied had a Nish Chaturvedi et al., demonstrated that stable anatomical result after the initial Lisinopril showed beneficial effect in surgery. On repeated surgical reducing the progression of diabetic interventions, 92.65% was recorded as retinopathy based on EUCLID protocol [31]. successful anatomical result whereas only

Journal of Clinical Trials and Regulations Volume 1 Issue 2

RECEPTOR GAMMA (PPAR-γ) and thiazolidinediones is a class of PEROXISOME antidiabetic drug was shown to have high PROLIFERATORACTIVATED affinity in 1955 [33]. Suppression of PPAR-γ AGONISTS leads to retinal leukostasis and retinal PPAR-γ is a ligand activated transcription leakage. Toshinori Murata et al., factor which belongs to a nuclear receptor demonstrated that PPAR-γ effectively superfamily. PPAR-γ is found in RPE inhibits VEGF induced choroidal cells, photoreceptor outer angiogenesis [34]. Kimimasa Muranaka et segments choriocapillaris and retinal al., concluded that suppression of PPAR-γ ganglion cells. Corneal angiogenesis and leads to retinal leukostasis and leakage. neovascularisation are effectively inhibited Rosiglitazone a PPAR-γ agonist inhibits by PPAR-γ but in diabetic retinopathy they retinal leukostasis and leakage [35]. are suppressed in the cells [32]. One of the Mechanism of PPAR-γ agonist is shown in natural ligands of PPAR-γ is 15d-PGJ2 Fig. 3.

Figure 3: Mechanism of PPAR-γ agonist for forestalling diabetic retinopathy.

CLINICAL TRIALS Table 2: Clinical Trials Currently Undertaken in India for Diabetic Retinopathy [36] Sample Drug Public Title Type of Trial Size PF-04523655 Versus Prospective, Randomized, Multi-Center, Laser Comparator Study Evaluating Efficacy and Interventional 160 Safety of PF-04523655 Versus Laser in Subjects Pfizer Limited, India with Diabetic Macular Edema (DEGAS) PHASE II Open Label, MULTICENTER, PROSPECTIVE, RANDOMIZED, AGE PF 04523655 VERSUS RELATED MACULAR DEGENERATION, RANIBIZUMAB COMPARATOR controlled, STUDY evaluating Interventional 150

PF 04523655 VERSUS RANIBIZUMAB IN the Pfizer Limited, India treatment of SUBJECTS WITH CHOROIDAL NEOVASCULARIZATION (Monet study) Nepafenac A clinical trial to study effects of NEVANAC®

in reduction of Macular Edema Interventional 260 Alcon Research ltd, incidence/severity post cataract surgery USA. Preservative-Free Preservative-Free Tafluprost (MK-2452) for the Interventional 248 Tafluprost or vehicle Treatment of Open-Angle Glaucoma or Ocular

Journal of Clinical Trials and Regulations Volume 1 Issue 2

Hypertension (MK-2452-002) Merck Sharp and Dohme, USA. 23G suture-less vitrectomy A study to find out whether vitrectomy is better than laser for diabetic patients with partial Interventional 64 P.B.M.A.s H.V. Desai bleeding into the vitreous jelly. Eye Hospital, India. Awareness of foot problem Awareness of foot problem and care among

diabetic population in India- a questionnaire- Observational 400 Manipal College of based survey. Allied Health Sciences, India. Evaluation of the eye and systemic conditions Eye and Diabetic Disease Observational 200 LV Prasad Eye Institute, India. Triamcinolone Acetonide It is a study of two modes of treatment; which are called Laser Photocoagulation alone and with Govt medical college drug Triamcinolone, in the patients which are Interventional 40 and Sir Takhatsinhji suffering from eye disease caused by Diabetes General Hospital Mellitus. Bhavnagar, India. Prevalence of A Study to Estimate the Prevalence of Depression Depression in Type 2 Diabetes Patients as Observational 260 Max Super Speciality compared to non-diabetic patients in a Tertiary Hospital, India. Care Centre Ayurvedic therapies Dept of AYUSH An observational study to assess the efficacy of Ministry of Health Govt Observational 50 Ayurvedic treatment in eyes affected by diabetes of India New Delhi, India. Intravitreal A 12-month, open label, multi-center study to Ranibizumab evaluate the efficacy and safety of intravitreal Aravind Eye Hospitals injections of ranibizumab 0.5 mg on Cystoid, PMS 300 & Postgraduate Institute Spongy & Mixed OCT patterns secondary to of Ophthalmology, Diabetic Macular Edema (DME) India. A clinical trial to study the levels of vascular Aqueous Tap, ERG, endothelial growth factor in the fluid in the front FFA, MAIA, SDOCT part of the eye in cases of occlusion of venous Interventional 30 Narayana Nethralaya, supply of the eye and to correlate with the India. clinical features and nerve thickness as obtained by scanning and nerve function tests To compare the safety and efficacy of Ranibizumab Ranibizumab of Intas Biopharmaceuticals Ltd. in Narayana Nethralaya, Interventional 100 comparison with Lucentis in patients of wet Age- India. related Macular Degeneration. Ayurvedic treatment INSTITUTE FOR POST GRADUATE Background Diabetic Retinopathy and its Interventional 40 TEACHING AND Ayurvedic Management. RESEARCH IN AYURVEDA, India. Ranibizumab 0.5 mg To assess the ranibizumab injections versus Interventional 252

Journal of Clinical Trials and Regulations Volume 1 Issue 2

Novartis Healthcare Pvt Sham control in patients with visual impairment. Ltd, India. Study to evaluate the efficacy and safety of two different dosing regimens of Ranibizumab 0.5 vs Ranibizumab Veteporfin PDT in Patients with vision loss due Novartis Healthcare Pvt Interventional 475 to creation of new blood vessels in choroid layer Ltd, India. of eye secondary to a rare type of short- sightedness where the eyeball continues to grow. Ranibizumab Study to evaluate the efficacy and safety of two

different regimens of 0.5 mg Ranibizumab in Interventional 644 Novartis Healthcare Pvt patients. Ltd, India. Mahagniwati RAPODAR AYU Clinical Study on Non proliferative Diabetic Interventional 30 MEDICAL COLLEGE, retinopathy India. Retinal image acquisition Using Intelligent Retinal Camera to detect Australian Government changes in the eyes, in cases of diabetes or Observational 2800 Cooperative Research increased fluid pressure in the eye. Centres Program, Australia. Pars plana vitrectomy Nethradhama super Role of retina surgery in vision loss due to Interventional 10 speciality eye hospital, diabetic retinopathy India. Complications of injection given in the eye Complications of injection given in the eye for Observational 100 Nethradhama retinal diseases superspeciality eye hospital, India. Mukkadi yoga, tungadrumadi taila, madhumehahar yoga, takradhara Management of early changes in eye (retina) due Institute for Post Interventional 100 to diabetic Graduate Teaching and Research in Ayurveda Gujarat Ayurved University, India. Ranibizumab To study the safety and efficacy of Ranibizumab Intas Pharmaceuticals of Intas Pharmaceuticals Ltd. in patients with Interventional 126 Ltd, India. visual impairment. A trial to compare the outcomes of new lens CT LUCIA 601PY having heparin coated surface with currently intraocular lens (IOL) Interventional 100 being used lens (without heparin coating) in AIIMS, India. diabetic patients with cataract Remote screening A clinical study to compare effectiveness of model remote screening model with standard screening Interventional 238. Carl Zeiss India Pvt method for Diabetic Retinopathy” Ltd, India Computer Automated Detection (CAD) Computer Automated programme in identifying the presence of Detection (CAD) Observational 1000 diabetic retinopathy (DR) and diabetic macular Google Inc, USA. edema (DME) in persons with diabetes

Journal of Clinical Trials and Regulations Volume 1 Issue 2

Table 2: Clinical Trials Currently Undertaken In Usa For Diabetic Retinopathy [37]: Drug Public Title Type Of Trial Sample Size OCT Biomarkers Oregon Health and Science OCT Biomarkers for Diabetic Retinopathy Observational 215 University : Macugen ® (pegaptanib Macugen for Proliferative sodium) Diabetic Retinopathy Study with Extended Interventional 30 Valley Retina Institute Dosing (M-PDRS ED) Pfizer Evaluation of Progression of Initiation of treatment of diabetes Diabetic Retinopathy with Rapid Observational 30 Temple University Correction of Hyperglycaemia Propranolol University of Propranolol for Diabetic Retinopathy Interventional 9 Wisconsin, Madison Doxycycline monohydrate Evaluation of Effect of Penn State University Doxycycline Verses Placebo on Interventional 33 Juvenile Diabetes Research Retinal Function and Diabetic Retinopathy Foundation Aflibercept Prevention of Macular Edema Sham In Patients with Diabetic Interventional 30 Regeneron Pharmaceuticals Retinopathy Undergoing Cataract Surgery The Cleveland Clinic Octreotide Acetate in Octreotide Acetate in Microspheres 20 Microspheres in Patients with Diabetic Interventional 583 Novartis Retinopathy Evaluation of Doxycyline Verses Doxycycline monohydrate Placebo for the Treatment of Penn State University Severe Non-proliferative or Interventional 28 Juvenile Diabetes Research Mild or Moderate Proliferative Diabetic Foundation Retinopathy Study to Evaluate Effects of Emixustat hydrochloride Emixustat Hydrochloride in Interventional 24 Acucela Inc. Subjects with Proliferative Diabetic Retinopathy Evaluation of Ranibizumab in Proliferative Lucentis (ranibizumab) Diabetic Interventional 40 Genentech, Inc. Retinopathy (PDR) Requiring Vitrectomy Intravitreal Treatment with Intravitreal Aflibercept Injection Aflibercept Injection For Interventional 20 (IAI) Proliferative Diabetic Regeneron Pharmaceuticals Retinopathy, The A.C.T Study Long-Term Follow-Up of Patients Enrolled in the Early National Eye Institute (NEI) Observational 170 Treatment Diabetic Retinopathy Study (ETDRS) Triamcinolone acetonide Vascular Remodelling and the Effects of (Kenalog) Angiogenic Inhibition in Diabetic Interventional 100 National Eye Institute (NEI) Retinopathy Protein Kinase C (PKC) Ruboxistaurin Inhibitor-Diabetic Retinopathy Phase 3 Interventional 685 Chromaderm, Inc Study Intravitreal Aflibercept as Indicated by Aflibercept Injection Real-Time Objective Imaging to Achieve Interventional 40 Greater Houston Retina Research Diabetic Retinopathy Improvement Procedure: Ophthalmic The Comparative Effectiveness of Telemedicine Telemedicine to Detect Diabetic Interventional 567 Legacy Health System Retinopathy

Journal of Clinical Trials and Regulations Volume 1 Issue 2

Table 3: Clinical Trials Currently Undertaken in Europe for Diabetic Retinopathy [37] Drug Public Title

Bevacizumab Evaluation of safety and efficacy on visual acuity outcome of intravitreal Ospedale Sacro Cuore-Don Calabria administration of Bevacizumab in patients with diabetic retinopathy

MelatoninDept. of Ophthalmology, Diabetic retinopathy: Effects of melatonin treatment on visual functions Rigshospitalet – Glostrup and circadian rhythm.

Calcium dobesilate Fundació Hospital Universitari Vall d'Hebron Effect of Calcium dobesilate in early stages of diabetic retinopathy - Institut de Recersa (VHIR)

Macugen Evaluation of the efficacy and safety of a Macugen monotherapy versus Johann Wolfgang Goethe- Combined Therapies in the Treatment of Diabetic Retinopathy – a single Universität Frankfurt centre, randomized, prospective Phase II trial

Single centre, exploratory, double-blind, placebo-controlled study to Vinpocetine investigate the efficacy and tolerability of vinpocetine in patients with Gedeon Richter Plc. non-proliferative diabetic retinopathy

A prospective, randomized study on intravitreal Ozurdex for preventing Intravitreal Ozurdex recurrent vitreous haemorrhage following pars plana vitrectomy for St Eriks Eye Hospital proliferative diabetic retinopathy

A phase IIa, randomized, placebo-controlled, double-blind, parallel EyeGene, Inc study to investigate the efficacy of EG-Mirotin subcutaneously Subcutaneous EG-Mirotin administered in multiple doses on diabetic macular edema in diabetic retinopathy

Fenofibrate University of Oxford A randomised placebo-controlled clinical trial of fenofibrate to prevent (Clinical Trials and Research progression of non-proliferative retinopathy in diabetes Governance)

A phase 2, randomised, double-masked, sham-controlled, multi-centre Ocriplasmin study to evaluate the efficacy and safety of Ocriplasmin in inducing total ThromboGenics NV Posterior Vitreous Detachment (PVD) in subjects

Intravitreal Bevacizumab Avastin Intravitreal Bevacizumab Avastin, Roche, United Kingdom for Universita Degli Studi Di Udine exudative maculopathies

Proof–of–concept study 1 (POC1): Evaluation of effect of doxycycline versus placebo on retinal function and posterior segment Doxycycline neovascularization in patients with severe non-proliferative or early diabetic retinopathy

Avastin Randomised Controlled Trial of Intravitreal therapy with Avastin Moorfields Eye Hospital NHS compared to Observation in Patients with Diabetic Ischaemic Macular Foundation Trust Oedema ‘The DIME study’

Intravitreal Ranibizumab (Lucentis) Intravitreal Ranibizumab (Lucentis) Therapy in Patients with Diabetic Moorfields Eye Hospital Ischaemic Macular Oedema (DIME)

PGF Aarhus University Hospital, Pharmacological intervention on diabetic retinopathy with PGF Department of Ophthalmology

Journal of Clinical Trials and Regulations Volume 1 Issue 2

PATENTS Table 4: USA Patents for Treatment and Diagnosis of Diabetic Retinopathy [38]. Patent Number Title of the Patent Date of Grant

CN-104173504- A method of treating diabetic retinopathy in Chinese medicine and their 21-09-2016 B use capsule

CN-104161849- A method of treating diabetic retinopathy in Chinese medicine tablets 24-08-2016 B and the use thereof CN-104161847- Quality inspection method of treating diabetic retinopathy in Chinese 24-08-2016 B medicine composition Method for prediction of progression of diabetic retinopathy and diabetic RU-2520826-C1 27-06-2014 macular oedema Method of conservative treatment of recurrent hemophthalmia in diabetic RU-2485944-C1 27-06-2013 retinopathy Method of treating diabetic retinal microangiopathy and diabetic RU-2392982-C1 27-06-2010 retinopathy

US-7247702-B2 Periocular drug delivery for diabetic retinopathy 24-07-2007

Method for predicting clinical manifestations of diabetic retinopathy in ii RU-2292549-C1 27-01-2007 type diabetes patients Compounds and method for the prevention and treatment of diabetic US-7115566-B2 03-10-2006 retinopathy

Methods of treating cataracts and diabetic retinopathy with tricyclic US-6916824-B1 12-07-2005 pyrones

CN-1201768-C Medication for treating diabetic retinopathy and its preparing method 18-05-2005 Compositions for treating diabetic retinopathy and methods of using US-6852688-B2 08-02-2005 same

US-6713253-B1 Detecting genetic predisposition to sight-threatening diabetic retinopathy 30-03-2004

Diagnosis of a person's risk of developing atherosclerosis or diabetic US-6312898-B1 retinopathy based on leucine 7 to proline 7 polymorphism in the prepro- 06-11-2001 neuropeptide Y gene US-6294538-B1 Compounds for treating and preventing diabetic complications 25-09-2001 Methods and compositions for the prevention and treatment of diabetes US-5871769-A 16-02-1999 mellitus

US-5728704-A Substituted pyrimidines for control of diabetic complications 17-03-1998

US-5639482-A Composition for control and prevention of diabetic retinopathy 17-06-1997

US-5561110-A Method for the treatment of the complications and pathology of diabetes 01-10-1996

Method for treating retinopathy and other small vessel disorders US-5019591-A 28-05-1991 associated with diabetes

WO- Protein for diagnosing diabetic retinopathy 2004007554-A1

Journal of Clinical Trials and Regulations Volume 1 Issue 2

Table 5: Indian Patents for Treatment and Diagnosis of Diabetic Retinopathy [39]. Application Number Title of the Patent Publication Date

An ensemble-based system for microaneurysm detection and 201641030501 09/03/2018 diabetic retinopathy grading

Set of biomarkers to identify early diabetic retinopathy, retinal 2251/CHE/2015 01/12/2017 angiogenic diseases and resistance to ocular Anti-VEGF therapy

Inhibition of aldose reductase by natural compounds (Agnuside, 4993/CHE/2015 eupalitin-3-o-galactoside, Picroside ii and 7-o-methylwogonin) 30/06/2017 to treat diabetic retinopathy

Quantification and rectification of diabetic retinopathy diseases 201721005790 24/03/2017 using the digital image processing software

Methods for the treatment of diabetic retinopathy and other 9886/DELNP/2014 31/08/2016 ophthalmic diseases

Method for detection of retinopathy of prematurity (ROP) and 2858/CHE/2012 08/04/2016 tool therefrom Amino acid compositions for the treatment of diabetic 5127/CHE/2012 11/07/2014 retinopathy “A synergistic herbal composition for preventing and treatment 3134/DEL/2011 03/05/2013 of diabetic retinopathy and cataract” 3478/DELNP/2011 Apparatus for monitoring and grading diabetic retinopathy" 30/03/2012 Herbal formulation for prevention and treatment of diabetic 1223/DEL/2009 24/12/2010 retinopathy

1318/MUM/2009 Innovative product against diabetic retinopathy 03/12/2010

94/CHE/2009 Automated system for early detection of diabetic retinopathy 23/07/2010

545/DELNP/2005 "Protein for diagnosing diabetic retinopathy" 27/11/2009 "A non-surgical method for preventing or reducing the rate of 8312/DELNP/2007 the progression of non-proliferative diabetic retinopathy and the 11/01/2008 treatment of other ocular conditions"

Treating diabetic retinopathy with angiotensin ii receptor 4788/DELNP/2005 12/10/2007 blockers"

Methods for treating ocular angiogenesis, retinal edema, retinal 6663/DELNP/2007 ischemia, and diabetic retinopathy using selective RTK 21/09/2007 inhibitors

Table 6: European Patents for Treatment and Diagnosis of Diabetic Retinopathy [40]. Application Number Title of the Patent Priority Date Application of Astilbin in preparation of drug for CN107802635 (A) 2017-12-07 treating diabetic retinopathy Folium ginkgo preparation for treating diabetic retinopathy as CN107753496 (A) 2017-10-18 well as preparation method and application thereof Traditional Chinese medicine for CN107661473 (A) 2017-09-29 treating diabetic retinopathy and preparation method thereof Diabetic retinopathy fundus photography standard image CN107506770 (A) 2017-08-17 generation method Serum/plasma miRNA marker related to type CN107385035 (A) 2017-07-18 2 diabetic retinopathy and use thereof CN107349362 (A) Drug combination for treatment of diabetic retinopathy 2017-07-14 CN107330260 (A) Clinical grading diagnosis and treatment data management 2017-06-23

Journal of Clinical Trials and Regulations Volume 1 Issue 2

system for diabetic retinopathy patients CN107330449 (A) Diabetic retinopathy sign detection method and device 2017-06-13 CN107423571 (A) Diabetic retinopathy recognition system based on fundus images 2017-05-04 Staging determination support system of diabetic retinopathy and JP2018027273 (A) method of supporting determination of staging 2016-08-19 of diabetic retinopathy Applications of composition in preparation of drug for treatment CN107432880 (A) 2016-05-28 of diabetic retinopathy v5 Composition for treating diabetic retinopathy comprising KR20170119902 (A) inhibitors of Integrin v5 and Screening method for the said 2016-04-20 inhibitors CA3008691 (A1) Method for preventing or treating diabetic retinopathy 2015-12-18 Biomarkers for diagnosis of age-related macular degeneration KR20170106269 (A) 2015-11-16 or diabetic retinopathy and diagnostic method using the same Injectable porous device for treatment of dry and wet age-related CN107809977 (A) 2015-06-24 macular degeneration or diabetic retinopathy Intravitreal Lysine Acetylsalicylate as Treatment US2018177805 (A1) 2015-05-26 for Diabetic Retinopathy Circulatory MicroRNAs (miRNAs) as Biomarkers US2018044733 (A1) for Diabetic Retinopathy (DR) and Age-Related Macular 2014-05-05 Degeneration Peptides for use in the topical treatment of retinal neurodegenerative diseases, in particular in early stages PL2968471 (T3) 2013-03-01 of diabetic retinopathy and other retinal diseases in which neurodegeneration plays an essential role Methods for treatment of diabetic retinopathy and other JP2018024702 (A) 2012-05-04 ophthalmic diseases

CONCLUSION Volume 221, Issue 2, pp. 95−102. Diabetic retinopathy has become more 2. Lang GE (2007), “Laser treatment of prominent in the recent years attributing to diabetic retinopathy”, In Diabetic various factors. The therapies like ANTI- Retinopathy, Karger Publishers., VEGF Drugs when coupled with laser Volume 39, pp. 48−68. therapy give promising results which can 3. Dowler JG (Jun 2003), “Laser prohibit vision loss to a greater extent as management of diabetic retinopathy”, compared to a single therapy. However, Journal of the royal society of there is still a need to develop non- medicine., Volume 96, Issue 6, pp. invasive methods for the drug targeting of 277−279. ANTI-VEGF drugs which may further 4. Raj Sharma (Apr 2007), “Diabetic decrease the complications and post Retinopathy Clinical Research treatments problems. Network. Comparison of modified- ETDRS and mild macular grid laser The use novel drug delivery systems such photocoagulation strategies for diabetic as Nano technology, use of site-specific macular edem”, Archives of carriers, etc can be developed to increase ophthalmology, Volume 125, Issue 4, patient compliance and help in recovery pp. 469. process while aiding and decreasing the 5. Tripathy K, Raj Sharma Y, Chawla R, trauma of the procedure. Gogia V, Kumar Singh S, Venkatesh P, Vohra R (1, Jun 2015), “Recent REFERENCES advances in management of diabetic 1. Neubauer AS, Ulbig MW (2007), macular edema”, Current diabetes “Laser treatment in diabetic reviews, Volume 11, Issue 2, pp. retinopathy”, Ophthalmologica, 79−97.

Journal of Clinical Trials and Regulations Volume 1 Issue 2

6. Paulus YM, Jain A, Gariano RF, 14. Dervenis N, Mikropoulou AM, Tranos Nomoto H, Schuele G, Sramek C, P, Dervenis P (Jun 2017), Charalel R, Palanker D, (2, Mar 2010), “Ranibizumab in the treatment of “Selective retinal therapy with a diabetic macular edema: a review of continuous line scanning laser”, In the current status, unmet needs, and Ophthalmic Technologies XX emerging challenges”, Advances in International Society for Optics and Therapy, Volume 34, Issue 6, pp. Photonics, Volume 7550, pp. 75500W. 1270−1282. 7. Park YG, Kim JR, Kang S, Seifert E, 15. Pai A, El Shafei MM, Mohammed OA, Theisen-Kunde D, Brinkmann R, Roh Al Hashimi M (1, Oct 2010), “Current YJ (1, Sep 2016), “Safety and efficacy concepts in intravitreal drug therapy of selective retina therapy (SRT) for for diabetic retinopathy”, Saudi the treatment of diabetic macular Journal of Ophthalmology, Volume edema in Korean patients”, Graefe's 24, Issue 4, pp. 143−149. Archive for Clinical and Experimental 16. Chen WL, Chen YM, Chu HS, Lin CT, Ophthalmology, Volume 254, Issue 9, Chow LP, Chen CT, Hu FR (8, Apr pp. 1703−1713. 2014), “Mechanisms controlling the 8. Miller JW, Kiss S, “The Pattern effects of bevacizumab (avastin) on the Scanning Laser (PASCAL®) inhibition of early but not late formed Photocoagulator for Diabetic corneal neovascularization. PLoS One., Retinopathy”, Journal-The Pattern Volume 9, Issue 4, pp. e94205. Scanning Laser (PASCAL®) 17. Ng EW, Shima DT, Calias P, Photocoagulator for Diabetic Cunningham Jr ET, Guyer DR, Retinopathy. Adamis AP (Feb 2006), “Pegaptanib, a 9. Dorin G (1, Jan 2003), “Subthreshold targeted anti-VEGF aptamer for ocular and micropulse diode laser vascular disease”, Nature reviews drug photocoagulation”, In Seminars in discovery, Volume 5, Issue 2, pp.123. ophthalmology Taylor & Francis, 18. Christian Swinney PA (2018), Volume 18, Issue 3, pp. 147−153. “Aflibercept. American Academy of 10. Stewart MW (1, Jun 2017), “A review Ophthalmology”, of ranibizumab for the treatment of 19. Tehrani S, Fraunfelder FW (14, Oct diabetic retinopathy”, Ophthalmology 2013), “Cryotherapy in and therapy, Volume 6, Issue 1, pp. ophthalmology”, Open Journal of 33−47. Ophthalmology, Volume 3, Issue 4, pp. 11. Krispel C, Rodrigues M, Xin X, Sodhi 103. A (15, Dec 2013), “Ranibizumab in 20. Benedett R, Olk RJ, Arribas NP, Okun diabetic macular edema”, World E, Johnston GP, Boniuk I, Escoffery Journal of Diabetes, Volume 4, Issue RF, Grand MG, Schoch LH (1, Jun 6, pp. 310. 1987), “Transconjunctival anterior 12. Rodriguez-Fontal M, Alfaro V, retinal cryotherapy for proliferative Kerrison JB, Jablon EP (1, Feb 2009), diabetic retinopathy”, Ophthalmology, “Ranibizumab for diabetic Volume 94, Issue 6, pp. 612−619. retinopathy”, Current diabetes reviews, 21. Nurözler Tabakcı B, Ünlü N, Volume 5, Issue 1, pp. 47−51. “Corticosteroid treatment in diabetic 13. Osaadon P, Fagan XJ, Lifshitz T, Levy macular edema”, J (May 2014), “A review of anti-VEGF 22. Calvo P, Ferreras A, Al Adel F, agents for proliferative diabetic Dangboon W, Brent MH (Mar 2018), retinopathy”, Eye, Volume 28, Issue 5, “Effect of an intravitreal pp. 510. dexamethasone implant on diabetic

Journal of Clinical Trials and Regulations Volume 1 Issue 2

macular edema after cataract surgery”, with glycemic control”, Diabetes Care, Retina (Philadelphia, Pa.), Volume 38, Volume 34, Issue 8, pp. 1838−1842. Issue 3, pp. 490. 30. Pradhan R, Fong D, March C, Jack R, 23. Gopal L, Sharma T (Nov 2007), “Use Rezapour G, Norris K, Davidson MB of intravitreal injection of (1, Nov 2002), “Angiotensin- triamcinolone acetonide in the converting enzyme inhibition for the treatment of age-related macular treatment of moderate to severe degeneration”, Indian journal of diabetic retinopathy in normotensive ophthalmology, Volume 55, Issue 6, type 2 diabetic patients: a pilot study”, pp. 431. Journal of Diabetes and its 24. Vedantham V, Kim R (1, Apr 2006), Complications, Volume 16, Issue 6, “Intravitreal injection of triamcinolone pp. 377−381. acetonide for diabetic macular edema: 31. Chaturvedi N, Sjolie AK, Stephenson Principles and practice”, Indian JM, Abrahamian H, Keipes M, journal of ophthalmology, Volume 54, Castellarin A, Rogulja-Pepeonik Z, Issue 2, pp. 133. Fuller JH (3, Jan 1998), EUCLID 25. Penfold PL, Gyory JF, Hunyor AB, Study Group. Effect of lisinopril on Billson FA (Nov 1995), “Exudative progression of retinopathy in macular degeneration and intravitreal normotensive people with type 1 triamcinolone A pilot study. Australian diabetes”, The Lancet, Volume 351, and New Zealand”, Journal of Issue 9095, pp. 28−31. ophthalmology, Volume 23, Issue 4, 32. Ciudin A, Hernández C, Simó R pp. 293−298. (2013), “Molecular implications of the 26. El-Asrar AM, Al-Mezaine HS (1, Apr PPARs in the diabetic eye”, PPAR 2011), “Advances in the treatment of research, diabetic retinopathy”, Saudi journal of 33. Song MK, Roufogalis BD, Huang TH ophthalmology, Volume 25, Issue 2, (2012), “Role of peroxisome pp. 113−122. proliferator activator receptor γ in 27. Bruni A, Gala-Lopez B, Pepper AR, diabetic retinopathy pathophysiology”, Abualhassan NS, Shapiro AJ (2014), J Diabetes Metab S., Volume 3, Issue “Islet cell transplantation for the 2, treatment of type 1 diabetes: recent 34. Murata T, He S, Hangai M, Ishibashi advances and future challenges”, T, Xi XP, Kim S, Hsueh WA, Ryan SJ, Diabetes, metabolic syndrome and Law RE, Hinton DR (1, Jul 2000), obesity: targets and therapy, Volume “Peroxisome proliferator-activated 7, Issue 211. receptor-γ ligands inhibit choroidal 28. Sjoelie AK, Dodson P, Hobbs FR neovascularization. Investigative (Feb2011), “Does renin‐angiotensin ophthalmology & visual system blockade have a role in science.;41(8):2309-17. preventing diabetic retinopathy? A 35. Muranaka K, Yanagi Y, Tamaki Y, clinical review”, International journal Usui T, Kubota N, Iriyama A, Terauchi of clinical practice, Volume 65, Issue Y, Kadowaki T, Araie M (1, Oct 2, pp. 148−153. 2006), “Effects of peroxisome 29. Harindhanavudhi T, Mauer M, Klein proliferator-activated receptor γ and its R, Zinman B, Sinaiko A, Caramori ML ligand on blood–retinal barrier in a (1, Aug 2011), “Renin Angiotensin streptozotocin-induced diabetic System Study (RASS) group. Benefits model”, Investigative Ophthalmology of renin-angiotensin blockade on & Visual Science, Volume 47, Issue retinopathy in type 1 diabetes vary 10, pp. 4547−4552.

Journal of Clinical Trials and Regulations Volume 1 Issue 2

36. Retrieved pathy from: https://clinicaltrials.gov/ 39. Retrieved from: http://ipindiaservices.g 37. Retrieved ov.in/publicsearch from: http://www.ctri.nic.in/Clinicaltri 40. Retrieved als/advsearch.php from: https://worldwide.espacenet.com/ 38. Retrieved from: https://patents.google.com/?q=di abetic+retinipathy&oq=diabetic+retini