Subconjunctival Routes Research Articles

Mathematical Models of Ocular Drug Delivery.

Drug delivery is an important factor for the success of ocular drug treatment. However, several physical, biochemical, and flow-related barriers limit drug exposure of anterior and posterior ocular target tissues during drug treatment via topical, subconjunctival, intravitreal, or systemic routes. Mathematical models encompass various barriers so that their joint influence on pharmacokinetics (PKs) can be simulated in an integrated fashion. The models are useful in predicting PKs and even pharmacodynamics (PDs) of administered drugs thereby fostering development of new drug molecules and drug delivery systems. Furthermore, the models are potentially useful in interspecies translation and probing of disease effects on PKs. In this review article, we introduce current modeling methods (noncompartmental analyses, compartmental and physiologically based PK models, and finite element models) in ocular PKs and related drug delivery. The roles of top-down models and bottom-up simulations are discussed. Furthermore, we present some future challenges, such as modeling of intra-tissue distribution, prediction of drug responses, quantitative systems pharmacology, and possibilities of artificial intelligence.

Subconjunctival injection of rapamycin-loaded polymeric microparticles for effective suppression of noninfectious uveitis in rats

Noninfective uveitis is a major cause of vision impairment, and corticosteroid medication is a mainstay clinical strategy that causes severe side effects. Rapamycin (RAPA), a potent immunomodulator, is a promising treatment for noninfective uveitis. However, because high and frequent dosages are required, it is a great challenge to implement its clinical translation for noninfective uveitis therapy owing to its serious toxicity. In the present study, we engineered an injectable microparticulate drug delivery system based on biodegradable block polymers (i.e., polycaprolactone-poly (ethylene glycol)-polycaprolactone, PCEC) for efficient ocular delivery of RAPA via a subconjunctival injection route and investigated its therapeutic efficacy in an experimental autoimmune uveitis (EAU) rat model. RAPA-PCEC microparticles were fabricated using the emulsion-evaporation method and thoroughly characterized using scanning electron microscopy, fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. The formed microparticles exhibited slow in vitro degradation over 28 days, and provided both in vitro and in vivo sustained release of RAPA over 4 weeks. Additionally, a single subconjunctival injection of PCEC microparticles resulted in high ocular tolerance. More importantly, subconjunctival injection of RAPA-PCEC microparticles significantly attenuated the clinical signs of EAU in a dose-dependent manner by reducing inflammatory cell infiltration (i.e., CD45+ cells and Th17 cells) and inhibiting microglial activation. Overall, this injectable microparticulate system may be promising vehicle for intraocular delivery of RAPA for the treatment of noninfective uveitis.

Beneficial Effect of Sirolimus-Pretreated Mesenchymal Stem Cell Implantation on Diabetic Retinopathy in Rats.

Diabetic retinopathy (DR) is a vision-threatening complication that affects virtually all diabetic patients. Various treatments have been attempted, but they have many side effects and limitations. Alternatively, stem cell therapy is being actively researched, but it faces challenges due to a low cell survival rate. In this study, stem cells were pretreated with sirolimus, which is known to promote cell differentiation and enhance the survival rate. Additionally, the subconjunctival route was employed to reduce complications following intravitreal injections. Diabetes mellitus was induced by intraperitoneal injection of 55 mg/kg of streptozotocin (STZ), and DR was confirmed at 10 weeks after DM induction through electroretinogram (ERG). The rats were divided into four groups: intact control group (INT), diabetic retinopathy group (DR), DR group with subconjunctival MSC injection (DR-MSC), and DR group with subconjunctival sirolimus-pretreated MSC injection (DR-MSC-S). The effects of transplantation were evaluated using ERG and histological examinations. The ERG results showed that the DR-MSC-S group did not significantly differ from the INT in b-wave amplitude and exhibited significantly higher values than the DR-MSC and DR groups (p < 0.01). The flicker amplitude results showed that the DR-MSC and DR-MSC-S groups had significantly higher values than the DR group (p < 0.01). Histological examination revealed that the retinal layers were thinner in the DR-induced groups compared to the INT group, with the DR-MSC-S group showing the thickest retinal layers among them. Subconjunctival injection of sirolimus-pretreated MSCs can enhance retinal function and mitigate histological changes in the STZ-induced DR rat model.

Human mesenchymal stem cells derived from adipose tissue showed a more robust effect than those from the umbilical cord in promoting corneal graft survival by suppressing lymphangiogenesis

BackgroundMesenchymal stem cells (MSCs) have shown promising potential in allograft survival. However, few reports have focused on comparing the immunosuppressive capacity of MSCs from different sources and administered via different routes in inhibiting transplant rejection. Moreover, virtually nothing is known about the role of MSCs in the regulation of graft neovascularization and lymphangiogenesis. In this study, we compared the efficacy of human adipose MSCs (hAD-MSCs) and human umbilical cord MSCs (hUC-MSCs) in vitro and in corneal transplantation models to explore the underlying molecular mechanisms and provide a powerful strategy for future clinical applications.MethodshAD-MSCs and hUC-MSCs were generated, and their self-renewal and multi-differentiation abilities were evaluated. The inhibitory effect of human MSCs (hMSCs) was examined by T-cell proliferation assays with or without transwell in vitro. Two MSCs from different sources were separately adoptively transferred in mice corneal transplantation (5 × 105 or 1 × 106/mouse) via topical subconjunctival or intravenous (IV) routes. Allograft survival was evaluated every other day, and angiogenesis and lymphomagenesis were quantitatively analyzed by immunofluorescence staining. The RNA expression profiles of hMSCs were revealed by RNA sequencing (RNA-seq) and verified by quantitative real-time PCR (qRT‒PCR), western blotting or ELISA. The function of the differentially expressed gene FAS was verified by a T-cell apoptosis assay.ResultshAD-MSCs induced stronger immunosuppression in vitro than hUC-MSCs. The inhibitory effect of hUC-MSCs but not hAD-MSCs was mediated by cell–cell contact-dependent mechanisms. Systemic administration of a lower dose of hAD-MSCs showed better performance in prolonging corneal allograft survival than hUC-MSCs, while subconjunctival administration of hMSCs was safer and further prolonged corneal allograft survival. Both types of hMSCs could inhibit corneal neovascularization, while hAD-MSCs showed greater superiority in suppressing graft lymphangiogenesis. RNA-seq analysis and confirmation experiments revealed the superior performance of hAD-MSCs in allografts based on the lower expression of vascular endothelial growth factor C (VEGF-C) and higher expression of FAS.ConclusionsThe remarkable inhibitory effects on angiogenesis/lymphangiogenesis and immunological transplantation effects support the development of hAD-MSCs as a cell therapy against corneal transplant rejection. Topical administration of hMSCs was a safer and more effective route for application than systemic administration.

Mise au point de la Société française du glaucome sur la place des nouvelles techniques chirurgicales dans le glaucome

The surgical management of glaucoma has been enriched in recent years by the arrival of new surgical techniques as a group known as MIGS (minimally invasive glaucoma surgery). The objective of these new techniques is to reduce intraocular pressure (IOP) while limiting the risk of complications of conventional filtering surgery and allowing faster visual recovery. MIGS can be classified into three main categories depending on the route used to promote the outflow of aqueous humor: the trabecular route, the suprachoroidal route and the subconjunctival route. MIGS using the subconjunctival route are also called minimally invasive bleb surgery (MIBS). These new techniques do not replace conventional filtering surgery, which remains the gold standard technique, but now offer new alternatives for the surgical management of glaucoma patients in combination with cataract surgery or as stand-alone procedures.

Local Myeloid-Derived Suppressor Cells Impair Progression of Experimental Autoimmune Uveitis by Alleviating Oxidative Stress and Inflammation.

To evaluate the immune regulatory effect of human cord blood myeloid-derived suppressor cells (MDSCs) in experimental autoimmune uveitis (EAU) models. MDSCs (1 × 106) or PBS were injected into established C57BL/6 EAU mice via the subconjunctival route on days 0 and 7. The severity of intraocular inflammation was evaluated for up to 3 weeks. Tissue injury and inflammation were analyzed using immunolabelled staining, real-time PCR, and ELISA. In addition, immune cells in draining lymph nodes (LNs) were quantified using flow cytometry. After 21 days, the clinical scores and histopathological grades of EAU were lower in the MDSCs group compared with the PBS group. Local administration of MDSCs suppressed the oxidative stress and the expression of TNF-α and IL-1β in the retinal tissues. In addition, it inhibited the activation of pathogenic T helper 1 (Th1) and Th17 cells in draining LNs. MDSCs increased the frequency of CD25+ Foxp3+ regulatory T cells and the mRNA expression of IL-10, as an immune modulator. MDSCs suppressed inflammation and oxidative stress in the retina and inhibited pathogenic T cells in the LNs in EAU. Therefore, ocular administration of MDSCs has therapeutic potential for uveitis.

Subconjunctival Delivery of Sorafenib-Tosylate-Loaded Cubosomes for Facilitated Diabetic Retinopathy Treatment: Formulation Development, Evaluation, Pharmacokinetic and Pharmacodynamic (PKPD) Studies.

Diabetic retinopathy (DR) is a microvascular complication associated with vascular endothelial growth factor (VEGF) overexpression. Therapeutic delivery to the retina is a challenging phenomenon due to ocular biological barriers. Sorafenib tosylate (ST) is a lipophilic drug with low molecular weight, making it ineffective at bypassing the blood-retinal barrier (BRB) to reach the target site. Cubosomes are potential nanocarriers for encapsulating and releasing such drugs in a sustained manner. The present research aimed to compare the effects of sorafenib-tosylate-loaded cubosome nanocarriers (ST-CUBs) and a sorafenib tosylate suspension (ST-Suspension) via subconjunctival route in an experimental DR model. In this research, ST-CUBs were prepared using the melt dispersion emulsification technique. The distribution of prepared nanoparticles into the posterior eye segments was studied with confocal microscopy. The ST-CUBs were introduced into rats' left eye via subconjunctival injection (SCJ) and compared with ST-Suspension to estimate the single-dose pharmacokinetic profile. Streptozotocin (STZ)-induced diabetic albino rats were treated with ST-CUBs and ST-Suspension through the SCJ route once a week for 28 days to measure the inhibitory effect of ST on the diabetic retina using histopathology and immunohistochemistry (IHC) examinations. Confocal microscopy and pharmacokinetic studies showed an improved concentration of ST from ST-CUBs in the retina. In the DR model, ST-CUB treatment using the SCJ route exhibited decreased expression levels of VEGF, pro-inflammatory cytokines, and adhesion molecules compared to ST-Suspension. From the noted research findings, it was concluded that the CUBs potentially enhanced the ST bioavailability. The study outcomes established that the developed nanocarriers were ideal for delivering the ST-CUBs via the SCJ route to target the retina for facilitated DR management.

Subconjunctival therapy by cubic liquid crystalline nanoparticles to deliver Triamcinolone acetonide for the management of diabetic Retinopathy: In vivo evidences

The expression of inflammatory markers and vascular endothelial growth factor (VEGF) was found to be upregulated in various posterior ocular disorders, including diabetic retinopathy (DR). Effective delivery of therapeutic agents to the retina poses a significant challenge in ophthalmic drug delivery due to biological ocular barriers. Triamcinolone acetonide (TA) was selected as the model corticosteroid drug targeting cytokines and VEGF in DR. However, despite TA’s low molecular weight and hydrophobicity, which enable it to bypass the conjunctival epithelial barrier, it doesn’t efficiently exert its effect at the target site. Nanocarriers have emerged as a solution to enhance drug delivery to the retina and improve bioavailability. This study aimed to compare the effects of Triamcinolone-loaded cubic liquid crystalline nanoparticles (TA-cubic LCNPs) and TA-Suspension in an experimental DR model administered via the subconjunctival (SCJ) route. The results demonstrated that TA-cubic LCNPs enhanced TA periocular delivery efficacy by reducing inflammatory and VEGF markers through the advanced glycation end products (AGE)/protein kinase C pathway. They were identified as promising nano-carriers, exhibiting potential for targeted delivery to the retina.

A comprehensive review of intravitreal immunosuppressants and biologicals used in ophthalmology.

Systemic immunosuppressants and biologicals have been a valuable tool in the treatment of inflammatory diseases and malignancies. The safety profile of these drugs has been debatable, especially in localized systems, such as the eye. This has led to the search for fairly local approaches, such as intravitreal, subconjunctival, and topical route of administration. Immunosuppressants have been used as a second-line drug in patients intolerable to corticosteroids or those who develop multiple recurrences on weaning corticosteroids. Similarly, biologicals have also been used as the next line of therapy, when adequate control of inflammation could not be attained or immunosuppressants were contraindicated to patients. Intravitreal immunosuppressants, such as methotrexate and sirolimus, have been extensively studied in noninfectious posterior uveitis, whereas limited studies have established the efficacy of intravitreal biologicals, such as infliximab and adalimumab. Most of these drugs have shown good safety profile and tolerability in animal studies alone and have not been studied further in human subjects. However, most of the studies in literature are single-case reports or case series which limits the level of evidence. In this comprehensive review, we discuss the mechanism of action, pharmacodynamics, pharmacokinetics, indications, efficacy, and side effects of different intravitreal immunosuppressants and biologicals that have been studied in literature.

Sirolimus loaded chitosan functionalized poly (lactic-co-glycolic acid) (PLGA) nanoparticles for potential treatment of age-related macular degeneration

The usefulness of sirolimus (SIR) in the treatment of diseases that involve retinal degeneration like age-related macular degeneration (AMD) has been well documented. However, the problem still remains probably owing to the peculiar environment of the eye and/or unfavourable physiochemical profile of SIR. In the present work, we aimed to fabricate sirolimus loaded PLGA nanoparticles (SIR-PLGA-NP) and chitosan decorated PLGA nanoparticles (SIR-CH-PLGA-NP) to be administered via non-invasive subconjunctival route. Both the nanoparticles were characterized in terms of size, zeta potential, DSC, FTIR and XRD analysis. Quality by Design (QbD) approach was employed during the preparation of nanoparticles and the presence of chitosan coating was confirmed through thermogravimetric analysis and contact angle studies. Cationic polymer modification showed sustained in-vitro SIR release and enhanced ex-vivo scleral permeation and penetration. Further, SIR-CH-PLGA-NP revealed enhanced cellular uptake and thus, reduced lipopolysaccharide (LPS)-induced free-radicals generation by RAW 264.7 cells. The prepared nanoparticles were devoid of residual solvent and were found to be safe in HET-CAM analysis, RBCs damage analysis and histopathology studies. Moreover, high anti-angiogenic potential was observed in SIR-CH-PLGA-NP compared with SIR-PLGA-NP in chorioallantoic membrane (CAM) test. Overall, the current work opens up an avenue for further investigation of CH-PLGA-NP as SIR nanocarrier in the treatment of AMD.

Subconjunctival antibiotics: an alternative to intracameral antibiotics for endophthalmitis prophylaxis in cataract surgery

Background: There has been an increase in the use of routine intracameral antibiotics for endophthalmitis prophylaxis in cataract surgery. However, this can be associated with serious adverse events. Previously, subconjunctival antibiotics were the preferred route but there is minimal literature directly comparing the two. Hence, the safest and most efficacious route of prophylactic antibiotic administration remains controversial. Purpose: To evaluate the efficacy and safety of subconjunctival with intracameral antibiotics for postoperative endophthalmitis (POE) prophylaxis in patients undergoing uncomplicated cataract surgery. Methods: A literature review was conducted in Cochrane and PubMed for studies that compared the efficacy of prophylactic subconjunctival and intracameral antibiotics for post-cataract endophthalmitis. Searches were not limited to English or study design. Results: Three observational studies showed that subconjunctival and intracameral antibiotics both reduced POE rates. Intracameral antibiotics demonstrated a high efficacy (OR = 0.25, 95% CI 0.13-0.46, p < 0.0001) but was also associated with increased potential complications. All studies were conducted in a sequential nature during which cataract surgery techniques and instrumentation have improved in recent years. Conclusion: In institutions with a high incidence of endophthalmitis, routine intracameral antibiotic use would be more appropriate. However, in facilities with lower rates of POE, the subconjunctival route of delivery can be an alternative due to its better safety profile.

Analysis of bleb morphology after CLASS with ultrasound biomicroscopy and clinical grading scale.

Filtration in the area subjected to CO2 laser-assisted sclerectomy surgery (CLASS) is described using ultrasound biomicroscopy (UBM) and the clinical grading scale to evaluate the mechanism of intraocular pressure (IOP) reduction. Twenty-eight patients with open-angle glaucoma underwent CLASS. The Indiana Bleb Appearance Grading Scale evaluation was performed 1 month after surgery to determine bleb height, extent, vascularity, and leakage. UBM was used to describe and measure the surgical area. Bleb morphology, the size of the scleral lake, scleral route, and trabeculodescemetic membrane (TDM) thickness were examined. One month after CLASS, IOP significantly decreased from 20.46 ± 3.92 mmHg to 12.71 ± 2.99 mmHg, and the anterior chamber depth significantly more shallow, from 2.75 ± 0.36 mm to 2.61 ± 0.33 mm(p < 0.05). Shallow uplift occurred in 71.43% of the blebs, and 64.29% of the blebs were within 1 to 2 h; 82.15% showed mild or moderate vascular hyperemia, and the Seidel test was negative. UBM showed that all eyes had an intact TDM, with a mean thickness of 99.3 ± 22.2 μm; 21 eyes (75%) had L-type (low reflective). The scleral lake anteroposterior length, height, and transversal length were 2.247 ± 1.831 mm, 0.520 ± 0.234 mm, and 3.312 ± 0.423 mm, respectively. The TDM thickness and postoperative IOP were positively correlated, and the size of the scleral lake was not correlated with IOP reduction. Four eyes (14.29%) exhibited cyclodialysis. UBM examination indicated the aqueous humor drainage route. In the early stage after CLASS, subconjunctival and choroidal drainage routes might be the major mechanism underlying IOP reduction. Mild and moderate congestion of bleb blood vessels warrant attention to avoid early bleb scarring.

Safety of intracameral cefuroxime in pars plana vitrectomy.

Postoperative endophthalmitis is a rare, but serious complication of pars plana vitrectomy (PPV). Subconjunctival cefuroxime injection has been the traditional choice for post vitrectomy endophthalmitis prophylaxis. Its effectiveness and safety in this context are however poorly understood and cases of retinal toxicity have been reported. The traditional standard subconjunctival antibiotic prophylaxis has been superceded in cataract surgery by intracameral antibiotic prophylaxis. The primary aim of this three centre non-randomised retrospective database cohort study of 7,532 PPV procedures was to identify the rate of endophthalmitis in cohorts of patients treated with intracameral or subconjunctival cefuroxime. A secondary aim was to estimate the achieved intraocular antibiotic concentrations of cefuroxime in eyes with intracameral versus subconjunctival administration using mathematical modelling. The overall incidence of postoperative endophthalmitis was 0.07% (5/7532). There were no cases of endophthalmitis in eyes receiving intracameral cefuroxime alone or in combination with subconjunctival cefuroxime (0/5586). Patients receiving subconjunctival cefuroxime alone had a higher incidence of endophthalmitis (0.22%, 4/1835), and there was one case of endophthalmitis in eyes not receiving any perioperative antibiotics (0.9%, 1/111). No cases of cefuroxime toxicity were identified. With subconjunctival cefuroxime, in the presence of a sclerotomy leak, we estimated the vitreous drug concentration to be higher than that for intracameral cefuroxime and potentially toxic. Intracameral cefuroxime appears to be a safe and efficient choice for prophylaxis against endophthalmitis after PPV. Small eyes with intraocular tamponade seem to be at particular risk of drug toxicity if cefuroxime is administered via the subconjunctival route.

Effects of VEGF Inhibitor Conbercept on Corneal Neovascularization Following Penetrating Keratoplasty in Rabbit Model.

PurposeTo evaluate the effects of the vascular endothelial growth factor inhibitor conbercept (KH902) on corneal neovascularization and wound healing following penetrating keratoplasty in rabbits.MethodsConbercept was administered to New Zealand white rabbits through topical and subconjunctival routes. Corneal neovascularization and wound healing were examined by slit-lamp photography and histological analyses. The expressions of vascular endothelial growth factor inhibitor, α-smooth muscle actin, and keratocan in the corneal grafts were measured by real-time quantitative polymerase chain reaction (RT-qPCR).ResultsThe anterior segment photographs demonstrated that corneal neovascularization started in the 2nd week. In the 4th week, histologically, the superficial corneal stroma layer showed disordered arrangement, and there were large numbers of dense inflammatory cells and blood vessels in the stroma layer. Vascular endothelial growth factor in the experimental groups was significantly decreased at all time points compared with the control group (both P = 0.001). Expression of α-smooth muscle actin in corneal grafts demonstrated an increase in time even it was lower in experimental groups, but the difference was not statistically significant (P equaled to 0.507 and 0.723, respectively). There were no significant differences with the expression of keratocan in all groups except that it significantly declined at the 4th week as to the second week in all groups and P values were 0.022, 0.020 and 0.014 in control (C), topical (E1), and subconjunctival (E2) group, respectively.ConclusionThe study found that conbercept inhibited the formation of corneal neovascularization without affecting keratocan-mediated corneal wound healing and there were no significant differences between topical administration of different doses of conbercept on the rabbit corneal neovascularization after penetrating keratoplasty in this study.

Sustained subconjunctival drug delivery systems: current trends and future perspectives.

One of the challenges of ocular drug delivery systems is sustainable delivery of the intended drug to the posterior segment of the eye. Periocular routes of drug delivery are a promising method to bridge this challenge. The purpose of this study is to investigate the recent advances and potentials of subconjunctival route and its pros and cons in comparison with other ocular drug delivery routes. In this literature review, the comprehensive search of publications was performed in MEDLINE/PubMed indicating investigations on subconjunctival drug delivery systems using relevant keywords. Based on the resultant detailed criteria to choose an appropriate ocular drug delivery route, it is revealed that most of these routes are either highly invasive and/or provide low bioavailability of drug to the target tissue. Nevertheless, subconjunctival drug delivery could be considered as one of the less invasive and easily accessible routes for delivering various drugs to both anterior and posterior segments of the eye. However, most of such researches are at the stage of animal study in their pipelines. Periocular route of drug delivery is one of the most efficient routes for delivering the drugs to both anterior and posterior segments of the eye. Subconjunctival sustained drug delivery is highly effective and less invasive compared to other periocular routes. This makes subconjunctival implants and injections one of the most proper ways of treating various ranges of ocular diseases and disorders, e.g., diabetic retinopathy, dry eye syndrome, glaucoma, etc.

Personalized Nano Delivery Strategy in Treating Uveitis

Uveitis is an inflammatory disease causes the damage of eye tissues and leads to the loss of vision once kept untreated. Early detection and identification of the disease are necessary for the prevention of the progressing inflammation and tissue damage. Existing treatment comprise of the administration of oral steroids, immunosuppressant, biological and adjuvant therapy. Even though topical, intravitreal and subconjunctival administration routes have been chosen for the drug administration, they fail to achieve the drug concentration to elicit a better therapeutic action due to the presence of ocular barriers such as tear, cornea conjunctiva, sclera, choroid membrane, retina, and blood-retinal barrier. Design of delivery systems that can prolong the precorneal habitation time increase the drug release as well as reduce the side effects such as methods to achieve prolonged can promise effective ocular drug delivery. Delivery systems such as hydrogels, liposomes, micro carrier systems, vitreous implants, medicated lenses, nanotechnology approaches such as nanocrystals, nanoemulsions, nanosuspensions, dendrimers, microneedles etc. exist as current research and the future research perspectives to achieve effective ocular drug delivery.

PSS63 - IDENTIFYING PATIENT PREFERENCES FOR GLAUCOMA TREATMENT: EVIDENCE FROM LITERATURE REVIEW

One of the main objectives of glaucoma treatment is to lower intraocular pressure through topical medication, laser, or more invasive procedures (surgery, or surgical implants). In addition, long-lasting drug depots may also soon be a treatment option. The aim of current review was to identify the patient preferences towards glaucoma treatment and relevant influencing factors. A comprehensive literature search was performed for studies published in English from inception through August 2017 in Embase, MEDLINE, MEDLINE-In Process, and Cochrane library. Studies reporting patient preferences for any glaucoma treatment were included. The review identified 32 studies (7 RCTs, 1 non-RCTs, 12 observational studies and 7 single-arm studies) including studies assessing treatment-switching (n=11) and factors influencing treatment preference (n=5). Patients receiving monotherapies had significantly higher treatment satisfaction compared to polytherapies (p=0.05). Topical agents (QD regimen) were more convenient compared to BID regimens (p=0.104). Among monotherapies, brimonidine was preferred over topical β-blockers (less efficacious) or dual therapies (less convenient); travoprost BAK-free over latanoprost; and bimatoprost over travoprost. Patients switching from PGA monotherapies or mono/adjunctive therapies were significantly more likely to accept fixed-dose combinations such as travoprost/timolol. Additionally, studies reported high patient willingness to accept a novel glaucoma treatment such as sustained drug delivery (via punctal plug, subconjunctival or intracameral route) and implant (p=0.011) based upon effectiveness and cost. Other factors influencing patient preference were clear center vision, outdoor mobility, travelling distance during follow-ups, and treatment-associated symptoms (vision blurring, drowsiness, or inhibition of sexual performance). No studies assessing surgical treatment options were identified. Evidence clearly indicates that glaucoma patients have preference towards more efficacious and less frequent medication regimens. In addition, patients are willing to accept novel treatment options such as surgical implants and sustained release medication depots. However, scarce evidence necessitates the need for more research focusing on patient preferences towards surgical treatment options.

The route of administration influences the therapeutic index of an anti-proNGF neutralizing mAb for experimental treatment of Diabetic Retinopathy.

Many neurodegenerative retinal diseases are treated with monoclonal antibodies (mAb) delivered by invasive intravitreal injection (IVT). In Diabetic Retinopathy there is a scarcity of effective agents that can be delivered using non-invasive methods, and there are significant challenges in the validation of novel therapeutic targets. ProNGF represents a potential novel target, and IVT administration of a function-blocking anti-proNGF mAb is therapeutic in a mouse model of DR. We therefore compared invasive IVT to less invasive systemic intravenous (IV) and local subconjunctival (SCJ) administration, for therapy of Diabetic Retinopathy. The IV and SCJ routes are safe, afford sustained pharmacokinetics and tissue penetration of anti-proNGF mAb, and result in long–term therapeutic efficacy that blocks retinal inflammation, edema, and neuronal death. SCJ may be a more convenient and less-invasive approach for ophthalmic use and may enable reduced frequency of intervention for the treatment of retinal pathologies.

Ocular tissue distribution and pharmacokinetic study of a small 13kDa domain antibody after intravitreal, subconjuctival and eye drop administration in rabbits

Domain antibodies (dAb's) comprise the smallest functional unit of human IgG and can be targeted to a range of different soluble cytokine and receptor targets in the eye. In particular their small size may offer advantage for ocular tissue penetration and distribution. To investigate this we used a 13kDa tool molecule to undertake a preliminary short term ocular tissue distribution and pharmacokinetic study in the rabbit eye. The dAb was administered by the intravitreal or subconjunctival route or, as topical eye drops for up to five days and dAb concentrations measured in vitreous, aqueous, conjunctiva, choroid-RPE, retina, iris, sclera, and ciliary body. The observed elimination half-live of the dAb (~3 days) in vitreous showed a similar elimination rate to that of a much larger (∼50kDa) Fab fragment whilst the half-life following subconjunctival administration was ∼24 h and, after eye drop dosing the dAb was detectable in aqueous and conjunctiva. These preliminary data show that the intravitreal half-life of dAb's are similar to much larger antibody fragments, offering the potential to deliver significantly more drug to target on a molar basis with a single intravitreal injection potentially enabling dosing frequencies of once a month or less. Subconjunctival injection may provide short duration therapeutic levels of dAb to the anterior and posterior chamber whilst topical eye drop delivery of dAbs may be useful in front-of-eye disease. These data indicate that small domain antibodies may have utility in ophthalmology. Further studies are warranted.

Subconjunctival Delivery of p75NTR Antagonists Reduces the Inflammatory, Vascular, and Neurodegenerative Pathologies of Diabetic Retinopathy.

The p75NTR is a novel therapeutic target validated in a streptozotocin mouse model of diabetic retinopathy. Intravitreal (IVT) injection of small molecule p75NTR antagonist THX-B was therapeutic and resolved the inflammatory, vascular, and neurodegenerative phases of the retinal pathology. To simplify clinical translation, we sought a superior drug delivery method that circumvents risks associated with IVT injections. We compared the pharmacokinetics of a single 40 μg subconjunctival (SCJ) depot to the reported effective 5 μg IVT injections of THX-B. We quantified therapeutic efficacy, with endpoints of inflammation, edema, and neuronal death. The subconjunctival depot affords retinal exposure equal to IVT injection, without resulting in detectable drug in circulation. At week 2 of diabetic retinopathy, the SCJ depot provided therapeutic efficacy similar to IVT injections, with reduced inflammation, reduced edema, reduced neuronal death, and a long-lasting protection of the retinal structure. Subconjunctival injections are a safe and effective route for retinal delivery of p75NTR antagonists. The subconjunctival route offers an advantageous, less-invasive, more compliant, and nonsystemic method to deliver p75NTR antagonists for the treatment of retinal diseases.