Nanomedicine for glaucoma: liposomes provide sustained release of latanoprost in the eye

Purpose: To report the development and therapeutic evaluation of a liposomal nanocarrier for sustained release of latanoprost, in the rabbit eye. Methods: We fabricated latanoprost-loaded egg-phosphatidylcholine (EggPC) liposomes using the film hydration technique. The delivery vehicles were nano-sized (Z avg = 109 ± 18 nm), had a narrow poly dispersity index (PDI = 0.19 ± 0.04), and a very high loading efficiency (94% ± 5%). Based on in vitro data, we evaluated this formulation for lowering intraocular pressure (IOP) in rabbit eyes. Following a single subconjunctival injection of the latanoprost loaded formulation, the eyes were clinically monitored and the IOP recorded. Results: Latanoprost-loaded EggPC liposomes demonstrated a high drug/lipid mole ratio of 0.181, remained stable for at least 6 months on storage (4°C), and at least 1 month at 25°C. A slow and sustained release of 60% of latanoprost was achieved by 14 days in the in vitro release study. The same formulation demonstrated a greater sustained IOP lowering effect compared with daily administration of topical latanoprost beyond 90 days (4.8 ± 1.5 vs 2.5 ± 0.9 mmHg; P < 0.001). No signs of inflammation were evident in the eyes from slit-lamp examination analysis. Conclusion: The loading required for a long-term sustained delivery of latanoprost for up to 90 days in the rabbit eyes was achieved with EggPC liposomes. A single injection of latanoprost-loaded EggPC liposomes can lower the IOP for up to 90 days, with a greater IOP lowering effect than daily topical administration of latanoprost.Published versio

Increased SPARC expression in primary angle closure glaucoma iris

Molecular Vision141886-189

Expression profile of inflammatory cytokines in aqueous from glaucomatous eyes

PURPOSE: To determine the proinflammatory cytokine profile of aqueous humor from glaucomatous eyes. METHODS: Aqueous humor samples were prospectively collected from 38 eyes (26 primary open angle glaucoma [POAG] and 12 primary angle closure glaucoma [PACG] eyes) of 37 medically treated glaucoma patients and 23 cataract subjects recruited in an institutional setting in this case-controlled study. The main outcome measure was to quantify the levels of 29 inflammatory cytokines in the aqueous of glaucoma and cataract subjects using a multiplexed cytokine analysis. Data on patient demographics, duration of glaucoma, preoperative intraocular pressure (IOP) as well as duration of anti-glaucoma therapy were also collected for correlation analysis. RESULTS: Mean duration of glaucoma was 53.8 months (range 1-360 months). Aqueous obtained from the glaucoma patients showed increased concentration of interleukin (IL)-9 (p=0.032), IL-12 (p=0.003), interferon (IFN)-α (p=0.034), IFN-γ (p=0.002), monokine induced by interferon-gamma (MIG or CXCL9) (p=0.006), and IL-10 (p=0.050), compared to the cataract group. The POAG group had higher IL-12 (p=0.011), IFN-γ (p=0.005), and CXCL9 (p=0.047) levels than controls, while the PACG group had higher interleukin-8 (CXCL8) (p=0.015) and CXCL9 (p=0.023) levels than the controls. No significant correlation was observed between aqueous cytokine level and preoperative IOP and duration of glaucoma. Duration of topical Timolol and Alphagan therapy correlated negatively with CXCL8 (r=-0.588, p=0.035), respectively. CONCLUSIONS: Primary glaucoma is associated with an aqueous inflammatory response and this is different between POAG and PACG groups. Duration of glaucoma treatment may have an effect on cytokine profile in the aqueous.Published versio

Study on Incentives for Glaucoma Medication Adherence (SIGMA): study protocol for a randomized controlled trial to increase glaucoma medication adherence using value pricing

BACKGROUND: Many glaucoma patients do not adhere to their medication regimens because they fail to internalize the (health) costs of non-adherence, which may not occur until years or decades later. Behavioural economic theory suggests that adherence rates can be improved by offering patients a near-term benefit. Our proposed strategy is to offer adherence-contingent rebates on medication and check-up costs. This form of value pricing (VP) ensures that rebates are granted only to those most likely to benefit. Moreover, by leveraging loss aversion, rebates are expected to generate a stronger behavioural response than equivalent financial rewards. METHODS/DESIGN: The main objective of the Study on Incentives for Glaucoma Medication Adherence (SIGMA) is to test the VP approach relative to usual care (UC) in improving medication adherence. SIGMA is a randomized, controlled, open-label, single-centre superiority trial with two parallel arms. A total of 100 non-adherent (Morisky Medication Adherence Scale ≤6) glaucoma patients from the Singapore National Eye Centre are block-randomized (blocking factor: single versus multiple medications users) into the VP and UC arms in a 1:1 ratio. The treatment received by VP patients will be strictly identical to that received by UC patients, with the only exception being that VP patients can earn either a 50 % or 25 % rebate on their glaucoma-related healthcare costs conditional on being adherent on at least 90 % or 75 % of days as measured by a medication event monitoring system. Masking the arm allocation will be precluded by the behavioural nature of the intervention but blocking size will not be disclosed to protect concealment. The primary outcome is the mean change from baseline in percentage of adherent days at month 6. A day will be counted as adherent when the patients take all their medication(s) within the appropriate dosing windows. DISCUSSION: This trial will provide evidence on whether adherence-contingent rebates can improve medication adherence among non-adherent glaucoma patients, and more generally whether this approach represents a promising strategy to cost-effectively improve chronic disease management. TRIAL REGISTRATION: NCT02271269 . Registered on 19 October 2014

Sustained Release of an Anti-Glaucoma Drug: Demonstration of Efficacy of a Liposomal Formulation in the Rabbit Eye

Topical medication remains the first line treatment of glaucoma; however, sustained ocular drug delivery via topical administration is difficult to achieve. Most drugs have poor penetration due to the multiple physiological barriers of the eye and are rapidly cleared if applied topically. Currently, daily topical administration for lowering the intra-ocular pressure (IOP), has many limitations, such as poor patient compliance and ocular allergy from repeated drug administration. Poor compliance leads to suboptimal control of IOP and disease progression with eventual blindness. The delivery of drugs in a sustained manner could provide the patient with a more attractive alternative by providing optimal therapeutic dosing, with minimal local toxicity and inconvenience. To investigate this, we incorporated latanoprost into LUVs (large unilamellar vesicles) derived from the liposome of DPPC (di-palmitoyl-phosphatidyl-choline) by the film hydration technique. Relatively high amounts of drug could be incorporated into this vesicle, and the drug resides predominantly in the bilayer. Vesicle stability monitored by size measurement and DSC (differential scanning calorimetry) analysis showed that formulations with a drug/lipid mole ratio of about 10% have good physical stability during storage and release. This formulation demonstrated sustained release of latanoprost in vitro, and then tested for efficacy in 23 rabbits. Subconjunctival injection and topical eye drop administration of the latanoprost/liposomal formulation were compared with conventional daily administration of latanoprost eye drops. The IOP lowering effect with a single subconjunctival injection was shown to be sustained for up to 50 days, and the extent of IOP lowering was comparable to daily eye drop administration. Toxicity and localized inflammation were not observed in any treatment groups. We believe that this is the first demonstration, in vivo, of sustained delivery to the anterior segment of the eye that is safe and efficacious for 50 days

Reflecting photonics: reaching new audiences through new partnerships – IYL 2015 and the Royal Horticultural Society Flower Show

The ‘Reflecting Photonics’ show garden was exhibited at the 2015 Royal Horticultural Society (RHS) Flower Show in Tatton Park, UK, to celebrate the International Year of Light and Light-based Technologies. Elks-Smith Garden Design alongside landscapers ‘Turf N’ Earth’ collaborated with researchers, marketing and outreach professionals from the University of Southampton to design, construct and exhibit a photonics-themed garden. The garden and supporting exhibition united science and art to reach new audiences – particularly family groups alongside other key influencers to the young – and showcased the world-leading research in optical fibers at the university in an accessible manner. Researchers and a publicity professional, funded by the EPSRC Centre for Innovative Manufacturing in Photonics, developed an integrated approach to the event’s public engagement and marketing. The overarching aim was to influence a positive change in the attitude of the garden visitors towards physics and photonics, with additional focus on promoting careers for women in STEM. The show garden won an RHS Gold Medal award and the coveted ‘People’s Choice Award’ for the best large garden. The project subsequently won the South East England Physics Network Public Engagement Innovation Project Award. Approximately 80,000 visitors saw the garden, with a further three million television viewers on a popular British gardening show. There were also over 75,400 Tweet impressions on social media. This paper discusses the project aims, explores the design of the garden and its relationship with the research, describes the work of the public engagement team, and outlines the impact of the event

SPARC Deficiency Results in Improved Surgical Survival in a Novel Mouse Model of Glaucoma Filtration Surgery

Glaucoma is a disease frequently associated with elevated intraocular pressure that can be alleviated by filtration surgery. However, the post-operative subconjunctival scarring response which blocks filtration efficiency is a major hurdle to the achievement of long-term surgical success. Current application of anti-proliferatives to modulate the scarring response is not ideal as these often give rise to sight-threatening complications. SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein involved in extracellular matrix (ECM) production and organization. In this study, we investigated post-operative surgical wound survival in an experimental glaucoma filtration model in SPARC-null mice. Loss of SPARC resulted in a marked (87.5%) surgical wound survival rate compared to 0% in wild-type (WT) counterparts. The larger SPARC-null wounds implied that aqueous filtration through the subconjunctival space was more efficient in comparison to WT wounds. The pronounced increase in both surgical survival and filtration efficiency was associated with a less collagenous ECM, smaller collagen fibril diameter, and a loosely-organized subconjunctival matrix in the SPARC-null wounds. In contrast, WT wounds exhibited a densely packed collagenous ECM with no evidence of filtration capacity. Immunolocalization assays confirmed the accumulation of ECM proteins in the WT but not in the SPARC-null wounds. The observations in vivo were corroborated by complementary data performed on WT and SPARC-null conjunctival fibroblasts in vitro. These findings indicate that depletion of SPARC bestows an inherent change in post-operative ECM remodeling to favor wound maintenance. The evidence presented in this report is strongly supportive for the targeting of SPARC to increase the success of glaucoma filtration surgery

Integrated Omics Reveals the Orchestrating Role of Calycosin in Danggui Buxue Tang, a Herbal Formula Containing Angelicae Sinensis Radix and Astragali Radix, in Inducing Osteoblastic Differentiation and Proliferation

Systems biology unravels the black box of signaling pathway of cells; but which has not been extensively applied to reveal the mechanistic synergy of a herbal formula. The therapeutic efficacies of a herbal formula having multi-target, multi-function and multi-pathway are the niches of traditional Chinese medicine (TCM). Here, we reported an integrated omics approach, coupled with the knockout of an active compound, to measure the regulation of cellular signaling, as to reveal the landscape in cultured rat osteoblasts having synergistic pharmacological efficacy of Danggui Buxue Tang (DBT), a Chinese herbal formula containing Angelicae Sinensis Radix and Astragali Radix. The changes in signaling pathways responsible for energy metabolism, RNA metabolism and protein metabolism showed distinct features between DBT and calycosin-depleted DBT. Here, our results show that calycosin within DBT can orchestrate the osteoblastic functions and signaling pathways of the entire herbal formula. This finding reveals the harmony of herbal medicine in pharmacological functions, as well as the design of drug/herbal medicine formulation. The integration of systems biology can provide novel and essential insights into the synergistic property of a herbal formula, which is a key in modernizing TCM