Purpose: To study the influence of molecular shape, conformability, net surface charge and tissue interaction on transscleral diffusion.Methods: Unfixed, porcine sclera was clamped in an Ussing chamber. Fluorophore labelled, neutral, albumin, dextran, or ficoll were placed in one hemi-chamber and the rate of transscleral diffusion was measured over 24 hours using a spectrophotometer. Experiments were repeated using dextrans and ficoll with positive, or negative, net surface charges.Fluorescence recovery after photobleaching (FRAP) was undertaken to compare transscleral diffusion with diffusion through a solution.All molecules were 70 kDa.Results: Using FRAP, mean ± SD diffusion coefficient (D) was highest for albumin, followed by ficoll, then dextran (p = 0.0005). Positive dextrans diffused fastest, followed by negative, then neutral dextrans (p = 0.0005). Neutral ficoll diffused the fastest, followed by positive then negative ficoll (p = 0.0008). For the neutral molecules, transscleral D was highest for albumin, followed by dextran, then ficoll (p < 0.0001). D was highest for negative ficoll, followed by neutral, then positive ficoll (p < 0.0001). By contrast, D was highest for positive dextran, followed by neutral, then negative dextran (p = 0.0021).Conclusions: Diffusion in free solution does not predict transscleral diffusion and the molecular-tissue interaction is important. Molecular size, shape, and charge may all markedly influence transscleral diffusion, as may conformability to a lesser degree, but all need to be considered when selecting or designing drugs for transscleral delivery.Drugs directed against vascular endothelial growth factor (VEGF) have proven efficacy in some of the most common retinal diseases. The ANCHOR and MARINA studies demonstrated efficacy in wet age-related macular degeneration (AMD), 1,2 and studies such as CRUISE, BRAVO 3,4 and several from the DRCnet Group have shown favourable results in retinal vein occlusion and diabetic macular oedema. Whilst the data in these studies have led to improved clinical care, the need for regular intravitreal injections represents a burdensome regimen of treatment. A less invasive mode of delivery would have potential advantages in terms of reduced cost, discomfort, and complication rate.Systemic administration is impeded by the blood-aqueous and blood-retinal-barriers. High drug concentrations may be required to overcome these barriers to diffusion, with the attendant risk of systemic side effects. 5 A topical route would have obvious advantages. Delivery to the retina is however difficult for several reasons, such as lacrimation, low corneal permeability to large molecules, counter directional intraocular convection, and importantly the long diffusional distance. 53 Blood flow in the conjunctiva, episclera and choroid can also reduce drug concentration. 33,50 Notwithstanding these potential difficulties, transscleral delivery has a number of potential advantages. 6,7,8,9 The sclera has a large and accessible surface area, and a high d...

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Rapamycin, like many other ophthalmological agents, has several therapeutic effects, yet its hydrophobic properties render it unsuitable for noninvasive topical administration. This experiment by Elsaid et al. 1 was constructed to find a suitable way to deliver this drug to the eye that is safe, rapid, effective, and inexpensive.Rapamycin, a lipophilic macrocyclic triene antibiotic formerly used to treat Candida albicans, was also found to have immunosuppressive, cytostatic, and antiangiogenic properties. Although its use is appealing in multiple eye diseases as an antiinflammatory and antiangiogenic agent, its hydrophilic properties resulted in its administration only via invasive routes.As a trial to enhance drug absorption and bioavailability via the topical route, rapamycin was loaded on micelles. These are nanocarriers composed of O-octanoyl-chitosan, which was prepared as described by Huang et al., 2 grafted to octanoyl and polyethylene glycol (PEG) molecules.The experiment was carried out on porcine eyes, in which the sclera is dissected, cut, and then clamped into Ussing chambers. The diffusion and permeability coefficients were obtained routinely through use of precalibrated linear regression graphs.The authors carried out various physicochemical tests to evaluate the properties of the micelles, both loaded and unloaded with rapamycin. A remarkable decline in the crystallinity of rapamycin was recorded via thermal analysis. This may be owing to the formation of intermolecular interactions between rapamycin and the core of the micelles. Chitosan was selected to promote scleral drug retention and permeation, and the PEG component also showed stability-enhancing effects. The critical micelle concentration (CMC) was found to be 16.6 lM at room temperature. This value was up to 1700-fold higher than that for the rapamycin-containing polymeric micelles of Lu et al. 3 This may be attributed to the positive charge of the chitosan component.The authors pioneered in using rapamycin-loaded micelles that were as small as 50 nm. This size seems to be ideal, as the particles are small enough to permeate across the sclera but large enough to enhance bioavailability. Moreover, this optimum size reduces immune-mediated attack, a factor further reduced by particle PEGylation. 4,5The aim of the work was to solubilize the drug, prolonging its ocular residence time and also enhancing its permeation. I believe that the aim was met through preparation of these OChiPEG micelles, which proved to have high drug entrapment efficiency and scleral retention properties.I suggest that several experiments like this using different carrier micelles be carried out so that we can discover various vehicles to safely and efficiently deliver essential therapeutic agents that still need an appropriate mode of delivery rather than unwanted hazardous intravitreal injection. 7719-7726. 3. Lu W, Li F, Mahato RI. Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonyl-propylene carbonate) micelles for rapamycin delivery: in vitro characteriz...

Background Hepatitis C virus (HCV) infection is a common cause of chronic hepatitis, which leads to cirrhosis of the liver and hepatocellular carcinoma. Chronic hepatitis can cause iron buildup in the liver and result in liver injury. The major iron metabolism regulator, the hepatic hormone hepcidin, inhibits iron absorption and recycling, and as hepcidin is suppressed by the virus, it contributes to the pathogenesis of the liver. Aim To assess serum iron markers in patients with chronic hepatitis C (CHC) as opposed to people who are healthy and a summary of interactions of HCV and iron overload. Patients and methods This case–control study was performed on 30 hepatitis C-infected Egyptian patients (group I) and 15 apparently healthy control (group II). Routine laboratory investigations, as well as serum hepcidin and iron marker assessments were performed. Results Throughout this study, the serum hepcidin level in patients significantly decreased relative to the control group (P<0.001). The patients showed significantly higher serum iron, transferrin saturation, alanine aminotransferase, and aspartate aminotransferase compared with the control group (P<0.001). Serum albumin in patients’ group was considerably decreased in comparison with the control (P<0.05). There was a highly statistically significant lower platelet count value in patients compared with the control group (P<0.001). The interaction between hepcidin and iron, transferrin, and alanine aminotransferase is significantly negative. Conclusion Hepatic iron deposition is a joint feature in patients with CHC. Chronic HCV infection may reduce serum hepcidin, which may lead to iron overload in these patients. So hepcidin is a surrogate marker for evaluation of iron overload in patients with CHC.