Clinical Results of Ab Interno Canaloplasty in Patients with Open-Angle Glaucoma.

PURPOSE: To report treatment outcomes of ab interno canaloplasty using the Visco360 and Omni system devices as a standalone procedure or combined with cataract surgery in patients with open-angle glaucoma (OAG). DESIGN: Retrospective, single-center, consecutive case series. STUDY PATIENTS: Eighty-nine eyes of 64 patients aged 43 to 91 with open-angle glaucoma treated with ab interno canaloplasty between January 2018 and September 2019. Eyes with previous incisional glaucoma surgery and eyes with less than 90 degrees of viscodilation were excluded. INTERVENTION: Patients underwent ab interno canaloplasty as a stand-alone procedure or in conjunction with cataract surgery. Ab interno canaloplasty was performed with either the Visco360 or Omni System devices (Sight Sciences, Menlo Park, CA). Treatment consisted of viscodilation without trabeculotomy. MAIN OUTCOME MEASURES: Primary outcome measures were mean IOP and mean number of glaucoma medications. Additional analysis included the impact of degrees of treatment on treatment outcomes. RESULTS: Preoperative mean IOP was 24.5 ± 8.3; the number of preoperative glaucoma medications was 2.5 ± 1.3. At 18 months postoperative, the mean IOP was reduced 36% to 15.8 ± 2.5 (P<0.001) and glaucoma medications were reduced 32% to 1.7 ± 1.5 (P<0.05). Higher preoperative IOP was significantly correlated with increased IOP lowering. Reduction of mean IOP and medications were not significantly different between standalone ab interno canaloplasty vs cataract surgery/ab interno canaloplasty. Reduction of mean IOP and medications were not significantly different between patients with 180 degrees of treatment vs 360 degrees of treatment. CONCLUSION: Ab interno canaloplasty reduces IOP and glaucoma medication use in patients with OAG whether as a standalone surgery or in combination with cataract surgery.

Multicenter External Validation of the Liverpool Uveal Melanoma Prognosticator Online: An OOG Collaborative Study.

Uveal melanoma (UM) is fatal in ~50% of patients as a result of disseminated disease. This study aims to externally validate the Liverpool Uveal Melanoma Prognosticator Online V3 (LUMPO3) to determine its reliability in predicting survival after treatment for choroidal melanoma when utilizing external data from other ocular oncology centers. Anonymized data of 1836 UM patients from seven international ocular oncology centers were analyzed with LUMPO3 to predict the 10-year survival for each patient in each external dataset. The analysts were masked to the patient outcomes. Model predictions were sent to an independent statistician to evaluate LUMPO3's performance using discrimination and calibration methods. LUMPO3's ability to discriminate between UM patients who died of metastatic UM and those who were still alive was fair-to-good, with C-statistics ranging from 0.64 to 0.85 at year 1. The pooled estimate for all external centers was 0.72 (95% confidence interval: 0.68 to 0.75). Agreement between observed and predicted survival probabilities was generally good given differences in case mix and survival rates between different centers. Despite the differences between the international cohorts of patients with primary UM, LUMPO3 is a valuable tool for predicting all-cause mortality in this disease when using data from external centers.

Predicting Skin Permeability by Means of Computational Approaches: Reliability and Caveats in Pharmaceutical Studies.

The skin is the main barrier between the internal body environment and the external one. The characteristics of this barrier and its properties are able to modify and affect drug delivery and chemical toxicity parameters. Therefore, it is not surprising that permeability of many different compounds has been measured through several in vitro and in vivo techniques. Moreover, many different in silico approaches have been used to identify the correlation between the structure of the permeants and their permeability, to reproduce the skin behavior, and to predict the ability of specific chemicals to permeate this barrier. A significant number of issues, like interlaboratory variability, experimental conditions, data set building rationales, and skin site of origin and hydration, still prevent us from obtaining a definitive predictive skin permeability model. This review wants to show the main advances and the principal approaches in computational methods used to predict this property, to enlighten the main issues that have arisen, and to address the challenges to develop in future research.

Sebomic identification of sex- and ethnicity-specific variations in residual skin surface components (RSSC) for bio-monitoring or forensic applications.

BACKGROUND: "Residual skin surface components" (RSSC) is the collective term used for the superficial layer of sebum, residue of sweat, small quantities of intercellular lipids and components of natural moisturising factor present on the skin surface. Potential applications of RSSC include use as a sampling matrix for identifying biomarkers of disease, environmental exposure monitoring, and forensics (retrospective identification of exposure to toxic chemicals). However, it is essential to first define the composition of "normal" RSSC. Therefore, the aim of the current study was to characterise RSSC to determine commonalities and differences in RSSC composition in relation to sex and ethnicity. METHODS: Samples of RSSC were acquired from volunteers using a previously validated method and analysed by high-pressure liquid chromatography-atmospheric pressure chemical ionisation-mass spectrometry (HPLC-APCI-MS). The resulting data underwent sebomic analysis. RESULTS: The composition and abundance of RSSC components varied according to sex and ethnicity. The normalised abundance of free fatty acids, wax esters, diglycerides and triglycerides was significantly higher in males than females. Ethnicity-specific differences were observed in free fatty acids and a diglyceride. CONCLUSIONS: The HPLC-APCI-MS method developed in this study was successfully used to analyse the normal composition of RSSC. Compositional differences in the RSSC can be attributed to sex and ethnicity and may reflect underlying factors such as diet, hormonal levels and enzyme expression.

Application of sebomics for the analysis of residual skin surface components to detect potential biomarkers of type-1 diabetes mellitus.

Metabolic imbalance in chronic diseases such as type-1 diabetes may lead to detectable perturbations in the molecular composition of residual skin surface components (RSSC). This study compared the accumulation rate and the composition of RSSC in type-1 diabetic patients with those in matched controls in order to identify potential biomarkers of the disease. Samples of RSSC were collected from the foreheads of type-1 diabetic (n = 55) and non-diabetic (n = 58) volunteers. Samples were subsequently analysed to identify individual components (sebomic analysis). There was no significant difference in the rate of accumulation of RSSC between type-1 diabetics and controls. In terms of molecular composition, 171 RSSC components were common to both groups, 27 were more common in non-diabetics and 18 were more common in type-1 diabetic patients. Statistically significant (P < 0.05) differences between diabetic and non-diabetic volunteers were observed in the recovered amounts of one diacylglyceride (m/z 594), six triacylglycerides (m/z 726-860) and six free fatty acids (m/z 271-345). These findings indicate that sebomic analysis can identify differences in the molecular composition of RSSC components between type-1 diabetic and non-diabetic individuals. Further work is required to determine the practical utility and identity of these potential biomarkers.

Effect of ethnicity, gender and age on the amount and composition of residual skin surface components derived from sebum, sweat and epidermal lipids.

BACKGROUND/PURPOSE: The superficial layer on the skin surface, known as the acid mantle, comprises a mixture of sebum, sweat, corneocyte debris and constituents of natural moisturizing factor. Thus, the phrase 'residual skin surface components' (RSSC) is an appropriate term for the mixture of substances recovered from the skin surface. There is no general agreement about the effects of ethnicity, gender and age on RSSC. The aim of this human volunteer study was to evaluate RSSC in relation to ethnicity, gender and age. A suitable acquisition medium for RSSC collection was identified and samples of RSSC were subsequently analysed using gas chromatography-mass spectrometry (GC-MS) and gravimetry. METHODS: A total of 315 volunteers participated in the study from a range of self-declared ethnic backgrounds. Six acquisition media were compared to determine the most suitable media for RSSC collection. The effect of age, gender and ethnicity on RSSC collection was evaluated by gravimetric analysis while GC-MS was used to determine the composition of RSSC. RESULTS: Of the six candidate materials assessed, cigarette paper provided the most practical and reproducible sample acquisition medium. There was no significant difference in the amount of RSSC collected when based on gender and ethnicity and no significant correlation between RSSC recovery and age. Up to 49 compounds were detected from human RSSC when analysed by GC-MS. CONCLUSIONS: The results of the present study suggest that RSSC can be effectively collected using cigarette paper and analysed by GC-MS. Ethnicity, gender and age had no significant impact on the quantity of RSSC recovered from the skin surface.

Pharmacokinetic evaluation of intranasally administered vinyl polymer-coated lorazepam microparticles in rabbits.

The intranasal (IN) administration of lorazepam is desirable in order to maximize speed of onset and minimise carry-over sedation; however, this benzodiazepine is prone to chemical hydrolysis and poor airway retention, and thus, innovative epithelial presentation is required. The aim of this study was to understand how the in situ self-assembly of a mucoretentive delivery system, formed by the dissolution of vinyl polymer-coated microparticles in the nasal mucosa, would influence lorazepam pharmacokinetics (PK). IN administration of the uncoated lorazepam powder (particle size, 6.7 ± 0.1 µm) generated a biphasic PK profile, which was indicative of sequential intranasal and oral absorption (n = 6; dose, 5 mg/kg). Coating the drug with the vinyl polymer, MP1 (9.9 ± 0.5 µm with 38.8 ± 14.0%, w/w lorazepam) and MP2 (10.7 ± 0.1 µm with 47.0 ± 1.0%, w/w lorazepam), allowed rapid systemic absorption (MP1, T (max) 14.2 ± 4.9 min; MP2, T (max) 9.3 ± 3.8 min) in rabbits and modified the PK profiles in a manner that suggested successful nasal retention. The poly(vinyl pyrrolidone)-rich MP2 system provided the best comparative bioavailability, it prolonged the early-phase nasal drug absorption and minimised drug mucociliary clearance, which correlated well with the intermolecular hydrogen-bond-driven vinyl polymer interactions observed in vitro.

Metastatic lung adenocarcinoma to the iris mimicking Cogan-Reese syndrome.

PURPOSE: Case report of metastatic lung cancer to the iris mimicking Cogan-Reese syndrome. METHODS: A 61-year-old female with a history of non-small cell lung cancer presented with unilateral elevated intraocular pressure (IOP) and multiple hyperpigmented iris nodules associated with an anterior iris membrane. The patient's IOP could not be controlled medically, so she underwent trabeculectomy with simultaneous iris biopsy. RESULTS: Histopathology revealed proliferation of glandular epithelium on the iris surface consistent with metastatic lung adenocarcinoma. CONCLUSIONS: Iris metastases have varied presentations, and one must consider metastatic disease in any patient with a history of cancer presenting with iris lesions. The formation of an iris membrane and nodules by metastatic adenocarcinoma to the iris may mimic Cogan-Reese syndrome.

Vinyl polymer-coated lorazepam particles for drug delivery to the airways.

A particle engineering method that adsorbs a microfine vinyl polymer coat to crystalline drug microparticles has been shown to be an effective way to control delivery. However, the means by which the functional performance of such microparticles is altered by the behaviour of the polymers in the microparticle coat remains unclear. The aim of this study was to determine the influence of vinyl polymer coating on the in vitro delivery characteristics of intranasal lorazepam microparticles. A series of four, similarly sized (ca. 10 µm), lorazepam-rich microparticles with different polymer coats were generated. The absorption of the polymer coats appeared to disrupt lorazepam solid state dimer formation in the microparticles, which manifested in a reduction in drug melting point. Mildly cohesive particles (aerodynamic diameter of 32 µm) that allowed rapid drug release (ca. 80% in 5 min) were generated when partially hydrolysed PVA dominated the microparticle coat, whilst fully hydrolysed PVA reduced particle cohesion and retarded drug release (ca. 15% release in 5 min). Infrared analysis showed that the properties of the microparticles were dictated by the strength of the hydrogen bonding in the polymer coat and not the strength of coat adsorption that was facilitated by hydrogen bond formation between the hydroxyl groups of the PVA and the hydroxyl group at position C3 of the lorazepam diazepine ring.

Free radical facilitated damage of ungual keratin.

Thioglycolic acid (TA) and urea hydrogen peroxide (urea H(2)O(2)) are thought to disrupt alpha-keratin disulfide links in the nail. However, optimal clinical use of these agents to improve the treatment of nail disorders is currently hindered by a lack of fundamental data to support their mechanism of action. The aim of this study was to investigate how the redox environment of ungual keratin, when manipulated by TA and urea H(2)O(2), influenced the properties of the nail barrier. Potentiometric and voltammetric measurements demonstrated that urea H(2)O(2) obeyed the Nernst equation for a proton coupled one-electron transfer redox process while TA underwent a series of redox reactions that was complicated by electrode adsorption and dimer formation. The functional studies demonstrated that nail permeability, measured through TBF penetration (38.51+/-10.94 microg/cm(2)/h) and nail swelling (244.10+/-14.99% weight increase), was greatest when relatively low concentrations of the thiolate ion were present in the applied solution. Limiting the thiolate ion to low levels in the solution retards thiolate dimerisation and generates thiyl free radicals. It appeared that this free radical generation was fundamental in facilitating the redox-mediated keratin disruption of the ungual membrane.

Transdermal drug delivery systems: skin perturbation devices.

Human skin serves a protective function by imposing physicochemical limitations to the type of permeant that can traverse the barrier. For a drug to be delivered passively via the skin it needs to have a suitable lipophilicity and a molecular weight < 500 Da. The number of commercially available products based on transdermal or dermal delivery has been limited by these requirements. In recent years various passive and active strategies have emerged to optimize delivery. The passive approach entails the optimization of formulation or drug carrying vehicle to increase skin permeability. However, passive methods do not greatly improve the permeation of drugs with molecular weights >500 Da. In contrast, active methods, normally involving physical or mechanical methods of enhancing delivery, have been shown to be generally superior. The delivery of drugs of differing lipophilicity and molecular weight, including proteins, peptides and oligonucletides, has been shown to be improved by active methods such as iontophoresis, electroporation, mechanical perturbation and other energy-related techniques such as ultrasound and needleless injection. This chapter details one practical example of an active skin abrasion device to demonstrate the success of such active methods. The in vitro permeation of acyclovir through human epidermal membrane using a rotating brush abrasion device was compared with acyclovir delivery using iontophoresis. It was found that application of brush treatment for 10 s at a pressure of 300 N m(-2) was comparable to 10 min of iontophoresis. The observed enhancement of permeability observed using the rotating brush was a result of disruption of the cells of the stratum corneum, causing a reduction of the barrier function of the skin. However, for these novel delivery methods to succeed and compete with those already on the market, the prime issues that require consideration include device design and safety, efficacy, ease of handling, and cost-effectiveness. This chapter provides a detailed review of the next generation of active delivery technologies.

Metabolism of butoxyethanol in excised human skin in vitro.

Glycol ethers are widely used in industrial and household applications because their chemical and physical properties make them versatile solvents, miscible with both water and organic media. Due to the ease with which the glycol ethers are absorbed through the skin and the potential for development of adverse health effects it is important to understand the extent to which local metabolism can contribute to local and systemic toxicity. Sections of previously frozen, full thickness excised human skin samples were placed on transwell supports and placed with the underside of the skin in contact with receptor fluid. The skin surface was dosed with 115.2 mg of neat butoxyethanol and the absorption and metabolism of butoxyethanol to butoxyacetic acid monitored over time. In total 64.94+/-0.04 mg of butoxyethanol or its metabolites were removed from the surface of the skin at 24h, representing the equivalent of 56% of the applied dose, the equivalent of 17.5% of the applied dose was recovered from the receiver fluid, 3% from within the skin and the remaining 23.5% of the dose was lost to the atmosphere through evaporation. After 24h a total of 31.5 microg of butoxyacetic acid had been produced representing approximately 0.03% of the applied dose. Therefore approximately 0.16% (31.5 microg as a percentage of the total amount of butoxyethanol reaching the receiver fluid (20.17 mg) of the absorbed butoxyethanol was metabolised to butoxyacetic acid during its passage through the skin. This suggested that, although enzyme activities capable of converting butoxyethanol to butoxyacetic acid are present in skin, metabolic conversion during percutaneous absorption was small and systemic exposure to the parent compound rather than the metabolite would occur following dermal exposure to butoxyethanol. This experiment demonstrates that it is possible to maintain metabolic activity in skin samples in an in vitro setup for short, but experimentally useful, periods.

The influence of water mixtures on the dermal absorption of glycol ethers.

Glycol ethers are solvents widely used alone and as mixtures in industrial and household products. Some glycol ethers have been shown to have a range of toxic effects in humans following absorption and metabolism to their aldehyde and acid metabolites. This study assessed the influence of water mixtures on the dermal absorption of butoxyethanol and ethoxyethanol in vitro through human skin. Butoxyethanol penetrated human skin up to sixfold more rapidly from aqueous solution (50%, 450 mg/ml) than from the neat solvent. Similarly penetration of ethoxyethanol was increased threefold in the presence of water (50%, 697 mg/ml). There was a corresponding increase in apparent permeability coefficient as the glycol ether concentration in water decreased. The maximum penetration rate of water also increased in the presence of both glycol ethers. Absorption through a synthetic membrane obeyed Fick's Law and absorption through rat skin showed a similar profile to human skin but with a lesser effect. The mechanisms for this phenomenon involves disruption of the stratum corneum lipid bilayer by desiccation by neat glycol ether micelles, hydration with water mixtures and the physicochemical properties of the glycol ether-water mixtures. Full elucidation of the profile of absorption of glycol ethers from mixtures is required for risk assessment of dermal exposure. This work supports the view that risk assessments for dermal contact scenarios should ideally be based on absorption data obtained for the relevant formulation or mixture and exposure scenario and that absorption derived from permeability coefficients may be inappropriate for water-miscible solvents.