No abstract

Thirty-six albino rabbits, randomly divided into six groups, were used to study their ocular tolerance to (a) 0.25 and 0.50% Timoptol^® preserved with 0.01% benzalkonium chloride, (b) 0.25 and 0.50% Timoptol-LP^®, a gel-forming solution preserved with 0.012% benzododecinium bromide, and (c) 0.25 and 0.50% Timabak^® unpreserved in the ABAK^® eyedrops dispenser. All eyedrops were applied in the right eye for 60 days. A clinical follow-up with slitlamp examination and break-up time evaluation was performed for 2 months. At the end of the experimentation, the animals were sacrificed and their eyes enucleated for histological analyses of the conjunctiva and cornea. There was no significant difference in the clinical examination between each group, except for the break-up time evaluation between Timoptol and Timabak at each concentration which was better with the unpreserved timolol. Histological results showed a significant difference in the corneal stroma edema between preserved and unpreserved timolol. This study confirms that using unpreserved timolol may be beneficial for the long-term treatment of glaucomatous patients as it increases tear film stability and decreases epithelial permeability and stromal aggression of the cornea.

The accumulation of N-retinylidene-N-retinylethanolamine (A2E, a toxic by-product of the visual pigment cycle) in the retinal pigment epithelium (RPE) is a major cause of visual impairment in the elderly. Photooxidation of A2E results in retinal pigment epithelium degeneration followed by that of associated photoreceptors. Present treatments rely on nutrient supplementation with antioxidants. 9’-cis-Norbixin (a natural diapocarotenoid, 97% purity) was prepared from Bixa orellana seeds. It was first evaluated in primary cultures of porcine retinal pigment epithelium cells challenged with A2E and illuminated with blue light, and it provided an improved photo-protection as compared with lutein or zeaxanthin. In Abca4-/- Rdh8-/- mice (a model of dry AMD), intravitreally-injected norbixin maintained the electroretinogram and protected photoreceptors against light damage. In a standard rat blue-light model of photodamage, norbixin was at least equally as active as phenyl-N-tert-butylnitrone, a free radical spin-trap. Chronic experiments performed with Abca4-/- Rdh8-/- mice treated orally for 3 months with norbixin showed a reduced A2E accumulation in the retina. Norbixin appears promising for developing an oral treatment of macular degeneration. A drug candidate (BIO201) with 9’-cis-norbixin as the active principle ingredient is under development, and its potential will be assessed in a forthcoming clinical trial.

We recently demonstrated that the 118 -135 putative transmembrane domain of prion protein (PrP) exhibited membrane fusogenic properties and induced apoptotic neuronal cell death of rat cortical neurons, independently of its aggregation state. The aim of the present study was to analyze the in vivo neurotoxicity of the prion fragment P118 -135 and to evaluate the potential role of the physiological isoform of PrP in the P118 -135-induced cell death. Here, we demonstrate that the nonfibrillar P118 -135 is cytotoxic to retinal neurons in vivo as monitored by intravitreal inoculation and recording of the electrical activity of retina and tissue examination. Moreover, knock-out PrP gene mice exhibit similar sensitivity to the nonfibrillar P118 -135-induced cell death and electrical perturbations, strongly suggesting that cell death occurs independently of PrP expression. Interestingly, a variant nonfusogenic P118 -135 peptide (termed P118 -135) had no effects on in vivo neuronal viability, suggesting that the P118 -135-induced cell death is mediated by its membrane destabilizing properties. These data have further been confirmed in vitro. We show that the fusogenic peptide P118 -135 induces death of cultured neurons from both wild-type and knock-out PrP gene mice via an apoptotic-mediated pathway, involving early caspase activation and DNA fragmentation. Altogether these results emphasize the neurotoxicity of the fusogenic nonfibrillar PrP transmembrane domain and indicate that fibril formation and PrP expression are not obligatory requirements for neuronal cell death. The use of synthetic prion peptides could provide insights into the understanding of neuronal loss mechanisms that take place during the development of the various types of spongiform encephalopathies.

In a prospective, randomised, double-masked, parallel-group, multi-centre study, 210 patients with primary open angle glaucoma or ocular hypertension were enrolled of whom 167 (timolol 0.1% gel 82, timolol 0.5% 85) completed the study as per protocol. The change in intraocular pressure between baseline and week 12 in the worse eye (‘at trough’) was 6.3 (SD 3.3) mm Hg on timolol 0.1% gel and 7.0 (2.9) mm Hg on timolol 0.5%; this difference was not statistically significant (p = 0.19). The difference between the two study groups in the change of intraocular pressure from baseline was 0.62 mm Hg; the 90% CI of –0.09 to +1.33 mm Hg was within the pre-specified limits of –1.5 to +1.5 mm Hg demonstrating equivalence between timolol 0.1% gel and timolol 0.5%. The plasma levels of timolol (ng/ml) at 12 weeks in the timolol 0.1% gel group were significantly less than that with timolol 0.5% both before instillation (mean 0.057, SD 0.131 and mean 0.470, SD 0.519 respectively, p = 0.025) and after instillation (mean 0.552, SD 0.992 and mean 2.473, SD 1.780 respectively, p = 0.008). Both treatments were well tolerated with no statistically significant difference between the groups in the occurrence of ocular or systemic adverse events.

Purpose: Artificial tears (ATs) are used routinely to alleviate the symptoms of mild to moderate dry eye. Preservative-free cationic emulsions (eg, Cationorm®) are an innovative approach for the management of signs and symptoms of dry eye. The aim of the present exploratory experiment was to evaluate the efficacy of this cetalkonium chloride (CKC)-containing cationic emulsion on debrided cornea and to characterize its effects on scraping-induced inflammation.Methods: Four ATs were assessed in a rat model of corneal scraping. The upper part of the corneal epithelium was scraped before a 5-day treatment, followed by clinical evaluations and fluorescein staining to evaluate cornea recovery. The anti-inflammatory efficacy of the ATs was assessed in vivo and in vitro.Results: In vivo confocal microscopy (IVCM) revealed a trend toward better corneal clinical signs (lower IVCM scores) for the animals treated with the unpreserved ATs. Benzalkonium chloride treatment decreased goblet cell count by 37.5%. While the soft-preserved Systane Balance® and Optive® and the preservative-free Vismed® had no effect on the goblet cell count, Cationorm increased this count by almost 40%. Interestingly, inflammatory cell infiltration in the stroma was at its lowest following treatment with the preservative-free Cationorm. Cationorm is also the only AT decreasing IL6- and IL8-stimulated secretion by 59% and 74%, respectively.Conclusion: By restoring an adequately hydrated ocular surface environment, the different ATs promote corneal epithelium healing. These data position Cationorm as a promising AT for the management of signs and symptoms of dry eye in patients with mild to moderate dry eye disease presenting chronic subclinical levels of ocular inflammation.

Once daily instillation of T1225 1.0% and 1.5% was shown to reach an AUIC markedly above the required threshold for an antibacterial activity against Gram-positive bacteria (25-35). These results suggest that a BID instillation is more likely to ensure antimicrobial activity against Gram-negative bacteria (threshold >100).

Both dosage regimens resulted in adequate and long-lasting azithromycin levels in the conjunctiva, the ocular target tissue relative to the expected therapeutic indication in man (bacterial conjunctivitis), and also in the cornea and tears.