Faik Orucov

Charged nanoparticles delivery to the eye using hydrogel iontophoresis.

Ocular iontophoresis has been investigated for many years as a non-invasive technique for enhancing ionized drug penetration through ocular tissues. In this study we assessed the penetration of charged fluorescent nanoparticles into rabbit eyes using hydrogel iontophoresis. Particle distribution into ocular tissues and penetration efficiency of negative nanoparticles compared with positive nanoparticles was also evaluated. Cathodal and anodal iontophoretic administrations were performed using polyacrylic hydrogels loaded with charged nanoparticle suspension (20-45 nm), applying a current intensity of 1.5 mA for 5 min onto the cornea and sclera. At pre-set time points post treatment, eyes were dissected and tissues were evaluated for fluorescence intensity. Strong fluorescence evidence was observed at anterior and posterior ocular tissues. Negative particle distribution profile revealed fast uptake into the outer ocular tissues, within 30 min post treatment, followed by particle migration into the inner tissues up to 12 h post treatment. The positively charged particles demonstrated better penetration abilities into inner ocular tissues compared to the negatively charge particles. This work provides an opening for the development of a new ocular therapeutic pathway using iontophoresis of extended release drug-loaded charged nanoparticles.

Topical and intravitreous administration of cationic nanoemulsions to deliver antisense oligonucleotides directed towards VEGF KDR receptors to the eye

Antisense oligonucleotides (ODNs) specific for VEGFR-2-(17 MER) and inhibiting HUVEC proliferation in-vitro were screened. One efficient sequence was selected and incorporated in different types of nanoemulsions the potential toxicity of which was evaluated on HUVEC and ARPE19 cells. Our results showed that below 10 microl/ml, a 2.5% mid-chain triglycerides cationic DOTAP nanoemulsion was non-toxic on HUVEC and retinal cells. This formulation was therefore chosen for further experiments. In-vitro transfection of FITC ODNs in ARPE cells using DOTAP nanoemulsions showed that nanodroplets do penetrate into the cells. Furthermore, ODNs are released from the nanoemulsion after 48 h and accumulate into the cell nuclei. In both ex-vivo and in-vivo ODN stability experiments in rabbit vitreous, it was noted that the nanoemulsion protected at least partially the ODN from degradation over 72 h. The kinetic results of fluorescent ODN (Hex) distribution in DOTAP nanoemulsion following intravitreal injection in the rat showed that the nanoemulsion penetrates all retinal cells. Pharmacokinetic and ocular tissue distribution of radioactive ODN following intravitreal injection in rabbits showed that the DOTAP nanoemulsion apparently enhanced the intraretinal penetration of the ODNs up to the inner nuclear layer (INL) and might yield potential therapeutic levels of ODN in the retina over 72 h post injection.

Methylprednisolone delivery to the back of the eye using hydrogel iontophoresis.

AIM The aim of this study was to evaluate methylprednisolone penetration into ocular structures after low-current trans-scleral hydrogel iontophoresis, as compared with the common intravenous (i.v.) treatment. METHODS Methylprednisolone hemisuccinate (MPH) iontophoresis was studied in rabbits, using drug-loaded hydrogels mounted on a portable iontophoretic device. Cathodal iontophoresis of 2.6 mA/cm(2) was applied for 5 min at two opposite sites on the sclera or for 10 min at the same site. Ocular drug levels were determined 2 h after iontophoretic treatment, then compared to mock iontophoresis and i.v. infusion of 10 mg/kg methylprednisolone. RESULTS Significantly higher methylprednisolone levels were found in ocular tissues after iontophoresis, compared with the control groups, except for the sclera concentrations, which were similar to the concentrations achieved after mock iontophoresis. Two (2) h after the trans-scleral iontophoretic treatment, 178.59 +/- 21.63 microg/g, 6.74 +/- 2.38 microg/ml, and 2.71 +/- 0.57 microg/mL were found in the retina, aqueous humor, and vitreous, respectively. No significant differences were found between one or two site treatments of trans-scleral iontophoresis. Nondetectable concentrations were found 2 h after the i.v. infusion of 10 mg/kg of methylprednisolone in all evaluated ocular tissues and fluids. CONCLUSIONS A short, low-current noninvasive iontophoretic treatment, using methylprednisolone-loaded hydrogels, has potential clinical value in treating ocular inflammatory diseases.

METHOTREXATE DELIVERY TO THE EYE USING TRANSSCLERAL HYDROGEL IONTOPHORESIS

Purpose: To evaluate methotrexate penetration and distribution profile in ocular structures after short low current transscleral hydrogel iontophoresis. Methods: Methotrexate iontophoresis was studied in rabbits using drug–loaded hydrogels mounted on a portable iontophoretic device. Drug distribution profile was evaluated 2, 4, and 8 hours after iontophoretic treatment of 1.6 mA/cm2 for 4 min. Ocular drug levels were also determined two hours after iontophoretic treatment of 5 mA/cm2, compared to mock iontophoresis and intravitreal injection of methotrexate. Results: Therapeutic drug levels were maintained for at least 8 h at the sclera and retina and for 2 h at the aqueous humor following the iontophoretic treatment. After increasing the current density, a twice–higher concentration was achieved at the vitreous and 8 to 20 time higher concentrations at the retina and sclera.Conclusions: A short low current non–invasive iontophoretic treatment using methotrexate–loaded hydrogels has a potential clinical value in treating ocular inflammatory diseases and intraocular lymphoma.

In Vitro and In Vivo Evaluation of Carboplatin Delivery to the Eye Using Hydrogel-Iontophoresis

Purpose: To investigate in vitro and in vivo hydrogel-iontophoresis delivery of carboplatin to the eye. Methods: Iontophoresis was applied on agar gels resembling the eye using different current intensities and durations. Transscleral iontophoresis was performed on healthy rabbits, applying 0, 1, and 3 mA current for 10 min. Results: Similar drug concentrations were obtained in all experimental groups, in in vitro and in vivo studies, regardless of the iontophoretic current applied. A 20-mm penetration depth was found for carboplatin at the agar model. High drug levels were found at the sclera and retina, while lower levels were found at ocular fluids. Conclusion: Carboplatin-iontophoretic application at the above conditions does not have an obvious advantage over passive penetration due to high diffusion properties and insufficient molecular charge. Passive carboplatin diffusion from loaded hydrogels inserted in the lower cul-de-sac should be further investigated as a potential clinical treatment for intraocular retinoblastoma.

Quantitative assessment of bandage soft contact lens wear immediately after LASIK.

PURPOSE To evaluate the efficacy and tolerability of overnight bandage soft contact lenses applied immediately after LASIK. METHODS Bandage soft contact lenses were applied immediately following bilateral simultaneous LASIK in 161 consecutive patients. Signs and symptoms associated with contact lens wear were prospectively recorded at 1 hour, 4 hours, and the following morning, using a standardized questionnaire. Contact lenses were removed at 1 hour if patients were symptomatic of intolerance. If no signs of contact lens intolerance appeared at 1 hour, the lenses were removed the following morning. No contact lenses were applied in 61 patients after LASIK. RESULTS One hour after the procedure, contact lenses were removed from 47 patients due to intolerance. In these patients, contact lens removal was associated with a significant decrease of the total score the next morning (0.31±0.55) compared to 1 hour (5.65±1.60, P<.0001). A similar decrease of the total score was noted in those patients who tolerated the contact lenses (0.20±0.52 vs 1.30±1.78) and those in whom the contact lenses were not applied (0.76±1.19 vs 3.24±1.93). Mucoid discharge at the lid margins was noted in 52.6% of patients and mild corneal edema was noted in 28.8% of patients with bandage soft contact lenses at 12 to 18 hours. CONCLUSIONS Bandage soft contact lens application after LASIK is associated with significant reduction of symptoms during the immediate postoperative period. However, removal of these lenses may be necessary shortly after the procedure.

Early Transient Visual Acuity Loss After LASIK Due to Steroid-induced Elevation of Intraocular Pressure

PURPOSE To report the clinical course of early transient reduction of uncorrected visual acuity (UCVA) after LASIK surgery resulting from steroid-induced elevation of intraocular pressure (IOP). METHODS Twenty-nine eyes of 15 patients who received topical corticosteroids after uneventful myopic LASIK surgery and had a decrease in UCVA within the first 3 weeks were evaluated retrospectively. RESULTS Intraocular pressure increased by 4 to 30 mmHg from preoperative to postoperative days 4 to 20. Twenty-seven of 29 eyes had a decrease in UCVA and/or best spectacle-corrected visual acuity (BSCVA). All eyes, except one, had edema without evidence of inflammation in the interface or the remainder of the cornea. Discontinuation of topical corticosteroids and application of anti-glaucoma medications resulted in a decrease of IOP to normal levels, reduction or disappearance of the edema, and recovery of BSCVA. CONCLUSIONS Early onset steroid-induced elevation of IOP after LASIK may cause corneal edema and a sudden decrease in UCVA. Rapid diagnosis and treatment can control IOP and recover the visual loss.

Prevalence of clinical asymptomatic retinal detachment in myopic population

Aim: To evaluate the prevalence of clinical asymptomatic retinal detachment (ARD) in myopic population. Methods: A retrospective study including all myopic individuals who underwent ophthalmic evaluation prior to excimer laser procedures at the Hadassah Center for Refractive Surgery between March 2002 and March 2006. Medical records were reviewed to extract demographics and refraction, and to identify patients who were diagnosed as having asymptomatic retinal detachment. Results: Data were collected on 6547 myopic individuals (12 815 eyes); of these, 2907 (44.4%) were males, and 3640 (55.6%) were females. The mean age was 31.5 (SD 10) years (range 18–64 years). The mean preoperative spheric equivalence was −4.42 (2.07) (range −0.75 to −16.00). The mean best spectacle-corrected visual acuity was 20/20 (range 20/32 to 20/12.5). Five eyes (0.039% or one of approximately 2563 eyes) of four patients had clinical ARD which was diagnosed during the routine preoperative examination. Three eyes underwent successful scleral buckling procedure while two patients were lost to follow-up. Conclusions: Clinical asymptomatic retinal detachment is uncommon, accounting for a minority of retinal detachments in myopes, and may be diagnosed during routine ophthalmoscopy prior to a refractive procedure.