Nobuhito Tabuchi

Efficacy of retinol palmitate eye drops for dry eye in rabbits with lacrimal gland resection.

Purpose We examined the efficacy of retinol palmitate (VApal) for dry eyes using dry eye model rabbits whose lacrimal glands were resected. Materials and methods After alkaline injury on keratoconjunctival epithelium, VApal eye drops were administered 6 times a day for 7 days. The efficacy of VApal was also compared with that of 0.1% hyaluronic acid eye drops. Results The fluorescein staining and rose bengal scores showed a significant decrease compared with the score in the vehicle group at 7 days (P < 0.05) in the 1000 IU/mL VApal group and at both 3 days (P < 0.05) and 7 days (P < 0.01) in the 1500 IU/mL VApal group. Histological examination revealed recovery of the corneal epithelium, and PAS staining disclosed the recovery of mucin-producing lower palpebral conjunctival goblet cells after 7 days in the 1500 IU/mL VApal group compared with the vehicle group. Results from impression cytology showed a significant increase in density of conjunctival goblet cells compared with that in the vehicle group after 7 days in the 1000 IU/mL VApal group and after 3 and 7 days in the 1500 IU/mL VApal group. There were no significant changes in tear flow in either group. Topical application of VApal at 1500 IU/mL showed greater improvement than 0.1% hyaluronic acid in both fluorescein and rose bengal score and in the density of conjunctival goblet cells. Conclusion It is suggested that VApal is effective for the improvement of keratoconjunctival epithelial damage associated with tear abnormalities, such as dry eyes.

Efficacy and safety of retinol palmitate ophthalmic solution in the treatment of dry eye: a Japanese Phase II clinical trial

Purpose The purpose of this study was to investigate the efficacy and safety of the administration of retinol palmitate (VApal) ophthalmic solution (500 IU/mL) for the treatment of patients with dry eye. Patients and methods This study included 66 patients with dry eye. After a 2-week washout period, patients were randomized (1:1) into either a VApal ophthalmic solution or a placebo group, and a single drop of either solution was administered six times daily for 4 weeks. Efficacy measures were 12 subjective symptoms, rose bengal (RB) and fluorescein staining scores, tear film breakup time, and tear secretion. Safety measures included clinical blood and urine analyses and adverse event recordings. Results In comparisons of the two groups, the mean change in RB staining score from baseline was significantly lower in the VApal group at 2 and 4 weeks (P<0.05 and P<0.01, respectively). Furthermore, the fluorescein clearance rate (fluorescein staining score) was significantly higher in the VApal group at 4 weeks (P<0.05). The VApal group showed a significant improvement in blurred vision at 1 and 2 weeks (P<0.01 and P<0.05, respectively), and the mean change in the total score for subjective symptoms from baseline was significantly lower in the VApal group at 1 week (P<0.05). In before- and after-intervention comparisons, the fluorescein and RB staining scores showed improvement in both groups. Improvement was noted for 11 subjective symptoms in the VApal group and for seven symptoms in the placebo group. No significant differences in adverse events and reactions were found between the groups. Conclusion VApal ophthalmic solution (500 IU/mL) is safe and effective for the treatment of patients with dry eye.

Membrane permeation of giant unilamellar vesicles and corneal epithelial cells with lipophilic vitamin nanoemulsions

Nanoemulsions of a lipophilic vitamin, retinol palmitate (vitamin A; VA), have a therapeutic effect on corneal damage. The nanoemulsion based on a triblock-type polymer surfactant with polyoxyethylene and polypropylene, EO100PO70EO100 (EOPO) showed superior efficacy, as compared with a nanoemulsion based on polyoxyethylene (60) hydrogenated castor oil (HCO). We studied the mechanism of VA nanoemulsions related to efficacy from the viewpoint of the interaction with plasma membrane-mimicking giant unilamellar vesicles (GUVs) and the plasma membrane permeation in corneal epithelial cells. When nanoemulsions and GUVs doped with fluorescent compounds were mixed each other, and observed by confocal laser microscopy, EOPO nanoemulsions induced endocytic morphological changes like strings and vesicles of the bilayer drawn inside a GUV by budding. Judging by isothermal titration calorimetry and ζ potential measurements, the EOPO nanoemulsions seemed to have stronger hydrophobic interactions with the lipid bilayer because of lower coverage of the core interface. Next, when the nanoemulsions prepared with a pyrene derivative of retinol (VApyr) were applied to corneal epithelial cells, the EOPO nanoemulsions greatly permeated the cells and gathered around the cell nucleus, as compared with HCO nanoemulsions. Furthermore, according to the three-dimensional images of the cell, it was found that the vesicles that absorbed nanoemulsions formed from the plasma membrane as real endocytosis, and were transported to the area around the nucleus. Consequently, it is likely that EOPO nanoemulsions entered the cell by membrane-mediated transport, delivering VA to the cell nucleus effectively and enhancing the effects of VA.