Enhanced healing of cat corneal endothelial wounds by epidermal growth factor.

PURPOSE: The authors investigated whether healing of cat corneal endothelial wounds could be enhanced in vivo by human epidermal growth factor (EGF). METHODS: EGF was administered in sodium hyaluronate to the anterior chamber of cats after an endothelial touch injury. Control contralateral eyes received sodium hyaluronate alone. At selected times after injury, the corneas were evaluated for thickness, the rate of endothelial wound closure, the endothelial cell density, any variation in cell size, the percentage of hexagonal cells, and endothelial cell mitosis. RESULTS: Two days after injury, endothelial wounds of eyes treated with EGF had healed an average of 65 +/- 4% of the initial 38.5 mm2 wound area; paired control eyes had healed an average of 59 +/- 4% (P < 0.05). Both EGF-treated and control wounds had resurfaced over 90% of the initial wound area on day 4 after injury, and the wounds were completely resurfaced by 7 and 14 days after injury in both treatment groups. On days 4 and 7 after injury, the EGF-treated corneas were 5% and 8% thicker (835 versus 796 microns and 786 versus 728 microns, respectively) than the paired control corneas (P < 0.03). On days 10 and 14 after injury, both EGF-treated and control corneas were 19% and 12% thicker, respectively, than prewound the corneal thickness (621 microns). Seven days after injury, the corneas treated with EGF had an average of 76 +/- 28% more (P < 0.05) endothelial cell nuclei labeled with tritiated thymidine compared with that of the paired control eyes (2472 versus 1543 labeled nuclei). Fourteen days after injury, the central endothelial cell density of EGF-treated corneas was an average of 38 +/- 11% higher than that of the paired control eyes (P < 0.01, 1708 versus 1235 cells/mm2). The percentage of hexagonal cells in the wound area was an average of 14 +/- 4% higher (P < 0.01) than that of the paired control eyes (82% versus 69%), and the coefficient of variation of the cell size for EGF-treated corneas was an average of 31% (P < 0.05) smaller than that of the paired control corneas (0.21 versus 0.29 [standard deviation]/mean cell size). CONCLUSIONS: A single intraocular application of EGF formulated in sodium hyaluronate after an endothelial cell injury significantly enhanced multiple parameters that are closely related to improved endothelial cell regeneration.

Diacetyl derivative of nadolol. I. Ocular pharmacology and short-term ocular hypotensive effect in glaucomatous eyes.

On topical application to rabbit eyes, the diacetate ester of nadolol was more easily absorbed into ocular tissue than nadolol and was enzymatically hydrolyzed to nadolol within the eye. In a 24-hour clinical study, the ocular hypotensive activities of 0.5% diacetyl nadolol, 2% diacetyl nadolol, 2% nadolol, and 0.5% timolol maleate in subjects with open-angle glaucoma or ocular hypertension were compared. Both concentrations of diacetyl nadolol significantly reduced intraocular pressure during the first six hours. Two percent diacetyl nadolol was as effective as 0.5% timolol maleate during the first eight hours. During the remainder of the testing period, timolol showed greater IOP control. Two percent diacetyl nadolol and 2% nadolol showed similar ocular hypotensive effects both in magnitude and duration in this short-term study.

Levobunolol. A three-month efficacy study in the treatment of glaucoma and ocular hypertension.

The ocular hypotensive effect and the safety of levobunolol hydrochloride (0.5% and 1%) were compared with vehicle in this double-masked study of 42 patients with chronic open-angle glaucoma or ocular hypertension. After a washout of ocular hypotensive medication, patients received one of the three test treatments in both eyes twice daily for three months. Both concentrations of levobunolol produced significant reductions in intraocular pressure, while decreases in vehicle-treated patients were minimal. Over the three-month study period, average pressure reductions were approximately 9.0 mm Hg in patients receiving either concentration of levobunolol and 0.5 mm Hg in patients receiving vehicle. Fewer patients were terminated from the study for inadequately controlled intraocular pressure in the levobunolol groups than in the vehicle group. No patients were terminated for drug-related adverse experiences.

Topically applied oxymetazoline. Ocular vasoconstrictive activity, pharmacokinetics, and metabolism.

Two double-blind, random-assignment clinical trials demonstrated the effectiveness of topical oxymetazoline hydrochloride in reducing histamine-induced hyperemia. Oxymetazoline hydrochloride at an optimum strength of 0.025% produced a marked and prolonged reduction of hyperemia, with the onset of effect occurring within one to five minutes of instillation. Safety indicators, including BP, heart rate, intraocular pressure, pupil size, and visual acuity, did not change significantly from baseline values. Oxymetazoline was absorbed slowly into the eye: only 0.006% of the original drug concentration was found in the aqueous humors of rabbits 30 minutes after instillation; the balance remained primarily in external ocular tissues. Metabolic studies in rabbits indicated that excreted amounts of unmetabolized radioactive oxymetazoline in urine following drug administration were similar (23%) for the ocular and nasal routes of application. The proportions of oxymetazoline metabolite to unchanged oxymetazoline were constant for all administration routes tested.

Levobunolol compared with timolol for the long-term control of elevated intraocular pressure.

Levobunolol hydrochloride (0.5% and 1%) and timolol maleate (0.5%) are being compared in an ongoing, double-masked, randomized study of 141 patients with ocular hypertension or chronic open-angle glaucoma. Baseline intraocular pressure (IOP) in the three treatment groups ranged from 26 to 27 mm Hg. During the first 15 months of the study, the two drugs have not proved to be significantly different in ocular hypotensive efficacy, with overall mean IOP decreases of 6.8 to 7.6 mm Hg. In addition, the two concentrations of levobunolol have been equally effective in controlling IOP. Neither drug has been associated with any significant ocular side effects. Both drugs have produced significant decreases (five to ten beats per minute) in mean heart rate. The effect on mean blood pressure has been less pronounced: overall decreases have been less than 4 mm Hg for both systolic and diastolic blood pressure. The results of this ongoing study suggest that levobunolol is as effective and as safe as timolol for the long-term control of IOP.

The ocular hypertensive effect of 0.25% fluorometholone in corticosteroid responders.

Fourteen subjects known to be corticosteroid responders participated in a double-masked, randomized study comparing the ocular hypertensive effect of 0.25% fluorometholone suspension with that of 0.1% dexamethasone sodium phosphate. Subjects instilled one drop of fluorometholone in one eye and one drop of dexamethasone in the fellow eye four times daily for up to six weeks. Although both medications increased intraocular pressure, endpoint substitution analysis demonstrated that mean intraocular pressure increases from baseline in the eyes treated with fluorometholone were significantly lower than those in the eyes treated with dexamethasone at weeks 2, 4, and 6 (P less than or equal to .05). Also, mean maximum intraocular pressure was significantly lower in the eyes treated with fluorometholone than in the eyes treated with dexamethasone (P = .001). These results indicated that 0.25% fluorometholone is less likely to increase intraocular pressure in corticosteroid responders than 0.1% dexamethasone.

A clinical evaluation of the effects of topically applied levobunolol and timolol on increased intraocular pressure.

Data from two short-term double-masked studies using 24 and 16 subjects suggest that topically applied levobunolol safely and effectively treats open-angle glaucoma and ocular hypertension. The onset of effect of a single drop of 0.5% levobunolol occurred within the first hour, producing a maximal hypotensive effect of more than 8 mm Hg after two hours. An intraocular pressure deceased of greater than or equal to 2 mm Hg was still observed after 24 hours for both concentrations of levobunolol tested (0.5% and 1%). Intraocular pressure decreases of more than 9 mm Hg persisted during a one-month trial in which patients were treated twice daily, confirming the results obtained in the 24-hour study. Systemic effects of both timolol (0.5%) and levobunolol (0.5% and 1%) included a consensual intraocular pressure-decreasing effect in the untreated eye and clinically significant reductions in heart rate. Diastolic blood pressure was decreased at two and four hours after administration of 0.5% levobunolol.

A dose-response study of piloplex for duration of action.

The duration of reduction in intraocular pressure after single-dose administration of three concentrations of piloplex and the vehicle of the drug was evaluated in 12 patients with open-angle glaucoma in a randomized, double-masked, crossover study. Piloplex lowered intraocular pressure in a dose-related fashion, with a duration of action of at least 14 hours.

Minimum concentration of levobunolol required to control intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension.

In a double-masked, randomized, comparison titration study to determine the effective dose of topically applied levobunolol, three concentrations of levobunolol (0.25%, 0.5%, and 1%) and of timolol (0.125%, 0.25%, and 0.5%) were evaluated in patients with mild open-angle glaucoma or ocular hypertension. Following a washout of ocular hypotensive medication, twice-daily treatment in both eyes was initiated with the lowest of the three doses of either drug. The concentration was increased if intraocular pressure remained uncontrolled. Intraocular pressure was controlled in 63% (15 of 24) of the patients tested with the lowest concentration of levobunolol and 69% (18 of 26) with the lowest concentration of timolol. Overall, 75% (18 of 24) of the patients in the levobunolol group and 73% (19 of 26) of the patients in the timolol group had adequately controlled intraocular pressure. At the lowest concentrations tested, mean decreases from baseline in intraocular pressure ranged from 6 to 8 mm Hg in both treatment groups.

Glaucoma treatment with once-daily levobunolol.

Although twice-daily instillation of topical beta-blockers is the standard regimen for treatment of increased intraocular pressure, once-daily therapy might improve patient compliance and provide greater safety. In a three-month, double-masked clinical trial, 92 patients with open-angle glaucoma or ocular hypertension received levobunolol 0.5% or 1% or timolol 0.5% once daily, in both eyes. Overall mean decreases in intraocular pressure were significantly greater in the groups treated with levobunolol than in the group treated with timolol. Intraocular pressure decreases averaged 7.0 mm Hg with levobunolol 0.5%, 6.5 mm Hg with levobunolol 1%, and 4.5 mm Hg with timolol. The intraocular pressures of 72% (18 of 25 patients) of those treated with levobunolol 0.5%, 79% (22 of 28 patients) of those treated with levobunolol 1%, and 64% (16 of 25 patients) of those treated with timolol were successfully controlled during the study. Heart rate and blood pressure decreases were minimal with both levobunolol and timolol. Study results indicated that once-daily treatment with levobunolol and, to a lesser extent, timolol is sufficient to control intraocular pressure successfully and safely.

Diacetyl nadolol: 3-month ocular hypotensive effect in glaucomatous eyes.

In a double-masked, 3-month clinical study the ocular hypotensive effects of diacetyl nadolol (DAN), timolol, and nadolol were compared. When applied topically to the eyes of glaucomatous patients timolol 0.5% was found to be significantly more effective than DAN 2% in controlling IOP at 3 of 10 evaluation periods. Fewer patients, however, developed tolerance to DAN 2% than to timolol 0.5%. DAN 0.5% was also effective in lowering intraocular pressure in 3 of 8 patients tested. Nadolol 2% had no long-term ocular hypotensive effect. Two of 8 patients treated with DAN 2% developed a bilateral periorbital dermatitis and were removed from the study even though their intraocular pressures were well controlled. No other clinically significant local or systemic side effects were observed during the course of the study.

Long-term ocular hypotensive effect of levobunolol: results of a one-year study.

Data for the first 12 months are reported for an ongoing, multicentre, clinical study comparing the long-term, ocular hypotensive efficacy and safety of topical levobunolol (0.5% and 1%) and timolol (0.5%). This study was a double-masked trial testing 88 patients with chronic open angle glaucoma or ocular hypertension. During the 12-month period drops were instilled twice daily into both eyes after a washout of prestudy ocular hypotensive medication. The effect of the three treatments in reducing intraocular pressure (IOP) was similar. Mean IOP reductions over the 12 months averaged 7.2 mmHg for the 0.5% levobunolol group, 6.2 mmHg for the 1% levobunolol group, and 6.0 mmHg for the timolol group. Decreases in mean heart rate of up to 5 beats per minute were observed in the 0.5% levobunolol group, up to 8 beats per minute in the 1% levobunolol group, and up to 4 beats per minute in the timolol group. Several patients were removed from the study owing to side effects possibly related to levobunolol treatment.

Enhancement of the ocular bioavailability of topical tobramycin with use of a collagen shield.

We compared the ocular bioavailability in rabbits of 0.3% tobramycin applied with a collagen shield with eyedrop tobramycin application. Groups of rabbits received either (1) a collagen shield presoaked in tobramycin with a tobramycin drop before and after shield application (Shield) or (2) three drops of tobramycin (Drops). Postmortem samples of the cornea, conjunctiva, and aqueous humor were obtained at various intervals after shield application or drop instillation. The corneas in a second set of rabbits were anesthetized and then chemically abraded with n-heptanol before receiving the same two dosing regimens as in the groups with intact corneas. At nearly all times in all three tissues, the Shield groups had higher mean concentrations of tobramycin than the Drops groups. The area under the concentration-time curve for the Shield group relative to the Drops group was 5.0- to 16.1-fold greater for rabbits with intact corneas (P < .05), and 1.8- to 3.7-fold greater for rabbits with abraded corneas (P < .05). The use of collagen shields together with standard ophthalmic concentrations of tobramycin may be useful in achieving higher concentrations of topically delivered drugs into the anterior segment of the eye.

Expanded polytetrafluoroethylene reinforcement material in glaucoma drain surgery.

PURPOSE: To determine whether a synthetic material, expanded polytetrafluoroethylene (E-PTFE), can be used successfully as a reinforcement material over the tubes of glaucoma drainage implants. METHODS: Patches of E-PTFE were sutured over the tubes of Baerveldt glaucoma drains implanted in the eyes of New Zealand white rabbits. Two material thicknesses were tested: 0.5 mm in four eyes and 0.25 mm in five eyes. Rabbit donor scleral patches were used in five eyes as the control. Total ocular health and intraocular pressure were monitored every 2 weeks after the procedure. Six months after implantation, the eyes were harvested and analyzed histologically. RESULTS: Two of the four eyes that received 0.5-mm thick E-PTFE patches showed some conjunctival melting over the anterior corners of the material close to the limbus. All five eyes that received 0.25-mm thick E-PTFE patches showed a healthy cellular wound healing response and no conjunctival melting. Cellular infiltration and collagen deposition in the E-PTFE materials showed integration of the patch material into the surrounding tissue. In the control eyes, marked thinning and resorption of the donor sclera immediately above the drainage tube was noted. CONCLUSION: Thin (0.25 mm) E-PTFE patches were well tolerated in all rabbit eyes tested. Thin E-PTFE should be investigated further as a functional alternative to donor sclera for reinforcement in glaucoma drain surgery.

Recombinant enkephalinase effectively inhibits substance P-induced miosis in the rabbit eye cup model.

Enkephalinase (EC 3.4.24.11) is a naturally occurring, membrane-bound peptidase that degrades substance P in vivo and in vitro. Addition of this neutral endopeptidase to a rabbit eye cup model partially inhibits substance P-induced contraction of the iris sphincter muscle. Inactivation of substance P is reversed by thiorphan, a specific inhibitor of enkephalinase. These results show that enkephalinase degradation of substance P produces metabolites that are physiologically inactive in iris contraction. We also observed that atropine acts synergistically with enkephalinase to completely abolish substance P-induced iris contraction suggesting that the action of substance P on the iris contains an acetylcholine-stimulatory effect which is not lost by enkephalinase treatment.

Efficacy and safety of topical oxymetazoline in treating allergic and environmental conjunctivitis.

This randomized, double-masked study evaluated the safety and efficacy of oxymetazoline 0.025% topical ophthalmic solution compared with its vehicle when used to treat allergic or environmental conjunctivitis. Thirty-nine patients with moderate bilateral conjunctival hyperemia instilled one drop of either oxymetazoline 0.025% solution or its vehicle twice daily for one week. At each evaluation the signs and symptoms of conjunctivitis were evaluated, complete eye examinations were performed, and heart rate and blood pressure were measured. An overall assessment of treatment efficacy was made at each follow-up evaluation. The signs and symptoms of conjunctivitis had significantly improved in the oxymetazoline-treated group when compared with those of the vehicle-treated group, and the ocular and systemic safety of each treatment was comparable.

Efficacy of cimetidine/pyrilamine eyedrops. A dose response study with histamine challenge.

Eighteen healthy volunteers participated in a histamine challenge, dose response study of cimetidine (H2 antagonist)/pyrilamine (H1 antagonist) eyedrops. This was a randomized, double-masked, multiple-crossover trial, consisting of six visits spaced 48 hours apart. At each visit, subjects were pretreated with one of six different doses of test medication in one randomly selected eye and with vehicle in the fellow eye. Five minutes later, one drop of 0.0075% histamine was instilled in both eyes. Conjunctival hyperemia and edema were graded at various time points during a 20-minute interval after the instillation of histamine. Results indicated that the cimetidine/pyrilamine combination was effective in preventing histamine-induced conjunctival hyperemia in normal volunteers; neither cimetidine nor pyrilamine was effective when administered alone.

One-month crossover trial comparing the intraocular pressure control of 3.4% Piloplex twice daily with 2.0% pilocarpine four times daily.

A one-month crossover trial comparing Piloplex 3.4% b.i.d. with pilocarpine 2.0% q.i.d. was conducted to compare the effectiveness of the 2 drugs in reducing the intraocular pressure of ocular hypertensive and open-angle glaucoma in subjects previously controlled with pilocarpine 2.0%. For both groups the mean IOP increased slightly from baseline with pilocarpine and decreased significantly from baseline with Piloplex. The side effects of both treatments were minor. Piloplex and pilocarpine treatment were both associated with eye dryness; Piloplex was associated with lacrimation in 2 subjects. This controlled study showed that Piloplex 3.4% b.i.d. was more effective than pilocarpine 2% q.i.d. in lowering intraocular pressure.

Levobunolol compared with timolol for the control of elevated intraocular pressure.

Two concentrations of levobunolol (0.5% and 1%) and one concentration of timolol (0.5%) were evaluated for the control of elevated intraocular pressure (IOP) in a double-masked, randomized study. Fifty-one patients received one of the three study treatments in both eyes bid for one year. Both drugs were equally effective in reducing IOP: The overall reduction in mean IOP was slightly more than 9 mm Hg in all three treatment groups. Levobunolol was as safe and effective as timolol for the long-term control of elevated IOP.