Journal of Ocular Pharmacology and Therapeutics

While α₂-adrenergic agonists, such as brimonidine tartrate, significantly reduce the intraocular pressure (IOP), the presence of vasoconstrictor postsynaptic α₂ receptors on vascular smooth muscle raise the possibility that brimonidine could potentially compromise ocular blood flow. Consequently, the ocular hemodynamic effects of brimonidine were studied in normal subjects.

Twelve healthy volunteers were included in this prospective, double-masked, placebo controlled, crossover-designed clinical trial. They received either brimonidine tartrate 0.2% or placebo b.i.d. for 2 weeks. Goldmann tonometry and color Doppler imaging (CDI) were performed at baseline, at 2 hr, 1 week, and 2 weeks after the treatment. Fundus angiography using a scanning laser ophthalmoscope was performed at baseline and 2 weeks after treatment to determine retinal arteriovenous passage time.

Brimonidine lowered IOP at 2 hr, 1 week, and 2 weeks (p = 0.058, p = 0.031, and p = 0.022, respectively). Brimonidine did not affect the retrobulbar arterial velocities measured by CDI, nor retinal arteriovenous passage time.

In conclusion, two-week treatment with brimonidine reduces IOP and does not reduce the bulk retinal or retrobulbar arterial perfusion in young healthy volunteers.

Our aim was to study the concentration of betaxolol in plasma after its topical ocular use during the normal 12 hr dosing interval. Twenty microliters of betaxolol 0.5% solution were applied into both eyes of nine glaucoma patients, and the plasma concentrations of the drug were measured 12 hr thereafter using a radioreceptor assay. The same amount of betaxolol was then applied ocularly, and its concentration in plasma was measured at 5, 10, 15, 30 min and 1, 2, 4 and 8 hr thereafter. The mean (SD) concentration of betaxolol in plasma twelve hr after the first dose was 0.4 (0.2) ng/ml. After the second dose, the patients showed a biphasic concentration vs. time curve, the first peak occurring at 8 (4) min, and the second peak at 210 (132) min; the mean (SD) peak concentrations being 1.1 (0.3) and 2.0 (1.1) ng/ml, respectively. The area under the concentration vs. time curve showed a 4-fold variation among our patients. Topically applied betaxolol was rapidly absorbed into systemic circulation, and concentrations were detectable even at 12 hr. The interindividual variation in the systemic absorption of betaxolol was large.

The aim of the study was to determine the effects of a dopaminergic drug, 2% ibopamine, on the pupil, intraocular pressure and other ocular and ultrasound biometric variables.

Thirty healthy subjects and 15 patients with primary open-angle glaucoma, aged from 40 to 78 years (mean age: 59.2 ± 11), were included in two prospective open controlled trials. In the first, the mydriatic effect of 2% ibopamine and its inhibition and reversibility were evaluated in 15 healthy subjects using the alpha₁-adrenergic drug, 0.5% dapiprazole. In the second, refraction, visual acuity, pupil diameter, intraocular pressure and 5 A-scan ultrasound biometric variables were evaluated in 15 healthy subjects and in 15 glaucoma patients.

As early as forty min after administration of 2% ibopamine, a marked mydriatic effect (7.3 vs 3.9 mm; P < 0.0001), which was completely inhibited or reversed by 0.5% dapiprazole, was detected. The drug induced no changes in refraction, visual acuity or Ascan ultrasound biometric variables in any of the subjects examined. In healthy subjects, the intraocular pressure values were not changed to a statistically significant extent (13.8 vs 14.8 mm Hg; P = 0.668), whereas a slight, though significant, hypertensive effect (24 vs 22.2 mm Hg; P = 0.002) was observed in the glaucoma patients.

The study confirms the intense mydriatic effect of 2% ibopamine with no changes in refraction, visual acuity or A-scan ultrasound biometric variables. The drug has no effect on intraocular pressure in healthy subjects, but induces a significant hypertensive effect in patients with initial glaucoma. This characteristic could be used for early diagnosis of primary open-angle glaucoma.

The effects of the nitrovasodilator, sodium azide, on intraocular pressure (IOP) and ciliary vascular tone were compared. IOP was measured in the bovine isolated eye that was perfused via the ciliary artery. Separately, vasodilator effects were assessed after raising the vascular tone using noradrenaline (10 μM). Aqueous humor formation (AHF) rate was estimated by a fluorescein dilution method. Cyclic GMP in the ciliary processes was measured by radioimmunoassay.

When compared with controls, sodium azide (10 nmole bolus dose) was found to lower IOP (2.2 ± 0.3 mm Hg; P < 0.01) via a reduction in AHF (12.19 ± 0.26 μl/min to 6.36 ± 0.53 μl/min; P < 0.001). Azide (1 μmole) also reduced ciliary vascular resistance (81.0 ± 5.5%; P < 0.01). However, the drug was 20× more potent as an ocular hypotensive than as a vasodilator (ED₅₀ 0.28 nmole on IOP, 5.55 nmole on vascular effect). Azide (10 nmole) also increased levels of ciliary cyclic GMP (127 ± 17 fmol/mg protein to 233 ± 27 fmol/mg protein; P < 0.01).

The IOP-lowering effect of azide does not appear to depend on its ability to activate guanylyl cyclase (GC) in vascular smooth muscle, but rather is likely a consequence of direct activation of ciliary epithelial GC.

To assess quantitatively the risks of ophthalmic beta-blocking agents for cardiovascular and respiratory adverse reactions, we analyzed the binding kinetics of beta-blocking agents to the beta-1 and beta-2 adrenoceptors. The relationship between the occupancies for beta-1 and beta-2 adrenoceptors and the effects on the exercise pulse rate or the forced expiratory volume in one second (FEV₁) after topical administration of carteolol, befunolol, timolol and betaxolol was analyzed using a ternary complex model. The beta-1 and beta-2 receptor occupancies after ophthalmic administration were calculated to be quite high as well as those after oral administration. The maximum occupancies for beta-1 and beta-2 receptors after ordinary ophthalmic administration were 52% and 88% for carteolol, 52% and 61% for befunolol, 62% and 82% for timolol, and 44% and 3% for betaxolol, respectively. Concave relationships were obtained between a decrease in exercise pulse rate and the beta-1 receptor occupancy and between a decrease in FEV₁ and beta-2 receptor occupancy, respectively. Nasolacrimal occlusion was estimated to decrease the exercise pulse rate and FEV₁ by 65% and 50%, respectively. The beta-1 and beta-2 adrenoceptor occupancies were proved to be the most appropriate indicators for cardiac and pulmonary adverse reactions evoked by ophthalmic beta-blocking agents.

Surgically-induced miosis commonly occurs during cataract extraction surgery, complicating removal of lens cortex and placement of a posterior chamber intraocular lens. To maintain intraoperative mydriasis, one bolus of epinephrine injection was used in our study. The pupillary response to various doses of intracameral epinephrine (0.1 ml of 1:25,000, 1:50,000, 1:100,000, 1:200,000, 1:400,000) was assessed in 60 consecutive patients. The pupil size was measured just prior to the incision, one min after epinephrine injection, after phacoemulsification and after irrigation/aspiration. There was no significant difference among the mean mydriatic responses to the epinephrine concentrations we tested. The 1:400,000 concentration appeared to be as effective as 1:25,000, but two cases of the 1:400,000 group failed to maintain the pupil diameter after irrigation/aspiration. In addition, we found that blood pressure did not elevate after injection of any concentration of epinephrine. We concluded that one bolus of an extremely dilute concentration of epinephrine (i.e., 1:400,000) injection might be effective in maintaining mydriasis during cataract surgery without systemic side effects.

The effects of locally administered brimonidine, clonidine, and p-aminoclonidine on microvessel caliber were compared in human retinal tissues grafted into the hamster cheek pouch. Clonidine and p-aminoclonidine, but not brimonidine, potently constricted human retinal microvessels over a broad concentration range. All three agonists elicited significant vasoconstriction in naive hamster cheek pouch microvasculature. The α₂-adrenoceptor antagonist, rauwolscine, inhibited p-aminoclonidine-induced constriction in naive hamster cheek pouch microvessels, but not p-aminoclonidine-induced effects in retinal grafts. Selective α₁-adrenoceptor agonists evoked vasoconstriction in retinal grafts only at relatively high concentrations. These differential effects on the retinal microvasculature could not be readily explained solely on the basis of α₁- or α₂-adrenoceptor involvement. Clonidine, p-aminoclonidine and brimonidine are also imidazoline derivatives that interact with putative non-adrenergic imidazoline-sensitive binding sites, the so-called I₁-imidazoline binding site subtype implicated by some investigators in mediation of peripheral vasoconstriction. As with p-aminoclonidine, the potent vasoconstriction in human retinal microvasculature elicited by moxonidine, an α-adrenergic agonist that has also been reported to exhibit selectivity for putative I₁-imidazoline binding sites, was not inhibited by the selective α-adrenoceptor antagonist, rauwolscine, nor by idazoxan, an antagonist characterized as having substantial activity at putative I₂-imidazoline binding sites. These data suggest the possible involvement of an unconventional non-adrenergic imidazoline-sensitive pathway in regulation of microvascular responses in the inner retina, and that drug activity mediated via such an imidazoline-sensitive component could potentially evoke deleterious effects in the retinal microvasculature.

Peroxiredoxins are widely distributed in nature and constitute a molecular family of antioxidant enzymes which decompose hydrogen peroxide and alkyl hydroperoxides. We have previously characterized a peroxiredoxin from bovine ciliary body and deduced its amino acid sequence from analysis of cDNA clones encoding the protein. In this work, we investigated the immunolocalization of this novel antioxidant enzyme and its mRNA expression in bovine eye tissues. High levels of immunoreactivity and mRNA for the enzyme were detected in corneal epithelium. Distinct immunoreactivity and mRNA expression for peroxiredoxin were also detected in uveal tissues, some of the retinal cell layers and ocular vasculature.

The purpose of this study was to evaluate the efficacy of combined albendazole and steroid treatment for uveitis caused by Toxocara canis in immunocompetent patients. Five patients (7 eyes) with ocular larva migrans syndrome (OLM) were used in this study. Toxocariasis was suspected based on clinical manifestations and confirmed by anti-toxocara IgG and Western blot analysis. Systemic albendazole (adults: 800 mg b.i.d.; children: 400 mg b.i.d.) was given in conjunction with steroids. Visual acuity before and after therapy, inflammatory response, side effects and toxicity were evaluated. Treatment resulted in an improved visual acuity in all patients. Mean initial Snellen visual acuity was 20/40, and mean final acuity was 20/20. There were no recurrences of uveitis throughout the observation period (average: 13.8 months; range: 3 days to 24 months). These findings suggest that albendazole, in combination with systemic steroids, is a useful regimen to treat ocular larva migrans syndrome.

To determine the ocular pharmacokinetics, physiological and histological effects of prinomastat (a matrix metalloprotease inhibitor), a total of seventy-seven eyes of New Zealand White rabbits received intravitreous and subtenon injections of prinomastat or of acidified water vehicle as control. Doses of 0.5 mg in 0.05 mL of prinomastat or acidified water were used for intravitreal injection. For the subtenon injections, doses of 5 mg prinomastat in 0.5 mL of acidified water were administered in the superotemporal quadrant. Intraocular pharmacokinetics were determined by analyzing vitreous samples at different postinjection time points using Liquid Chromatography-Mass Spectroscopy/Mass Spectroscopy (LC-MS/MS). The toxicity was evaluated by biomicroscopy, electroretinography (ERG), pneumatonometry, and histology. No toxicity was found with either administration method. At day 14 after intravitreal injection, levels of prinomastat in the vitreous and choroid were 1.4 ng/mg and 7.8 ng/mg, respectively. The retinal levels of prinomastat were 22 ng/mg at 24 hr and dropped below 1 ng/mg at 48 hr. Prinomastat remained well above minimum effective concentration in the choroid for at least four weeks after a single intravitreal injection, suggesting that local intravitreal injection may have potential in treating choroidal neovascularization.