Specific hypotensive and antihypertensive ocular effects of d-isoproterenol in rabbits.

d-Isoproterenol (ISO) applied topically to the rabbit eye specifically lowered intraocular pressure. Thus, it effectively reduced normal intraocular pressure and inhibited intraocular pressure elevation induced by water load without causing other obvious local or systemic pharmacologic effects. By comparison, dl-ISO was pharmacologically nonspecific in that amounts required to reduce intraocular pressure also produced significant and marked tachycardia. Furthermore, maximal intraocular pressure reduction was less with dl-than with d-ISO. Accordingly, and in consideration of reported clinical experience with dl-ISO in glaucomatous man, the d-isomer should be the preferred form of ISO for treating glaucoma. d-ISO should offer advantages over any other topical medication used currently in the treatment of this condition. Toxicity studies employing large, topical doses of drug in rabbit eyes showed that d-ISO was free from ocular irritation as well as systemic toxicologic effects and should be safe for controlled studies in man.     

Topical ocular hypotensive medication and lens opacification: evidence from the ocular hypertension treatment study

PURPOSE: To determine whether topical ocular hypotensive medication is associated with refractive changes, visual symptoms, decreased visual function, or increased lens opacification. DESIGN: Multi-center clinical trial. METHODS: We compared the medication and observation groups of the Ocular Hypertension Treatment Study (OHTS) during 6.3 years of follow-up with regard to the rate of cataract and combined cataract/filtering surgery, and change from baseline in visual function, refraction, and visual symptoms. A one-time assessment of lens opacification was done using the Lens Opacities Classification System III (LOCS III) grading system. RESULTS: An increased rate of cataract extraction and cataract/filtering surgery was found in the medication group (7.6%) compared with the observation group (5.6%) (hazard ratio [HR] 1.56; 95% confidence interval [CI] 1.05 to 2.29). The medication and observation groups did not differ with regard to changes from baseline to June 2002 in Humphrey visual field mean deviation, Humphrey visual field foveal sensitivity, Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity, refraction, and visual symptoms. For the medication and observation groups, LOCS III readings were similar for nuclear color, nuclear opalescence, and cortical opacification. There was a borderline higher mean grade for posterior subcapsular opacity in the medication group (0.43 +/- 0.6 SD) compared with the observation group (0.36 +/- 0.6 SD) (P = .07). CONCLUSIONS: We noted an increased rate of cataract extraction and cataract/filtering surgery in the medication group as well as a borderline higher grade of posterior subcapsular opacification in the medication group on LOCS III readings. We found no evidence for a general effect of topical ocular hypotensive medication on lens opacification or visual function.     

Topical cyclosporine to control ocular surface disease in patients with chronic glaucoma after long-term usage of topical ocular hypotensive medications

Purpose

To evaluate changes in ocular surface and central corneal sub-basal nerve fiber layer (SBNFL) after topical cyclosporin therapy in chronic glaucoma patients on long-term topical antiglaucoma therapy.

Methods

A prospective comparative study of ocular surface evaluation of chronic glaucoma patients on long-term topical therapy treated concurrently with a topical cyclosporine 0.05% twice daily for 6 months and controls was done. The study parameters evaluated at recruitment and at the 6-month follow-up included details of topical antiglaucoma medications, visual acuity, intraocular pressure, ocular surface evaluation parameters (TBUT, Schirmers I, ocular surface staining scores and ocular surface disease (OSD) index score (OSDI)), central corneal sensation (Cochet Bonnett aesthesiometer), and central confocal microscopy to study the SBNFL density (SBNFLD).

Results

Thirty-two eyes of 16 patients with chronic glaucoma and 30 eyes of 15 normal subjects as controls were studied. Mean TBUT, pre/post CsA treatment was 8.67±3.01/12.24±1.83 s (P=0.007). Mean conjunctival/corneal staining scores pre/post CsA treatment were 3.38±1.93/1.50±0.718 (P=0.00) /5.19±1.82/1.81±0.78 (P=0.098), respectively. Mean OSDI pre/post CsA treatment scores were 30.63±14.61/14.76±6.06 (P=0.007). Mean corneal sensations scores pre/post CsA treatment were 4.64±0.46/4.94±0.39 (P=0.002). Central corneal SBNFLD pre and post CsA treatment was 8811.35±2985.29/10335.13±4092.064 μm/mm² (P=0.0001).

Conclusions

Schirmer''s test, ocular surface staining scores, OSDI, corneal sensations, and corneal SBNFLD showed a statistically significant improvement following a 6-month concurrent topical CsA therapy.     

Enhanced ocular hypotensive response to timolol in rabbits with prior dexamethasone treatment.

The purpose of this study was to determine glucocorticoid modulation of ocular pressure to timolol applied topically to rabbit eyes that were pretreated with dexamethasone. Rabbits were pretreated with five applications of topical 0.007% of dexamethasone (0.01% dexamethasone phosphate) or saline drops, administered at ten min intervals. The eyes were then treated with timolol maleate drops at concentrations of free base of 0.00007%, 0.0007%, 0.007% and 0.07%. An additional group of rabbits received dexamethasone pre-treatment only. Intraocular pressure was measured for the next four hr. Enhanced lowering of intraocular pressure was observed with dexamethasone pretreatment. Rabbits receiving the smaller dose of timolol had the least decrease in pressure. The most significant decreases in pressures occurred at 45 min after the administration of timolol with an average difference of 4.8 mm Hg between the timolol- and dexamethasone/timolol-treated eyes for the three largest concentrations of timolol. This synergism between glucocorticoids and beta-adrenergic blockers in lowering IOP may be potentially useful in the therapy of ocular hypertension and glaucoma.     

Topical ocular instillation of nitric oxide synthase inhibitors and intraocular pressure in rabbits.

PURPOSE: It has been reported that intravenous injection of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl esther (L-NAME) causes a rapid decrease of intraocular pressure (IOP) in rabbits. This study investigates the effect of topical ocular application of different NOS inhibitors on a raise of IOP induced by an acute water intake (rabbit water loading model). METHODS: Forty New Zealand (albino) male rabbits received randomly (within thirty minutes) in their right eye three 50 microliters installations of either 0.9% NaCl, 0.5% timolol maleate (beta-adrenoreceptor antagonist), 0.5% 7-nitroindazole (7-NI; NOS inhibitor), 0.5% L-NAME, or 0.5% 2-amino-5,6-dihydro-6-methyl-1,3,-thiazine (AMT; NOS inhibitor) before an oral water gavage (60 ml/kg). IOP was measured (TonoPen) before and after topical instillation (time 0), and then 15, 30, 60, 90, and 120 minutes after water intake. RESULTS: In right eyes, the area under the curve (AUC) of the IOP difference versus time (arbitrary units) was 527 +/- 284 for NaCl, 255 +/- 178 for timolol, 466 +/- 242 for 7-NI, 604 +/- 195 for L-NAME, and 394 +/- 202 for AMT. Values of AUC were only significantly lower (p < 0.05) in the timolol-treated group. In left eyes, no significant difference (p > 0.05) could be observed in values of AUC between groups. CONCLUSIONS: Under the present experimental conditions (including concentration and bioavailability of the drugs used), topical application of the NOS inhibitors 7-NI, L-NAME, and AMT does not prevent an IOP increase induced by water intake in rabbits.     

Topical timolol, at conventional, unilateral doses causes bilateral ocular beta-blockade in rabbits

The studies described herein reveal that unilateral 0.3% and 1% doses of timolol produce marked beta-adrenoceptor blockade in treated and in contralateral eyes which did not receive timolol. This indicates that unilateral, conventional topical doses of timolol administered to rabbits cause bilateral ocular beta-adrenoceptor blockade. In addition, 0.1% and 1% doses of timolol applied to one eye resulted in blockade of cardiovascular beta-adrenoceptors. Thus, the most likely explanation for bilateral ocular beta-blockade would be systemic absorption of timolol from the treated eye and redistribution to the fellow eye. Since contralateral eyes would not provide an adequate control in circumstances where a large dose of timolol is administered unilaterally, caution must be exercised in interpreting data obtained in laboratory animals with doses of timolol similar to those employed clinically. A 0.01% dose of timolol appears adequate to achieve marked, unilateral ocular beta-adrenoceptor blockade in rabbits.     

Topical diclofenac sodium, dexamethasone and placebo compared in a model of immunogenic uveitis in rabbits

Unacceptable side effects involved in topical steroid usage for uveitis have prompted the search for alternative antiinflammatory drugs for the treatment of ocular inflammation. Cyclooxygenase inhibitors have been widely used for systemic inflammatory conditions over the last two decades and are therefore natural candidates to be studied for uveitis therapy. Previous studies of cyclooxygenase inhibitors in uveitis models yielded inconclusive and sometimes contradicting results. The authors compared the clinical effect of topical dexamethasone, diclofenac and placebo in an immunogenic uveitis model produced in ovalbumin immunized NZW rabbits challenged with ovalbumin in the vitreous. Nine clinical parameters of inflammation were compared employing a double blind placebo controlled protocol. Three groups of 16 eyes each, were assigned for each preparation and were followed for nine days with biomicroscopic examinations. Diclofenac was superior or equal to dexamethasone for iris hyperemia (p=0.059) and conjunctival injection (p=0.02), equal for corneal haziness and AC fibrin, yet inferior for corneal endothelial debris, iris fibrin and AC cells and flare (p<0.05). Placebo was inferior (p<0.05) to the other groups for the above mentioned parameters excluding fibrin precipitation on the iris that was greater in diclofenac treated eyes. While some clinical criteria of inflammation responded better to steroids than to diclofenac, the results of this study show that others responded better or equal to diclofenac. The authors hypothesize that although diclofenac reduces prostaglandin levels it may induce high levels of leukotrienes that maintain cellular exudation.     

Topical diclofenac sodium,dexamethasone and placebo compared in a model of immunogenic uveitis in rabbits

Unacceptable side effects involved in topical steroid usage for uveitis have prompted the search for alternative antiinflammatory drugs for the treatment of ocular inflammation. Cyclooxygenase inhibitors have been widely used for systemic inflammatory conditions over the last two decades and are therefore natural candidates to be studied for uveitis therapy. Previous studies of cyclooxygenase inhibitors in uveitis models yielded inconclusive and sometimes contradicting results. The authors compared the clinical effect of topical dexamethasone, diclofenac and placebo in an immunogenic uveitis model produced in ovalbumin immunized NZW rabbits challenged with ovalbumin in the vitreous. Nine clinical parameters of inflammation were compared employing a double blind placebo controlled protocol. Three groups of 16 eyes each, were assigned for each preparation and were followed for nine days with biomicroscopic examinations. Diclofenac was superior or equal to dexamethasone for iris hyperemia (p=0.059) and conjunctival injection (p=0.02), equal for corneal haziness and AC fibrin, yet inferior for corneal endothelial debris, iris fibrin and AC cells and flare (p<0.05). Placebo was inferior (p<0.05) to the other groups for the above mentioned parameters excluding fibrin precipitation on the iris that was greater in diclofenac treated eyes. While some clinical criteria of inflammation responded better to steroids than to diclofenac, the results of this study show that others responded better or equal to diclofenac. The authors hypothesize that although diclofenac reduces prostaglandin levels it may induce high levels of leukotrienes that maintain cellular exudation.     

Effects of ocular hypotensive agents on the circadian rhythm in intraocular pressure in rabbits as measured by telemetry

PURPOSE: To establish a telemetry system for measuring intraocular pressure (IOP) in rabbits and to evaluate the effects of topical application of ocular hypotensive agents on the circadian rhythm of IOP. SUBJECTS AND METHODS: We developed a telemetry system in rabbits housed under a 12-hour light-dark cycle (light and dark phases: 7:00-19:00, 19:00-7:00, respectively). The IOP resulting from a single topical application of ocular hypotensive agents was measured by telemetry during the light phase and the dark phase. RESULTS: The values measured by the telemetry were positively correlated to the value of the anterior chamber pressure measured by a transducer in range from 5 to 50 mmHg (r = 0.987). A single topical application of timolol maleate (0.5%), dorzolamide hydrochloride (1%), and dipivefrine hydrochloride (0.1%) caused no significant reduction in IOP in the light phase, but they did in the dark phase. A single topical application of bunazosin hydrochloride (0.01% or 0.1%) had significant ocular hypotensive effects in both phases. CONCLUSION: These findings indicate that the different effects of ocular hypotensive agents on circadian rhythms of IOP can be measured by the telemetry. Telemetry may be useful for evaluation of ocular hypotensive agents and the circadian rhythm of IOP.     

Association between ocular herpes simplex virus and topical ocular hypotensive therapy

PURPOSE: To evaluate whether use of particular topical hypotensive therapies is associated with ocular herpes simplex virus (OHSV). MATERIALS AND METHODS: This population-based, retrospective, cohort study used claims records from the Protocare Sciences managed care database (United States). Data were extracted from September 1, 1996 through June 30, 2002. An OHSV event was either a medical claim from the utilization database coded with an International Classification of Diseases Ninth Revision (ICD-9) code for OHSV (ICD-9 = 054.4, 054.40-054.44, 054.49) or a pharmacy claim for vidarabine or trifluridine ophthalmic solution. RESULTS: A total of 93,869 eligible glaucoma patients, 21 different ocular hypotensive agents, and 192,840 agent-utilizing patient combinations were identified. In all, 411 patients had an OHSV event; 272 of 411 patients had at least 1 ocular hypotensive agent dispensed prior to the OHSV event but not preceding the event by less than 7 days. Of these, 219 had only 1 ocular hypotensive agent dispensed on the last fill date prior to the OHSV event, yielding an overall OHSV event rate of 0.11%. There was no significant association between OHSV event rates and agent use for either the set of 21 agents (P = 0.260; chi2) or when 14 products having < 5% usage were combined (P = 0.058). Prevalence rates were estimated as 161 per 100,000 population for 2000 to 2001 and 165 per 100,000 for 1999 to 2001. CONCLUSIONS: Ocular herpes simplex virus is extremely rare in patients treated with ocular hypotensive therapies, and its prevalence is similar to that found in the general population. The current analysis revealed no association between the use of particular topical ocular hypotensive therapies and OHSV.     

L-653,328: an ocular hypotensive agent with modest beta receptor blocking activity

L-653,328 is the acetate ester of L-652,698 ((S)-3-tert-butylamino-1-[4-[2(hydroxy)ethyl]phenoxy]2-propanol). The penetration of L-652,698 into the albino rabbit eye was enhanced when the compound was instilled as its prodrug acetate ester. The instillation (one drop of 50 microliter) of 0.01, 0.05 and 0.1% solutions of L-653,328 significantly decreased in a dose-dependent manner the elevated intraocular pressure (IOP) of alpha-chymotrypsinized rabbits by 3.2, 4.7 and 6.1 mm Hg, respectively. A 0.01% solution of L-652,698 failed to significantly lower IOP, whereas this dose of timolol (3.8 mm Hg) and betaxolol (3.3 mm Hg) was effective. L-652,698 was active at 0.05% and 0.1%. Extraocular beta-adrenoceptor blockade was quantified in ganglion-blocked, conscious rabbits by determining effects on heart rate and blood pressure changes to i.v. isoproterenol (0.5 microgram/kg). Doses of timolol blocking isoproterenol-induced hypotension and tachycardia by 50% were 0.0065% and 0.03%, respectively. The corresponding doses for betaxolol were greater than 3% (43% inhibition) and 0.3%. Heart rate and blood pressure changes to isoproterenol were blocked by 18 and 36%, respectively, after the instillation of a 3% solution of L-653,328. The reduced propensity of L-653,328 for extraocular beta-adrenoceptor blockade stems from the modest affinity of L-652,698, its active moiety, for beta-adrenoceptors. The Ki values of L-652,698 for displacement of 125I-iodocyanopindolol binding to beta 1-(left ventricle) and beta 2-binding sites (iris + ciliary body) in the rabbit were 5.7 microM and 7.3 microM, respectively. In marked contrast, the corresponding values for timolol were 12 nM and 1.8 nM.(ABSTRACT TRUNCATED AT 250 WORDS)     

The central ocular hypotensive effect of clonidine

Summary Clonidine was administered into the left vertebral artery of anesthetized cats. A dose-response curve of the lowering effect on intraocular pressure (IOP) has been made and compared with the dose-response curve obtained after intravenous administration. A more pronounced decrease in IOP after the first route of administration became evident. The effect is not secondary to a stronger reduction of blood pressure by centrally injected clonidine.Distribution experiments with ¹⁴C-clonidine revealed no direct connection between the vertebral arteries and the blood supply of the eye. For 2 h the concentrations in the eye are somewhat lower than after intravenous administration. Therefore, the IOP-lowering effect is not due to a direct influence of clonidine on the eye.It is submitted that the clonidine-induced reduction in IOP is at least in part due to a central mechanism, in which the stimulation of central -adrenoceptors and adrenergic neurons may be involved. The relevance of this hypothesis with regard to a possible central regulation of IOP is discussed.     

Ocular hypotensive activity of the adenosine agonist (R)-phenylisopropyladenosine in rabbits.

Adenosine A1 agonists have been shown to induce a variety of pharmacological effects. In New Zealand White rabbits, the topical administration of 500 micrograms of the relatively selective adenosine A1 receptor agonist R(-) phenylisopropyladenosine (R-PIA) produced a biphasic response in IOP in the ipsilateral eye: an initial ocular hypertension (3.5 +/- 1.4 mm of Hg) at 0.5 hour, followed by significant reduction in IOP (5 to 8 mm of Hg) from 2 to 6 hours postadministration. The IOP response to 50 and 165 micrograms of R-PIA demonstrated that the ocular hypotensive response to R-PIA was dose-related; however, no initial hypertension was observed at these lower doses. The ocular response to R-PIA was primarily unilateral with only a small reduction in contralateral IOP at 1 hour observed in animals treated with 500 micrograms. No significant change in pupil diameter was observed with any dose of R-PIA. Pretreatment with the adenosine antagonist CPT (10 mg/kg; i.p.) significantly inhibited the ocular hypotensive response to R-PIA. However, pretreatment with the cyclooxygenase inhibitor indomethacin (50 mg/kg; i.p.) did not alter the change in IOP induced by R-PIA. The administration of R-PIA once a day for five days demonstrated that tolerance does not develop in rabbits with repeated administration. These data demonstrate that the adenosine A1 agonist R-PIA can lower IOP. The unilateral nature and the inhibition by CPT supports the idea that this response is mediated by adenosine receptors located in the eye.(ABSTRACT TRUNCATED AT 250 WORDS)