The effects of topically applied epinephrine and timolol on intraocular pressure and aqueous humor cyclic-AMP in the rabbit

Intraocular pressure and aqueous humor cyclic-AMP concentrations were measured in albino rabbits following topical treatment of one eye with a single dose of 2% epinephrine alone, 0·5% timolol alone, or epinephrine after timolol pretreatment. Most animals demonstrated a significant hypotensive response 6 hr after epinephrine treatment, which lasted at least an additional 6 hr. However, aqueous humor c-AMP was significantly elevated 30 min after epinephrine treatment, peaked between 60 and 240 min, and declined to baseline by 6 hr before a significant ocular hypotensive response was noted. Timolol treatment alone had no significant effect on either intraocular pressure or aqueous c-AMP. However, in epinephrine-treated animals which were pre-treated with timolol, the c-AMP response was blocked, with no significant alteration of the hypotensive response. Previous reports in the literature suggested a causal relationship between elevated aqueous humor c-AMP and fall in IOP. On the basis of the present work, this relationship is questionable.     

A comparison of the ocular hypotensive efficacy of twice-daily 0.25% levobunolol to 0.5% timolol in patients previously treated with 0.5% timolol

Treatment with noncardioselective beta-adrenoceptor antagonists (e.g., 0.5% timolol or 0.5% levobunolol) is standard practice for lowering elevated intraocular pressure (IOP). However, because there are risks and side effects associated with the use of these agents, a lower, yet still effective, dose may be preferred. We gave 0.5% timolol twice daily for 30 days to 143 patients. In a double-masked, randomized fashion, we then assigned patients to continue to receive 0.5% timolol twice daily or 0.25% levobunolol twice daily for 8 weeks. The mean unmedicated baseline IOP for both groups was approximately 25 mm Hg. After 30 days of timolol pretreatment, the mean IOP in both groups decreased to approximately 19 mm Hg (p = 0.210). After the 30-day timolol pretreatment period, and subsequent randomization to either 0.5% timolol or 0.25% levobunolol treatment, there was little change in overall mean IOP (0.03 mm Hg decrease for levobunolol, 0.06 mm Hg increase for timolol; p = 0.811) from the timolol pretreatment baseline. One patient assigned to the timolol treatment group was terminated from the study due to inadequate control of IOP. We conclude that the mean IOP lowering effect of 0.25% levobunolol is equivalent to 0.5% timolol, and switching patients from twice-daily 0.5% timolol to twice-daily 0.25% levobunolol poses no significant risk of decreased ocular hypotensive efficacy.     

Effects and interactions of epinephrine, norepinephrine, timolol, and betaxolol on outflow facility in the cynomolgus monkey

Total outflow facility was determined in cynomolgus monkeys by two-level constant pressure perfusion. Topical epinephrine increased facility by 30% to 35% three to four hours after dosing, whether given as a single 600-micrograms dose or as twice daily 600-micrograms doses for three days. A single 5.5-micrograms intracameral dose of epinephrine or norepinephrine increased facility by 65% to 70% three to four hours after dosing. A single 180-micrograms topical dose of timolol or betaxolol had no effect on facility three to four hours later. Timolol pretreatment prevented the facility-increasing effect of both topical epinephrine and intracameral norepinephrine, but betaxolol pretreatment prevented neither. These findings indicate that no cumulative facility-increasing effect of epinephrine, beyond the acute (three hour) facility-increasing effect, develops within three days; there may be a facility-decreasing effect of large topical epinephrine doses on the vascular structures external to the trabecular meshwork; there is no, or only subthreshold, facility-affecting ambient beta-adrenergic tone in the meshwork; and the facility-increasing effect of both epinephrine and norepinephrine is mediated by beta 2-adrenergic receptors in the trabecular endothelium.     

Timolol maleate 0.5% versus timolol maleate in gel forming solution 0.5% (Timolol GFS) in open angle glaucoma in India. Preliminary safety and efficacy study

PURPOSE: To compare the efficacy and safety profile of Timolol maleate 0.5% versus Timolol gel forming solution (GFS) 0.5% in open angle glaucoma in Indian eyes. METHODS: In a prospective crossover study 52 patients of open angle glaucoma, well controlled intraocular pressure (IOP) on 0.5% timolol maleate solution were switched over to timolol GFS once a day, after a washout period of one month. A diurnal IOP measurement was done after 6 weeks and compared with patients on timolol maleate 0.5% twice a day. In addition, side effects reported or observed were compared. RESULTS: Statistically significant difference was not observed in ocular hypotensive effect of the two treatment. The side-effects in both the treatment groups were similar except for higher incidence of blurring of vision in patients on timolol GFS. The compliance was better with timolol GFS, but was not statistically significant. CONCLUSION: The results of this study suggest that the more convenient 0.5% timolol in gel forming solution can be offered as an equally efficacious and well-tolerated alternative to twice daily 0.5% timolol solution in open angle glaucoma.     

Ocular and cardiovascular response to topical carteolol 2% and timolol 0.5% in healthy volunteers.

Ocular and cardiovascular effects of carteolol 2%, timolol 0.5%, and dummy eyedrops have been measured in a single dose double-blind crossover study in six healthy volunteers. Both drugs lowered intraocular pressure and reduced exercise-induced tachycardia. Neither produced a significant change in resting heart rate or blood pressure. The two agents appear comparable as regards ocular hypotensive and cardiovascular effects.     

Timolol lowers intraocular pressure but does not inhibit the development of experimental myopia in chick

Reports of intraocular pressure (IOP) being higher in myopes than emmetropes and of myopes being over-represented in glaucoma statistics, are consistent with a role of IOP in the excessive eye growth typically associated with myopia. We tested the hypothesis, based on these observations, that ocular hypotensive drugs would slow myopia progression using the chick as an animal model and timolol as an example of such a drug. To induce myopia, chicks (n = 56) were fitted with either monocular translucent diffusers or -15 D spectacle lenses from day 8. The drug treatment protocol comprised topical applications of 0.4% benoxinate, a local anaesthetic (to improve drug absorption), followed either by 0.5% timolol or distilled water (control), either daily (1000 hr) or twice daily (1000, 1600 hr). Refractive errors and ocular dimensions were measured on days 12 and 17. We also verified the ocular hypotensive effect of timolol in both normal (n = 8) and myopic (n = 12 diffusers; n = 12-15 D lenses) chicks. Here, we took baseline IOP measurements, instilled timolol and then monitored IOP over a further 5-9 hr. We found no difference in the amount of myopia produced in the timolol and control groups at either measurement time point (e.g. day 17, once per day application, diffusers: -26.9 +/- 3.3 D vs -22.7 +/- 9.1 D; lenses: -14.9 +/- 3.8 D vs -14.9 +/- 3.6 D). This was in spite of the fact that timolol did lower IOP in both normal and myopic chicks (27 and 18% reduction, respectively) While timolol does have an ocular hypotensive effect in the chick, it does not inhibit the development of myopia in this animal model.     

Comparison of the effects of timolol and other adrenergic agents on intraocular pressure in the rabbit.

The effect of timolol, propranolol, epinephrine, and isoproterenol on intraocular pressure (IOP) (measured by tonometry) were compared after topical administration in conscious rabbits. Epinephrine and isoproterenol decreased IOP in normotensive rabbits, whereas propranolol had no effect. Timolol produced only a slight and inconsistent lowering of IOP in normotensive rabbits. All four agents reduced IOP elevated by an oral water load; the adrenergic agonists were substantially more active than the two beta-adrenergic blocking agents. In alpha-chymotrypsin-induced ocular hypertension, epinephrine, isoproterenol, and timolol were essentially equally effective, whereas propranolol exhibited only weak activity. In this latter model, timolol did not lose its effectiveness after multiple instillations (three/day) over an 8-day period. The concentration of timolol in the acqueous humor after topical application of effective hypotensive doses was relatively high as compared to that found in plasma. In addition, topical doses of timolol required to lower IOP were considerably greater than those needed to reduce or block the ocular hypotensive activity of isoproterenol. The mode of action and therapeutic implications of beta-adrenergic blocking agents in glaucoma are discussed.     

The effect of latanoprost on circadian intraocular pressure

The presence of a circadian variation of both intraocular pressure (IOP) and aqueous humor flow has been demonstrated in several studies. It must therefore be considered important to monitor IOP and evaluate the efficacy of ocular hypotensive drugs over the 24 hours of the day. The efficacy of latanoprost on IOP during both day and night has been evaluated and the most important results from four such studies are reviewed. The studies reviewed here clearly demonstrate that topical administration of latanoprost 0.005% once daily provided a steady reduction of the IOP during both day and night. Given as a single dose to healthy volunteers, latanoprost resulted in a sustained effect with a significant IOP reduction over 24 hours, and the reduction was still present, however less pronounced, even after 48 hours. Latanoprost administered once daily for 4 weeks to patients with glaucoma or ocular hypertension was more effective in reducing the IOP over 24 hours than timolol gel solution 0.5% once daily, timolol aqueous solution 0.5% twice daily, or dorzolamide 2% three times daily. Latanoprost applied once daily thus provided a better effect on the IOP together with a stable and sustained IOP reduction during both day and night.     

A Comparative Study of a Preservative-Free Latanoprost Cationic Emulsion (Catioprost) and a BAK-Preserved Latanoprost Solution in Animal Models

Abstract Purpose: Benzalkonium chloride (BAK), a common preservative in eye drops, can induce ocular surface toxicity that may decrease glaucoma therapy compliance. The ocular hypotensive effect, pharmacokinetic (PK) profiles, and local tolerance of a preservative-free latanoprost 0.005% cationic emulsion (Catioprost(?)), and a BAK-preserved latanoprost 0.005% solution (Xalatan(?)), were compared. Methods: The ocular hypotensive effect was evaluated in monkeys with elevated intraocular pressure (IOP) induced by laser photocoagulation of the trabecular meshwork. Each monkey (n=8) received both latanoprost formulations once daily for 5 consecutive treatment days in a crossover design with at least a 2-week washout period between treatments. IOP was measured at baseline (on day 1, no instillation), on vehicle treatment day (day 0), and on treatment days 1, 3, and 5 before drug instillation and then hourly for 6?h. In rabbits, the ocular and systemic concentrations of latanoprost free acid were determined following a single instillation and the local tolerance of twice daily instillations over 28 days was assessed. Results: Both the preservative-free and BAK-preserved latanoprost formulations shared the same efficacy profile with the maximum IOP reduction occurring 2?h after each morning dose (-15%, -20%, and -26%; -15%, -23%, and -23% on days 1, 3, and 5, respectively) and lasting through 24?h. The equivalence in efficacy was confirmed by the PK data demonstrating similar area under the curves (AUCs). While both formulations were well tolerated, the incidence of conjunctival hyperemia was reduced by 42% with the BAK-free latanoprost cationic emulsion. Conclusions: In animal models, a preservative-free latanoprost cationic emulsion was as effective as Xalatan(?) for lowering IOP with an improved ocular tolerance profile.     

A short term study of the additive effect of timolol and brimonidine on intraocular pressure

PURPOSE: To evaluate the additive ocular hypotensive effect of the combination of brimonidine and timolol on intraocular pressure (IOP) reduction in patients with glaucoma. METHODS: This was a prospective, randomized, double-masked, crossover study in 20 patients with primary open angle glaucoma (POAG) on therapy receiving timolol maleate 0.5% twice daily, with IOP greater than or equal to 22 mmHg in one eye. The treatment period was 3 weeks and during this period timolol + brimonidine or timolol + placebo were applied topically twice daily and IOP, blood pressure, heart rate and pupil size were measured. RESULTS: Combined therapy (timolol + brimonidine) had clinically significant IOP-lowering effect during the treatment period P < 0.01). The mean diurnal IOP was significantly reduced by an average of 5.1-5.9 mmHg (21.2-24.5%) compared with baseline value. The timolol + placebo combination had no clinically significant IOP-lowering effect (P > 0.05). No clinically significant side effects were observed during the treatment of both groups. CONCLUSIONS: This study showed that the combination of topically applied brimonidine and timolol cause a marked and sustained IOP reduction.     

Ocular hypertensive response to beta-adrenoceptor agonists

Acute administration of non-selective and relatively selective beta-adrenoceptor agonists elicit a monophasic fall in IOP. The present study indicates that unilateral application of certain beta-agonists on consecutive days can result in marked ocular hypertension. 1-Epinephrine, reproterol and 1-isoproterenol evoked an elevation of IOP on the second and third day after topical administration of a 2% solution in normal rabbits and in rabbits with surgically transected extraocular muscles. In contrast, the same concentration of d-isoproterenol produced hypotensive responses only when administered once daily for three consecutive days. Since d-isoproterenol did not cause a rise in IOP during chronic administration, the mechanism involved in the hypertensive response appears to be more sensitive to the levorotatory form. Administration of timolol inhibited the ocular hypertensive effect of epinephrine and reproterol. Since timolol lowers IOP by depressing formation of aqueous, it is suggested that the rise in IOP following chronic administration of beta-agonists possibly involves an increase in aqueous humor production.     

Timolol promotes reactivation of latent HSV-1 in the mouse iontophoresis model

The present study examined the effect of topical timolol, a nonspecific beta 1 and beta 2 blocker on reactivation and ocular shedding of latent HSV-1 in an improved mouse iontophoresis model. Latent trigeminal ganglionic infection was established in Balb/C mice following inoculation by corneal scarification with HSV-1 W strain, a clinical isolate, and confirmed by co-cultivation. On day 30, postinfection (pi), the mice were divided into two groups, and treatment begun with coded eye drops (timolol 0.5% or placebo) BID OU for 5 days. On day 31 pi, iontophoresis with 1% 6-hydroxydopamine was performed, and daily treatment with topical epinephrine and 1% prednisolone was administered. Reactivation and recovery of latent HSV-1 was determined by daily ocular swabs, and characteristic HSV-1 cytopathic effect in Vero cells. Results demonstrated that the timolol-treated group had a significantly greater number of positive eyes, multiple shedding episodes, and total shedding days compared to the control group. We conclude that beta blockade promotes recurrent ocular shedding induced by epinephrine in the mouse iontophoresis latency model.     

Pharmacokinetic basis for nonadditivity of intraocular pressure lowering in timolol combinations

The authors determined whether the ocular absorption of topically applied timolol in the pigmented rabbit was affected significantly by coadministration with either pilocarpine or epinephrine in the same drop to explain the nonadditivity in intraocular pressure lowering (IOP) seen clinically. They instilled 25 microliters of 0.65% timolol maleate solution (equivalent to 0.5% timolol), both in the presence and absence of 2.6% pilocarpine nitrate or 1% epinephrine bitartrate, into pigmented rabbit eyes. The time course of timolol concentration in the conjunctiva, anterior sclera, corneal epithelium, corneal stroma, aqueous humor, iris-ciliary body, and lens was monitored for 360 min by using reversed-phase high-performance liquid chromatography. The area under the timolol concentration-time curve in all but one of the anterior segment tissues was reduced by 20-50% (mean, 40%) when timolol was coadministered with pilocarpine and by 20-70% (mean, 42%) when timolol was coadministered with epinephrine. Such an effect was not a result of alterations in corneal permeability or aqueous humor turnover rate, nor was it related to the extent of systemic absorption caused by pilocarpine and epinephrine. Rather, the reduction in ocular timolol absorption may have been caused by the accelerated washout of timolol by tears stimulated by the coadministered drugs and, to a lesser extent, by the loss of timolol through binding to the increased amount of tear proteins induced by the coadministered drugs. Thus, the nonadditivity in IOP lowering from timolol-pilocarpine and timolol-epinephrine combinations is probably caused by changes in precorneal timolol clearance.     

The short-term IOP-lowering effect of brimonidine 0.2% and dorzolomide 2% combination in primary open-angle glaucoma

PURPOSE: To evaluate the ocular hypotensive effect of dorzolamide 2% in primary open-angle glaucoma (POAG) patients with intraocular pressure (IOP) of at least 22 mmHg despite ongoing twice daily treatment with brimonidine 0.2%. PATIENTS AND METHODS: Nineteen eyes of 19 patients with POAG and IOP >or= 22 mmHg, on twice daily brimonidine therapy, were included in the study. Intraocular pressure and adverse effects were recorded on days 2, 7, 14 and 30 after adding dorzolamide three times daily to the treatment. RESULTS: Mean pretreatment IOP was 27.6 +/- 2.2 mmHg. This decreased to 24.2 +/- 2.2 mmHg after a mean duration of 23.8 +/- 12.1 days. After dorzolamide was added to the treatment, mean IOP was 20.8 +/- 2.3 mmHg on day 2, 19.3 +/- 2.2 mmHg on day 7, 18.0 +/- 2.5 mmHg on day 14 and 17.2 +/- 2.3 mmHg on day 30. The differences between pre- and post-treatment IOP values were statistically significant (p < 0.0001, anova test). CONCLUSION: Dorzolamide administered three times daily has significant additive ocular hypotensive effect in POAG patients whose IOP is elevated despite ongoing treatment with brimonidine.     

Effects of betaxolol/timolol on epinephrine stimulated cyclic-AMP levels in human trabecular meshwork cells

The effects of timolol and betaxolol were compared for blocking beta agonist stimulation of cyclic-AMP in cultured human trabecular meshwork cells. Epinephrine (10^–5 M) produced a large and rapid increase in HTM cyclic-AMP; timolol (10^–6 M), at concentrations readily achieved in the aqueous humor after 0.5% eyedrops, completely blocked this effect. Recovery from timolol treatment appeared to be relatively slow, with only a 30–40% recovery observed by 9 hours. In comparison, betaxolol (10^–6 M) produced a smaller blockade of the epinephrine effects; a rapid recovery from the betaxolol effects was observed, with a greater than half-maximal response to epinephrine observed 15 minutes after removal of this beta blocker. These findings may help to explain the clinical observations of an outflow facility effect of epinephrine when used in combination protocols with betaxolol, but not with timolol.     

Timolol induces HSV-1 ocular shedding in the latently infected rabbit

Timolol iontophoresis into the eye can induce herpes simplex virus type 1 (HSV-1) shedding in rabbits latently infected with HSV-1 strain McKrae. Anodal iontophoresis of 0.01% timolol was done at 0.8 mAmp for 8 min once a day for 3 consecutive days. Viral shedding was determined by the presence of HSV-1 in the preocular tear film obtained by eye swabs. In two experiments, iontophoresis of 0.01% timolol resulted in all eyes (18/18) shedding HSV-1 for an average duration of 4.3 days. When 5.0% timolol was applied topically to rabbit eyes supersensitized by iontophoresis of 6-hydroxydopamine (6-HD), all eyes (10/10) shed virus for an average duration of 2.9 days. All eyes (12/12) receiving iontophoresis of 6-HD, pre- and posttreatment with topical application of 5.0% timolol, and posttreatment with topical application of 1.0% epinephrine shed virus for an average duration of 3.6 days. Eyes treated with topical application of 5.0% timolol alone showed no difference in HSV-1 ocular shedding, compared with untreated eyes. We concluded that both iontophoresis of 0.01% timolol and topical application of 5.0% timolol to adrenergically supersensitized eyes induced HSV-1 shedding reliably and with a high frequency, and that topically applied timolol does not block the HSV-1 ocular shedding induced by epinephrine in adrenergically supersensitized eyes.     

The short-term effect of adding brimonidine 0.2% to timolol treatment in patients with open-angle glaucoma.

Brimonidine, a highly selective alpha(2)-adrenoceptor agonist, was studied to determine its ocular hypotensive effect and side effects in patients with elevated intraocular pressure (IOP) while on continuing therapy with timolol. This was a prospective, randomized, placebo-controlled study in 15 patients with primary open-angle or pseudoexfoliation glaucoma on therapy receiving timolol 0.5% twice daily, with IOP greater than or equal to 22 mm Hg in one eye. IOP measurements, blood pressure and pulse rate were assessed on 2 days at a baseline and 1, 2, 4, 6 and 8 h later. A single drop of brimonidine 0.2% or placebo was added to treatment with timolol. The reductions in IOP at all time intervals observed with brimonidine + timolol were significantly greater than those with timolol + placebo. The maximum mean net decrease in IOP was 19.23 +/- 10.60% at 4 h. Statistically significant decreases in systemic blood pressure and pulse rate without clinical symptoms were observed in the group receiving brimonidine + timolol. This study suggests that a combination of brimonidine and timolol may have potential in the treatment of glaucoma. Further clinical trials with brimonidine are indicated to assess its further role as adjunctive agent.     

Ocular hypotensive effects of monoamine oxidase-A inhibitors in rabbit

The effects of monoamine oxidase-A (MAO-A) inhibitors with epinephrine on intraocular pressure in the pigmented rabbit were studied. MAO-A inhibitors were used topically with or without various concentrations of epinephrine. For the measurement of intraocular pressure, applanation pneumatonography was used and tissue MAO activities were determined by radiometric assay. After topical administration with clorgyline, MAO-A activities in the bulbar conjunctiva and the iris-ciliary body were remarkably inhibited, whereas MAO-B inhibition was minimal. Maximal reduction of intraocular pressure with 0.05% epinephrine was 3.2 mmHg. Single administration of clorgyline, amiflamine, moclobemide or CGP 11305-A caused decreases in the intraocular pressure of 2.0, 2.5, 1.8 and 2.4 mmHg, respectively. In the coadministration experiments with epinephrine, the ocular hypotensive effects of epinephrine were potentiated with clorgyline, amiflamine, moclobemide and CGP 11305-A (6.6, 4.8, 5.6 and 5.8 mmHg). On the contrary, they were not influenced by the MAO-B inhibitor deprenyl. These results indicated that MAO-A inhibitors potentiated the ocular hypotensive effects of epinephrine, and that the coadministration of a reversible MAO-A inhibitor with epinephrine might be useful for patients with glaucoma.     

Effect of topical indomethacin and timolol maleate on intraocular pressure in normal subjects

In a prospective randomized double-masked crossover study in ten healthy volunteers, conducted to determine if the intraocular hypotensive effect of timolol eyedrops was significantly affected by the concomitant use of the topically administered prostaglandin inhibitor, indomethacin, we found that significant ocular hypotension was achieved with timolol alone. This was not changed by the concurrent administration of indomethacin. The results provide further evidence that prostaglandins are not involved in the control of normal intraocular pressure.     

A 12 week study comparing the fixed combination of latanoprost and timolol with the concomitant use of the individual components in patients with open angle glaucoma and ocular hypertension

BACKGROUND: To compare the intraocular pressure (IOP) lowering effect and safety of the fixed combination of latanoprost and timolol with that of the concomitant use of the individual components. METHODS: A 12 week, double masked, randomised, crossover, multicentre study of patients with open angle glaucoma or ocular hypertension and IOP controlled on ocular hypotensive treatment (mean < or =21 mmHg). Patients received either a once daily morning dose of the fixed combination of latanoprost 0.005% and timolol 0.5% or once daily evening latanoprost 0.005% and twice daily timolol 0.5% for six weeks and then switched to the other combination. The primary efficacy endpoint was the within-patient difference in diurnal IOP between fixed and unfixed treatment combinations after six weeks of treatment; a one sided 97.5% confidence interval (CI) for the mean difference in IOP <1.0 mmHg indicated the fixed combination was not inferior to the unfixed combination. Adverse events were recorded at each visit. RESULTS: In all, 190 patients were included in observed cases analyses (93 fixed to unfixed combination; 97 unfixed to fixed combination). Mean IOP at baseline was 16.9 mmHg in both groups. The mean diurnal IOP was 17.0 mmHg after fixed combination treatment and 15.9 mmHg after unfixed combination therapy (p<0.0001). The difference in mean within-patient diurnal IOP was 1.1 mmHg favouring the unfixed combination (95% CI 0.8 to 1.4 mmHg). Both treatments were tolerated well. CONCLUSIONS: Although the primary efficacy endpoint was not met, once daily administration of the fixed combination of latanoprost and timolol was found to be safe and effective. The fixed combination provides a convenient alternative to the three instillations required with the individual components.