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PubMed1990

Steady-state pattern electroretinogram following long term unilateral administration of timolol to ocular hypertensive subjects.

To determine whether long-term reduction of intraocular pressure leads to a corresponding preservation of the pattern electroretinogram (PERG), PERGs were studied in 21 patients with ocular hypertension who had received unilateral timolol therapy for a minimum of 6 years. The mean difference in intraocular pressure (IOP) between the placebo-treated and the timolol-treated eyes (over 6 years) was 2.4 mm Hg. Steady-state PERGs (16.0 rps) were obtained simultaneously in both eyes of each patient, with four check sizes (0.25, 0.5, 1.0 and 2.0 degrees). Significant (p less than 0.05) steady-state PERG deficits (i.e., amplitude more than two standard deviations below the mean value of age-matched controls) were observed in 16 eyes of 12 patients (10 placebo-treated and 6 timolol-treated eyes). The mean PERG amplitude did not differ significantly between the placebo-treated and timolol-treated eyes. However, a significant correlation (r = -0.423) in the IOP differences between the placebo-treated and timolol-treated eyes and the corresponding PERG amplitude differences was noted in three of the four test conditions (i.e. 0.25, 0.5, and 1.0 degrees). These results suggest that reducing IOP may preserve ganglion cell function in some patients with ocular hypertension.

Aged↗

PubMed1996

A complex interaction between topical verapamil and timolol on intraocular pressure in conscious rabbits.

Calcium channel blockers have complex actions on aqueous humour dynamics that seem to depend on the route of drug administration. When applied topically, verapamil and nifedipine effectively lower intraocular pressure. However, these drugs also produce a slight reduction in aqueous humor outflow through the trabecular meshwork whereby they could modify the effect of other drugs on intraocular pressure. As calcium channel blockers could be effective in the management of ocular hypertension and low-tension glaucoma, the aim of the present work was to assess the interaction between verapamil and timolol when both drugs are topically applied to the eye of albino rabbits. Intraocular pressure was measured with a manual applanation tonometer. The effects of 5-6 different doses of each drug alone and the effects of five mixtures of both drugs at fixed concentration ratios (timolol: verapamil 4:1, 2:1, 1:1, 1:2 and 1:4) were evaluated. After measuring baseline intraocular pressure, one 50 microliters drop of the different solutions was instilled in the left eye. Measures of the intraocular pressure were repeated at intervals of 30 min until the maximal effect was reached. Each set of experiments was carried out in a group of 9-11 rabbits. Dose-response curves were fitted with a nonlinear regression microcomputer programme. The median effect plot was constructed as proposed by Chou and Talalay (1981, 1983, 1984). In order to analyse the nature of the interaction between both drugs, the observed effect was compared with the theoretically expected one and the combination indices, that relate the doses of verapamil and timolol present in the mixtures with the doses of both drugs separately which are equieffective with the combination, were calculated. The effects of verapamil and timolol followed the principle of the mass action law when administered alone. Nevertheless, no adequate dose-response relationship was obtained when the mixtures of both drugs were applied. In general, the observed effects were lower than the expected ones. Combination indices also indicate the presence of antagonism, except for the lowest concentrations of mixtures where verapamil predominates. In this case, combination indices suggest summation of effects or synergy. Both drugs seem to decrease intraocular pressure by reducing aqueous humor secretion through different mechanisms. However, due to the reduction of aqueous humor outflow caused by verapamil, the ocular hypotensive effect of timolol may be antagonized when high doses of verapamil are administered.

Administration, Topical↗

PubMed1992

Acetazolamide but not timolol lowers aqueous humor flow in sleeping humans.

The effect of timolol, acetazolamide, and the combination of the two drugs on the rate of aqueous formation in 18 healthy human subjects was measured during the day and at night in a placebo-controlled, double-masked, randomized study. In the absence of any drugs, aqueous flow during the day was 2.61 +/- 0.82 (mean +/- SD) microliters/min and at night, 1.08 +/- 0.59, a 59% lower flow rate when compared with the daytime value (P < 0.0001). When compared with these aforementioned control values, timolol alone reduced the rate of aqueous flow by 39% (P < 0.0001) in awake subjects but had no statistically significant effect on the flow rate in sleeping subjects (P = 0.33). Acetazolamide alone reduced aqueous flow during the day by 21% compared with the control flow rate (P = 0.02) and at night by 24% below the nocturnal flow rate in the sleeping eye (P = 0.04). The combination of the two drugs reduced flow during the day by an additional 13% (P = 0.024) compared with the flow rate achieved by timolol alone, and by an additional 32% (P < 0.0001) compared with the flow rate reduction attained by acetazolamide alone. There was no statistically significant difference in the nocturnal flow rates achieved by acetazolamide alone or in combination with timolol (P = 0.37). These data confirm previous studies demonstrating the effect of timolol, acetazolamide, and sleep on the rate of aqueous humor formation. Unlike a previous study, it was found that acetazolamide lowers the aqueous flow below the already low nocturnal flow rate that occurs spontaneously in the sleeping eye.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetazolamide↗

PubMed1994

Topical timolol with and without benzalkonium chloride: epithelial permeability and autofluorescence of the cornea in glaucoma.

Epithelial permeability and autofluorescence of the cornea were determined by fluorophotometry in 21 patients with open-angle glaucoma or ocular hypertension using timolol medication with the preservative benzalkonium chloride (BAC) and 2 weeks after changing to timolol medication without BAC. The investigation was performed to determine whether removal of BAC would reduce toxic effects on the cornea and complaints of sensations of burning or dry eye. Corneal epithelial permeability decreased significantly after changing medication (mean decrease per patient 27%, P = 0.025). Corneal autofluorescence increased significantly after changing medication suggesting an alteration in corneal metabolism (mean increase per patient 6%, P = 0.003). Timolol without BAC was found to be as effective as timolol with BAC in reducing intraocular pressure (P = 0.4). Removal of BAC from timolol resulted in an improvement of corneal epithelial barrier function and in a reduction of complaints. The improvement was found to be proportional to the duration of the preceding BAC-containing therapy.

Administration, Topical↗

PubMed1993

Pharmacokinetics and beta-blocking effects of transdermal timolol.

The pharmacokinetic profiles of transdermal timolol 6 and 24 mg (as 5 and 20% w/v patches) was studied in four healthy young volunteers. To assess its bioavailability, the pharmacokinetics of an IV infusion of timolol maleate 5 mg was also determined in the same subjects. When the 20% (w/v) timolol patch was applied, the mean bioavailability was 74.4%. Plasma timolol concentrations were below the detection limit when a 5% patch was applied to the same skin area in all four subjects, except for one in whom the bioavailability was 23.6%. Weak erythema developed at the application site in all of the volunteers after application of the 20% (w/v) patch. However, erythema did not develop in any volunteer when the 5% patch was applied. The beta-blocking effect was determined by exercise testing. Similar plasma levels generated similar changes in exercise-induced heart rate after the transdermal and intravenous administration of timolol.

Administration, Cutaneous↗

PubMed1981

Dose-related interaction between timolol and adrenaline.

The effects on IOP of a combination of oral timolol maleate and adrenaline eye drops were investigated in a double-blind randomized trial using health volunteers. Timolol was given in two doses, 20 and 5 mg a day. One percent adrenaline eye drops were given to one eye, placebo to the other. The results showed a significant additive effect of adrenaline with the smaller dose of timolol, but with the larger dose of timolol the effect of adrenaline was antagonistic. These results may be due to an incomplete beta-blockade with the smaller dose of timolol, but a complete blockade with the larger dose.

Dose-Response Relationship, Drug↗

PubMed1989

Vasoconstrictive effect of topical timolol on human retinal arteries.

Timolol is widely used in glaucoma treatment without sufficient knowledge of its vascular retinal effects. In this study, we measured the retinal vessel diameters before and after instillation of 0.5% timolol twice daily in one eye for 1 week, using photographic enlargements (x44). A total of 12 normal, caucasian subjects aged 25-39 years (average, 30.6 +/- 4.2 years) participated in this study. In all, 75% of the subjects had a diminution of retinal arterial size in the treated eye. The mean arterial diametric decrease was 4.1% in treated eyes compared with both untreated eyes and pretreatment values of treated eyes. These diminutions were statistically significant according to Student's paired t-test (P less than 0.05). No statistical difference was found in venous diameters (t = -0.065). Results showed that 0.5% timolol may have a vasoconstrictive effect on the retinal arteries of normal human subjects after 1 week of unilateral instillation twice daily. We suggest that this arterial vasoconstriction could be caused by the effect of timolol on the vascular beta-2 receptors. Further investigations are warranted to determine whether timolol also acts on ciliary arteries and whether arterial vasoconstriction participates in lowering intraocular pressure.

Adult↗

PubMed2002

A comparison of the fixed combination of latanoprost and timolol with its individual components.

PURPOSE: To evaluate the intraocular pressure (IOP)-reducing effect of the fixed combination of 0.005% latanoprost and 0.5% timolol compared with the individual monotherapies. METHODS: A 6-month, randomised, double-masked, controlled multicentre study followed by 6 months of open-label treatment was carried out in patients with glaucoma or ocular hypertension with pre-enrolment IOP >/=25 mmHg on glaucoma medication or >/=30 mmHg if untreated. Following a 2- to 4-week run-in period on timolol twice daily, 436 patients were randomised: 140 to fixed combination therapy once daily in the morning, 147 to latanoprost once daily in the morning and 149 to timolol twice daily. During the open-label extension, patients received fixed combination drug once daily in the morning. RESULTS: The difference in mean change from baseline in diurnal IOP from week 2 to week 26 was -1.2 mmHg between fixed combination and latanoprost (95% confidence interval. CI: -1.8 to -0.5; P<0.001; repeated-measures analysis of covariance). The corresponding difference between fixed combination and timolol was -1.9 mmHg (95% CI -2.5 to -1.2; P<0.001). No long-term drift in IOP was detected in patients treated for 12 months with fixed combination. All treatments were well tolerated with no major differences among groups in the incidence of clinically relevant adverse events. CONCLUSION: The fixed combination of 0.005% latanoprost and 0.5% timolol administered once daily in the morning for 6 months was more effective in reducing IOP than the individual components alone and was effective over 12 months.

Aged↗

PubMed1986

Relative effects of propranolol and timolol on ventricular fibrillation threshold and hemodynamics in the dog.

The relationship between the antifibrillatory and hemodynamic effects of propranolol and timolol was tested in 32 dogs divided into three groups. In closed-chest animals (group 1), the maximal increase of the ventricular fibrillation threshold (VFT) from the control state was 67.3 +/- 22.6% (n = 5, p less than 0.01) for propranolol and 95.8 +/- 18.8% (n = 9, p less than 0.005) for timolol. These effects were paralleled by a decrease in the cardiac index of 34.7 +/- 10.2% (p less than 0.05) and 32.5 +/- 9.4% (p less than 0.02) for propranolol and timolol, respectively. The mean systemic arterial pressure (SAP) also decreased by 25.0 +/- 8.8% (p less than 0.05) and 19.2 +/- 5.1% (p less than 0.01). In open-chest animals (group 2), timolol increased the VFT by 86.6 +/- 27% (n = 5, p less than 0.05) and decreased the cardiac index by 57.3 +/- 6.3% (p less than 0.005) and the mean SAP by 28.5 +/- 2.9% (p less than 0.02). In open-chest animals with stabilized peripheral hemodynamics (group 3), VFT increased by 354 +/- 130% (p less than 0.05) and 437 +/- 144% (p less than 0.05) after the maximal administered doses of propranolol (n = 6) and timolol (n = 7), respectively. These results suggest that the electrophysiologic and hemodynamic effects of beta blockade are parallel and interdependent, with the hemodynamic deterioration markedly blunting the beneficial electrophysiologic effects.

Animals↗

PubMed1986

Repeated exercise and redistribution thallium-201 scintigrams in patients with myocardial infarction treated with timolol or placebo.

Repeat exercise thallium-201 scintigrams were performed 2 weeks, 3 months, and 6 months in 27 patients following their first myocardial infarction. All patients were treated with timolol or matching placebo, administered intravenously starting within 5 hours of onset of chest pain. The extent of transient perfusion defects in 15 timolol-treated patients increased significantly between 2 weeks and 3 months compared to a decrease in 12 placebo-treated patients (p less than 0.05). Between 3 and 6 months the extent of transient defects did not change in the two groups, and there was no difference between the groups. The extent of permanent defects was not significantly different between the timolol- and placebo-treated patients on any occasion. However, patients in the timolol group had a decrease in permanent defects with time in contrast to patients in the placebo group (p less than 0.05). Thus, early intervention with timolol in the acute phase of myocardial infarction may have consequences for the postinfarction phase, as reflected in repeat thallium-201 scintigrams.

Adult↗

PubMed1992

Effect of timolol on cardiopulmonary exercise performance in men after myocardial infarction.

The effect of the nonselective beta blocker timolol on maximal cardiopulmonary exercise performance was evaluated in 28 men with previous myocardial infarction without effort angina (mean age 63 +/- 8 years). Patients were randomized to placebo or timolol (10 mg twice daily) for 4 weeks and then crossed over to the alternative therapy in a double-blind manner. At the completion of each treatment period, patients underwent symptom-limited maximal cardiopulmonary exercise on a cycle ergometer. Exercise time, heart rate, oxygen consumption (VO2), oxygen (O2) pulse and respiratory exchange ratio were measured at peak exercise and at a submaximal exercise level defined at a respiratory exchange ratio of 1.00. Timolol treatment reduced peak heart rate from 153 +/- 11 to 102 +/- 14 beats/min (-33%, p less than 0.001). Exercise time decreased from 680 +/- 91 to 633 +/- 78 seconds (-7%, p less than 0.001). Peak VO2 decreased from 25.3 +/- 4.7 to 21.4 +/- 3.5 ml/min/kg (-15%, p less than 0.001). O2 pulse increased from 12.9 +/- 1.9 to 16.7 +/- 2.3 ml/beat (+29%, p less than 0.001). Peak respiratory exchange ratio did not change significantly, indicating comparable effort. At submaximal exercise, defined at a respiratory exchange ratio of 1.00, there was no difference in exercise time between placebo and timolol. Heart rate decreased with timolol compared with placebo, from 126 +/- 16 beats/min by 31% (p less than 0.001), VO2 decreased from 18.5 +/- 4.3 ml/min/kg by 10% (p less than 0.001), O2 pulse increased from 11.5 +/- 2.0 ml/beat by 30% (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1978

A comparison of the effects of timolol and epinephrine on intraocular pressure.

We conducted a double-masked, six-week crossover study comparing bilateral twice-a-day therapy with timolol maleate (0.1%, 0.25%, and 0.5%) and epinephrine hydrochloride (0.5%, 1.0%, 2.0%) in 36 otherwise untreated patients. Increasing concentrations of each drug were administered until an arbitrary level of control was achieved before each of the six-week follow-up periods. Seventeen patients were controlled by both drugs and four patients were controlled by neither drug. Timolol, but not epinephrine, was effective in ten patients, whereas epinephrine, but not timolol, was effective in two patients. Three patients did not complete the study. The mean decrease in intraocular pressure from baseline was significantly greater with timolol than with epinephrine both before crossover and overall at both the lowest and highest concentrations of drug used. Significantly toxicity was produced in four patients during treatment with epinephrine, but in no patients during treatment with timolol.

Adult↗

PubMed1986

Comparison of two treatment schedules for combined timolol and dipivefrin therapy.

In a prospective, randomized, single-masked, cross-over study, 18 patients with primary open-angle glaucoma were treated for one month with each of the following regimens: timolol 0.5% twice daily, timolol 0.5% plus dipivefrin 0.1% twice daily given ten minutes apart, and timolol 0.5% plus dipivefrin 0.1% given twice daily four hours apart. An eight-hour intraocular pressure curve was obtained before treatment and at the end of each monthly regimen. When added to timolol therapy, dipivefrin produced a small but statistically significant additional mean decrease in intraocular pressure. The difference in intraocular pressure reduction between the two regimens for combined timolol and dipivefrin therapy was not statistically significant.

Adult↗

PubMed1977

Protective action of timolol in acute myocardial ischemia.

Timolol, a beta-adrenoceptor blocking agent with little or no cardiodepressant activity, was studied in acute myocardial ischemia in cats. Timolol, at a dose of 25 mug/kg, blocked 75 to 80% of the cardiac response to isoproterenol. This dose also significantly reduced heart rate in cats subjected to acute myocardial ischemia by ligation of the left coronary artery. Timolol significantly prevented the spread of ischemic damage in the myocardium as assessed by (a) curtailing the increase in plasma creatine phosphokinase (CPK) activity, (b) preventing the loss of CPK from the ischemic portion of the myocardium, and (c) restoring the elevated S-T segment of the electrocardiogram toward normal. Timolol did not significantly retard the increase in fragility of lysosomes in ischemic myocardial tissue. The mechanism of the protective effect to timolol on the ischemic myocardium appears to be via reducing myocardial oxygen demand by decreasing heart rate.

Adrenergic beta-Antagonists↗

PubMed1988

Binding of the beta-blockers timolol and H 216/44 to ocular melanin.

The eyes from pigmented rabbits were instilled with the beta-adrenoceptor antagonists H 216/44 or timolol. After a single instillation (1.9 mumol), the iris and ciliary body contained H 216/44, which decreased with a half-life of approx. 43 days. Daily instillation caused a gradual increase in the content of H 216/44 and timolol in the iris and ciliary body, the steady-state concentration of timolol being 10 times higher than that of H 216/44. The concentrations of H 216/44 were seven times higher in the iris and ciliary body of pigmented rabbits than in albino animals. H 216/44 was reversibly bound to the melanosomes from the iris and ciliary body and not metabolized in this tissue. In vitro binding of timolol and H 216/44 to bovine melanosomes showed comparable multi-site binding curves. The binding of chlorpromazine was substantially higher. The beta-blockers could be more readily released from the melanosomes with aqueous solutions of salt and ethanol than with distilled water. It is concluded that both H 216/44 and timolol bind reversibly to ocular melanin. The differences in binding characteristics in vitro may only partly explain the differences in the in vivo binding to ocular melanin in the rabbit eye.

Adrenergic beta-Antagonists↗

PubMed1992

Light-dark variations in ocular timolol concentrations following topical solution instillation in the pigmented rabbit.

The objective of this study was to determine whether ocular absorption of topically applied timolol in the pigmented rabbit varied with the time of drop instillation. Twenty-five microliters of a 0.65% timolol maleate solution were instilled in the pigmented rabbit eye at 0600, 0900, 1200, 1500, 1800, 2100, 2400, or 0300 hr. Timolol concentrations in the conjunctiva, sclera, corneal epithelium, corneal stroma, aqueous humor, and iris-ciliary body at 15 and 30 min post-dosing were monitored using reversed phase HPLC. Ocular timolol concentrations were higher when the drug was administered during the light period (0900-1800 hr) than when it was administered during the dark period (1800-0600 hr). There exist, therefore, light-dark variations in the ocular absorption of topically applied timolol.

Absorption↗

PubMedDate not supplied

Timolol in the therapy of "ocular hypertension".

Timolol has been shown to be at least as effective as pilocarpine and epinephrine in the therapy of open angle glaucoma. To date there appear to have been few serious side effects from timolol when it has been used in patients without cardiac or pulmonary disease. The decision whether and when to treat a patient with elevated intraocular pressure depends upon a weighing of risk of glaucoma damage versus the side effects of the drugs used in therapy. The use of the beta blocking agents, particularly timolol, in the therapy of ocular hypertension is considered. Reports on the efficacy and safety of timolol are cited, and the author's reevaluation of their own series of patients treated with timolol for 17-36 months is discussed.

Adrenergic beta-Antagonists↗

PubMed1983

Combined timolol and epinephrine therapy for open angle glaucoma.

A survey of the literature concerning the interaction of timolol and epinephrine in lowering intraocular pressure, and a study comparing the efficacy of timolol and dipivefrin (a prodrug of epinephrine) to that of timolol and pilocarpine are presented. These observations suggest that timolol-epinephrine therapy is less effective than timolol-pilocarpine treatment, although the former combination has clinical value in some patients, and it is possible that this can be enhanced when special schedules for drug administration are used.

Drug Therapy, Combination↗