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PubMed1985

Six-year follow-up of the Norwegian Multicenter Study on Timolol after Acute Myocardial Infarction.

The original Norwegian Multicenter Study on Timolol after Myocardial Infarction was a double-blind, randomized study comparing the effect of timolol with that of placebo for up to 33 months after acute myocardial infarction. The initial results showed that the cumulated mortality rate was 39.4 per cent lower among 945 patients randomly assigned to timolol treatment than among 939 patients randomly assigned to placebo (P = 0.0003). After the end of the double-blind period the majority of participating patients in the timolol group continued to receive beta-adrenergic blockade, whereas the majority of placebo-treated patients continued without such blockade. During an extended follow-up of participating patients up to 72 months after randomization, the mortality curves of the two groups continued to rise in parallel. Cumulated mortality rates were 32.3 per cent in the placebo group and 26.4 per cent in the timolol group (P = 0.0028). We conclude that the previously observed early beneficial effect of beta-adrenergic blocking therapy is maintained for at least six years after infarction.

Adrenergic beta-Antagonists↗

PubMed2003

Comparison of the efficacy of the fixed-combination timolol/dorzolamide versus concomitant administration of timolol and dorzolamide.

The purpose of this study was to compare the efficacy of the fixed-combination solution of timolol 0.5%/dorzolamide 2% with the concomitant administration of its components, timolol 0.5% twice a day and dorzolamide 2% twice a day. Ninety-eight patients adequately controlled with a concomitant regimen of timolol and dorzolamide were switched to the fixed-combination regimen of the same components. Intraocular pressures at baseline and 4 weeks after the change in regimen were recorded. The mean baseline intraocular pressure (IOP) was 16.0 +/- 5.6 mmHg. Four weeks after the change in medication to the fixed-combination regimen, the mean IOP was 14.5 +/- 5.6 mmHg. The mean IOP change from baseline was -1.5 +/- 3.9 mmHg. The difference between the two treatment modalities was found to be statistically significant (p-value < 0.001). Eighty-one (83%) patients were considered successfully switched after 4 weeks of fixed-combination therapy, and seventeen eyes (17%) were deemed unsuccessful because a rise in IOP was detected. In conclusion, the fixed combination of timolol 0.5%/dorzolamide 2% twice a day provided equivalent or better intraocular pressure reduction in most patients who were successfully controlled on concomitant administration of its components, timolol and dorzolamide.

Adrenergic beta-Antagonists↗

PubMed1985

Comparative effects of SCH 19927 and timolol on intraocular pressure of conscious rabbits and relative systemic beta-blockade resulting from topical administration.

SCH 19927, the RR isomer of labetalol, has been shown to possess beta-blocking and vasodilator properties. It was compared to timolol for ability to lower intraocular pressure (IOP) in conscious rabbits. Its potential for systemic beta-blockade after topical administration was also assessed. Dose-related reductions in IOP followed topically applied SCH 19927 (0.1-1.0%). Timolol in concentrations less than 0.5% was not effective in lowering IOP. Timolol (0.1 and 0.5%) strongly inhibited tachycardia induced by iv isoproterenol. A 1.0% concentration of SCH 19927 was less effective than 0.5% timolol in inhibiting the isoproterenol-induced tachycardia; 0.1% SCH 19927 caused only minor inhibitory actions. Thus, not only is SCH 19927 at least as potent in lowering IOP in conscious rabbits, its topical administration results in less systemic beta-blockade than does timolol.

Animals↗

PubMed1985

Lack of metabolism of timolol by ocular tissues.

The ocular metabolism of timolol has been studied in the iris/ciliary body, vitreous humor, neuro-retina and cornea from an albino rabbit, pigmented rabbit and cynomolgus monkey by incubating tissues isolated from these animals with radiolabeled drug for 20 hours at 37 degrees C in Hanks' balanced salts solution. After removal of the tissues by centrifugation and subsequent deproteinization, supernatants were mixed with unlabeled timolol and analyzed by isocratic reverse phase high performance liquid chromatography with liquid scintillation counting and ultraviolet detection. Although this analytical system readily demonstrated the production of timolol metabolites by rat liver, the production of timolol metabolites by ocular tissues could not be demonstrated. With most samples high recoveries of unmetabolized timolol were obtained. The lowest level of recovery of unmetabolized drug as compared to a control (drug added after the tissue had been incubated) was obtained for the iris/ciliary body from the pigmented rabbit suggesting that pigment had bound the drug. Our results suggest that deleterious side effects sometimes seen with the drug or its lack of efficacy with rabbits is not due to ocular metabolism by these tissues.

Animals↗

PubMed1985

Systemic absorption of topically applied ocular timolol.

Symptoms and findings arising from the systemic beta blockade caused by topical ocularly applied timolol appear shortly after drug application. We studied the systemic absorption of 20 microliters of 0.5% timolol instilled unilaterally in the lower conjunctival cul-de-sac in 6 volunteers. At 3 min one subject, at 5 min three and at 8 min all but one showed measurable (greater than or equal to 215 pg/ml) timolol concentrations in the plasma. The rapid systemic absorption of topically applied ocular timolol observed in our study is consistent with the rapid appearance of the cardiovascular and pulmonary side effects reported in connection with timolol eye drop therapy.

Adult↗

PubMed1987

Effect of timolol on intraocular pressure elevation following argon laser iridotomy.

Argon laser iridotomy was performed in 123 eyes of 83 patients with primary angle-closure glaucoma. Sixty-three eyes received argon laser iridotomies with timolol pretreatment and the other 60 eyes served as controls. There were 43 eyes (71.7%) in the control group and 32 eyes (50.7%) in the timolol-pretreated group, whose intraocular pressure increased significantly over baseline level 2 hours after laser treatment. There was statistical difference in the incidence of intraocular pressure elevation in these two groups. Seven eyes (11.7%) in the control group and 4 eyes (6.2%) in the timolol-pretreated group had intraocular pressure elevation at least 11 mmHg over baseline. Additional 28 patients, who received argon laser iridotomy bilaterally, one eye with timolol pretreatment and the other eye served as a matched control, revealed that eyes which were timolol pretreated had statistically significant less intraocular pressure elevation.

Administration, Topical↗

PubMed1998

A comparison of trabeculectomy with topically applied timolol in a rabbit ocular hypertension model.

The difference in intraocular pressure (IOP) dynamics between trabeculectomy and topical instillation of timolol was compared in a rabbit ocular hypertension model. Twenty New Zealand white rabbits trabeculectomized with subconjunctival retention of 0.3 mL C3F8 gas in the right eyes were used as animal models. One week and three weeks after the operation, the left eyes of the rabbits were given three drops of 0.5% timolol, and IOP dynamics were compared between the two fellow eyes after intravenous infusion of 0.9% NaCl sterile solution. There were four parameters available in comparing IOP dynamics: Time Needed to Reach Peak IOP (TNRPI); Ascending Slope (AS); Peak IOP (PI); and Time Needed to Return to the Original IOP (TNROI). By this method, it was noted that, at the 7th day after the operation, the eyes trabeculectomized with subconjunctival retention of C3F8 gas had lower IOPs than the eyes that received topical instillation of timolol (baseline IOP: 14.7 +/- 4.2 vs. 19.5 +/- 2.5, p < 0.001, PI: 16.4 +/- 5.2 vs. 26.2 +/- 9.3, p < 0.001). In addition, at the 21st postoperative day, after intravenous infusion of 0.9% NaCl solution, the operated eyes showed less IOP spiking than the eyes that received topical instillation of timolol (TNRPI: 5.7 +/- 2.1 vs. 3.9 +/- 2.3, p = 0.014; AS: 0.8 +/- 0.5 vs. 2.7 +/- 2.6, p = 0.003; PI: 21.2 +/- 7.8 vs. 27.9 +/- 8.6, p = 0.014; and TNROI: 8.4 +/- 6.5 vs. 12.6 +/- 7.3, p = 0.06). These results suggested that trabeculectomy, rather than topical timolol, yielded better protection against IOP spiking in a transient rabbit ocular hypertension model.

Administration, Topical↗

PubMed2004

The effects on the intraocular pressure and visual field resulting from a switch in the treatment from timolol to betaxolol.

Patients with primary open-angle glaucoma (POAG) were dosed twice-daily with 0.5% timolol maleate for 2 years, followed by 2 years of twice-daily dosing with 0.5% betaxolol hydrochloride. The changes in intraocular pressure (IOP) and effects on visual field by each treatment were monitored over this 4-year period. Both the timolol and betaxolol treatments controlled IOP. The mean MD (mean deviation in visual field) values at 24 months of the timolol treatment were -6.18 dB (decibels) and -5.32 dB. Mean MD baseline values following 24 months of the timolol treatment produced 2.31 dB and 0.95 dB reductions in sensitivity in the right and left eyes, and the reduction in the right eye was statistically significant (p < 0.01). The mean MD values after 24 months of the betaxolol treatment were -3.82 dB in the right eyes, an increase of 2.36 dB, and -4.05 dB in the left eyes, up by 1.28 dB. The results from this clinical trial demonstrated that betaxolol was superior over timolol in improving mean retinal sensitivity.

Adult↗

PubMed2005

The efficacy of timolol in gel-forming solution after morning or evening dosing in Asian glaucomatous patients.

AIMS: The aim of this study was to determine the effectiveness of timolol gel-forming solution as a monotherapy and to compare the efficacy of timolol gel-forming solution morning instillation versus at night application in Asians with newly diagnosed open-angle glaucoma. METHODS: A retrospective, comparative, parallel group study was conducted on 78 eligible patients diagnosed with open-angle glaucoma who received topical timolol gel-forming solution either on morning (AM dosing group; 39 patients) or evening (PM dosing group; 39 patients) as monotherapy treatment. Intraocular pressure was taken at baseline, 1, 3, 6, and 12 months post-treatment. RESULTS: Mean baseline intraocular pressure (IOP) for timolol gel-forming solution in general was 22.7 +/- 6.6 mmHg with the mean IOP reduction of 5.7 +/- 5.3 mmHg (23.1% reduction). The mean IOP reduction of the AM dosing group was 7.5 +/- 5.2 mmHg (31.0% reduction) and 3.9 +/- 4.9 mmHg (15.1% reduction) in the PM dosing group (P = 0.0002). There was a statistically significant difference of IOP reductions between AM and PM dosing group at 1 month (P = 0.041), 3 months (P = 0.037) and 12 months (P = 0.015) post-treatment. Seventy-five percent (24) of good responders was in the AM group and 67.4% (31) of poor responders were patients in the PM group. CONCLUSION: Timolol gel-forming solution is effective in reducing IOP in Asian eyes. Morning dosing was more effective in lowering the IOP compared to evening dosing.

Adult↗

PubMed2005

Comparison of the effects of brimonidine 0.2% and timolol 0.5% on retinal nerve fiber layer thickness in ocular hypertensive patients: a prospective, unmasked study.

AIMS: The aim of this study was to compare the effects of brimonidine and timolol on retinal nerve fiber layer (RNFL) thickness in ocular hypertensive patients. METHODS: This was a prospective, comparative, and unmasked study. For 12 months, 38 eyes of 19 patients with primary open-angle glaucoma received brimonidine tartrate 0.2%, and 40 eyes of 20 patients received timolol maleate 0.5%. Intraocular pressure (IOP) was measured every 2 months, and RNFL thickness was assessed using Scanning laser polarimetry (GDx) at baseline and at 12 months. RESULTS: Mean IOP reduction was similar in both groups. Within each treatment group, the RNFL thickness for ellipse average (P = 0.004), superior (P = 0.035), temporal (P = 0.003), inferior (P < 0.0001), and nasal averages (P = 0.044) were significantly decreased from baseline in timolol at 12 months. However, the RNFL thickness for ellipse average and four quadrants showed no significant change from baseline in brimonidine. The between-group difference in RNFL change showed a significant reduction for ellipse average (P = 0.02), temporal (P = 0.005), and inferior averages (P = 0.016) following timolol therapy, as compared to brimonidine. CONCLUSIONS: There appear to be less progression for RNFL damage following brimonidine 0.2% therapy compared to timolol 0.5% in ocular hypertensive patients over 1 year. This finding does not correlate with IOP reduction.

Adult↗

PubMed2005

Comparison of latanoprost monotherapy and combined therapy of 0.5% timolol and 1% dorzolamide in chronic primary angle-closure glaucoma (CACG) in Japanese patients.

To compare the efficacy, adverse effects, and patient compliance of latanoprost monotherapy with unfixed combination therapy with 0.5% timolol maleate and 1% dorzolamide in the treatment of chronic primary angle-closure glaucoma (CACG), 36 Japanese patients with CACG following laser iridotomy (LPI) were treated for 12 weeks with instillation of latanoprost alone or with unfixed combination therapy of 0.5% timolol maleate and 1% dorzolamide hydrochloride. After 12 weeks of treatment, latanoprost reduced intraocular pressure (IOP) from 22.2 +/- 2.0 mmHg to 14.8 +/- 1.9 mmHg (33% reduction); timolol maleate and dorzolamide hydrochloride also reduced IOP from 22.5 +/- 2.2 mmHg to 17.1 +/- 2.7 mmHg (24% reduction). Latanoprost monotherapy significantly lowered IOP compared with unfixed combination therapy of 0.5% timolol maleate and 1% dorzolamide hydrochloride. Furthermore, a systemic adverse effect of bradycardia was not observed in the latanoprost monotherapy group. Concerning compliance, no significant difference was observed between the two groups. Thus, latanoprost monotherapy is more effective than unfixed combination therapy with 0.5% timolol maleate and 1% dorzolamide in the treatment of CACG following relief of pupillary block in Japanese patients.

Aged↗

PubMed1982

Effects of timolol on blood flow distribution in the feline myocardium with acute regional ischaemia during controlled haemodynamic conditions.

The beta-adrenergic blocking agent timolol was given to cats with acute coronary artery ligation under controlled haemodynamic conditions. Regional myocardial tissue flow was measured by the distribution of labelled microspheres. Timolol reduced cardiac contractility and left ventricular end-diastolic pressure rose, whereas heart rate and ventricular systolic pressure were kept constant by atrial pacing and aortic clamping. The systolic period increased following timolol administration under these conditions. Myocardial blood flow remained unchanged in central ischaemic and border areas, whereas flow increased both endocardially and epicardially in normally perfused area following timolol administration. Without pacing there was a significant flow reduction in the epicardium of the normally perfused area, compared with the situation where heart rate was constant. Under controlled haemodynamic conditions, therefore, timolol appears to improve coronary perfusion in normal myocardium, whereas blood flow to ischaemic myocardium remains essentially unchanged.

Animals↗

PubMed1983

Long-term effect of beta-blockade with timolol on maximal work capacity following myocardial infarction.

In a double-blind, randomized, placebo controlled trial 74 patients surviving a myocardial infarction (MI) were stress tested three and twelve months following MI. Thirty-eight patients received the beta blocking agent timolol and 36 patients received placebo. There was no significant difference in the mean total exercise capacity of the two groups. Most of the patients treated with timolol discontinued the exercise test because of exhaustion, but the placebo treated patients usually stopped the test because of chest pain, exhaustion or a fall in blood pressure. Patients treated with timolol had significantly less increase in heart rate, systolic blood pressure and rate-pressure product during exercise compared to placebo. We conclude that beta-blockade with timolol after MI does not affect work capacity, but timolol-treated patients perform the same work with a lower rate-pressure product.

Adult↗

PubMed1989

Effect of coenzyme Q10 on hemodynamic response to ocular timolol.

Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial membrane and plays an important role in the maintenance of normal cardiac function. To evaluate the effects of ocular timolol on the cardiovascular system and determine the protective effect of CoQ10, 16 patients with glaucoma were studied using impedance cardiography. Following instillation of 1 mg timolol maleate in each eye, heart rate (HR) and stroke index (SI) decreased, and total peripheral resistance index (TPRI) increased significantly. Reexamination was performed after 6 weeks of 90 mg oral CoQ10. Despite decreases in HR, percent changes in HR were significantly less after CoQ10 at 120 min. Stroke index showed an initial increase which was not observed without CoQ10. These data suggest that CoQ10 delayed the appearance of inotropic blockade of timolol and hastened the disappearance of chronotropic blockade. Additional study of six normal volunteers with 6 weeks of oral CoQ10 showed a similar decrease of intraocular pressure after timolol instillation as compared to those without CoQ10. Thus, administration of oral CoQ10 in patients receiving ocular timolol may be useful in mitigating cardiovascular side effects without affecting intraocular pressure in the treatment of glaucoma.

Administration, Oral↗

PubMed2001

Effect on intraocular pressure during 24 hours after repeated administration of the fixed combination of latanoprost 0.005% and timolol 0.5% in patients with ocular hypertension.

PURPOSE: To measure the effect on intraocular pressure (IOP) for 24 hours after repeated administration of the fixed combination of latanoprost 0.005% and timolol 0.5%. METHODS: A randomized, double-masked placebo-controlled crossover study including 20 patients with ocular hypertension was carried out. Patients were randomized to treatment with the fixed combination of latanoprost and timolol or with placebo. The eyedrop was taken at 8 AM. After 2 weeks of treatment, the patients were hospitalized, and the IOP was measured at 8 AM, and thereafter every other hour until midnight, and also at 3 AM, 6 AM, and 8 A.M. After a washout period of 4 weeks, they switched to the other eyedrop, and after 2 weeks of treatment were hospitalized and the IOP measurements were repeated at the same intervals. RESULTS: The mean 24-hour IOP was 14.7 +/- 0.3 mm Hg (mean +/- standard error of the mean) for latanoprost and timolol and 19.4 +/- 0.3 mm Hg for placebo. This corresponds to a significant IOP difference of 4.7 +/- 0.4 mm Hg (95% confidence interval 3.8-5.8; P < 0.001) between the two treatments in favor of the combination. At all measured time points, except at 3 AM, the mean IOP was lower with latanoprost and timolol than with placebo. During daytime measurements the mean IOP was 13.9 +/- 0.7 mm Hg for the fixed combination and 19.5 +/- 0.7 mm Hg for the placebo. Corresponding figures at nighttime were 16.1 +/- 0.7 mm Hg and 19.2 +/- 0.7 mmHg, respectively. CONCLUSIONS: The fixed combination of latanoprost and timolol significantly reduced IOP after administration once daily for 2 weeks in patients with ocular hypertension. A reduction of IOP during a 24-hour period was seen, with a greater IOP reduction during daytime compared with nighttime. The fixed combination applied once daily could be a convenient alternative to concomitant therapy with its individual components.

Adrenergic beta-Antagonists↗

PubMed2004

Dorzolamide/Timolol fixed combination versus concomitant administration of brimonidine and timolol in patients with elevated intraocular pressure: a 3-month comparison of efficacy, tolerability, and patient-reported measures.

BACKGROUND: To compare the intraocular pressure (IOP) lowering effect, tolerability, and patient-reported measures of the dorzolamide/timolol fixed combination and the concomitant administration of brimonidine and timolol after 3 months. METHODS: Four hundred ninety-two patients with ocular hypertension, primary open-angle glaucoma, exfoliative glaucoma, or pigmentary glaucoma participated in this randomized, observer-masked, multicenter study. Following 3 weeks of timolol monotherapy, patients with a peak IOP of > or = 2 mm Hg were randomized to receive either fixed combination dorzolamide/timolol twice daily or concomitant brimonidine plus timolol twice daily for 3 months. The IOP-lowering effects at peak and trough, tolerability, and patient-reported convenience and satisfaction were measured at months 1 and 3. RESULTS: At month 3 peak, the dorzolamide/timolol group had an adjusted mean (SE) change from baseline IOP of -4.30 (0.24) mm Hg versus -5.27 (0.23) mm Hg in the brimonidine-plus-timolol group, with a treatment difference of 0.97 mm Hg (95% CI: 0.40, 1.53). At the month 3 trough timepoint and both month 1 timepoints, the 95% CIs of the treatment differences were within the prespecified comparability boundary of +/- 1.5 mm Hg. The incidence of drug-related adverse experiences was similar between treatment groups. Patient-reported assessments of convenience and satisfaction showed no statistically significant differences between treatment groups. CONCLUSIONS: The IOP-lowering effect of the dorzolamide/timolol fixed combination and concomitant brimonidine plus timolol were comparable at 3 of the 4 timepoints measured. Patient-reported measures and the incidence of adverse experiences in both treatment groups were similar.

Adult↗

PubMed1981

Effect of timolol on late ventricular arrhythmias after acute myocardial infarction.

This is a subproject of the Norwegian timolol myocardial infarction study carried out at one of the clinical centers. High risk patients surviving either a reinfarction or large initial infarction were randomized to placebo (44 pts) or timolol (37 pts). A 24 hour ECG was obtained the day before randomization (at baseline, 7-28 days after the acute attack) then 3 days, 1 month and 6 months after start of therapy. During this period the number of patients with one or more of ventricular couplets, bigemini, ventricular tachycardia or early cycle premature ventricular contractions (PVC) (i.e. complex ventricular arrhythmias) and the average number of PVC per hour increased significantly in the placebo group but not in the timolol group. The results indicate that there is an increased severity and incidence of ventricular arrhythmias in the first 6 months after myocardial infarction. Timolol effectively inhibited this trend. The importance of timolol as an antiarrhythmic agent may therefore be to prevent subclinical infarction extension and secondary ventricular arrhythmias related to the size of the myocardial damage.

Arrhythmias, Cardiac↗

PubMed1985

Timolol and atenolol: relationships between oxidation phenotype, pharmacokinetics and pharmacodynamics.

The pharmacokinetics and pharmacodynamics of atenolol and timolol were studied in six extensive and four poor metabolisers of debrisoquine. There was a significant correlation between the debrisoquine to 4-hydroxydebrisoquine ratio and the area under the plasma concentration time curve (AUC) for timolol (rs = 0.75, P less than 0.02). The mean of the AUC values for timolol was significantly greater in the poor metabolisers than in the extensive metabolisers (P less than 0.05). There was a significant correlation between the debrisoquine to 4-hydroxydebrisoquine ratio and beta-adrenoceptor blockade 24 h after dosing with timolol (rs = 0.66, P less than 0.05). The mean degree of beta-adrenoceptor blockade was significantly greater in the poor metabolisers than in the extensive metabolisers 24 h after dosing with timolol (P less than 0.01). There was no relation between the debrisoquine to 4-hydroxydebrisoquine ratio and the pharmacokinetics or pharmacodynamics of atenolol.

Adrenergic beta-Antagonists↗