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PubMed1990

Effect of timolol maleate on the retinal circulation of human eyes with ocular hypertension.

We studied the effect of topical timolol maleate 0.5% on the retinal circulation of eyes with ocular hypertension using laser Doppler velocimetry and monochromatic fundus photography. Patients with ocular hypertension had normal eye examinations and had documented elevated intraocular pressures of 23 mmHg or higher on two or more separate occasions. In a double-masked randomized design, one eye of each subject received timolol maleate 0.5% and the fellow eye received placebo. Vessel diameter, maximum velocity of red blood cells, and volumetric blood flow rate were determined in a major retinal vein of each eye just prior to the instillation of drops, and then 2 hr later. In comparison to the baseline value, there was an increase of 12.0% in average red blood cell velocity (P less than 0.005, statistically significant) and of 8.4% in volumetric blood flow rate in the timolol-treated eyes (P less than 0.05, statistically significant). No significant changes in these quantities were observed in the placebo-treated eyes. Also, no significant change in venous diameter was detected in the placebo- and the timolol-treated eyes. In comparison to the baseline, a significantly larger increase in red blood cell velocity was observed in the timolol-treated eyes than in the placebo-treated eyes (P less than 0.05). The difference between the increase in blood flow observed in the timolol-treated eyes and the placebo-treated eyes achieved a probability value of P = 0.058. The increase in blood flow observed in the timolol-treated eyes may be related to the increase in perfusion pressure produced by this drug.

Administration, Topical↗
PubMed1989

Timolol treatment prevents or delays glaucomatous visual field loss in individuals with ocular hypertension: a five-year, randomized, double-masked, clinical trial.

A 5-year, randomized, double-masked, clinical trial was conducted to determine whether treatment with topical timolol maleate was effective in preventing or delaying the onset of glaucomatous visual field loss in subjects with ocular hypertension. Sixty-five individuals considered to be at moderate risk for developing open-angle glaucoma were recruited for the study. In each patient, one eye was chosen randomly to receive timolol twice-daily while the fellow eye received diluent (placebo). Timolol administration reduced IOP from baseline in the treated eyes over the course of the study by a mean +/- SD of 4.9 +/- 3.4 mm Hg. Timolol administration also produced a mean +/- SD contralateral reduction of IOP from baseline in the untreated fellow eyes of 2.9 +/- 3.1 mm Hg. The mean +/- SD difference in IOP between the treated and untreated eyes during the study was 2.3 +/- 2.6 mm Hg. Over the course of the study reproducible visual field loss developed in 4 timolol treated eyes and 10 placebo treated eyes (P = .039, McNemar test). Clinical progressive optic disc cupping was noted in four treated and eight untreated eyes (P = .11, McNemar test). In the 42 subjects who completed a minimum 4-year follow-up, baseline and final optic disc photographs were analyzed using a computer image analysis system to determine changes in the area of disc pallor. The mean +/- SD increase in optic disc pallor was 0.86% +/- 2.4% in the timolol treated eyes and 1.80% +/- 3.6% in the placebo treated eyes. This difference was statistically significant (P = .04, paired t-test). This study provides evidence that medical treatment prevents or delays the onset of glaucomatous visual field loss and optic disc damage in individuals with ocular hypertension. The magnitude of the protective effect of timolol was partially obscured by the contralateral reduction of IOP in the placebo treated fellow eyes.

Adult↗
PubMed1987

Improved corneal penetration of timolol by prodrugs as a means to reduce systemic drug load.

A major problem in the use of timolol in glaucoma therapy is its relatively high incidence of cardiovascular and respiratory side effects. This report presents preliminary evidence for the feasibility of a prodrug approach to minimize systemic absorption of timolol using a reduced topical dose made possible by improved corneal drug penetration. The results indicate that the O-acetyl, propionyl, butyryl, and pivalyl ester prodrugs of timolol were virtually completely hydrolyzed between 30 and 150 min when incubated with plasma, aqueous humor, and ocular tissue homogenates of pigmented rabbits. Moreover, the in vitro corneal penetration of all but the O-pivalyl prodrug was 2-3 times higher than timolol. This was accompanied by a four- to sixfold increase in aqueous humor concentration at 5 and 30 min post-instillation of 15 mM solutions, although the plasma timolol concentration at the same time points was either unaltered or slightly reduced. Collectively, these preliminary findings suggest that at least a twofold reduction in the topical dose of timolol is possible by using prodrugs, thereby reducing timolol concentration in the systemic circulation and possibly the incidence of cardiovascular and respiratory side effects.

Animals↗
PubMed1983

The Timolol Myocardial Infarction Study: an evaluation of selected variables.

The Timolol Myocardial Infarction Study was a completely randomized program of 1884 survivors of myocardial infarction comparing timolol maleate, 10 mg twice daily, with placebo for the secondary prevention of sudden death and reinfarction. In that study, timolol maleate reduced total mortality (152 placebo vs 98 timolol) and the incidence of first nonfatal reinfarctions (131 placebo vs 90 timolol). This report evaluates the effect of timolol in selected categories--age, sex, infarction site, heart size, transmural infarction, diabetes, smoking, multiple reinfarctions and pulse. These data document two important facts. First, the effects of timolol in the total sample were also seen in different subpopulations, and there were no major subgroups for which this positive effect would not be expected. Second, the consistency of the effects observed with respect to pulse, transmural infarction, age and infarct site are in contrast to some previous studies with practolol, propranolol, and alprenolol. Thus, beta blockers may not be identical with respect to reducing the mortality and morbidity associated with acute myocardial infarction.

Aged↗
PubMed1983

A multicenter study on timolol in secondary prevention after myocardial infarction.

Patients who survive the acute phase of myocardial infarction have a high mortality in the following years. The mortality is largely due to sudden cardiac death or recurrent myocardial infarction. The main purpose of the present study was to clarify whether long-term treatment with the beta-adrenergic blocking agent timolol would improve prognosis in such patients. In order to recruit the sufficient number of patients to resolve this question a multicenter study was performed. This study, named "The Norwegian Multicenter Study On Timolol After Myocardial Infarction" was designed as a randomized, double-blind, placebo controlled trial. Twenty hospitals in Norway collaborated within an organizational structure aiming to achieve a maximum of standardization of study procedures. From a representative population of patients less than 75 years of age surviving the acute episode of infarction 52% were recruited for the study. The recruitment rate was high at all hospitals. The 1884 patients included were stratified into 3 risk groups before randomization. Risk Group I (18%) were patients with a recurrent infarction. Risk Group II (58%) were patients with a first infarction considered to be at high risk of sudden cardiac death. The rest, Risk Group III (22%) were patients at low risk. The placebo and timolol groups were similar with respect to most of the important baseline characteristics. Minor differences in a few characteristics did not affect the overall results as was shown by various statistical procedures including the Cox's proportional hazards regression model. The patients were followed 12 - 33 months after discharge from hospital with regular clinical examinations performed by the study investigators at the hospitals. Compliance was very good and no patient was lost to follow-up although 23.3% in the placebo group and 29.1% in the timolol group were withdrawn from the study regimen. The study demonstrated that long-term treatment with timolol improved prognosis in survivors of acute myocardial infarction. The most important finding was a highly statistically significant difference in life table mortality of 39.3% between the placebo group (21.9%) and the timolol group (13.3%) (p=0.0003). This difference was first of all due to a lower rate of sudden cardiac death in the timolol group (7.7%) compared to the placebo group (13.9%) (p=0.0001) when including events in the so-called "per protocol period".(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1978

[The effect of timolol eye drops on the intraocular pressure in simple glaucoma (author's transl)].

The intraocular pressure response to timolol ophthalmic solution, a beta-adrenergic blocking agent, was tested in two groups of open angle glaucoma patients using the 0,1% and the 0,5% solution. The 0.5% concentration gave a mean IOP reduction of 13 mm Hg in 39 glaucomatous eyes, corresponding to 46% of the pretreatment pressure level. The 0,1% concentration resulted in an average pressure decrease of 11,5 mm Hg in 22 glaucomatous eyes, corresponding to 40% of the pretreatment pressure levels. With both solutions a reduction of the first day's response was noted after repeated administration of timolol. In all patients tested timolol was tolerated well subjectively and objectively without any side effects. Timolol did not affect blood pressure or pulse rate. Tear production was not reduced after topical application of timolol. Pupillary diameter and facility of outflow were not changed significantly under therapy. It is concluded, that timolol acts primarily by reduction of aqueous inflow. The advantages of timolol as antiglaucomatous drug not affecting visual functions like miotics are discussed.

Adult↗
PubMed1995

[Effect of topical timolol on microcirculation in the rabbit optic nerve head evaluated with a laser speckle microcirculation analyser].

The effect of topical 0.5% timolol on the microcirculation in albino rabbit optic nerve head (ONH) tissue was examined using a laser speckle microcirculation analyser. In the first experiment, normalized blue (NB) in ONH, a quantitative index of peripheral blood flow in ONH, intraocular pressure (IOP), blood pressure (BP) and pulse rate (PR) were measured under general anesthesia before, and 30, 60, 90 and 120 minutes after a 20 microliters instillation of timolol in one eye and a placebo in the other eye in a masked randomized manner. In the second experiment, one eye of another group of rabbits received timolol twice daily for 20 days and a placebo in the fellow eye in a randomized masked manner. The NB in ONH and IOP were measured before treatment and 2 hours after the last instillation on the 20th day. After a single instillation of timolol, PR showed a maximum reduction of 11% and the IOP in the timolol-treated eyes showed a maximum decrease of 18%, but the NB in ONH and BP did not show any significant change during the experiment. After the 20-day treatment, IOP showed a maximum decrease of 28% in the timolol-treated eyes and 17% in the placebo-treated eyes. The NB in the timlol-treated eyes increased significantly (p < 0.01), but in the placebo-treated eyes it showed no significant change. Thus, the long-term use of topical timolol may increase peripheral blood flow in ONH tissue in the living rabbit eye.

Administration, Topical↗
PubMed1976

Effects of timolol and hydrochlorothiazide on blood-pressure and plasma renin activity. Double-blind factorial trial.

The effects of timolol (10 mg thrice daily) and hydrochlorothiazide (50 mg/day) have been compared in a double-blind factorial trial in 20 patients with essential hypertension. There were four randomised test phases of 8 weeks each during which patients received timolol alone, hydrochlorothiazide alone, timolol plus hydrochlorothiazide, and no treatment (placebo). Blood-pressure was measured weekly, alternately at the outpatient clinic and at the patient's home. Supine mean arterial pressure fell from 119 mm Hg in the placebo phase to 110 mm Hg in the hydrochlorothiazide phase, 106 mm Hg in the timolol phase, and 101 mm Hg in the combined timolol plus hydrochlorothiazide phase. Factorial analysis revealed that these effects of the two drugs were additive without any potentiation or antagonism. Mean plasma-renin activity (P.R.A.) was 5-02 ng/ml/3 h in the placebo phase falling to 1-79 in the timolol phase and rising to 9-54 in the diuretic phase, but remaining unchanged in the combined treatment phase (5-40 ng/ml/3 h). The data suggest that the hypotensive action of timolol is not dependent on the concomitant fall in P.R.A. The methods described provide a valuable tool for quantitating the effects of a given drug, and hence a valid basis for objective comparison.

Adrenergic beta-Antagonists↗
PubMed1976

Effect of timolol versus propranolol on hypertension and hemodynamics.

The effect of timolol versus propranolol on hypertension, hemodynamics, and plasms renin activity was evaluated in 20 men. After two weeks of placebo, 11 men received timolol 30 to 60 mg daily, and nine men received propranolol, 240 to 480 mg daily, for five weeks in a double-blind randomized study. The 20 men then received placebo again for two weeks. Right heart catheterization was performed in all 20 patients after two weeks of the first placebo and after five weeks of timolol or propranolol. Equipotent doses of timolol and propranolol were equally effective in significantly lowering supine and upright systolic and diastolic blood pressure and heart rate recorded on an outpatient basis. Equipotent doses of timolol and propranolol caused similar hemodynamic effects including similar significant depression of cardiac index. Equipotent doses of timolol and propranolol caused similar marked depression of plasma renin activity. The hypotensive action of timolol and of propranolol was unrelated to their effect on plasma renin activity.

Adrenergic beta-Antagonists↗
PubMed1978

Timolol. A new drug for management of chronic simple glaucoma.

Timolol maleate, a potent beta-adrenergic antagonist, reduces intraocular pressure in rabbits. With topical application in one eye, a significant reduction in pressure is seen in the contralateral, untreated eye also. When used in conjunction with timolol, other adrenergic amines, such as norepinephrine and epinephrine, produce an additional hypotensive response. On the other hand, pretreatment with timolol does inhibit the ocular hypotensive response to topically applied albuterol. No further reduction in pressure is seen after application of this beta-adrenergic agonist to eyes pretreated with timolol. In a double-blind study with patients who had previously been receiving various medications for control of elevated intraocular pressures, timolol was as effective as pilocarpine in reducing intraocular tension. Many common complaints associated with pilocarpine therapy, including miosis, ocular irritation, and blurred vision, were not encountered with timolol therapy.

Adult↗
PubMed1979

Timolol maleate: efficacy and safety.

A randomized, double-masked trial of various concentrations of timolol maleate ophthalmic solution (0.1%, 0.25%, 0.5%, and 1.0%) vs placebo demonstrated that all concentrations of timolol effectively lowered intraocular pressure (IOP). A 0.5% solution of timolol was as effective in reducing IOP as the 1.0% concentration. Blood pressure, visual acuity, and pupillary diameter were not altered significantly by any concentration of timolol tested during this study. There was a dose-dependent decrease in resting pulse rate with increasing concentrations of timolol. No objective signs of drug intolerance were found on external ocular examination, nor were any subjective symptoms elicited on questioning the subjects. Timolol applied topically twice daily in concentrations of 0.1% to 0.5% appeared to be an effective and safe ocular hypotensive agent.

Adult↗
PubMed1980

Timolol and epinephrine: a clinical study of ocular interactions.

In a crossover design study, we assessed effects on intraocular pressure, pupillary diamter, pulse rate, and blood pressure over six hours of one drop of 0.5% timolol maleate and 2% epinephrine hydrochloride in one eye. Both eyes of each patient had been pretreated for one week with twice-daily applications pf epinephrine or timolol, respectively. In random sequence, 20 patients (40 eyes) participated in both phases of the study. Pretreatment with timolol significantly reduced the ocular hypotensive effect of epinephrine (from 15.3% to 4.6%); epinephrine pretreatment did not affect the pressure reduction of timolol. Pretreatment with timolol enhanced the mydriatic effect of epinephrine (from 35.8% to 71.9% pupillary dilation); pretreatment with epinephrine resulted in an apparent mydriatic effect for timolol.

Aged↗
PubMed1982

Timolol and acetazolamide. A study of concurrent administration.

A five-week clinical trial of the concurrent administration of topical timolol maleate and oral acetazolamide was conducted to determine the additivity of the ocular hypotensive effects of the two drugs. One drop of 0.5% timolol maleate, every 12 hours, produced a mean reduction in outflow pressure from baseline of 36.0%. When added to an eye pretreated with oral acetazolamide, timolol caused an additional mean decrease in outflow pressure of 27.6%. Acetazolamide, 500 mg orally every 12 hours, produced a mean reduction in outflow pressure from baseline of 48.6%. When added to an eye receiving topical timolol, oral acetazolamide caused an additional mean decrease in outflow pressure of 43.2%. Concurrent administration of oral acetazolamide and topical timolol reduced outflow pressure only slightly less than the predicted reduction assuming full additivity of the drugs. This study supported the clinical usefulness of concurrent administration of acetazolamide and timolol to lower intraocular pressure.

Acetazolamide↗
PubMed1983

Topical timolol and the nursing mother.

A 34-year-old nursing woman with elevated intraocular pressure voluntarily and without our knowledge applied 0.5% timolol maleate twice daily to her right eye. A milk sample 1.5 hours after administration of drug showed a much higher level of timolol (5.6 ng/mL) than a plasma sample drawn at the same time (0.93 ng/mL). Three control milk specimens showed no measurable levels of timolol. The patient's milk sample 12 hours after her last timolol dose contained 0.5 ng/mL of timolol. On the basis of our calculations, timolol should be used with caution by nursing mothers.

Administration, Topical↗
PubMed1989

Topical timolol administration reduces the incidence of glaucomatous damage in ocular hypertensive individuals. A randomized, double-masked, long-term clinical trial.

We conducted a randomized, double-masked, long-term clinical trial to determine whether topical timolol therapy was effective in delaying or preventing the onset of glaucomatous damage in moderate-risk ocular hypertensive subjects. In 62 patients, one eye was chosen randomly to receive timolol therapy twice daily while the fellow eye received placebo. During the course of the study, the mean +/- SD difference in intraocular pressure between the timolol-treated and the placebo-treated eyes was 2.3 +/- 2.6 mm Hg. Reproducible visual field loss developed in 4 timolol-treated eyes and 10 placebo-treated eyes. Progressive optic disc cupping was noted in 4 timolol-treated and 8 placebo-treated eyes. Using a computerized image analysis system, the mean +/- SD increase in optic disc pallor during the course of the study was 0.86% +/- 2.4% in the timolol-treated eyes as opposed to 1.80% +/- 3.6% in the placebo-treated eyes. This study provides evidence that lowering intraocular pressure by medical treatment reduces the incidence of glaucomatous damage in ocular-hypertensive individuals.

Administration, Topical↗
PubMed1996

A 90-day study of the efficacy and side effects of 0.25% and 0.5% apraclonidine vs 0.5% timolol. Apraclonidine Primary Therapy Study Group.

OBJECTIVE: To compare long-term intraocular pressure (IOP)-lowering efficacy of 0.25% and 0.5% apraclonidine hydrochloride with 0.5% timolol maleate. DESIGN: Multicenter, randomized, double-masked trial. Adult patients of either sex diagnosed as having open-angle glaucoma or ocular hypertension were enrolled following appropriate washout from all ocular hypotensive medications. Morning IOPs of 22 to 35 mm Hg were required for entry. Patients received 0.25% or 0.5% apraclonidine 3 times a day or 0.5% timolol twice a day for 90 days. Intraocular pressure was measured at 8 AM (before morning dosing) and at 4 PM (8 hours after dosing) on days 1, 30, and 90, and only at 8 AM on day 14. RESULTS: All 3 medications significantly reduced IOP from baseline at all observation times (P < .001): 0.5% apraclonidine reduced IOP more than 0.25% apraclonidine; no significant difference was observed between 0.5% apraclonidine and 0.5% timolol 8 hours after dosing on days 1, 30, and 90; and a significant difference (P < .05) in favour of 0.5% timolol over 0.25% apraclonidine was observed 8 hours after dosing on day 30. At all morning visits following evening dosing, 0.5% timolol significantly reduced IOP more than both concentrations of apraclonidine. CONCLUSIONS: Both 0.25% and 0.5% apraclonidine significantly reduce IOP when used as primary ocular hypotensive medication. Although 0.25% and 0.5% apraclonidine reduce IOP to a similar degree as 0.5% timolol 8 hours after morning dosing, neither concentration is as effective for reducing morning IOP after evening dosing.

Administration, Topical↗
PubMed1985

The importance of pre- and postinfarction angina on timolol-related reduction in mortality and reinfarction.

The importance of a history of angina pectoris on long-term timolol treatment after myocardial infarction was studied with respect to mortality and reinfarction. The analyses were performed retrospectively using cohorts from the Norwegian timolol multicenter study. In patients without angina pectoris prior to the infarction, timolol treatment reduced mortality by 61% and the occurrence of first nonfatal reinfarction by 16.9% as compared with placebo. Patients with preinfarction angina had a reduction in mortality of 21.8% and in first nonfatal reinfarction of 48.6%. The frequency of angina pectoris increased from 38% in both treatment groups before the infarction to 59% in the placebo group and 52% in the timolol group the first 6 months after the infarction. In patients without postinfarction angina pectoris, timolol treatment reduced mortality by 30.7% and the number of first nonfatal reinfarctions by 22.7%. The reductions in mortality and reinfarction in patients with postinfarction angina were 43.8% and 38.5%, respectively. Thus, the decision for timolol treatment after myocardial infarction should not be dependent on pre- and postinfarction angina.

Angina Pectoris↗
PubMed1983

A multiclinic double-blind comparison of timolol and hydrochlorothiazide alone and in combination in th e treatment of essential hypertension.

In a multicenter randomized double-blind trial, we compared the antihypertensive effects of 12 weeks of therapy using timolol maleate, a new beta-adrenergic blocking agent, alone and in combination with hydrochlorothiazide, and hydrochlorothiazide alone in 70 outpatients with mild to moderate uncomplicated essential hypertension (61 of whom completed the study). All three groups showed significant blood pressure reductions in both supine and standing positions which were most marked in the timolol-hydrochlorothiazide group (154/103 leads to 129/85 mm Hg). A good or excellent therapeutic response was obtained in 20 of 21 patients in the timolol-hydrochlorothiazide group. In 16 of 20 patients receiving timolol alone, and in 10 of 20 receiving hydrochlorothiazide alone. Adverse reactions were minimal in all treatment groups but highest in the hydrochlorothiazide group. It was concluded that timolol-hydrochlorothiazide combination is more effective than either drug alone for management of hypertension and that timolol alone or with hydrochlorothiazide is well tolerated.

Adult↗