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PubMed1975

Timolol: a preliminary report of its pharmacological properties and therapeutic efficacy in angina and hypertension.

Timolol (MK 950) is a new beta-adrenergic receptor blocking drug. It has little or no membrane stabilising ('quinidine-like') or partial agonist (intrinsic sympathomimetic) activity and thus resembles sotalol. On a weight for.weight basis, timolol is more potent than sotalol or propranolol. A 2.5 mg dose of timolol causes about the same reduction in resting heart rate as 20mg of propranolol. Results of placebo-controlled and of comparative trials with other beta-adrenergic receptor blocking drugs, have shown that timolol effectively lowers blood pressure without producing orthostatic or exercise hypotension. Findings of an international multicentre trial in angina pectoris, indicate that timolol is effective in reducing the frequency of anginal attacks and the consumption of glyceryl trinitrate for their relief.

Adrenergic beta-Antagonists↗
PubMed1975

Timolol maleate, a new beta-adrenergic receptor blocking agent.

Some pharmacodynamic properties of an oxypropanolamine substituted novel heterocyclic compound are described. Initial studies involve comparison of the racemic mixture, dl-timolol maleate, with the beta-adrenergic receptor blocking agent propranolol in the rat, dog and cat. dl-Timolol maleate is shown to be a potent inhibitor of cardiovascular beta-adrenergic receptors activated by isoproterenol or adrenergic nerve stimulation. Blockade of alpha-adrenergic receptors is not observed even after extremely high doses. The compound is approximately 3 times more potent than propranolol in suppressing isoproterenol-induced cardioacceleration by the i.v. route of administration. dl-Timolol maleate is also extremely well absorbed when given orally, being then about 10 times more active than propranolol. Unlike propranolol, neither dl-timolol maleate nor its optical isomers possess demonstrable local anesthetic activity. Similar to propranolol and other beta-adrenergic receptor blocking agents, activity of the compound resides predominantly in the l-isomer (timolol maleate.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Physiological disposition and metabolism of timolol in man and laboratory animals.

Timolol [3-(3-tert.-butylamino-2-hydroxypropoxy)-4-morpholino-1,2,5-thiadiazole], was rapidly absorbed, metabolized, and effectively excreted in man, rats, and dogs. Peak plasma levels of timolol-14C were observed in these species 1-2 hr after oral administration. Generally, less than 20% of the radioactivity was present in the plasma in the unmetabolized form. The intact drug had a plasma half-life of 28 min in the rat, 48 min in the dog, and 5.5 hr in man. After oral administration of timolol-14C to humans approximately 72% of the dose was excreted in 84 hr, with 66% in the urine and 6% in the feces. In the rat, 58% of an oral dose was excreted in the urine and 26% in the feces. The dog excreted 68% of an oral dose in the urine and 19% in feces in 72 hr. Following intravenous administration, rats excreted 50% in the urine and 28% in the feces, which suggests that extensive biliary excretion occurred. Timolol was extensively metabolized. Approximately 50% of the radioactivity was identified in dog urine as the lactic acid metabolite. An additional metabolite was tentatively identified as the 3-oxomorpholino derivative of timolol. Approximately 20% of the dose in man was excreted in the urine unchanged. Two metabolites, resulting from cleavage of the morpholine ring, were identified as 1-tert-butylamino-3-[4-(2-hydroxyethylamino)-1,2,5-thiadiazol-3-xloxyl-2-propanol, accounting for 10% of the urine radioactivity, and t-tert-butylamino-[4-(N-2-hydroxyethylglycolamido)-1,2,5-thiadiazol-3-yloxy]-2-propanol, accounting for 30%. A minor metabolite, resulting from hydroxylation of a terminal methyl group, accounted for an additional 3% of the urine radioactivity.

Animals↗
PubMed1998

Additive effect of dorzolamide on aqueous humor flow in patients receiving long-term treatment with timolol.

OBJECTIVE: To determine the additive effect on aqueous humor flow of short-term dorzolamide treatment in patients with glaucoma receiving long-term treatment with timolol. SUBJECTS AND METHODS: Thirty-nine patients with glaucoma, 19 at Mayo Clinic, Rochester, Minn, and 20 at the University of Uppsala, Uppsala, Sweden, who had been receiving timolol treatment in both eyes for at least 1 year were studied. Aqueous flow was measured with fluorophotometry and intraocular pressure with tonometry. The effect of dorzolamide was compared with placebo when added to the long-term treatment regimen with timolol. RESULTS: Dorzolamide reduced aqueous humor flow by 24% +/- 11% (mean +/- SD). The intraocular pressure as compared with placebo in the US cohort was reduced by 10% +/- 6% and in the Swedish cohort by 18% +/- 9%. CONCLUSIONS: Dorzolamide, a carbonic anhydrase inhibitor, has additive effects as an ocular hypotensive agent with timolol, a beta-adrenergic antagonist, even though both drugs are suppressors of aqueous humor flow. Dorzolamide's effect on flow in these patients is the same as reported previously in normal subjects who are not taking a beta-adrenergic antagonist.

Adrenergic beta-Antagonists↗
PubMed2003

The effect of latanoprost, brimonidine, and a fixed combination of timolol and dorzolamide on circadian intraocular pressure in patients with glaucoma or ocular hypertension.

OBJECTIVE: To compare the circadian intraocular pressure (IOP) reductions induced by latanoprost, brimonidine tartrate, and a fixed combination of timolol maleate and dorzolamide hydrochloride in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). METHODS: In this crossover study, 10 patients with POAG and 10 with OHT were treated with latanoprost once a day, brimonidine twice a day, and a fixed combination of timolol and dorzolamide twice a day for 1 month. Four 24-hour tonometric curves were obtained for each patient. Intraocular pressure (IOP) was measured at 3, 6, and 9 AM, and at noon and at 3, 6, and 9 PM, and at midnight, using a handheld electronic tonometer with the patient in supine and sitting positions and a Goldmann applanation tonometer with the patient sitting at the slitlamp. MAIN OUTCOME MEASURE: Reduction of circadian IOP. RESULTS: All the drugs significantly reduced IOP compared with the baseline at all times, except for brimonidine at midnight, 3 AM, and 6 AM. Latanoprost was more effective than brimonidine in lowering IOP at 3 and 6 AM and at 3 PM (P=.03), and the combination of timolol and dorzolamide was more effective than brimonidine at 3 and 9 AM (P=.04) and at 3 and 6 PM (P =.05) and more effective than latanoprost at 9 AM (P=.05). CONCLUSION: Latanoprost and the fixed combination of timolol and dorzolamide led to similar circadian reductions in IOP, whereas brimonidine was less effective, particularly during the night.

Antihypertensive Agents↗
PubMed1981

Timolol and epinephrine in primary open angle glaucoma. Transient additive effect.

A randomized, double-blind clinical study was conducted on patients with primary open angle glaucoma to determine whether timolol and epinephrine have an additive effect in lowering intraocular pressure. Sixteen patients were randomly assigned to one of two treatment sequences (timolol alone, supplemented after two weeks with epinephrine, and vice versa). An initial additive effect in lowering IOP was found in both sequences. However, after several weeks of combined therapy, complete loss of additive effect was found. Patients who were treated first with epinephrine for two weeks and then supplemented with timolol had significantly lower IOPs, for at least two weeks, than patients in the reverse treatment sequence. Epinephrine treatment alone caused a significant increase in facility of outflow, but this effect did not occur with simultaneous timolol treatment. The results are discussed in terms of possible fundamental beta- and alpha-adrenergic influences on aqueous dynamics and their potential clinical relevance.

Adult↗
PubMed1981

One-hour intraocular pressure response to timolol. Lack of correlation with long-term response.

The initial topical administration of 1 drop of 0.25% timolol maleate in 25 nontreated ocular hypertensive patients resulted in a significant reduction of mean intraocular pressure one hour later, from a baseline of 28.1 +/- 5.3 (mean +/- SD) mm Hg to 18.5 +/- 4.5 mm Hg. Two patients (8%) failed to show at least a 10% decreases in IOP one hour after the initial administration. After three to four weeks of twice a day unilateral therapy with 0.25% timolol, mean IOP increased to 21.1 +/- 4.2 mm Hg. At this time seven patients (28%) failed to obtain a 10% decrease in IOP from topical timolol administration. Changing to 0.5% timolol for three to four weeks did not cause an additional significant lowering of IOP (20.4 +/- 3.5 mm Hg). At this time five patients (20%) had less than a 10% reduction in IOP. The one-hour response failed to predict future IOP nonresponsiveness.

Administration, Topical↗
PubMed1986

Effect of timolol on aqueous humor protein concentration in the human eye.

We performed a double-masked, controlled study investigating the increase in the protein concentration in aqueous humor after topical timolol maleate administration. Forty patients scheduled to undergo intracapsular cataract surgery were included in the study. Either timolol ophthalmic solution or the vehicle of timolol alone (control) were applied topically in a randomized fashion, and aqueous humor was collected during surgery. Protein concentrations were determined by gel-filtration chromatography. The total protein concentration as well as the concentration of high and medium molecular weight proteins were significantly elevated in the timolol-treated group. The relation of the levels of the three different molecular weight classes did not differ significantly between the two groups, indicating that undisturbed protein filtration in the face of reduced aqueous humor production--and not a change in the permeability of the blood-aqueous barrier--is responsible for the increase in concentration.

Aqueous Humor↗
PubMed1988

Long-term evaluation of 0.25% levobunolol and timolol for therapy for elevated intraocular pressure.

In a one-year, double-masked, randomized study, the ocular hypotensive efficacy of twice-daily treatment with 0.25% levobunolol hydrochloride or timolol maleate was evaluated in 78 patients with glaucoma or ocular hypertension (phase 1). If intraocular pressure (IOP) was not well controlled during the study, the concentration of medication was increased to 0.5%, and the patient was followed up for an additional three months (phase 2). During phase 1, the mean IOP was reduced by 4.6 mm Hg in the timolol treatment group and by 5.1 mm Hg in the levobunolol treatment group. Seventy-one percent (29/41) of the patients in the timolol treatment group and 70% (26/37) of the patients in the levobunolol treatment group successfully completed phase 1. Of those patients who required the higher concentration of medication, 89% (8/11) in the timolol treatment group and 75% (3/4) in the levobunolol treatment group successfully completed phase 2. Higher concentration, however, did not produce greater IOP reduction. No statistically or clinically significant differences between the groups were noted in any of the efficacy or safety variables evaluated.

Adult↗
PubMed1990

.008% timolol ophthalmic solution. A minimal-effect dose in a normal volunteer model.

A double-masked, randomized, placebo-controlled, rising-dose, single-dose study was undertaken to assess the effect of low concentrations of timolol maleate ophthalmic solution (0.008%, 0.025%, 0.08%, and 0.25%) on intraocular pressure and its diurnal variation in healthy, normal volunteers. A single dose of 0.008% timolol exhibits a definite but minimal-effect on intraocular pressure in this normal volunteer model, causing a significant peak mean decrease in intraocular pressure from its value immediately predose. This decrease was 1.8 mm Hg (a peak mean percent decrease of 12.8%) at 2 hours postdose compared with an increase of 0.1 mm Hg (+2.5%) during a pre-study curve due to normal diurnal variation. One drop of 0.008% solution represents a single dose of approximately 2.5 micrograms of timolol. A slight contralateral ocular hypotensive effect appears to be present for 0.25% timolol at 2 hours postdose although it just failed to reach statistical significance.

Adult↗
PubMed1990

The effect of adding prostaglandin F2 alpha-isopropylester to timolol in patients with open angle glaucoma.

Prostaglandin F2 alpha-isopropylester (PGF2 alpha-IE) (0.5 microgram) or placebo was added twice daily for 1 week to one eye in each of 30 patients with open angle glaucoma not adequately controlled with timolol treatment. Compared with placebo, PGF2 alpha-IE reduced the intraocular pressure of these timolol-treated eyes significantly. The absolute difference in mean change between PGF2 alpha-IE and placebo groups was 4.5 mm Hg with a 95% confidence interval of 3.1 to 6.6 mm Hg, corresponding to a mean reduction of initial intraocular pressure of 17.4% in eyes treated with PGF2 alpha-IE. Conjunctival or episcleral hyperemia was seen in all eyes treated with PGF2 alpha-IE for up to 4 hours but not in eyes treated with timolol and placebo, and aqueous flare was not observed in any eye. Thirteen of 15 patients treated with PGF2 alpha-IE, compared with only 3 of 15 who received placebo, reported mild to moderate subjective discomfort in the treated eye in the form of a foreign-body sensation that lasted for up to 2 hours. These results demonstrate that PGF2 alpha-IE, in a dose that has previously been shown to reduce intraocular pressure in normotensive volunteers or in patients with glaucoma who are taking no other medications, also significantly reduces the intraocular pressure of patients with glaucoma whose pressures are not adequately controlled on a twice-daily regimen of timolol.

Dinoprost↗
PubMed1991

A simple method of determining the time course of timolol's effects on aqueous flow in humans.

We have devised a simple method of determining the time course of the effects of timolol maleate on aqueous flow using changes in aqueous protein concentrations. Aqueous protein concentrations were measured with a laser flare-cell meter. First, the value of the coefficient of protein entry into the anterior chamber (kin) was determined in both eyes of 10 normal subjects. One week later, aqueous protein concentration changes were measured in both eyes of the same subjects before and after instillation of timolol in one eye. From these changes and the value of kin, changes in the aqueous flow rate were calculated using an equation formulating protein kinetics in the anterior chamber. Results of a separate experiment showed that instillation of topical timolol did not change the kin, justifying use of the kin as determined without considering timolol in the calculation. The calculated flow rate had a maximum decrease of 30% +/- 10% (mean +/- SEM, n = 10) 4 hours after instillation in treated eyes and of 10% +/- 6% 3 hours after instillation in fellow, untreated eyes.

Administration, Topical↗
PubMed1994

Effects of topical ethacrynic acid ointment vs timolol on intraocular pressure in glaucomatous monkey eyes.

OBJECTIVE: To evaluate the long-term effects of ethacrynic acid (ECA) ointment, compared with timolol maleate on intraocular pressure (IOP) in cynomolgus monkey eyes with argon laser-induced glaucoma. METHODS: In a 5-day study, IOP was measured for 7 hours after once-daily topical applications of ECA ointment to four glaucomatous monkey eyes. For this study, ECA ointment was given in 0.5%, 1.0%, 1.5%, or 2.5% concentrations. In a separate 30-day study, IOP was measured after once-daily topical applications of ECA ointment in concentrations of 0.75% or 1.5%. The results were compared with IOP after the application of 0.5% timolol maleate administered twice daily on weekdays and once daily on weekends. RESULTS: In the 5-day study, 2.5% ECA ointment had the greatest effect on lowering IOP, with a maximum reduction of 8.5 +/- 2.9 mm Hg (mean +/- SEM). A more pronounced reduction in IOP was observed on the fifth day of treatment for each of the four concentrations. In the 30-day study, 1.5% ECA ointment or 0.5% timolol maleate reduced IOP as much as 11.5 +/- 3.7 mmHg and 14.0 +/- 4.5 mmHg, respectively. With repetitive dosing, the effect on IOP after using 1.5% ECA ointment increased with time. Mild eyelid edema, conjunctival hyperemia, and discharge were observed in some eyes treated with the highest concentrations. One eye of four treated with 1.5% ECA ointment for 30 days developed a superficial corneal erosion in the 30-day study. CONCLUSIONS: The ECA ointment reduced IOP in glaucomatous monkey eyes. This reduction was evident by the fifth day of treatment with all the concentrations tested. The reduction in IOP produced by once-daily treatment with 1.5% ECA ointment was comparable with that of 0.5% timolol maleate administered twice daily. Therefore, drugs in this class of compound may prove to be useful in glaucoma therapy.

Administration, Topical↗
PubMed1997

Effect of timolol on the diurnal intraocular pressure in exfoliation and primary open-angle glaucoma.

OBJECTIVE: To describe and compare the diurnal intraocular pressure (IOP) variation in patients with exfoliation glaucoma (EXG) and primary open-angle glaucoma (POAG) who were treated with a solution of timolol maleate (0.5%) twice daily. DESIGN: Consecutive Greek patients who were newly diagnosed as having EXG or POAG were prospectively investigated; they underwent 24-hour diurnal IOP measurements first without therapy and then 6 months afterward while they were being treated with timolol maleate (0.5%). After matching for age, 38 pairs of patients with these 2 types of glaucoma were compared. RESULTS: Untreated patients with EXG had significantly higher IOP values for all time points assessed and a greater mean range of IOPs (11.8 mm Hg for EXG vs 7.6 mm Hg for POAG; P < or = .001). Following therapy with timolol maleate (0.5%) given twice daily, patients with EXG had higher IOP values for the measurements that were obtained at 6 and 10 AM, 10 PM, and 2 AM, a higher mean range of IOPs (7.0 mm Hg for EXG vs 5.6 mm Hg for POAG; P = .03), and a higher maximum IOP (mean, 24.9 mm Hg for EXG vs 20.9 mm Hg for POAG; P = .003). The reduction of the range of diurnal variation of IOP was more pronounced in patients with EXG than in patients with POAG (40% vs 26%; P = .04). Twenty-two (58%) of 38 patients with EXG and 20 (53%) of 38 patients with POAG had peak IOP values that were found outside office hours. Only 5 (13%) of the patients with EXG exhibited an IOP of 18 mm Hg or less at all time points compared with 12 (32%) of the patients with POAG (P = .05). CONCLUSION: Despite a greater initial IOP reduction in the patients with EXG treated with timolol, a higher IOP and significant fluctuation in the diurnal curve of IOP during the time in which patients received therapy still characterized EXG from POAG.

Adrenergic beta-Antagonists↗
PubMed1978

Timolol kinetics in chronic renal insufficiency.

A single-dose kinetic study of oral timolol, 20 mg, was undertaken in 3 groups of volunteers with varying degrees of renal function--(1) 10 normal subjects (N); (2) 9 patients with moderate chronic renal insufficiency (MCRI; C cr, 20 to 50 ml/min); (3) 4 patients with end-stage renal disease (ESRD)--to assess the need for dosage modification as renal function diminishes. There were borderline statistical differences in absorption between groups. The mean peak concentration (C max) was 84.3 +/- 44.8 ng/ml at 0.8 +/- 0.4 hr for N and 87.1 +/- 22.8 ng/ml at 1.7 +/- 1.2 hr (p, NS) for MCRI. N and MCRI mean half-lives (5.2 +/- 2.6 hr and 4.0 +/- 1.2 hr) were not statistically different. Salivary levels correlated with plasma levels in 3 N and 1 MCRI patient. Group differences in blood pressure and pulse response to timolol seems to reflect differences present at baseline with percent change from baseline identical for the two groups except at 12 to 24 hr. Administration of timolol on an interdialysis day revealed similar kinetic and physiologic response in the normal and the MCRI group. During dialysis, timolol, 20 mg, induced significant hypotension and bradycardia.

Adult↗
PubMedDate not supplied

Clinical pharmacologic observations on timolol. I. Disposition and effect in relation to plasma level in normal individuals.

The disposition profiles of a new beta-adrenergic blocking drug, timolol, were investigated at 11 different times in normal individuals after a single oral dose. The disposition of timolol follows first-order kinetics and may be adequately described by a one-compartment model. The pharmacokinetic data were not significantly different among the three dose levels examined. After the single oral doses, overall elimination half-life was 3.2 +/- 0.2 hours (mean +/- S.E.M.), with an observed peak time of 2.0 +/- 0.2 hours; extrapolated volume of distribution was 1.81 +/- 0.15 liter/kg; and the total plasma clearance was 557 +/- 61 ml/min. Approximately 20 per cent of elimination from the human body was dependent on the kidney. The area under the curve from zero to infinity and the peak concentration observed were dose dependent. A linear relationship was found between timolol plasma concentrations and beta-adrenergic blocking effects (per cent inhibition), as estimated from exercise-induced tachycardia. Timolol is a beta blocker which must await further clinical trials for the assessment of therapeutic implications in relation to plasma levels.

Adult↗
PubMedDate not supplied

Clinical pharmacologic observations on timolol. II. Antihypertensive effect and kinetic disposition on twice-daily dosing in patients with mild or moderate hypertension.

Timolol given on a twice-daily schedule has shown both antihypertensive effectiveness and plasma renin-suppressing action in eight patients with mild or moderate hypertension. However, the causal relationship between the drug plasma level, blood pressure fall, and change in plasma renin activity was not so clearly demonstrated in the present study. The disposition profiles of timolol at the steady state show an elimination half-life of 4.7 +/- 0.7 hours and a total plasma clearance of 225 +/- 21 ml/min. These values are found to be different from those of our previous observations obtained in normal individuals. Although the range of mean timolol concentrations at steady state varies to a certain extent among different patients, the dosage regimens for patients who will receive treatment for certain chronic disease states (e.g., arrythmias, obstructive cardiomyopathy, and angina pectoris, but not hypertension) in relation to plasma levels should be based on the disposition data obtained under steady state conditions. Bronchospasm developed in one of eight patients whose timolol level was found to be higher than the average of other patients given the same dosage.

Adult↗
PubMed1998

Effect of betaxolol, timolol and nimodipine on human and pig retinal arterioles.

This study tested the hypothesis that the beta-adrenergic antagonists betaxolol and timolol, cause retinal arteriolar vasodilatation in addition to their ability to reduce intraocular pressure (IOP), and compared their vasodilatory ability with that of a known Ca2+ channel entry blocker nimodipine in donor human and pig isolated perfused retinal arterioles. This study was performed using a microperfusion technique specifically established to allow investigations in arterioles as small as the first order human and pig retinal arterioles (approximately 100 microns diameter). The scarcity of viable human tissue was overcome by the successful development of controlled rate freezing and cryopreservation techniques which were able to preserve the vascular responsiveness of the retinal arterioles, thus enabling multiple experiments to be performed on segments of retinal arterioles from each individual donor eye. Furthermore, relaxation by acetylcholine in noradrenaline contracted pig retinal arterioles showed that endothelial cell function was well maintained after cryopreservation (n = 8). Baseline diameters of retinal arterioles used in the main studies were: cryopreserved human 92.3 +/- 3.4 microns (n = 44), fresh pig 94.7 +/- 2.2 microns (n = 42), and cryopreserved pig 94.3 +/- 2.3 microns (n = 30). Precontraction with extraluminal endothelin-1 (ET-1) 10(-9) M reduced the diameters to 74.3 +/- 0.9%, 71.6 +/- 1.6% and 72.5 +/- 0.9% respectively. Intraluminally applied nimodipine and betaxolol caused a significant dose dependent dilatation (P < 0.001) in human retinal arterioles with a threshold of 10(-12) M. Timolol did not produce a significant dilatation in human arterioles. Timolol produced a small but significant dilatation in fresh and cryopreserved pig arterioles but the dilatation with betaxolol and nimodipine was significantly larger. The nimodipine and betaxolol dose response curves were not significantly different in human arterioles, but nimodipine produced significantly greater dilatation than betaxolol (P < 0.001) in fresh and cryopreserved pig arterioles. Both nimodipine and betaxolol were significantly more effective vasodilators than timolol (P < 0.001) in human and pig retinal arterioles.

Adrenergic beta-Antagonists↗