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PubMed2004

An evaluation of the fixed-combination of latanoprost and timolol for use in open-angle glaucoma and ocular hypertension.

Glaucoma is one of the leading causes of irreversible blindness worldwide. Although there is no cure for this chronic disease, medical treatment is aimed at reducing levels of intraocular pressure (IOP) using ocular hypotensive agents. Very often, patients require more than one IOP-reducing drug, resulting in complex medication regimens that may be difficult to maintain and that can lead to non-compliance. A fixed-combination (FC) ophthalmic solution consisting of the prostaglandin, latanoprost (0.005%), and the beta-blocker, timolol (0.5%), is now available. The primary mechanism of action of latanoprost is to increase uveoscleral outflow whereas timolol lowers IOP levels by decreasing the formation of aqueous humor in the ciliary epithelium. Due to the unique mechanism of action of latanoprost, once-daily dosing of one drop of FC latanoprost/timolol results in additional IOP reduction compared with either drug administered separately. FC latanoprost/timolol is well-tolerated and has a safety profile similar to that of its individual components. This combination drug provides a safe, effective and convenient alternative for the treatment of patients with elevated IOP levels uncontrolled with monotherapy.

Antihypertensive Agents↗

PubMed1982

Effects of ACTH on the zona glomerulosa of sodium-loaded timolol maleate-treated rats: stereology and plasma hormone concentrations.

The effect of chronic ACTH administration on the growth and aldosterone secretion of the zona glomerulosa of sodium-loaded timolol maleate-treated rats was investigated by stereological and radioimmunological techniques. Combined sodium loading and timolol maleate administration induced a significant atrophy of the zona glomerulosa and its cells. The plasma concentration of aldosterone was significantly decreased, while that of corticosterone did not vary. ACTH administration completely reversed zona glomerulosa atrophy, and the plasma concentration of corticosterone was noticeably enhanced, whereas that of aldosterone underwent a further decrease. This data suggests that in the absence of the other adrenoglomerulotrophic factors, ACTH stimulates the growth of the zona glomerulosa, but transforms its parenchymal elements to a functional fasciculata cell type.

Adrenal Glands↗

PubMed2001

Effects of a beta-adrenergic blocking agent timolol on intra ocular pressure responses induced by stimulation of cervical sympathetic nerve in the cat.

We clarified whether the intraocular pressure (IOP) response elicited by stimulation of the cervical sympathetic nerve (CSN) is influenced by changes in the baseline of IOP level and by beta-adrenergic blockade. The CSN was stimulated electrically for 30 seconds (10 V, 0.1-100 Hz, 2 milliseconds pulse duration) in urethane (100 mg/kg i.v.)-chloralose (50 mg/kg i.v.)-anesthetized, paralyzed cats. The IOP was monitored manometrically, and a controlled saline infusion was delivered into the anterior chamber to gradually increase IOP. CSN stimulation was delivered at the various baseline IOP levels so obtained. When required, a beta-adrenergic blocker timolol (2%) was delivered into the conjunctival cul-de-sac. The normal IOP in our cats was 25+/-3 mmHg. This value decreased transiently on CSN stimulation. The amplitude of this IOP response depended on stimulus frequency and the pre-stimulus baseline IOP level. Topical administration of timolol increased the IOP response to CSN stimulation at a given baseline level. These results suggest that beta-adrenergic blockade increases the alpha-adrenergic mediated-IOP reduction elicited by CSN stimulation at given baseline IOP level.

Adrenergic Fibers↗

PubMed2001

Effect of topical administration of 2% dorzlamide hydrochloride or 2% dorzlamide hydrochloride-0.5% timolol maleate on intraocular pressure in clinically normal horses.

OBJECTIVE: To evaluate the effect of topical administration of 2% dorzolamide hydrochloride or 2% dorzolamide hydrochloride-0.5% timolol maleate on intraocular pressure (IOP) in clinically normal horses. ANIMALS: 18 healthy adult horses without ocular abnormalities. PROCEDURE: The IOP was measured at 5 time points (7 AM, 9 AM, 11 AM, 3 PM, 7 PM) over 11 days. On days 1 and 2, baseline values were established. On days 3 through 5, horses received 2% dorzolamide HCI (group D, n = 9) or 2% dorzolamide HCl-0.5% timolol maleate (group DT, 9) in 1 randomly assigned eye every 24 hours immediately following each daily 7 AM IOP measurement. On days 6 through 9, each drug was given every 12 hours (7 AM and 7 PM) in the treated eye. Measurements on days 10 and 11 assessed return to baseline. Mixed linear regression models compared mean IOP difference for each drug at each time period. RESULTS: Mean IOP decreased significantly in all eyes during the 2 dose/d period, compared with the baseline, 1 dose/d, and follow-up periods. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of either drug every 24 hours for short-term treatment does not reduce IOP significantly. Administering either drug every 12 hours induced a significant reduction of IOP; however, controlling for all variables, the reduction was less than 2 mm Hg.

Administration, Topical↗

PubMed1995

Effects of timolol, terbutaline and forskolin on IOP, aqueous humour formation and ciliary cyclic AMP levels in the bovine eye.

We have studied the effects of terbutaline, timolol, forskolin and 8-bromo cyclic AMP on aqueous humour formation, intraocular pressure and on ciliary epithelial cyclic AMP levels, either in presence or in absence of IBMX, using the bovine isolated arterially perfused eye, excised ciliary processes and cultured ciliary epithelium. Both terbutaline, a beta-adrenoceptor agonist, and timolol, a beta-adrenoceptor antagonist, caused significant reduction in aqueous humour formation and intraocular pressure but produced no effect on ciliary epithelial cyclic AMP content in the absence of IBMX. Even a three times higher dose of terbutaline was entirely ineffective in producing any effect on ciliary cyclic AMP in the perfused eye. On the other hand, terbutaline at the IOP-reducing dose, produced a significant increase in cyclic AMP when injected after 30 min perfusion with IBMX. Incubation of excised ciliary processes or cultured ciliary epithelial cells with terbutaline (10(-6) to 10(-4) M) produced concentration-dependent increases in cyclic AMP, in both tissues, even in the absence of IBMX. Forskolin, which stimulates cyclic AMP synthesis without interacting with cell surface receptors, was found to produce highly significant increases in ciliary cyclic AMP content both in presence and in absence of IBMX but had no effect on aqueous humour formation in the isolated eye. IBMX perfused at concentrations of 1 mM or 10 microM had no effect on basal levels of ciliary cyclic AMP but the 1 mM concentration produced a marked and significant reduction in IOP. Direct application of 8-bromo cyclic AMP, a cell permeable analogue, more resistant to hydrolysis by phosphodiesterases, had also no effect on aqueous humour formation in the perfused eye. It is concluded that in the bovine arterially perfused eye, the correlation between the aqueous humour formation rate and ciliary epithelial cyclic AMP content is unclear.

1-Methyl-3-isobutylxanthine↗

PubMed2003

Mass spectrometric study of the photooxidation of the ophthalmic drugs timolol and pindolol.

A mass spectrometric study of the photooxidation products of the ophthalmic drugs pindolol (1-[1H-indol-4-yloxyl]-3-[isopropylamino]-2-propanol) and timolol (S-[-]-1-[t-butylamino]-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxyl]-2-propanol) in water has been performed by LC-MS. Based on these data and the assumption that photooxidation mainly occurs through singlet molecular oxygen attack, a possible reaction mechanism is proposed. The mechanistic pathways involve singlet oxygen attack to the pindolol indole ring and oxidation of the pindolol isopropyl or timolol terbutyl methyl groups.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

[Many years of personal observation on the effect of timolol for arresting development of keratoconus].

On examining about 300 patients with keratoconus in the period of 20 years the authors detected in a number of cases variations of the intraocular pressure. By means of a pneumo-tonometer Digilab 30R periodic variations of the IOP were measured in 76 patients and daily variations in 42. The statistical analysis showed that the application of Timolol and reduction of the IOP variations has a decisive influence on the improvement of objective changes and the visual acuity without correction. Presently in our Department Timolol is used successfully in 160 patients. There was no deterioration in either patient at that time and many patients showed an improvement of the condition of keratoconus.

Adult↗

PubMed2004

[Timolol topical ophthalmic combination].

The primary standard therapy in patients with open-angle glaucoma and ocular hypertension is carried out by means of monotherapy with synthetic prostaglandin analogues. Most of the glaucoma patients need more than one medication for adequate intraocular pressure control. Timolol represents the basic component of these combinations. Timolol topical ophthalmic combinations with dorzolamide (Cosopt), pilocarpine, latanoprost (Xalacom), travoprost and unoprostone are thoroughly described. Most antiglaucoma medications achieve on one side directly baroprotection by decreasing intraocular pressure and on the other side they produce indirectly vasoprotection, that is secondary to intraocular pressure lowering. The Cosopt, due to its Dorzolamide component, makes an exception since it produces directly both baroprotection by aqueous humor flow suppression and vasoprotection by increasing the blood flow within the retina, choroid, optic nerve head and retrobulbar area. Given these considerations as well as the fact that the ocular hypotensive effect of both the Cosopt and the latanoprost are equally potent, a question seems reasonable according to accepted standard i.e. Cosopt or latanoprost as primary glaucoma therapy?

Administration, Topical↗

PubMed1992

[Bradyarrhythmias secondary to the use of ophthalmic timolol. A report of 3 cases].

Three cases of symptomatic bradycardia due to topical ocular timolol administration are reported. Two patients had syncope related to atrioventricular block, and the other one complained of dizziness due to sinus bradycardia. Heart disease was not present in any case, although a right bundle branch block was observed in one patients. A normal sinus rhythm resumed in all patients after discontinuation of timolol.

Aged↗

PubMed1978

[Results of a double-blind study comparing the effects of timolol and pilocarpine in 110 patients with chronic open-angle glaucoma].

Following a seventeen weeks study including 110 patients with open-angle glaucoma, 81,8% of the patients treated by timolol, administered twice a day, had a satisfactory control of their intraocular pressure, against only 41,8% of those patients treated by pilocarpine, administered four times a day. The side effects liable to timolol are clinically reduced, in a osit with pilocarpine which is followed by a series of well-known subjective and objective signs often causing discomfort to the patients.

Aged↗

PubMed1978

[Timolol maleate: results of its long-term action in the treatment of chronic primary open-angle glaucoma].

Three groups of patients with chronic open-angle glaucoma, who had ineluded in the previous study, had been treated with timolol twice daily for more than a year. The long-term results confirm the efficacity noted in the medium-term survey, and the absence of side-effects, especially those related to the pulse rate and blood pressure in some of the patients. Drug associations had been necessary:--pilocarpin,--acetazolamid, seem to have the best synergic action with timolol.

Female↗

PubMed1992

Effects of timolol, betaxolol, and levobunolol on human tenon's fibroblasts in tissue culture.

Evidence has been found suggesting that long-term therapy with topical antiglaucoma medications may decrease the success of glaucoma filtering surgery. To investigate this question further, the antiproliferative effects of the preservative benzalkonium chloride and three pure and commercially available beta-adrenergic antagonist preparations (timolol, betaxolol, and levobunolol) were studied on tissue cultures of human Tenon's capsule fibroblasts. Each drug preparation was tested on three different cell lines. Fibroblast growth was measured with tritiated thymidine uptake and hexosaminidase assays. Trypan blue uptake was used to assess cell viability microscopically. The commercially available preparations containing benzalkonium chloride and those of betaxolol and levobunolol without the preservative had similar inhibitory doses for 50% of cells. The timolol preparation without preservative was significantly less toxic than its commercially available one. The three tested beta-adrenergic blockers did not stimulate fibroblast proliferation directly in this in vitro model. Even when the cultures were washed free of the drugs, growth continued to be suppressed, suggesting that the inhibition was not reversible. An increase in fibroblasts and inflammatory cells after long-term antiglaucoma medical therapy thus may be caused not by a direct stimulation of cell proliferation but by chronic inflammation from the irritating effects of antiglaucoma medications and/or their preservatives.

Benzalkonium Compounds↗

PubMedDate not supplied

12-week study comparing the fixed combination of brimonidine and timolol with concomitant use of the individual components in patients with glaucoma and ocular hypertension.

PURPOSE: To evaluate the efficacy and safety of fixed-combination brimonidine tartrate 0.2%/timolol 0.5% ophthalmic solution dosed BID and demonstrate non-inferiority to concomitant use of brimonidine tartrate 0.2% BID and timolol 0.5% BID in glaucoma and ocular hypertension patients with intraocular pressure (IOP) uncontrolled on monotherapy. METHODS: Randomized, multicenter, double-masked, parallel-group study involving 371 patients with inadequate IOP control (IOP from 22 to 34 mmHg) after > or =3 weeks of run-in on any monotherapy. Patients were treated with fixed-combination brimonidine/timolol BID (fixed-combination group, n = 188) or concomitant brimonidine BID and timolol BID (concomitant group, n = 183). IOP was assessed pre-dose and 2 hours after morning dosing at weeks 2, 6, and 12. RESULTS: A total of 355 patients (96%) completed the study. Patient demographics, run-in monotherapy, and baseline mean IOP on monotherapy were comparable between treatment groups. During follow-up, the mean reduction from baseline IOP was significant (p < 0.001) at all time points and ranged from 4.4 to 5.3 mmHg in each group. Brimonidine/timolol fixed combination was as effective as concomitant therapy with respect to mean IOP and mean change from baseline IOP at all time points and visits. Between-group differences were < or =0.35 mmHg for mean IOP and < or 0.30 mmHg for mean change from baseline IOP; none were significant. No unexpected side effects were associated with the fixed combination. Both treatments were well tolerated with no difference in adverse events between groups. CONCLUSIONS: Brimonidine/timolol fixed-combination therapy is as safe and effective as concomitant treatment with the individual components. Its simplified dosing regimen has the potential to improve compliance.

Antihypertensive Agents↗

PubMedDate not supplied

A comparison of travoprost, latanoprost, and the fixed combination of dorzolamide and timolol in patients with pseudoexfoliation glaucoma.

PURPOSE: To compare the intraocular pressure (IOP) lowering effect and safety of latanoprost, travoprost given every evening, and the fixed combination dorzolamide + timolol (DTFC) given twice daily in pseudoexfoliation glaucoma (PXG). METHODS: This randomized, prospective, investigator-masked study has been conducted with 50 PXG patients. Patients were assigned to one of three groups: travoprost 0.004%, fixed combination of dorzolamide 2%+timolol 0.5%, or latanoprost 0.005% for 6 months. At baseline and 0.5, 1, 2, 3, 4, 5, and 6 months of therapy, IOP (8 am, 10 am, 4 pm), blood pressures, and pulse rates were measured, and ophthalmologic examination was performed. The side effects were recorded at each visit. RESULTS: Forty-two of the 50 patients initially enrolled completed this study. Withdrawn patients included one (latanoprost) for lack of efficacy, five (three travoprost, one latanoprost, one DTFC) for adverse events, and two (one latanoprost, one DTFC) for loss of follow-up. Each of the three drugs considerably reduced the IOP in PXG cases throughout the 6 months. Mean IOP reduction at 6 months was -9.3+/-2.9 mmHg in the travoprost group, -8.2+/-1.2 mmHg in the latanoprost group, and 11.5+/-3.3 mmHg in the DTFC group. Comparing the groups, DTFC is more effective than latanoprost and travoprost in lowering IOP (p<0.05). There was no difference between travoprost and latanoprost. The most common treatment-related adverse event was conjunctival hyperemia. Intensity of ocular hyperemia was greater in the travoprost group compared with the latanoprost and DTFC groups (p<0.05). There were no significant effects on systemic safety parameters. CONCLUSIONS: The results demonstrated that DTFC is more effective in reducing IOP than latanoprost and travoprost. Latanoprost and travoprost had similar ocular hypotensive effects in patients with PXG. All three drugs were well tolerated; there were fewer ocular side effects attributable in the latanoprost group.

Aged↗

PubMedDate not supplied

[Severe bronchial spasm crises induced by topical administration of eyedrops with timolol base, a non-selective beta blocking agent].

Since their introduction in clinical practice beta-blocker drugs are known to be able to induce bronchospasm. However, this adverse effect may develop only in subjects with asthma, chronic bronchitis and/or airways hyper-reactivity. Although this potentially adverse effect of beta-blockers on the airways has long been recognized, its mechanism in inducing bronchospasm remains unclear. The Authors report a case of severe bronchoconstrictive episodes with respiratory failure following the administration of a timolol ophthalmic solution in a 51 yr old woman. Pharmacokinetics, preventive and therapeutic aspects of timolol eyedrop-induced bronchospasm are discussed.

Bronchial Spasm↗

PubMed1990

Cardiovascular effects of befunolol, betaxolol and timolol eye drops.

A double-blind cross-over study was carried out on 15 glaucoma patients so as to verify the effects of three the beta blockers, beta-1 selective betaxolol, non-selective timolol and befunolol an agent with intrinsic sympathomimetic activity on the heart rate, monitored by a Holter apparatus, and with the blood pressure measured in standing and supine positions before and after eight days of topical therapy. The results showed that timolol induced a significant decrease in minimum heart rate (-4.2 +/- 2.9) (p less than 0.001) and in diastolic blood pressure in standing position (-8.0 +/- 12.5 mmHg) (p less than 0.05), betaxolol decreased systolic pressure in orthostatism (-7.5 +/- 12.3 mmHg) and in clinostatism (-12.1 +/- 16.2 mmHg) and diastolic pressure in orthostatism (-6.25 +/- 9.4 mmHg) (p less than 0.05). Befunolol alone did not alter the heart rate or blood pressure.

Adrenergic beta-Antagonists↗

PubMed1990

[Retroperitoneal fibrosis with eye-drops containing timolol].

Retroperitoneal fibrosis occurred in a 62-year-old man who had been treated during 4 years eye-drops containing timolol. The disease was diagnosed after a sudden episode of nephritic colic. The recovery was progressive and uneventful. No corticosteroid therapy was used. Six months later the patient remained free of symptoms. Although an idiopathic origin could not be excluded, the causal relationship with timolol treatment is likely due to the chronology of events and the lack of other causes.

Colic↗

PubMed1990

The effects of timolol on intraocular pressure and exercise heart rate in poor and extensive debrisoquine metabolizers.

The effects of a single 20 mg oral dose of timolol, a non-selective beta-adrenoceptor antagonist which is subject to hydroxylation in the liver, on intraocular pressure and heart rate were compared in four poor and five extensive debrisoquine metabolizers, using non-contact tonometry and bicycle ergometry. The beta blockade of timolol on exercise heart rate was significantly higher in poor than in extensive metabolisers with no significant difference on resting heart rate or intraocular pressure.

Adult↗