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PubMed1989

The time-course of intraocular pressure in timolol-treated and untreated glaucoma suspects.

We studied the behavior of intraocular pressure in glaucoma suspects randomly selected to receive either topical timolol or no treatment over the course of a long-term prospective follow-up study. All patients who after six years of follow-up showed no localized field defects or disk changes, or whose pressures were not dangerously increased (24 treated and 22 untreated patients), were included in the present study. Overall, the two groups showed an increase in pressure followed by a gentle leveling off and a decrease toward the end of the follow-up period. The pressure-time curves of the two groups were parallel and vertically separated by 4.94 mm Hg. When pressure-time relationships were determined in individual patients, the categorical group differences were not statistically significant. Our results suggest that most glaucoma suspects did not exhibit a random time-course of intraocular pressure and that the effect of treatment was simply to lower the pressure-time curve of the treated group by a fixed level throughout the six-year follow-up period.

Drug Evaluation↗
PubMed1978

Comparative dromotropic activity of timolol and propranolol in anesthetized dogs.

The comparative dromotropic activity of timolol (TML) and propranolol (PPL) was studied by means of His bundle electrograms in two groups of pentobarbital-anesthetized dogs: group I, 7 non-atropinized dogs; group II, 8 atropinized dogs. beta-Blocking agents were injected in 4 cumulative doses in each dog at 3 days' interval. The effects upon heart rate (HR), and A-V nodal (AH), His--Purkinje (HV) and intraventricular (QS) conduction times were measured. The dromotropic effects of PPL and TML during atrial electrical stimulation and their effects upon chronotropic and dromotropic isoprenaline-induced changes were compared. TML exerted a 9--10 times more potent negative chronotropic effect than PPL and a 4--5 times more potent negative dromotropic effect than PPL on AH conduction time. PPL and TML increased the duration of HV only in higher doses. This effect which was not modified by isoprenaline may be related to their membrane depressant effect. Neither TML, nor PPL nor isoprenaline modified QS duration. TML was 25 times more potent than PPL to antagonize the chronotropic action of isoprenaline and 11--8 times more potent than PPL to antagonize the dromotropic action of isoprenaline upon AH. Parasympathic blockade with atropine did not modify the negative dromotropic activity of PPL and TML but modified their chronotropic effects.

Animals↗
PubMedDate not supplied

The role of clinical drug trial methodology with respect to studies of new drugs. Clinical trials of timolol.

The use of the Randomized Clinical Trial (RCT) to assess the safety and efficacy of a new drug or treatment can provide a clear evaluation of the relative benefits and risks of the new therapy as compared to the longer-established treatment methodology. In some cases, such as insulin, the benefits are immediately apparent; in other cases, such as photocoagulation for proliferative diabetic retinopathy, the consensus is not so easily obtained, and the clinical trial can supply the answer. Furthermore, the RCT provides the opportunity to identify adverse reactions, in particular those which present with a seemingly unrelated or unexpected set of symptoms. In conducting clinical trials of timolol, researchers must be alert for beta-adrenergic antagonist effects, such as were seen with practolol, and should be especially careful to note early, mild reactions which may be the forerunners of later, more severe or irreversible adverse effects.

Diabetic Retinopathy↗
PubMedDate not supplied

Patient compliance and the "usefulness product" of timolol.

The practical value of any therapy depends upon a combination of effectiveness of the agent (or procedure) and the extent to which the patient complies in its proper administration. Thus, it might be said that the multiple of effectiveness times compliance equals the "usefulness product." Among the various glaucoma therapies, this product seems to range from about 30%--90%. Timolol's effectiveness in lowering intraocular pressure combined with its low incidence of side effects yields a high usefulness product, and this may decrease the incidence of surgery required for the treatment of the open-angle glaucomas.

Evaluation Studies as Topic↗
PubMed1983

Laboratory and clinical studies on the mechanism of action of timolol.

Timolol is now widely used in the treatment of glaucoma but its mechanism of action is unclear. The drug decreases aqueous humor formation by the ciliary processes and is a potent beta-adrenergic antagonist. However, the physiological basis for such a drug to decrease intraocular pressure has not been clearly demonstrated.

Adrenergic Fibers↗
PubMed2004

Switching from latanoprost to fixed-combination latanoprost-timolol: a 21-day, randomized, double-masked, active-control study in patients with glaucoma and ocular hypertension.

BACKGROUND: Approximately 40% of patients with glaucoma are concomitantly prescribed >or=2 different intraocular pressure (IOP)-lowering medications. An effective and well-tolerated fixed combination of agents requiring once-daily instillation may improve patient compliance. OBJECTIVE: The purpose of this study was to compare the efficacy and safety profile of the fixed combination latanoprost 0.005% + timolol maleate 0.5% QD with those of latanoprost 0.005% monotherapy QD in patients whose elevated IOP (>or=21 mm Hg) was inadequately controlled by latanoprost. METHODS: This 21-day, randomized, double-masked, active-control study was conducted at 49 study sites in Argentina, Brazil, Colombia, Mexico, Peru, the United States, and Venezuela. Adults with glaucoma or ocular hypertension who had failed to reach an IOP of <21 mm Hg while receiving latanoprost for at least 28 days were enrolled. After an additional 28 days of latanoprost run-in, patients were randomly assigned to continue latanoprost monotherapy or to switch to the fixed combination for 21 days. The intent-to-treat (ITT) population included all patients who received at least 1 dose of double-masked study medication; the per-protocol (PP) analysis included patients who completed the study without a major protocol violation and who had IOP measurements both at baseline and at day 21. The primary end point was the proportion of patients whose IOP was decreased >or=2 mm Hg from the baseline level on day 21. Proportions of patients demonstrating IOP decreases >or=3, >or=4, or >or=5 mm Hg from the baseline level and of patients reaching an 10P or=3, >or=4, or >or=5 mm Hg (for each target level, P < 0.001 vs latanoprost group) or final IOP 18 mm Hg (fixed -combination, 35.1%; latanoprost, 17.8%; P < 0.001). Both treatments were well tolerated. Similar proportions of patients in the fixed-combination and latanoprost groups reported at least 1 treatment-emergent AE (10.9% and 12.1%, respectively). CONCLUSION: In this selected population of patients with an inadequate initial IOP response to latanoprost, switching to fixed-combination latanoprosttimolol resulted in a greater decrease in IOP and similar tolerability compared with continuing latanoprost therapy.

Aged↗
PubMedDate not supplied

Dorzolamide versus pilocarpine as adjunctive therapies to timolol: a comparison of patient preference and impact on daily life.

The purpose of this study was to compare 2% dorzolamide three times daily with 2% pilocarpine four times daily to determine patient preference, tolerability, and impact on daily life in patients concurrently receiving 0.5% timolol twice daily for treatment of elevated intraocular pressure (IOP). Seventy-five patients were enrolled in this 4-week, randomized, two-period, crossover study. The Comparison of Ophthalmic Medications for Tolerability questionnaire was used to assess patient preference and perception of side effects and activity limitations resulting from the study medications. IOP measurements were obtained 2 hours after drops were instilled and visual field tests were performed at baseline and at the end of each crossover period. Significantly more patients receiving pilocarpine than dorzolamide reported adverse experiences and discontinued the drug because of these adverse experiences. Similarly, patients reported more interference with their daily life because of side effects and activity limitations when receiving pilocarpine. Vision difficulties, accommodation difficulties, and brow ache were reported more often and were considered more bothersome by patients receiving pilocarpine. Bitter/unusual taste was reported more frequently and was considered more bothersome by patients receiving dorzolamide. Patients also reported missing fewer doses and were more satisfied with their medication when receiving dorzolamide. All of these changes were considered statistically significant. IOP control was not significantly different with either dorzolamide or pilocarpine. However, patients experienced a significant worsening of the mean defect of automated visual field examinations when receiving pilocarpine. At the end of the study, among patients with a preference, dorzolamide was preferred to pilocarpine by a ratio of more than 9:1. Overall, 81.9% of patients preferred dorzolamide. Thus dorzolamide demonstrated better tolerability and less adverse impact on daily life than pilocarpine.

Adrenergic beta-Antagonists↗
PubMed2003

Twenty-four-hour diurnal curve comparison of commercially available latanoprost 0.005% versus the timolol and dorzolamide fixed combination.

PURPOSE: To evaluate the efficacy and safety of commercially available latanoprost 0.005% given every evening versus timolol 0.5% and dorzolamide 2% fixed combination (TDFC) given twice daily to white Greeks with primary open-angle glaucoma and ocular hypertensive patients. DESIGN: A single-masked, two-center, crossover comparison with two 6-week treatment periods occurring after at least a 3-week medicine-free period. Diurnal curve intraocular pressures were taken at 2:00 AM, 6:00 AM, 10:00 AM, 2:00 PM, 6:00 PM, and 10:00 PM. PARTICIPANTS: Thirty-four subjects with primary open-angle glaucoma or ocular hypertension were enrolled. INTERVENTIONS: Latanoprost 0.005% given every evening and TDFC twice daily. MAIN OUTCOME MEASURES: The primary efficacy variable was diurnal intraocular pressure. RESULTS: Thirty-three patients completed the study. On the last day of treatment, the mean diurnal intraocular pressure for latanoprost was 15.9 +/- 2.3 mmHg and for TDFC was 15.3 +/- 2.0 mmHg (P = 0.05). Individual time points for intraocular pressure were not statistically different between groups except at the 10:00 PM time point, when the mean for TDFC was 14.6 +/- 2.7 mmHg and for latanoprost was 16.6 +/- 3.1 mmHg (P < 0.006). Eighteen patients overall preferred latanoprost versus 2 patients for the fixed combination, generally because of the greater convenience of once daily dosing. Adverse events were not significantly different between groups except that a bitter taste was found more frequently with TDFC (n = 9) than with latanoprost (n = 0; P = 0.009). Despite screening to exclude intolerance to beta-blockers, a single patient had to discontinue the TDFC because of new-onset asthma. CONCLUSIONS: This study indicates that the 24-hour diurnal intraocular pressure is lowered more, by a small but statistically significant amount, with TDFC compared with latanoprost in primary open-angle glaucoma and ocular hypertensive patients.

Adult↗
PubMed1979

Timolol therapy in secondary angle-closure glaucoma post penetrating keratoplasty.

Timolol maleate (o.25% or 0.5% twice a day) was used in 13 eyes of 13 patients with secondary angle-closure glaucoma post penetrating keratoplasty uncontrolled on miotics, carbonic anhydrase inhibitors, or both. When added to each patient's current regimen, tomolol controlled 9 of the 13 eyes that no longer required cyclocryotherapy, and it was well tolerated locally and systemically. Its ocular hypotensive effect appears to supplement miotics and carbonic anhydrase inhibitors.

Carbonic Anhydrase Inhibitors↗
PubMed1980

Adverse reactions from timolol administration.

Five hundred forty-seven reports of adverse reactions to timolol maleate received by the National Registry for Drug-induced Ocular Side Effects during an eleven-month period were reviewed. Approximately half the reports concerned systemic reactions affecting the cardiac, pulmonary, central nervous, gastrointestinal, and dermatologic systems. Most serious were depression, anxiety, and confusion; bradycardia and arrhythmias; and pulmonary airway obstruction. Half of the ocular side effects concerned external ocular disease, of which superficial punctate keratitis and corneal anesthesia were the most remarkable. Ten percent of the reports described a visual disturbance which, in many cases, was not associated with refractive error.

Cardiovascular Diseases↗
PubMed1982

Effect of chronically administered timolol on aqueous humor flow in patients with glaucoma.

A prospective analysis of the effect of chronically administered timolol on the rate of aqueous humor flow through the anterior chamber was performed in 15 eyes of 13 subjects with chronic open-angle glaucoma. After one week's treatment, the flow of each treated eye was lower than it had been prior to treatment. After one year's treatment, the flow of 13 of 15 treated eyes was lower than it had been prior to treatment. However, the flow was higher in 12 of 15 eyes after a year's treatment than it had been after a week's treatment. These data suggest that the ciliary body or other structures in the eye must partly adapt to the chronic administration of this drug. The mechanism of the adaptation is unknown.

Adult↗
PubMed2001

In vitro transdermal iontophoretic transport of timolol maleate: effect of age and species.

Transdermal iontophoresis would be a promising method for the systemic delivery of water soluble and ionic drugs of relatively high molecular size, including peptides. In the present study, the effect of biological parameters such as age of the animal and species variation (rat, rabbit, mouse, guinea pig and human) on the transdermal iontophoretic transport was studied using timolol maleate (TM) as a model drug. The iontophoretic transport of TM across the skins obtained from the rats of different age groups was found to be similar. The results of the present study suggest that the age of the animal (Wistar rats: 1-8 months) did not appear to influence the transdermal iontophoretic transport of TM significantly. The amount of TM transported during iontophoresis (2 h) was significantly different among the different skin species. But the total amount of TM transported up to 24 h (2 h iontophoresis+22 h post-iontophoretic passive diffusion) was not significantly different among the different species studied. The present study provides further evidence that iontophoresis technique reduces the interspecies differences in the transdermal permeation of drugs, which is normally observed in passive diffusion of drugs. However, it must be noted that excised skins have been used in the present study to investigate the role of age and species variation on the iontophoretic transport of TM. The influence of these parameters under in vivo conditions might be different considering the physiological differences in different species and in the animals of different age groups.

Administration, Cutaneous↗
PubMed2002

Controlled transport of timolol maleate through artificial membranes under passive and iontophoretic conditions.

The passive and iontophoretic permeability of timolol maleate (TM) through porous and dense artificial membranes was investigated in order to select the most optimal membrane for a transdermal drug delivery system. For the meso-porous membranes (pore diameter 2-50 nm), the TM permeability for passive diffusion and iontophoresis was practically the same. For the micro-porous membranes (pore diameter<2 nm), a significant transport contribution of iontophoresis was observed, which was more pronounced when higher current densities were applied. The electrical resistance of all the porous membranes was lower than the electrical resistance of human skin. For dense membranes, passive and iontophoretic TM permeability was significantly lower than for porous membranes and in most cases their electrical resistance was comparable or even higher than the resistance of human skin. For most of the membranes studied the average adsorption of TM at 37 degrees C was low (0.02-0.33 mg/cm(2)) and independent of the TM concentration. For the meso-porous mixed cellulose acetate-cellulose nitrate membrane the TM adsorption was significantly higher and increased with the TM concentration. Based on our results, the optimum membrane for an iontophoretic transdermal TM delivery system is the LFC 1 micro-porous membrane because it mainly controls the TM delivery (TM iontophoretic permeability: 0.86 x 10(-6) cm/s), has very low electrical resistance (0.9-1.5 komega cm(2)) and the TM adsorption to it is low (0.15 mg/cm(2)). The therapeutic plasma TM concentration is achievable by application of this membrane in realistic sizes (5-64 cm(2)) and by application of current densities between 0.13 and 0.5 mA/cm(2).

Adsorption↗
PubMed2002

In vitro and in vivo evaluation of Pluronic F127-based ocular delivery system for timolol maleate.

The purpose of this study was to develop Pluronic F127 (PF127) based formulations of timolol maleate (TM) aimed at enhancing its ocular bioavailability. The effect of isotonicity agents and PF127 concentrations on the rheological properties of the prepared formulations was examined. In an attempt to reduce the concentration of PF127 without compromising the in situ gelling capabilities, various viscosity enhancing agents were added to PF127 solution containing 0.5% TM. The viscosity and the ability of PF127 gels to deliver TM, in vitro, in absence and presence of various viscosity enhancing agents were also evaluated. At the used concentration, some of the examined isotonicity agents had effect on the viscosity of TM gel. However, the viscosity of gel increased as the PF127 concentrations increased. The viscosity of formulations containing thickening agents was in the order of PF-MC 3%>PF-HPMC 2%>PF-CMC 2.5%>PF127 15%. The slowest drug release was obtained from 15% PF127 formulations containing 3% methylcellulose. In vivo study showed that the ocular bioavailability of TM, measured in albino rabbits, increased by 2.5 and 2.4 fold for 25% PF127 gel formulation and 15% PF127 containing 3% methylcellulose, respectively, compared with 0.5% TM aqueous solution.

Adrenergic beta-Antagonists↗
PubMed2000

Solubilization of timolol maleate in reversed micellar systems. Measurement of particle size using SAXS and PCS.

Small angle X-ray scattering (SAXS) and photon correlation spectroscopy (PCS) are two methods to measure particle sizes in the order of 10 nm magnitude, which can be used to characterize reversed micellar systems, in this case reverse micelles consisting of lecithin and isopropyl myristate (IPM). In this study these micelles are loaded with different concentrations of the amphiphilic anti-glaucoma drug timolol maleate (TM). The PCS results are consistent with those yielded by SAXS, showing a decrease of particle size with higher TM concentration. In addition, SAXS is capable to give information about the particle shape. This kind of evaluation yields an ellipsoidal shape for micelles with low drug loads, which transform into nearly spherical micelles at higher drug concentrations.

Dose-Response Relationship, Drug↗
PubMed2000

Transdermal iontophoretic delivery of timolol maleate in albino rabbits.

The use of transdermal iontophoresis is a promising technique for the systemic delivery of water soluble and ionic drugs of relatively large molecular size. The present study investigates the skin pre-treatment with Azone (laurocapram) and iontophoresis on the pharmacodynamic effect of timolol maleate (TM) in vivo in albino rabbits. The pharmacodynamic effect of TM was evaluated by transdermal delivery and compared with an intravenous (i.v.) administration. Iontophoresis of TM (0.1 mg/ml) produced a significant inhibition in the isoprenaline (ISP)-induced tachycardia. Iontophoresis with higher concentration of TM (1 mg/ml) produced a 100% inhibition of the ISP induced tachycardia. Pre-treatment of skin with Azone (3% v/v emulsion) eliminated the lag time and prolonged the duration of action of iontophoresis from 4 to 6 h. The AUC of Azone treated group was significantly higher than that of the untreated group (P<0.05). Further, the AUC with iontophoretic delivery and pre-treatment of Azone was comparable to that of intravenous TM (30 microg/kg). In conclusion, iontophoresis in combination with Azone can increase the transdermal delivery of TM, whereby the required transport rate can be achieved with a lower drug concentration.

Administration, Cutaneous↗
PubMed2002

Application of TLC-densitometry, first-derivative UV-spectrophotometry and ratio derivative spectrophotometry for the determination of dorzolamide hydrochloride and timolol maleate.

Three methods are described for the simultaneous determination of dorzolamide hydrochloride (DORZ) and timolol maleate (TIM) in ophthalmic solutions. The first method is based on application of thin layer chromatographic separation of both drugs followed by the densitometric measurements of their spot areas. After separation on silica gel GF(254) plates, using methanol-ammonia 25% (100:1.5 v/v) as the mobile phase, the chromatographic zones corresponding to the spots were scanned at 253 and 297 nm, respectively. The calibration function was established in the ranges of 2-18 microg for DORZ and 0.5-4.5 microg for TIM. The second method depends on first derivative ultraviolet spectrophotometry, with zero-crossing measurement method. The first derivative values D(1) at 250.2 and 312.5 nm were selected for the assay of DORZ and TIM, respectively. Calibration graphs follow Beer's law in the range 10-64 and 2.5-16 microg ml(-1), respectively. The third method is based on ratio first derivative spectrophotometry. The signals in the first derivative of the ratio spectra at 244 and 306.2 nm were selected to determine DORZ and TIM in the mixture and calibration graphs are linear in the range of 5-40 and 5.0-17.5 microg ml(-1), respectively. The proposed methods were successfully applied to the determination of these compounds in synthetic mixtures and in pharmaceutical preparations. The proposed methods are simple, rapid and suitable for quality control application.

Antihypertensive Agents↗