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PubMed2003

Transdermal delivery of timolol by electroporation through human skin.

The purpose was to achieve therapeutic fluxes of timolol by transdermal delivery using skin electroporation. The transdermal transport of timolol through human stratum corneum was studied in three compartment diffusion cells. The electrodes, buffer composition and pulse conditions were optimized. Timolol maleate concentration in the donor compartment was 40 mg/ml. Square wave pulses were applied. Electroporation enhanced the transdermal transport of timolol by 1-2 orders of magnitude as compared to passive diffusion. Even though the current application lasted for only 10 s, the transdermal transport remained high after pulsing for at least 6 h. Higher fluxes were obtained with Pt electrodes close to the skin and a phosphate buffer. 10 pulses of 400 V-10 ms were more efficient than 10 low voltage-long duration pulses. Therapeutic fluxes of timolol (>50 microg/cm(2) per h) through human stratum corneum were achieved by electroporation.

Administration, Cutaneous↗
PubMed2000

Stability indicating HPTLC determination of timolol maleate as bulk drug and in pharmaceutical preparations.

Timolol was the first beta blocker to be used as an anti-glaucoma agent and to date remains as the standard because none of the newer beta blockers were found to be more effective. The high performance thin layer chromatographic method of analysis of timolol maleate is reported. The mobile phase selected was ethyl acetate-methanol-isopropyl alcohol-ammonia (25%) (80:20:2:1, v/v/v/v). The calibration curve of the drug was linear in the range of 100-600 ng. The spectrodensitometric analysis was carried out at 294 nm. The mean (+/- RSD) values of slope, correlation coefficient and intercept were 2487.5 (+/- 0.9), 0.996 (+/- 0.081) and 90463 (+/- 1.1), respectively. The system precision and the method precision were excellent with an RSD of 2.8 and 1.004, respectively. The limits of detection and quantitation were 10 and 40 ng, respectively. The mean percent recovery was found to be 98.6. Timolol maleate was degraded by exposing the drug to heat, acid and base. The degraded products were found to be well separated from the pure drug with significantly different Rf values suggesting a stability indicating analysis method for quantification of timolol maleate in pharmaceutical preparations and as bulk drug. The method was utilized to analyze timolol maleate from conventional eye drops and novel sustained release solid polymeric ocular inserts and oral preparations. The reported method is simple, selective, precise, accurate, time saving and economic as compared to reported HPLC methods.

Adrenergic beta-Antagonists↗
PubMed1984

Comparative effects of propranolol, timolol and metoprolol on myocardial infarct size after experimental coronary artery occlusion.

The effects of equiblocking doses of three beta-adrenergic blocking agents, propranolol, timolol and metoprolol, on myocardial infarct size were evaluated in 28 dogs after acute experimental coronary artery occlusion. Heart rate, arterial pressure and arterial free fatty acid concentration were measured in an attempt to evaluate their effects on the extent of myocardial injury. The zone at risk of infarction in each dog 1 minute after left anterior coronary artery occlusion was assessed by injecting highly radioactive albumin microspheres into the left atrium, and the hypoperfused zone was determined by autoradiography. After 15 minutes, the dogs were randomized into four groups: control dogs (n = 7), propranolol-treated dogs (1.2 mg/kg intravenously, n = 7), timolol-treated dogs (0.2 mg/kg intravenously, n = 7) and metoprolol-treated dogs (1.2 mg/kg intravenously, n = 7). After 6 hours, the dogs were killed. The left ventricle was sliced and stained with triphenyl-tetrazolium chloride for measurement on infarct size. The same slices were then autoradiographed for measurement of the hypoperfused zone. The percent of hypoperfused zone that evolved to infarction (the ratio of infarct size to hypoperfused zone) was 90.4 +/- 1.9% in the control group, 72.4 +/- 2.4% in the propranolol-treated dogs (p less than 0.05 versus control group); 57.9 +/- 4.4% in the timolol-treated dogs (p less than 0.01 versus control group; p less than 0.05 versus propranolol) and 54.4 +/- 3.7% in the metoprolol-treated dogs (p less than 0.01 versus control group; p less than 0.05 versus propranolol). Thus, propranolol, timolol and metoprolol reduced myocardial infarct size in dogs by 20, 36 and 40%, respectively, after experimental coronary artery occlusion. Metoprolol and timolol protected the ischemic myocardium more effectively than did propranolol.

Animals↗
PubMed1997

Levobunolol 0.5% and timolol 0.5% to prevent intraocular pressure elevation after neodymium:YAG laser posterior capsulotomy.

PURPOSE: To evaluate the prophylactic effect of levobunolol 0.5%, timolol 0.5%, or vehicle in reducing the incidence of postoperative intraocular pressure (IOP) spikes of 5 and 10 mm Hg or more in patients having neodymium:YAG (Nd:YAG) laser posterior capsulotomy. SETTING: Miami Vision Center, Coral Gables, Florida; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; Cincinnati Eye Institute, Cincinnati, Ohio; South Texas Cataract and Glaucoma Center, San Antonio, Texas; Mid-South Eye Foundation, Memphis, Tennessee, USA. METHODS: This prospective, double-masked, randomized study comprised 144 patients having Nd:YAG laser posterior capsulotomy in one eye. One drop of the test medication was administered preoperatively and one drop on the evening after surgery; IOP was measured preoperatively and 1,2,3 and 24 hours postoperatively. RESULTS: Intraocular pressure elevations of 5 mm Hg or more were seen in 1 of 60 patients (2%) in the levobunolol group, 4 of 54 (7%) in the timolol group, and 10 of 28 (36%) in the vehicle group. These elevations occurred significantly more frequently in the vehicle group than in the levobunolol (P < .001) or timolol (P < .004) groups. Elevations of 10 mm Hg or more were found in 2 of 28 patients (7%) treated with vehicle but were not observed in the patients treated with levobunolol or timolol. CONCLUSIONS: Levobunolol 0.5% or timolol 0.5% administered preoperatively and again in the evening after Nd:YAG laser capsulotomy effectively blunted the IOP rise that frequently follows laser surgery.

Adrenergic beta-Antagonists↗
PubMed2000

Latanoprost versus timolol gel to prevent ocular hypertension after phacoemulsification and intraocular lens implantation.

PURPOSE: To evaluate the efficacy of latanoprost and timolol gel in preventing ocular hypertension in the early period after phacoemulsification and posterior chamber intraocular lens (PC IOL) implantation. SETTING: Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China. METHODS: This prospective randomized double-masked clinical trial comprised patients with uncomplicated cataract having phacoemulsification with PC IOL implantation. They were randomly assigned to 1 of 3 groups: postoperative application of timolol 0.5% gel-forming solution (Timoptol-XE(R)) (Group 1), latanoprost 0.005% (Group 2), and control (Group 3). Intraocular pressure (IOP) was measured 2, 4, and 24 hours postoperatively. The anterior chamber was examined for the levels of cells and flare using slitlamp biomicroscopy. RESULTS: Group 1 had a significantly greater reduction in mean IOP 2, 4, and 24 hours after phacoemulsification and PC IOL implantation than Group 3 (P <.05). There were no significant differences between Groups 2 and 3 at any interval (P. 05). No excessive postoperative anterior chamber inflammation was observed in any group. CONCLUSIONS: A single dose of latanoprost given after phacoemulsification and PC IOL implantation did not produce a significant IOP-lowering effect when compared with a control group in the first 24 hours postoperatively. A single dose of timolol gel produced a significant postoperative IOP decrease as soon as 2 hours and up to 24 hours after surgery. Timolol gel and latanoprost are safe, but timolol is more effective than latanoprost in preventing postoperative ocular hypertension.

Adrenergic beta-Antagonists↗
PubMed1999

Influence of betaxolol and timolol on the venous tone in glaucoma patients.

The aim of this study was the assessment of physiological venous reflexes in 40 glaucoma patients treated with topically applied timolol maleate 0.50% and betaxolol HCL 0.50%. They were divided into two groups of twenty each; one group being given timolol and the other betaxolol. The assessment of the venous tone was performed by testing venous reflexes. We found no statistically significant difference between timolol and betaxolol; however, when the influence of circulating catecholamines and the other vasoactive substances was excluded by suprasphygmatic insufflation of a pediatric cuff, a significant difference was found in the Valsalva's maneuver (125.5 +/- 8.1 vs 85.0 +/- 34.3 venoconstrictive units VCUs, p = 0.03). The IOP was significantly decreased in both treatment group, although the pressure reduction effect was more pronounced in the timolol group. Our study suggests that timolol and betaxolol have a slightly different mode of action on the venous side of circulation under topical medications. It is possible that the use of betaxolol topically may reduce a systemic venoconstriction.

Administration, Topical↗
PubMed2001

Latanoprost versus combined therapy with timolol plus dorzolamide: IOP-lowering effect in open-angle glaucoma.

PURPOSE: To compare the effect on intraocular pressure of latanoprost versus timolol plus dorzolamide in open-angle glaucoma. METHODS: Thirty-five patients with open-angle glaucoma were randomized, 18 to latanoprost once daily and 17 to timolol plus dorzolamide twice daily. Intraocular pressure and ocular side effects were recorded at baseline, and after 2 weeks and 3 months of treatment. RESULTS: Latanoprost reduced the intraocular pressure 1.09 and 1.58 mm Hg more than timolol plus dorzolamide after 2 weeks and 3 months of treatment, respectively. These differences were statistically significant (p<0.05) at the end of the study. After 3 months of treatment, 32.3% of the eyes in the latanoprost group reduced the intraocular pressure in 30% or more with respect to baseline, while 15.6% of the eyes in the timolol plus dorzolamide group achieved this reduction. CONCLUSIONS: Latanoprost administered once daily reduced the intraocular pressure at least as well as timolol plus dorzolamide twice daily in patients with open-angle glaucoma.

Adrenergic beta-Antagonists↗
PubMed2003

Evaluation of retinal haemodynamics and retinal function after application of dorzolamide, timolol and latanoprost in newly diagnosed open-angle glaucoma patients.

PURPOSE: The purpose of this prospective, randomized, cross-over study was to investigate and compare the microcirculatory effects of timolol, dorzolamide and latanoprost in newly diagnosed primary open-angle glaucoma (POAG) patients. Haemodynamics were assessed using fluorescein angiography by means of a scanning laser ophthalmoscope (SLO). Visual function and visual field indices were evaluated during all drug treatment phases. METHODS: Fourteen patients with newly diagnosed POAG (age 55 +/- 7 years; 10 male, four female) were recruited for the study. At baseline examination, blood pressure, heart rate, intraocular pressure (IOP), SLO angiograms, and contrast sensitivity (CS) were analysed. Patients then randomly received timolol, dorzolamide or latanoprost treatment for 4 weeks. Patients then returned and all procedures were repeated and assessed. Arteriovenous passage times (AVPs), peripapillary arterial and venous diameters were assessed from SLO angiograms, using digital image processing. Calculated ocular perfusion pressure was determined for each treatment phase. RESULTS: Intraocular pressure was significantly lowered by each drug compared to baseline (p < 0.0001). Arteriovenous passage times were significantly shortened after dorzolamide application compared to baseline (p = 0.009), whereas neither timolol nor latanoprost treatment resulted in significant AVP changes. Peripapillary arterial and venous diameters, systolic and diastolic blood pressure, heart rate and ocular perfusion pressures were not significantly altered during any treatment phase. Contrast sensitivity testing at 6 cycles/degree (c.p.d.) revealed a significant rise after dorzolamide compared to timolol (p = 0.007). CONCLUSION: Our results suggest that dorzolamide treatment significantly shortened AVP times in newly diagnosed open-angle glaucoma patients, whereas timolol and latanoprost had no significant effect. Given that prolonged AVP times have been associated with disease progression in glaucoma; dorzolamide treatment may benefit optic nervehead preservation by increasing ocular perfusion.

Adrenergic beta-Antagonists↗
PubMed1980

Timolol and hydrochlorothiazide-amiloride in primary hypertension.

Fifty-five patients with primary hypertension, World Health Organization (WHO) stages I and II, were randomly allocated to a 9-mo multicenter, controlled, double-blind, crossover study with timolol, a nonselective beta adrenoceptor blocker, and hydrochlorothiazide combined with the potassium-sparing drug amiloride (AHCT). In 54% of the patients the blood pressure responded to timolol, in 87% to AHCT, and in 91% to a combination of the two. The diurectic was more effective than the beta blocker in patients with low-renin hypertension, who all responded to AHCT. Overall, there was no correlation between pretreatment plasma renin activity (PRA) and hypothensive effect of either drug. Timolol reduced PRA by 58% and plasma aldosterone (PA) by 23% while AHCT increased these levels threefold. Combination therapy increased PA while PRA returned towards baseline, suggesting greater aldosterone stimulation by the diuretic component. Serum triglycerides rose during timolol treatment alone and in combination. Both timolol and AHCT are effective antihypertensives. In combination they normalize blood pressure in most patients with primary hypertension (WHO stages I and II). Determination of PRA is useful as a guide to the choice of the first treatment in searching out low-renin hypertensive patients, who are best treated with diuretics.

Adult↗
PubMed1981

Short- and long-term therapy of mild essential hypertension with timolol.

The short and long-term antihypertensive action of timolol, a beta blocker, was assessed in 36 mild hypertensives in a 32-wk, double-blind, placebo-controlled study followed by an additional 96 wk of timolol in 17 responders. Diastolic blood pressure (DBP) and heart rate (HR) declined during the first phase from 103 to 93 mm Hg and from 73 to 61 bpm (P less than 0.01) but there was long-term timolol subjects (DBP 89 mm Hg at 32 wk and 88 mm Hg at 96 wk [NS] and HR 62 and 65 bpm [NS]). Although stimulated plasma renin activity in the entire group decreased from 1.08 to 0.28 ng/ml/hr (P less than 0.001), blood pressure reduction did not correlate with this decline (r = 0.29) or with serum timolol level (r = 0.29). In 20 patients who underwent treadmill was not altered. Thus, timolol is effective in reducing mild high blood pressure during short-term therapy and in maintaining this effect over the long term in responsive subjects. It is therefore potentially useful in chronic essential hypertension.

Adult↗
PubMed1981

Exercise duration to angina at two and twelve hours after timolol.

Eight patients who improved their exercise duration to angina or marked fatigue (greater than or equal to 25%) on timolol 10 to 30 mg twice daily over that on placebo 8 to 14 mo previously were subjects in a double-blind, randomized, crossover 4-wk study of the effect of timolol on exercise duration 2 and 12 hr after medication. One patient was discontinued from the study because unstable angina developed on placebo. Mean exercise duration on timolol over control was increased at 12 hr (p less than 0.02) and at 2 hr ( p less than 0.001) after drug. There was an increase in exercise duration greater than or equal to 25% on timolol over control compared with placebo in three of seven patients (43%) 12 hr after drug and in seven of seven (100%) 2 hr after drug. Timolol 10 to 30 mg twice daily prolongs exercise duration to angina or marked fatigue at 2 hr after drug and in some responders at 12 hr after drug.

Angina Pectoris↗
PubMed1998

Comparison of short- and long-term effects of betaxolol and timolol on human retinal circulation.

PURPOSE: To determine the short- and long-term effects of betaxolol and timolol on human retinal circulation. METHODS: In a double-masked, randomised, placebo-controlled study we evaluated the effects of both a one-drop application and a twice-daily 2-week application of either topical 0.5% betaxolol hydrochloride or topical 0.5% timolol maleate on the retinal circulation in 12 healthy volunteers. Laser Doppler velocimetry was used to detect changes in the retinal venous blood flow. RESULTS: In both betaxolol- and timolol-treated eyes, intraocular pressure decreased significantly compared with baseline values after both 90 min and 2 weeks. In betaxolol-treated eyes, retinal blood flow did not change significantly after 90 min, but increased significantly (14 +/- 9%; p = 0.02) compared with baseline after 2 weeks. In timolol-treated eyes, retinal blood flow decreased significantly (18 +/- 5%: p = 0.04) compared with baseline after 90 min, and also decreased significantly (14 +/- 6%; p = 0.04) compared with baseline after 2 weeks. CONCLUSIONS: Retinal blood flow increases as a long-term effect of betaxolol and decreases as both a short- and long-term effects of timolol.

Adrenergic beta-Antagonists↗
PubMed1998

The effect of timolol drops on respiratory function.

PURPOSE: Recently, attention has been focused on the adverse drug reactions of topical timolol, especially with regard to respiratory function in the elderly. This study was designed to assess whether timolol causes an alteration in lung function in patients without pre-existing respiratory disease and who have not suffered the impact of long-term beta 2 blockade. METHODS: A placebo-controlled randomised, double-masked, cross-over study was carried out on 20 ocular hypertensive patients with intraocular pressures over 21 mmHg, normal optic discs and full visual fields by Humphrey perimetry. Subjects received single-dose units of timolol maleate 0.5% drops or normal saline drops. Both were instilled in one eye or systemically (sublingually). The peak expiratory flow rate (PFR), forced expiratory volume (FEV), vital capacity (VC) and FEV/VC (%) ratio were all measured both before and after each type of drop and route of administration. RESULTS: Two hours after instillation of timolol there was no change in PFR (p = 0.67) or VC (p = 0.40), but there was a fall in FEV (p = 0.038) and the FEV/VC (%) ratio (p = 0.041). The fall was greatest after topical administration. CONCLUSIONS: Our results show that in our group of patients there was a tendency towards mild bronchial obstruction after topical timolol, although this was not clinically significant.

Administration, Oral↗
PubMed1976

Quantitative effects of timolol and hydrochlorothiazide on blood pressure, heart rate and plasma renin activity: results of a double-blind factorial trial in patients with essential hypertension.

1. The anti-hypertensive actions of timolol and hydrochlorothiazide were analysed in a double-blind 2 x 2 factorial trial in twenty patients with essential hypertension. Each patient went through four phases of 8 weeks in randomized order, receiving timolol alone, hydrochlorothiazide alone, timolol plus hydrochlorothiazide, and placebo. 2. Supine mean arterial pressure fell from 119 mmHg in the placebo phase, to 110 mmHg during the thiazide phase, 106 mmHg during the timolol phase, and to 101 mmHg during the combined timolol plus hydrochlorothiazide phase. 3. Factorial analysis revealed that the hypotensive actions of the beta-receptor-blocking drug and the diuretic were additive, without any synergism or antagonism. 4. Plasma renin activity measured in ng 3 h-1 ml-1 rose from 5-02 in the placebo phase to 9-54 in the diuretic phase, but fell to 1-79 in the beta-receptor blockade. It was unchanged in the combined therapy phase, despite the greater drop in blood pressure. These results suggest that the fall in plasma renin activity during beta-receptor blockade is of little importance in the hypotensive action of beta-receptor-blocking drugs.

Adult↗
PubMed1976

Evaluation of the effect of timolol alone and in combination with hydrochlorothiazide and amiloride in the treatment of mild to moderate arterial hypertension: a double-blind, controlled study.

1. The effects of timolol alone and in combination with a fixed dose of hydrochlorothiazide and amiloride have been studied in a double-blind, controlled study in fifty-four patients with mild to moderate essential hypertension. 2. After a 4 weeks placebo period patients were randomly assigned to enter groups receiving timolol alone (group A), hydrochlorothiazide + amiloride (group B) or timolol + hydrochlorothiazide + amiloride (group C). Each treatment was carried out for 6 weeks. 3. The use of timolol (10 mg), hydrochlorothiazide (25 mg) and amiloride (2-5 mg) in a combination tablet given twice daily gave better control of blood pressure in patients with mild to moderate essential hypertension than did equivalent dosages of timolol alone or of hydrochlorothiazide and amiloride. 4. Clinical and laboratory side effects were minimal.

Adult↗
PubMed2006

[Effect of timolol on central corneal thickness and endothelial cell density].

BACKGROUND: The measurement of corneal thickness plays an increasing role in glaucoma screening and diagnosis. The influence of a variety of drugs on corneal thickness is well established. Especially for antiglaucomateous drugs this effect seems to be important. However, little is known about the influence of beta receptor antagonists on corneal thickness. The aim of this study was to provide evidence of the effect of timolol on central corneal thickness and endothelial cell density. MATERIALS AND METHODS: Ten healthy volunteers (five women and five men) with a mean age of 29 years (range 25 to 56 years) were examined in a double-blind, prospective and randomised pilot study. Intraocular pressure, corneal thickness and endothelial cell density was estimated before as well as fifteen minutes, 24, 48, 72 and 96 hours after application of timolol 0.5 % eye drops twice daily. The partner eye received sodium hyaluronate eye drops twice daily and served as a control. RESULTS: The application of timolol showed a decrease of intraocular pressure from initially 12 mmHg to 9 mmHg after four days (p = 0,0188) as well as an increase of corneal thickness from 537 microm to 557 microm after four days (p = 0,0659). There was no change of intraocular pressure (p = 0,9935) or corneal thickness (p = 0,9998) in the control eyes. There was also no effect of timolol (p = 0,2782) or sodium hyaluronate (p = 0,1940) on endothelial cell density. CONCLUSIONS: The study provides evidence of the influence of beta receptor antagonists on corneal thickness. This effect may be caused by receptor mediated influences on corneal ion and fluid transport. Further studies are needed to show if the increase of corneal thickness after application of topical timolol has clinical importance.

Adult↗
PubMed1981

[Comparative studies of the pressure-lowering effect of timolol and phospholine iodide (author's transl)].

A comparative study of the intraocular pressure-lowering effects of timolol and phospholine iodide in cases of aphakic glaucoma was carried out. The authors compared the I.O.P.-lowering effect of these two drugs in 30 eyes (30 patients) with aphakic glaucoma over an eight-month observation period. The following was established after a statistical analysis of the material: 1. The I.O.P.-lowering effect of timolol in aphakic glaucoma cases is almost identical with the effect of the drug in cases of chronic open-angle glaucoma. 2. The administration of phospholine iodide in such cases leads to a stable I.O.P. regulation and it seems that this therapy should be preferred to treatment with timolol. 3. Timolol therapy in cases of aphakic glaucoma should be considered an enrichment of the known treatment methods. 4. The administration of timolol requires constant follow-up and if this is not possible therapy with pilocarpine or phospholine iodide should be preferred.

Aged↗
PubMed1980

[Treatment of narrow-angle glaucoma with timolol (author's transl)].

The authors report on seven patients with narrow-angle glaucoma treated for up to six months with Timolol eye drops. Prior to treatment with Timolol the patient's eyes had remained unregulated despite miotics therapy, or it had been impossible to continue with miotics due to subjective intolerance. Timolol eye drops achieved a significant lowering of pressure in all seven patients and satisfactory pressure stabilization was achieved either with Timolol eye drops alone or in combination with pilocarpine or Carbachol eye drops. In one patient who had unregulated glaucoma and who was on Carbachol/acetazolamide therapy, satisfactory stabilization was achieved by additional application of Timolol.

Aged↗