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PubMed1988

Application site dependent ocular absorption of timolol.

Ocular absorption of timolol in rabbits was studied after topical ocular administration of 3H-timolol in an eyedrop or in silicone cylindrical devices that released timolol at 7.2 micrograms/h. The devices were applied in either the inferior or superior conjunctival sac. Timolol concentrations were nearly equal in the inferior and superior portions of ocular tissues when the drug was administered in an eyedrop. Administration in the devices resulted in unequal timolol distribution in the cornea, conjunctiva, sclera, and iris-ciliary body. Timolol concentrations were higher in the part of each tissue that was closer to the site of the device application. Unequal concentrations of timolol in the superior and inferior part of the eye and very low timolol concentrations in the aqueous humor indicated that timolol was absorbed mainly via a noncorneal route from the device placed in the inferior conjunctival sac. Induced blinking at one minute intervals did not change ocular absorption of timolol. Compared with inferior conjunctival sac applications, placement of the devices in the superior conjunctival sac resulted in increased corneal and total ocular absorption of timolol as indicated by higher timolol concentrations in the aqueous humor and by a smaller difference between concentrations in the superior and inferior portions of the examined tissues. The application site dependent ocular absorption indicated that controlled release of timolol in the tear fluid did not result in a uniform timolol distribution in the preocular tear fluid of rabbit eyes.

Absorption↗
PubMed1989

Effects of D-timolol on intraocular pressure (IOP), beta blocking activity, and the dynamic changes of drug concentrations in aqueous humor.

L-timolol has been used successfully in the treatment of glaucoma. Because of its powerful beta blocking activity, however, more and more side effects have been reported. D-timolol, an optic isomer of L-timolol with much less beta blocking activity, was noted to have similar ocular hypotensive effects through inhibition of aqueous production as L-timolol. Thus, it is expected that D-timolol may reduce the side effects considerably if it is used in the clinics. In this study, we observed the ocular hypotensive effect of 0.5% D-timolol in normotensive and water-loaded rabbits as well as in patients with glaucoma or ocular hypertension. A significant reduction of intraocular pressure (IOP) which lasted at least six hours was observed. No side effects, either locally or systemically, were found. The concentration of D-timolol was traced in rabbits' aqueous humor after topical administration. The drug quickly appeared in the aqueous 30 minutes after instillation of 100 microliters 1% D-timolol. The peak concentration was 1916.5 ng/ml. It declined to a minimum in four hours, although the hypotensive effect could last at least six hours. For estimating the beta blocking potency of D-timolol, radioligand binding assay was employed to calculate the Ki value from isolated cell membrane of rabbits' lung. It showed that the beta blocking potency of D-timolol was much less than that obtained from L-timolol. It is concluded that D-timolol may be a valuable antiglaucoma agent comparable to L-timolol in lowering the IOP. The side effects induced by beta blocking agents we are using currently might be considerably reduced with D-timolol.

Adolescent↗
PubMed1990

Development of D-timolol for the treatment of glaucoma and ocular hypertension.

It has been found that D-timolol is equipotent or slightly less potent than L-timolol to lower the intraocular pressure (IOP) in normotensive rabbits, water loaded ocular hypertensive rabbits, alpha-chymotrypsin induced glaucoma rabbits, hypertonic saline infused IOP recovery model of rabbits, normotensive human volunteers, glaucoma patients and ocular hypertensive human individuals. Although L-timolol has been used widely for the treatment of glaucoma and ocular hypertension, it produces numerous side effects including cardiovascular disturbances, asthmatic attack, psychological depression, etc. Since D-timolol has much weaker affinity toward beta-adrenergic receptors, it was found to have 1/80-1/300 the beta-adrenergic blocking potency of L-timolol to block beta-adrenergic receptors in guinea pig tracheal preparations and 1/90 of L-timolol to block beta-adrenergic receptors in guinea pig atrial preparations. As a result, D-timolol showed no subjective nor objective side effects on pupil size, conjunctiva, cornea, blood pressure and pulse rate. Further, D-timolol was reported to increase retinal and choroid blood flow in rabbits without affecting overall ocular blood flow. On the contrary, L-timolol was found to significantly reduce the overall ocular blood flow and retinal and choroid blood flows in rabbits, although it might slightly increase the retinal blood flow in normotensive individuals. D-Timolol was well absorbed across the cornea as L-timolol and produced the duration of action as long as L-timolol. These results indicate that D-timolol could be a better agent than L-timolol for the treatment of glaucoma and ocular hypertension.

Animals↗
PubMed2005

Association between low plasma levels of ophthalmic timolol and haemodynamics in glaucoma patients.

OBJECTIVES: The aims of the study were to assess the correlation between the plasma concentration of ophthalmic timolol and cardiovascular parameters, and the influence of timolol on advanced haemodynamic variables, such as stroke (SI), cardiac (CI) and systemic vascular resistance (SVRI) indices and arterial pulse wave velocity (PWV). METHODS: Twenty-five glaucoma or ocular hypertensive patients were treated with 0.5% aqueous and 0.1% hydrogel formulations of timolol using a randomised, double-masked, crossover, multicentre design. All the patients were subjected to passive head-up tilt, electrocardiography, exercise test and measurement of plasma concentration of timolol. In the analysis, the data on the two treatments were combined, and the Spearman correlation coefficients between the plasma level of timolol and physiological effects were calculated. RESULTS: During the head-up tilt test before rising the bed up, the resting heart rate (HR; R=-0.52, P=0.001) and PWV (R=-0.34, P=0.04) were inversely correlated with timolol level. In the upright position, ophthalmic timolol effectively suppressed the rise in HR (R=-0.36, P=0.03). The SI did not change with timolol concentration, while CI diminished as timolol concentration rose (R=-0.39, P=0.02). The SVRI correlated with timolol concentration (R=0.38, P=0.02). In the exercise test, correlation between HR and plasma level of timolol steadily grew stronger as the load increased, reaching R=-0.60 (P<0.0001) at the maximum load. Systolic and diastolic arterial pressures were not associated with the timolol concentration. CONCLUSION: The plasma concentration of ophthalmic timolol correlates with several haemodynamic effects. As HR decreases, SVRI increases and blood pressure is kept unchanged.

Adrenergic beta-Antagonists↗
PubMed1986

The effect of acute and chronic administration of timolol on cardiac sympathetic neural discharge, arrhythmia, and beta adrenergic receptor density associated with coronary occlusion in the cat.

The effect of timolol (5 mg/kg, p.o., b.i.d. 7 or 14 days) on cardiac beta adrenergic receptor density, the times to arrhythmia (AR) and death (D), heart rate, mean arterial blood pressure, and postganglionic cardiac sympathetic neural discharge after acute coronary occlusion in cats was examined. In the control animals, receptor densities in the left and right atria did not differ, but were lower than the right ventricle. Left ventricle and septum receptor densities were higher, with the left ventricle the highest. The importance of the gradation of beta receptors with increasing density from base to apex appears to be its relation to cardiac contractile function. Occlusion in cats not treated with timolol did not alter the cardiac beta receptor densities. After timolol for 7 or 14 days, no occlusion, receptor density increased in left ventricle and septum although the increase was only significant after 14 days. A comparison of the beta adrenergic receptor densities in cats pretreated with timolol for 7 or 14 days with or without occlusion revealed that, in general, a decrease (p greater than 0.05) occurred for the occlusion group. Timolol decreased heart rate and blood pressure prior to occlusion. The mean times to AR and D were not significantly increased by either dosing regimen of timolol, although the trend was for an increase in the time to D after 7 days of timolol and an increase in the time to AR and D after 14 days of timolol. When compared with data obtained in saline cats, chronic timolol produced minimal changes in postganglionic cardiac sympathetic neural discharge. Timolol given chronically (p.o.) or acutely (5 mg/kg, i.v. given 15 min prior to occlusion) also did not prevent the cardiac sympathetic discharge associated with the development of AR. The time to AR and D in the acutely treated cats was increased but not significantly. Since cardiac sympathetic neural discharge increased as blood pressure fell in the control period but did not increase after occlusion in the timolol treated animals, the combination of timolol and occlusion may have modified neural discharge via an action on the baroreceptor mechanism. That chronic administration of timolol produces an effect not present in cats in which only occlusion was done is supported by the observation that chronic treatment produced an occlusion-induced decrease in beta adrenergic receptor density.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1989

Beta-adrenoceptor antagonist activities and binding affinities of timolol enantiomers in rat atria.

S-Timolol is an effective anti-glaucoma drug, but has potentially hazardous side effects. Recently, R-timolol, also, has been reported to be effective in lowering elevated intraocular pressure. In the present study, the beta-adrenoceptor antagonist activities and binding of R- and S-enantiomers of timolol have been examined on rat atrial preparations. The beta-antagonistic activities were investigated using spontaneously beating rat heart atria. Both timolol enantiomers inhibited (-)-isoprenaline-induced chronotropic action competitively. S-Timolol was about 54 times more potent than R-timolol. The apparent binding affinities of timolol enantiomers to beta 1- and beta 2-adrenoceptors were determined by a radioligand binding assay using (-)-[125I]iodocyanopindolol (ICYP) as a marker and CGP 20712 A as a beta 1- and ICI 118,551 as a beta 2-adrenoceptor antagonist. Both enantiomers of timolol inhibited ICYP binding in nanomolar concentrations with Hill coefficients near unity. Neither enantiomer showed selectivity between beta 1- and beta 2-adrenoceptors, but R-timolol was approximately 30 times less active than S-timolol. It is concluded that R-timolol is a relatively potent non-selective beta-adrenoceptor blocking agent, but may possibly exert a more localized beta-adrenoceptor action in the eye than S-timolol, thus improving the safety of ocular timolol therapy.

Adrenergic beta-Antagonists↗
PubMed2004

Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study.

PURPOSE: To compare the toxicity of latanoprost and preserved and unpreserved timolol on conjunctival cells. Expression of inflammatory markers and MUC5AC-related mucin production were evaluated by impression cytology in a case-control ex vivo study. The proapoptotic effect of the same drugs was also evaluated in vitro in a conjunctival cell line and compared with that of benzalkonium chloride (BAC). METHODS: Impression cytology (IC) specimens were obtained from a series of normal subjects and from patients with glaucoma treated for at least 1 year with latanoprost eye drops or preserved or unpreserved timolol. All groups were comparable in age and duration of treatment. Expression of HLA-DR, intercellular adhesion molecule (ICAM)-1, and mucin was evaluated in a masked manner by flow cytometry. For the in vitro study, a human conjunctiva-derived cell line was treated with 0.02% BAC-containing latanoprost or timolol, unpreserved timolol, or 0.02% BAC alone for 15 minutes, followed or not by 4 or 24 hours of cell recovery in normal medium. Cell viability and chromatin condensation were evaluated using microplate cold light cytofluorometry with the neutral red and the Hoechst 33342 tests, respectively. The Hoechst-neutral red ratio was defined for the apoptosis assay, and cytoskeleton changes were assessed by confocal microscopy. RESULTS: No difference was found between normal eyes and those receiving unpreserved timolol. Preserved latanoprost and timolol significantly increased the inflammatory marker expression and decreased MUC5AC expression, but to a significantly higher extent in the preserved timolol group compared with latanoprost. In vitro, 0.02% BAC-containing timolol and latanoprost triggered conjunctival cell apoptosis-however, to a significantly lesser extent than did 0.02% BAC alone. Unpreserved timolol did not cause any cell toxicity. CONCLUSIONS: These ex vivo and in vitro studies demonstrate that BAC-containing latanoprost and timolol exhibit higher proinflammatory and proapoptotic effects on conjunctival cells than does unpreserved timolol. Latanoprost caused less toxicity, however, than preserved timolol, and both drugs were less toxic than BAC alone. These results suggest a potential protective effect of the prostaglandin analogue and to a lesser extent of timolol against the toxicity of BAC in conjunctival cells.

Adolescent↗
PubMed1999

The efficacy and safety of the dorzolamide-timolol combination versus the concomitant administration of its components.

OBJECTIVE: To evaluate whether a fixed combination of 2% dorzolamide and 0.5% timolol given twice daily showed equivalent efficacy to the concomitant administration of 2% dorzolamide given three times daily and 0.5% timolol given twice daily in patients whose intraocular pressure (IOP) remained elevated during monotherapy with 0.5% timolol twice daily. DESIGN: Multicenter, parallel, randomized, double-masked clinical trial with an open-label extension. PARTICIPANTS AND INTERVENTION: In the masked phase, 242 patients received either the dorzolamide-timolol combination twice daily and placebo three times daily or dorzolamide three times daily and timolol twice daily for up to 3 months. In the open-label extension, 220 patients received the dorzolamide-timolol combination twice daily for up to 9 months. MAIN OUTCOME MEASURES: The criterion for establishing treatment equivalency was a 95% or greater confidence that the absolute difference in the mean change in IOP from baseline was less than 1.5 mmHg between treatments. RESULTS: During 3 months of treatment, the dorzolamide-timolol combination reduced IOP relative to the 0.5% timolol baseline by approximately 14% at hour 0 (just before the morning dose), 20% at hour 2, and 15% at hour 8. The IOP-lowering effect of concomitant therapy with dorzolamide and timolol was approximately 16% at hour 0, 20% at hour 2, and 17% at hour 8. At hours 0, 2, and 8, there was greater than 97% confidence that the treatments were equivalent. During the open-label extension, the mean IOP reduction ranged from 14% to 15% at hour 0 and from 20% to 21% at hour 2. The treatment groups were generally comparable in terms of adverse events, symptoms, ocular signs, visual acuity, visual fields, physical examination, and laboratory measures. CONCLUSIONS: The IOP-lowering effect of the dorzolamide-timolol combination is comparable to that of dorzolamide three times daily plus timolol twice daily and is maintained for up to 1 year. The dorzolamide-timolol combination provides clinically important reduction in IOP relative to baseline treatment with timolol alone and is generally well-tolerated for up to 1 year.

Adrenergic beta-Antagonists↗
PubMed1991

Pharmacokinetic basis for nonadditivity of intraocular pressure lowering in timolol combinations.

The authors determined whether the ocular absorption of topically applied timolol in the pigmented rabbit was affected significantly by coadministration with either pilocarpine or epinephrine in the same drop to explain the nonadditivity in intraocular pressure lowering (IOP) seen clinically. They instilled 25 microliters of 0.65% timolol maleate solution (equivalent to 0.5% timolol), both in the presence and absence of 2.6% pilocarpine nitrate or 1% epinephrine bitartrate, into pigmented rabbit eyes. The time course of timolol concentration in the conjunctiva, anterior sclera, corneal epithelium, corneal stroma, aqueous humor, iris-ciliary body, and lens was monitored for 360 min by using reversed-phase high-performance liquid chromatography. The area under the timolol concentration-time curve in all but one of the anterior segment tissues was reduced by 20-50% (mean, 40%) when timolol was coadministered with pilocarpine and by 20-70% (mean, 42%) when timolol was coadministered with epinephrine. Such an effect was not a result of alterations in corneal permeability or aqueous humor turnover rate, nor was it related to the extent of systemic absorption caused by pilocarpine and epinephrine. Rather, the reduction in ocular timolol absorption may have been caused by the accelerated washout of timolol by tears stimulated by the coadministered drugs and, to a lesser extent, by the loss of timolol through binding to the increased amount of tear proteins induced by the coadministered drugs. Thus, the nonadditivity in IOP lowering from timolol-pilocarpine and timolol-epinephrine combinations is probably caused by changes in precorneal timolol clearance.

Absorption↗
PubMedDate not supplied

Pharmacogenetic explanation for excessive beta-blockade following timolol eye drops. Potential for oral-ophthalmic drug interaction.

OBJECTIVE: To determine whether the effects of topically administered timolol in an individual would be dependent on the presence or absence in that individual of the P-450 enzyme CYP2D6 and whether the effects of topically administered timolol would be increased and its metabolism decreased by the oral administration of quinidine, a known inhibitor of CYP2D6. DESIGN: Single-blind randomized crossover comparison of topical timolol, placebo, and the effects of inhibition of timolol metabolism by oral quinidine. SETTING: Clinical research center of an academic medical center. PARTICIPANTS: Eight male extensive metabolizers (EMs) and five male poor metabolizers (PMs) of debrisoquin. INTERVENTION: Two drops of 0.5% timolol or artificial tears were administered into each nostril in random order, and placebo or 50 mg of quinidine was administered orally to the EMs in random order, followed 30 minutes later by either the timolol or placebo drops. MAIN OUTCOME MEASUREMENT: Plasma timolol concentrations were measured by high-pressure liquid chromatography, while the extent of beta-blockade was determined by the suppression of exercise-induced rise in heart rate. RESULTS: The exercise heart rate was reduced following timolol eye drops compared with placebo in both EMs (P < .001) and PMs (P < .001) with significantly greater heart rate reduction (P = .01) and higher plasma timolol concentration in PMs compared with EMs (P = .03). Administration of quinidine with timolol eye drops to EMs resulted in a further significant reduction in heart rate (P = .02) and increase in plasma timolol concentration (P = .04). CONCLUSIONS: An individual's debrisoquin phenotype is an important determinant of beta-blockade following timolol eye drops, and metabolism of timolol is inhibited and beta-blockade increased by coadministration of oral quinidine. Clinicians should be aware of the potential for drug interactions that occur when orally administered drugs inhibit the metabolism of a topically administered drug.

Administration, Oral↗
PubMed2002

Combined therapy of pilocarpine or latanoprost with timolol versus latanoprost monotherapy.

Adjunctive intraocular pressure (IOP)-lowering therapy is widely used today, as one-third of all patients being treated for glaucoma need additional therapy to reach and maintain healthy IOPs. Timolol, latanoprost, and pilocarpine are three potent drugs that have been used in combination to reduce IOP. Timolol reduces the production rate of aqueous humor to achieve the IOP decrease. Latanoprost and pilocarpine both affect aqueous outflow, although by different mechanisms. The IOP efficacy of combined therapy with timolol and pilocarpine compared with timolol and latanoprost or with latanoprost alone has been investigated in three multicenter, randomized, clinical trials in Europe. This is a review of those published trials. In 2 of the 3 studies, the additional IOP lowering effect of latanoprost 0.005% administered once daily was compared with pilocarpine 2% administered 3 times daily in patients with primary open-angle glaucoma (POAG) or ocular hypertension currently on monotherapy with timolol 0.5% twice daily. These 6-month studies found that the timolol and latanoprost combination reduced IOP more and was better tolerated with fewer side-effects than the timolol and pilocarpine combination. At 6 months, there was no evidence of long-term drift in IOP with timolol and latanoprost. This combined therapy provides an effective and safe option for lowering IOP in glaucoma patients. These results suggest that the timolol/latanoprost combination is preferable to the timolol/pilocarpine combination not only with regard to side effects but also to the magnitude of IOP reduction. Two of the 3 studies compared latanoprost monotherapy with timolol and pilocarpine combined therapy in patients with POAG, various other glaucomas, or ocular hypertension. Treatment was for 6 weeks or 6 months. In both studies, latanoprost was more effective and better tolerated than the combination of timolol and pilocarpine. These results suggest that latanoprost alone should be tried before the addition of pilocarpine to timolol therapy is considered. The convenience of daily administration of a single drop of latanoprost versus multiple drops of timolol and pilocarpine should improve patient compliance.

Adrenergic beta-Antagonists↗
PubMed2000

Water-activated, pH-controlled patch in transdermal administration of timolol. II. Drug absorption and skin irritation.

The feasibility of the water-activated, pH-controlled silicone reservoir devices for transdermal administration was investigated using timolol maleate as a model drug. Timolol patches were applied to the arm of 12 volunteers for 81 h, two patches per subject. Timolol absorption from patches was compared to that from a peroral timolol tablet formulation (Blocanol((R)) 10 mg). Furthermore, in vivo plasma levels of timolol were compared with those predicted by kinetic simulations. Skin irritation induced by timolol patches was assessed by visual scoring and color reflectance measurements. With water-activated, pH-controlled patches both steady-state concentrations of timolol in plasma and its duration could be controlled. However, a considerable, inter-individual variability in the transdermal absorption of timolol was observed. This is due to the high fractional skin control in timolol delivery. Timolol patches were well tolerated by subjects. Skin irritation induced by the combination of timolol with long-term occlusion was mild, and after removal of the patches, skin changes were practically reversed in 24 h. Simulation model was useful in prediction of timolol levels in plasma after transdermal administration.

Administration, Cutaneous↗
PubMed1994

Controlled ocular timolol delivery: systemic absorption and intraocular pressure effects in humans.

Timolol eyedrops may cause systemic side-effects in glaucoma patients due to absorption of the drug into systemic circulation. In a previous study, timolol concentrations in plasma were reduced if timolol was administered in ocular inserts instead of eyedrops. We compared the intraocular pressure lowering effect and systemic absorption of timolol inserts to those of 0.5% timolol eyedrops in humans. Inserts of silicone tubing released 90.3 +/- 13.9 micrograms of timolol in 24 hours in vivo. Timolol inserts afforded similar decreases in intraocular pressure in open-angle glaucoma patients as did b.i.d. eyedrops, but produced lower peak timolol concentrations in plasma, 0.70 +/- 0.10 ng/ml and 0.24 +/- 0.05 ng/ml, respectively. After eyedrops, peak concentrations were achieved at 15.0 +/- 2.2 min, while application of an insert resulted in a delayed peak (tmax = 623 +/- 195 min). The insert resulted in a higher systemically absorbed fraction of the timolol dose than the eyedrop, but the peak timolol concentration and daily absorbed amount of timolol were decreased. The release rate of timolol from the inserts in vivo was only slightly less than that in vitro. Silicone devices are useful for clinical testing of controlled delivery properties of ocular drugs.

Absorption↗
PubMed2001

Additive IOP-reducing effect of latanoprost in patients insufficiently controlled on timolol.

PURPOSE: To evaluate the effect on intraocular pressure (IOP) of switching from timolol to latanoprost or adding latanoprost to timolol in patients with open angle glaucoma or ocular hypertension where IOP is not adequately controlled with timolol. METHODS: This was a 6-week, double-masked, randomised multi-centre study. 53 patients with primary open angle glaucoma, capsular glaucoma, or ocular hypertension with an IOP of at least 21 mmHg on current therapy were recruited. After a run-in period of at least 2 weeks on timolol, 5 mg/ml twice daily, patients were randomised to one of three groups. One group continued on timolol, one switched from timolol to latanoprost, 50 microg/ml once daily, and a third group received latanoprost in addition to timolol. The efficacy was evaluated by comparing IOP at 9 AM at baseline and after 6 weeks of treatment. RESULTS: IOP at baseline and after 6 weeks of treatment (mean +/- SEM) were 24.2 +/- 0.9 and 23.8 +/- 1.0 mmHg (n = 16) for patients continuing on timolol, 26.3 +/- 1.2 and 19.6 +/- 1.1 mmHg (n = 17) for patients switching to latanoprost, and 23.2 +/- 1.0 and 17.5 +/- 0.8 mmHg (n = 17) for patients with combined treatment. Adding latanoprost to timolol reduced IOP with 5.9 +/- 0.9 mmHg (p < 0.001) and switching from timolol to latanoprost reduced IOP with 5.0 +/- 0.9 mmHg (p < 0.001), which caused in each group a significant IOP reduction of about 25%. CONCLUSIONS: The effect of latanoprost was additive to that of timolol, and a good effect on IOP reduction was also achieved by switching from timolol to latanoprost, suggesting that a switch in many patients is an effective alternative to combination treatment.

Adult↗
PubMed2003

Retention of reversibly thermo-gelling timolol on the human ocular surface studied by video meniscometry.

PURPOSE: To investigate the retention of reversibly thermo-gelling timolol (TG-timolol) on the human ocular surface using video meniscometry. METHODS: The study population consisted of 14 healthy volunteers with no external eye disease. Fifteen microl TG-timolol were instilled into one eye of each subject and the same volume of aqueous, timolol ophthalmic solution was instilled in the fellow eye, in a masked fashion. Tear meniscus curvature was monitored at the center of the lower meniscus in each eye, using a newly-developed video meniscometer, before and at one-minute intervals for ten minutes after, the instillation. The radius of meniscus curvature (R) was calculated from printed video-images using the concave mirror formula. The change in R with time after instillation was compared for the two groups. RESULTS: The change in meniscus radius with time t [defined as deltaR(t) = R(t) - R(0)] showed a significant exponential regression in both the TG-timolol and the timolol groups. There was a significant difference in the value of deltaR(5) and deltaR(10) between eyes with TG-timolol [deltaR(5) = 0.29 mm, deltaR(10) = 0.18mm] and eyes with timolol only [deltaR(5) = 0.10mm, deltaR(10) = 0.06 mm] [deltaR(5): P < 0.001, deltaR(10): P < 0.001]. The area under each regression curve of deltaR(t), an indicator of vehicle retention, was greater in the eyes treated with TG-timolol than in those receiving timolol only (2.09 vs. 0.56, P < 0.001). CONCLUSIONS: The present study demonstrated that the reversibly thermo-gelling timolol was better retained at the ocular surface than conventional, aqueous timolol.

Antihypertensive Agents↗
PubMed2003

Comparison of the short-term effects on the human corneal surface of topical timolol maleate with and without benzalkonium chloride.

PURPOSE: To compare the short-term effects of timolol maleate with and without preservative (0.005% benzalkonium chloride) on pre-corneal tear film stability and corneal epithelial barrier function. SUBJECTS AND METHODS: The study population consisted of 20 healthy volunteers. To obtain baseline values, 7 days before the experiment the non-invasive breakup time of the pre-corneal tear film was measured using a tear specular microscope; corneal fluorescein uptake was measured with a fluorophotometer. Unpreserved or preserved 0.5% timolol was applied to one eye; the contralateral eye was exposed to the other drug. At 30 minutes after instillation, the pre-study tests were repeated. RESULTS: Preserved timolol did, while unpreserved timolol did not, significantly reduce the non-invasive breakup time from the baseline values (baseline and post-exposure values 11.4 and 6.8 seconds, respectively, P = 0.008 for preserved timolol, and 11.7 vs. 11.0 seconds, P = 0.55 for unpreserved timolol). Corneal fluorescein uptake, on the other hand, was significantly increased upon exposure to either preserved or unpreserved timolol (baseline and post-exposure values 37.5 and 82.0 ng/ml, P < 0.001 for preserved timolol, and 35.4 vs. 57.6 ng/ml, P < 0.001 for unpreserved timolol). Preserved timolol exerted the greater effect (P = 0.028). CONCLUSIONS: Exposure to preserved timolol resulted in significant instability in the pre-corneal tear film. Moreover, it disrupted the corneal epithelial barrier function to a greater degree than unpreserved timolol. The elimination of preservatives may be desirable in efforts to protect the integrity of the corneal surface and its interaction with the tear film.

Administration, Topical↗
PubMed1990

Improved ocular: systemic absorption ratio of timolol by viscous vehicle and phenylephrine.

Increasing the ocular absorption of timolol relative to its systemic absorption is important clinically because ophthalmic timolol may cause serious respiratory, cardiac, and central nervous system side effects. The authors evaluated the effects of phenylephrine coadministration and solution viscosity on the aqueous humor:plasma and iris ciliary body:plasma ratios of peak timolol concentrations after ocular application. Timolol eye drops (5 mg/ml, 25 microliters) were administered to the eyes of pigmented rabbits. Coadministered phenylephrine (0.8-8.2 mg/ml) decreased the systemic peak concentrations of timolol significantly. Since ocular absorption of timolol was not affected by phenylephrine, the ocular:systemic concentration ratios were improved four- to fivefold. Phenylephrine slows down the systemic absorption of timolol by constricting the conjunctival and nasal capillaries. The ratios of the aqueous humor:plasma and iris ciliary body:plasma peak concentration of timolol were improved three- to ninefold in the presence of sodium carboxymethylcellulose compared with nonviscous eye drops. The improved ocular penetration is probably due to the longer corneal contact, and the decreased rate of systemic absorption may be caused by the slower spreading of the solution on the nasal mucosa. Compared with timolol eye drops, the ratio of the eye:plasma peak timolol concentrations was improved tenfold by using viscous eye drops with phenylephrine. Systemic concentrations of ophthalmic timolol and possibly related side effects can be decreased when timolol is instilled in a viscous vehicle with a low phenylephrine concentration.

Absorption↗
PubMed1985

Secondary prevention after myocardial infarction: subgroup analysis of patients at risk in the Norwegian Timolol Multicenter Study.

Timolol treatment after myocardial infarction is generally related to a significant reduction in both mortality and reinfarction compared with placebo. Retrospective analyses of the timolol study are performed on subgroups of patients with a high placebo mortality. The present study shows that these patients are target groups for secondary prevention, as they benefit most from timolol treatment after myocardial infarction. In patients 65-75 years of age, the number of cardiac deaths and reinfarctions prevented by timolol treatment is twice as high as that of patients below 65 years of age. Timolol treatment is well tolerated in the older age group and the contraindications for timolol treatment are independent of age up to 75 years. The reduction in mortality and reinfarction is independent of heart size at baseline. However, in patients with cardiomegaly and compensated heart failure on treatment with digitalis and diuretics, timolol treatment may be of special importance because of the very high incidence of cardiac death in this group of patients. In patients with compensated heart failure on treatment with digitalis and diuretics, timolol treatment does not precipitate heart failure. Patients with stable diabetes mellitus basically behave like nondiabetic patients regarding inclusion rate, side effects, and timolol-related reduction in mortality and reinfarction. Decisions concerning secondary prevention with timolol should be independent of preinfarction and postinfarction angina. In conclusion, 70-80% of all the patients below 75 years of age surviving myocardial infarction, without contraindication to beta-blocker treatment, can be treated with timolol 10 mg twice daily to reduce mortality and reinfarction. In contrast to previous routines, secondary prevention with beta blockers should be especially directed to high-risk patients.

Clinical Trials as Topic↗