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PubMed1998

Effects of timolol and betaxolol on choroidal blood flow in the rabbit.

This study evaluated the effects of the topical beta1-adrenergic antagonist betaxolol and the non-selective beta-adrenergic antagonist timolol on the choroidal pressure-flow relationship. Pentobarbital-anesthetized rabbits were instrumented with hydraulic occluders on the aorta and inferior vena cava to control MAP, an ear artery cannula to measure mean arterial pressure (MAP), and two vitreous cannulas to control and measure intraocular pressure (IOP). Choroidal blood flow was measured by laser Doppler flowmetry with the fiber-optic probe tip positioned over the posterior pole. Choroidal pressure-flow curves were obtained before and 30 min after topical application of 0.1 ml of betaxolol (Betoptic, 0.5%, n=10), timolol (Timoptic, 0.5%, n=10) or saline (n=8) by varying the MAP without controlling the IOP and by raising IOP while holding the MAP constant at 70 mmHg. The IOP was significantly reduced by betaxolol and timolol but not by saline. MAP was also slightly, but significantly, reduced after betaxolol but not after timolol or saline. However, the systemic hypotensive response to isoproterenol (8 microgram/kg, i.v.) was blunted after betaxolol and timolol indicating appreciable systemic absorption of both drugs. Timolol, but not betaxolol or saline, caused a significant, small increase in baseline choroidal vascular resistance. Timolol also attenuated the IOP response to MAP; however, none of the treatments had a significant effect on the choroidal pressure-flow relationship. We conclude that both drugs reach the systemic circulation after topical application, but neither betaxolol nor timolol alter the choroidal response to acute changes in perfusion pressure.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

The determination of additive effect and intraocular pressure lowering effects of 0.05% bromocriptine and 0.25% timolol.

It has been confirmed that topically applied bromocriptine has a satisfactory intraocular pressure (IOP) lowering effect without serious ocular or systemic side effects. We compared the IOP lowering effects of 0.05% bromocriptine and 0.25% timolol and determined whether they have an additive effect in lowering IOP in normal volunteers. In a double-blind, randomised, prospective, single-dose study, we measured IOP in 24 ocular normotensive subjects before (baseline) and 2, 4 and 6 hours after topical instillation of the following drugs: timolol and bromocriptine alone (n: 14), timolol+bromocriptine, timolol+placebo, bromocriptine+placebo (n: 10). Both bromocriptine and timolol have a significant IOP lowering effect (p < 0.01) compared with the baseline value during the study period. There were no significant differences in IOP lowering effect between timolol and bromocriptine at 2 and 4 hours (p > 0.05), but timolol was more efficacious than bromocriptine at 6 hours (p < 0.05). An additive effect in lowering IOP was not found. Although timolol and bromocriptine have no additive effect in lowering IOP, topically applied bromocriptine may be used in the treatment of glaucoma.

Administration, Topical↗
PubMed1985

Effect of ophthalmic administration of S-596 (Arotinolol) on intraocular pressure and haemodynamics in health volunteers: comparison with timolol.

The effects on intraocular pressure (IOP) and haemodynamics of two beta-blockers, arotinolol and timolol, administered topically to the eye, were studied in 6 healthy volunteers in a cross-over trial. 0.5% timolol or 0.5% arotinolol ophthalmic solutions drop was instilled in both eyes of the volunteers at an interval of 48 hours. Timolol lowered IOP by about 31.9% 1 hour after administration and the effect continued until 3 h, whilst arotinolol lowered it significantly 2 h after instillation and the same maximum effect as that of timolol was obtained after 3 h. Arotinolol was detected in blood in all subject and timolol in blood in one subject, although it was found in all subjects in urine. Both drugs lowered heart rate at rest and attenuated the increase in the double product (products of blood pressure and heart rate) at exercise. The effect of timolol on the double products was larger. Thus, arotinolol and timolol decreased IOP to similar extent, although the maximal effect of arotinolol was delayed. Arotinolol as well as timolol affected haemodynamics through absorption into circulation, but the former had less effect on haemodynamics during exercise.

Adult↗
PubMed2005

Polymorphisms of genes CYP2D6, ADRB1 and GNAS1 in pharmacokinetics and systemic effects of ophthalmic timolol. A pilot study.

OBJECTIVE: To test the hypotheses that (1) CYP2D6 genotype is associated with pharmacokinetics of ophthalmic timolol and (2) variation in genotypes of ADRB1 (beta(1)-adrenoceptor) and GNAS1 (alpha-subunit of G-protein) modulate heart rate (HR), and systolic (SAP) and diastolic (DAP) arterial pressure responses to timolol. METHODS: Nineteen glaucoma patients and eighteen healthy volunteers were treated with 0.5% aqueous and 0.1% hydrogel formulations of ophthalmic timolol using a randomised cross-over design. The participants conducted head-up tilt and maximum exercise test at four visits. Plasma concentration of timolol was measured twice for glaucoma patients and ten times for healthy volunteers on each visit. Also, the genotypes for CYP2D6, ADRB1 and GNAS1 were determined. RESULTS: Among healthy volunteers using aqueous timolol, poor metabolisers (PMs, n=2) of CYP2D6 had higher maximum plasma concentrations (C(max), values 2.63 and 2.94 ng/ml), longer elimination half-lives ( T(1/2), 5.49 and 6.75 h), and higher area-under-curve (AUC, 19.54 and 23.25 ng.h/ml) than intermediate [IMs, n=6, mean+/-SD 1.73+/-0.59 ng/ml (not significant), 3.30+/-0.48 h, 11.32+/-3.72 ng.h/ml], extensive (EMs, n=8, 1.60+/-0.72 ng/ml, 3.24+/-1.24 h, 8.52+/-6.12 ng.h/ml) and ultra-rapid (UMs, n=2, values 1.23 and 1.67 ng/ml, 2.22 and 2.52 h, 6.16 and 6.94 ng.h/ml) metabolisers. The IMs, EMs and UMs did not differ from each other for any of the kinetic variables. Also, the elevation of HR from rest to maximum level tended to differ between PMs and IMs, and between PMs and UMs. The pharmacokinetics and pharmacodynamics between the CYP2D6 groups did not differ with statistical significance when hydrogel timolol was used. Upon head-up tilt, the Ser49 homozygotes (n=26) had higher SAP (P=0.03) and DAP (P<0.01) than the Gly carriers (n=11). The change in DAP from rest to maximum during exercise was lower (P<0.01) in subjects with CC alleles of GNAS1 (n=13) than those with at least one T allele (n=24). CONCLUSION: The CYP2D6 poor metabolisers may be more prone to systemic adverse events with aqueous timolol than extensive metabolisers. Since CYP2D6 genotyping is not routine clinical practice, using 0.1% timolol hydrogel instead of 0.5% aqueous preparation will increase patient safety.

Adrenergic beta-Antagonists↗
PubMed1998

Interaction between timolol eyedrops and oral nicardipine or oral diltiazem in healthy Japanese subjects.

OBJECTIVE: Timolol is widely used for the topical therapy of glaucoma. Adverse cardiovascular effects include slowing of the heart rate and weakening of myocardial contractility. We investigated pharmacodynamic interactions with respect to cardiovascular and ocular responses between timolol ophthalmic solution and either nicardipine, which does not directly inhibit cardiac conduction, or diltiazem, which does. METHODS: Two studies utilized a randomized, double-blind, Latin-square, placebo-controlled design involving four separate treatments given at least 1 week apart. Eight healthy male Japanese volunteers received a single drop of 0.5% timolol or artificial tears in each eye with or without a single oral dose of nicardipine (40 mg), and with or without a single oral dose of diltiazem (60 mg). Subjects exercised on a bicycle ergometer before and 1.5 and 3 h after dosing. At these times, heart rate and blood pressure were measured at rest and after exercise. The intraocular pressure was measured at rest. RESULTS: One drop of 0.5% timolol per eye significantly reduced the exercise-induced increase in heart rate and blood pressure, and intraocular pressure at rest. The timolol ophthalmic solution suppressed the reflex sympathetic cardiac stimulation that resulted from the primarily vasodilative action of nicardipine. No additional reduction in heart rate occurred when the ophthalmic timolol solution was administered in conjunction with diltiazem. The concomitant use of timolol and nicardipine or diltiazem did not induce an additional reduction in intraocular pressure. Oral nicardipine or diltiazem did not reduce intraocular pressure. Care should be taken when using topical timolol in patients with cardiovascular or respiratory diseases.

Administration, Oral↗
PubMed2000

Comparison of latanoprost monotherapy to dorzolamide combined with timolol in patients with glaucoma and ocular hypertension.A 3-month randomised study.

BACKGROUND: The purpose of the study was to compare the effects on intraocular pressure (IOP) of adding dorzolamide to timolol or of switching from timolol to latanoprost monotherapy in glaucoma patients inadequately controlled on timolol. METHODS: The study was designed as a 3-month randomised, open-label, multicentre study comprising 183 patients with primary open-angle glaucoma, capsular glaucoma with IOP above 22 mmHg on treatment with one or two ocular hypotensive drugs, or ocular hypertension with IOP above 27 mmHg. After a 2- to 4-week run-in period on timolol, 0.5% twice daily, the patients were randomised to treatment with either latanoprost, 0. 005% once daily, or the combination of timolol, 0.5% twice daily, and dorzolamide, 2% twice daily. The mean diurnal IOP after 3 months of treatment was compared with baseline. RESULTS: Switching from timolol to latanoprost reduced mean diurnal IOP by 4.5+/-0.2 mmHg (mean+/-SEM, ANCOVA; 20%), and adding dorzolamide to timolol reduced mean diurnal by 4.4+/-0.2 mmHg (mean+/-SEM, ANCOVA; 20%). No serious side effects were observed with either treatment. CONCLUSION: Latanoprost monotherapy can be an alternative to combined treatment with two aqueous flow suppressors in patients whose IOP is insufficiently controlled by timolol alone.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Change in corneal permeability to timolol after laser in situ keratomileusis and photorefractive keratectomy in rabbit.

PURPOSE: To evaluate the change in corneal permeability to timolol 1 month after laser in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) in rabbits. METHODS: LASIK or PRK was performed on one eye of each of 20 rabbits. One month later, 20 microl of 0.5% timolol was instilled into the 10 LASIK eyes, 10 PRK eyes, and the 20 control contralateral eyes. One hour later, 150 microl of aqueous humor was collected from all eyes, and the concentration of timolol in the aqueous humor was measured by high-performance liquid chromatography. The effect of LASIK and PRK on the corneal permeability to timolol was analyzed. RESULTS: The average timolol concentrations in the aqueous humor of the ten eyes 1 month after LASIK and in the ten contralateral eyes were 1.16 +/- 0.58 microg/ml and 1.07 +/- 0.39 microg/ml (average +/- SD, P = 0.678), respectively. The average timolol concentrations in the aqueous humor of the ten eyes 1 month after PRK and in the ten contralateral eyes were 1.24 +/- 0.43 microg/ml and 1.12 +/- 0.30 microg/ml (P = 0.483), respectively. The average ratio of timolol concentration in the aqueous humor of the LASIK or PRK eyes 1 month after surgery to that of the contralateral normal eyes was 1.18 +/- 0.58 or 1.19 +/- 0.67 (P = 0.972), respectively. CONCLUSIONS: LASIK and PRK do not affect corneal permeability to timolol 1 month after surgery.

Animals↗
PubMed1984

Effects of timolol and propranolol on inducible sustained ventricular tachyarrhythmias in dogs with subacute myocardial infarction.

Timolol and propranolol reduce the incidence of cardiac death after myocardial infarction (MI). To explore possible mechanisms of this reduction in mortality, the antiarrhythmic effects of these 2 beta blockers were compared in a dog model of inducible sustained ventricular tachycardia (VT) or fibrillation (VF) 4 to 6 days after experimental closed-chest MI. Dogs with inducible VT or VF underwent drug studies with timolol and propranolol; the sequence of drug administration was randomized. Timolol doses were 0.1, 0.3, and 1.0 mg/kg; propranolol doses were 1.0, 3.0 and 10.0 mg/kg. Timolol and propranolol were equally effective in abolishing inducible VT or VF: 77% of instances of inducible VT or VF responded to 1 or both beta blockers. The VF threshold was significantly elevated by both timolol and propranolol; the elevation in the VF threshold was significantly greater in "responders," i.e., dogs in whom VT was prevented by beta blockade (15 +/- 9 vs 8 +/- 9 mA, p less than 0.05). The ventricular effective refractory period was prolonged by both drugs; again, more so in the responders than in the nonresponders (16 +/- 9 vs 8 +/- 14 mA, p less than 0.05). The QTc interval was not significantly affected by either beta blocker. Among the responders, no difference was detected between timolol and propranolol in the extent to which the effective refractory period was prolonged or the VF threshold elevated. However, the highest dose of propranolol decreased the mean blood pressure significantly more than the comparable dose of timolol. In conclusion, timolol and propranolol are equally effective in abolishing inducible VT or VF in the dog after subacute MI.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure.

PURPOSE: To compare the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure (IOP) in patients with ocular hypertension or early glaucomatous changes. DESIGN: Prospective, open-label, experimental study with crossover design. METHODS: Eighteen patients with ocular hypertension or early glaucomatous changes (aged 41 to 79 years) each received topical treatments with timolol (0.5% Timoptic-XE), latanoprost (0.005% Xalatan), and no IOP-lowering medication, for at least 4 weeks. Timolol was given once in the morning upon awakening and latanoprost once in the evening at bedtime. At the end of each treatment period, the patient was housed in a sleep laboratory for 24 hours and IOP was measured every 2 hours using a pneumatonometer. Measurements were taken sitting and supine during the 16-hour diurnal/wake period and only supine during the 8-hour nocturnal/sleep period. Mean diurnal and nocturnal IOP levels were compared among the treatments with timolol, latanoprost, and no medication. RESULTS: In the diurnal period, the mean IOP under the timolol or the latanoprost treatment was significantly less than the mean IOP under no medication in both the sitting and the supine positions. There was no statistical difference between the timolol and latanoprost treatments. In the nocturnal period, supine IOP with timolol treatment was not different from the supine IOP with no medication but was significantly higher than supine IOP with the latanoprost treatment. CONCLUSION: Although both once-daily timolol and latanoprost were effective in lowering IOP during the diurnal period, only latanoprost reduced IOP during the nocturnal period.

Adult↗
PubMed1997

Cardiovascular effects of topical carteolol hydrochloride and timolol maleate in patients with ocular hypertension and primary open-angle glaucoma. Night Study Group.

PURPOSE: To compare the effects of topical timolol maleate 0.5% and carteolol hydrochloride 1% on pulse rate and blood pressure. METHODS: In a randomized, double-masked, parallel-design, multicenter clinical trial, we compared the effects of timolol and carteolol on pulse rate and blood pressure measured by 24-hour ambulatory blood pressure monitoring in 169 adult patients with either ocular hypertension or primary open-angle glaucoma. RESULTS: From noon to 8 PM, baseline mean pulse rate of 82 to 83 beats per minute (bpm) had decreased by 4 to 6 bpm in both groups after 4 weeks of therapy with timolol or carteolol. From midnight to 4 AM, the pulse rate in the carteolol group was significantly above baseline (P = .005), while the timolol group was significantly below baseline (P < .001). Four times as many patients became bradycardic (heart rate, < 60 bpm) on timolol (18.4%) as did patients on carteolol (4.5%) from midnight to 4 AM. More than twice as many patients exhibited a resolution of their bradycardia with carteolol (46.7%) as did patients treated with timolol (18.2%) from midnight to 4 AM. Overall cardiovascular adverse effects were reported significantly more frequently in the timolol than the carteolol group (P = .002). CONCLUSIONS: Timolol causes significantly lower mean heart rate during the nighttime and more nocturnal bradycardia than carteolol does in patients with ocular hypertension and primary open-angle glaucoma. These differences may be because of the intrinsic sympathomimetic activity of carteolol.

Administration, Topical↗
PubMed1999

Brimonidine tartrate 0.2% twice daily vs timolol 0.5% twice daily: 1-year results in glaucoma patients. Brimonidine Study Group.

PURPOSE: To compare the long-term efficacy and safety of brimonidine 0.2% twice daily with timolol 0.5% twice daily in patients with glaucoma or ocular hypertension. METHODS: Of the 926 patients enrolled in the study, 837 met the protocol entry criteria and received either brimonidine 0.2% twice daily (n = 466) or timolol 0.5% (n = 371) twice daily in each eye for 1 year. RESULTS: Brimonidine and timolol significantly reduced mean intraocular pressure (P < .001) from baseline levels at every scheduled follow-up visit, both at hour 2 (peak) and hour 12 (trough). At weeks 1 and 2 and months 3 and 12, significantly greater mean decreases in intraocular pressure (P < .040) at peak were observed in patients treated with brimonidine than those treated with timolol. The mean intraocular pressure decrease at trough was significantly greater for timolol than for brimonidine at each follow-up visit (P < .001). With the exception of ocular allergy (in 11.5% of patients using brimonidine and less than 1% using timolol), fewer than 3% of patients in either treatment group withdrew from the study prematurely as a result of a specific adverse event. Patients receiving timolol experienced significant decreases in heart rate (P < .001) from baseline at all follow-up visits. No significant changes in heart rate were seen in patients treated with brimonidine. Neither medication produced clinically significant changes in blood pressure. CONCLUSION: Brimonidine is safe and effective in the long-term lowering of intraocular pressure in patients with glaucoma or ocular hypertension, with efficacy comparable to that of timolol but without a notable negative chronotropic effect on the heart.

Adrenergic alpha-Agonists↗
PubMed2002

Protective effects of timolol against the neuronal damage induced by glutamate and ischemia in the rat retina.

The purpose of this study was to determine whether timolol, an ocular hypotensive drug, has retinal neuroprotective effects in experimental in vitro and in vivo models. For in vitro studies, we used retinal neuron cultures from rat embryos and purified retinal ganglion cells (RGCs) from newborn rats. In the former, neurotoxicity was induced using 1 mM glutamate and cell viability was assessed. In RGCs, neurotoxicity was induced using 25 microM glutamate for 3 days and cell viability was assessed. For the in vivo study, we used a rat model of retinal ischemic injury induced by elevating intraocular pressure (IOP) by raising the hydrostatic pressure. The retinal damage was evaluated by counting the number of cells in the ganglion cell layer (GCL) and by examining the a- and b-waves in the electroretinogram (ERG). For the intraocular distribution study, 0.5% [3H]timolol was topically applied to rat eyes, and these were enucleated after various intervals and divided into parts. Each part was combusted and the radioactivity measured. Timolol (0.1 and 1 microM) markedly reduced the glutamate-induced neuronal cells in retinal neuron cultures and in RGCs. After ischemic-reperfusion, both the number of cells in the GCL and a- and b-waves in the ERG decreased; however, topically applied 0.5% timolol reduced these effects. Topically applied 0.5% timolol was detected at a concentration of approximately 1 microg/g wet tissue in retina-choroid at 30 min after its application. In conclusion, timolol was effective against retinal neuron damage both in vitro and in vivo. Furthermore, topically applied timolol reached the retina-choroid. These findings suggest that timolol has a direct neuroprotective effect against retinal damage.

Action Potentials↗
PubMed1987

Topical timolol, at conventional, unilateral doses causes bilateral ocular beta-blockade in rabbits.

The studies described herein reveal that unilateral 0.3% and 1% doses of timolol produce marked beta-adrenoceptor blockade in treated and in contralateral eyes which did not receive timolol. This indicates that unilateral, conventional topical doses of timolol administered to rabbits cause bilateral ocular beta-adrenoceptor blockade. In addition, 0.1% and 1% doses of timolol applied to one eye resulted in blockade of cardiovascular beta-adrenoceptors. Thus, the most likely explanation for bilateral ocular beta-blockade would be systemic absorption of timolol from the treated eye and redistribution to the fellow eye. Since contralateral eyes would not provide an adequate control in circumstances where a large dose of timolol is administered unilaterally, caution must be exercised in interpreting data obtained in laboratory animals with doses of timolol similar to those employed clinically. A 0.01% dose of timolol appears adequate to achieve marked, unilateral ocular beta-adrenoceptor blockade in rabbits.

Administration, Topical↗
PubMed1995

Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. A comparison with timolol. Scandinavian Latanoprost Study Group.

PURPOSE: To compare the effect on intraocular pressure (IOP) and side effects of 0.005% latanoprost applied once daily, morning or evening, with 0.5% timolol applied twice daily. METHODS: A 6-month randomized, double-masked, multicenter study with three parallel groups was undertaken. Two hundred sixty-seven patients were randomized, 84 to timolol, 89 to latanoprost in the morning for 3 months and then in the evening for another 3 months, and 94 to latanoprost with the treatment schedule reversed. RESULTS: After 6 months, timolol reduced diurnal IOP from 24.6 to 17.9 mmHg (27%); latanoprost applied in the morning, from 25.5 to 17.7 mmHg (31%); and latanoprost applied in the evening, from 24.8 to 16.2 mmHg (35%). The efficacy of latanoprost applied in the evening was statistically superior to latanoprost applied in the morning and to timolol (P < 0.001). Latanoprost induced a slight increase in conjunctival hyperemia in 31.4% of treated patients, compared with 15.9% for timolol. Sporadic episodes of mild punctate corneal epithelial erosions were three times as frequent in latanoprost-treated eyes as in timolol-treated eyes. The most significant ocular side effect was increased pigmentation of the iris observed in five and suspected in seven more latanoprost-treated eyes. All these eyes had a mixed green-brown or blue/gray-brown iris color. Timolol reduced heart rate by 3 beats/minute (P < 0.005). CONCLUSIONS: The effect on diurnal IOP of latanoprost applied once daily in the evening is superior to that of timolol. The main difference in side effects is increased pigmentation of the iris induced by latanoprost, most likely due to stimulation of melanogenesis in iris stromal melanocytes.

Adrenergic beta-Antagonists↗
PubMed1998

Twelve-month results of an ongoing randomized trial comparing brimonidine tartrate 0.2% and timolol 0.5% given twice daily in patients with glaucoma or ocular hypertension. Brimonidine Study Group 2.

OBJECTIVE: To compare the long-term safety and ocular-hypotensive efficacy of brimonidine tartrate 0.2% with timolol maleate 0.5% administered twice daily in patients with glaucoma or ocular hypertension. DESIGN: A double-masked, parallel-group, active-controlled, multicenter clinical trial of 12 months' duration. PARTICIPANTS: Four hundred eighty-three patients with glaucoma or ocular hypertension were enrolled. Of these, 463 were evaluated according to the protocol criteria (280 in the brimonidine tartrate group and 183 in the timolol group). INTERVENTIONS: Brimonidine tartrate 0.2% or timolol maleate 0.5% was administered twice daily. MAIN OUTCOME MEASURES: The primary efficacy variable was intraocular pressure (IOP). RESULTS: Brimonidine and timolol produced significant (P < 0.001) and sustained mean reductions in IOP throughout the 1-year follow-up when measured at hour 0 (trough) and at hour 2 (peak). At weeks 1 and 2 and month 12, significantly greater mean decreases in IOP measured at peak (P < or = 0.007) were observed in patients treated with brimonidine as compared to timolol, whereas the mean decreases in IOP measured at trough was significantly greater in patients treated with timolol as compared to brimonidine (P < 0.001) at all follow-up visits. Both drugs were well-tolerated. The incidence of adverse events was similar in both treatment groups, except for ocular allergy, oral dryness, and conjunctival follicles, which occurred more frequently in the brimonidine group, and burning-stinging, which occurred more frequently in the timolol group. Patients receiving timolol experienced significant decreases in heart rate at all follow-up visits. CONCLUSIONS: Topically applied twice daily for 12 months, brimonidine tartrate 0.2% was safe and effective in lowering IOP in patients with glaucoma or ocular hypertension.

Adrenergic alpha-Agonists↗
PubMed2005

Pharmacokinetic and pharmacodynamic analysis of systemic effect of topically applied timolol maleate ophthalmic gelling vehicle (Rysmon TG).

PURPOSE: The objective of this study was to evaluate the degree of systemic absorption and the systemic side effect after instillation of timolol maleate ophthalmic gelling vehicle in human. METHODS: A volunteer study was employed, and a randomized crossover design with the two phases was used. In one phase, the volunteers instilled a single drop of the 0.5% timolol maleate ophthalmic gelling vehicle; in the other phase, the volunteers instilled a single drop of the 0.5% timolol maleate ophthalmic solution. The plasma concentration of timolol and the heart rates were studied during the following 120 min and 60 min, respectively. RESULTS: The area under the blood concentration time curve (AUC) in timolol maleate ophthalmic gelling vehicle was lower than that in timolol maleate ophthalmic solution (p < 0.05). No differences were observed in heart rates between ophthalmic gelling vehicle and ophthalmic solution. The correlation between the calculated occupancy of beta-adrenergic receptors and the systemic side effects after instillation could be successfully analyzed with a pharmacokinetic and pharmacodynamic model, showing the predictability of the model for the systemic side effects of timolol. CONCLUSIONS: The result of our analysis clearly shows that timolol maleate ophthalmic gelling vehicle reduced the systemic absorption below that of ophthalmic solution, but the degree in difference of systemic effects was negligible.

Absorption↗
PubMed1991

Systemic absorption of ocular timolol in poor and extensive metabolizers of debrisoquine.

The oxidation of timolol exhibits genetic polymorphism of debrisoquine type. After oral administration, poor metabolizers have high timolol concentrations in plasma and show an intensified systemic beta-blockade. Since the contribution of debrisoquine metabolizer status on timolol eyedrop therapy is not known we determined the systemic absorption of ocularly applied timolol in healthy subjects classified either extensive or poor metabolizers. Unlike after oral timolol ocular drug administration caused higher peak drug concentrations in plasma in extensive metabolizers. The variation in the systemic absorption of ocular timolol contributed more than the debrisoquine oxidation phenotype to timolol plasma levels after a single ocular timolol application.

Absorption↗
PubMed1992

Duration and long-term efficacy of phenylephrine-induced reduction in the systemic absorption of ophthalmic timolol in rabbits.

Co-administration of phenylephrine decreases systemic timolol absorption after a single topical ocular dose of timolol in rabbits. This is probably due to vasoconstriction in the conjunctiva of the eye and nasal mucosa. In this study, we evaluated the duration of action and long-term efficacy of phenylephrine in reducing the systemic absorption of ophthalmic timolol in pigmented rabbits. Although co-administered phenylephrine had a short duration of interaction with systemic timolol absorption (20-60 min), its effect on systemic timolol absorption was substantial. The long-term vasoconstrictive effect of phenylephrine was studied by administering timolol-phenylephrine eyedrops into the eyes of rabbits once a day for two months. Systemic peak concentrations of timolol following timolol-phenylephrine eyedrop administration remained unchanged throughout the study. Phenylephrine may be useful additive in decreasing the systemic concentrations of ophthalmic drugs.

Absorption↗