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PubMed1983

Action mechanism of timolol to lower the intraocular pressure in rabbits.

The effect of timolol on the active transport system in the iris root-ciliary body of rabbits was studied to elucidate the action mechanism of timolol. Neither Na+-K+-adenosine triphosphatase (ATPase) nor Mg++-ATPase was inhibited by timolol at 1 X 10(-4) M concentration. None of the energy production parameters (oxygen consumption, glucose metabolism, and lactic acid formation) was inhibited by timolol either. Further, the biosynthesis of prostaglandins E2 and F2 alpha was not affected by timolol at 1 X 10(-3) M. The blood flow to the eye was measured with a 85Sr-microsphere method. It was found that the blood flow in the iris root-ciliary body and choroid was significantly reduced by a topical application of 0.25% timolol. The dopamine concentration in the iris root-ciliary body was reduced by timolol at 1 X 10(-5) M concentration. Neither epinephrine nor norepinephrine concentration was altered by timolol. The results indicate that timolol reduces the rate of aqueous humor formation through reduction of blood flow to the ciliary process rather than via the inhibition of the active transport system or that of prostaglandin biosynthesis.

Animals↗
PubMed1984

Efficacy and safety of timolol for prevention of supraventricular tachyarrhythmias after coronary artery bypass surgery.

Forty-one patients undergoing coronary artery bypass grafting were randomly assigned to receive prophylactic timolol or placebo, given in a double-blind fashion. beta-Adrenoceptor-blocking therapy was stopped at least one half-life before surgery. Three to 7 hr after surgery (304 +/- 56 min), 0.5 mg of timolol or placebo was given intravenously twice daily in a double-blind manner. When oral medications were resumed postoperatively, 10 mg of timolol twice daily or placebo was continued orally. Continuous electrocardiograms were recorded for 24 hr before and for 7 days after surgery with a standard cassette recorder. No patient received digoxin. Both groups were comparable for frequency of preoperative supraventricular arrhythmias, left ventricular ejection fraction, duration of cardiopulmonary bypass, aortic cross-clamp time, number of bypass grafts, and total duration of monitoring. Analysis of arrhythmias was done by hand counts, and supraventricular arrhythmias were divided into supraventricular tachycardia and atrial fibrillation and/or flutter. Timolol decreased the frequency of supraventricular tachycardia (581 episodes placebo vs 84 timolol; p less than .05) and of atrial fibrillation and/or flutter (291 episodes placebo vs five timolol; p less than .05). Timolol decreased the number of patients with severe (heart rate greater than 200 beats/min, duration greater than 50 beats) episodes of supraventricular tachycardia (four placebo vs 0 timolol; p less than .05) and also decreased the number of episodes of severe (heart rate greater than 200 beats/min, duration greater than 5 min) atrial fibrillation and/or flutter (16 placebo vs one timolol; p less than .005). There were differences in the durations of supraventricular arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Fibrillation↗
PubMed2000

Drug interaction between cimetidine and timolol ophthalmic solution: effect on heart rate and intraocular pressure in healthy Japanese volunteers.

Systemic adverse effects of timolol ophthalmic solution given at usual therapeutic doses have been well characterized. Timolol is partially metabolized by cytochrome P450 (CYP) 2D6. Cimetidine inhibits the activity of cytochrome P450, including CYP2D6, leading to reduced systemic clearance of concomitant drugs. Coadministration of cimetidine has been speculated to affect the pharmacological effects of timolol ophthalmic solution, resulting in increased blood concentration. To evaluate whether administration of cimetidine with timolol ophthalmic solution increased the degree of beta-blockade, 12 healthy Japanese male volunteers ages 19 to 26 received cimetidine (400 mg), on oral placebo, timolol maleate 0.5% (0.05 mL to each eye), or placebo eye drops in a randomized, double-blind, Latin-square design. The oral drug alone was given for 3 days, and on the 4th day, eye drops were applied after oral drug administration. At baseline and 1, 3, and 6 hours after eye drop administration, blood pressure and heart rate (HR) were measured before and after exercise. Intraocular pressure (IOP) was measured at rest. A visual analog scale (VAS) was used to assess subjective bodily feelings in exercise tolerance after every physical exercise. The exercise HR, exercise systolic blood pressure (SBP), and resting SBP were reduced following timolol with and without cimetidine compared with the placebo (p < 0.01, respectively). Administration of cimetidine with timolol ophthalmic solution resulted in additional reductions of the resting HR and IOP. VAS detected a significant reduction in exercise tolerance from timolol ophthalmic solution (p < .05). In conclusion, administration of cimetidine with timolol ophthalmic solution increased the degree of beta-blockade.

Adrenergic beta-Antagonists↗
PubMed2003

Peak pressures: crossover study of timolol and latanoprost.

PURPOSE: To compare the diurnal efficacy and action on peak intraocular pressures (IOP) of 0.005% latanoprost and 0.5% timolol as primary therapy in 60 eyes having dark brown irides with primary open angle glaucoma (POAG). METHODS: A prospective, comparative, observer-masked, crossover, interventional trial including the mean of both eyes of 30 patients with POAG who were randomly started on either latanoprost once daily or timolol twice daily. Three months after treatment with one drug, the second drug was substituted. A masked observer carried out diurnal assessments of IOP before the start of therapy and at 3 and 7 months. The fourth month was the washout period for the first drug. RESULTS: The average baseline IOP was 23.36 +/- 2.14 mm Hg, which was reduced by 8.8 +/- 2.2 mmHg with latanoprost (p < 0.01) and by 6.75 +/- 1.9 mm Hg with timolol (p = 0.01). The reduction was greater for latanoprost (p < 0.005). The average peak IOP at baseline was 27.6 +/- 2.22 mmHg. The effective fall in IOP at the time of new peaks in subsequent diurnal recordings of IOP compared to the baseline diurnal curve was 8.9 mm Hg with latanoprost (p < 0.005) and 5.77 mm Hg with timolol (p < 0.01). This difference in IOP reduction between the two drugs was statistically significant (p < 0.01). Latanoprost had a lower efficacy in peak IOP reduction in eyes with evening peak of IOP than in those with morning peak (p < 0.005). The efficacy of timolol was lower overall compared to latanoprost, but was similar in all circadian rhythms. The shift in timing of IOP peak was greater with latanoprost compared to timolol (4.34 hours vs -0.72 hours, p < .01). A total of 90% of patients on latanoprost and 33.3% on timolol achieved a reduction of > 30% in baseline mean IOP. The average of the trough IOP recorded in each of the individual baseline IOP curves was 19.05 +/- 2.05 mm Hg. CONCLUSIONS: Greater mean and peak IOP reduction was achieved with latanoprost compared to timolol. Dampening of the circadian rhythm was better with latanoprost. Latanoprost appears to be more effective than timolol at all points in time with greater efficacy in eyes with morning peaks compared to evening peaks.

Administration, Topical↗
PubMed2003

The efficacy and safety of brimonidine 0.2% compared with timolol 0.5% in glaucoma: a randomized clinical trial on Taiwanese patients.

BACKGROUND: Brimonidine is a highly selective alpha-2 adrenergic receptor agonist with intraocular pressure (IOP) reducing effect. We conducted this study in Taiwan to compare the safety and efficacy ofbrimonidine 0.2% with timolol 0.5% for the treatment of glaucoma. METHODS: A prospective, randomized, single-masked, 1-month clinical efficacy and safety trial was conducted from March to September 2000. Forty glaucoma patients were enrolled--29 in the brimonidine group and 11 in the timolol group. Patients instilled their study medications twice daily for 4 weeks, and were followed at baseline visit, weeks 2 and 4. Demographic data, reduction of IOP, safety and adverse events were obtained and analyzed. RESULTS: Both drugs showed sustained ocular hypotensive efficacy in the study period. At baseline, the mean IOP was 24.48 +/- 2.29 mmHg in the brimonidine group and 23.32 +/- 0.82 mmHg in the timolol group. The IOP readings after treatment were significantly lower than their baseline levels in both groups at all visits (p < 0.001). At peak, the mean decreases from the baseline IOP ranged from 5.22 +/- 0.30 mmHg to 6.96 +/- 0.33 mmHg for brimonidine and from 4.55 +/- 0.49 mmHg to 6.64 +/- 0.53 mmHg for timolol. At trough, the mean decreases from baseline ranged from 3.72 +/- 0.32 mmHg to 4.55 +/- 0.32 mmHg for brimonidine and 3.82 +/- 0.52 mmHg to 4.27 +/- 0.51 mmHg for timolol. No significant between-group differences were seen at peak or trough at all visits. The clinical success rate was 86.2% in the brimonidine group and 81.8% in the timolol group, making no statistically significant difference between them (p = 0.817). 17.2% of patients in brimonidine group and 9.0% patients in timolol group reported mild adverse events. Ocular allergy occurred in 10.3% of patients in brimonidine group. No significant changes in visual acuity, biomicroscopy or ophthalmoscopy were observed in both groups. Mean systolic and diastolic blood pressure remained relatively stable in both groups except in week 2 (p = 0.016) when brimonidine had lower systolic blood pressure. However, brimonidine showed no significant difference in week 4 from baseline. The mean heart rate in the brimonidine group was relatively unchanged over the study period. Patients receiving timolol experienced statistically significant mean heart rate decreases from baseline (p = 0.020) in week 4. CONCLUSIONS: Topically applied twice daily for one month, brimonidine tartrate 0.2% has clinical effectiveness equivalent to timolol 0.5% in Taiwanese patients with glaucoma. It has a safe systemic profile with minimum effect on the heart.

Adrenergic alpha-Agonists↗
PubMed2003

Timolol + latanoprost: new preparation. Last-resort eye drops.

(1) First-line drug treatment of chronic open-angle glaucoma or intraocular hypertonia is based on monotherapy with timolol eye drops. Patients in whom several single-agent treatments have failed can use combinations of timolol + dorzolamide (a carbonic anhydrase inhibitor) or a betablocker + pilocarpine (a parasympathomimetic agent). (2) An eye-drop preparation is now available in which 0.5% timolol is combined with 0.005% latanoprost, a prostaglandin F2alpha analogue. (3) A clinical trial indicated that the timolol + latanoprost combination was more effective than the timolol + dorzolamide combination on intraocular pressure, but the report of this study is too scanty to accept these results at face value. Once-a-day dosing with timolol + latanoprost has not been compared with a betablocker + pilocarpine combination. (4) Patients using the timolol + latanoprost combination are exposed to the adverse effects of both latanoprost (especially ocular irritation and brown iris discoloration) and the betablocker. (5) It is not known whether the once-a-day dosing of the timolol + latanoprost combination is a significant advantage, especially in terms of adherence to treatment. (6) In practice, the arrival of the timolol + latanoprost combination changes virtually nothing for patients with chronic open-angle glaucoma, except for those with no other alternative.

Antihypertensive Agents↗
PubMed1992

Timolol movement across isolated iris-ciliary body of albino rabbit.

The outward (from the aqueous to the stromal side) and the inward (from the stromal to the aqueous side) movement of [14C]timolol across the isolated iris-ciliary body of the albino rabbit were studied using Ussing's chamber under short-circuit conditions and timolol concentrations of 0.025-60 microM. The tissue permeability in both directions decreased gradually as the timolol concentration was increased, while at higher concentrations tissue permeability was almost constant. This finding indicated that the timolol movement in both directions consists of passive diffusion and a possibly active mechanism, with the former contributing mainly at higher concentrations. The tissue permeability for passive diffusion was calculated as 7.2 x 10(-6) cm/second. The outward timolol movement by a possibly active mechanism was saturated against the concentrations tested. In addition, the outward timolol movement was significantly reduced by ouabain, 2,4-dinitrophenol and low temperature. These results suggested that the non-passive component of the outward timolol movement was carrier-mediated active transport, and Lineweaver-Burk plots gave the half-saturation concentration (Km) value of 0.098 microM. On the other hand, the inward timolol movement by a possible active mechanism was not saturated. Neither ouabain nor 2,4-dinitrophenol inhibited it. Thus the non-passive component of the inward timolol movement was thought to be different from that of the outward movement.

2,4-Dinitrophenol↗
PubMed1987

Timolol induces HSV-1 ocular shedding in the latently infected rabbit.

Timolol iontophoresis into the eye can induce herpes simplex virus type 1 (HSV-1) shedding in rabbits latently infected with HSV-1 strain McKrae. Anodal iontophoresis of 0.01% timolol was done at 0.8 mAmp for 8 min once a day for 3 consecutive days. Viral shedding was determined by the presence of HSV-1 in the preocular tear film obtained by eye swabs. In two experiments, iontophoresis of 0.01% timolol resulted in all eyes (18/18) shedding HSV-1 for an average duration of 4.3 days. When 5.0% timolol was applied topically to rabbit eyes supersensitized by iontophoresis of 6-hydroxydopamine (6-HD), all eyes (10/10) shed virus for an average duration of 2.9 days. All eyes (12/12) receiving iontophoresis of 6-HD, pre- and posttreatment with topical application of 5.0% timolol, and posttreatment with topical application of 1.0% epinephrine shed virus for an average duration of 3.6 days. Eyes treated with topical application of 5.0% timolol alone showed no difference in HSV-1 ocular shedding, compared with untreated eyes. We concluded that both iontophoresis of 0.01% timolol and topical application of 5.0% timolol to adrenergically supersensitized eyes induced HSV-1 shedding reliably and with a high frequency, and that topically applied timolol does not block the HSV-1 ocular shedding induced by epinephrine in adrenergically supersensitized eyes.

Administration, Topical↗
PubMed1980

Pharmacological effects of topical timolol in the rabbit eye.

The ability of timolol to act as a beta-adrenergic antagonist in the cornea and in the iris--ciliary body of albino rabbits is reported. In vitro, timolol potently blocks the isoproterenol-stimulated synthesis of cAMP. In the iris-ciliary body, the apparent inhibition constant (K1) for timolol is 0.6 nM, indicating that timolol is approximately seven times more potent than propranolol. Topical timolol (0.5% and 4%) rapidly inhibits the beta-adrenergic--stimulated synthesis of cAMP in both corneal and iris--ciliary body tissues. Within 3 hr, however, the iris--ciliary body tissue regains its ability to produce large amounts of cAMP when challenged in vitro with isoproterenol. The washout of timolol from corneal tissue is more protracted. Intraocular pressure measurements by anterior chamber cannulation of anesthetized rabbits indicate that topical timolol (0.5% and 4%) has no significant influence on intraocular pressure. These concentrations of timolol significantly decrease heart rate but do not affect femoral arterial blood pressure. Because of the marked potency of timolol clinically, we conclude that the effects of the drug in the rabbit do not completely account for its therapeutic efficacy in humans, which must depend on more complex pharmacological actions.

Adrenergic beta-Antagonists↗
PubMed1983

Topical timolol and epinephrine: biochemical actions and interactions in the rabbit eye in vivo.

The effects of topical 0.5% timolol maleate and 1% or 2% levo-epinephrine hydrochloride on aqueous humor cyclic-AMP and intraocular pressure were assessed in 97 normotensive New Zealand white rabbits in vivo. The study was conducted using three experimental protocols: (A) timolol and epinephrine individually, (B) timolol and epinephrine in coadministration, and (C) timolol and epinephrine in crossover, applied either in a single dose, twice a day for two days, and/or twice a day for six days. These studies demonstrated that timolol has complex biochemical actions, one of which is beta-adrenergic antagonism. By itself, timolol had no effect on cyclic-AMP levels. However, when used in both single-dose coadministration and in pretreatment in six-day crossover with epinephrine, it significantly diminished the cyclic-AMP elevation produced by a single dose of epinephrine. In the six-day crossover protocol, pretreatment with timolol also significantly reduced the ocular hypotensive effect of a single dose of epinephrine, thereby correlating biochemical cause with clinical effect. Yet, timolol alone had no ocular hypotensive effect. Therefore, timolol's biochemical actions in this animal model cannot explain its marked clinical efficacy in man, which appears to depend on more complex pharmacologic actions.

Administration, Topical↗
PubMed1983

Comparisons of the interaction of propranolol and timolol with model and biological membrane systems.

The nonspecific interaction of the beta-adrenergic blocking drugs, propranolol and timolol, with model and biological membranes has been investigated. Radioisotope measurements of the association of these drugs with dimyristoyl lecithin (DMPC) bilayers showed that both propranolol and timolol had a significantly greater molar association (mole of drug per mole of lipid) with DMPC above its phase transition temperature than below. Timolol had a much lower molar association with DMPC as compared with propranolol both above and below the phase transition temperature. For the DMPC model membrane system, the molar association of propranolol as measured by radioisotope and inferred from calorimetric studies was similar. Neutron diffraction utilizing propranolol deuterated in the naphthalene moiety showed that the naphthalene moiety of propranolol partitions into the hydrocarbon core of the DMPC lipid bilayer, and that the charged amine side chain is most likely positioned in the aqueous phospholipid head group region. For timolol, the association as measured by radioisotope methods was apparently greater than the partitioning inferred from calorimetric studies using freezing point depression analysis, suggesting a more complex interaction of timolol as compared with propranolol with the DMPC lipid bilayer. The association of propranolol and timolol with sarcoplasmic reticulum vesicles (SR) was similar to that with highly purified protein-depleted SR lipids, and DMPC above its phase transition. The association of propranolol with the SR membrane (mole of propranolol per mole of SR phospholipid) correlated with its ability to inhibit calcium uptake, whereas only a fraction of the total association of timolol with the SR membrane appeared to lead to inhibition of calcium uptake. These results suggest that the major nonspecific interactions of propranolol and timolol are with the SR membrane lipids, and that the magnitude of their interactions depends on both the lipid solubility of the drug and the physical state of the fatty acyl chains of the membrane. Both propranolol and timolol appear to perturb the functional properties of the calcium pump protein in the SR membrane (inhibition of ATP-induced calcium uptake) indirectly by partitioning into the bulk lipid matrix of the SR lipid bilayer, although other sites of interaction cannot be excluded.

Animals↗
PubMed1980

[Results of long-term treatment of glaucoma with timolol ophthalmic solution (author's transl)].

A previous double-blind study carried out for 17 weeks on 50 patients with open-angle glaucoma reported on the results of treatment with Timolol and Pilocarpine eye drops. On completion of a long-term study with Timolol over a two-year period, the remaining findings can now be given. Of the 25 patients treated twice a day with 0.1% to 0.5% Timolol eye drops, intraocular pressure was not adequately controlled in six patients with the use of Timolol alone, and treatment had to be discontinued after three to five weeks. In the remaining 19 patients, intraocular pressure was controlled well over the entire two-year period, but in some cases it was necessary after a while to increase the dosage to a higher concentration. The following checks were carried out regularly in accordance with a fixed schedule: intraocular pressure, tonographic examination, visual acuity, pupil size, visual field, pulse and blood pressure, tear production (Schirmer test), slit-lamp biomicroscopy and fundaloscopy. Evaluation of the results shows that in the long term Timolol reduced intraocular pressure by 31%. There were no changes in visual acuity, visual field, excavation and degeneration of the optic disc, or slit lamp examination findings. During treatment with Timolol the mean pulse rate decreased by 12%, and there was a drop in blood pressure of 3.8% systolic and 2.8% diastolic. Moreover, tear production decreased by 10.2%. During the entire observation period there were no local or systemic side-effects, nor any adverse reaction. The six patients whose intraocular pressure was not reduced satisfactorily by Timolol alone were treated successfully with a combination of Timolol and miotics. A dosage without additional Timolol would not have sufficed for any of the patients.

Clinical Trials as Topic↗
PubMed1993

[The bioavailability of transdermal therapeutic system of timolol].

A matrix-type transdermal therapeutic system of timolol (TTS-timolol) was well prepared. The patch consisted of backing membrane layer, timolol reservoir layer, pressure sensitive adhesive layer and protective layer. A sensitive and reliable HPLC-UV method for the determination of plasma level of timolol in healthy volunteers was developed. Effective therapeutic plasma level of timolol (4 ng/ml) was attained 4 h after application of the timolol patches and was maintained within 32 h while the patch was removed at 24 h. The pharmacokinetic behavior of this transdermal therapeutic system (TTS)-timolol in human showed zero order absorption and well fitted to a one compartment model. The pharmacokinetic parameters are: Tmax = 18.8 h; Cmax = 11.2 ng/ml; AUC = 265.7 ng/ml.h; Vss = 120.0 L; K = 0.084 h-1. In comparison with the results of oral administration of timolol tablets, TTS-timolol possesses some advantages: stable plasma level, long effective time and convenient administration.

Administration, Cutaneous↗
PubMed2001

Aqueous humor flow in normal human eyes treated with brimonidine and timolol, alone and in combination.

OBJECTIVE: To compare the effect on aqueous humor flow and intraocular pressure (IOP) of topically applied 0.2% brimonidine tartrate with topically administered 0.5% timolol maleate, alone and in combination. DESIGN: A randomized, double-masked, placebo-controlled study of 20 human subjects was carried out. The topical drugs were instilled twice daily the day before and again on the morning of the day of the measurements. Aqueous humor flow was measured by clearance of topically applied fluorescein with a fluorophotometer, and IOP was measured with an applanation tonometer. RESULTS: Brimonidine reduced the aqueous humor flow by 33.1%; timolol, by 49.9%; and the combination of brimonidine and timolol, by 58.9%. Brimonidine reduced the IOP by 20.3%; timolol, by 22.9%; and the combination of brimonidine and timolol, by 34.7%. CONCLUSIONS: Brimonidine suppressed aqueous humor flow, but not as effectively as timolol. However, the effects on the IOP of both drugs separately were comparable. The short-term effect of brimonidine was partly additive to timolol, and the combination treatment caused a further reduction in aqueous humor flow and IOP. The IOP reduction by timolol could be explained solely by aqueous humor flow reduction. Much of the IOP reduction caused by brimonidine, but not all, could be explained by suppression of the aqueous humor flow, suggesting an additional mechanism for the ocular hypotensive effect of brimonidine.

Administration, Topical↗
PubMed2002

One-year, randomized study comparing bimatoprost and timolol in glaucoma and ocular hypertension.

OBJECTIVE: To compare bimatoprost with timolol maleate in patients with glaucoma or ocular hypertension. METHODS: In 2 identical, multicenter, randomized, double-masked, 1-year clinical trials, patients were treated with 0.03% bimatoprost once daily (QD) (n = 474), 0.03% bimatoprost twice daily (BID) (n = 483), or 0.5% timolol maleate BID (n = 241). MAIN OUTCOME MEASURES: Diurnal intraocular pressure (IOP) at 8 AM, 10 AM, and 4 PM and safety variables (IOP was also measured at 8 PM at selected sites). RESULTS: Bimatoprost QD provided significantly lower mean IOP than timolol at every time of the day at each study visit (P<.001). This was also true for bimatoprost BID at most time points, but the efficacy was not as good as that of the QD regimen. At 10 AM (peak timolol effect) at month 12, the mean reduction in IOP from baseline was 7.6 mm Hg (30%) with bimatoprost and 5.3 mm Hg (21%) with timolol (P<.001). A significantly higher percentage of patients receiving bimatoprost QD (58%) than timolol (37%) achieved IOPs at or below 17 mm Hg (10 AM, month 12; P<.001). The most common adverse effect with bimatoprost was hyperemia (significantly higher with bimatoprost QD than timolol; P<.001). CONCLUSIONS: Bimatoprost QD provides sustained IOP lowering superior to timolol or bimatoprost BID and achieves low target IOPs in significantly more patients.

Adrenergic beta-Antagonists↗
PubMed1980

Ocular hypotensive effects of timolol in cat eyes.

The effects of timolol on the aqueous humor (AH) formation and AH outflow in cat eyes were simultaneously studied with a continuous infusion method under constant intraocular pressure. The rate of AH formation was reduced 28%, 56%, and 71%, respectively, by 0.005%, 0.025%, and 0.15% of timolol solution infused intracamerally. There was no significant change of AH outflow after the administration of timolol. It was noted that the pupil was dilated by 0.025% and 0.15% timolol solutions. To determine the action mechanism of timolol to inhibit AH formation, experiments of carbonate dehydratase inhibition were performed with various concentrations of timolol. No appreciable enzyme inhibition was noted with timolol at concentrations up to 0.5%. It is thus concluded that the action mechanism of timolol to inhibit AH formation differs from that of carbonate dehydratase inhibitors.

Animals↗
PubMed1981

Long-term drift and continued efficacy after multiyear timolol therapy.

The clinical courses of 41 patients who received timolol maleate for experimental protocols were reviewed. We reevaluated the conditions of 17 patients with the elevated pressures of primary open angle glaucoma who had received timolol alone or in combination with other glaucoma medications for a maximum of 35 months (average, 26 months). Withdrawal of timolol led to an average intraocular pressure rise of 5 mm Hg. Eight patients treated with timolol alone showed a progressive, significant, 3-mm Hg upward rise, or "long-term drift" in IOP during the follow-up period. Pressure rise after timolol withdrawal, however, was not significantly less than pressure reduction when timolol was initiated. At least two weeks are required for "washout" or disappearance of timolol effect after timolol is withdrawn, and re-treatment for one week restores IOP to prewithdrawal levels.

Acetazolamide↗
PubMed1991

A sensitive radioligand binding assay for timolol in plasma.

A sensitive and reproducible radioreceptor assay (RRA) is described for the determination of low picogram levels of timolol in plasma. The plasma or serum samples (1 mL) are prepared by selectively extracting timolol with lipophilic solvents or, alternatively, only plasma (serum) proteins are precipitated prior to binding assay. The recovery of timolol is at least 90% during the sample preparation. In the radioligand binding assay, timolol and the nonselective beta-antagonist [3H](-)-CGP-12177 compete for the binding sites present in the rat reticulocyte membranes. The detection limit for timolol (30 pg/mL) exceeds 50 times the sensitivity of the GC-MS techniques for timolol. The RRA results and GC results obtained from the same clinical samples correlate excellently (r = 0.99). There was no evidence for interference caused by timolol metabolites in the RRA. Timolol concentrations in plasma following its oral and even ocular administration were possible to monitor using the RRA. The method can be modified to also measure several other beta-antagonist drugs in picogram per milliliter quantities.

Adrenergic beta-Antagonists↗