Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops

BACKGROUND: To investigate the pharmacological basis of systemic side effects of ophthalmic timolol, we estimated the systemic bioavailability of 0.5% timolol eyedrops and compared cardiopulmonary effects of intravenous and ophthalmic timolol. METHODS: In a randomized crossover study we administered 0.2 mg timolol either intravenously or ocularly to eight healthy volunteers. After drug administration we measured heart rate, arterial blood pressure, forced expiratory volume in 1s, forced vital capacity, and intraocular pressure (IOP). Plasma timolol concentrations were determined using a beta-adrenoceptor binding assay. RESULTS: The peak concentration of ophthalmic timolol in plasma, (C(max)=1.14+/-0.34 ng/ml, mean+/-SD, n=8) was measured in most subjects within 15 min after drug administration. The mean area under the curve from zero to infinitum (AUC(0-)(infinity)) was 6.46+/-2.49 ng/ml per hour after intravenous and 4.78+/-1.90 ng/ml per hour (means+/-SD, n=8) after ocular administration. The systemic bioavailability (F) of the eyedrop was 78.0+/-24.5% (mean+/-SD, n=8). Heart rate, arterial blood pressure, and pulmonary functions were similar after intravenous and ocular timolol administration, whereas IOP was lowered more effectively by the ophthalmic than the intravenous dose. CONCLUSIONS: Ophthalmic timolol resembled intravenous timolol in terms of systemic bioavailability, plasma kinetics, and cardiopulmonary effects. Clinicians should pay attention to the high systemic bioavailability of ophthalmic timolol, because intensive systemic beta-blockade can be highly hazardous to aged patients suffering from cardiopulmonary diseases.     

Improved systemic safety and risk–benefit ratio of topical 0.1% timolol hydrogel compared with 0.5% timolol aqueous solution in the treatment of glaucoma

Purpose  

The purpose of the study was to compare the systemic safety and risk–benefit ratio of 0.1% timolol hydrogel and 0.5% aqueous timolol eye drops in the treatment of glaucoma.     

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.     

2%美开朗与0.5%噻吗心安滴眼液治疗开角型青光眼与高眼压症的临床对照研究

目的以噻吗心安滴眼液作对照,在原发性开角型青光眼和高眼压症患者中评价美开朗滴眼液的降眼压、内在拟交感活性作用。方法选择开角型青光眼和高眼压症患者50例50眼,随机分为美开朗组和噻吗心安组2组,各25例25眼。美开朗组滴用2%美开朗眼液,噻吗心安组滴用0.5%噻吗心安眼液,一日2次,共12周,比较两种滴眼液的降眼压作用及局部和全身副作用。结果两组患者用药后眼压均下降,与用药前相比均有显著性差异(P<0.01)。两组间眼压下降值无显著性差异(P>0.05)。用药12周,美开朗组心率平均降低3.6次,噻吗心安组心率平均降低6.5次,两者相比有显著性差异。结论美开朗滴眼液对开角型青光眼和高眼压症患者具有明显的降眼压作用,和噻吗心安滴眼液局部降眼压作用相同,但对心率的抑制作用比噻吗心安小。     

Timolol 0.1% gel (Nyogel 0.1% once daily versus conventional timolol 0.5% solution twice daily: a comparison of efficacy and safety

In a prospective, randomised, double-masked, parallel-group, multi-centre study, 210 patients with primary open angle glaucoma or ocular hypertension were enrolled of whom 167 (timolol 0.1% gel 82, timolol 0.5% 85) completed the study as per protocol. The change in intraocular pressure between baseline and week 12 in the worse eye ('at trough') was 6.3 (SD 3.3) mm Hg on timolol 0.1% gel and 7.0 (2.9) mm Hg on timolol 0.5%; this difference was not statistically significant (p = 0.19). The difference between the two study groups in the change of intraocular pressure from baseline was 0.62 mm Hg; the 90% CI of -0.09 to +1.33 mm Hg was within the pre-specified limits of -1.5 to +1.5 mm Hg demonstrating equivalence between timolol 0.1% gel and timolol 0.5%. The plasma levels of timolol (ng/ml) at 12 weeks in the timolol 0.1% gel group were significantly less than that with timolol 0.5% both before instillation (mean 0.057, SD 0.131 and mean 0.470, SD 0.519 respectively, p = 0.025) and after instillation (mean 0.552, SD 0.992 and mean 2.473, SD 1.780 respectively, p = 0.008). Both treatments were well tolerated with no statistically significant difference between the groups in the occurrence of ocular or systemic adverse events.     

A three-month, multicenter, double-masked study of the safety and efficacy of travoprost 0.004%/timolol 0.5% ophthalmic solution compared to travoprost 0.004% ophthalmic solution and timolol 0.5% dosed concomitantly in subjects with open angle glaucoma or ocular hypertension

PURPOSE: The primary objective of this study was to compare the intraocular pressure (IOP)-lowering efficacy of travoprost 0.004%/timolol 0.5% fixed combination to the concomitant administration of travoprost 0.004% (TRAVATAN) and timolol 0.5% in subjects with open angle glaucoma or ocular hypertension. METHODS: This was a randomized, multicenter, double-masked, active-controlled, parallel group study. Three hundred sixteen patients with open angle glaucoma or ocular hypertension were randomly assigned to travoprost 0.004%/timolol 0.5% ophthalmic solution fixed combination once daily in the morning or concomitant administration of timolol 0.5% once daily in the morning and travoprost 0.004% ophthalmic solution once daily in the evening. The efficacy and safety of the fixed combination were compared with concomitant therapy over three months. The primary efficacy outcome measure was mean intraocular pressure. RESULTS: Both travoprost 0.004%/timolol 0.5% fixed combination and the concomitant administration of travoprost 0.004% and timolol 0.5% produced statistically significant reductions from baseline in IOP, with mean IOP ranging from 15.2 to 16.5 mm Hg in the patients using travoprost 0.004%/timolol 0.5% fixed combination compared with 14.7 to 16.1 mm Hg in the concomitant group. The upper 95.1% confidence limit for the differences in mean IOP (fixed combination minus concomitant) was < or =1.5 mm Hg at 7 of 9 visits, including all three 8 AM time points, 24-hours post-dose. Mean IOP reductions from baseline ranged from 7.4 to 9.4 mm Hg in the fixed combination group compared with 8.4 to 9.4 mm Hg with concomitant therapy. Safety analysis demonstrated equivalent safety between the two treatment groups. CONCLUSIONS: A fixed combination of travoprost 0.004% and timolol 0.5% produced clinically relevant IOP reductions in patients with open angle glaucoma or ocular hypertension that were comparable to concomitant therapy with its components. Safety and tolerability of the fixed combination were also equivalent to concomitant therapy. Travoprost 0.004%/timolol 0.5% fixed combination offers IOP reduction equivalent to concomitant therapy, with potential benefits that include convenience (fewer bottles and drops per day), improved compliance, cost savings (based on fewer co-payments), and elimination of potential washout effects.     

Timolol maleate 0.5% versus timolol maleate in gel forming solution 0.5% (Timolol GFS) in open angle glaucoma in India. Preliminary safety and efficacy study

PURPOSE: To compare the efficacy and safety profile of Timolol maleate 0.5% versus Timolol gel forming solution (GFS) 0.5% in open angle glaucoma in Indian eyes. METHODS: In a prospective crossover study 52 patients of open angle glaucoma, well controlled intraocular pressure (IOP) on 0.5% timolol maleate solution were switched over to timolol GFS once a day, after a washout period of one month. A diurnal IOP measurement was done after 6 weeks and compared with patients on timolol maleate 0.5% twice a day. In addition, side effects reported or observed were compared. RESULTS: Statistically significant difference was not observed in ocular hypotensive effect of the two treatment. The side-effects in both the treatment groups were similar except for higher incidence of blurring of vision in patients on timolol GFS. The compliance was better with timolol GFS, but was not statistically significant. CONCLUSION: The results of this study suggest that the more convenient 0.5% timolol in gel forming solution can be offered as an equally efficacious and well-tolerated alternative to twice daily 0.5% timolol solution in open angle glaucoma.     

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.     

Comparative efficacy of gel-forming and ophthalmic solutions of 0.5% timolol in open-angle glaucoma

We compared the efficacy in lowering intraocular pressure (IOP) of 0.5% timolol maleate gel-forming solution (GFS) once daily with 0.5% timolol maleate ophthalmic solution twice daily in patients with open-angle glaucoma. In both treatment groups (30 eyes each), IOP was measured at baseline and weeks 2, 4, 8, 12, and 24. The mean decrease of IOP at trough ranged from 5.5 to 5.9 mm Hg for timolol GFS and from 6.1 to 6.5 mm Hg for timolol solution. The authors have stated that they do not have a significant financial interest or other relationship with any product manufacturer or provider of services discussed in this article.     

A comparison of the ocular hypotensive efficacy of twice-daily 0.25% levobunolol to 0.5% timolol in patients previously treated with 0.5% timolol

Treatment with noncardioselective beta-adrenoceptor antagonists (e.g., 0.5% timolol or 0.5% levobunolol) is standard practice for lowering elevated intraocular pressure (IOP). However, because there are risks and side effects associated with the use of these agents, a lower, yet still effective, dose may be preferred. We gave 0.5% timolol twice daily for 30 days to 143 patients. In a double-masked, randomized fashion, we then assigned patients to continue to receive 0.5% timolol twice daily or 0.25% levobunolol twice daily for 8 weeks. The mean unmedicated baseline IOP for both groups was approximately 25 mm Hg. After 30 days of timolol pretreatment, the mean IOP in both groups decreased to approximately 19 mm Hg (p = 0.210). After the 30-day timolol pretreatment period, and subsequent randomization to either 0.5% timolol or 0.25% levobunolol treatment, there was little change in overall mean IOP (0.03 mm Hg decrease for levobunolol, 0.06 mm Hg increase for timolol; p = 0.811) from the timolol pretreatment baseline. One patient assigned to the timolol treatment group was terminated from the study due to inadequate control of IOP. We conclude that the mean IOP lowering effect of 0.25% levobunolol is equivalent to 0.5% timolol, and switching patients from twice-daily 0.5% timolol to twice-daily 0.25% levobunolol poses no significant risk of decreased ocular hypotensive efficacy.     

A comparison of morning and evening instillation of a combination travoprost 0.004%/timolol 0.5% ophthalmic solution

PURPOSE: To compare the intraocular pressure lowering efficacy and side effect profile of travoprost 0.004%/timolol 0.5% ophthalmic solution dosed in the morning and evening. METHODS: This was a multicenter, prospective, randomized, double-masked, parallel group clinical study of 92 patients with open-angle glaucoma (with or without pseudoexfoliative or pigmentary glaucoma) or ocular hypertension. After a washout of existing glaucoma medications, patients were randomly assigned to receive one drop of travoprost 0.004%/timolol 0.5% in the morning or evening for 6 weeks. The main outcome measures were mean intraocular pressure (IOP) assessed at 9 am, 11 am, and 4 pm, and safety variables. RESULTS: Travoprost 0.004%/timolol 0.5% ophthalmic solution, dosed in the morning or evening, controlled IOP consistently throughout the day. Mean IOP ranged from 16.5 to 16.7 mmHg in the morning treatment group and from 16.1 to 17.2 mmHg in the evening treatment group. Travoprost 0.004%/timolol 0.5% ophthalmic solution produced statistically significant and clinically relevant reductions in IOP from baseline; mean reductions ranged from approximately 8 to 10 mmHg (32% to 38%). Travoprost 0.004%/timolol 0.5% ophthalmic solution was safe and well tolerated with the most frequently reported adverse event being ocular hyperemia, which occurred in 12.5% of patients in the morning treatment group and 13.6% of patients in the evening treatment group. CONCLUSIONS: Travoprost 0.004%/timolol 0.5% given once daily, either in the morning or evening, is a safe and effective treatment for open-angle glaucoma and ocular hypertension. It may be beneficial for patients judged to be inadequately controlled on a prostaglandin analogue or ophthalmic beta-blocker alone.     

A 1-year study to compare the efficacy and safety of once-daily travoprost 0.004%/timolol 0.5% to once-daily latanoprost 0.005%/timolol 0.5% in patients with open-angle glaucoma or ocular hypertension

PURPOSE: The objective of the study was to compare the intraocular pressure (IOP)-lowering efficacy and safety of travoprost 0.004%/timolol 0.5% ophthalmic solution (Trav/Tim) to latanoprost 0.005%/timolol 0.5% ophthalmic solution (Lat/Tim), dosed once daily in the morning, in patients with open-angle glaucoma (OAG) or ocular hypertension (OH). METHODS: This was a randomized, double-masked, multicenter, parallel group, active-controlled study conducted at 41 sites. At the eligibility visit the patients were randomized (1:1) to the assigned masked medication if they met inclusion/exclusion criteria, and the mean IOP values in the eligible eyes were > or =24 mmHg at 9 AM and > or =21 mmHg at 11 AM and 4 PM. Patients were excluded if the mean IOP in either eye was >36 mmHg. Patients were instructed to administer the assigned medication each morning at 9 AM. During the treatment phase of the study, IOP was measured at 9 AM at week 2, week 6, month 3, and month 9. At the month 6 and month 12 visits, IOP was measured at 9 AM, 11 AM, and 4 PM. Statistical methods included a repeated measures analysis of variance (ANOVA); to test for noninferiority, a 95% confidence interval for the treatment group difference was constructed based on the ANOVA results for each time point at month 12. RESULTS: Patients (n=408) with OAG or OH were enrolled at 41 sites. One patient withdrew prior to receiving medication so 207 in the Trav/Tim group and 200 in the Lat/Tim group were evaluable for safety. Baseline demographic characteristics as well as IOP values showed no statistical differences between the two groups. Trav/Tim provided lower mean IOP values than Lat/Tim that were statistically significant at the week 2 9 AM (p=0.0081), month 6 9 AM (p=0.0056), and month 6 11 AM (p=0.0128) time points and at 9 AM time point pooled across all visits (p=0.0235) when mean IOP was 0.6 mmHg lower in the Trav/Tim group. Treatment-related adverse events were mild in both groups. Although hyperemia was reported from a higher percentage of patients in Trav/Tim group, differences in average hyperemia scores between the two groups were not considered clinically relevant. CONCLUSIONS: Travoprost 0.004%/timolol 0.5% ophthalmic solution produced mean IOP levels that are statistically noninferior to latanoprost 0.005%/timolol 0.5% ophthalmic solution. Furthermore, at 9:00 AM, 24 hours after dosing, IOP was statistically lower for travoprost 0.004%/timolol 0.5% pooled across all visits. Travoprost 0.004%/timolol 0.5% fixed combination ophthalmic solution is an effective treatment for reducing IOP and it is safe and well-tolerated in patients with OAG or OH.     

A comparison of the efficacy and tolerability of 0.5% timolol maleate ophthalmic gel-forming solution QD and 0.5% levobunolol hydrochloride BID in patients with ocular hypertension or open-angle glaucoma.

The purpose of this study was to compare the ocular hypotensive efficacy and tolerability of 0.5% timolol maleate ophthalmic gel-forming solution (timolol gel) and 0.5% levobunolol hydrochloride (levobunolol). This was a randomized, double-masked, multi-center, active-controlled, 2-period, crossover study. After a 3-week, single-masked placebo run-in phase, patients with ocular hypertension or open-angle glaucoma and an intraocular pressure (IOP) > or = 22 mmHg were randomized to receive timolol gel QD or levobunolol BID for 6 weeks followed by a 3-week, placebo washout period. Patients were then crossed over to the alternate treatment for 6 weeks. IOP and heart rate (HR) were measured at 3 and 6 weeks after the start of therapy with either timolol gel or levobunolol. Of 133 patients randomized, 116 received both treatments. Timolol gel QD was comparable to levobunolol BID in reducing trough and peak IOP. At trough, HR was marginally increased with timolol gel and was decreased with levobunolol (p = < 0.001). At peak, HR was decreased with both treatments, but the decrease was significantly less with timolol gel than with levobunolol (p = 0.049). Significantly more patients experienced at least one adverse event (p = 0.024), adverse events related to special senses (p = 0.002), and burning and stinging (p < 0.001) with levobunolol compared to timolol gel. The study demonstrates that timolol gel QD has IOP-lowering effects comparable to those of levobunolol BID with fewer adverse experiences and less effect on HR.     

Plasma timolol concentrations of timolol maleate: timolol gel-forming solution (TIMOPTIC-XE®) once daily versus timolol maleate ophthalmic solution twice daily

Purpose: The objective of this study was to compare plasma concentrations of timolol following multiple dosing of the therapeutic regimens of timolol maleate ophthalmic gel-forming solution (Timolol GS; TIMOPTIC-XE®) and timolol maleate ophthalmic solution. Timolol maleate ophthalmic gel-forming solution is also referred to as Timolol GS, i.e. gel-forming solution. Methods: This was a masked observer, two-period crossover study in six normal male subjects randomized to receive either Timolol GS, 0.5% (TIMOPTIC-XE,) once daily (0530 hours) or timolol maleate ophthalmic solution (0.5% TIMOPTIC®) twice daily (0530 and 1730 hours) for 8 days, in both eyes. On Day 8, a blood sample was obtained prior to treatment, as well as 1, 2, 4, 8, 10, 12, 13, 14, 16, and 24 hours following the morning instillation. After a 7-day inter-period washout interval, subjects received the opposite treatment. Results: Timolol GS (TIMOPTIC-XE): Plasma concentrations of timolol rarely exceeded 0.375 ng/ml (the lower limit of assay quantification). For all subjects, peak plasma concentrations of timolol averaged <0.3 ng/ml within 4 hours after the last dose. The highest single observation was 0.49 ng/ml in one subject (at hour 2). Timolol solution: For all subjects, peak plasma concentrations of timolol averaged about 0.5 ng/ml and 0.3 ng/ml within 4 hours following the first and second dose, respectively, on Day 8. The highest single observation was 0.95 ng/ml in one subject (at hour 2). Conclusions: The data suggest that there is less systemic exposure to timolol following once-daily therapy with Timolol GS 0.5% compared with twice daily therapy with timolol maleate ophthalmic solution 0.5%.     

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.     

A six-week, parallel, randomized, double-blind study comparing the efficacy and safety of the 0.5% timolol/2.0% MK-507 combination b.i.d. to the concomitant administration of 0.5% timolol b.i.d. and 2.0% MK-507 b.i.d.

This was a 6-week, parallel, randomized, double-blind study comparing the efficacy and safety of the 0.5% timolol/2.0% MK-507 combination b.i.d. to the concomitant administration of 0.5% timolol b.i.d. and 2.0% MK-507 b.i.d. Patients with ocular hypertension or open-angle glaucoma from 21 to 85 years of age were enrolled in this study. Each of them should have intraocular pressure (IOP) of 20 mmHg or more in the study eye after they completed the wash-out period. The patients enrolled were randomly assigned to either combination (0.5% timolol/2.0% MK-507 b.i.d. and placebo b.i.d.) or concomitant (0.5% timolol b.i.d. and 2.0% MK-507 b.i.d.) treatment. During the study, no systemic or topical medication affecting IOP other than test drugs were allowed. A total of 20 randomized patients were included in the intention-to-treat population for analysis of data. The ten were assigned to the combination treatment and others were assigned to the concomitant treatment. There was no statistically significant difference between the two study treatments in terms of gender distribution, average age, and average IOP at the trough and the peak before starting the test medications. Mean reduction of the IOP from baseline to the final visit at the trough was 5.04 mmHg in the combination treatment and was 2.73 mmHg in the concomitant treatment. Mean reduction of the IOP at the peak was 2.19 mmHg in the combination treatment and was 2.53 mmHg in the concomitant treatment. There were no statistically significant differences in the above analyses between the two treatments. Safety evaluation was carried out, and number of adverse events in each treatment group did not differ substantially. Ocular signs and symptoms were evaluated in each visit, and all of the between-treatment values were not different significantly, either. Laboratory tests were performed, and showed no significant differences between pre- and post-treatment periods. None of these was found to be clinically serious, either. We concluded that the 0.5% timolol/2.0% MK-507 combination b.i.d. is equivalent in the efficacy of lowering IOP as well as safety compared to the concomitant administration of 0.5% timolol b.i.d. and 2.0% MK-507 b.i.d. in patients with ocular hypertension or open-angle glaucoma.     

Brimonidine 0.2% vs unoprostone 0.15% both added to timolol maleate 0.5% given twice daily to patients with primary open-angle glaucoma or ocular hypertension

PURPOSE: To compare the efficacy and safety of brimonidine 0.2% vs unoprostone 0.15%, both added to timolol maleate 0.5% each given twice daily. METHODS: In this prospective, multi-centred, double-masked, crossover comparison, patients were randomized to one treatment group for a 6-week treatment period, and then crossed over to the opposite treatment. Measurements were performed at 0800, 1000, 1600, 1800, and 2000 h at baseline and at the end of each treatment period. RESULTS: In all, 33 patients entered this trial and 29 completed. The baseline trough intraocular pressure (IOP) was 23.3+/-2.4 and the diurnal curve IOP was 22.0+/-1.3 mmHg. For the brimonidine and timolol maleate treatment group, the trough IOP was 21.6+/-3.3 and the diurnal curve IOP was 19.8+/-2.1 mmHg, while the timolol and unoprostone treatment showed a trough IOP of 20.9+/-3.8 and a diurnal curve IOP of 19.3+/-2.4 mmHg. There was no significant difference between treatment groups at any time point for the diurnal curve, or in the reduction from baseline (P>0.05). Both treatments failed to statistically reduce the IOP from baseline at 1800 h. There was no difference between treatment groups regarding ocular and systemic unsolicited adverse events, but patients admitted to more dryness (P=0.02) and burning upon instillation (P<0.0001) with unoprostone by survey. CONCLUSION: Brimonidine 0.2% or unoprostone 0.15% added to timolol maleate 0.5% provide similar efficacy and safety throughout the daytime diurnal curve.     

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.     

Intraocular pressure over 24 hours after repeated administration of latanoprost 0.005% or timolol gel-forming solution 0.5% in patients with ocular hypertension

PURPOSE: To compare the effect on intraocular pressure (IOP) over 24 hours after 4 weeks of treatment with latanoprost 0.005% and timolol gel 0.5%. DESIGN: Randomized, open, crossover single-center study. PARTICIPANTS: Twenty-seven patients with ocular hypertension. METHODS: The patients were randomly assigned to 4 weeks of latanoprost 0.005% once daily or timolol gel 0.5% once daily, with a 4-week washout period before switching therapy. MAIN OUTCOME MEASURES: Measurement of IOP during 24 hours of hospitalization. Blood pressure and heart rate were also measured repeatedly over the 24 hours. Daytime mean IOP, nighttime mean IOP, and 24-hour mean IOP were calculated as IOP area under the curve (AUC) divided by time in hours. RESULTS: The mean IOP during daytime (7 AM to 10 PM) was 13.5 +/- 0.4 mmHg (daytime IOP, AUC/15 hours, least square mean +/- standard error of the mean [SEM]) in the latanoprost group, and 14.8 +/- 0.4 mmHg in the timolol gel group. This difference of 1.3 +/- 0.3 mmHg was statistically significant in favor of latanoprost (P < 0.001; 95% confidence interval [CI], 0.7, 2.0). The mean IOP at night (10 PM to 7 AM) was 13.7 +/- 0.4 mmHg for latanoprost (nighttime IOP, AUC/9 hours, least square mean +/- SEM) and 15.9 +/- 0.5 mmHg for timolol gel, with a difference of 2.2 +/- 0.3 mmHg (P < 0.001; 95% CI, 1.5, 2.8). At every measured time point during the 24 hours, latanoprost reduced IOP more than timolol. There was no difference between the two treatment groups regarding blood pressure and heart rate. CONCLUSIONS: Latanoprost reduced mean 24-hour IOP, mean daytime IOP, and mean nighttime IOP statistically significantly more than timolol. Also, latanoprost reduced IOP more effectively at every measured time point over the 24 hours compared with timolol gel.     

Comparison of topical travoprost eye drops given once daily and timolol 0.5% given twice daily in patients with open-angle glaucoma or ocular hypertension.

PURPOSE: This 9-month study compared the intraocular pressure (IOP)-lowering efficacy and safety of once-daily travoprost ophthalmic solutions (0.0015% and 0.004%) with twice-daily timolol 0.5%. PATIENTS AND METHODS: This study was conducted using a double-masked, randomized, parallel-group design; adult patients with open-angle glaucoma or ocular hypertension (IOP between 24 and 36 mm Hg, inclusive at 9 am and between 21 and 36 mm Hg, inclusive, at 11 am and 4 pm on two eligibility visits after an appropriate washout of previous treatments). In both eyes, the travoprost vehicle (placebo) was instilled at 9 am and travoprost (0.0015% or 0.004%) was instilled at 9 pm, or timolol 0.5% was instilled at both times. The primary efficacy variable was mean IOP measured at 9 am, 11 am, and 4 pm at baseline and follow-up visits. RESULTS: Five hundred seventy-three patients were randomized to the study treatments. Mean IOP, which was combined across study visits, was lower with travoprost 0.004% than with timolol 0.5% at 9 am (P = 0.0246), 11 am (P = 0.0039), and 4 pm (P = 0.0004). Intraocular pressure was lower with travoprost 0.004% than with travoprost 0.0015% at 11 am (P = 0.0314), the time of peak drug activity. Mean IOP was consistently lower with travoprost 0.0015% than with timolol 0.5%. Mean IOP reductions from baseline were significantly (P less than equal 0.0001) greater with travoprost 0.004% (8.0-8.9 mm Hg) than with timolol 0.5% (6.3-7.9 mm Hg). The most frequent related adverse events were hyperemia, pruritus, discomfort, pain, and iris pigmentation changes. The local tolerance was better in the timolol group compared with patients receiving travoprost. There were no serious unexpected treatment-related adverse events in any group. CONCLUSIONS: Travoprost 0.004% reduced diurnal mean intraocular pressure significantly more than timolol 0.5%. Both concentrations of travoprost were well tolerated and safe for use in patients with open-angle glaucoma or ocular hypertension.