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Efficacy and safety of tafluprost 0.0015% versus latanoprost 0.005% eye drops in open-angle glaucoma and ocular hypertension: 24-month results of a randomized, double-masked phase III study

Purpose:  The objective of the study was to compare the long‐term efficacy and safety of tafluprost 0.0015% with latanoprost 0.005% eye drops in patients with open‐angle glaucoma or ocular hypertension.

Ophthalmic timolol: Plasma concentration and systemic cardiopulmonary effects

Timolol maleate is a non‐selective β‐adrenoceptor antagonist currently used mainly as an ocular preparation for the treatment of glaucoma and ocular hypertension. Despite the topical administration, ophthalmic timolol causes systemic adrenergic β‐blocking because of absorption from the eye into the systemic circulation. Gel formulations of ophthalmic timolol have been developed to reduce systemic absorption and adverse effects in comparison with conventional aqueous solution formulations. Timolol is metabolized by the polymorphic cytochrome P450 2D6 enzyme (CYP2D6). The changes in heart rate (HR) are the most striking effects of the systematically absorbed fraction of ophthalmic timolol, with 0.5 % aqueous formulations presenting larger effects than 0.1 % hydrogel formulations, especially during exercise. Plasma levels of ophthalmic timolol correlate with the changes in HR. Neither 0.5 % aqueous nor 0.1 % hydrogel formulations of timolol have exerted noteworthy effects on systolic (SAP) or diastolic (DAP) arterial pressures, probably because of a compensatory increase in systemic vascular resistance due to the attenuation of HR. Ophthalmic timolol does not exert remarkable effects on pulmonary parameter peak expiratory flow (PEF) and forced expiratory volume in 1 s (FEV1) in non‐asthmatic patients. CYP2D6 activity is clearly associated with the pharmacokinetic parameters, particularly when 0.5 % aqueous solution of timolol is used: peak plasma concentration, elimination half‐life and area‐under‐the‐curve are highest in CYP2D6 poor metabolizers. Finally, since there is a correlation between the plasma level of timolol and several haemodynamic effects – especially HR in the state of elevated β‐adrenergic tonus – the CYP2D6 poor metabolizers may be more prone to bradycardia during treatment with (aqueous) ophthalmic timolol.

A Phase II Study on the Duration and Stability of the Intraocular Pressure-Lowering Effect and Tolerability of Tafluprost Compared With Latanoprost

PURPOSE Tafluprost is a novel prostaglandin F(2alpha)-receptor agonist shown to lower intraocular pressure (IOP) in healthy humans and patients with elevated IOP. We investigated the efficacy, safety, and tolerability of tafluprost 0.0015% compared with latanoprost 0.005% in patients with primary open-angle glaucoma, exfoliation glaucoma, or ocular hypertension. METHODS This was a randomized, double-masked, active-controlled, parallel-group, multinational, and multicenter phase II study. Patients received either tafluprost 0.0015% (n = 19) or latanoprost 0.005% (n = 19), both once daily. The extent and duration of action of the IOP-lowering effects at Day 42 and Day 43 were the primary efficacy endpoints. Efficacy and safety parameters were analyzed throughout. RESULTS Maximum IOP reduction was achieved by Day 7 and was sustained until Day 42 in both groups (mean [standard deviation] change from baseline -9.7 [3.3] mm Hg for tafluprost and -8.8 [4.3] mm Hg for latanoprost). The overall treatment group difference was 0.17 mm Hg (95% confidence interval -1.27 to 1.61; P = 0.811). The IOP-lowering effect was maintained for >or=24 h after the last dose in both groups. Most adverse events were ocular and were similar in frequency and severity between groups. There were 3 severe adverse events, all ocular, and all in the tafluprost group (3/19 = 16%). CONCLUSIONS Tafluprost and latanoprost have comparable effects on the extent, duration, and stability of IOP reduction, and are well tolerated in patients.

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

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

Corneal penetration of fluoroquinolones: Aqueous humor concentrations after topical application of levofloxacin 0.5% and ofloxacin 0.3% eyedrops

Purpose: To investigate the penetration of topically applied levofloxacin 0.5% and ofloxacin 0.3% eyedrops into the aqueous humor of patients having cataract surgery. Setting: Hochkreuzklinik Eye Hospital, Bonn, Germany. Methods: In this randomized, investigator‐masked study, 69 patients received 4 drops of either levofloxacin 0.5% or ofloxacin 0.3% eyedrops within 1 hour (60 min, 45 min, 30 min, and 15 min) of elective cataract surgery. Aqueous humor samples of at least 50 μL were drawn from the anterior chamber at the beginning of the cataract operation. The concentrations of the fluoroquinolones in the anterior chambers were measured using high‐performance liquid chromatography. To exclude a dilution effect of the anterior chamber (AC), they were related to the AC volumes (measured by 3‐dimensional modeling of central Orbscan [Bausch & Lomb] slit‐image photos) and AC depths (measured by ultrasound). Results: The mean concentration of levofloxacin (1139.9 ng/mL ± 717.1 [SD]) in the aqueous humor was significantly higher (P = .0008) than that of ofloxacin (621.7 ± 368.7 ng/mL). The aqueous humor concentrations correlated negatively with the measured volumes and depths of the ACs. Conclusions: The new fluoroquinolone, levofloxacin, is more soluble in water enabling the use of higher drug concentrations (0.5%) compared with other currently available fluoroquinolone eyedrops (0.3%). The concentration AC with levofloxacin eyedrops was about 2‐fold that reached with ofloxacin eyedrops. The concentration of the antibacterial isomer was approximately 3.5 to 4 times higher when levofloxacin was administered, assuming negligible stereoselective uptake.

Ophthalmic timolol in a hydrogel vehicle leads to minor inter-individual variation in timolol concentration in aqueous humor

Ophthalmic timolol has been used for decades in the treatment of glaucoma and ocular hypertension, traditionally in aqueous 0.5% eye drops. Recently a timolol 0.1% hydrogel has been developed to improve systemic safety. The aim of the present study was to compare aqueous humor timolol concentrations after administration of 0.1% hydrogel and aqueous 0.5% timolol in patients scheduled for a cataract operation. The concentration in the aqueous humor was 210+/-175 ng/ml (mean+/-S.D.) 2h after administration of timolol 0.1% hydrogel and 538+/-304 ng/ml after aqueous 0.5% timolol. In the aqueous 0.5% timolol group more patients had unnecessarily high concentrations of timolol in the aqueous humor. beta(1)-receptors and beta(2)-receptors were practically 100% occupied after administration of both products. The hydrogel proved to be an excellent formulation in giving smaller inter-individual variation in penetration of timolol into the aqueous humor. Only a weak correlation was seen between corneal thickness and the aqueous humor concentration of timolol in the aqeuous 0.5% timolol group. In conclusion, in contrast to the conventional aqueous 0.5% timolol, 0.1% timolol hydrogel caused only slight inter-individual variation in timolol concentration in the aqueous humor.

Intraocular pressure decrease with preservative-free fixed and unfixed combination of tafluprost and timolol in pseudoexfoliative glaucoma

Abstract We investigated the intraocular pressure (IOP) lowering efficacy of preservative-free fixed and non-fixed combination of tafluprost 0.0015% and timolol 0.5% in pseudoexfoliative glaucoma (XFG). A per protocol worse eye analysis was made on all XFG patients who participated in a recent 6 month, prospective, randomized, double-masked, parallel group, multicenter phase III study. The mean time-wise IOP decreased by 8.62 to 10.25 mmHg (31.8 to 36.7%) in the fixed dose combination arm (15 patients) and by 5.38 to 11.35 mmHg (21.3 to 41.2%) in the non-fixed combination arm (13 patients), respectively (p < 0.001 for all comparisons). The results show that a preservative-free fixed dose combination of tafluprost and timolol provides a clinically significant IOP reduction in XFG, and may offer an advantage for the XFG patients with dry eye, due to its preservative-free nature.

Handling Test of Eye Drop Dispenser—Comparison of Unit-Dose Pipettes with Conventional Eye Drop Bottles

PURPOSE The aims of this study were to investigate how elderly people handle single-use eye drop dispensers (unit-dose pipettes) and to compare the performance with conventional eye drop bottles. METHODS In this open-label study, the handling of unit-dose pipettes and conventional eye drop bottles was compared in 41 elderly people who had little or no prior regular use of eye drop dispensers. The participants tested both types of dispenser once, and the following 7 variables were studied: ease/difficulty of opening the dispenser; influence of the size for handling of the dispenser; influence of the shape for handling of the dispenser; observation of the contents in the dispenser; the feeling of the dispenser in the hand; ease/difficulty of drop instillation on the eye from the dispenser; and overall performance of the eye drop dispenser. The dispensers contained isotonic saline, and a visual analog scale was used for assessment of each of the above variables. RESULTS The mean age of the participants was 73 years. A statistically significant difference in favor of the unit-dose pipettes was found with respect to observation of the contents in the dispenser, ease of administration, and the overall performance. Women regarded the unit-dose pipettes generally better than the bottles, but such a difference was not seen in men. CONCLUSIONS The study participants managed the unit-dose pipettes at least as well as the conventional eye drop bottles. If anything, the unit-dose pipettes appeared to be easier to use.

Preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% in patients with open-angle glaucoma and ocular hypertension: results of an open-label observational study

Background Efficacy, tolerability and safety of the novel preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5% (Taptiqom®) were investigated in an observational study in Germany. Objective To assess efficacy, tolerability and safety of the preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5% in a real-life setting. Methods Intraocular pressure (IOP) was recorded for each eye at baseline (any previous therapy or untreated) and 4–16 weeks after changing medical treatment to or initiating treatment with the preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5%. Change in IOP was evaluated over the study period for all patients and for specific pretreatment subgroups. Clinical signs such as conjunctival hyperemia and lid-parallel conjunctival folds (LIPCOF) were recorded using standardized comparative photographs. Corneal staining, subjective symptoms and local comfort were measured using a four-step scale. All adverse events were recorded. Results Among 1,157 patients enrolled, 1,075 patients were treated with the preservative-free fixed combination as the only medication at the final visit. Medical treatment was initiated in 741 patients because of an insufficient IOP-lowering effect of the prior medication. In 343 patients, medication was changed because of tolerability issues. The preservative-free fixed combination lowered IOP significantly in the subgroup of naïve patients, all subgroups with prior monotherapy and patients with prior fixed combinations: naïve patients: −8.9 mmHg, alpha- 2-agonists: −6.4 mmHg, beta-blockers: −5.7 mmHg, carbonic anhydrase inhibitors: −5.2 mmHg, prostaglandins: −4.7 mmHg, fixed-combination prostaglandins/timolol: −2.4 mmHg. At the final visit, clinical signs and subjective symptoms were improved in patients with prior medical therapy. Local comfort was rated as “very good” or “good” by 89.1% of patients at the final visit. Only few adverse events occurred during the treatment period. Conclusion The preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5% was effective, well tolerated and showed a good safety profile.