Comparison of the efficacy and tolerability of preservative-free and preservative-containing formulations of the dorzolamide/timolol fixed combination (COSOPT™) in patients with elevated intraocular pressure in a randomized clinical trial.

BACKGROUND: The aim of this study was to compare the efficacy and tolerability of preservative-free (PF) and preservative-containing (PC) formulations of the dorzolamide/timolol fixed combination (COSOPT™) in patients with elevated intraocular pressure (IOP). METHODS: A parallel, randomized, double-masked study was conducted. After a 3-week run-in on timolol, patients with ocular hypertension, as confirmed by an IOP ≥22 mmHg, were randomized 1:1 to receive PF or PC dorzolamide/timolol twice daily for 12 weeks. IOP was measured at hour 0 (drug trough) and hour 2 (drug peak) at baseline (last day of 3-week timolol run-in), and weeks 2, 6 and 12. RESULTS: A total of 261 patients were randomized. Mean baseline IOPs were 23.7 mmHg for both treatments at hour 0 and 21.2 mmHg for PF dorzolamide/timolol and 21.4 mmHg for PC dorzolamide/timolol at hour 2. At all study time points (trough and peak at weeks 2, 6, and 12), the difference between treatments in mean change from baseline IOP was <0.5 mmHg. The 95% confidence intervals for the estimated treatment difference (PF minus PC) in mean change from baseline IOP at week 12 was -0.86 to 0.23 mmHg for trough (primary endpoint) and -0.39 to 0.67 mmHg for peak (secondary endpoint). The most common adverse events were ocular burning/stinging, reported by 16.0% and 21.5% of patients receiving PF and PC dorzolamide/timolol respectively, and taste perversion, reported by 3.1% and 5.4% of patients receiving PF and PC dorzolamide/timolol respectively. CONCLUSIONS: In patients with elevated IOP, PF and PC dorzolamide/timolol were equivalent in efficacy for change in trough and peak IOP, and had generally similar tolerability.

A randomized trial assessing dorzolamide in patients with glaucoma who are younger than 6 years.

OBJECTIVE: To evaluate dorzolamide hydrochloride in patients younger than 6 years who have an elevated intraocular pressure or glaucoma. DESIGN: A 3-month, controlled, randomized, double-masked, multicenter, clinical trial. Patients were randomized to 2% dorzolamide 3 times daily or timolol maleate gel-forming solution (0.25% for patients <2 years and 0.5% for patients > or =2 but <6 years) once daily plus placebo twice daily. If the intraocular pressure was not controlled through monotherapy, younger patients received concomitant dorzolamide 3 times daily and 0.25% timolol gel-forming solution once daily and older patients received a fixed combination of 2% dorzolamide and 0.5% timolol twice daily. The primary safety variable was the proportion of patients who discontinued therapy for a drug-related adverse experience. Intraocular pressure reduction was a secondary measure. RESULTS: One younger patient (1.8%) of 56 randomized to dorzolamide discontinued concomitant therapy because of bradycardia. Two older patients (3.0%) of 66 discontinued dorzolamide because of ocular adverse experiences. The most frequent ocular adverse experiences were discharge and ocular hyperemia (younger cohort) and ocular hyperemia and burning/stinging (older cohort). At week 12, the mean change in intraocular pressure for dorzolamide was statistically significant from baseline (-7.3 mm Hg [-20.6%] and -7.1 mm Hg [-23.3%]) in the younger and older cohorts, respectively; P<.001 for both. CONCLUSION: Dorzolamide was generally well tolerated and demonstrated efficacy for up to 3 months in patients younger than 6 years.

Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression.

The efficacy and safety of a selective NK(1) antagonist, L-759274, was investigated in outpatients with diagnosis of major depressive disorder with melancholic features, following evidence obtained with the novel compound aprepitant that Substance P (NK(1)) antagonists may provide a unique mechanism of antidepressant activity. A randomized, double-blind placebo-controlled study was carried out. Patients, male or female, aged 18-60, scoring >/=25 points on total of first 17 items of 21-item Hamilton Depression Scale (HAMD), and scoring >/=4 (moderately ill) on Clinical Global Impressions-Severity Scale were randomized to oral L-759274 40 mg daily (n=66) or placebo (n=62) for 6 weeks. For patients receiving L-759274, improvement (mean decrease from baseline) in HAMD-17 total score was 10.7 points, compared with a mean 7.8 point improvement in patients receiving placebo (p<0.009). Mean scores for item 1 of HAMD-17 (depressed mood) also improved to a greater extent in the active group compared with the placebo group (0.3 points, p<0.058). Compared with placebo, mean scores on Clinical Global Impressions-Improvement Scale improved significantly by the end of the trial (p=0.009). L-759274 was generally safe and well-tolerated. The incidence of sexual side effects was on par with that observed in patients receiving placebo, and the incidences of gastrointestinal effects were low. Antidepressant actions have now been observed with two different highly selective NK(1) antagonists (aprepitant and L-759274). NK(1) antagonism is a replicated and generally well-tolerated antidepressant mechanism.

Self-Directed Treatment of Intermittent Heartburn: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Evaluation of Antacid and Low Doses of an H(2)-Receptor Antagonist (Famotidine).

BACKGROUND: Heartburn, a common symptom, is self-treated with oral antacids. Efficacy of antacids has not been demonstrated for individual, spontaneous heartburn episodes. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group study of self-directed treatment for episodic heartburn comparing famotidine (FAM) 5, 10, or 20 mg and antacid (11 mEq ANC) to placebo (PBO) during a 4-week period. Twenty-nine US investigators enrolled a total of 565 outpatients, ages 18--81 years (mean 44.1 years) with heartburn but not seeking care for heartburn. Treatment of spontaneous heartburn episodes was permitted as needed, up to twice daily, with self-administered test drug. An open-label, backup antacid was provided to use if test drug did not provide adequate relief. Patients assessed heartburn relief hourly and recorded use of backup antacid. Relief was defined as complete relief of symptoms without the use of backup antacid. RESULTS: The media proportion of episodes relieved was: PBO, 41%; FAM 5 mg, 59%, 0.05 less-than-or-equal p < 0.10; FAM 10 mg, 70%, p < 0.001; FAM 20 mg, 69%, p < 0.001; antacid, 62%, p < 0.05 (p-values versus PBO). Supplemental analyses incorporating time to relief confirmed that famotidine and antacid provided more rapid and more frequent relief than placebo (odds ratio for relief relative to PBO: FAM 5 mg, 1.55, p = 0.003; FAM 10 mg, 1.94, p < 0.001; FAM 20 mg, 2.13, p < 0.001; antacid 1.57, p = 0.003). The tolerability profile was similar with famotidine, antacid, and placebo. CONCLUSIONS: The positive results with antacid demonstrated for the first time the efficacy of antacid in self-treatment of individual heartburn episodes and provided internal validation of this study paradigm. Patients in this study self-medicated effectively using low doses of famotidine on an as needed basis for spontaneous episodes of heartburn.

Efficacy and tolerability of the dorzolamide 2%/timolol 0.5% combination (COSOPT) versus 0.005% (XALATAN) in the treatment of ocular hypertension or glaucoma: results from two randomized clinical trials.

PURPOSE: To compare the efficacy of the fixed dorzolamide 2%/timolol 0.5% combination (COSOPT) versus latanoprost 0.005% (XALATAN). METHODS: Two 3-month, parallel group, randomized, observer-masked and patient-masked, multicentre, clinical trials were performed in patients with ocular hypertension or open-angle glaucoma. Study 1 (n=256) was conducted in the United States and Study 2 (n=288) was conducted in Europe/Israel. Patients could be included whether or not they were currently taking ocular hypotensive therapy, and regardless of the effectiveness of any previous therapy. Patients were washed out from their usual ocular hypotensive medications and then those with a baseline intraocular pressure (IOP) >/= 24 mmHg were randomized to either the dorzolamide/timolol combination eye drops twice daily or latanoprost eye drops once daily in both eyes. Efficacy was assessed by daytime diurnal IOP (the mean of measurements made at 0800, 1000, 1400 and 1600 h). RESULTS: At baseline, the mean daytime diurnal IOP was 26.1 mmHg in the dorzolamide/timolol combination group versus 25.6 mmHg in the latanoprost group in Study 1, and 25.3 mmHg in the dorzolamide/timolol combination group versus 24.7 mmHg in the latanoprost group in Study 2. After 3 months, the mean daytime diurnal IOP was 18.9 mmHg for the dorzolamide/timolol combination versus 18.4 mmHg for latanoprost in Study 1, and 17.4 mmHg for the dorzolamide/timolol combination versus 17.5 for latanoprost in Study 2. The difference between treatments in mean IOP change at 3 months was -0.04 mmHg [95% confidence interval (CI) -0.85, 0.77] in Study 1, and -0.57 mmHg (95% CI -1.31, 0.16) in Study 2. The probability that the true difference lay between -1.5 and 1.5 mmHg, the predefined bounds for equivalence, was >0.950 in both studies. Both treatments were well tolerated over 3 months, although ocular stinging occurred more frequently with the dorzolamide/timolol combination. CONCLUSIONS: The dorzolamide/timolol combination and latanoprost were equally effective at lowering IOP.