Unoprostone as adjunctive therapy to timolol: a double masked randomised study versus brimonidine and dorzolamide.

AIMS: To compare the safety and efficacy of unoprostone, brimonidine, and dorzolamide as adjunctive therapy to timolol in patients with primary open angle glaucoma or ocular hypertension. METHODS: This was a randomised, double masked, parallel group, multicentre (14) study. After using timolol maleate 0.5% monotherapy twice a day for 2 weeks, patients (n = 146) with an early morning intraocular pressure (IOP) between 22 and 28 mm Hg, inclusively, received unoprostone isopropyl 0.15% (n = 50), brimonidine tartrate 0.2% (n = 48), or dorzolamide hydrochloride 2.0% (n = 48) twice daily as adjunctive therapy to timolol maleate 0.5% for another 12 weeks. Safety was based on comprehensive ophthalmic examinations, adverse events, and vital signs. Efficacy was based on mean change from baseline in the 8 hour diurnal IOP at week 12. Baseline was defined as values obtained after 2 weeks of timolol monotherapy. RESULTS: Each drug was safe and well tolerated. Burning/stinging was the most common treatment emergent adverse event. No clinically relevant changes from baseline were observed for any ophthalmic examination or vital signs. At week 12, each adjunctive therapy produced statistically significant (p<0.001) reductions from timolol treated baseline in the mean 8 hour diurnal IOP (-2.7 mm Hg, unoprostone; -2.8 mm Hg, brimonidine; -3.1 mm Hg, dorzolamide). The extent of IOP reduction did not differ significantly between unoprostone and either brimonidine (p = 0.154) or dorzolamide (p = 0.101). CONCLUSION: Unoprostone was safe and well tolerated and provided a clinically and statistically significant additional reduction in IOP when added to stable monotherapy with timolol. Furthermore, unoprostone was not significantly different from brimonidine and dorzolamide as adjunctive therapy to timolol.

The effects of unoprostone isopropyl 0.12% and timolol maleate 0.5% on diurnal intraocular pressure.

PURPOSE: To compare the effect of unoprostone isopropyl 0.12% to that of timolol maleate 0.5% solution given twice daily on the diurnal curve of intraocular pressure (IOP) in patients with primary open-angle glaucoma or ocular hypertension. METHODS: In this investigator-masked, single-center, parallel-group comparison, 36 patients with primary open-angle glaucoma or ocular hypertension were randomized in a 2:1 ratio to receive either unoprostone isopropyl 0.12% or placebo/timolol maleate 0.5% solution, respectively. A placebo-controlled diurnal curve on day 0 and active-controlled diurnal curves at weeks 2 and 4 were performed at 0, 2, 4, 6, 8, 10, 12, and 24 hours. At week 2, administration of unoprostone isopropyl twice daily was compared with administration of timolol maleate twice daily. At week 4, administration of unoprostone isopropyl three times daily was compared with administration of timolol maleate twice daily. RESULTS: At the 24-hour 8:00 AM trough at week 2, administration of unoprostone isopropyl twice daily decreased IOP from 23.4 +/- 2.0 mmHg at baseline to 19.3 +/- 4.4 mmHg, and timolol maleate reduced IOP from 24.4 +/- 2.6 mmHg to 17.5 +/- 2.9 mmHg. At the 8:00 AM trough at week 4, unoprostone isopropyl given three times daily produced an IOP of 19.6 +/- 3.3 mmHg and timolol maleate resulted in an IOP of 19.4 +/- 3.0 mmHg. No statistical differences between groups were observed at any time point during either diurnal curve. Safety was similar in the two treatment groups, with no differences between groups in conjunctival hyperemia, anterior segment inflammation, or iris color change. CONCLUSION: Results of this short-term pilot trial indicate that unoprostone isopropyl may be safe and effective in reducing IOP from baseline when given twice or three times daily.

Suicidal risk during controlled clinical investigations of fluvoxamine.

BACKGROUND: Suicide is a serious risk factor in major depressive disorder. Paradoxical emergence of suicidal ideation or behavior during antidepressant treatment has been reported in isolated cases. An evaluation was undertaken to assess the risk of suicidality during treatment with fluvoxamine, a serotonin selective reuptake inhibitor. METHOD: Meta-analyses were conducted on pooled data from double-blind, randomized, placebo-controlled, parallel-group clinical trials. The primary outcome measure was the suicide item of the Hamilton Rating Scale for Depression. Tests for emergence of substantial suicidal ideation and improvement or worsening in suicidal ideation were performed using the Mantel-Haenszel adjusted incidence difference. The Breslow-Day test was used to test for lack of homogeneity across trials. Secondary analysis, which consisted of Pearson's chi-square test, was used to confirm the Mantel-Haenszel result. RESULTS: In comparison to placebo, fluvoxamine was associated with significantly greater improvement in suicidal ideation (p = .01) and significantly less worsening of suicidal ideation (p < .01). No differences were found in the emergence of substantial suicidal ideation. CONCLUSION: These findings demonstrate that fluvoxamine is not associated with an increased risk of emergence of substantial suicidal thoughts among depressed patients. On the contrary, the results are suggestive of a protective effect of fluvoxamine upon the risk of suicidal ideation.

Fluvoxamine versus imipramine and placebo: a double-blind comparison in depressed patients.

Approximately 20 million patients suffer from major depressive disorder each year, indicating a need for antidepressant agents that are synonymous with effectiveness, tolerability and patient compliance. The authors examined the effects of fluvoxamine, a selective serotonin reuptake inhibitor, in the treatment of outpatients meeting DSM-III-R criteria for major depressive disorder. A randomized, double-blind, parallel group, placebo- and imipramine-controlled single center study was conducted in 150 outpatients. Patients were randomized to receive up to 150 mg/day of fluvoxamine as a single bedtime dose, 240 mg/day of imipramine on a twice-daily (BID) schedule, or placebo for six weeks. Efficacy measurements included HAM-D, MADRS, CGI, Raskin-Covi and SCL-56 scales. The HAM-D total score indicated that both active treatment groups showed significantly (p < or = 0.05) greater therapeutic benefit than did placebo. Severely depressed patients (HAM-D > or = 30) responded better to fluvoxamine in five of six measures. Side-effects from fluvoxamine were similar to those reported for other selective serotonin reuptake inhibitors (nausea, somnolence) and were well tolerated. Imipramine was associated with anticholinergic effects such as dry mouth and dizziness. The pharmacokinetic properties of fluvoxamine which allow the drug to be administered as a single daily dose should aid in the maintenance of patient compliance, while offering significant clinical benefit in the improvement of depressive symptoms.

Modification of the error-rate bounded classification scheme for use with two MIC break points.

In antimicrobic susceptibility testing, minimum inhibitory concentration (MIC) susceptibility break points are defined by correlation of bacteriologic-clinical outcome data with MIC data for the infecting organisms. Disk diffusion [that is, zone-diameter (Z)] correlates are then established that provide for the prediction of organism susceptibility, while misclassification errors are kept to a minimum. The determination of Z break points through an error-rate-bounded classification scheme was first proposed by Metzler and DeHaan (1972). This method involves one MIC break point that separates susceptible and resistant strains. More recently, researchers have preferred to use two MIC break points (susceptible and resistant) that separate susceptible, moderately susceptible, and resistant strains. There is no known methodology for determining the Z break points for this latter situation, other than enumerating solutions for all feasible Z break-point pairs and choosing among the results. Our interest lay in presenting a methodology for determining the Z break points once the MIC break points are established. By deriving an index as a function of Z break points, a search method for finding the optimal Z break points is given. For the data set examined, our index interval solution required only a small percentage of solutions to be examined.