ABSTRACT
Objectives: This analysis evaluated the long-term safety, tolerability and efficacy of darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder ...(OAB) in patients ≥ 65 years of age.
Methods: Patients who completed one of two 12-week, placebo-controlled, double-blind, feeder studies received once-daily (o.d.) treatment with darifenacin 7.5 mg for the first 2 weeks of the 2-year, open-label extension study. The dose could be subsequently adjusted (7.5 or 15 mg o.d.) according to need. Safety and tolerability were assessed, and efficacy variables/endpoints were evaluated from patient diary data.
Results: 214 patients (65–89 years) entered and 137 (64.0%) completed the 2-year extension study, amounting to 308 patient-years’ drug exposure. Darifenacin was well tolerated with no new safety concerns. The most common adverse events (AEs) were dry mouth and constipation, which infrequently resulted in discontinuation (2.3% and 4.2%, respectively). Darifenacin produced significant improvements in OAB symptoms that were maintained over the 2-year period (median reduction from feeder-study baseline to 2 years: –11.0 –83.7% for incontinence episodes/week and –1.2 –12.4% for micturitions/day, both p < 0.05), with 44.4% patients achieving ≥ 90% reduction in incontinence episodes at 2 years.
Conclusions: Darifenacin demonstrated good tolerability and safety in older patients with OAB. The improvement in OAB symptoms was sustained throughout the 2-year extension, resulting in high treatment persistence rates. Results were comparable with those in the overall OAB population from this study, indicating that darifenacin treatment is effective and well tolerated irrespective of age.
This study evaluated the efficacy, tolerability, and safety of darifenacin, an M3 selective receptor antagonist (M3 SRA), in patients with overactive bladder (OAB). In a multicenter, double-blind, ...placebo-controlled dose-ranging study, 439 adult OAB patients (85.4% female) were randomized to darifenacin controlled-release tablets 7.5 mg (n = 108), 15 mg (n = 107) or 30 mg (n = 115) qd, or placebo (n = 109) for 12 weeks. Darifenacin significantly reduced the median number of incontinence episodes/week (-68.7, -76.5, and -77.3% from baseline at 7.5, 15, and 30 mg, respectively, vs -46% with placebo, all p < 0.01) and dose relatedly improved micturition frequency, frequency and severity of urgency, nocturia, and bladder capacity. Darifenacin was well tolerated. Adverse events were commonly mild to moderate dry mouth and constipation. There were no safety concerns. Darifenacin is effective and well tolerated in the treatment of OAB, with 7.5 and 15 mg doses offering flexibility of dosing for optimal treatment outcome.
Purpose
Venous thromboembolism (VTE) is a frequent and serious problem in intensive care units (ICU). Anticoagulant treatments have demonstrated their efficacy in preventing VTE. However, when the ...bleeding risk is high, they are contraindicated, and mechanical devices are recommended. To date, mechanical prophylaxis has not been rigorously evaluated in any trials in ICU patients.
Methods
In this multicenter, open-label, randomized trial with blinded evaluation of endpoints, we randomly assigned 407 patients with a high risk of bleeding to receive intermittent pneumatic compression (IPC) associated with graduated compression stockings (GCS) or GCS alone for 6 days during their ICU stay. The primary endpoint was the occurrence of a VTE between days 1 and 6, including nonfatal symptomatic documented VTE, or death due to a pulmonary embolism, or asymptomatic deep vein thrombosis detected by ultrasonography systematically performed on day 6.
Results
The primary outcome was assessed in 363 patients (89.2 %). By day 6, the incidence of the primary outcome was 5.6 % (10 of 179 patients) in the IPC + GCS group and 9.2 % (17 of 184 patients) in the GCS group (relative risk 0.60; 95 % confidence interval 0.28–1.28;
p
= 0.19). Tolerance of IPC was poor in only 12 patients (6.0 %). No intergroup difference in mortality rate was observed.
Conclusions
With the limitation of a low statistical power, our results do not support the superiority of the combination of IPC + GCS compared to GCS alone to prevent VTE in ICU patients at high risk of bleeding.
Vaccines based on conserved pneumococcal proteins are being investigated because serotype coverage by pneumococcal polysaccharide and polysaccharide conjugate vaccines is incomplete and may ...eventually decrease due to serotype replacement. Here, we examined the functionality of human antibodies induced by a candidate bivalent choline-binding protein A- pneumococcal histidine triad protein D (PcpA-PhtD) vaccine. Pre- and post-immune sera from subjects who had been vaccinated with the PcpA-PhtD candidate vaccine were tested in an established passive protection model in which mice were challenged by intravenous injection with Streptococcus pneumoniae serotype 3 strain A66.1. Serum antibody concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Bacterial surface binding by serum antibodies was determined by a flow cytometry-based assay. Sera from 20 subjects were selected based on low activity of pre-immune samples in the passive protection model. Bacterial surface binding correlated more strongly with anti-PcpA (0.87; p < 0.0001) than with anti-PhtD (0.71; p < 0.0001). The odds ratio for predicting survival in the passive protection assay was higher for the anti-PcpA concentration (470 95% confidence interval (CI), 46.8 to >999.9) than for the anti-PhtD concentration (3.4 95% CI, 1.9 to 5.6) or bacterial surface binding (9.4 95% CI, 3.6 to 24.3). Pooled post-immune serum also protected mice against a challenge with S. pneumoniae serotype 3 strain WU2. Both anti-PcpA and anti-PhtD antibodies induced by the bivalent candidate vaccine mediate protection against S. pneumoniae. The results also showed that the ELISA titer might be useful as a surrogate for estimating the functional activity of antibodies induced by pneumococcal protein vaccines.
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