A randomized crossover study to evaluate Ro 115-1240, a selective alpha1A/1L-adrenoceptor partial agonist in women with stress urinary incontinence.

OBJECTIVES: To investigate the potential therapeutic benefits of the selective alpha1A/1l-adrenoceptor partial agonist Ro 115-1240 in women with mild-to-moderate stress urinary incontinence (SUI). PATIENTS AND METHODS: Thirty-seven women with mild-to-moderate SUI were enrolled in a randomized, placebo-controlled crossover study. Patients received 1.5 mg Ro 115-1240 twice daily or matching placebo for 2 or 4 weeks. Voiding diaries were used to record the number of SUI episodes, urge incontinence episodes and pads used. Sitting blood pressures and heart rate were recorded at each visit. RESULTS: Ro 115-1240 was associated with a significantly lower mean weekly number of SUI episodes than placebo (8.4 vs 6.0; P= 0.0079), a 28% relative improvement over placebo. There was also a significantly lower mean number of pads used and wet pads changed/week with Ro 115-1240 than with placebo (P = 0.0055 and 0.0066, respectively). The most frequently reported treatment-emergent adverse events were scalp tingling, headache, chills, piloerection, and pruritus. Generally these events were transient and mild to moderate. There was a slightly lower mean sitting heart rate with Ro 115-1240 than with placebo, but no difference in mean systolic or diastolic blood pressure between treatments. CONCLUSIONS: This study suggests that selective alpha1A/1l-adrenoceptor partial agonists have the potential to improve the symptoms of SUI with little or no cardiovascular effect. These results are encouraging and a randomized controlled trial of Ro 115-1240 in a larger population with SUI is warranted to substantiate these findings.

Effect of meal timing not critical for the pharmacokinetics of tegaserod (HTF 919).

This study assessed the pharmacokinetic profiles of administering tegaserod (HTF 919) at different time intervals with respect to a meal. It was a randomized, open-label, two-phase, five-period crossover study. In the first phase, 18 healthy subjects received a single 12 mg oral dose of tegaserod administered either 30 or 15 minutes prior to the start of the 600-calorie, fat-rich breakfast. In the second phase, subjects received a single 12 mg oral dose of tegaserod 1 minute before, 2.5 hours after the start of meal, or with a continued 4-hour postdose fast. Safety assessment and plasma samples for the determination of drug concentration were obtained for 24 hours postdose. Noncompartmental analysis results indicated that the AUC of tegaserod was reduced by almost half under fed conditions compared to the fasted condition. Exploratory analyses were implemented to further investigate the absorption characteristics of tegaserod under different fed conditions. A numerical deconvolution approach was used to obtain the tegaserod oral absorption versus time profiles under both fasted and fed conditions. The tegaserod oral absorption versus time profiles were then fitted by NONMEM to a model containing two absorption phases. Based on the absorption analyses, we found that the reduction in the bioavailability of tegaserod under fed conditions was primarily due to a decrease in the extent of absorption and less so to a decrease in the absorption rate(s). Therefore, although the timing of administration of food does not appear to significantly alter the pharmacokinetics of tegaserod, the administration of food reduces the AUC by approximately 50%.

Lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with lamivudine and zidovudine administered concurrently and the effect of food on absorption.

A single-center, open-label, three-way crossover study was conducted in 24 healthy subjects to assess (1) the bioequivalence of a combined lamivudine 150 mg/zidovudine 300 mg tablet relative to the separate brand-name components administered concurrently and (2) the effect of food on the bioavailability of the drugs from the combination tablet. The subjects were randomly assigned to receive each of the following three treatments, separated by a 5- to 7-day washout period: one lamivudine/zidovudine combination tablet after an overnight fast, one lamivudine 150 mg tablet and one zidovudine 300 mg tablet simultaneously after an overnight fast, or one lamivudine/zidovudine combination tablet 5 minutes after completing a standardized high-fat breakfast (67 g fat, 58 g carbohydrate, and 33 g protein). Serial blood samples were collected up to 24 hours postdose for the determination of lamivudine and zidovudine plasma concentrations. Standard pharmacokinetic parameters were estimated. Treatments were considered bioequivalent if 90% confidence intervals for the ratio of least squares (LS) means for the lamivudine and zidovudine area under the plasma concentration-time curve (AUC infinity) and maximum observed plasma concentration (Cmax) fell entirely within 0.80 to 1.25 for log-transformed parameters. The combined lamivudine/zidovudine tablet was bioequivalent in the extent (AUC infinity) and rate of absorption (Cmax and time of Cmax [tmax]) to the individual brand-name drug components administered concurrently under fasted conditions. Geometric LS mean ratios and 90% confidence intervals for AUC infinity and Cmax were 0.97 (0.92, 1.03) and 0.94 (0.84, 1.06), respectively, for lamivudine and 0.99 (0.91, 1.07) and 0.97 (0.82, 1.15), respectively, for zidovudine. The extent of absorption of lamivudine and zidovudine from the combination tablet was not altered by administration with meals, indicating that this formulation may be administered with or without food. However, food slowed the rate of absorption, delayed the tmax, and reduced the Cmax of lamivudine and zidovudine. These changes were not considered clinically important. All formulations were well tolerated under fasted and fed conditions.