W 34: Urodynamic Measurement of Urethral Closure Function in Healthy Japanese Women: A Single Dose Study of Duloxetine
SOUSEIKAI Global Clinical Research Center Japan
This urodynamic study in healthy Japanese women was performed to evaluate the effects of duloxetine, the SNRI for urethral function, and to determine an appropriate method for making go/no-go decisions in early drug development to treat stress urinary incontinence (SUI).
ORAL PRESENTATION SCHEDULED: Session 2B at 1:20 - 1:30 PM
The urethral pressure profiles at rest and the motor threshold (MT) for urethral sphincter contraction in response to transcranial magnetic stimulation (TMS) were measured before and 6h after the administration of 40 mg duloxetine in 10 healthy female subjects (Ages: 20 to 55 years old).
The demographics of female subjects in this study had a mean age of 21.6 years and a mean body mass index of 19.4 kg/m2. The procedures were well tolerated by all subjects. A single oral dose of duloxetine significantly increased the mean and maximal urethral closure pressure at rest calculated over the entire urethra. When the functional urethral length was divided into three sections, duloxetine significantly increased the mean and maximal urethral closure pressure at rest over the proximal and middle-third of the urethra. The individual MTs for urethral sphincter contraction in response to TMS were determined as the minimum intensity that produced urethral pressure spikes and were expressed as a percentage of maximum stimulator output. None of the subjects reported any pain or discomfort during magnetic stimulation at the midline over the cranial motor cortex. The individual MTs for urethral sphincter contraction in response to TMS were able to be determined in all subjects at both baseline and follow-up with duloxetine. An oral administration of duloxetine significantly lowered the MT in response to TMS (61.5% vs. 72.0%, p = 0.02).
Pharmacological targets for the treatment of SUI include adrenergic receptors in the urethral smooth muscle and serotonergic receptors in the spinal cord. Thus many new drugs, specifically designed for these receptors, are currently under development for SUI. In this urodynamic study, urethral closure pressure at rest was measured to evaluate the drug effects on urethral smooth muscle. Furthermore, because the nerve endings from the central nervous system terminate at Onuf’s nucleus and synapse with the pudendal nerve, the MTs in response to TMS were determined in healthy Japanese female subjects for evaluation of drug effects on Onuf’s nucleus in the spinal cord. Our data indicated the facilitatory effects of duloxetine, a serotonin and noradrenaline reuptake inhibitor, on the noradrenergic pathway-mediated smooth muscle functions and the contractions of the urethral striated sphincters via Onuf's nucleus. It is thus reasonable that the proposed method is potentially useful to reduce the attrition rate by providing decision-making data in early clinical studies of new drugs being developed to treat SUI.