The effect of single oral doses of duloxetine, reboxetine, and midodrine on the urethral pressure in healthy female subjects, using urethral pressure reflectometry

TY - JOUR

T1 - The effect of single oral doses of duloxetine, reboxetine, and midodrine on the urethral pressure in healthy female subjects, using urethral pressure reflectometry

AU - Klarskov, Niels

AU - Cerneus, Dirk

AU - Sawyer, William

AU - Newgreen, Donald

AU - van Till, Olivier

AU - Lose, Gunnar

N1 - © 2017 Wiley Periodicals, Inc.

PY - 2018/1

Y1 - 2018/1

N2 - AIMS: To evaluate the effect on urethral pressure of reference drugs known to reduce stress urinary incontinence symptoms by different effect size and mechanisms of action on urethral musculature under four test conditions in healthy female subjects using urethral pressure reflectometry.METHODS: Healthy females aged 18-55 years were recruited by advertising for this phase 1, single site, placebo-controlled, randomized, four-period, crossover study. The interventions were single oral doses of 10 mg Midodrine, 80 mg Duloxetine, 12 mg Reboxetine, and placebo. The endpoints were the opening urethral pressure measured in each period at four time points (predose and 2, 5.5, and 9 h after dosing).RESULTS: Twenty-nine females were enrolled; 25 randomized and 24 completed the study. The opening urethral pressure was higher in all measurements with filled bladder compared with empty bladder, and during squeezing compared to the resting condition. All three drugs increased the opening urethral pressure during all four conditions with a ranking of their effect on urethral pressure matching their reported clinical effect (difference vs. placebo at their reported time of peak plasma concentrations [Tmax ] during resting with filled bladder: Midodrine 9.3 cmH2 O [95%CI 3.0, 15.5], Duloxetine 24.2 cmH2 O [95%CI 17.9, 30.5], and Reboxetine 44.9 cmH2 O [95% CI 40.2, 52.8] cmH2 O).CONCLUSIONS: Urethral pressure reflectometry is capable of detecting drug-induced changes in urethral tone in various conditions. The magnitude of drug-induced changes by the test drugs seems to match their clinical profile and differences in mode of action.

AB - AIMS: To evaluate the effect on urethral pressure of reference drugs known to reduce stress urinary incontinence symptoms by different effect size and mechanisms of action on urethral musculature under four test conditions in healthy female subjects using urethral pressure reflectometry.METHODS: Healthy females aged 18-55 years were recruited by advertising for this phase 1, single site, placebo-controlled, randomized, four-period, crossover study. The interventions were single oral doses of 10 mg Midodrine, 80 mg Duloxetine, 12 mg Reboxetine, and placebo. The endpoints were the opening urethral pressure measured in each period at four time points (predose and 2, 5.5, and 9 h after dosing).RESULTS: Twenty-nine females were enrolled; 25 randomized and 24 completed the study. The opening urethral pressure was higher in all measurements with filled bladder compared with empty bladder, and during squeezing compared to the resting condition. All three drugs increased the opening urethral pressure during all four conditions with a ranking of their effect on urethral pressure matching their reported clinical effect (difference vs. placebo at their reported time of peak plasma concentrations [Tmax ] during resting with filled bladder: Midodrine 9.3 cmH2 O [95%CI 3.0, 15.5], Duloxetine 24.2 cmH2 O [95%CI 17.9, 30.5], and Reboxetine 44.9 cmH2 O [95% CI 40.2, 52.8] cmH2 O).CONCLUSIONS: Urethral pressure reflectometry is capable of detecting drug-induced changes in urethral tone in various conditions. The magnitude of drug-induced changes by the test drugs seems to match their clinical profile and differences in mode of action.

U2 - 10.1002/nau.23282

DO - 10.1002/nau.23282

M3 - Journal article

C2 - 28419624

SN - 0733-2467

VL - 37

SP - 244

EP - 249

JO - Neurourology and Urodynamics

JF - Neurourology and Urodynamics

IS - 1

ER -