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

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 [T_max] during resting with filled bladder: Midodrine 9.3 cmH₂O [95%CI 3.0, 15.5], Duloxetine 24.2 cmH₂O [95%CI 17.9, 30.5], and Reboxetine 44.9 cmH₂O [95% CI 40.2, 52.8] cmH₂O).

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.     

Pubovesical ligament: A separate structure from the urethral supports (“pubo-urethral ligaments”)

The position and mobility of the vesical neck influences not only continence but also the initiation of micturition. During an examination of urethral topography, there appeared to be two structures running from the region around the vesical neck to the pelvic walls which might influence vesical neck function. These structures, the urethral supports (“pubo-urethral ligaments”) and pubovesical ligaments, have previously been considered to be synonymous terms for a single structure. To investigate this disparity, 1,500 serial histologic sections from eight normal cadavers were examined, 28 cadavers were dissected, and whole pelvis cross sections from an embalmed cadaver were studied. Our observations indicate that there are two structures which run from the region around the proximal urethra and vesical neck to attach to the pelvic walls. The pubovesical ligaments are an extension of the detrusor muscle and its adventitia. They attach to the pubic bone and arcus tendineus fasciae pelvis. Their structure suggests that they contract to assist in vesical neck opening but would be poorly suited to provide support for the proximal urethra. The other structures represent the urethral supports (“pubo-urethral ligaments”) which connect the vagina and periurethral tissues to the muscles of the pelvic diaphragm and to the pelvic fasciae. Their structure appears to be adequate to explain urethral support. There are, therefore, two structures running from the tissues around the vesical neck to the pelvic walls. The structure of the pubovesical ligament suggests that it could assist in vesical neck opening, and the urethral supports could determine urethral position.     

Clinical experience with urethral retro-resistance pressure measurement: a prospective pre- and postoperative evaluation in women with stress urinary incontinence

AIMS: To identify possible correlations of urethral retro-resistance pressure (URP) with clinically and urodynamically proven stress urinary incontinence (SUI) and the outcome of anti-incontinence surgery. MATERIALS AND METHODS: URP was measured using the Monitorr system in women with clinically and urodynamically proven SUI without prolapse before and after anti-incontinence surgery (colposuspension n = 8, tension-free vaginal tape n = 6, tension-free transobturator tape n = 34). RESULTS: Forty-eight women (mean age 61.8 +/- 8.9 years) were evaluated preoperatively and on average 10 weeks postoperatively. Mean URP was 75.6 +/- 20.8 cm H(2)O preoperatively versus 75.4 +/- 17.9 cm H(2)O postoperatively (P = 0.898). The type of anti-incontinence surgery performed had no significant effect on postoperative URP. While no association was found between age and URP (P = 0.35), there was a positive correlation between URP and body mass index (BMI; r = 0.49, P = 0.0004). There was no correlation of URP with the preoperative pad test (P = 0.17) and urethral closure pressure at rest (P = 0.51). Finally, URP did not correlate significantly with the preserved length of the continence zone (0-1/3-2/3-3/3) as determined by the urethral stress profile (P = 0.37-0.72) or with the objective cure rate (negative pad test). CONCLUSIONS: Preoperative URP does not correlate with SUI in all women, has no predictive value, and does not correlate with the outcome of anti-incontinence surgery. However, there seems to be an association with biomechanical factors such as obesity, which may open up a new area of application for URP measurement in urogynecologic diagnosis.     

Effect of voluntary attention on urethral pressure

We have systematically and simultaneously recorded vesical pressure and maximum urethral closure pressure (MUCP) in 109 women consulting for urinary incontinence over an extended period of time. During the recording, we asked them to peform a mental calculation (MC) test and other tests designed to induce an effort of voluntary attention. We found a significant increase in MUCP during the MC. At rest, 57 women displayed urethral pressure variations (UPV) higher than 15 cm H₂O. MC inhibited UPV in 80% of these cases. Such variations have never yet been reported. The effect of MC can be compared to an orienting reaction, which normally increases the sympathetic tonus. The role of the smooth and striated muscle fibers of the urethra, in the observed changes in urethral pressure, is discussed in light of the literature data.     

A comparison of the cough and standing urethral pressure profile in the diagnosis of stress incontinence

Controversy over the accuracy of the urethral pressure profile (UPP) and its role in the diagnosis of stress urinary incontinence (SUI) is unresolved. Different UPP methods and techniques have been introduced. In this study, we examined 78 female patients with mixed symptoms of stress and urge incontinence. Each had a history, physical examination, cystoscopy, and urodynamic assessment, which consisted of a cystometrogram (CMG), UPP (supine and standing), and “cough profile” by the Brown and Wickham (BW) method and also UPP (supine) and “cough profile” with the microtip transducer (MTT). The final diagnosis in 38 patients was SUI (group I) and in 40 patients, no SUI (group II). The maximum urethral closure pressure (MUCP) supine and standing was significantly lower in group I, but there was no significant difference between the two groups in the transmission index (TI) of the “cough profile.” MUCP standing showed the least overlap between the two groups, and with a cutoff point at 40 cm H₂O, the overall diagnostic accuracy was 69%, with 39% sensitivity and 98% specificity. By combining MUCP supine and standing and using cutoff points at 40 cm H₂O and 35 cm H₂O, respectively, the overall diagnostic accuracy was 72%, with 47% sensitivity and 95% specificity. We believe that the UPP is a useful ancillary tool in the assessment of complicated cases of urinary incontinence in the female.     

Urethral retro-resistance pressure: a new clinical measure of urethral function

AIMS: The urethral retro-resistance pressure (URP) is a new retrograde measurement of urethral function. URP is the pressure required to achieve and maintain an open sphincter. The assessment of any potential diagnostic measure must include an evaluation in individuals both with and without disease. In this study, we examined URP values in women without urinary incontinence. METHODS: Four centers enrolled 61 women who did not report symptoms of urinary incontinence, and who had negative standing stress tests (SST). Each center was to perform three consecutive URP measurements on each subject. At two centers, 32 subjects returned in 3-7 days for three additional URP measurements. We compared the average URP in this asymptomatic population to the average URP from women symptomatic of stress urinary incontinence (SUI) derived from a previous study. We evaluated the within-subject variation of the URP measurement at a single visit and the within-subject change in URP over time using test and retest values. RESULTS: The mean age was 33 +/- 9 years and the mean body mass index (BMI) was 24 +/- 6. URP values were normally distributed. The mean URP at visit 1 was 112.6 +/- 39.2 cm H2O (n = 60). This was statistically significantly different from the mean URP of symptomatic women (69.9 cm H2O, P < 0.0001). The within-subject standard deviation of URP at visit 1 was 12.6 +/- 12.6 cm H2O (n = 60) and at retest visit was 9.3 +/- 6.2 cm H2O (n = 32). For the retest cases, the mean URP at visit 1 was 113.9 +/- 39.9 cm H2O (n = 32) and at retest visit was 125.5 +/- 33.9 cm H2O (n = 32) (Wilcoxon Signed Rank test, P = 0.145). CONCLUSIONS: The mean URP measurement obtained in this study of asymptomatic women showed significantly higher values when compared to our study in women with SUI. The URP measurements were consistent within the same subject. Furthermore, there was no statistically significant difference in the URP measurement from visit 1 to retest visit. The data suggest that URP shows promise as a physiological urethral pressure measurement.     

Clinical significance of axial variations in female urethral pressure profiles

It has been demonstrated that when urethral pressure profiles are measured with microtip transducers on relatively stiff catheters, there is an important difference in the profile when measured with the transducers facing anteriorly and posteriorly. It has been suggested that patients with demonstrable genuine stress urinary incontinence had notably lower posteriorly derived urethral pressure profiles than anteriorly derived pressure profiles. A clinical consideration of this factor has been studied in 25 patients; 19 had accepted urodynamic evidence of genuine stress urinary incontinence and 6 did not. The use of posteriorly derived pressure profiles in comparison with anteriorly derived as a test for genuine stress urinary incontinence showed a sensitivity of 84% and specificity of only 33.3%. However, when correlated with patients showing lack of anatomic support of vaginal and paraurethral structures, the sensitivity and specificity is significant. Anatomic considerations leading to these findings are suggested.     

Mid‐urethral synthetic slings in the treatment of urodynamic female stress urinary incontinence without concomitant pelvic prolapse repair: 4‐year health‐related quality of life outcomes

Study Type – Therapy (outcomes research)
Level of Evidence 2c

OBJECTIVE

To report 4‐year health‐related quality of life (HRQL) outcome data after retropubic mid‐urethral synthetic sling (MUS) surgery without concomitant prolapse repair for treating female stress urinary incontinence (SUI) in a single institution.

PATIENTS AND METHODS

The data were prospectively collected, which yielded 21 consecutive patients with a mean (range) age of 67.6 (41–81) years who underwent retropubic MUS with ≥4 years follow‐up. Before surgery, all patients underwent history, examination, pad usage, and multichannel fluoroscopic urodynamics according to International Continence Society standards. In all, 19 patients had urethral hypermobility with an abdominal leak‐point pressure (ALPP) of >90 cmH₂0 and two had intrinsic sphincter deficiency with an ALPP of <60 cmH₂0. The MUS were all placed under no tension. All patients were cystoscoped with both 30 and 70° lens at the end of the procedure with a fully distended bladder to exclude bladder or urethral injury. The validated Kings Health Questionnaire (KHQ) was used both before and after surgery to assess HRQL measures. All patients were assessed at 3 months, and then at least three times thereafter.

RESULTS

The paired Student’s t‐test was used on the mean KHQ scores before and after MUS surgery (4 years follow‐up). There were statistically significant improvements in all nine domains on the KHQ between preoperative and 3 months after MUS surgery (P < 0.01), with the most significant being in ‘General Health Perceptions’, ‘Incontinence Impact’, ‘Physical Limitations’, and ‘Role Limitations’. Improvement in HRQL persisted up to 4 years in all domains. Bladder perforation occurred in two patients with uneventful resolution. Two patients required very short‐term catheterization (<5 days). In the present series, there was no sling revision, division, infection or erosion. No patients developed de novo urgency or urge UI after MUS surgery. The pad‐free rate in the present series was 85.7%.

CONCLUSION

In our institution, HRQL improvement at 3 months after retropubic MUS surgery predicts persistence of improvement at 4 years. This is useful clinically in counselling our patients for treatment efficacy. Tension‐free placement is associated with minimal risk of postoperative retention or de novo overactive bladder. Although patient numbers are modest, these data contribute to the scarce longer term (≥4 years) HRQL data on the MUS, which is a safe and durable procedure with a minimal complication profile.     

自制可调TVT吊带术后腹压漏尿点压和最大尿道闭合压变化分析

目的观察自制可调TVT吊带术后腹压漏尿点压(VLPP)和最大尿道闭合压(MCP)变化,探讨自制TVT吊带临床效果。方法女性压力性尿失禁患者134例,术前行尿流动力学检查测定VLPP、MCP,行自制TVT吊带手术治疗后随访患者再次检测VLPP和MCP,分析检查结果。结果按照世界尿控协会(ICS)标准有39例患者未检出VLPP,剩余95例患者VLPP手术前为(77.2±21.6)cm H2O(1cm H2O=0.098 k Pa),手术后为(99.7±26.3)cm H2O,二者比较差异具有统计学意义(P<0.05)。MCP手术前(32.5±14.3)cm H2O,手术后(57.2±13.3)cm H2O,二者差异具有统计学意义(P<0.05)。结论自制TVT吊带术后可以取得较满意的手术效果,并具有灵活的术后调整性,较传统手术具有自身优势。     

Urethral instability: Diagnosis based on variations of the maximum urethral pressure in normal climacteric women

The existence of urethral instability as a pathological entity is debated, and this discussion is hampered by the lack of rational guidelines for its diagnosis. The literature is not uniform, as different authors have chosen arbitrary values of urethral pressure fluctuations for characterizing the condition. To attempt to clarify the situation, 85 healthy climacteric women have been examined. They had normal flow rates and were found to be normal on videocystourethrography. Their urethral pressure profile traces (microtransducer technique) were examined for fluctuations in the maximum urethral pressure (MUP). Given that the MUP decreases with age and that in this data set fluctuation in the MUP (Δ MUP) is dependent upon the MUP, the ratio of Δ MUP divided by MUP has been examined. Statistical analysis of the derived distribution suggests that fluctuations of MUP that are greater than one-third of the resting MUP fall outside the 99% confidence limit and so should be regarded as abnormal. If, when this occurs, the patient is regarded as having urethral instability, then the incidence of urethral instability in our normal climacteric women is 14 ± 4%. We suggest that this method of analysis should be employed to arrive at a rational statistical threshold for the diagnosis of urethral instability. Only then will it be possible to explore the clinical implications of this condition.