A first-in-human study of PDC31 (prostaglandin F2α receptor inhibitor) in primary dysmenorrhea.

STUDY QUESTION: What is the safe and pharmacodynamically active dose range for PDC31 (prostaglandin F2α receptor inhibitor) in patients with primary dysmenorrhea (PD)? SUMMARY ANSWER: The 1 mg/kg/h dose of PDC31 appears to be safe and potentially effective in reducing intrauterine pressure (IUP) and pain associated with excessive uterine contractility when given as a 3-h infusion in patients with PD. WHAT IS KNOWN ALREADY: PDC31 has previously been shown to reduce the duration and strength of PGF2α-induced contractions in human uterine myometrial strip models and to delay delivery in animal models of preterm labor. STUDY DESIGN, SIZE, DURATION: This was a prospective, multi-center, dose-escalating first-in-human Phase I study conducted from March 2011 to June 2012. A total of 24 women with PD were enrolled and treated with one of five doses (0.01, 0.05, 0.15, 0.3, 0.5 and 1 mg/kg/h) of PDC31 given as a 3-h infusion. Patients were observed for a further 24 h. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted at four hospitals in Europe in non-pregnant, menstruating women with PD. Women with PD (n = 24) received PDC31 infused over 3 h within 8-10 h of the onset of menstruation. IUP and pain monitoring through the visual analog scale (VAS) was assessed prior to, during and following the infusion. Patients were observed for dose-limiting toxicities and other adverse events. Pharmacokinetic samples were also taken to profile the drug. MAIN RESULTS AND THE ROLE OF CHANCE: A 3-h infusion of PDC31 was safe up to and including doses of 1 mg/kg/h. Most adverse events were mild (n = 15; 83.3%) and not considered associated with PDC31 (n = 14; 77.8%). PDC31 infusion decreased uterine activity based on IUP and pain (VAS) scores. IUP was decreased by 23% over all dose levels, reaching a minimum at 135-150 min. There appeared to be a dose-dependent effect on IUP, with the high dose group (1 mg/kg/h) showing the largest decrease in IUP. There was a statistically significant linear dose-effect and concentration-effect relationship for several IUP parameters over the evaluation period of 60-180 min. A dose differentiating effect on pain was seen with the two highest doses. PDC31 demonstrated uncomplicated, linear pharmacokinetics with a terminal half-life of ∼2 h. LIMITATIONS, REASONS FOR CAUTION: This was a first-in-human study and exposure to PDC31 was limited for safety reasons. As such, pharmacodynamic parameters were assessed at a two-sided Type I error of 20%, an appropriate level for the exploratory nature of this study without a placebo control arm. This limited the chance of false positive findings to one in five. WIDER IMPLICATIONS OF THE FINDINGS: Like PD, preterm labor is associated with prostaglandin-mediated uterine contractions; therefore, the findings of this study support further development of PDC31 as a treatment for both PD and preterm labor. STUDY FUNDING/COMPETING INTERESTS: This work was funded by PDC Biotech GmbH, Vienna, Austria. B.B., R.M.L., L.W., R.J.S., K.J.B. and C.F.S. received reimbursement for the conduct of this study from PDC Biotech GmbH. W.H., M.S. and R.P.S. are paid consultants for PDC Biotech GmbH. P.G. is a paid consultant and shareholder of PDC Biotech GmbH. TRIAL REGISTRATION NUMBER: NCT01250587 at www.clinicaltrials.gov.

Impact of mode of delivery on levator morphology: a prospective observational study with three-dimensional ultrasound early in the postpartum period.

OBJECTIVE: To evaluate morphology and integrity of the levator ani muscle (LAM) with three-dimensional ultrasound early in the postpartum period. DESIGN: Prospective cross-sectional observational study. SETTING: University hospital in Germany. POPULATION: Women after vaginal delivery and caesarean section with no previous vaginal delivery. METHODS: Three-dimensional perineal ultrasound was performed between 48 and 72 hours postpartum. The axial plane at the level of minimal hiatal dimension and tomographic ultrasound imaging were used to determine LAM biometry and defect. MAIN OUTCOME MEASURES: Primary outcome was to compare hiatal dimensions and levator defect following vaginal delivery or caesarean section. For secondary outcomes, we evaluated the role of caesarean section in protecting levator integrity, and the possible involvement of the first stage of labour in LAM changes. RESULTS: In all, 157 women participated: 81 (51.6%) following vaginal delivery (70 spontaneous and 11 operative deliveries) and 76 (48.4%) following caesarean section (55 elective and 21 emergency caesarean sections). All biometric indices of the levator were higher after vaginal delivery (P<0.001), except for LAM thickness. LAM defects were found to be significantly associated with vaginal delivery, with relative risk 7.5 (P<0.001). Following vaginal delivery, 32 (39.5%) levator defects were found: 27 (38.5%) after spontaneous delivery and five (45.4%) after operative delivery. Four (5.2%) women had a levator defect following emergency caesarean section. CONCLUSION: Vaginal delivery modifies and damages the LAM: the risk of levator defect after vaginal delivery is more than seven times higher than after caesarean section. Despite this, emergency caesarean section seems to have no complete preventive effect on LAM trauma.

[Measurement of the infrapubic angle using 3D perineal ultrasound and its relationship to obstetrical parameters]. / Die Messung des infrapubischen Winkels in der 3-D-Perineal-Sonografie und seine Beziehung zu geburtshilflichen Parametern.

PURPOSE: Ultrasound has achieved an indispensable role in urogynecology. The introduction of 3 D technology has enabled sonographers to visualize structures in the axial plane. The angle of the infrapubic arc may enable us to presume the shape of the pelvis. Our aim was to describe a method for measuring the infrapubic angle and the interpubic space with 3 D perineal ultrasound through 3 D rotation, correlating them with the length of the 2nd stage of labor and the rate of levator defects. MATERIALS AND METHODS: Women after vaginal delivery were recruited and underwent a 3 D perineal ultrasound on 2nd - 3 rd day postpartum. Volume datasets were analyzed to measure the infrapubic angle and the interpubic space independently by 2 urogynecologists. The interobserver reliability and the correlation between infrapubic arc angle and the length of the 2nd stage of labor and the occurrence of levator defects were calculated. RESULTS: 110 women were enrolled. With a correlation coefficient of 0.76, the relationship between the infrapubic angle measurements of the two observers was very good. A moderate to good correlation was found for the assessment of the interpubic gap, with r = 0.69. Between the infrapubic angle and length of the 2nd stage of labor, no statistical correlation for both observer measurements (p = 0.31; p = 0.78, respectively) was found. Also the correlation between the infrapubic arc angle and the occurrence of levator avulsions was not significant (p = 0.59; p = 0.39, respectively). CONCLUSION: 3 D ultrasound technology enables us to identify and evaluate the interpubic gap and the infrapubic arc with a high inter-observer reproducibility. However, from our data, the infrapubic angle does not seem to influence the length of the 2nd stage of labor and the occurrence of levator defects.

The IUGA/ICS classification of complications of prosthesis and graft insertion: a comparative experience in incontinence and prolapse surgery.

INTRODUCTION AND HYPOTHESIS: This is a presentation of case series after the use of alloplasic material in urogynaecology. METHODS: From 2004 to 2010, a total 179 patients with complications have been referred directly after the use of alloplastic material in incontinence and prolapse surgery. Of this total, 125 patients had a previous vaginal sling plasty because of urinary stress incontinence, while 54 patients underwent a prolapse surgery with mesh use. Symptoms and findings are expressed by the recently introduced International Urogynecological Association/International Continence Society (IUGA/ICS) terminology. RESULTS: The most frequent findings after vaginal sling plasty were bladder outlet obstruction, pain and tape exposure. The most frequent findings after prolapse surgery were pain and mesh erosion. The IUGA/ICS classification does not give the possibility to express functional disorders. Most revisions were done more than 2 months after surgery. After incontinence surgery, mostly the vaginal area of suture line was affected; after prolapse surgery, the vagina and the trocar passage were affected. CONCLUSIONS: Mesh complication and affected site after prolapse surgery do differ from those after incontinence surgery. The IUGA/ICS classification of mesh complication facilitates the comparison of mesh complication.

Patient goals after incontinence procedures: does the single-incision sling satisfy them?

OBJECTIVE: This study was undertaken to describe short-term postoperative achievement of subjective preoperative goals for single-incision MiniArc slings, in comparison with tension-free vaginal tape (TVT). METHOD: Patients submitted to mid-urethral sling (TVT and MiniArc) procedures for stress urinary incontinence (SUI) in two centers were included in this prospective study. Before surgery, the patients completed a preoperative open-ended questionnaire, in which they described their personal outcomes goals for SUI surgery and the degree of severity of their symptoms. At the first postoperative check, they were asked to assess the degree to which their goals had been met and the degree of postoperative incontinence symptoms; their grade of satisfaction was evaluated with IIQ-7, UDI-6 and a 0-10 visual analog scale. RESULTS: One hundred and eight patients (TVT n=51, MiniArc n=57) were included in this study. Incontinence symptom relief and improvement of quality of life were the most commonly described preoperative goals. Six to eight weeks after surgery, 47 patients (92.1%) after TVT and 53 (92.9%) women after single-incision slings were objectively cured (P=1). After surgery, more than 90% of the patients in both groups achieved their preoperative goals. Symptom scores improved significantly and were comparable in both groups. CONCLUSION: Our results show that self-reported achievement of preoperative goals of patients submitted to single-incision slings are comparable at the first follow-up with patients who have undergone the classic mid-urethral sling.