Oral prucalopride in children with functional constipation.

BACKGROUND AND OBJECTIVES: Prucalopride is a selective, high-affinity 5-HT4 receptor agonist with gastrointestinal prokinetic activities. The aim of this study was to evaluate the pharmacokinetics, efficacy, safety, and tolerability of prucalopride oral solution in children, ages 4 years or older to 12 years or younger, with functional constipation. METHODS: A single oral dose of 0.03 mg/kg prucalopride was administered to 38 children to characterize prucalopride pharmacokinetics (NCT01674166). Thereafter, 37 children entered an open-label extension period in which 0.01 to 0.03 mg/kg of prucalopride was administered once per day for 8 weeks to investigate efficacy, safety, and tolerability (NCT01670669). RESULTS: Mean (standard deviation [SD]) Cmax, tmax, and AUC∞ (area under the plasma concentration-time curve from time 0 to infinity) were 3.8 (0.6) ng/mL, 1.8 (0.9) hour, and 65.3 (10.6) ng · h · mL, respectively, with limited (16%) variability in Cmax and AUC∞. Mean (SD) t1/2 was 19.0 (3.1) hours. On average, mean (SD) renal clearance (0.25 [0.08] L · h · kg) accounted for 54% of the apparent total plasma clearance (0.46 [0.07] L · h · kg). The apparent volume of distribution was 12.6 (2.6) L/kg. Prucalopride treatment resulted in a mean bowel movement frequency of 6.8/week, normal stool consistency, and reduced frequency of fecal incontinence. During the 8-week extension, 70% of study participants had at least 1 adverse event (all but 1 of mild/moderate intensity, 19% considered related to prucalopride). No children discontinued prucalopride because of adverse events. CONCLUSIONS: The pharmacokinetic profile of a single dose of prucalopride oral solution (0.03 mg · kg · day) generally resembled the profile in adults (2-mg tablet) but reflected lower systemic exposure in children. Prucalopride treatment for 8 weeks demonstrated an apparent favorable efficacy and tolerability profile in children with functional constipation.

Endovascular treatment of atherosclerotic lesions in the superficial femoral artery and proximal popliteal artery using the sinus-SuperFlex-635 stent: twelve-month results from the HERO Registry.

BACKGROUND: The aim of this study was to evaluate the safety and performance of the sinus-SuperFlex-635 self-expandable nitinol stent (Optimed GmbH) for the treatment of steno-occlusive lesions in the superficial femoral artery (SFA) and proximal popliteal artery (PPA). METHODS: The prospective, multicenter, observational HERO study recruited 117 eligible patients (83 men; mean age 69.4±9.7y) from 7 centers in Belgium. RESULTS: A total of 129 stents were successfully deployed in 121 lesions in 117 patients (100%). The patients presented with symptomatic ≥50% stenosis or chronic total occlusion (CTO) (30.6%). Mean lesion length was 71.4±56.3 mm. Moderate to severe calcification was present in 82.6% of the lesions. Acute lesion success (<30% residual stenosis) was achieved in 96.0%. There were no in-hospital serious adverse events. Duplex ultrasound-driven primary patency at 12 months was recorded in 84 of 107 (78.5%) lesions. The overall target lesion revascularization (TLR) rate was 8.4% at 12 months; the target extremity revascularization (TER) rate was 4.7%. Clinical assessment at 12 months demonstrated improvement by at least 1 Rutherford class, without the need for TLR (i.e. primary sustained clinical improvement) in 83.9% of patients and with the need for TLR in 90.6% of patients (i.e. secondary sustained clinical improvement). CONCLUSIONS: Based on the high primary patency, low stent fracture rate and significant clinical improvement, combined with refined stent design and long stent availability, the sinus-SuperFlex-635 self-expandable nitinol stent proves its value in the treatment of complex femoropopliteal lesions.

A phase 1 randomized study evaluating the effect of omeprazole on the pharmacokinetics of a novel 5-hydroxytryptamine receptor 4 agonist, revexepride (SSP-002358), in healthy adults.

BACKGROUND: About 30% of patients with gastroesophageal reflux disease continue to experience symptoms despite treatment with proton pump inhibitors. The 5-hydroxytryptamine 4 receptor agonist revexepride (SSP-002358) is a novel prokinetic that stimulates gastrointestinal motility, which has been suggested as a continued cause of symptoms in these patients. The aim of this study was to assess whether revexepride pharmacokinetics were affected by co-administration of omeprazole, in preparation for a proof-of-concept evaluation of revexepride added to proton pump inhibitor treatment. METHODS: In this phase 1, open-label, randomized, two-period crossover study, healthy adults aged 18-55 years were given a single dose of revexepride 1 mg or revexepride 1 mg + omeprazole 40 mg. Pharmacokinetic parameters were assessed for up to 48 hours after administration of the investigational product. Adverse events, clinical chemistry and hematology parameters, electrocardiograms, and vital signs were monitored. RESULTS: In total, 42 participants were enrolled and 40 completed the study. The median age was 24 years (18-54 years), 55% were women and 93% were white. The pharmacokinetic parameters of revexepride were similar without or with omeprazole co-administration. The mean area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) was 23.3 ng · h/mL (standard deviation [SD]: 6.33 ng · h/mL) versus 24.6 ng · h/mL (SD: 6.31 ng · h/mL), and maximum plasma concentrations (Cmax) were 3.89 ng/mL (SD: 1.30 ng/mL) and 4.12 ng/mL (SD: 1.29 ng/mL) in participants without and with omeprazole, respectively. For AUC0-∞ and Cmax, the 90% confidence intervals for the ratios of geometric least-squares means (with:without omeprazole) were fully contained within the pre-defined equivalence limits of 0.80-1.25. Mean apparent terminal phase half-life was 9.95 hours (SD: 2.06 hours) without omeprazole, and 11.0 hours (SD: 3.25 hours) with omeprazole. CONCLUSION: Co-administration of the 5-hydroxytryptamine receptor 4 agonist revexepride with omeprazole did not affect the pharmacokinetics of revexepride in healthy adults.

Suppression of the E-effect during the subjective visual vertical test.

The subjective visual vertical was measured in 38 healthy subjects. The head was alternately roll-tilted to the right and to the left, and the start position of the light bar was alternately set clockwise and counterclockwise. When the head is tilted less than 60-70 degrees a deviation of the subjective visual vertical in the opposite direction to the head tilt is expected. This phenomenon has been reported in various studies as the E-effect. The present study demonstrates however that the E-effect is suppressed if the start position of the light bar is presented relatively parallel to the length axis of the tilted head.

Utricular sensitivity and preponderance assessed by the unilateral centrifugation test.

Utricular sensitivity and preponderance of the right or left utricle can be assessed by means of the unilateral centrifugation test. In this test, subjects are rotated about an earth vertical axis at a velocity of 400 degrees per second. During the ongoing rotation, the subject is gradually translated 4 cm first to the right, and then to the left, along an interaural axis, to a position at which one utricle becomes aligned with the axis of rotation, and at this point is subjected only to gravitational forces. At this eccentric position, the contralateral utricle is exposed to the combination of gravity and a centrifugal acceleration of 0.4g, corresponding to an apparent roll-tilt of 21.7 degrees. This stimulus induces ocular counterrolling (OCR), which is measured on-line using three-dimensional video-oculography (VOG). We observed that ocular counterrolling appears as a linear function of the gravito-inertial acceleration tilt of the head centre (GIA(HC)) during the lateral translation. We present a theoretical model for this linear relationship that contains two parameters: 1) the slope of the linear regression is a measure for the utricular sensitivity and 2) the intercept of the linear regression is a measure of the preponderance of the right or left utricle. The strength of the model is supported by data obtained from 28 healthy subjects and 14 patients with unilateral vestibular deafferentiation (UVD) due to acoustic neuroma surgery.

The interutricular distance determined from external landmarks.

Knowledge of the exact distance between the utricles is important in new vestibular tests, such as the unilateral centrifugation (UC) test for the unilateral examination of the utricles. During this test, subjects are rotated at constant velocity and simultaneously laterally displaced along an interaural axis so that one labyrinth becomes aligned with the axis of rotation. When the axis of rotation crosses precisely through one labyrinth, only the opposite labyrinth is stimulated. To achieve this setup, precise knowledge of the interutricular distance is needed. The purpose of this study is to investigate the correlation between the interutricular distance (IUD), measured on T2-weighted magnetic resonance images, and specific external measures of head dimensions such as distance nasion-inion, intermastoid distance (IMD), distances between the temporomandibular joints and between the lateral margins of the orbits. Data have been collected in a series of 50 subjects (25 men and 25 women). On MR images we found a mean IUD of 7.22 cm (SD = 0.42 cm). There was a strong correlation between the IUD measured on MR images and the intermastoid distance. A linear combination of the IMD, nasion-inion distance and height of the subjects could predict the IUD very satisfactory (R = 0.85, adjusted R2=0.723). We also determined a measure of eccentricity of the vestibular labyrinths. The 95% prediction interval for the asymmetry appeared to be less than 4.3%.

Effect of prucalopride on the pharmacokinetics of oral contraceptives in healthy women.

BACKGROUND: Prucalopride is a selective, high-affinity, 5-hydroxytryptamine 4 (5-HT4) receptor agonist, which is approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Women of childbearing potential, many of whom will be using oral contraceptives, comprise a large proportion of patients seeking medical therapy for constipation. OBJECTIVE: The aim of this study was to evaluate the effect of prucalopride on the absorption and steady-state pharmacokinetics of oral contraceptives in healthy women. METHODS: Sixteen women (aged 18-45 years) were enrolled in this open-label, two-way crossover trial (ClinicalTrials.gov identifier: NCT01036893) and given two 5-day treatments with a once-daily oral contraceptive (ethinylestradiol 0.035 mg + norethisterone 1 mg), alone and in combination with prucalopride 2 mg once daily. Treatments were separated by a 7 ± 2-day washout period. On days 1 and 5, blood samples were obtained pre-dose and at regular intervals post-dose up to 24 and 48 hours, respectively, to determine ethinylestradiol and norethisterone plasma concentrations. Prucalopride plasma concentrations were determined pre-dose and 3 hours post-dose on days 1 and 5, and 24 hours post-dose on day 6. Safety was assessed. RESULTS: Thirteen participants completed the study. One participant was thought to be non-compliant on days 3 and/or 4, and was excluded from the day 5 analysis. On days 1 and 5, maximum plasma concentrations of both oral contraceptive constituents were attained in ~1 hour and were unaffected by prucalopride administration. On day 5, steady-state prucalopride and oral contraceptive concentrations had been achieved. Prucalopride did not affect the pharmacokinetics of the oral contraceptives: point estimates for the maximum plasma concentration and area under the plasma concentration-time curve values and their associated 90 % confidence intervals were contained within predefined equivalence limits (80-125 %). Prucalopride was well tolerated, with a safety profile consistent with those observed in previous studies. CONCLUSION: Co-administration of prucalopride with an oral contraceptive did not result in any clinically meaningful pharmacokinetic interactions and was well tolerated.