Search

Context: Women's health disorders are commonly treated by agents that suppress the hypothalamic-pituitary-gonadal axis. NK3 receptor antagonism modulates this axis with distinct pharmacology compared to existing therapies., Objective: The study aim was to evaluate safety, pharmacokinetics, and pharmacodynamics on gonadotropins and sex hormones after single- and multiple-dose administration of an NK3R antagonist to healthy men and women., Design and Setting: This was a first-in-human, double-blind, placebo-controlled, combined single and multiple ascending dose trial., Participants: Forty-one men and 24 regularly cycling women participated in the study., Intervention(s): In part 1 of the study, men received single oral doses of 3-180 mg or placebo. In part 2, men received placebo or 20, 60, or 180 mg each day for 10 days. In part 3, women received placebo or 20, 60, or 180 mg each day for 21 days, where dosing was initiated on day 3 ± 2 after menses., Main Outcome Measure(s): Safety, tolerability, pharmacokinetics, and pharmacodynamics on circulating levels of LH, FSH, testosterone, estradiol, and progesterone, in addition to physiological biomarkers of endometrial thickening, follicle growth, and the duration of the menstrual cycle were evaluated., Results: ESN364 was well-tolerated and rapidly bioavailable with linear pharmacokinetics and no drug accumulation with repeated, daily oral administration. Drug treatment dose-dependently decreased basal LH, but not FSH, and consequently decreased estradiol and progesterone (in women) as well as testosterone (in men). The hormonal changes in women corresponded to delayed ovulation, decreased endometrial thickening, impeded follicular maturation, and prolongation of the menstrual cycle. Drug effects were rapidly reversible., Conclusions: Oral administration of the NK3R antagonist, ESN364, suppressed the hypothalamic-pituitary-gonadal axis in healthy volunteers by selective modulation of gonadotropin secretion, leading to a restrained decrease in ovarian hormone levels in women. These results suggest that ESN364 may offer therapeutic benefit in the treatment of women's health disorders with a mitigated risk of menopausal-like adverse events.

Objectives: We sought to validate Cognitive Research Corporation's Driving Simulator (CRCDS Mini-Sim) for studies of drug safety with respect to driving ability., Methods: A total of 30 healthy subjects were randomized to receive placebo or 7.5 mg zopiclone, a hypnotic known to impair driving, in random order during the 2 treatment periods of a 2 period crossover design., Results: Evening administration of 7.5 mg zopiclone increased next-day standard deviation of lateral lane position (SDLP) by 2.62 cm on average compared with evening administration of placebo, and caused significant effects on symmetry analysis. The magnitude of the change in SDLP is highly similar to changes previously observed using on-the-road driving methods., Conclusions: Further validation of the CRCDS Mini-Sim is warranted to develop this platform for drug safety studies.

Objective: To investigate indications, features and outcome of pediatric tracheotomy in our ENT department., Methods: A retrospective chart review of all pediatric patients who underwent tracheotomy between 1992 and 2006 in the Children's Hospital of the Universitair Ziekenhuis Brussel. The main parameters of the study were age, gender, indications, morbidity and mortality rate, time and success of decannulation., Results: Twenty-nine children younger than 16 years of age, 21 males and 8 females, underwent tracheotomy. Indications for tracheotomy fell into two main groups: chronic diseases requiring ventilation support (55%) and relief of airway obstruction (45%). Tracheotomies were mainly performed in young children, 76% were under 3 years of age. In this age group, upper airway obstruction was the most frequent indication. The complication rate was 36%, and the nontracheotomy-related mortality rate was 25%. The tracheotomy-related mortality rate was 3.5%. Successful decannulation was possible in 28% after a mean duration of 24 months after surgery. Of the remaining 72% for whom decannulation was not performed, 35% died mainly because of the underlying disease. Those infants failing decannulation (65%) had neurologic disorders., Conclusions: In accord with the literature, where a shift towards very young patients and towards indications related to chronic ventilatory support is observed, in this series tracheotomies were mainly performed for the youngest children. Relief of upper airway obstruction was the most frequent indication. Morbidity and mortality rates among this specific patient population should not be ignored.