A prospective, randomized, pharmacodynamic study of quick-starting a desogestrel progestin-only pill following ulipristal acetate for emergency contraception.

STUDY QUESTION: Is there a pharmacodynamic interaction between ulipristal acetate (UPA) 30 mg for emergency contraception and a daily progestin-only contraceptive pill, desogestrel (DSG) 0.75 mg, when initiated the next day? SUMMARY ANSWER: In this study, DSG impaired the ability of UPA to delay ovulation, but UPA had little impact on the onset of contraceptive effects due to DSG. WHAT IS KNOWN ALREADY: UPA is a progesterone receptor modulator used for emergency contraceptive (EC) at the dose of 30 mg. UPA delays ovulation by at least 5 days when administered in the mid to late follicular phase. In theory, potent progestins could reactivate progesterone signaling that leads to follicle rupture, thereby impacting the effectiveness of UPA as EC. In addition, UPA could alter the onset of the contraceptive effect of progestin-containing contraceptives started immediately after UPA. STUDY DESIGN, SIZE, DURATION: A single-blind (for observer), placebo-controlled, partial crossover study was conducted in two sites [Dominican Republic (DR) and the Netherlands (NDL)] over 11 months from October 2012 to September 2013. Healthy female volunteers participated in two of the three treatment cycles separated by a washout cycle. Treatment combinations studied were as follows: (i) a single 30 mg dose of UPA followed by 75 µg per day DSG for 20 days, (ii) a single 30 mg dose of UPA followed by 20 days of placebo matching that of DSG (PLB2) or (iii) one tablet of placebo-matching UPA (PLB1) followed by 75 µg per day DSG for 20 days. Participants were randomized to one of the three treatment sequences (UPA + DSG/UPA + PLB2, PLB1 + DSG/UPA + DSG and UPA + PLB2/PLB1 + DSG) when a lead follicle was ≥ 14 to <16 mm diameter on transvaginal ultrasound imaging (TVU). PARTICIPANTS/MATERIAL, SETTING, METHODS: A total of 71 women were included, and 49 were randomized to a first treatment combination of the three period sequences (20 in the DR and 29 in the NDL); 41 of the 49 continued and completed two treatment combinations (20 in the DR and 21 in the NDL). MAIN RESULTS AND THE ROLE OF CHANCE: Initiating DSG treatment the day after UPA significantly reduced the ovulation delaying effect of UPA (P = 0.0054). While ovulation occurred in only one of the 29 UPA-only cycles (3%) in the first 5 days, it occurred in 13 of the 29 (45%) UPA + DSG cycles. LIMITATIONS, REASONS FOR CAUTION: This was a small, descriptive, pharmacodynamic study in which some findings differed by study site. Distinguishing between a cystic corpus luteum and a luteinized unruptured follicle (LUF) by TVU was difficult in some cases; however, the investigators reached consensus, when the study was still blinded, regarding ovulation based on hormone levels and careful review of daily TVU images. WIDER IMPLICATIONS OF THE FINDINGS: Initiating the use of a DSG progestin-only pill (POP) immediately after UPA reduces the ability of UPA to delay ovulation and thus may decrease its efficacy as EC. If starting a DSG POP after using UPA for EC, and possibly any progestin-only method, consideration should be given to delaying for at least 5 days after UPA intake in order to preserve the ovulation delaying effects of UPA.

A phase II-III trial of olesoxime in subjects with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: To assess the efficacy and safety of olesoxime, a molecule with neuroprotective properties, in patients with amyotrophic lateral sclerosis (ALS) treated with riluzole. METHODS: A double-blind, randomized, placebo-controlled, multicenter trial of 18 months' duration was conducted in 512 subjects, with probable or definite ALS and a slow vital capacity (SVC) ≥70%, receiving 330 mg olesoxime daily or matching placebo and 50 mg riluzole twice a day in all. The primary intention-to-treat (ITT) outcome analysis was 18 months' survival. Secondary outcomes were rates of deterioration of the revised ALS functional rating scale (ALSFRS-R), focusing on the 9-month assessment, SVC and manual muscle testing. Blood levels, safety and tolerability of olesoxime were also assessed. RESULTS: At 18 months, 154 of the 512 ITT patients had died (79 of 253 placebo, 75 of 259 olesoxime). Estimated overall survival according to Kaplan-Meier analysis was 67.5% (95% CI 61.0%-73.1%) in the placebo group and 69.4% (95% CI 63.0%-74.9%) in the olesoxime group; hence survival was not significantly different between treatment arms (P = 0.71, stratified bulbar/spinal log-rank). The other efficacy end-points evaluated were also negative, with the exception of a small difference in ALSFRS-R global score at 9 months in favor of olesoxime but not sustained after 18 months' treatment nor evident in either the stratified bulbar or spinal subpopulations. Treatment did not raise any safety concerns. CONCLUSIONS: Olesoxime, although well tolerated, did not show a significant beneficial effect in ALS patients treated with riluzole.

Effects of fedotozine on gastric emptying and upper gastrointestinal symptoms in diabetic gastroparesis.

BACKGROUND: Delayed gastric emptying and upper gastrointestinal symptoms occur frequently in patients with diabetes mellitus. AIM: To evaluate the effects of fedotozine on gastric emptying and gastrointestinal symptoms in diabetic gastroparesis. METHODS: Thirty-one diabetic patients (20 type 1, 11 type 2) with gastroparesis were randomized to receive fedotozine (30 mg as the tartrate) or placebo t.d.s. Measurements of gastric emptying (100 g ground beef labelled with 20 MBq 99mTc-sulphur colloid chicken liver and 150 mL 10% dextrose labelled with 10 MBq 113mIn-DTPA) and gastrointestinal symptoms were performed before and after 12-16 days of treatment. Data are the mean +/- s.d. RESULTS: Of the 31 patients enrolled, two were excluded from analysis. Data from the remaining 29 patients (18 type 1, 11 type 2; 22 female, seven male), aged 42.7 +/- 11.1 years (of whom 14 were randomized to fedotozine and 15 to placebo), were analysed. Fedotozine had no effect on either gastric emptying (solid retention at 100 min; fedotozine: baseline, 84 +/- 15%; treatment, 73 +/- 23% vs. placebo: baseline, 83 +/- 10%; treatment, 70 +/- 20%) or liquid 50% emptying time (fedotozine: baseline, 59 +/- 32 min; treatment, 58 +/- 38 min vs. placebo: baseline, 44 +/- 9 min; treatment, 43 +/- 21 min) or gastrointestinal symptoms (fedotozine: baseline, 4.4 +/- 2.9; treatment, 4.1 +/- 3.9 vs. placebo: baseline, 4.9 +/- 4.2; treatment, 4.8 +/- 3.9). CONCLUSIONS: Fedotozine has no effect on gastric emptying in patients with diabetic gastroparesis.

[Influence of rectal preparation by enema on cell proliferation in the normal rectal mucosa in man]. / Influence de la préparation rectale par lavement sur la prolifération cellulaire dans la muqueuse rectale normale de l'homme.

In order to study the potential influence of rectal enemas on epithelial cell proliferation, two groups of 13 patients without any disease of the digestive tract were compared, one group having received two warm enemas (Normacol) prior to proctoscopic examination. Cell proliferation was studied by in vitro incorporation of tritiated thymidine in mucosal biopsies and radioautographic analysis of the number and position of labeled nuclei in the glands. The mean number of labeled cells per gland and the mean labeling index were significantly higher in group i (with enemas) than in group II (without enema). In group I there was an extension of the proliferative compartment towards the surface with less than 50 p. 100 of labeled cells located in the lower third of glands. Intraindividual variations of labeling index from gland to gland were more important in group I than in group II. In group I, eight out of 13 patients had rectal glands with elevated labeling indices (15 p. 100) in contrast to one patient in group II. Our results suggest that proliferation abnormalities observed in group I are related to enema administration and indicate that this type of rectal preparation should preferably be excluded whenever cell kinetic parameters are studied in the rectal mucosa.

[Continuous ambulatory enteral feeding in hospitalized adults: prospective experience in 98 patients]. / Nutrition entérale continue ambulatoire à l'hôpital, chez l'adulte: expérience prospective chez 98 malades.

The goal of this study, which describes a personal technique of continuous enteral nutrition (CEN) in hospitalized adults on an ambulatory basis, was: to prospectively evaluate, over a 2-year period, its efficacy and tolerance in 98 patients requiring CEN for at least 15 days; to compare its efficacy and tolerance with those of conventional non-ambulatory CEN on a prospectively randomized basis in 16 patients. Ambulatory CEN was given at the rate of 35-45 kcal/kg/d (lipids: 35 p. 100; carbohydrates: 45 p. 100); during day-time, a portable system, including pump, tubes and low-viscosity nutrient solutions, allowed ambulation. Ninety-eight consecutive patients with a minimal level of physical autonomy were treated for intestinal (n = 47), pancreatic (n = 20), esophagogastric (n = 17) diseases, or for malnutrition of other causes for an average of 38 days (15 to 141). The average weight gain (m +/- SD) was 1.2 +/- 5.5 p. 100 of ideal body weight (IBW) and the average nitrogen gain was 0.7 +/- 3.8 g/24 h; weight gain proved significantly lower in patients with inflammatory bowel disease receiving steroids. The clinical tolerance proved excellent, except for 5 cases of transient diarrhea and 9 cases of reposition of the nasogastric tube. A decrease in cholesterolemia below 3.9 mmol/l was noted in 25 p. 100 of patients during CEN. No significant difference between ambulatory and non-ambulatory CEN was observed in terms of evolution of body weight and other anthropometric variables, nitrogen balance, albuminemia, and oxygen consumption; conversely, the CEN experience, evaluated by patients on analogical visual scales, was significantly better endured in the ambulatory group.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of peripheral kappa agonist fedotozine versus placebo in treatment of irritable bowel syndrome. A multicenter dose-response study.

The efficacy and safety of the peripheral kappa agonist fedotozine was evaluated in a double-blind, multicenter study involving 238 patients with the irritable bowel syndrome. After a two-week washout, patients were assigned to one of four groups to receive either placebo or fedotozine three times a day at doses of 3.5, 15, or 30 mg for six weeks. Patient assessment of mean symptom intensity indicated that the 30-mg dose of fedotozine was superior to placebo in relieving maximal daily abdominal pain (P = 0.01), mean daily pain (P = 0.007), and abdominal bloating (P = 0.02). Changes in bowel function and defecation disorders could not be evaluated reliably. According to the investigators, the highest dose of fedotozine markedly reduced overall disease severity (P = 0.003) and the pain component of the symptomatic profile (P = 0.009). Clinical and laboratory safety was very good. Fedotozine 30 mg three times a day therefore appears to be effective and safe in the treatment of the abdominal pain and bloating associated with IBS.

Epithelial cell proliferation in the rectal stump of patients with ileorectal anastomosis for ulcerative colitis.

Epithelial cell proliferation in the rectal stump after ileorectal anastomosis for ulcerative colitis was studied in 19 patients. This was achieved through in vitro incorporation of tritiated thymidine in mucosal biopsies and radioautographic analysis of the number and position of labelled nuclei in the crypts. Rectal biopsies from nine unoperated patients with ulcerative colitis and from 10 controls, were processed simultaneously. Except for one, all patients were clinically in remission. The crypt length and number of labelled cells per crypt column were found to be similar in the rectal mucosa from the three groups of subjects. The mean labelling index, although low 8.9%, was higher (p less than 0.05) in operated patients compared with controls; but the dispersion of individual values was similar in both groups. There was an extension of the proliferative compartment towards the surface in 88% of unoperated patients and in 60% of operated patients. In addition, there was a shift of the major zone of proliferation from the lower to the middle third of the crypt in 17% of operated patients and from the lower to the upper third of the crypt in 14% of unoperated patients. No correlation was found between the labelling index and either the age of patient, the duration of disease or the period elapsed after ileorectal anastomosis. Interestingly, among operated patients with a colitis for over 10 years, 42% had a quite normal proliferative pattern with a corresponding mean postoperative period of 7.5 years.

The kappa agonist fedotozine relieves hypersensitivity to colonic distention in patients with irritable bowel syndrome.

BACKGROUND & AIMS: Visceral hypersensitivity plays a major role in the pathophysiology of inflammatory bowel syndrome (IBS). Opioid kappa receptors on afferent nerves may modulate it and may be the target of new IBS treatments. The aim of this study was to evaluate the effects of fedotozine, a potent and selective kappa agonist, on responses to colonic distention and colonic compliance in patients with IBS. METHODS: Fourteen patients with IBS (Rome criteria; 50 +/- 12 years; 6 men and 8 women) were included in a randomized double-blind, crossover trial comparing the effect of an intravenous infusion of 100 mg fedotozine or saline on sensory thresholds elicited by left colon phasic distention (4-mm Hg steps for 5 minutes) up to a sensation of abdominal pain. Colonic compliance was compared by the slope of the pressure-volume curves built on placebo and on fedotozine. RESULTS: In the fedotozine group, thresholds of first perception (28.7 +/- 5.9 mm Hg) and pain (34.7 +/- 5.5 mm Hg) were significantly greater than with placebo (23.3 +/- 4.5 and 29.0 +/- 3.5 mm Hg, respectively; P = 0.0078). Colonic compliance was 9. 20 +/- 3.87 mL. mm Hg-1 with placebo and 8.73 +/- 3.18 mL. mm Hg-1 with fedotozine (not significant). CONCLUSIONS: Fedotozine increases thresholds of perception of colonic distention in patients with IBS without modifying colonic compliance. Fedotozine seems capable of reversing visceral hypersensitivity observed in these patients and could have some beneficial action on their symptoms.

Efficacy and safety of the peripheral kappa agonist fedotozine versus placebo in the treatment of functional dyspepsia.

BACKGROUND: Peripheral kappa receptor agonists may provide a new therapeutic approach for the treatment of functional dyspepsia. AIMS: To evaluate, in a large multicentre trial, the use of the kappa receptor agonist fedotozine to improve symptoms associated with functional dyspepsia. METHODS: Two or more of the following persistent symptoms were required for inclusion: epigastric pain, early satiety, epigastric fullness or distension, nausea, vomiting, and a feeling of slow digestion. On completing a two week placebo washout, 271 patients were randomised into two groups to receive 30 mg fedotozine three times daily or placebo for six weeks under double blind conditions. RESULTS: The improvement in the overall intensity of dyspeptic symptoms (main efficacy criterion) was significantly more pronounced in the fedotozine group (p = 0.002) compared with placebo, as was epigastric pain (p = 0.004) and nausea (p = 0.01); the improvement in postprandial fullness was nearly significant (p = 0.052). Inability to finish a meal and slow digestion were unaffected. The patient global score, the average of the five individual symptoms, was notably ameliorated with fedotozine (p = 0.021). The safety of fedotozine was excellent. CONCLUSIONS: Fedotozine at 30 mg three times daily is safe and more effective than placebo for the relief of key symptoms associated with functional dyspepsia.