Impact of patient characteristics on the clinical efficacy of mongersen (GED-0301), an oral Smad7 antisense oligonucleotide, in active Crohn's disease.

BACKGROUND: In a phase 2 study, mongersen, an oral antisense oligonucleotide targeting Smad7, was effective in inducing clinical remission in approximately 60% of patients with active Crohn's disease (CD). AIM: In a post hoc analysis to evaluate those patient disease characteristics that may have influenced the efficacy and safety of mongersen therapy. METHODS: Patients with steroid-dependent/resistant, active CD were randomised to mongersen 10, 40 or 160 mg/day or placebo for 2 weeks; patients were followed for 10 weeks. Clinical remission [Crohn's Disease Activity Index (CDAI) score <150] and clinical response (CDAI score reduction ≥100 points) were assessed at weeks 2, 4 and 12 for these subgroups: disease duration <5/≥5 years, human serum C-reactive protein (hsCRP) <3/≥3 mg/L, and CDAI at baseline ≤260/>260. Additional patient baseline and disease characteristics were explored. RESULTS: Clinical remission and response rates were significantly higher in patients receiving mongersen 40 and 160 mg/day but not 10 mg/day vs. placebo and independent of disease duration and hsCRP. Patients with baseline CDAI ≤260 had significantly higher remission rates with 40 and 160 mg/day. In patients with baseline CDAI >260, remission rates were statistically greater with 160 mg/day and numerically better with 40 mg/day vs. placebo. Adverse event rates were similar across treatment groups. Mongersen was safe and well tolerated. CONCLUSIONS: Patients with higher CDAI scores achieved clinical remission most frequently with the highest mongersen dose. Disease duration and baseline human serum C-reactive protein did not appear to significantly impact efficacy of mongersen in this study (EudraCT Number: 2011-002640-27.).

An open-label, parallel, multiple-dose study comparing the pharmacokinetics and gastric acid suppression of rabeprazole extended-release with esomeprazole 40 mg and rabeprazole delayed-release 20 mg in healthy volunteers.

BACKGROUND: Novel rabeprazole extended-release (ER) formulations were developed to provide prolonged gastric acid suppression and potentially improved clinical outcomes in GERD patients. AIM: To evaluate the pharmacodynamics and pharmacokinetics of six rabeprazole-ER formulations vs. esomeprazole 40 mg and rabeprazole delayed-release (DR) 20 mg. METHODS: Helicobacter pylori-negative healthy subjects were randomised to receive one of eight treatments once daily for 5 days. Twenty-four-hour intragastric pH was monitored on days -1, 1 and 5. Rabeprazole plasma concentrations were measured on day 5. RESULTS: A total of 248 subjects (N=31/group) were enrolled in the study. On day 5, rabeprazole-ER groups provided mean durations of 18.5-20.2 h (77.0-84.1% of 24-h) with intragastric pH >4.0 vs. esomeprazole 40 mg (15.9 h/66.1% of 24-h) and rabeprazole-DR 20 mg (15.2 h/63.2% of 24-h). A similar increase was observed on day 1. While percentage of daytime (8 am-10 pm) with intragastric pH >4.0 on day 5 was overall similar across the groups, percentage of night-time (10 pm-8 am) with intragastric pH >4.0 was higher with the rabeprazole-ER groups (57.0-72.4%) vs. esomeprazole 40 mg (32.8%) and rabeprazole-DR 20 mg (34.0%). CONCLUSION: Rabeprazole-ER once daily for 5 days demonstrated a significantly longer duration of gastric acid suppression in 24 h vs. esomeprazole 40 mg and rabeprazole-DR 20 mg. The increase in acid suppression was predominantly due to prolonged acid suppression during the night-time; this was supported by the extended-release pharmacokinetic characteristics.

Randomised clinical trial: a novel rabeprazole extended release 50 mg formulation vs. esomeprazole 40 mg in healing of moderate-to-severe erosive oesophagitis - the results of two double-blind studies.

BACKGROUND: Current PPIs may not achieve desired outcomes in some GERD patients due to limited duration of acid inhibition. AIM: To evaluate a novel rabeprazole extended release (ER), which provides longer duration of drug exposure and acid suppression, in healing and symptomatic resolution of moderate-severe erosive oesophagitis. METHODS: Patients with LA grade C or D oesophagitis were randomised to rabeprazole-ER 50 mg or esomeprazole 40 mg once daily in two identical 8-week double-blind trials (N = 2130). Two primary endpoints were tested sequentially: (1) healing by 8 weeks [hypothesis: rabeprazole-ER non-inferior to esomeprazole (non-inferiority margin = 8%)], (2) healing by 4 weeks [hypothesis: rabeprazole-ER superior to esomeprazole (P < 0.05)]. The secondary endpoint was sustained heartburn resolution at 4 weeks. RESULTS: Rabeprazole-ER was non-inferior to esomeprazole in week-8 healing (80.0% vs. 75.0%; 77.5% vs. 78.4%). Week-4 healing (54.8% vs. 50.3%; 50.9% vs. 50.7%) and sustained heartburn resolution (48.3% vs. 48.2%; 53.2% vs. 52.5%) were not significantly different. Post hoc combined results for grade D revealed rabeprazole-ER vs. esomeprazole differences in week-8 healing = 10.4% (95% CI: -1.4%, 22.2%) and week-4 healing = 12.0% (P = 0.048). CONCLUSIONS: Rabeprazole-ER is as effective as esomeprazole in healing moderate-severe oesophagitis and achieves similar rates of heartburn resolution. Subgroup analysis suggests the possibility of benefit in severe oesophagitis, but this requires further evaluation (ClinicalTrials.gov: NCT00658528 and NCT00658775).

Pressure sores in children--the acute hospital perspective.

There is very little published literature on pressure sores in children and most of the existing literature is qualitative. Using literature from paediatric and adult studies, a schedule was designed to collect quantitative data on aspects that may predispose children to pressure injury. The schedule was piloted in an incidence and a prevalence study at the Royal Liverpool Children's NHS Trust. The sample size was 82 children for the incidence study and 183 children for the prevalence study. Six children in the incidence study and 12 children in the prevalence study sustained pressure injury. Data indicated that factors most strongly associated with pressure injury were nutritional status, mobility and consciousness level. Other factors that were implicated in increasing susceptibility to pressure injury were skin condition, body weight, haemodynamic status and hydration. Infants and young children most frequently sustained pressure injury on the occipital scalp area and heels. Although this was a small study, it produced some useful preliminary data, and was a valuable exercise to develop a tool for data collection on a larger scale.

Expression of transforming growth factors alpha and beta in colonic mucosa in inflammatory bowel disease.

BACKGROUND & AIMS: Transforming growth factors (TGFs) alpha and beta are key regulatory peptides that modulate mucosal cell populations critical to inflammatory bowel disease. The aim of this study was to assess TGF-alpha and TGF-beta expression in human colonic mucosa. METHODS: TGF-alpha and TGF-beta expression was assessed in colonic mucosa from patients with ulcerative colitis, patients with Crohn's disease, and controls by Northern blot analysis, in situ hybridization, and bioassay. RESULTS: TGF-alpha messenger RNA expression localized to the villous tips of the small intestine and the surface epithelium of the colon. TGF-alpha expression was enhanced 2.3-fold in inactive ulcerative colitis mucosa relative to active ulcerative colitis, Crohn's disease, or normal controls. Enhanced expression correlated with duration of disease. TGF-beta expression was increased in affected mucosa from both patients with ulcerative colitis and Crohn's disease with active disease. TGF-beta1 messenger RNA expression in ulcerative colitis and Crohn's disease localized mostly to cells of the lamina propria with the highest concentration in inflammatory cells closest to the luminal surface. CONCLUSIONS: TGF-alpha may contribute to epithelial hyperproliferation and the increased risk of malignancy in long-standing ulcerative colitis. TGF-beta may be a key cytokine during periods of active inflammation, modulating epithelial cell restitution and functional features of cells within the lamina propria.

Contemporary transatlantic developments concerning compelled medical treatment of pregnant women.

This paper had identified a contemporary ethicolegal dilemma concerning the circumstances, if any, in which a pregnant woman's refusal of medical treatment may be judicially overridden either in her interests or those of the unborn child. On the one hand, the obstetrician will be concerned about the interests of both his patients in potentially life-threatening situations when they can be protected by what might be regarded as relatively straightforward procedures and where to fail to take those steps might expose the practitioner (at least outside New Zealand where its accident compensation legislation has impact in this regard) to allegations of negligence. On the other hand, the imposition of treatment in these circumstances will necessarily interfere with the woman's rights of autonomy and self-determination. In such cases also, the conduct of medical procedures in the face of an express prohibition by the woman may give rise to liability for battery. (In New Zealand, such a potential liability would not, in the writer's view, be affected by the prohibition on proceedings for damages for medical misadventure as contained in the Accident Rehabilitation and Compensation Insurance Act 1992.) At the heart of an analysis of this issue is the status of the fetus as it is the fact of the woman patient's pregnancy which distinguishes the cases discussed in this paper from others in which the Courts have had to deal with refusals of treatment by those competent to do so. In regard to this aspect, the approach of the Courts in various jurisdictions has arguably been confused and contradictory.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: This article reviews and analyzes US and UK court decisions concerning the circumstances (if any) in which medical treatment of a pregnant woman is lawful in the absence or refusal of consent. This issue is of practical importance to physicians and raises ethicolegal issues about the relative and competing rights of a pregnant woman and the fetus. A brief overview is provided of the general principles of consent and relevance, and situations in which the "doctrine of necessity" (which allows treatment to be given without consent) may and may not be invoked are outlined. The general status of the fetus as contained in relevant civil law and the right of the fetus to sue as a result of injury inflicted in utero are then reviewed in light of key decisions made in England and Australia. Court decisions on whether a fetus can be "warded" and placed under an order of guardianship are also reviewed. Three US cases in which the courts were asked to override a pregnant woman's refusal to consent to treatment are then detailed. In one case, the pregnant woman was ordered to undergo a sonogram and to submit to a Cesarean section if the placenta was still malpositioned. In a second case, a Cesarean was ordered for a woman near death from cancer. This action was overturned after the fact (and the woman's and baby's deaths) by an appeals court. In the third case, the court refused to order a Cesarean section when doctors predicted the fetus would not otherwise survive. In Britain, the court allowed a blood transfusion to a lapsed Jehovah's Witness who was comatose and had miscarried as the result of a traffic accident. The second case, in which the ruling has been criticized, permitted a Cesarean in a woman whose fetus was malpositioned. These rulings have centered on the status of the fetus and have, therefore, suffered from confusion. They have also suffered from hasty decisions made in perceived emergency situations. In the US, maternal rights are outweighing fetal rights. It has been concluded that courts should not compel pregnant women to submit to medical treatment and any judicial authority in these matters should arise from legislation.

The effect of vasoactive intestinal polypeptide on the lower esophageal sphincter in achalasia.

Vasoactive intestinal polypeptide (VIP) is one of the main neurotransmitters implicated in the relaxation of the lower esophageal sphincter (LES). The effect of exogenous VIP on LES motor activity was determined by esophageal manometry. LES pressure (LESP) and LES relaxation were compared in four healthy volunteers and in six patients with achalasia. The effects of intravenous doses of 1.5, 3, and 5 pmol.kg-1.min-1 of VIP were compared with placebo. Neither placebo nor 3 and 5 pmol.kg-1.min-1 of VIP produced any effect on esophageal motility in healthy volunteers. In achalasia the three doses of VIP caused a dose-dependent decrease in LESP with a significant improvement in LES relaxation. A dose of 5 pmol.kg-1.min-1 produced a maximal decrease of 51% in LESP. A beta-adrenergic agonist, isoproterenol, caused a decrease in LESP both in healthy volunteers and in patients with achalasia without improving LES relaxation. In summary, intravenous VIP improved LES relaxation and caused a decrease in LESP in patients with achalasia without affecting LESP in healthy volunteers, indicating that the LES muscle in achalasia is supersensitive to VIP. The current study suggests that a selective damage in the noncholinergic nonadrenergic innervation of the esophagus is in part responsible for the motor alteration seen in these patients. The findings and the inability of isoproterenol to improve LES relaxation despite decreasing LESP support a role in VIP as a indicator of LES relaxation.

Effect of local instillation of alcohol on sphincter of Oddi motor activity: combined ERCP and manometry study.

The effect of local instillation of alcohol on sphincter of Oddi motor activity was determined by endoscopic manometry. Sphincter of Oddi pressures and motor function were compared in eight cholecystectomized subjects with normal sphincter of Oddi motor function and in four patients with chronic alcoholic pancreatitis. The effect of local instillation of 3 ml of 40% alcohol was compared with water instillation. In cholecystectomized subjects, alcohol produced a significant increase of basal sphincter of Oddi pressure from 21.0 +/- 2.8 mm Hg to 95.8 +/- 83 mm Hg (p less than 0.01) without significant changes in the amplitude, duration, and frequency of phasic contractions. In patients with alcoholic chronic pancreatitis, alcohol instillation resulted in a significant increase of basal sphincter of Oddi pressure from 32.5 +/- 4.8 mm Hg to 225.1 +/- 105 mm Hg without changes in amplitude, duration, and frequency of phasic contractions. Two patients with chronic alcoholic pancreatitis had a tonic contraction of the sphincter of Oddi with transitory and mild epigastric pain. Local instillation of alcohol increases sphincter of Oddi motor activity which may play a role in the pathogenesis of alcoholic pancreatitis.

High vasoactive intestinal polypeptide plasma levels in patients with Barrett's esophagus.

We have evaluated the correlation between vasoactive intestinal polypeptide (VIP) plasma concentration and severity of gastroesophageal reflux in patients with Barrett's esophagus and the possible differences in the VIP values of these patients compared with healthy volunteers. We also evaluated the relation between VIP plasma concentration and lower esophageal sphincter (LES) pressure in 24 patients with Barrett's esophagus. The mean VIP plasma concentration in 14 patients with severe gastroesophageal reflux was 25.6 +/- 0.75 pg/ml, significantly higher than the mean value observed in 10 patients with moderate reflux (18.9 +/- 0.67 pg/ml) (p less than 0.01). The mean LES resting pressure was significantly lower in the group of patients with severe gastroesophageal reflux than that observed in patients with moderate reflux (3 +/- 0.64 and 10.3 +/- 0.69 mm Hg, respectively; p less than 0.01). The mean VIP plasma concentration in 11 healthy volunteers (20.6 +/- 0.65 pg/ml) was significantly lower than the mean value observed in the subgroup of patients with severe gastroesophageal reflux (p less than 0.01). VIP values in patients with moderate reflux were not significantly different from those observed in our volunteers. There was a significant correlation between LES pressure and VIP plasma level (r = -0.9253; p less than 0.01). In conclusion, it is possible that the decreased LES resting pressure observed in patients with Barrett's esophagus and severe gastroesophageal reflux may be due to impairment of the VIPergic innervation, resulting in an increased local VIP release with possible overflow to peripheral plasma.

Sphincter of Oddi manometry in healthy volunteers.

In this study we describe in detail the characteristics of sphincter of Oddi motor function in a large group of healthy subjects. Studies were obtained in 50 healthy volunteers. The findings showed a sphincter of Oddi segment that had a basal pressure of 14.8 +/- 6.3 mm Hg (X +/- SD). Phasic contractions were superimposed on the basal pressure. They had an amplitude of 119.7 +/- 32 mm Hg, a duration of 4.7 +/- 1 sec, and a frequency of 5.7 +/- 1.2 contractions/min. In 40 subjects the propagation sequence of phasic contractions could be evaluated and were simultaneous in 53%, antegrade in 35%, and retrograde in 11% of the waves. In 20 subjects, pressure measurements done at the common bile duct sphincter waves. In 20 subjects, pressure measurements done at the common bile duct sphincter were similar to those obtained at the pancreatic duct sphincter. In 10 subjects, pressure values obtained at the common bile duct sphincter within a week were similar. Our study should help to establish standards for normal manometric values of the sphincter of Oddi and emphasizes the importance of having a healthy volunteer group from which to obtain the normal values of sphincter of Oddi motor function.

Effect of nifedipine on sphincter of Oddi motor activity: studies in healthy volunteers and patients with biliary dyskinesia.

The effect of nifedipine on sphincter of Oddi (SO) motor activity was determined by endoscopic manometry. Sphincter of Oddi pressures and motor function were compared in 21 healthy volunteers and in 9 patients with SO dyskinesia. The effects of sublingual doses of 10 or 20 mg of nifedipine were compared with placebo. Neither placebo nor 10 mg of nifedipine produced any effect on SO motor activity. In healthy volunteers 20 mg of nifedipine produced a moderate but significant decrease in basal SO pressure from 12.0 to 6.7 mmHg as well as in the amplitude, duration, and frequency of phasic contractions. In patients with SO dyskinesia 20 mg of nifedipine also resulted in a significant but more profound decrease of the basal SO pressure from 47.1 to 17.3 mmHg as well as in a decrease of amplitude, duration, and frequency of the phasic contractions. Neither placebo nor 10 or 20 mg of nifedipine has any effect on the sequence of phasic contractions. In summary, nifedipine may have a possible therapeutic role in the treatment of SO dyskinesia.

An evaluation of the Coulter Diff3 50, an automated differential leukocyte counter.

The Coulter Diff3 50 analyzes Wright stained films using computerized pattern recognition. It is capable of reporting on the differential leukocyte count, red cell morphology, platelet sufficiency and the reticulocyte count. Although the precision of the differential leukocyte and reticulocyte counts is better than that of the manual method, correlation is poor and monocyte classification is a major problem. The Diff3 50 is useful for examining relatively normal films and for follow-up counts, but in our experience it has proven more unreliable and costly than expected.