Lubiprostone does not influence visceral pain thresholds in patients with irritable bowel syndrome

Background In clinical trials, lubiprostone reduced the severity of abdominal pain. The primary aim was to determine whether lubiprostone raises the threshold for abdominal pain induced by intraluminal balloon distention. A secondary aim was to determine whether changes in pain sensitivity influence clinical pain independently of changes in transit time. Methods Sixty‐two patients with irritable bowel syndrome with constipation (IBS‐C) participated in an 8‐week cross‐over study. All subjects completed a 14‐day baseline ending with a barostat test of pain and urge sensory thresholds. Half, randomly selected, then received 48 μg day^?1 of lubiprostone for 14 days ending with a pain sensitivity test and a Sitzmark test of transit time. This was followed by a 14‐day washout and then a crossover to 14 days of placebo with tests of pain sensitivity and transit time. The other half of the subjects received placebo before lubiprostone. All kept symptom diaries. Key Results Stools were significantly softer when taking lubiprostone compared to placebo (Bristol Stool scores 4.20 vs 3.44, P < 0.001). However, thresholds for pain (17.36 vs 17.83 mmHg, lubiprostone vs placebo) and urgency to defecate (14.14 vs 14.53 mmHg) were not affected by lubiprostone. Transit time was not significantly different between lubiprostone and placebo (51.27 vs 51.81 h), and neither pain sensitivity nor transit time was a significant predictor of clinical pain. Conclusions & Inferences Lubiprostone has no effect on visceral sensory thresholds. The reductions in clinical pain that occur while taking lubiprostone appear to be secondary to changes in stool consistency.     

Orodispersible sublingual piribedil to abort OFF episodes: A single dose placebo‐controlled,randomized, double‐blind,cross‐over study

S90049, a novel sublingual formulation of the non‐ergoline D₂‐D₃ agonist piribedil, has a pharmacokinetic profile promising to provide rapid relief on motor signs in Parkinson's disease (PD). We assessed the efficacy and safety of S90049 in aborting OFF episodes responding to subcutaneous apomorphine in PD patients with motor fluctuations. This was a single‐dose double‐blind double‐placebo 3 × 3 cross‐over study. Optimal tested doses were determined during a previous open‐label titration phase (S90049 median dose: 60 mg, apomorphine: 5 mg). Primary endpoint was the maximal change versus baseline in UPDRS motor score (ΔUPDRS III) assessed after drug administration following an overnight withdrawal of antiparkinsonian medications. Thirty patients (age: 60 ± 8 years, PD duration: 12 ± 6 years, UPDRS III OFF: 37 ± 15) participated. S90049 wassuperior to placebo on ΔUPDRS III (?13 ± 12 versus ?7 ± 9 respectively; estimated difference ?5.2, 95% Confidence Interval (CI)[?10.4;0.05], P = 0.05). This was also true for secondary outcomes: number of patients switching from OFF to ON (17 on S90049 vs. 8 on placebo, P = 0.03), time to turn ON (P = 0.013) and duration of the ON phase (P = 0.03). In the 17 patients who switched ON on S90049, ΔUPDRS III was similar on S90049 (?21.2 ± 10.1) and apomorphine (?23.6 ± 14.1) (estimated difference: 4.0 95% CI [?2.9;10.9]). S90049 was well tolerated: no serious or unexpected adverse event occurred. A single dose of up to 60 mg of S90049 given sublingually was superior to placebo in improving UPDRS III and aborting a practical OFF in patients with advanced PD. Testing greater doses might improve response rate. © 2009 Movement Disorder Society     

Determining an optimal dose of linaclotide for use in Japanese patients with irritable bowel syndrome with constipation: A phase II randomized,double‐blind,placebo‐controlled study

Background

Clinical testing to determine a suitable dose of linaclotide for Japanese patients with irritable bowel syndrome with constipation (IBS‐C) was needed.

Methods

This was a randomized, double‐blind, placebo‐controlled, dose‐finding trial. Japanese patients with IBS‐C diagnosed using Rome III criteria (n = 559, men/women: 49/510) were randomly assigned to 1 of 4 linaclotide doses (0.0625, 0.125, 0.25, or 0.5 mg) or placebo for the 12‐week treatment period. The primary endpoint was responder rate of global assessment of relief of IBS symptoms during 12 weeks. The secondary endpoints included responder rates of complete spontaneous bowel movement (CSBM), SBM and abdominal pain/discomfort relief and others.

Key Results

The primary endpoint was 23.2%, 36.2%, 38.7%, 34.8%, and 38.3% in placebo (n = 112), 0.0625 (n = 116), 0.125 (n = 111), 0.25 (n = 112), and 0.5 (n = 107) mg of linaclotide groups with the difference from the placebo group in each linaclotide group (13.0%, 15.5%, 11.6%, 15.1%, P > .05). Monthly responder rate of global assessment of relief of IBS symptoms at month 3 (48.6%), responder rate of CSBM during 12 weeks (45.8%), and responder rate of abdominal pain/discomfort relief during 12 weeks (32.7%) in the 0.5 mg were significantly higher than those in placebo group (29.5%, P < .01; 25.9%, P < .01; and 18.8%, P < .05 respectively). The most frequent adverse event in the linaclotide groups was diarrhea.

Conclusions & Inferences

This study suggests that a linaclotide dose of 0.5 mg may be appropriate in Japanese patients with IBS‐C.     

Randomized,placebo‐controlled trial of incobotulinumtoxina for upper‐limb post‐stroke spasticity

Introduction: Efficacy and safety of incobotulinumtoxinA in post‐stroke upper‐limb spasticity were studied. Methods: Subjects randomized 2:1 to incobotulinumtoxinA (fixed dose 400 U) or placebo, with fixed doses for the primary target clinical pattern (PTCP; flexed elbow, 200 U; flexed wrist, 150 U; clenched fist, 100 U). Doses for non‐primary patterns were flexible within predefined ranges. Results: At week 4, incobotulinumtoxinA led to larger improvements in PTCP Ashworth scale (AS) scores than placebo [least‐squares mean change ± standard error: –0.9 ± 0.06 (n = 171) vs. –0.5 ± 0.08 (n = 88); P < 0.001], and more subjects were PTCP AS responders (≥1‐point improvement) with incobotulinumtoxinA (69.6%) than with placebo (37.5%; P < 0.001). Investigator's Global Impression of Change confirmed superiority of incobotulinumtoxinA vs. placebo (P = 0.003). IncobotulinumtoxinA was associated with functional improvements, as demonstrated in responder rates for Disability Assessment Scale principal target at week 4 (P = 0.007). Adverse events were mainly mild/moderate, and were reported by 22.4% (incobotulinumtoxinA) and 16.8% (placebo) of subjects. Conclusions: IncobotulinumtoxinA significantly improved upper‐limb spasticity and associated disability, and was well‐tolerated. Muscle Nerve 53: 415–421, 2016     

The role of rectal chloride secretion in childhood constipation

Background Disturbance in fluid secretion, driven by chloride secretion, might play a role in constipation. However, disturbed chloride secretion in those patients has yet to be evaluated. Therefore, the aim of this study was to compare chloride secretion in rectal biopsies of children with functional constipation (FC) to those without constipation. Methods To measure changes in short circuit current (I_sc in μA cm^?2) reflecting chloride secretion, intestinal biopsies from children with constipation, to either exclude or diagnose Hirschsprung’s disease, and from children without constipation (controls) undergoing colonoscopy for screening of familial adenomatous polyposis, juvenile polyps or inflammatory bowel disease (IBD), were compared and studied in Ussing chambers. Following electrogenic sodium absorption blockade by amiloride, chloride secretory responses to calcium‐linked (histamine, carbachol) and cAMP‐linked (IBMX/forskolin) secretagogues were assessed. Key Results Ninety‐six patients (46 FC) participated; nine FC patients (n = 1 congenital syndrome and n = 8 technical problems) and 13 controls (n = 6 IBD; n = 7 technical problems) were excluded. No significant difference was found in mean (±SE) basal chloride currents between children with FC and controls (9.6 ± 1.1 vs 9.2 ± 0.8; P = 0.75, respectively). Responses to calcium‐linked chloride secretagogues (histamine and carbachol) were significantly higher in controls (33.0 ± 3.0 vs 24.5 ± 2.3; P = 0.03 and 33.6 ± 3.4 vs 26.4 ± 2.7; P = 0.05 following histamine and carbachol, respectively). Conclusions & Inferences Calcium‐linked chloride secretion is disturbed in children with FC. Whether this defect occurs at the level of histamine receptors, components of receptor‐linked signal transduction pathways or basolateral Ca²⁺‐sensitive K⁺ channels enhancing the electrical driving force for apical chloride secretion, remains to be explored.     

Safety and efficacy of ghrelin agonist TZP‐101 in relieving symptoms in patients with diabetic gastroparesis: a randomized,placebo‐controlled study

Background Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP‐101, is in clinical development for treatment of gastroparesis. This double‐blind, randomized, placebo‐controlled study evaluated the safety and efficacy of multiple TZP‐101 doses in patients with moderate to severe symptomatic diabetic gastroparesis. Methods Patients were admitted to the hospital and adaptively randomized to receive a single 30‐min intravenous infusion of 20, 40, 80, 160, 320, or 600 μg kg^?1 TZP‐101, (n = 57) or placebo, (n = 19) for four consecutive days. Symptoms were evaluated daily with the patient‐rated Gastroparesis Cardinal Symptom Index (GCSI) and Gastroparesis Symptom Assessment (GSA). Clinicians rated gastroparesis symptoms on treatment day 4. Key Results The 80 μg kg^?1 dose was identified as the most effective dose. On day 4, there was statistically significant improvement compared with placebo in the severity of GCSI Loss of Appetite and Vomiting scores for that dose group (P = 0.034 and P = 0.006). In addition, at the 80 μg kg^?1 dose, the proportion of patients with at least 50% improvement in vomiting score was significantly different (P = 0.019) compared with placebo. Meal‐related GSA scores for Postprandial fullness were significantly improved in the 80 μg kg^?1 TZP‐101 group compared with placebo (P = 0.012). Clinicians rated the 80 μg kg^?1 group better improved than placebo for overall symptom assessment (P = 0.047). Safety profiles were similar in the placebo and TZP‐101 groups and all doses were well‐tolerated. Conclusions & Inferences TZP‐101 appears to be safe, well‐tolerated, and effective at acutely addressing several gastroparesis symptoms.     

A double‐blind,placebo‐controlled study of prucalopride in elderly patients with chronic constipation

Background Constipation affects up to 50% of the elderly; this study evaluates the efficacy, safety, and tolerability of the selective 5‐HT₄ agonist prucalopride in chronically constipated elderly patients. Methods Three hundred chronic constipation patients aged ≥65 years were randomized to prucalopride (1, 2, or 4 mg once daily) or placebo for 4 weeks. The primary endpoint was the percentage of patients with ≥3 spontaneous complete bowel movements (SCBM) per week. Secondary endpoints included the percentage with an increase of ≥1 SCBM per week, BM frequency, constipation‐related symptoms, quality of life (QoL), safety, and tolerability. Key Results More patients achieved ≥3 SCBM per week with prucalopride than with placebo. This difference was largest and significant during the first week of 4 mg prucalopride (P ≤ 0.05). Significantly more patients in each prucalopride group achieved an increase of ≥1 SCBM per week from baseline vs placebo (e.g. 60% with 1 mg prucalopride vs 34% with placebo at week 4; P ≤ 0.05). More patients had improvement in PAC‐QOL satisfaction score of ≥1 with 1 mg prucalopride than with placebo (P ≤ 0.05); the same was true for PAC‐SYM stool symptoms (1 and 4 mg prucalopride; P ≤ 0.05). Treatment‐emergent adverse events were similar between groups: the most frequently reported with prucalopride were headache and gastrointestinal events. There were no clinically significant differences between prucalopride and placebo for vital signs, laboratory assessments, or ECG variables. Conclusions & Inferences Prucalopride, in the dose‐range tested (1–4 mg once daily), has beneficial effects on bowel movements, symptoms, and QoL, and is safe and well‐tolerated in elderly patients with chronic constipation.     

Electrophysiology in chronic inflammatory demyelinating polyneuropathy with IGIV

Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) received immune globulin intravenous, 10% caprylate/chromatography purified (IGIV‐C, Gamunex; n = 59) or placebo (n = 58) every 3 weeks for up to 24 weeks (first period) in a randomized, double‐blind, parallel‐group, response‐conditional, crossover study. Motor and sensory nerves were assessed at baseline and endpoint/week 24. A nonsignificant trend toward improvement in the proximal amplitude of the most severely affected motor nerve was observed with IGIV‐C (0.69 ± 1.86 mV) versus placebo (0.47 ± 2.29 mV), and a greater improvement of 1.08 ± 2.15 mV with IGIV‐C versus 0.46 ± 2.03 mV with placebo (P = 0.089) was observed with exclusion of data from Erb's point stimulation. Greater improvements from baseline favoring IGIV‐C were observed for 127/142 electrophysiologic parameters. The averaged motor amplitudes from all motor nerves significantly improved with IGIV‐C versus placebo [treatment difference, 0.62 mV; 95% confidence interval (CI), 0.05, 1.20; P = 0.035], and conduction block decreased significantly (treatment difference, ?5.54%; 95% CI, ?10.43, ?0.64; P = 0.027), particularly in the lower limbs. Overall, the data suggest that IGIV‐C improves electrophysiologic parameters in CIDP. Muscle Nerve, 2009     

Lower functional gastrointestinal disorders: evidence of abnormal colonic transit in a 287 patient cohort

Background Abnormalities of colonic motility were reported in relatively small studies of patients with lower functional gastrointestinal disorders (FGID) including irritable bowel syndrome (IBS). The influence of gender and body mass on the observed motor pathophysiology is unclear. We sought to compare colonic transit in patients within different lower FGID subgroups and healthy controls, controlling for gender and BMI, and to determine whether BMI independently influences colonic motility. Methods We evaluated a scintigraphic gastrointestinal and colonic transit database of 287 lower FGID patients associated with constipation (IBS‐C, or functional constipation, n = 118), diarrhoea (IBS‐D or functional diarrhoea, n = 139) or mixed bowel function (IBS‐M, n = 30) and 170 healthy controls. We measured colon filling at 6 h (CF 6 h), and overall colonic transit at 8, 24 and 48 h. Key Results Colon filling at 6 h did not differentiate health from FGID. Colonic transit was abnormal at 24 h (GC24 of <1.50 or >3.86) in 29.7% of all lower FGID patients. There was a significant overall association between colonic transit and subject group (healthy controls and FGID subgroups) at 8 (P = 0.01), 24 (P < 0.001) and 48 h (P < 0.001) in particular for those with diarrhoea or constipation at 24 and 48 h (P < 0.05), even after adjusting for age, gender and BMI. In addition, BMI was associated with colonic transit after adjusting for age, gender and subject group. Conclusions & Inferences Abnormal transit is documented non‐invasively with scintigraphy in 30% of lower FGID patients; transit measurement may help document pathophysiology and inform selection of therapy in lower FGID.     

A double‐blind,placebo‐controlled trial of rosiglitazone for clozapine‐induced glucose metabolism impairment in patients with Schizophrenia

Objective: The primary purpose of this 8‐week double‐blind, placebo‐controlled trial of rosiglitazone 4 mg/day was to examine its effect on insulin sensitivity index (SI) and glucose utilization (SG) in clozapine‐treated subjects with schizophrenia with insulin resistance. Method: Eighteen subjects were randomized and accessed with a Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) at baseline and at week 8 to estimate SG and SI. Results: Controlling for the baseline, comparing the rosiglitazone group with placebo group, there was a non‐significant improvement in SG (0.016 ± 0.006–0.018 ± 0.008, effect size = 0.23, P = 0.05) with a trend of improvement in SI in the rosiglitazone group (4.6 ± 2.8–7.8 ± 6.7, effect size = 0.18, P = 0.08). There was a significant reduction in small low‐density lipoprotein cholesterol (LDL‐C) particle number (987 ± 443–694 ± 415, effect size = 0.30, P = 0.04). Conclusion: Rosiglitazone may have a role in addressing insulin resistance and lipid abnormalities associated with clozapine.     

Metabolic effects of adjunctive aripiprazole in clozapine‐treated patients with schizophrenia

Fan X, Borba CPC, Copeland P, Hayden D, Freudenreich O, Goff DC, Henderson DC. Metabolic effects of adjunctive aripiprazole in clozapine‐treated patients with schizophrenia. Objective: This study examined the effects of adjunctive aripiprazole therapy on metabolism in clozapine‐treated patients with schizophrenia. Method: In an 8‐week randomized, double‐blind, placebo‐controlled study, subjects received either aripiprazole (15 mg/day) or placebo. At baseline and week 8, metabolic parameters were assessed by the frequently sampled intravenous glucose tolerance test, nuclear magnetic resonance spectroscopy and whole‐body dual‐energy X‐ray absorptiometry (DXA). Results: Thirty subjects completed the study (16 in the aripiprazole group and 14 in the placebo group). Glucose effectiveness measured by the frequently sampled intravenous glucose tolerance test improved significantly in the aripiprazole group (0.003 ± 0.006 vs. ?0.005 ± 0.007/min, P = 0.010). The aripiprazole group showed significant reductions in both plasma low‐density lipoprotein (LDL) levels (?15.1 ± 19.8 vs. 4.4 ± 22.5 mg/dl, P = 0.019) and LDL particle numbers (?376 ± 632 vs. ?36 ± 301 nm , P = 0.035). Further, there was a significant reduction in the lean mass (?1125 ± 1620 vs. 607 ± 1578 g, P = 0.011) measured by whole‐body DXA scan in the aripiprazole group. All values were expressed as mean ± standard deviation, aripiprazole vs. placebo. Conclusion: Adjunctive therapy with aripiprazole may have some metabolic benefits in clozapine‐treated patients with schizophrenia.     

Effects of peer‐assisted training during the neurology clerkship: a randomized controlled study

Objective: To determine the efficacy of peer‐assisted clinical skills training for students during their neurology clerkship. Methods: Students (n = 122) were randomized to get clinical skills training from either student (peer) instructors (experimental group) or from experienced clinical staff (control group). The remaining schedule during the clerkship did not differ between both groups. Primary endpoint was students’ practical skills and knowledge tested at the end of the course by a written test and objective structured clinical examination (OSCE). Secondary endpoints were evaluation of the practical training and self‐estimated gain in theoretical and practical competence. Results: In the written test, the peer‐trained group (n = 66) scored 69.5 ± 10.2 (95% CI 67–72) points of 100 and the postgraduates‐trained group (n = 56) 66.7 ± 11.4 (95% CI 63.6–69.8) (P = 0.15). In the OSCE the peer‐trained group scored 93.7 ± 6.3 (95% CI 92.1 to 95.2) points of 100 and the postgraduates‐trained group 92 ± 5.1 (95% CI 90.6 to 93.4) (P = 0.11). In the evaluation and self‐assessment items, there was no significant difference between the two groups except for the postgraduates’ higher competence (P = 0.004). Conclusion: Peer‐trained students pass written exam and OSCE as efficient as postgraduates‐trained students. Self‐assessed learning success is equally rated in both groups.     

Muscular adaptations and insulin‐like growth factor‐1 responses to resistance training are stretch‐mediated

Introduction: Modulation of muscle characteristics was attempted through altering muscle stretch during resistance training. We hypothesized that stretch would enhance muscle responses. Methods: Participants trained for 8 weeks, loading the quadriceps in a shortened (SL, 0–50° knee flexion; n = 10) or lengthened (LL, 40–90°; n = 11) position, followed by 4 weeks of detraining. Controls (CON; n = 10) were untrained. Quadriceps strength, vastus lateralis architecture, anatomical cross‐sectional area (aCSA), and serum insulin‐like growth factor‐1 (IGF‐1) were measured at weeks 0, 8, 10, and 12. Results: Increases in fascicle length (29 ± 4% vs. 14 ± 4%), distal aCSA (53 ± 12% vs. 18 ± 8%), strength (26 ± 6% vs. 7 ± 3%), and IGF‐1 (31 ± 6% vs. 7 ± 6%) were greater in LL compared with SL muscles (P < 0.05). No changes occurred in CON. Detraining decrements in strength and aCSA were greater in SL than LL muscles (P < 0.05). Conclusions: Enhanced muscle in vivo (and somewhat IGF‐1) adaptations to resistance training are concurrent with muscle stretch, which warrants its inclusion within training. Muscle Nerve 49 : 108–119, 2014     

Atomoxetine treatment in adults with attention‐deficit/hyperactivity disorder and comorbid social anxiety disorder

Background: To evaluate the effect of atomoxetine (ATX) on attention‐deficit/hyperactivity disorder (ADHD) and comorbid social anxiety disorder in adults. Methods: Randomized, double‐blind, placebo‐controlled, conducted in adults with ADHD and social anxiety disorder. Patients received 40–100 mg ATX (n=224) or placebo (n=218) for 14 weeks following a 2‐week placebo lead‐in period. Efficacy measures included the Conners' Adult ADHD Rating Scale: Investigator‐Rated: Screening Version (CAARS:Inv:SV), Liebowitz Social Anxiety Scale (LSAS), Clinical Global Impression‐Overall‐Severity (CGI‐O‐S), State‐Trait Anxiety Inventory (STAI), Social Adjustment Scale‐Self Report (SAS), and Adult ADHD Quality of Life Scale‐29 (AAQoL). Safety and tolerability were also assessed. Results: ATX mean change (?8.7±10.0) from baseline (29.6±10.4) on CAARS:Inv:SV Total ADHD Symptoms score was significantly greater than placebo mean change (?5.6±10.2) from baseline (31.2±9.4; P<.001). ATX mean change (?22.9±25.3) from baseline (85.3±23.6) on LSAS Total score was significant compared to placebo mean change (?14.4±20.3) from baseline (82.1±21.3; P<.001). The visit‐wise analysis revealed greater improvement on the CAARS:Inv:SV Total ADHD Symptoms score and LSAS Total score for ATX at every time point throughout the study (P values ≤.012). Mean changes in CGI‐O‐S, STAI‐Trait Anxiety scores, and AAQoL Total score were significantly greater for ATX compared to placebo. Mean change for both groups on STAI‐State Anxiety scores was comparable. Improvement on SAS for ATX compared to placebo was not significant. Rates of insomnia, nausea, dry mouth, and dizziness were higher with ATX than with placebo. Discontinuation rates due to treatment‐emergent adverse events were similar between groups. Conclusions: ATX monotherapy effectively improved symptoms of ADHD and comorbid social anxiety disorder in adults and was well tolerated. Depression and Anxiety, 2009. Published 2009 Wiley‐Liss, Inc.     

Effect of 5‐HT4 receptor agonist mosapride citrate on rectosigmoid sensorimotor function in patients with irritable bowel syndrome

Background The 5‐HT₄ receptor agonist, mosapride citrate, accelerates gastric emptying. However, the effect of mosapride on colonic function has not been well investigated. We examined whether mosapride changes rectosigmoid motility and perception in patients with irritable bowel syndrome (IBS). Methods Thirty‐seven patients with IBS and 18 healthy subjects were studied. All subjects underwent a rectosigmoid barostat test to measure pain perception to intraluminal distention and resting smooth muscle motility for 20 min in the fasting state. Irritable bowel syndrome patients were then randomly assigned to receive either mosapride 15 mg (n = 19) or placebo (n = 18) orally with 200 mL water. Rectosigmoid motility and perception were measured again for 60 min following dosing. Rectosigmoid tone and contractility were evaluated in each 10‐min period. Key Results The pain threshold in the patients was significantly lower than that in controls (P < 0.01). There were no differences between mosapride and placebo groups in pain threshold, barostat bag volume, or number of contractions at baseline. Mosapride significantly decreased the mean bag volume (P < 0.01; group × period interaction by two‐way anova ) and increased the mean number of contractions (P < 0.05) compared with placebo, but did not affect the perception. In IBS patients with constipation (i.e., excluding diarrhea‐predominant subjects), mosapride (n = 13) increased rectosigmoid tone (P < 0.01) and contractions (P < 0.05) more than placebo (n = 14). Conclusions & Inferences Mosapride stimulates colonic motility without any adverse effect. These findings suggest that mosapride may have the potential to treat IBS patients with constipation and/or functional constipation. Further clinical trials are warranted to confirm the efficacy of this agent.     

Gastrointestinal‐specific anxiety: an important factor for severity of GI symptoms and quality of life in IBS

Background Gastrointestinal (GI)‐specific anxiety (GSA) has been proposed to influence symptom severity and quality of life (QOL) in patients with irritable bowel syndrome (IBS). The Visceral Sensitivity Index (VSI) is a recently developed, reliable and valid measure of GSA. Our aim was to evaluate the association between GSA, GI symptom severity, and QOL in IBS patients. Methods Sixty healthy subjects and 306 patients fulfilling the Rome II criteria for IBS were studied. Demographic and disease‐related factors were assessed. Patients completed VSI and GI Symptom Rating Scale (GSRS) and questionnaires to determine psychological symptom severity (Hospital Anxiety and Depression Scale), QOL (Short form 36), and presence of functional GI disorders (Rome II Modular Questionnaire). Key Results Compared with healthy subjects, patients with IBS had more severe GSA (34.7 ± 16.9 vs. 2.2 ± 4.4 [mean ± standard deviation]; P < 0.0001). In the IBS group, more severe GSA was seen in patients with more severe GI symptoms (P < 0.0001), general anxiety (P < 0.0001) and depression (P < 0.0001), and with lower socioeconomic status (P < 0.05). In a regression analysis, GSA was the strongest predictor for GI symptom severity (GSRS total score), followed by number of Rome II diagnoses, presence of meal‐related IBS symptoms, and gender (R² = 0.34). Gastrointestinal‐specific anxiety was also, together with general anxiety, depression, socioeconomic status, and gender, found to be independently associated with mental QOL (R² = 0.62). Conclusions & Inferences Gastrointestinal‐specific anxiety seems to be an important factor for GI symptom severity and QOL in patients with IBS.     

Effect of itopride on gastric emptying in longstanding diabetes mellitus

Abstract Delayed gastric emptying (GE) occurs in 30–50% of patients with longstanding type 1 or 2 diabetes, and represents a major cause of morbidity. Current therapeutic options are limited. We aimed at evaluating the effects of itopride on GE in patients with longstanding diabetes. Twenty‐five patients (20 type 1, 5 type 2; 10 males, 15 females; mean age 45.2 ± 2.7 years; body mass index 27.5 ± 0.9 kg m^?2; duration of diabetes 20.2 ± 2.4 years) were enrolled in a double‐blind, placebo‐controlled, randomized, crossover trial. Subjects received both itopride (200 mg) and placebo t.i.d. for 7 days, with a washout of 7–14 days. GE (scintigraphy), blood glucose (glucometer) and upper gastrointestinal (GI) symptoms (questionnaire) were measured following each treatment period. The test meal comprised 100 g ground beef (^99mTc‐sulphur colloid) and 150 mL of 10% dextrose [⁶⁷Ga‐ethylenediaminetetraacetic acid (EDTA)]. There was a slight trend for itopride to accelerate both solid (P = 0.09) and liquid (P = 0.09) GE. With itopride treatment, the emptying of both solids and liquids tended to be more accelerated, as the emptying with placebo was slower (solids: r = 0.39, P = 0.057; liquids: r = 0.44, P < 0.03). Twelve (48%) patients had delayed solid and/or liquid GE on placebo and in this group, itopride modestly accelerated liquid (P < 0.05), but not solid (P = 0.39), emptying. Itopride had no effect on mean blood glucose during the GE measurement (placebo: 9.8 ± 0.6 mmol L^?1vs itopride: 9.6 ±0.6 mmol L^?1), or GI symptoms (placebo: 1.4 ± 0.4 vs itopride: 1.8 ± 0.5). Itopride, in a dose of 200 mg t.i.d. for 7 days, tends to accelerate GE of liquids and solids in longstanding diabetes. The magnitude of this effect appears to be modest and possibly dependent on the rate of GE without itopride.     

A Prospective Open‐Label Trial of Lamotrigine Monotherapy in Children and Adolescents with Bipolar Disorder

Aim: To evaluate the safety and efficacy of lamotrigine monotherapy as an acute treatment of bipolar mood elevation in children with bipolar spectrum disorders. Method: This was a 12‐week, open‐label, prospective trial of lamotrigine monotherapy to assess the effectiveness and tolerability of this compound in treating pediatric bipolar disorder. Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impressions‐Improvement scale (CGI‐I), Children's Depression Rating Scale (CDRS), and Brief Psychiatric Rating Scale (BPRS). Adverse events were assessed through spontaneous self‐reports, vital signs weight monitoring, and laboratory analysis. Results: Thirty‐nine children with bipolar disorder (YMRS at entry: 31.6 ± 5.5) were enrolled in the study and 22 (56%) completed the 12‐week trial. Lamotrigine was slowly titrated to an average endpoint dose of 160.7 ± 128.3 in subjects <12 years of age (N = 22) and 219.1 ± 172.2 mg/day in children 12–17 years of age (N = 17). Treatment with lamotrigine was associated with statistically significant levels of improvement in mean YMRS scores (?14.9 ± 9.7, P < 0.001) at endpoint. Lamotrigine treatment also resulted in significant improvement in the severity of depressive, attention‐deficit/hyperactivity disorder (ADHD), and psychotic symptoms. Lamotrigine was generally well tolerated with marginal increase in body weight (47.0 ± 18.0 kg vs. 47.2 ± 17.9 kg, P= 0.6) and was not associated with abnormal changes in laboratory parameters. Several participants were discontinued due to skin rash; in all cases, the rash resolved shortly after discontinuation of treatment. No patient developed Steven Johnson syndrome. Conclusions: Open‐label lamotrigine treatment appears to be beneficial in the treatment of bipolar disorder and associated conditions in children. Future placebo‐controlled, double‐blind studies are warranted to confirm these findings.     

Impaired intestinal gas propulsion in manometrically proven dysmotility and in irritable bowel syndrome

Background Intestinal manometry is the current gold standard for diagnosing small bowel dysmotility; however, the functional significance of abnormal manometry is unknown. Our aim was to determine whether, and to what extent, intestinal gas propulsion is impaired in patients with manometrically proven dysmotility compared with healthy controls and patients with IBS. Methods Clearance and tolerance of a jejunal gas load (12 mL min^?1 for 2 h) were measured in 15 patients with severe abdominal symptoms and intestinal dysmotility evidenced by manometry, 15 patients with IBS and 15 healthy subjects. Thereafter, the effect of neostigmine (0.5 mg i.v. bolus) vs placebo (i.v. saline) was tested in six dysmotility patients. Key Results After 2‐h gas infusion, patients with dysmotility developed significantly more gas retention (717 ± 91 mL) than IBS patients (372 ± 82 mL; P = 0.0037) and healthy subjects (17 ± 67 mL; P < 0.0001 vs dysmotility; P = 0.0060 vs IBS). Despite the greater retention in dysmotility patients, abdominal perception (2.5 ± 0.6 score) and distension (7 ± 2 mm girth increment) were similar to IBS (3.9 ± 0.6 score and 7 ± 2 mm, respectively). In dysmotility patients, neostigmine produced immediate clearance of gas, and by 30 min had reduced gas retention (by ?552 ± 182 vs 72 ± 58 mL after saline; P = 0.008), abdominal symptoms (by ?0.8 ± 0.3 score vs 0.3 ± 0.2 after saline; P = 0.019) and distension (girth change ?5 ± 1 mm; P = 0.003 vs?2 ± 2 mm after saline). Conclusion & Inferences Patients with manometric dysmotility have markedly impaired intestinal gas propulsion. In IBS patients, impaired gas propulsion is less pronounced but associated with concomitant sensory dysfunction and poor tolerance of gas retention.     

Clinical Evaluation of the Daily Assessment of Symptoms‐Anxiety (DAS‐A): A New Instrument to Assess the Onset of Symptomatic Improvement in Generalized Anxiety Disorder

Introduction: Rapid onset of symptomatic improvement is a desirable characteristic of new generalized anxiety disorder (GAD) treatments. A validated rating scale is needed to assess GAD symptoms during the first days of treatment. Aims: To provide clinical data to support the validation of the Daily Assessment of Symptoms‐Anxiety (DAS‐A), a new instrument to assess onset of symptomatic improvement in GAD. Methods: We assessed the ability of the DAS‐A to detect onset of symptomatic improvement during the first week of therapy in 169 GAD patients randomized to paroxetine 20 mg/day, lorazepam 4.5 mg/day, or placebo for 4 weeks. Results: On the primary outcome measure, average change from baseline over the first 6 days of DAS‐A assessments, lorazepam (?14.5 ± 1.8 [LS mean, SE]; P= 0.006 vs. placebo) showed a significant improvement versus placebo (?7.85 ± 1.7), whereas paroxetine (?8.3 ± 1.7; P= 0.83 vs. placebo) did not. Lorazepam produced a significant treatment effect on the DAS‐A at 24 h (P= 0.0004), whereas paroxetine did not (P= 0.5666). Both active drugs produced statistically significant improvement versus placebo on the DAS‐A total change score (last‐observation carried forward method; LOCF, endpoint). On the DAS‐A total change score (observed cases analysis), lorazepam produced statistically significant improvement versus placebo at weeks 1, 2, and 4 (P < 0.05; no week 3 visit), whereas paroxetine, separated from placebo at weeks 2 and 4 (P < 0.05). Both active drugs produced results on the Hamilton Anxiety Rating Scale (HAM‐A) at weeks 1 through 4 that were similar to those found on the DAS‐A. Conclusions: These data indicate that the DAS‐A can detect symptomatic improvement in GAD patients treated with lorazepam during the first week of treatment, and, in a secondary analysis, as early as 24 h.