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.     

Altered profiles of intestinal microbiota and organic acids may be the origin of symptoms in irritable bowel syndrome

Background The profile of intestinal organic acids in irritable bowel syndrome (IBS) and its correlation with gastrointestinal (GI) symptoms are not clear. We hypothesized in this study that altered GI microbiota contribute to IBS symptoms through increased levels of organic acids. Methods Subjects were 26 IBS patients and 26 age‐ and sex‐matched controls. Fecal samples were collected for microbiota analysis using quantitative real‐time polymerase chain reaction and culture methods, and the determination of organic acid levels using high‐performance liquid chromatography. Abdominal gas was quantified by image analyses of abdominal X‐ray films. Subjects completed a questionnaire for GI symptoms, quality of life (QOL) and negative emotion. Key Results Irritable bowel syndrome patients showed significantly higher counts of Veillonella (P = 0.046) and Lactobacillus (P = 0.031) than controls. They also expressed significantly higher levels of acetic acid (P = 0.049), propionic acid (P = 0.025) and total organic acids (P = 0.014) than controls. The quantity of bowel gas was not significantly different between controls and IBS patients. Finally, IBS patients with high acetic acid or propionic acid levels presented with significantly worse GI symptoms, QOL and negative emotions than those with low acetic acid or propionic acid levels or controls. Conclusions & Inferences These results support the hypothesis that both fecal microbiota and organic acids are altered in IBS patients. A combination of Veillonella and Lactobacillus is known to produce acetic and propionic acid. High levels of acetic and propionic acid may associate with abdominal symptoms, impaired QOL and negative emotions in IBS.     

Gabapentin for the treatment of carpal tunnel syndrome: a randomized controlled trial

Objective: Based on its efficacy in treating neuropathic pain, gabapentin may be effective for the treatment of carpal tunnel syndrome (CTS). The purpose of this study was to evaluate the efficacy of gabapentin for symptom relief in CTS. Methods: We conducted a randomized, double‐blinded, placebo‐controlled trial recruiting patients with newly diagnosed idiopathic CTS of more than a period of three months. Diagnosis was based on characteristic symptoms with electrophysiological confirmation. Patients were randomly assigned to an active group receiving gabapentin (starting dose 300 mg once daily to a target of 900 mg daily) or a placebo group. Primary end‐point was the global symptom score (GSS), which was measured at baseline, two, and eight weeks. Results: There was no significant difference in baseline variables between the two treatment groups. Hundred and forty patients were enrolled in the study, of whom 71 were randomly assigned to gabapentin group and 69 assigned to placebo group. Both gabapentin and placebo produced significant improvement in symptoms at two and eight weeks. The GSS at 2 and 8 weeks was 16.4 (SD 9.4) and 13.4 (SD 9.7), respectively, in the active group versus 14.9 (SD 9.0) and 12.5 (SD 8.9) in the control group (P < 0.01). But by eight weeks, the mean reduction in symptom severity of patients on gabapentin [−10.4 (SD 10.8)] was not significant when compared with placebo [−8.7 (SD 8.1), P < 0.39]. Adverse events were not severe and included dizziness, somnolence, and headache. Conclusions: Gabapentin did not produce a significant reduction in symptom severity compared with placebo over an eight‐week period.     

Postinfectious irritable bowel syndrome: follow-up of a patient cohort of confirmed cases of bacterial infection with Salmonella or Campylobacter

Background Gastrointestinal infections have been proposed to predict subsequent irritable bowel syndrome (IBS) but large‐scale infectious events are rare and long‐term data are missing. Methods We identified 576 individuals with a Salmonella or Campylobacter infection between 2000 and 2009 that were followed by a short postal questionnaire asking for the presence of current symptoms in 2010. In case of agreement (n = 90), an extended postinfectious (PI)‐IBS questionnaire was mailed including the Hospital Anxiety Depression Scale and the Patient Health Questionnaire. Key Results A total of 189 patients reported back (36%); 98 had a Salmonella and 91 had a Campylobacter infection, of which 56 reported persistent symptoms (9.7% of the initial sample). Fifty‐one patients returned the PI‐IBS questionnaire. Of 48 patients with complete data, 15 reported no or mild symptoms of abdominal pain or discomfort while 17 had moderate and 16 severe symptoms. Twenty‐two met Rome IBS criteria, 14 (29%) reported GI symptoms before the infection. Patients with moderate and/or severe PI‐IBS symptoms were significantly more often females, were more often infected by Salmonella than by Campylobacter, had more severe symptoms during the initial infection, and had more often GI symptoms prior to the infection. They reported higher anxiety, depression, and somatisation scores, but were not different with respect to acute stool habits. Conclusions & Inferences Nearly 10% of patients with an intestinal bacterial infection report postinfectious symptoms up to 10 years after the infectious event. They represent a clinically important population with high psychiatric comorbidity and somatic symptom burden.     

Distinct microbial populations exist in the mucosa-associated microbiota of sub-groups of irritable bowel syndrome

Background There is increasing evidence to support a role for the gastrointestinal microbiota in the etiology of irritable bowel syndrome (IBS). Given the evidence of an inflammatory component to IBS, the mucosa‐associated microbiota potentially play a key role in its pathogenesis. The objectives were to compare the mucosa‐associated microbiota between patients with diarrhea predominant IBS (IBS‐D), constipation predominant IBS (IBS‐C) and controls using fluorescent in situ hybridization and to correlate specific bacteria groups with individual IBS symptoms. Methods Forty‐seven patients with IBS (27 IBS‐D and 20 IBS‐C) and 26 healthy controls were recruited to the study. Snap‐frozen rectal biopsies were taken at colonoscopy and bacterial quantification performed by hybridizing frozen sections with bacterial‐group specific oligonucleotide probes. Key Results Patients with IBS had significantly greater numbers of total mucosa‐associated bacteria per mm of rectal epithelium than controls [median 218 (IQR – 209) vs 128 (121) P = 0.007], and this was chiefly comprised of bacteroides IBS [69 (67) vs 14 (41) P = 0.001] and Eubacterium rectale–Clostridium coccoides [52 (58) vs 25 (35) P = 0.03]. Analysis of IBS sub‐groups demonstrated that bifidobacteria were lower in the IBS‐D group than in the IBS‐C group and controls [24 (32) vs 54 (88) vs 32 (35) P = 0.011]. Finally, amongst patients with IBS, the maximum number of stools per day negatively correlated with the number of mucosa‐associated bifidobacteria (P < 0.001) and lactobacilli (P = 0.002). Conclusions & Inferences The mucosa‐associated microbiota in patients with IBS is significantly different from healthy controls with increases in bacteroides and clostridia and a reduction in bifidobacteria in patients with IBS‐D.     

Efficacy and safety of oral lubiprostone in constipated patients with or without irritable bowel syndrome: a randomized,placebo‐controlled and dose‐finding study

Background Lubiprostone is a prostone analog with a novel mechanism of action involving type‐2 chloride channel activation. The aim of this work was to perform a dose‐finding study for lubiprostone for the treatment of constipation with or without irritable bowel syndrome (IBS) in Japan. Methods A total of 170 patients (128 without IBS and 42 with IBS) with chronic idiopathic constipation (CIC) randomly received a placebo (n = 42) or 16 μg (n = 41), 32 μg (n = 43), or 48 μg (n = 44) of lubiprostone daily for 2 weeks. Key Results There was a statistically significant and dose‐dependent increase in change from baseline in the weekly average number of spontaneous bowel movements at week 1 (placebo: 1.5 ± 0.4; 16 μg: 2.3 ± 0.4, 32 μg: 3.5 ± 0.5; and 48 μg: 6.8 ± 1.1, per week, mean ± SE; P < 0.0001). These primary endpoint results were significant on stratified analysis when patients were limited to those without IBS (P < 0.0001). The primary endpoint in patients with IBS treated with 48 μg of lubiprostone was significantly better than those given placebo (P = 0.0086). Dose dependency was also seen for the secondary efficacy endpoints. Lubiprostone produced no serious side effects. Conclusions & Inferences Our results suggest that lubiprostone produced a steady and effective improvement in the symptoms of CIC with or without IBS in a dose‐dependent manner with a good safety profile and tolerability in a Japanese population.     

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.     

Efficacy of prednisone for the treatment of ocular myasthenia (EPITOME): A randomized,controlled trial

Introduction: In this study we evaluated the safety, tolerability, and efficacy of prednisone in patients with ocular myasthenia gravis (OMG) concurrently treated with pyridostigmine. Methods: This investigation was a randomized, double‐blind, placebo‐controlled trial. Participants whose symptoms failed to remit on pyridostigmine were randomized to receive placebo or prednisone, initiated at 10 mg every other day, and titrated to a maximum of 40 mg/day over 16 weeks. The primary outcome measure was treatment failure. Results: Fewer subjects were randomized than the 88 planned. Of the 11 randomized, 9 completed 16 weeks of double‐blind therapy. Treatment failure incidence was 100% (95% CI 48%–100%) in the placebo group (n = 5) vs. 17% (95% CI 0%–64%) in the prednisone group, P = 0.02 (n = 6). Median time to sustained minimal manifestation status (MMS) was 14 weeks, requiring an average prednisone dose of 15 mg/day. Adverse events were infrequent and generally mild in both groups. Conclusions: A strategy of low‐dose prednisone with gradual escalation appears to be safe, well‐tolerated, and effective in treating OMG. Muscle Nerve 53: 363–369, 2016     

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.     

Tianeptine vs amitriptyline for the treatment of irritable bowel syndrome with diarrhea: a multicenter, open-label, non-inferiority, randomized controlled study

Background Tricyclic antidepressants have good efficacy in irritable bowel syndrome with diarrhea (IBS‐D), but their clinical use is limited by considerations of tolerability. Tianeptine, another antidepressant, acts as a selective serotonin reuptake enhancer. We compared tianeptine with amitriptyline for the treatment of patients with IBS‐D. Methods We undertook a multicenter, randomized, open‐label, non‐inferiority clinical study that compared tianeptine with amitriptyline, each in combination with probiotics, for the treatment of IBS‐D. Subjects were randomized to receive tianeptine (37.5 mg)/probiotics (Bacillus subtilis + Streptococcus faecium) or amitriptyline (10 mg)/probiotics (Bacillus subtilis + Streptococcus faecium) for 4 weeks. A total of 228 patients were analyzed by the intention‐to‐treat approach. The primary efficacy endpoint was the proportion of patients who had global relief of IBS symptoms at week 4. The secondary efficacy endpoints were intensity of abdominal pain/discomfort, stool frequency/consistency, quality of life, and overall satisfaction with treatment. Key Results At week 4, non‐inferiority of the tianeptine group to the amitriptyline group (treatment difference ?15.1%; 95% CI ?26.6% to ?3.8%) was shown, with 81.1% (99 of 122 patients) of the patients in the tianeptine group and 66.0% (70 of 106 patients) in the amitriptyline group reporting global relief of IBS symptoms. The secondary endpoints also demonstrated non‐inferiority of the tianeptine group to the amitriptyline group. Adverse events such as dry mouth and constipation were significantly lower in the tianeptine group than the amitriptyline group (P < 0.05). Conclusions & Inferences Tianeptine is not inferior to amitriptyline for treating IBS‐D in terms of both efficacy and tolerability.     

Factors associated with co‐morbid irritable bowel syndrome and chronic fatigue‐like symptoms in functional dyspepsia

Background It is unclear which factors explain the high co‐morbidity between functional dyspepsia (FD) and other functional somatic syndromes. The aim of this study is to investigate the association between gastric sensorimotor function, psychosocial factors and ‘somatization’ on the one hand, and co‐morbid irritable bowel syndrome (IBS) and chronic fatigue (CF)‐like symptoms on the other, in FD. Methods In 259 tertiary care FD patients, we studied gastric sensorimotor function with barostat (sensitivity, accommodation). We measured psychosocial factors (abuse history, alexithymia, trait anxiety, depression, panic disorder) and ‘somatization’ using self‐report questionnaires, and presence of IBS and CF‐like symptoms. Hierarchical multiple logistic regression was used to determine which of these factors were independently associated with co‐morbid IBS and CF‐like symptoms, including testing of potential mediator effects. Key Results Co‐morbid IBS or CF‐like symptoms respectively were found in 142 (56.8%) and 102 (39.4%) patients; both co‐morbidities were not significantly associated (P = 0.27). Gastric accommodation (β = 0.003, P = 0.04) and ‘somatization’ (β = 0.17, P = 0.0003) were independent risk factors for IBS (c = 0.74, P < 0.0001); the effect of adult abuse (β = 0.72, P = 0.20) was mediated by ‘somatization’. Depression (β = 0.16, P = 0.008) and ‘somatization’ (β = 0.18, P = 0.004) were overlapping risk factors for CF‐like symptoms (c = 0.83, P < 0.0001); the effects of alexithymia and lifetime abuse were mediated by depression and ‘somatization’, respectively. Conclusions & Inferences ‘Somatization’ is a common risk factor for co‐morbid IBS and CF‐like symptoms in FD and mediates the effect of abuse. Gastric sensorimotor function and depression are specific risk factors for co‐morbid IBS and CF‐like symptoms, respectively.     

Prucalopride in the treatment of chronic constipation in patients from the Asia‐Pacific region: a randomized,double‐blind,placebo‐controlled study

Background The study evaluated efficacy and safety of the 2 mg dose of prucalopride compared to placebo in patients with chronic constipation (CC) from the Asia‐Pacific region. Methods Randomized, placebo‐controlled, parallel‐group, phase III study with 2‐week run‐in, 12‐week treatment phase, and 1‐week follow‐up. Adult patients with CC (≤2 spontaneous bowel movements per week) received 2 mg prucalopride or placebo, once‐daily, for 12 weeks. Primary efficacy measure was percentage of patients with average of ≥3 spontaneous complete bowel movements (SCBMs) per week (Responders) during the 12‐week treatment. A key secondary endpoint was Responders during first 4 weeks of treatment. Other efficacy assessments were based on patient diaries, their assessments of symptoms and quality of life, and investigator’s assessment on efficacy of treatment. Safety assessments included adverse events, laboratory values, and cardiovascular events. Key Results Efficacy and safety were evaluated for 501 patients who received study drug. On the primary endpoint, prucalopride was significantly more effective than placebo with 83 (33.3%) vs 26 (10.3%) patients having a weekly average of ≥3 SCBMs during the 12‐week treatment (P < 0.001). Respective percentages were 34.5%vs 11.1% over first 4 weeks (P < 0.001). On other secondary endpoints, clinical improvement was generally larger and statistically superior (P < 0.001) in the prucalopride group. Most frequently reported adverse events were diarrhea, nausea, abdominal pain, and headache. Conclusion & Inferences Prucalopride 2 mg given once‐daily significantly improved bowel function, associated symptoms, and satisfaction in CC over a 12‐week treatment period, and was safe and well tolerated by patients in the Asia‐Pacific region.     

Serum correlates of the placebo effect in irritable bowel syndrome

Background In diseases defined primarily by the subjective nature of patient self‐report, placebo effects can overwhelm the capacity of randomized controlled trials to detect medication‐placebo differences. Moreover, it is unclear whether such placebo effects represent genuine psychobiological phenomena or just shifts in selective attention. Knowledge of predictors of the placebo response could improve the design of clinical trials and the delivery of personalized medical care. Methods In patients with irritable bowel syndrome (IBS), a subset of our previous study that were randomized to placebo treatment (sham acupuncture) or no‐treatment group (waitlist), we tested an enriched panel of 10 serum biomarkers at the enrolment and the 3rd week of intervention, using a multiplex electrochemiluminescent immunoassay. Key Results More pronounced changes overtime in serum levels of osteoprotegerin (OPG) have been found in patients who received placebo treatment compared with the waitlist group (P = 0.039). Moreover, serum levels of OPG at baseline were found to be higher (P = 0.0167) in patients who subsequently achieved adequate relief (AR) of their IBS symptoms, independently of their treatment group. Besides, serum levels of TNF‐related weak inducer of apoptosis (TWEAK) at baseline were also higher (P = 0.0144) in patients who reported AR and in particular in those who received the placebo treatment. Conclusions & Inferences These two measurable biological parameters associated with placebo, namely serum OPG and TWEAK, provide a proof of principle for discovering putative molecular signatures of placebo response in IBS and perhaps in other illnesses with patient self‐reported outcomes.     

Relationships between pelvic floor symptoms and function in irritable bowel syndrome

Background  Pelvic floor dyssynergia (PFD) within irritable bowel syndrome (IBS) is often overlooked and the relationship between symptoms and physiology is relatively unexplored. Our aims were to determine relationships between clinical features and anorectal function in non‐diarrhea predominant IBS (non‐D IBS) patients and whether certain clinical or physiological features predict PFD in IBS. Methods  Two groups of patients were evaluated. Group I: 32 female non‐D IBS patients with ≥2 symptoms suggesting PFD underwent comprehensive symptom and anorectal function assessment. Group II: 32 female non‐D IBS patients recruited from the community underwent symptom assessment. Key Results  Prevalence of PFD symptoms was similar in both groups. In group I patients, increased frequency of digitation was associated with a longer balloon expulsion time (P = 0.03). Higher scores for anal pain were associated with both a low resting anal pressure (P = 0.04) and a shorter duration of maximum squeeze (P = 0.03). Reduced perineal descent was associated with anxiety (P = 0.03) and depression (P = 0.01). A shorter duration of maximum squeeze was associated with higher parity (P = 0.02) and previous hysterectomy (P = 0.047). Duration of PFD symptoms was higher (P = 0.02) and maximum tolerated volume was lower (P = 0.05) in 22 patients with a physiological diagnosis of PFD compared to 10 without PFD. No symptoms independently predicted a physiological diagnosis of PFD. Conclusions & Inferences  Important relationships between certain PFD symptoms and disordered anorectal physiology have been demonstrated in these non‐D IBS patients. However, symptoms alone could not predict PFD, and certain clinical features should therefore highlight the need for comprehensive anorectal function tests.     

Clinical efficacy of istradefylline (KW‐6002) in Parkinson's disease: A randomized,controlled study

The objectives of this study were to evaluate the efficacy of istradefylline at an oral dose of 20 mg or 40 mg once daily for 12 weeks in Parkinson's disease (PD) patients with motor complications on levodopa therapy based on the change in the daily OFF time compared with placebo and to assess the safety at these doses. A total of 363 subjects were randomly assigned to receive 20 mg/day istradefylline (n = 119), 40 mg/day istradefylline (n = 125), or placebo (n = 119). The primary outcome variable was the change from baseline at endpoint in daily OFF time based on patients' ON/OFF diaries. At endpoint, the daily OFF time reduced from baseline by 1.31 hours for 20 mg/day istradefylline (P = 0.013 as compared to the placebo), 1.58 hours for 40 mg/day istradefylline (P < 0.001), and 0.66 hours for placebo; istradefylline significantly reduced the daily OFF time compared with placebo. The UPDRS Part III subscale score (ON state) reduced by 5.7 at endpoint in both istradefylline groups and 3.7 in the placebo group (P = 0.006 for 20 mg/day and P = 0.006 for 40 mg/day group as compared with placebo). The most commonly reported drug‐related treatment emergent adverse event (TEAE) was dyskinesia, which occurred in 2.5% (3/119) of subjects receiving placebo, 8.5% (10/118) receiving 20 mg/day istradefylline, and 6.4% (8/125) receiving 40 mg/day istradefylline. We conclude that istradefylline at 20 mg and 40 mg once daily is effective in relieving wearing‐off fluctuations of PD patients. In addition, istradefylline was well tolerated at both doses. © 2010 Movement Disorder Society     

Tryptophan catabolism in females with irritable bowel syndrome: relationship to interferon‐gamma,severity of symptoms and psychiatric co‐morbidity

Abstract Irritable bowel syndrome (IBS) has been linked with abnormal serotonin functioning and immune activation. Tryptophan forms the substrate for serotonin biosynthesis, but it can alternatively be catabolized to kynurenine (Kyn) by the enzyme indoleamine 2,3‐dioxygenase (IDO), the main inducer of which is interferon‐gamma. The primary aim of this study was to test the hypothesis that IBS is associated with increased tryptophan (Trp) catabolism along the Kyn pathway due to increased IFN‐γ levels. Plasma Kyn, Trp and IFN‐γ levels were measured in 41 female IBS subjects and 33 controls. Indoleamine 2,3‐dioxygenase activity was assessed using the Kyn to Trp ratio. Psychiatric co‐morbidity was assessed using the Patient Health Questionnaire, and severity of IBS assessed using self‐report ordinal scales. Irritable bowel syndrome subjects had increased Kyn concentrations compared with controls (P = 0.039) and there was a trend for Kyn:Trp to be increased in the IBS group (P = 0.09). There was a positive correlation between IBS severity and Kyn:Trp (r = 0.57, P < 0.001). Those with severe IBS symptoms had increased Kyn:Trp (P < 0.005) compared to those with less severe symptoms and controls, and were over twice as likely to have depression or anxiety compared to those with less severe IBS (RR = 2.2, 95% CI 1.2–3.9). No difference in IFN‐γ levels was observed between groups; however, IFN‐γ was positively correlated with Kyn:Trp in IBS (r = 0.58, P = 0.005) but not controls (r = 0.12, P = 0.5). Females with IBS have abnormal Trp catabolism. The Kyn:Trp is related to symptom severity, and those with severe IBS symptoms have increased shunting of Trp along the Kyn pathway which contributes to the abnormal serotonergic functioning in this syndrome.     

Food supplements and diet as treatment options in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a chronic functional bowel disorder affecting 5.7% of the general population. Most patients relate their symptoms of IBS to foods they consume with diet being the most frequently reported factor impacting their life. However, although some foods may trigger symptoms, others may provide symptom relief. Indeed, several foods and diets have been investigated for their effectiveness in relieving IBS symptoms. In this issue of Neurogastroenterology and Motility, a double‐blind randomized placebo‐controlled trial in 160 patients with IBS demonstrated Aloe vera not to be effective in improving IBS symptoms. The aim of this review is to discuss the evidence on the effect of food supplements and diets in the management of IBS. Specifically, this review examines the evidence for aloe vera, peppermint oil, probiotics, fiber and prebiotics, healthy eating, the low FODMAP diet, and the gluten‐free diet.     

Efficacy and safety of incobotulinumtoxinA (NT 201, Xeomin) in the treatment of blepharospasm—A randomized trial

IncobotulinumtoxinA (NT 201, Xeomin) is a highly purified botulinum neurotoxin type A formulation, free from complexing proteins. A randomized, placebo‐controlled, double‐blind trial of efficacy and safety compared incobotulinumtoxinA (up to 50 U per eye) to placebo administered in a single treatment session to patients with blepharospasm. All patients had documented satisfactory response to 2 previous treatments with botulinum neurotoxin type A other than incobotulinumtoxinA and had Jankovic Rating Scale severity subscores ≥ 2. Patients (n = 109) were randomized in a 2:1 ratio to incobotulinumtoxinA or placebo and followed up to 20 weeks; 94% completed the study. A significant difference was observed in the primary efficacy variable (change in Jankovic Rating Scale severity subscore rated by an independent rater 6 weeks following treatment), favoring incobotulinumtoxinA by 1.0 point (95% CI [0.5–1.4]; P < .001). Functional impairment, as measured by the Blepharospasm Disability Index, improved by 0.5 points (95% CI [0.2–0.7]; P = .002) compared with placebo. There was a strong correlation between the 2 scale scores. In addition, all secondary outcome measures favored incobotulinumtoxinA. Patients rated the mean therapeutic effect of incobotulinumtoxinA significantly better than placebo (P < .001). Adverse events were reported in 70.3% of incobotulinumtoxinA patients and 58.8% of placebo patients. Eyelid ptosis (18.9% vs 5.9%), dry eye (18.9% vs 11.8%), and dry mouth (14.9% vs 2.9%) occurred most frequently. Tolerability was rated good/very good by 91.9% of incobotulinumtoxinA versus in 85.2% of placebo patients. In conclusion, incobotulinumtoxinA was well tolerated and was associated with statistically significant and clinically relevant reductions in blepharospasm severity and functional impairment. © 2011 Movement Disorder Society     

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.     

Antibodies to flagellin indicate reactivity to bacterial antigens in IBS patients

Abstract One of the several possible causes of irritable bowel syndrome (IBS) is thought to be low‐grade mucosal inflammation. Flagellin, the primary structural component of bacterial flagellae, was shown in inflammatory bowel disease patients to activate the innate and adaptive immunity. It has not yet been conclusively established if IBS patients show reactivity to luminal antigens. In 266 patients [112 IBS, 61 Crohn’s disease (CD), 50 ulcerative colitis (UC) and 43 healthy controls (HC)], we measured antibodies to flagellin (FAB, types A4‐Fla2 and Fla‐X), anti‐Saccharomyces cerevisiae antibodies (ASCA) (both ELISA), antipancreas antibodies (PAB) and perinuclear antineutrophil cytoplasmatic antibodies (p‐ANCA) (both IF). All IBS patients had normal fecal calprotectin (mean 21 μg mL^?1, SD 6.6) and fulfilled the ROME II criteria. Frequencies of antibodies in patients with IBS, CD, UC and HC, respectively, are as follows (in per cent): antibodies against A4‐Fla2: 29/48/8/7; antibodies against Fla‐X: 26/52/10/7; ASCA: 6/59/0/2; p‐ANCA: 0/10/52/0; and PAB: 0/28/0/0. Antibodies against A4‐Fla2 and Fla‐X were significantly more frequent in IBS patients than in HC (P = 0.004 and P = 0.009). Antibodies to A4‐Fla2 and Fla‐X were significantly more frequent in IBS patients with antecedent gastroenteritis compared to non‐postinfectious IBS patients (P = 0.002 and P = 0.012). In contrast to ASCA, PAB and p‐ANCA, antibodies against A4‐Fla2 and Fla‐X were found significantly more often in IBS patients, particularly in those with postinfectious IBS, compared to HC. This observation supports the concept that immune reactivity to luminal antigens has a putative role in the development of IBS, at least in a subset of patients.