l‐Carnitine Attenuates Cardiac Remodelling rather than Vascular Remodelling in Deoxycorticosterone Acetate‐Salt Hypertensive Rats

Abstract: l ‐Carnitine is an important co‐factor in fatty acid metabolism by mitochondria. This study has determined whether oral administration of l ‐carnitine prevents remodelling and the development of impaired cardiovascular function in deoxycorticosterone acetate (DOCA)‐salt hypertensive rats (n = 6–12; #p < 0.05 versus DOCA‐salt). Uninephrectomized rats administered DOCA (25 mg every 4th day s.c.) and 1% NaCl in drinking water for 28 days developed cardiovascular remodelling shown as systolic hypertension, left ventricular hypertrophy, increased thoracic aortic and left ventricular wall thickness, increased left ventricular inflammatory cell infiltration together with increased interstitial collagen and increased passive diastolic stiffness and vascular dysfunction with increased plasma malondialdehyde concentrations. Treatment with l ‐carnitine (1.2% in food; 0.9 mg/g/day in DOCA‐salt rats) decreased blood pressure (DOCA‐salt 169 ± 2; + l ‐carnitine 148 ± 6# mmHg), decreased left ventricular wet weights (DOCA‐salt 3.02 ± 0.07; + l ‐carnitine 2.72 ± 0.06# mg/g body‐wt), decreased inflammatory cells in the replacement fibrotic areas, reduced left ventricular interstitial collagen content (DOCA‐salt 14.4 ± 0.2; + l ‐carnitine 8.7 ± 0.5# % area), reduced diastolic stiffness constant (DOCA‐salt 26.9 ± 0.5; + l ‐carnitine 23.8 ± 0.5# dimensionless) and decreased plasma malondialdehyde concentrations (DOCA‐salt 26.9 ± 0.8; + l ‐carnitine 21.2 ± 0.4# μmol/l) without preventing endothelial dysfunction. l ‐carnitine attenuated the cardiac remodelling and improved cardiac function in DOCA‐salt hypertension but produced minimal changes in aortic wall thickness and vascular function. This study suggests that the mitochondrial respiratory chain is a significant source of reactive oxygen species in the heart but less so in the vasculature in DOCA‐salt rats, underlying the relatively selective cardiac responses to l ‐carnitine treatment.     

Changes in hepatic lipogenic and oxidative enzymes and glucose homeostasis induced by an acetyl‐l‐carnitine and nicotinamide treatment in dyslipidaemic insulin‐resistant rats

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Once daily MMX mesalazine for the treatment of mild-to-moderate ulcerative colitis: a phase II, dose-ranging study

Background SPD476 (MMX? mesalazine), is a novel, once daily, high‐strength mesalazine formulation (1.2 g/tablet) that utilizes Multi Matrix System? (MMX) technology to delay and extend delivery of the active drug throughout the colon. Aim To assess the safety and efficacy of MMX mesalazine in patients with mild‐to‐moderately active ulcerative colitis, in a pilot, phase II, randomized, multicentre, double‐blind, parallel‐group, dose‐ranging study (SPD476‐202). Methods Thirty‐eight patients with mild‐to‐moderately active ulcerative colitis were randomized to MMX mesalazine 1.2, 2.4 or 4.8 g/day given once daily for 8 weeks. Remission ulcerative colitis‐disease activity index (UC‐DAI) ≤1, a score of 0 for rectal bleeding and stool frequency, and ≥1‐point reduction in sigmoidoscopy score from baseline was the primary end point. Results Week 8 remission rates were 0%, 31% and 18% of patients receiving MMX mesalazine 1.2, 2.4 and 4.8 g/day respectively. No statistically significant difference in remission was observed between treatment groups. MMX mesalazine 2.4 and 4.8 g/day groups demonstrated greater improvement in overall UC‐DAI and component scores from baseline, compared with the 1.2 g/day group. Conclusion MMX mesalazine given as 2.4 or 4.8 g/day once daily is well tolerated and effective for the treatment of mild‐to‐moderately active ulcerative colitis.     

MMX Multi Matrix System mesalazine for the induction of remission in patients with mild-to-moderate ulcerative colitis: a combined analysis of two randomized, double-blind, placebo-controlled trials

BACKGROUND: MMX mesalazine [LIALDA (US), MEZAVANT XL (UK and Ireland) MEZAVANT (elsewhere)] utilizes MMX Multi Matrix System (MMX) technology which delivers mesalazine throughout the colon. Two phase III studies have already evaluated MMX mesalazine in patients with active, mild-to-moderate ulcerative colitis. Aim To provide more precise estimates of the efficacy of MMX mesalazine over placebo by combining the patient populations from the two phase III studies. Methods Combined data from two 8-week, double-blind, placebo-controlled trials were analyzed. Patients randomized to MMX mesalazine 2.4 g/day (once daily or 1.2 g twice daily), 4.8 g/day (once daily) or placebo were reviewed. The primary end point was clinical and endoscopic remission (modified Ulcerative Colitis-Disease Activity Index of /=1-point reduction in sigmoidoscopy score from week 0). Results Data from 517 patients were analysed. 8-week remission rates were 37.2% and 35.1% in the MMX mesalazine 2.4 g/day and 4.8 g/day groups, vs. 17.5% on placebo (P < 0.001, both comparisons). 8-week complete mucosal healing rates were 32% in both MMX mesalazine groups compared with 16% on placebo. Adverse event frequency was similar in all groups. Conclusion MMX mesalazine is effective and generally well tolerated for inducing clinical and endoscopic remission of active, mild-to-moderate ulcerative colitis.     

Mildronate treatment alters γ-butyrobetaine and l-carnitine concentrations in healthy volunteers

Objectives In this study, we aimed to investigate the effects of long‐term administration of the cardioprotective drug mildronate on the concentrations of l ‐carnitine and γ‐butyrobetaine in healthy volunteers. Methods Mildronate was administered perorally, at a dosage of 500 mg, twice daily. Plasma and urine samples were collected weekly. Daily meat consumption within an average, non‐vegetarian diet was monitored. l ‐Carnitine, γ‐butyrobetaine and mildronate concentrations were measured using the UPLC/MS/MS method. Key findings After 4 weeks, the average concentrations of l ‐carnitine in plasma significantly decreased by 18%. The plasma concentrations of γ‐butyrobetaine increased about two‐fold, and this effect was statistically significant in both the male and female groups. In urine samples, a significant increase in l ‐carnitine and γ‐butyrobetaine levels was observed, which provides evidence for increased excretion of both substances during the mildronate treatment. At the end of the treatment period, the plasma concentration of mildronate was 20 µm on average. There were no significant differences between the effects observed in female and male volunteers. Meat consumption partially reduced the l ‐carnitine‐lowering effects induced by mildronate. Conclusions Long‐term administration of mildronate significantly lowers l ‐carnitine plasma concentrations in non‐vegetarian, healthy volunteers.     

MMX mesalazine for the induction of remission of mild-to-moderately active ulcerative colitis: efficacy and tolerability in specific patient subpopulations

Background  Two phase III studies have evaluated mesalazine (mesalamine) with MMX (Multi Matrix System) technology in patients with active mild-to-moderate ulcerative colitis.
Aim  To determine the efficacy of MMX mesalazine for the induction of clinical and endoscopic remission in specific subgroups of patients with active, mild-to-moderate ulcerative colitis.
Methods  Data from two double-blind, placebo-controlled trials were analysed (517 out-patients). Patients were randomized to receive MMX mesalazine [2.4 g/day (once daily or 1.2 g twice daily) or 4.8 g/day (once daily)] or placebo for 8 weeks.
Results  The percentages of patients treated with MMX mesalazine, 2.4 or 4.8 g/day, in clinical and endoscopic remission at week 8 were similar and significantly ( P  < 0.05) greater than placebo in subgroups stratified by disease extent, disease severity and gender and among patients not previously receiving low-dose 5-aminosalicylic acid. Among patients transferring directly from prior low-dose oral 5-aminosalicylic acid, MMX mesalazine 4.8 g/day was significantly ( P  = 0.018) more effective than placebo in inducing clinical and endoscopic remission. Efficacy over placebo did not reach significance in patients transferring directly to MMX mesalazine 2.4 g/day.
Conclusion  MMX mesalazine is effective in active UC regardless of disease extent, disease severity, gender and previous, low-dose, 5-ASA therapy.     

The impact of migraine on daily activities: effect of topiramate compared with placebo

ABSTRACT

Objective: Assess the impact of migraine preventive therapy on patient-reported routine daily activities using the Migraine Specific Questionnaire (MSQ) and the Medical Outcomes Study Short Form-36 (SF-36) in patients with migraine who participated in a 26-week, randomized, double-blind, placebo-controlled trial of topiramate for migraine prevention.

Methods: Patients were required to have 3–12 migraines and ≤ 15 headache days/month during the baseline phase. Patients who failed > 2 adequate regimens of migraine preventive therapy were excluded. MSQ and SF‐36 data were collected at baseline, weeks 8, 16, and 26 from 469 patients receiving either topiramate 50, 100, or 200?mg/day or placebo. Patients entered a double-blind, 8‐week titration period followed by an 18‐week maintenance period. Two activity-related MSQ domains (Role Restrictive [RR] and Role Prevention [RP]) and two activity-related SF‐36 domains (Role Physical [SF‐36‐RP] and Vitality [SF‐36‐VT]) were prospectively designated as the outcome measures. Changes in MSQ and SF‐36 scores during the double-blind phase relative to prospective baseline scores were compared between topiramate- and placebo-treated groups. Specifically, a mixed-effect piecewise linear regression model was used to estimate average domain score over time, and areas under the domain-over-time curve (AUC) were compared using a 2‐sided t‐test, with multiplicity adjustment.

Results: In the intent-to-treat population (N = 469), topiramate (all doses) significantly improved mean MSQ‐RR domain scores versus placebo (topiramate 50?mg/day, p = 0.035; topiramate 100?mg/day; p < 0.001; topiramate 200?mg/day, p = 0.001). Topiramate-associated improvements in mean MSQ‐RP domain scores were significant versus placebo only for topiramate 100?mg/day (?p = 0.045). SF‐36‐RP and SF‐36‐VT domain scores improved (not significant versus placebo) for topiramate 100 and 200?mg/day. Changes in these MSQ and SF‐36 domain scores significantly correlated with changes in mean monthly migraine frequency.

Conclusion: Improvements in patient-reported outcomes specific for migraine (measured by the MSQ) were significantly better for patients receiving topiramate than for those receiving placebo. Improvements in the prospectively selected MSQ and SF‐36 domains were significantly correlated with the decrease in mean monthly migraine frequency observed with topiramate treatment.     

Oral beclometasone dipropionate in the treatment of active ulcerative colitis: a double-blind placebo-controlled study

AIM: To evaluate efficacy and safety of oral beclometasone dipropionate (BDP) when added to 5-ASA in the treatment of patients with active ulcerative colitis. METHODS: In a 4-week, placebo-controlled, double-blind study, patients with extensive or left-sided mild to moderate active ulcerative colitis were randomized to receive oral 5-ASA (3.2 g/day) plus BDP (5 mg/day) or placebo. Clinical, endoscopic and histologic features, and haematochemical parameters were recorded at baseline and at the end of the study. RESULTS: One hundred and nineteen patients were enrolled and randomly treated with BDP plus 5-ASA (n = 58) or placebo plus 5-ASA (n = 61). Both treatment groups showed a statistically significant decrease of disease activity index (DAI) and histology score at the end of treatment (P = 0.001, each). DAI score was lower in the BDP group than in the placebo group (P = 0.014), with more patients in clinical remission in the BDP group (58.6% vs. 34.4%, P = 0.008). Serum cortisol levels significantly decreased in BDP group vs. baseline (P = 0.002), but without signs of pituitary-adrenal function depletion. A low incidence of adverse events was observed in both groups. CONCLUSIONS: Oral BDP in combination with oral 5-ASA is significantly more effective than 5-ASA alone in the treatment of patients with extensive or left-sided active ulcerative colitis.     

Pharmacological Evaluation of a β‐Hydroxyphosphonate Analogue of l‐Carnitine in Obese Zucker fa/fa Rats

In this study, we evaluated the effect of an analogue of l ‐carnitine on parameters involved with Metabolic Syndrome in obese Zucker rats. Twenty‐four rats were treated for 5 weeks with l ‐carnitine (300 mg/kg) and its analogue at two concentrations (100 and 250 mg/kg) to assess their impact on glucose, triglycerides and cholesterol in liver and blood samples, as well as the amount of liver glycogen. Liver slices were also analysed. The analogue reduced the levels of glucose, triglycerides and cholesterol in liver and the level of triglycerides in serum. At 100 mg/kg, the analogue proved more effective than l ‐carnitine in improving the biochemical alterations present in liver. The amount of liver glycogen content was higher in obese animals treated with both l ‐carnitine and the analogue. No changes on insulin and leptin were observed in animals treated. l ‐carnitine and its analogue reduced the microvesicular fatty infiltration in liver. This study demonstrated that the analogue tested is more potent and efficient than l ‐carnitine and improves the pharmacological profile of l ‐carnitine.     

Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13‐week,randomized trial

ABSTRACT

Objective: This trial evaluated the efficacy and safety of pregabalin dosed twice daily (BID) for relief of neuro-pathic pain associated with postherpetic neuralgia (PHN).

Research design and methods: The 13‐week, double-blind, placebo-controlled study randomized 370 patients with PHN to pregabalin (150, 300, or 600?mg/day BID) or placebo.

Main outcome measures: Primary efficacy measure was endpoint mean pain score from daily pain diaries. Secondary efficacy measures included endpoint mean sleep-interference score from daily sleep diaries and Patient Global Impression of Change (PGIC). Safety evaluations included adverse events (AEs), physical and neurologic examinations, 12-lead ECG, vital signs, and laboratory testing.

Results: Pregabalin provided significant, dose-proportional pain relief at endpoint: difference from placebo in mean pain score, 150?mg/day, –0.88, p = 0.0077; 300?mg/day, –1.07, p = 0.0016; 600?mg/day, –1.79, p = 0.0003. Weekly mean pain scores significantly improved as early as week 1. Sleep interference in all pregabalin groups was also significantly improved at endpoint, compared with placebo (?p < 0.001), beginning at week 1 (?p < 0.01). At study termination, patients in the 150 (p = 0.02) and 600?mg/day (p = 0.003) groups were more likely to report global improvement than were those in the placebo group.

Most AEs were mild or moderate. Among pregabalin-treated patients, 13.5% withdrew due to AEs, most commonly for dizziness (16 patients, 5.8%), somnolence (8, 2.9%), or ataxia (7, 2.5%).

Conclusions: Pregabalin, dosed BID, reduced neuropathic pain associated with PHN and was well tolerated. It also reduced the extent to which pain interfered with sleep. Pregabalin's effects were seen as early as week 1 and were sustained throughout the 13‐week study.     

Early symptomatic response and mucosal healing with mesalazine rectal suspension therapy in active distal ulcerative colitis--additional results from two controlled studies

Aliment Pharmacol Ther 2011; 34: 747–756

Summary

Background Rapid resolution of symptoms and endoscopic inflammation in ulcerative colitis (UC) represent important treatment goals. Aims To establish times to bleeding cessation and endoscopic healing for topical and oral mesalazine in active distal UC, a post hoc analysis of two published studies was performed. Methods Study I (Sutherland 1987) compared mesalazine rectal suspension to placebo, while Study II (Safdi 1997) compared topical suspensions, either alone or in combination with oral mesalazine, and oral alone. Cessation of rectal bleeding (RB) was defined as absence of bleeding on four consecutive days. Endoscopic remission was defined as DAI mucosal healing (MH) subscore = 0 and clinical remission as MH subscore = 0–1 and ≥ 1‐point improvement, plus RB subscore = 0. Results Study I: By Day 2, 31.4% of subjects using topical monotherapy reported no RB vs. 5.5% in the placebo arm (P < 0.0006); median time to RB cessation was 8 days. Significantly higher rates of endoscopic (25.0% vs. 7.8%, P < 0.005) and clinical remission (48.6% vs. 9.6%, P < 0.0001) were observed at Week 3. Study II: A significantly higher proportion of subjects achieved RB cessation with combination therapy vs. oral therapy, commencing by Day 8. By Week 3, a significantly higher proportion of subjects using combination therapy achieved clinical remission compared to oral therapy alone (57.9% vs. 18.2%, P < 0.05). Conclusions Topical mesalazine suspension, either alone or in combination with oral mesalazine, led to earlier rectal bleeding cessation and mucosal healing. These data support use of topical therapy for more rapid treatment benefit in active distal ulcerative colitis.     

Efficacy of low and higher dose extended-release venlafaxine in generalized social anxiety disorder: a 6-month randomized controlled trial

Rationale There is a need for new pharmacological treatments for generalized social anxiety disorder (GSAD), which is a common, often disabling condition.Objective To compare the efficacy and safety over 6 months duration of two dose ranges of venlafaxine extended-release (ER) with placebo in patients with GSAD.Method Twenty-eight-week, double-blind, multi-center study in 386 adult outpatients with DSM-IV GSAD. Patients were randomized to placebo, venlafaxine ER fixed low dose (75 mg/day), or venlafaxine ER flexible higher dose (150–225 mg/day). Primary efficacy variable was change on the Liebowitz Social Anxiety Scale (LSAS). Secondary efficacy variables included, among others, the proportion of responders on the CGI Global Improvement Item (score 1 or 2), and the proportion of remitters (defined as an LSAS score of 30).Results Improvement on the LSAS was greater with venlafaxine ER (at 75 mg/day or 150–225 mg/day) than placebo, and was sustained throughout the 6-month trial. Of patients receiving venlafaxine ER (at any dose), 58% responded to treatment compared to 33% of those receiving placebo (P<0.001); corresponding remission rates were 31% and 16% (P<0.01). There were no differences in outcome according to venlafaxine ER dosage.Conclusions Venlafaxine ER was effective in the treatment of GSAD. The comparable efficacy at low and higher doses may indicate that norepinephrine reuptake blockade does not contribute to therapeutic effect in GSAD. This hypothesis should be tested using agents with specific actions on norepinephrine reuptake blockade.     

Oral beclometasone dipropionate in the treatment of extensive and left-sided active ulcerative colitis: a multicentre randomised study

AIM: To explore the efficacy and safety of the topically acting steroid beclometasone dipropionate (BDP) in an oral controlled release formulation in the treatment of extensive or left-sided ulcerative colitis. METHODS: In a multicentre, randomised, parallel-group, single-blind study, patients with active mild to moderate ulcerative colitis were randomised to a 4-week treatment with BDP 5 mg/day o.d. vs. 5-ASA 0.8 g t.d.s. The primary efficacy variable was the decrease of Disease Activity Index (DAI) (clinical symptoms and endoscopic appearance of mucosa). Safety was evaluated by monitoring adverse events, vital signs, haematochemical parameters and adrenal function. RESULTS: One hundred and seventy-seven patients were enrolled and randomly treated with BDP (n = 90) or 5-ASA (n = 87). Mean DAI score decreased in both treatments groups (P < 0.0001 vs. baseline for both groups). Clinical remission was achieved in 63.0% of patients in the BDP group vs. 62.5% in the 5-ASA group. A significant DAI score improvement (P < 0.05) in favour of BDP was observed in patients with extensive disease. Both treatments were well tolerated. Mean plasma cortisol levels were significantly reduced vs. baseline in BDP recipients, but without signs of pituitary-adrenal function depletion. CONCLUSION: Oral BDP gave an overall treatment result in patients with active ulcerative colitis without signs of systemic side-effects.     

Randomised clinical trial: the effectiveness of Lactobacillus reuteri ATCC 55730 rectal enema in children with active distal ulcerative colitis

Background Intestinal microbiota manipulation, one of the pathogenetic components of inflammatory bowel disease (IBD), has become an attractive therapy for ulcerative colitis (UC). Aim To assess in children with active distal UC the effectiveness of Lactobacillus (L) reuteri ATCC 55730 enema on inflammation and cytokine expression of rectal mucosa. Methods A total of 40 patients (median age: 7.2 years range 6–18) with mild to moderate UC were enrolled in a prospective, randomised, placebo‐controlled study. They received an enema solution containing 10¹⁰ CFU of L. reuteri ATCC 55730 or placebo for 8 weeks, in addition to oral mesalazine. Clinical endoscopic and histological scores as well as rectal mucosal expression levels of IL‐10, IL‐1β, TNFα and IL‐8 were evaluated at the beginning and at the end of the trial. Results Thirty‐one patients accomplished the trial (17 males, median age 13 year, range 7–18). Mayo score (including clinical and endoscopic features) decreased significantly in the L. reuteri group (3.2 ± 1.3 vs. 8.6 ± 0.8, P < 0.01) compared with placebo (7.1 ± 1.1 vs. 8.7 ± 0.7, NS); furthermore, histological score significantly decrease only in the L. reuteri group (0.6 ± 0.5 vs. 4.5 ± 0.6, P < 0.01) (placebo: 2.9 ± 0.8 vs. 4.6 ± 0.6, NS). At the post‐trial evaluation of cytokine mucosal expression levels, IL‐10 significantly increased (P < 0.01) whereas IL‐1β, TNFα and IL‐8 significantly decreased (P < 0.01) only in the L. reuteri group. Conclusions In children with active distal ulcerative colitis, rectal infusion of L. reuteri is effective in improving mucosal inflammation and changing mucosal expression levels of some cytokines involved in the mechanisms of inflammatory bowel disease.     

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

Aliment Pharmacol Ther 2011; 33: 845–854

Summary

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 phamacokinetic characteristics.

     

Acetyl‐l‐Carnitine Ameliorates Caerulein‐induced Acute Pancreatitis in Rats

Abstract: In the present study, we have addressed the possible protective role of acetyl‐l ‐carnitine in caerulein‐induced acute pancreatitis in male Swiss albino rats. Acute pancreatitis paradigm was developed by challenging animals with a supramaximal dose of caerulein (20 µg/kg, SC) four times at hourly intervals. Caerulein induced acute pancreatitis that was well‐characterized morphologically and biochemically. Severe oedema with marked increased relative pancreatic weight, marked atrophy of acini with increased interacinar spaces, vacuolization, and extensive leucocytic infiltration were diagnostic fingerprints of the pancreatitis phenotype. A biochemical test battery that confirmed the model comprised increased plasma amylase and lipase activities, calcium levels as well as increased pancreatic enzymatic myeloperoxidase and glutathione‐S‐transferase activities, beside increased pancreatic contents of nitric oxide and malondialdehyde and reduced pancreatic glutathione level. Prior administration of acetyl‐l ‐carnitine (200 mg/kg, IP) for seven consecutive days ahead of caerulein challenge alleviated all the histological and biochemical manifestations of acute pancreatitis. These results suggest a possible protective role of the carnitine ester in such a murine acute pancreatitis model probably via regulation of the oxidant/antioxidant balance, beside modulation of the myeloperoxidase and nitric oxide systems, which are involved in the inflammatory cascade that most often associate the disease.     

Faecal chitinase 3-like-1: a novel biomarker of disease activity in paediatric inflammatory bowel disease

Aliment Pharmacol Ther 2011; 34: 941–948

Summary

Background Chitinase 3‐like‐1 (CHI3L1) is up‐regulated in the inflamed mucosa of inflammatory bowel disease (IBD). Aim To evaluate the usefulness of a faecal CHI3L1 assay, as a reliable marker for predicting the severity of paediatric IBD. Methods Faecal samples were obtained from ulcerative colitis (UC, n = 94), Crohn’s disease (CD, n = 87), and healthy individuals (n = 56). The faecal CHI3L1 and calprotectin levels were determined by ELISA. For endoscopic evaluation, the sum of the Matts’ score for UC and the simple endoscopic score for CD (SES‐CD) were used. Ileal lesions were evaluated by ultrasonography. Results Faecal CHI3L1 levels were significantly elevated in active UC (median 366.6 ng/g, n = 44) and active CD (median 632.7 ng/g, n = 48) patients, as compared with healthy individuals (median 2.2 ng/g, n = 56). In UC patients, the faecal CHI3L1 levels were positively correlated with the sum of the Matts’ score (r = 0.73, P < 0.01, n = 42). In CD patients, there was a significant correlation between faecal CHI3L1 levels and endoscopic activity as determined by the SES‐CD scoring system (r = 0.61, P < 0.01, n = 25). The faecal CHI3L1 levels of patients with wall thickening of their small intestine were significantly higher than those of healthy controls or patients without wall thickening. The cutoff value of 13.7 ng/g for fecal CHI3L1(the 95th percentile of the control value) predicted active lesions in IBD patients with a sensitivity of 84.7% and a specificity of 88.9%. Conclusion Faecal CHI3L1 assays may be useful for predicting the severity and activity of mucosal inflammation in IBD.     

Clinical trial: esomeprazole for moderate‐to‐severe nighttime heartburn and gastro‐oesophageal reflux disease‐related sleep disturbances

Aliment Pharmacol Ther 2010; 32: 182–190

Summary

Background Nighttime heartburn, common among patients with gastro‐oesophageal reflux disease (GERD), is associated with substantial clinical effects. GERD‐related sleep disturbances are underappreciated and undertreated. Aim To evaluate the efficacy of esomeprazole on GERD‐related nighttime heartburn and associated sleep disturbances. Methods In this multicentre, randomized, double‐blind, placebo‐controlled study, patients with moderate‐to‐severe nighttime heartburn and GERD‐related sleep disturbances (endoscopies not required) received esomeprazole 20 mg or placebo each morning for 4 weeks. Heartburn symptoms and GERD‐related sleep disturbances were evaluated using the validated Pittsburgh Sleep Quality Index and validated Work Productivity and Activity Impairment Questionnaire. Results The analysis included 262 patients (esomeprazole, n = 137; placebo, n = 125). Significantly more patients receiving esomeprazole achieved nighttime heartburn relief (primary end point) than those receiving placebo (34.3% vs. 10.4%; P < 0.0001). Secondary end points such as relief of GERD‐related sleep disturbances (P = 0.006), days without GERD‐related sleep disturbances (P = 0.0003) and complete resolution of sleep disturbances (P < 0.0001) favoured esomeprazole over placebo. Sleep quality, work productivity and regular daily activities also improved significantly with esomeprazole vs. placebo. Conclusions Esomeprazole 20 mg is effective for patients with moderate‐to‐severe nighttime heartburn and GERD‐related sleep disturbances, improving heartburn symptoms, sleep quality, work productivity and functionality.

     

Randomised clinical trial: ghrelin agonist TZP-101 relieves gastroparesis associated with severe nausea and vomiting--randomised clinical study subset data

Aliment Pharmacol Ther 2011; 33: 679–688

Summary

Background Limited therapeutic options exist for severe gastroparesis, where severe nausea and vomiting can lead to weight loss, dehydration and malnutrition due to inadequate caloric and fluid intake. TZP‐101 (ulimorelin) is a ghrelin receptor agonist that accelerates gastric emptying and improves upper gastrointestinal symptoms in diabetic patients with gastroparesis. Aim To assess effects of TZP‐101 in diabetic gastroparesis patients with severe nausea/vomiting and baseline severity scores of ≥3.5 (range: 0–5) on the Gastroparesis Cardinal Symptom Index (GCSI) Nausea/Vomiting subscale. Methods Patients were hospitalised and received four single daily 30‐min infusions of one of six TZP‐101 doses (range 20–600 μg/kg) or placebo. Efficacy was assessed by symptom improvement. Results At baseline, 23 patients had a mean severity score for GCSI Nausea/Vomiting of 4.45 ± 0.44. Statistically significant improvements over placebo occurred in the 80 μg/kg group for end of treatment changes from baseline in GCSI Nausea/Vomiting subscale (reduction in score of ?3.82 ± 0.76, P = 0.011) and the GCSI Total score (?3.14 ± 0.78, P = 0.016) and were maintained at the 30‐day follow‐up assessment (?2.02 ± 1.63, P = 0.073 and ?1.99 ± 1.33, P = 0.032 respectively). The proportion of days with vomiting was reduced significantly (P = 0.05) in the 80 μg/kg group (mean of 1.2 days of vomiting for four treatment days) compared with placebo (mean of 3.2 days of vomiting across 4 treatment days). Conclusions TZP‐101 substantially reduced the frequency and severity of nausea and vomiting as well as overall gastroparesis symptoms. The results are consistent with gastrointestinal motility effects of TZP‐101, supporting further investigation of TZP‐101 in the management of severe gastroparesis.

     

Efficacy and safety of bisacodyl in the acute treatment of constipation: a double-blind, randomized, placebo-controlled study

Summary

Background

Although laxatives are a first‐line treatment for constipation, there are few randomized placebo‐controlled trials assessing their efficacy.

Aim

To determine the effect and safety of oral bisacodyl on stool frequency and consistency in patients with idiopathic constipation.

Methods

55 patients (age 19–89 years) with idiopathic constipation were recruited from eight primary care practices and randomized to receive bisacodyl, 10 mg once daily, or placebo, on three successive days following a 3‐day run‐in period. Patients recorded stool frequency and consistency and adverse events.

Results

In each treatment group, 27 patients were evaluable for efficacy. The mean number of stools per day was significantly greater in the bisacodyl‐treated group (1.8/day) compared with placebo (0.95/day) over the treatment phase (P = 0.0061). Mean stool consistency score improved from ‘hard’ (run‐in) to between ‘soft’ and ‘well‐formed’ during bisacodyl treatment, remaining between ‘moderately hard’ and ‘hard’ for placebo treatment (P < 0.0001). The investigator's global efficacy score was superior for the bisacodyl group compared with placebo. Both treatments were well tolerated. Serum electrolyte levels and incidence of adverse events were comparable between treatment groups.

Conclusions

Bisacodyl is effective and safe in improving stool frequency and consistency in acute treatment of idiopathic constipation.