Clinical trial: once-daily mesalamine granules for maintenance of remission of ulcerative colitis - a 6-month placebo-controlled trial

Aliment Pharmacol Ther 2010; 32: 990–999

Summary

Background Ulcerative colitis (UC) is a chronic relapsing and remitting idiopathic inflammatory bowel disorder. Aim To evaluate once‐daily mesalamine (mesalazine) granules (MG) for maintenance of remission of UC. Methods Randomized, double‐blind, placebo‐controlled trial of patients (n = 209 MG, n = 96 placebo) with UC in remission [revised Sutherland Disease Activity Index (SDAI) rectal bleeding = 0, mucosal appearance <2] who took MG 1.5 g or placebo once‐daily for up to 6 months. Primary efficacy endpoint: the percentage of patients who remained relapse‐free at month 6/end of treatment. Relapse was defined as SDAI rectal bleeding score ≥1 and a mucosal appearance score ≥2, a UC flare, or initiation of medication to treat a UC flare. Results The percentage of relapse‐free patients at month 6/end of treatment was higher with MG than placebo (78.9% vs. 58.3%, P < 0.001) in the intent‐to‐treat analysis. Significant differences (P ≤ 0.025) favouring MG were observed for most secondary endpoints including improvement in rectal bleeding, physician’s disease activity rating, stool frequency, the SDAI at month 6/end of treatment, patients classified as a treatment success and relapse‐free duration. The incidence of adverse events was similar between groups. Conclusions Once‐daily mesalamine (mesalazine) was effective in maintaining remission of UC for 6 months.     

Clinical trial: oral colon‐release parnaparin sodium tablets (CB‐01‐05 MMX®) for active left‐sided ulcerative colitis

Aliment Pharmacol Ther 31, 375‐386

Summary

Background The administration of parnaparin sodium as oral colon‐release tablets (CB‐01‐05 MMX^®) has been proposed as a novel approach for the treatment of ulcerative colitis (UC). Aim To assess the efficacy and the tolerability of 8 weeks’ oral daily administration of 210 mg of parnaparin sodium compared with placebo in subjects treated with stable‐doses of oral aminosalicylates. Methods This multicenter, randomized, double‐blind proof of concept trial compared the efficacy of CB‐01‐05 MMX^® 210 mg tablets to placebo in 141 subjects with mild to moderately active left‐sided UC treated with stable‐doses of aminosalicylates. The efficacy was assessed by clinical activity index (CAI), endoscopic index (EI) and histological score (HS). Results A total of 121 subjects (61 in test group and 60 in control group) formed the per protocol (PP) population. After 8 weeks of treatment, clinical remission was achieved in 83.6% of the CB‐01‐05 MMX^® group, and in 63.3% in the comparator group (P = 0.011). This effect was also significantly evident in the test group at week 4 (P = 0.028). A significant difference was also detected in rectal bleeding, (disappeared respectively in 75.4% and 55.0%; P = 0.018), and in mucosal friability (recovered respectively in 80.3% and in 56.7%; P = 0.005). Conclusions CB‐01‐05 MMX^® was safe and significantly effective in treating subjects with mild‐to‐moderate left‐sided UC treated with stable‐doses of aminosalicylates.     

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.     

Primary human sinonasal epithelial cell culture model for topical drug delivery in patients with chronic rhinosinusitis with nasal polyposis

Objectives The primary human sinonasal epithelial cell culture (HSNEC) allows for in‐vitro modelling of mucosal responses to topical therapy. Cultures grown from healthy donors may underestimate changes in individuals with chronic sinonasal disease thereby yielding inaccurate results with respect to this large patient population. The purpose of this study was to analyse HSNECs derived from patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) to determine whether expected disease dependent variables salient to topical drug delivery persist in culture. Methods Cultures were grown from patients with CRSwNP. Ciliary beat frequency (CBF) (basal and stimulated), permeability (trans and paracellular), inflammatory response, and glucocorticoid dose response were measured and compared with healthy controls. Key findings Methylcholine stimulated CBF was greater in CRSwNP versus controls (ΔCBF_60min 7.25 ± 1.02 vs 0.89 ± 1.04 Hz, respectively). Paracellular permeability was greater in CRSwNP versus controls (basolateral dextran_120min 18.97 ± 3.90 vs 11.31 ± 4.35 µg/ml, respectively). Lipopolysaccharide (0.1 mg/ml) stimulated interleukin‐6 (IL‐6) and IL‐8 secretion was increased in CRSwNP versus controls (IL‐6 Δbaseline 1738.72 ± 654.82 vs 1461.61 ± 533.51%, respectively; IL‐8 Δbaseline 137.11 ± 0.83 vs 111.27 ± 0.67%, respectively). CRSwNP cultures were more sensitive than controls to dexamethasone (1 µg/ml) dependent IL‐6 and IL‐8 suppression. Conclusions HSNECs derived from patients with CRSwNP retained their primary phenotype with respect to ciliary function, epithelial permeability, irritant induced inflammatory cytokine secretion, and glucocorticoid dose response.     

The effects of clonidine on symptoms and anorectal sensorimotor function in women with faecal incontinence

Aliment Pharmacol Ther 2010; 32: 681–688

Summary

Background Women with faecal incontinence and rectal urgency have increased rectal stiffness and sensation. Aim To evaluate the effects of clonidine, an α₂‐adrenergic agonist, in faecal incontinence. Methods In this open‐label uncontrolled study, bowel symptoms and anorectal functions (anal pressures, rectal compliance, and sensation) were assessed before and during treatment with transdermal clonidine (0.2 mg daily, 4 weeks) in 12 women with urge‐predominant faecal incontinence. Results Clonidine reduced the frequency (17.8 ± 3.1 before vs. 8.8 ± 3.9 after, P = 0.03) and number of days with faecal incontinence (11.8 ± 1.6 before vs. 6.1 ± 1.8 after, P = 0.02), faecal incontinence symptom severity score (max = 13, 8.3 ± 0.7 vs. 5.6 ± 0.9, P < 0.01), and allowed patients to defer defecation for a longer duration (P = 0.03). Although overall effects on anorectal functions were not significant, the treatment‐associated reduction in faecal incontinence episodes was associated with increased rectal compliance (r = ?0.58, P < 0.05) and reduced rectal sensation. (r = ?0.73, P = 0.007 vs. desire to defecate pressure threshold). Conclusions Clonidine improves symptoms in women with faecal incontinence; this improvement is associated with increased rectal compliance and reduced rectal sensitivity. A controlled study is necessary to confirm these observations.

     

Effects of rifampicin on porphyrin metabolism in healthy volunteers

Pregnane X receptor (PXR) is known to stimulate haem synthesis, but detailed knowledge on the effects of PXR activation on porphyrin metabolism in humans is lacking. We utilized a randomized, crossover, open (blinded laboratory) and placebo-controlled trial with 600-mg rifampicin or placebo dosed for a week to investigate the effects of PXR activation on erythrocyte, plasma, faecal and urine porphyrins. Sixteen healthy volunteers participated on the trial, but the number of volunteers for blood and urine porphyrin analyses was 15 while the number of samples for faecal analyses was 14. Rifampicin increased urine pentaporphyrin concentration 3.7-fold (mean 1.80 ± 0.6 vs. 6.73 ± 4.4 nmol/L, p = 0.003) in comparison with placebo. Urine coproporphyrin I increased 23% (p = 0.036). Faecal protoporphyrin IX decreased (mean 31.6 ± 23.5 vs. 19.2 ± 27.8 nmol/g, p = 0.023). The number of blood erythrocytes was slightly elevated, and plasma bilirubin, catabolic metabolite of haem, was decreased. In conclusion, rifampicin dosing elevated the excretion of certain urinary porphyrin metabolites and decreased faecal protoporphyrin IX excretion. As urine pentaporphyrin and coproporphyrin I are not precursors in haem biosynthesis, increased excretion may serve as a hepatoprotective shunt when haem synthesis or porphyrin levels are increased.     

Randomised clinical trial: otilonium bromide improves frequency of abdominal pain, severity of distention and time to relapse in patients with irritable bowel syndrome

Aliment Pharmacol Ther 2011; 34: 432–442

Summary

Background Otilonium bromide (OB) is a spasmolytic agent that blocks L‐Type Calcium channels in human colonic smooth muscle. Aim To study the efficacy of OB in symptom control in irritable bowel syndrome (IBS). Methods A total of 356 patients (46.16 ± 19 years, 71% female) with IBS participated in a double‐blind, randomised, parallel placebo‐controlled phase IV study. OB (40 mg t.d.s.) or placebo was administered for 15 weeks, and follow‐up was extended 10 additional weeks. Results Otilonium bromide (n = 179) and placebo (n = 177) groups had comparable demographics, symptom severity and IBS subtype. Both OB and placebo reduced abdominal pain and IBS symptoms. The effect of OB was significantly greater than placebo in the reduction of weekly frequency of episodes of abdominal pain at the end of treatment period (primary endpoint, ?0.90 ± 0.88 vs. ?0.65 ± 0.91, P = 0.03), reduction of abdominal bloating (?1.2 ± 1.2 vs. ?0.9 ± 1.1, P = 0.02) and global efficacy by patient assessment (1.3 ± 1.1 vs. 1.0 ± 1.1, P = 0.047). Intensity of abdominal pain, proportion of patient responders, safety and quality of life scores were similarly affected by OB and placebo. During follow‐up, the therapeutic effect of OB remained greater than placebo in terms of withdrawal rate due to symptom relapse (10% vs. 27%, P = 0.009), global efficacy of treatment and relapse‐free probability (P = 0.038). Conclusions This placebo‐controlled double‐blind study shows that otilonium bromide is safe, well tolerated and superior to placebo in reducing the frequency of abdominal pain, severity of abdominal bloating and protecting from symptom relapse in IBS. These results further confirm that patients with IBS can improve during and following treatment with otilonium bromide.

     

The effects of acute citalopram dosing on gastric motor function and nutrient tolerance in healthy volunteers

Aliment Pharmacol Ther 2011; 33: 395–402

Summary

Background It is unclear whether endogenous serotonin release is involved in the regulation of gastric motility and food intake. Aim To study the effect of acute administration of the selective serotonin reuptake inhibitor citalopram on gastric motor function in man. Methods Nineteen healthy volunteers underwent a gastric barostat, gastric emptying and/or a drinking test after dosing with either placebo or citalopram (20 mg intravenously). In the barostat protocol, a flaccid bag was introduced in the stomach and inflated at intra‐abdominal pressure +2 mmHg, volume was recorded before and after administration of a liquid meal (300 kcal). Gastric emptying for solids and liquids was simultaneously assessed using the ¹⁴C‐octanoic acid/¹³C‐glycine breath test. During the drink test, volunteers drank at a rate of 15 mL/min until maximal satiation. Citalopram was compared with placebo using t‐tests and mixed model analysis. Results Citalopram induced a significant preprandial gastric relaxation (volume increase of 154 ± 55 mL vs. ?38 ± 33 mL after placebo dosing; P < 0.05), whereas the postprandial volume increase was significantly decreased after citalopram treatment (F_12.80 = 4.78, P < 0.0001; maximum volume increase was 304 ± 40 vs. 201 ± 54 mL after placebo and citalopram treatment respectively). Citalopram enhanced solid (123 ± 17 vs. 77 ± 6 min, P < 0.05) but not liquid emptying (62 ± 6 vs. 57 ± 4 min). Satiation scores during the drink test were lower after citalopram (F_19.153 = 2.02, P = 0.01; volunteers drank 998 ± 129 vs. 765 ± 79 mL after citalopram and placebo treatment respectively). Conclusion The observed effects indicate a role for serotonin in the control of gastric motility and food intake.

     

Randomised clinical trial: preventive treatment with topical rectal beclomethasone dipropionate reduces post-radiation risk of bleeding in patients irradiated for prostate cancer

Aliment Pharmacol Ther 2011; 34: 628–637

Summary

Background Radiotherapy is an established treatment modality for prostate cancer; however, up to a third of patients develops a radiation‐induced proctopathy. Aim To assess the effect of topical beclomethasone dipropionate (BDP) in the prevention of radiation‐induced proctopathy in patients undergoing radiotherapy for prostate cancer through a double‐blind, placebo‐controlled, randomised trial. Methods Patients were randomised either to BDP or to placebo (PL). Patients received daily a 3 mg BDP enema or identical‐looking PL during radiotherapy and, subsequently, two 3 mg BDP suppositories or PL for 4 more weeks. Clinical and endoscopic evaluations before, 3 and 12 months after the end of radiotherapy were assessed with the RTOG/EORTC toxicity scales, the modified Simple Clinical Colitis Activity Index (SCCAI), the modified Inflammatory Bowel disease Quality of Life Index (IBDQ) and the Vienna Rectoscopy Score (VRS). Results From June 2007 to October 2008, 120 patients were randomised to the BDP (n = 60) and PL (n = 60) arms and were followed up for 12 months. The overall assessment of rectal side effects did not show significant differences between the two groups of treatment. However, when only rectal bleeding was considered, a significantly reduced risk was observed in patients on BDP (OR 0.38; 95% CI 0.17–0.86; P = 0.02; NNT = 5). Patients on BDP had also significantly lower VRS scores (P = 0.028) and significantly higher IBDQ scores (P = 0.034). Conclusions Preventive treatment with topical rectal BDP during radiotherapy for prostate cancer significantly reduces the risk of rectal bleeding and radiation‐induced mucosal changes and improves patient’s quality of life, but does not influence other radiation‐induced symptoms.     

Clinical trial: endoscopic evaluation of naproxen etemesil,a naproxen prodrug,vs. naproxen – a proof‐of‐concept,randomized, double‐blind,active‐comparator study

Aliment Pharmacol Ther 2010; 32: 1091–1101

Summary

Background Nonsteroidal anti‐inflammatory drugs are associated with upper gastrointestinal mucosal injury. Naproxen etemesil is a lipophilic, non‐acidic, inactive prodrug of naproxen that is hydrolysed to pharmacologically active naproxen once absorbed. We hypothesized that with lesser topical exposure to naproxen from the prodrug, there would be reduced gastroduodenal mucosal injury compared with naproxen. Aim To compare the degree of endoscopic mucosal damage of naproxen etemesil vs. naproxen. Methods This multicentre, randomized, double‐blind, double‐dummy trial compared oral naproxen etemesil 1200 mg twice daily (n = 61) with naproxen 500 mg twice daily (n = 59) for 7.5 days in 120 healthy subjects (45–70 years; mean 51 years; 58% female) with baseline total modified gastroduodenal Lanza score ≤2 (no erosions/ulcers) on endoscopy. The primary endpoint was mean total modified gastroduodenal Lanza score on day 7. A secondary endpoint was incidence of gastric ulcers. Results The day 7 mean total modified gastroduodenal Lanza score was 2.8 ± 1.7 for naproxen etemesil vs. 3.5 ± 2.0 for naproxen (P = 0.03), and significantly fewer naproxen etemesil‐treated subjects (3.3%) developed gastric ulcers compared with naproxen‐treated subjects (15.8%) (P = 0.02). Conclusion In this first proof‐of‐concept study, naproxen etemesil was associated with significantly lower gastroduodenal mucosal injury compared with naproxen after 7 days of exposure (Clinical trial number: NCT00750243).     

Delayed release phosphatidylcholine as new therapeutic drug for ulcerative colitis – a review of three clinical trials

Importance of the field: As the pathogenesis of ulcerative colitis (UC) is unknown, a causative therapy is lacking. Therefore, some UC patients suffer from disease activity despite symptomatic anti-inflammatory treatment strategies. We claim that reduction of phosphatidylcholine (PC) in colonic mucus impairs the mucosal barrier and, thus, causes attacks of the commensal bacterial flora to induce colitis. Thus, mucus PC substitution could provide a causal therapy for UC.

Areas covered in this review: A delayed released oral PC preparation (rPC) was found to substitute for the lack of PC in rectal mucus. In non-steroid-treated active UC, 53% of rPC-treated patients reached remission compared with 10% of placebo patients (p < 0.001). In a second trial with chronic-active, steroid-dependent UC patients, steroid withdrawal with a concomitant achievement of remission (CAI ≤ 3) or clinical response (≥ 50% CAI improvement) was reached in 15 rPC-treated patients (50%) but only in 3 (10%) placebo patients (p = 0.002).

What the reader will gain: The concept that missing PC in colonic mucus is the main pathogenetic factor for development of UC. PC can be substituted by rPC, which cures the disease in the majority of patients.

Take home message: rPC is, to our knowledge, the first causative therapeutic option for patients with UC.     

辛伐他汀对冠心病的抗炎作用

目的 :观察辛伐他汀对冠心病病人C反应蛋白 (CRP)、肿瘤坏死因子α(TNF α)、白细胞介素6 (IL 6 )和白细胞介素 8(IL 8)的抑制效应。方法 :冠心病病人 6 0例 ,分为辛伐他汀组和对照组 ,每组30例。对照组给予阿司匹林泡腾片、培哚普利、美托洛尔等治疗 ,辛伐他汀组在此基础上服用辛伐他汀 2 0mg ,po ,qn。疗程均 8wk。结果 :治疗后辛伐他汀组血清中CRP ,TNF α ,IL 6和IL 8浓度明显降低 [(5 .0±s 0 .6 )mg·L- 1vs (3.7± 0 .6 )mg·L- 1,(6 .4± 1.4 )ng·L- 1vs (5 .6± 1.4 )ng·L- 1,(4.4± 1.2 )ng·L- 1vs (4.2± 1.2 )ng·L- 1,(2 8±7)ng·L- 1vs (2 7± 7)ng·L- 1,P <0 .0 5或P <0 .0 1],而对照组则无明显改变 (P >0 .0 5 )。结论 :辛伐他汀能够降低冠心病病人血清中CRP和炎症因子 ,显示其抗炎作用     

The effects of midodrine on the natriuretic response to furosemide in cirrhotics with ascites

Aliment Pharmacol Ther 2010; 32: 1044–1050

Summary

Background Resistance to loop diuretics is common in patients with ascites. Diminished glomerular filtration rate (GFR) is thought to mediate resistance to loop diuretics. Midodrine, a commonly used alpha‐1 agonist, has been shown to improve GFR in non‐azotemic patients with cirrhosis. Aim To conduct a randomized, double‐blind, placebo‐controlled, cross‐over study to test the hypothesis that midodrine significantly increases natriuretic response of IV furosemide in non‐azotemic cirrhotics with ascites. Methods All subjects participated in both phases, which were (i) furosemide IV infusion + oral midodrine 15 mg administered 30 min before furosemide (ii) furosemide IV infusion + oral placebo administered 30 min before furosemide. Primary outcomes were 6‐h urine sodium excretion and 6‐h total urine volume. Results A total of 15 patients (men: 8; age: 52.7 ± 7.6 years; serum creatinine: 1.06 ± 0.2 mg/dL) were studied. Total 6‐h urine sodium excretion was 109 ± 42 mmol in the furosemide + midodrine treatment phase and was not significantly different from that in the furosemide + placebo treatment phase (126 ± 69 mmol, P = 0.6). Similarly, mean 6‐h total urine volume was not significantly different between two groups (1770 ± 262 mL vs. 1962 ± 170 mL, P = 0.25). Conclusions Oral midodrine does not increase the natriuretic response to furosemide in non‐azotemic cirrhotic patients with ascites. Orally administered midodrine does not increase natriuretic response to furosemide in non‐azotemic cirrhotic patients with ascites.     

Clinical trial: short‐term effects of combination of satavaptan,a selective vasopressin V2 receptor antagonist,and diuretics on ascites in patients with cirrhosis without hyponatraemia – a randomized,double‐blind,placebo‐controlled study

Aliment Pharmacol Ther 31 , 834–845

Summary

Background There is little information on the effects of vaptans in patients with cirrhosis. Aim To investigate the short‐term effects of satavaptan, a selective vasopressin V₂ receptor antagonist on ascites in cirrhosis without hyponatraemia. Methods A total of 148 patients with cirrhosis, ascites and serum sodium >130 mmol/L were included in a multicentre, double‐blind, randomized, controlled study of 14 days comparing three fixed doses of satavaptan (5 mg, 12.5 mg or 25 mg once daily) vs. placebo. Average MELD scores were: 13.4, 12.3, 13.8 and 13.1 respectively. All patients received spironolactone 100 mg/day plus furosemide 20–25 mg/day. Results Satavaptan treatment was associated with a decrease in ascites (mean change in body weight was ?0.36 kg (±3.03) for placebo vs. ?2.46 kg (±3.11), ?2.08 kg (±4.17) and ?2.28 kg (±3.24) for the 5 mg, 12.5 mg and 25 mg doses respectively; P = 0.036, P = 0.041 and P = 0.036 for satavaptan 5, 12.5 and 25 mg/day vs. placebo respectively). Thirst and slight increases in serum sodium were more common in patients treated with satavaptan compared with placebo, while other adverse events were similar. Conclusions The administration satavaptan for a 14‐day period is associated with reduction in ascites in patients with moderately severe cirrhosis without hyponatraemia under diuretic treatment.

     

Effects of psyllium therapy on stool characteristics, colon transit and anorectal function in chronic idiopathic constipation

Background: Psyllium is widely used in the symptomatic therapy of constipation. Its effects on colonic function and their correlation with symptomatic response have not been defined. Methods: After a 4-week baseline, placebo, run-in phase, 22 subjects with idiopathic constipation confirmed by prospectively administered stool diaries were randomly assigned to receive either psyllium (5 g b.d., 11 patients) or placebo (11 patients) for 8 weeks, followed by another 4-week wash-out, placebo phase. A colon transit study and anorectal manometry were performed at the beginning and at the end of each study phase. Subjects recorded, in diaries, their daily stool frequency, difficulty with defecation and weekly stool weight. Results: Stool frequency increased significantly after 8 weeks of psyllium treatment (3.8 ± 0.4 vs. 2.9 ± 0.1 stools/week, P < 0.05) as did stool weight (665.3 ± 95.8 g vs. 405.2 ± 75.9 g, P < 0.05). Subjects also reported an improvement in stool consistency (stool consistency score: 3.2 ± 0.2 vs. 3.8 ± 0.2, P < 0.05) and pain on defecation (pain score: 2.0 ± 0.4 vs. 2.6. ± 0.5, P < 0.05) on psyllium. Colon transit and anorectal manometry parameters were unchanged on psyllium. Subjects treated with placebo did not show any change in either subjective or objective measures of constipation. Conclusions: Psyllium increases stool frequency and weight and improves stool consistency in idiopathic constipation. These effects are not associated with significant changes in either colonic or rectal motor function. We suggest that the beneficial effects of psyllium in constipation are primarily related to a facilitation of the defecatory process.     

Clinical trial: effect of active lactic acid bacteria on mucosal barrier function in patients with diarrhoea-predominant irritable bowel syndrome

Background The intestinal permeability is increased in patients with diarrhoea‐predominant irritable bowel syndrome (D‐IBS). Aim To determine the possible efficacy of lactic acid bacteria on the increased intestinal permeability in D‐IBS. Methods Treatment was employed for 4 weeks in a randomized single blind placebo controlled study with 30 D‐IBS patients. Patients were given either probiotic fermented milk (Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus acidophilus and Bifidobacterium Longum) or milk beverage containing no bacteria. The clinical symptoms were scored and intestinal permeability was measured by a triple sugar test before and after treatment. Results Small bowel permeability was measured as the ratio of lactulose and mannitol recovery and colonic permeability was measured as the total mass of sucralose excretion (mg). After probiotics treatment, small bowel permeability decreased significantly from 0.038 (0.024) at baseline to 0.023 (0.020) (P = 0.004), the proportion of patients with increased small bowel permeability was lower than baseline (28.6% vs. 64.3%, P = 0.023). However, colonic permeability improved neither in the probiotics group nor in the placebo group at week 4. Treatment with probiotics significantly decreased the mean global IBS scores compared with the baseline scores (9.62 ± 1.05 vs. 7.64 ± 1.24, P < 0.001). Conclusion Short‐term active lactic acid bacteria treatment for D‐IBS improved mucosal barrier function.     

Effect of gliclazide modified release on adiponectin,interleukin‐6, and tumor necrosis factor‐α plasma levels in individuals with type 2 diabetes mellitus

ABSTRACT

Objective: The aim of the study was to evaluate the effect of gliclazide modified release (MR) treatment on adiponectin, interleukin 6 (IL-6), and tumor necrosis factor-α (TNF‐α) plasma concentrations in type 2 diabetic patients.

Research design and methods: 24 randomly selected type 2 diabetic patients, aged 61.2 ± 15.4 years, with poorly controlled glucose level (mean glycated hemoglobin [HbA_1c] 7.6 ± 1.1%) despite treatment with diet and/or oral hypoglycemic agents, were included in the study. All of the patients, after a 2‐week run-in period, were given gliclazide MR for 12 weeks. At baseline, and after gliclazide MR treatment, HbA_1c and plasma concentrations of IL‐6, TNF‐α, and adiponectin were measured.

Results: Gliclazide MR treatment produced significant reductions in fasting plasma glucose (from 7.6 ± 1.4 to 6.6 ± 1.2?mmol/L, p < 0.01), HbA_1c (from 7.6 ± 1.1 to 6.9 ± 0.8%, p < 0.01), and plasma IL‐6 concentrations (from 2.5 ± 1.8 to 1.8 ± 1.2?pg/mL, p < 0.05). A significant increase in plasma adiponectin level was noted (from 6.4 ± 3.3 to 7.6 ± 4.4?µg/mL, p < 0.05). Plasma TNF‐α concentrations and homeostasis model assessment of insulin resistance (HOMA‐IR) decreased after treatment, but these changes did not reach statistical significance.

Conclusions: Gliclazide MR improves glycemic control and, in addition, has a positive influence on the plasma level of some inflammatory markers and adiponectin. Increased plasma adiponectin and decreased plasma IL‐6, and TNF‐α levels may explain, at least in part, the anti-atherogenic action of this drug reported elsewhere.     

Effect of pramlintide as an adjunct to basal insulin on markers of cardiovascular risk in patients with type 2 diabetes

ABSTRACT

Objective: Intensification of insulin therapy in patients with type 2 diabetes, while improving glycemic control, often leads to an increase in body weight and other markers of cardiovascular risk. The effects of pramlintide as an adjunct to basal insulin titration (without mealtime insulin) on glycemia and cardiovascular risk markers were examined.

Research design and methods: This was a post hoc analysis of a 16-week, double-blind, placebo-controlled study in patients with type 2 diabetes (N?=?211) using insulin glargine (without mealtime insulin)?±?oral agents. Patients were randomized to treatment with placebo or pramlintide (60 or 120?µg with major meals), and insulin glargine was titrated to target a fasting plasma glucose concentration of ≥70 to <100?mg/dL.

Main outcome measures: Endpoints included the change from baseline to Week 16 in body weight, high sensitivity C-reactive protein (hsCRP), triglycerides, HDL, LDL, and blood pressure.

Results: Pramlintide-treated patients lost weight and placebo-treated patients gained weight during 16 weeks of treatment (?1.6?±?0.3?kg vs. +0.7?±?0.3?kg, p?<?0.001; mean?±?SE). hsCRP was reduced in pramlintide-treated versus placebo-treated patients (?0.8?±?0.2?mg/L vs. 0.1?±?0.2?mg/L, p?<?0.01; mean?±?SE). Patients with baseline hsCRP?>?3?mg/L (high cardiovascular risk) demonstrated greater hsCRP reductions with pramlintide versus placebo treatment at Week 16 (p?<?0.05). Patients with baseline triglycerides ≥150?mg/dL or ≥200?mg/dL (high cardiovascular risk) showed significant reductions from baseline in triglyceride concentrations with pramlintide (?43?±?14?mg/dL or ?59?±?19?mg/dL; p?<?0.05; mean?±?SE) but not with placebo (1?±?29?mg/dLor ?3?±?54?mg/dL; mean?±?SE). No significant differences between pramlintide and placebo were observed for changes in HDL, LDL, or blood pressure. Pramlintide treatment was generally well tolerated. The most frequent adverse event related to pramlintide was mild-to-moderate nausea (31% pramlintide vs. 10% placebo). Pramlintide added to basal insulin did not increase the incidence of hypoglycemia. A limitation of the study was its relatively short duration.

Conclusions: Pramlintide, as an adjunct to basal insulin, was associated with improvements in several cardiovascular risk markers, warranting long-term clinical studies to determine its potential effects on cardiovascular risk.     

Randomised clinical trial: the efficacy and safety of propionyl-L-carnitine therapy in patients with ulcerative colitis receiving stable oral treatment

Aliment Pharmacol Ther 2011; 34: 1088–1097

Summary

Background Ulcerative colitis (UC) is characterised by impaired fatty‐acid oxidation; l ‐carnitine has a key role in fatty‐acid metabolism and short‐chain fatty acids such as butyrate and propionate are important energy source for intestinal epithelial cells. Aim To evaluate efficacy and safety of colon‐release propionyl‐l ‐carnitine (PLC) in patients with mild‐to‐moderate UC receiving stable oral aminosalicylate or thiopurine therapy. Methods In a multicentre, phase II, double‐blind, parallel‐group trial, patients were randomised to receive PLC 1 g/day, PLC 2 g/day or placebo. Main inclusion criteria were as follows: age 18–75; disease activity index (DAI) score 3–10 inclusive, be under oral stable treatment with aminosalicylate or thiopurine. The primary endpoint was clinical/endoscopic response, defined as a decrease in DAI score ≥ 3 points or remission, defined as a DAI score ≤ 2 with no individual sub‐score > 1. Results Of 121 patients who were randomised, 57 of 79 (72%) patients receiving PLC (combined 1 g and 2 g cohort) had a clinical/endoscopic response vs. 20 of 40 (50%) receiving placebo (P = 0.02). Specifically, in PLC 1 g/day group, 30 of 40 (75%) patients had clinical/endoscopic response (P = 0.02 vs. placebo) and 27 of 39 (69%) in the PLC 2 g/day group (P = 0.08 vs. placebo). Rates of remission were 22/40 (55%), 19/39 (49%), 14/40 (35%) in the PLC 1 g, PLC 2 g, and placebo groups, respectively. PLC had a similar safety profile to placebo; the most common adverse events were gastrointestinal. Conclusion Propionyl‐l ‐carnitine 1 g/day should be investigated further as a co‐treatment for mild‐to‐moderate ulcerative colitis (NCT‐01026857).