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- Long-Term Experience With Pancreatic Enzyme Replacement Therapy (ZENPEP®) in Infants With Exocrine Pancreatic Insufficiency Associated With Cystic Fibrosis. [JOURNAL ARTICLE]
- J Pediatr Gastroenterol Nutr 2014 Jul 21.
The objective was to determine whether infants with CF, who developed EPI in early infancy, would tolerate long-term treatment with ZENPEP (pancrelipase) delayed-release capsules, containing 3000 USP units of lipase/capsule and demonstrate consistent long-term growth. The most common TEAEs were diarrhea, vomiting, and constipation (mild or moderate). At study completion, median weight-for-age percentiles increased from 22nd to 49th, median length-for-age percentiles increased from 36.5th to 42nd, and median weight-for-length percentiles increased from 41.5th to 55.5th. Long-term treatment (up to 12 months) of infants with EPI due to CF with Zenpep was well tolerated and associated with improved growth parameters. This is the first long-term study of pancreatic enzyme replacement therapy conducted in this patient population.
- Efficacy and safety of low-dose submicron diclofenac for the treatment of osteoarthritis pain: a 12-week, phase 3 study. [JOURNAL ARTICLE]
- Curr Med Res Opin 2014 Jul 22.:1-29.
Abstract Objective: NSAIDs, such as diclofenac, are the most commonly used medications to treat osteoarthritis (OA), but they are associated with dose-related adverse events (AEs). Low-dose submicron diclofenac was developed using a new, proprietary dry milling process that creates submicron drug particles (SoluMatrix Fine Particle Technology (*)), enabling effective treatment at lower doses than other commercially available diclofenac drug products. This phase 3 study evaluated the efficacy and safety of low-dose submicron diclofenac 35mg three times daily (tid) and twice daily (bid) in patients with OA pain. Research design and methods: This double-blind study enrolled patients ≥40 years of age with clinically and radiographically confirmed (Kellgren-Lawrence grade II-III) hip or knee OA. Eligible patients were chronic NSAID and/or acetaminophen (APAP) users with baseline Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) pain subscale scores ≥40 mm by Visual Analog Scale and an OA flare (≥15-mm increase in WOMAC pain subscale score following discontinuation of NSAIDs/APAP at screening). Patients were randomized to submicron diclofenac 35mg tid, submicron diclofenac 35mg bid, or placebo for 12 weeks. ClinicalTrials.gov identifier: NCT01461369 Main outcome measures: Efficacy parameters included mean change from baseline in WOMAC pain subscale score at week 12 (primary efficacy parameter) and in average total WOMAC score over 12 weeks. Results: Submicron diclofenac 35mg tid significantly improved WOMAC pain subscale scores from baseline at 12 weeks (-44.1;p=0.0024) compared with placebo (-32.5). Submicron diclofenac 35mg bid provided numerical improvement in pain at week 12 that did not reach statistical significance (-39.0;p=0.0795) compared with placebo. Submicron diclofenac 35mg tid (-35.9;p=0.0002) and 35mg bid (-30.3;p=0.0363) improved the average total WOMAC score in treated patients over 12 weeks compared with placebo (-23.2). The most frequent AEs in the submicron diclofenac-treated groups were diarrhea, headache, nausea, and constipation. The inclusion of patients with a documented requirement for analgesic therapy (OA "flare") at baseline and the high rates of rescue medication usage in the placebo group may have impacted the study outcome for the submicron diclofenac treatment groups. Conclusions: Low-dose submicron diclofenac is an effective therapeutic option for the treatment of OA pain.
- Efficacy and tolerance of lactitol supplementation for adult constipation: a systematic review and meta-analysis. [Journal Article, Review]
- Clin Exp Gastroenterol 2014.:241-8.
Constipation is a common complaint in adults. Lactitol is an osmotic disaccharide laxative that increases fecal volume and stimulates peristalsis. In this paper, we present the first meta-analysis on the efficacy and tolerance of lactitol for adult constipation.We searched MEDLINE(®) and Embase, with no date or language restrictions, for studies of lactitol supplementation on adult constipation. A random-effects meta-analysis was performed on pre- to posttreatment changes in stool frequency and consistency with lactitol among all studies, as well as a comparison of efficacy and tolerance outcomes in randomized controlled trials (RCTs) of lactitol versus lactulose.A total of eleven studies representing 663 distinct patients were included in the final analysis, including five single-arm studies, four RCTs comparing lactitol with lactulose, one RCT comparing lactitol with placebo, and one nonrandomized controlled trial comparing lactitol with stimulant laxatives. Weekly stool frequency was significantly increased with lactitol compared with baseline (standardized mean difference [SMD]: 1.56, P<0.001). Stool consistency also improved over the supplementation period with lactitol (SMD: 1.04, P<0.001). Approximately one-third of patients experienced an adverse event; however, symptoms were generally mild and rarely (5%) resulted in study withdrawal. In RCTs of lactitol versus lactulose, lactitol was slightly more effective than lactulose in increasing weekly stool frequency (SMD: 0.19, P=0.06). No statistically significant differences between lactitol and lactulose were identified in any other efficacy or tolerance outcome. Lactitol demonstrated favorable efficacy and tolerance in individual studies when compared to stimulant laxatives and placebo.Lactitol supplementation is well tolerated and improves symptoms of adult constipation. The efficacy and tolerance of lactitol and lactulose are similar, with a trend for more frequent stools with lactitol. Limited evidence suggests lactitol is superior to stimulant laxatives and placebo for relieving constipation symptoms.
- Comparative pharmacokinetics of rhein in normal and loperamide-induced constipated rats and microarray analysis of drug-metabolizing genes. [JOURNAL ARTICLE]
- J Ethnopharmacol 2014 Jul 18.
Rhein is a pharmacological active component found in Rheum palmatum L. that is the major herb of the San-Huang-Xie-Xin-Tang (SHXXT), a medicinal herbal product used as a remedy for constipation.Here we have investigated the comparative pharmacokinetics of rhein in normal and constipated rats. Microarray analysis was used to explore whether drug-metabolizing genes will be altered after SHXXT treatment.The comparative pharmacokinetics of rhein in normal and loperamide-induced constipated rats was studied by liquid chromatography with electrospray ionization tandem mass spectrometry (LC-MS/MS). Gene expression profiling in drug-metabolizing genes after SHXXT treatment was investigated by microarray analysis and real-time polymerase chain reaction (RT-PCR).A validated LC-MS/MS method was applied to investigate the comparative pharmacokinetics of rhein in normal and loperamide-induced constipated rats. The pharmacokinetic results demonstrate that the loperamide-induced constipation reduced the absorption of rhein. The Cmax significantly reduced by 2.5-fold, the AUC decreased by 27.8%; however, the elimination half-life (t1/2) was prolonged by 1.6-fold. The Tmax and mean residence time (MRT) were significantly prolonged by 2.8-fold, and 1.7-fold, respectively. The volume of distribution (Vss) increased by 2.2-fold. The data of microarray analysis on gene expression indicate that five drug-metabolizing genes, including Cyp7a1, Cyp2c6, Ces2e, Atp1b1, and Slc7a2 were significantly altered by the SHXXT (0.5g/kg) treatment.The loperamide-induced constipation reduced the absorption of rhein. Since among the 25, 338 genes analyzed, there were five genes significantly altered by SHXXT treatment. Thus, information on minor drug-metabolizing genes altered by SHXXT treatment indicates that SHXXT is relatively safe for clinical application.
- Banana Resistant Starch and Its Effects on Constipation Model Mice. [JOURNAL ARTICLE]
- J Med Food 2014 Jul 21.
Abstract Banana resistant starch (BRS) was extracted to investigate the structural properties of BRS, its effects on the gastrointestinal transit, and dejecta of normal and experimentally constipated mice. The mouse constipation model was induced by diphenoxylate administration. The BRS administered mice were divided into three groups and gavaged with 1.0, 2.0, or 4.0 g/kg body weight BRS per day. The small intestinal movement, time of the first black dejecta, dejecta granules, weight and their moisture content, body weight, and food intake of mice were studied. Results showed that the BRS particles were oval and spindly and some light cracks and pits were in the surface. The degree of crystallinity of BRS was 23.13%; the main diffraction peaks were at 2(θ) 15.14, 17.38, 20.08, and 22.51. The degree of polymerization of BRS was 81.16 and the number-average molecular weight was 13147.92 Da, as determined by the reducing terminal method. In animal experiments, BRS at the dose of 4.0 g/kg body weight per day was able to increase the gastrointestinal propulsive rate, and BRS at the doses of 2.0 and 4.0 g/kg body weight per day was found to shorten the start time of defecation by observing the first black dejecta exhaust. However, there were no influences of BRS on the dejecta moisture content, the dejecta granules and their weight, body weight, or daily food intake in mice. BRS was effective in accelerating the movement of the small intestine and in shortening the start time of defecation, but did not impact body weight and food intake. Therefore, BRS had the potential to be useful for improving intestinal motility during constipation.
- Clinical Usefulness of Hydromorphone-OROS in Improving Sleep Disturbances in Korean Cancer Patients: A Multicenter, Prospective, Open-label Study. [JOURNAL ARTICLE]
- Cancer Res Treat 2014 Jul 21.
To evaluate the efficacy of hydromorphone-OROS (HM-OROS) in reducing sleep disturbance and relieving cancer pain.120 cancer patients with pain (numeric rating scale (NRS)≥4) and sleep disturbance (NRS≥4) were evaluated. The initial HM-OROS dosing was based on previous opioid dose (HM-OROS : oral morphine=1:5). Dose adjustment of the study drug was permitted at the investigator's discretion. Pain intensity, number of breakthrough pain episodes, and quality of sleep were evaluated.A total of 120 patients received at least one dose of HM-OROS; 74 of them completed the final assessment. Compared to the previous opioids, HM-OROS reduced the average pain NRS from 5.3 to 4.1 (p<0.01), worst pain NRS from 6.7 to 5.4 (p<0.01), sleep disturbance NRS from 5.9 to 4.1 (p<0.01), incidence of breakthrough pain at night from 2.63 to 1.53 times (p<0.0001), and immediate-release opioids use for the management of breakthrough pain from 0.83 to 0.39 times per night (p=0.0011). Of the 74 patients who completed the treatment, 83.7% indicated that they preferred HM-OROS to the previous medication. The adverse events (AEs) were somnolence, asthenia, constipation, dizziness, and nausea.HM-OROS was efficacious in reducing cancer pain and associated sleep disturbances. The AEs were manageable.
- Circular muscle contraction in the mice rectum plays a key role in morphine-induced constipation. [JOURNAL ARTICLE]
- Neurogastroenterol Motil 2014 Jul 13.
Although opioids induce intestinal muscle contraction and provoke constipation, the intestinal region(s) that contribute to the constipation have remained unclear. We report here a region-specific response of intestinal muscle contraction to morphine and its correlation with in vivo constipation.Regions of mice small and large intestines were dissected histologically and circular muscle contractile responses were measured using isometric transducers. Bead expulsion assays were performed to assess in vivo constipation.The strongest contraction in response to morphine was detected in the rectum. The distal and transverse colon also showed strong contractions, whereas weak responses were detected in the proximal colon, jejunum, and ileum. Regarding the sustainability of muscle contractions during morphine exposure, prolonged waves were detected only in the rectum, while the waves diminished gradually in other regions. To identify the mechanism(s) underlying this difference, we focused on nitric oxide synthase (NOS). In the distal colon, decreased contraction during morphine exposure was recovered by application of a NOS inhibitor (L-NAME), while a NOS substrate (L-arginine) enhanced contractile degradation. In contrast L-NAME and L-arginine modestly affected the sustained contraction in the rectum. To confirm the correlation with constipation, beads were inserted into the transverse colon, distal colon, or rectum after morphine administration and expulsion times were examined. Beads tended to stop at the rectum even when inserted in the deeper colonic regions.The rectum showed the greatest response to morphine in both in vitro and in vivo analyses, therefore it may play a key role for opioid-induced constipation.
- Immunotherapy trial as diagnostic test in evaluating patients with presumed autoimmune gastrointestinal dysmotility. [JOURNAL ARTICLE]
- Neurogastroenterol Motil 2014 Jul 20.
Chronic gastrointestinal dysmotility greatly impacts the quality of life. Treatment options are limited and generally symptomatic. Neural autoimmunity is an under-recognized etiology. We evaluated immunotherapy as an aid to diagnosing autoimmune gastrointestinal dysmotility (AGID).Twenty-three subjects evaluated at the Mayo Clinic for suspected AGID (August 2006-February 2014) fulfilled the following criteria: (1) prominent symptoms of gastrointestinal dysmotility with abnormalities on scintigraphy-manometry; (2) serological evidence or personal/family history of autoimmune disease; (3) treated by immunotherapy on a trial basis, 6-12 weeks (intravenous immune globulin, 16; or methylprednisolone, 5; or both, 2). Response was defined subjectively (symptomatic improvement) and objectively (gastrointestinal scintigraphy/manometry studies).Symptoms at presentation: constipation, 18/23; nausea or vomiting, 18/23; weight loss, 17/23; bloating, 13/23; and early satiety, 4/23. Thirteen patients had personal/family history of autoimmunity. Sixteen had neural autoantibodies and 19 had extra-intestinal autonomic testing abnormalities. Cancer was detected in three patients. Preimmunotherapy scintigraphy revealed slowed transit (19/21 evaluated; gastric, 11; small bowel, 12; colonic, 11); manometry studies were abnormal in 7/8. Postimmunotherapy, 17 (74%) had improvement (both symptomatic and scintigraphic, five; symptomatic alone, eight; scintigraphic alone, four). Nine responders re-evaluated had scintigraphic evidence of improvement. The majority of responders who were re-evaluated had improvement in autonomic testing (six of seven) or manometry (two of two).This proof of principle study illustrates the importance of considering an autoimmune basis for idiopathic gastrointestinal dysmotility and supports the utility of a diagnostic trial of immunotherapy.
- Lymphangioma of the ileocecal valve clinically masquerading as a submucosal small intestinal GIST: Report of a case and literature review. [JOURNAL ARTICLE]
- Saudi J Gastroenterol 2014 July-August; 20(4):262-264.
Lymphangiomas are rare tumors affecting the gastrointestinal tract, and may be seen in the bowel, gall bladder, and pancreas. They resemble hemangiomas, but consist of spaces of variable sizes containing lymph. In this report, we describe the case of a 53-year-old male who presented with abdominal pain and constipation. Computerized tomography (CT) scan showed a polypoidal lesion at the ileocecal valve which was thought to be a gastrointestinal stromal tumor. Resected specimen did, however, show a lymphangioma. We also describe the clinicopathologic features of gastrointestinal lymphangiomas with a literature review.
- Association of help-seeking behavior with depression and anxiety disorders among gastroenterological patients in Saudi Arabia. [JOURNAL ARTICLE]
- Saudi J Gastroenterol 2014 July-August; 20(4):233-240.
Background/Aims: There is a high prevalence of depression and anxiety disorders among gastroenterological outpatients. Relatively few studies have been done on the help-seeking behavior among those who suffer from gastrointestinal symptoms with or without psychiatric disorders. We aimed to characterize the help-seeking behavior of gastroenterological outpatients and to evaluate if this behavior is linked to the presence of depression and anxiety. Patients and Methods: A cross-sectional study was carried out in gastroenterology clinics in four hospitals in Riyadh between February and September 2013. A self-administrated questionnaire was developed and administered to patients. Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) questionnaires were used to diagnose depression and anxiety, respectively. Results: A total of 440 patients completed the study questionnaire. The average age was 36.0 ± 12.8 years and 69% of the patients were males. Complaints included abdominal pain (58%), heartburn (29%), diarrhea or constipation (25%), appetite or weight changes (22%), and nausea or vomiting (16%). Depression was diagnosed in 36%, while anxiety was diagnosed in 28% of the patients. The first intervention was use of medications (68%) and undergoing endoscopy (16%), while few patients initially used herbs or Islamic incantation (7.5%). This first intervention was done primarily (59%) in private sector hospitals rather than government sector hospitals (36%). The rates of depression and anxiety in our patients were higher among those who suffered from multiple complaints for longer durations and with less satisfaction with the offered services. Conclusion: Depression and anxiety are common comorbidities in gastroenterological outpatient population, especially those who have a chronic course of multiple gastrointestinal complaints.