Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND: The association between inhibition of tumour necrosis factor alpha (TNF-α) and new onset of neurological adverse events (AEs) is unclear. AIMS: To evaluate neurological AEs with TNF-α inhibitors reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) utilising a standardised scoring tool for drug-induced AEs. METHODS: A search of FAERS for neurological AEs (January 1, 2000 to December 31, 2009) reported with infliximab, adalimumab, certolizumab and etanercept was performed. Full-text reports were accessed using the Freedom of Information Act and scored using Naranjo score, while accounting for temporal association, previous conclusive reports of the neurological AE with any TNF-α inhibitor, and alternate explanations including underlying disease, concomitant medications and comorbidities, such as diabetes mellitus. RESULTS: There were 772 reports. Most were in patients who had rheumatoid arthritis (393, 50.9%) followed by inflammatory bowel disease (140, 18.1%). No significant differences in age or gender were seen between IBD patients compared with rheumatological diseases (P = 0.584 and P = 0.055 respectively). Etanercept was reported most (327, 42.4%) followed by infliximab (276, 35.8%) (P = 0.008). Peripheral neuropathy was the most common neurological AE (296 reports, 38.3%) followed by central nervous system and/or spinal cord demyelination (153 reports, 19.8%). Majority (551, 71.4%) of the reports were of 'possible' AE with the remaining 'probable' AE and none identified as 'definite' AE. CONCLUSION: While several neurological AEs have been described, definite association between de novo development of these AEs and exposure to TNF-α inhibitors was not established using the Naranjo score.

Increased risk of osteoporosis-related fractures in patients with irritable bowel syndrome.

UNLABELLED: We sought to determine whether patients with irritable bowel syndrome (IBS) have an increased risk of osteoporosis and related fractures using the Nationwide Emergency Department Sample (NEDS). Patients with IBS had increased adjusted odds of osteoporosis and osteoporotic fractures compared to the non-IBS control group, controlling for known risk factors for osteoporosis. Screening measures to identify osteoporosis in this group are advised. INTRODUCTION: Ulcerative colitis, Crohn's disease, and celiac disease have well-described augmented risk of osteoporosis and related fractures. We sought to determine whether IBS also indicates an increased risk of osteoporosis and related fractures. METHODS: The 2008 NEDS database was used to determine the adjusted odds of osteoporosis and related fractures in IBS patients. Only fractures (pathologic wrist (733.12), vertebrae (733.13), and femur fractures (733.14), traumatic wrist (813.x), vertebrae (805.x-806.x), and hip fractures (820.x-821.x)) with a secondary diagnosis of osteoporosis (733.0x) were included in the analysis. A multivariate logistic regression analysis was performed, controlling for known risk factors for osteoporosis and related fractures. RESULTS: We identified 317,857 ED visits in patients with a diagnosis of IBS. Of these, 17,752 carried a diagnosis of osteoporosis and 694 IBS patients had a concurrent diagnosis of a pathologic fracture of the wrist, hip, or vertebrae. A total of 1,503 IBS patients had a concurrent diagnosis of a traumatic fracture of the wrist, hip, or vertebra. Overall, patients with IBS had an increased adjusted odds of osteoporosis (odds ratio (OR) 4.28, 95% confidence interval (CI) 4.21-4.35) and osteoporotic fractures (OR 2.36, CI 2.26-2.47) compared to the non-IBS control group. The highest adjusted odds of fracture was seen at the wrist (OR 2.41, CI 2.10-2.77 compared to controls). CONCLUSIONS: IBS patients are at an increased risk of osteoporosis and related fractures. Screening measures to identify osteoporosis and prevent fractures are advised.

Renal risks of sodium phosphate tablets for colonoscopy preparation: a review of adverse drug reactions reported to the US Food and Drug Administration.

AIM: Sodium-phosphate-containing colonoscopy preparations cause renal failure by the development of calcium phosphate nephropathy. Although Fleet's Phospho-Soda has been removed from the US market, sodium phosphate tablets sold as OsmoPrep and Visicol remain available. Our aim was to analyse renal risks of the sodium phosphate tablets. METHOD: We conducted a retrospective study using the US Food and Drug Administration Adverse Event Reporting System, a voluntary reporting system available for public access. Renal adverse events were identified using search terms including renal impairment, increased blood urea nitrogen, increased creatinine, renal failure, acute renal failure, chronic renal failure, acute phosphate nephropathy, nephrocalcinosis, renal tubular necrosis, haemodialysis, nephropathy toxic, dialysis, peritoneal dialysis, renal injury, renal tubular disorder, decreased glomerular filtration rate and decreased creatinine clearance. Patient age, gender and body weight were compared with data for the general population in the National Health and Nutrition Examination Survey (NHANES). RESULTS: In total 2,097,223 files were extracted from the US Food and Drug Administration website for 2004-2008 and the first 9 months of 2009. Of these, 178 patients on tablet preparations (71% women) were identified, with increasing numbers of renal adverse drug reactions reported from tablet preparations each year. The mean weight for women with renal complications from tablet preparations was 68.57 ± 1.78 kg, significantly lower than the national average weight of 74 ± 0.5 kg for the same age group (P = 0.003) in NHANES. CONCLUSION: Renal adverse drug reactions from sodium phosphate tablets are more common in women with a mean body weight lower than the national average weight.

Increased serum phosphate levels and calcium fluxes are seen in smaller individuals after a single dose of sodium phosphate colon cleansing solution: a pharmacokinetic analysis.

BACKGROUND: Sodium phosphate containing colonoscopy preparations may cause electrolyte disturbances and calcium-phosphate nephropathy. Decreased body weight is an unexplored risk factor for complications with sodium phosphate ingestion. AIM: To perform a pharmacokinetic analysis of a single dose of Fleet Phospho-Soda in smaller and larger individuals. METHODS: Seven subjects weighing <55 kg (Group I) and six weighing >100 kg (Group II) consumed 45 mL Fleet Phospho-Soda. Serum electrolytes were measured. Hydration was closely maintained by monitoring weight, fluid intake and total body water. RESULTS: Marked increases in serum phosphate were seen in Group I compared to Group II. For example, mean serum phosphate at 120 min was 7.8 +/- 0.5 mg/dL in Group I and 5.1 +/- 0.8 mg/dL in Group II (P < 0.001). Normalized area under the phosphate vs. time curve for Group I was 1120 +/- 190 mg/dL*min and 685 +/- 136 mg/dL*min for Group II (P < 0.001). Twelve-hour urine calcium was lower in Group I (16.4 +/- 7.6 mg) than in Group II (39.2 +/- 7.8 mg, P < 0.001). CONCLUSIONS: Increased serum phosphate occurs in smaller individuals after ingestion of sodium phosphate preparations, even with strict attention to fluid intake. Smaller body weight poses a potential risk for calcium-phosphate nephropathy.

A dynamic model of colonic concentrations of delayed-release 5-aminosalicylic acid (Asacol).

BACKGROUND: 5-ASA in a pH sensitive tablet (Asacol) is administered as three doses/day to treat ulcerative colitis. Once daily dosing may improve patient adherence. Simulation of colonic levels of 5-ASA can be used to compare dosing regimens. AIM: To create a dynamic model of colonic concentrations of delayed-release 5-aminosalicylic acid (Asacol). METHODS: Using published data, we created a computer model with STELLA software to simulate amounts of colonic 5-ASA in the total colon, right, transverse, descending and sigmoid/rectum after daily and three time/day Asacol. RESULTS: The model predicted similar total and regional amounts of 5-ASA with both regimens. Distribution of 5-ASA was 38% in the right colon, 33% in the transverse colon and 14% each in the descending and sigmoid/rectal colon. Simulated increases in colonic motility and defecation rate exaggerated this 5-ASA distribution, resulting in negligible amounts of 5-ASA in the sigmoid/rectal region. CONCLUSIONS: This computer model suggests that Asacol can be administered as a single daily dose. The model supports experimental and clinical observations that alternate dose or route of administration may be necessary to achieve adequate 5-ASA amounts in the distal colon during acute exacerbations of ulcerative colitis. This simulation cannot account for all sources of variability in the clinical setting, but provides a rationale for further investigation.

Electrolyte profiles within the ileoanal pouch: measurement by an in vivo equilibrium dialysis technique.

BACKGROUND: Patients with an ileoanal pouch have high rates of fluid and electrolyte loss. These improve with pouch adaptation. There is limited information concerning secretion and absorption in the stable ileoanal pouch. A new method to measure and characterize electrolytes in the ileoanal pouch is described. METHODS: Following an in vitro study, nine patients with a stable ileoanal pouch had consecutive placement of dialysis bags consisting of a semi-permeable membrane containing 5 ml of 10% dextran in normal saline into the ileoanal pouch. These were left in place for 15, 30, 60, and 120 min. After determining that 60 min was the optimal timing for measurement of electrolyte concentrations, 12 normal volunteers underwent a similar in vivo dialysis study with dialysis bags withdrawn at 60 min. Sodium, chloride, potassium, phosphorus, calcium and magnesium concentrations in the dialysis bags were compared between the two groups. RESULTS: In the in vitro and in vivo studies, the measured electrolytes reached equilibrium within 60 min. Statistically significant differences between sodium concentrations (160.9 +/- 30.2 vs. 116.8 +/- 13.8 mmol/l, respectively) and phosphorus concentrations (6.8 +/- 5.2 vs. 1.8 +/- 0.7 mg/dl, respectively) at 60 min in ileoanal pouch patients and volunteers were found (p<0.001). There were no statistical differences in the other measured electrolytes between the two groups. CONCLUSION: An in vivo dialysis technique is described for measuring electrolyte concentrations within the ileoanal pouch. Differences in sodium and phosphate concentrations may reflect incomplete adaptation of the ileoanal pouch, and are a potential explanation for increased stool frequency in these patients.

A pilot study of thalidomide for patients with symptomatic mesenteric panniculitis.

BACKGROUND: Mesenteric panniculitis is a rare condition with no standard therapy. AIM: To assess the safety and efficacy of thalidomide for the treatment of patients with symptomatic mesenteric panniculitis using a newly established clinical disease activity index (Mesenteric Panniculitis Subjective Assessment Score). METHODS: In an open-label pilot study, five patients with symptomatic mesenteric panniculitis received oral thalidomide, 200 mg nightly, for 12 weeks. The primary end-point was a reduction in the Mesenteric Panniculitis Subjective Assessment Score by > or = 20% at 12 weeks or complete remission (absence of symptoms). RESULTS: Four (80%) of the five patients responded. The median Mesenteric Panniculitis Subjective Assessment Score at baseline was 39 and at week 12 was 25 (average decrease of 44%). One patient achieved complete remission by week 4, which was sustained. At 12 weeks, three (75%) patients experienced a global response, five (100%) patients had a > or = 20% (range, 29-98%) decrease in erythrocyte sedimentation rate and three (75%) patients had a > or = 20% (range, 61-93%) decrease in C-reactive protein. Abdomino-pelvic computed tomography scans were unchanged in all five patients. There were no serious adverse events. CONCLUSIONS: Thalidomide is safe, well tolerated and efficacious in the treatment of some patients with symptomatic mesenteric panniculitis. Further study is indicated.

Gastro-oesophageal reflux disease in obesity: pathophysiological and therapeutic considerations.

Gastro-oesophageal reflux disease (GERD) is common in obese patients. Apart from the physical discomfort and the economic burden, GERD may increase morbidity and mortality through its association with oesophageal carcinoma. The pathophysiology of GERD differs between obese and lean subjects. First, obese subjects are more sensitive to the presence of acid in the oesophagus. Second, hiatal hernia, capable of promoting GERD by several mechanisms, is more prevalent among the obese. Third, obese subjects have increased intra-abdominal pressure that displaces the lower oesophageal sphincter and increases the gastro-oesophageal gradient. Finally, vagal abnormalities associated with obesity may cause a higher output of bile and pancreatic enzymes, which makes the refluxate more toxic to the oesophageal mucosa. The altered body composition associated with obesity affects the pharmacokinetics of drugs. There are no data regarding the efficacy of any of the drugs used for GERD treatment. The dosages of cimetidine and ranitidine should be calculated according to the patient's ideal body weight, not their actual weight. Of the operative procedures used for weight loss, Roux-en-Y gastric bypass was found to be most effective for GERD, while gastric banding was associated with a high prevalence of reflux. This review outlines the pathophysiology and the treatment of GERD in obesity with emphasis on the therapeutic considerations in this population of patients.

Thalidomide treatment for refractory Crohn's disease: a review of the history, pharmacological mechanisms and clinical literature.

Several recent case reports and clinical trials have demonstrated that thalidomide is emerging as an efficacious alternative in the treatment of selected patients with refractory Crohn's disease. The effects of thalidomide are at least partly mediated by down-regulation of tumour necrosis factor (TNF)-alpha, a potent proinflammatory cytokine. However, thalidomide is also known to inhibit angiogenesis, and it has several other well-described immunomodulatory properties. Clinical studies have confirmed that previously refractory Crohn's disease patients respond to thalidomide, and many enter clinical remission. Efficacy usually occurs within 4 weeks. Thalidomide also has steroid-sparing properties, and it is particularly useful in treating oral and fistulous complications of Crohn's disease. Although it is usually tolerable, careful monitoring is recommended to prevent toxicities, such as birth defects and peripheral neuropathy. This review provides a detailed summary of the literature to date on the use of thalidomide treatment for Crohn's disease. Special attention is directed towards its history, mechanisms, and proposed role. The recent development of thalidomide analogues is also discussed briefly.

Review article: current therapeutic options for radiation proctopathy.

Radiation proctopathy is a common unfortunate complication following radiation therapy of pelvic malignancies. Symptoms of chronic radiation proctopathy include haematochezia, urgency, constipation, tenesmus, diarrhoea and rectal pain. Currently, a wide variety of pharmacological options, endoscopic cautery techniques and surgical procedures have been proposed for the treatment of chronic radiation proctopathy. Although these have been proposed primarily as treatment for rectal bleeding, the control of other symptoms has been noted with some of these agents. Pharmacological options include 5-aminosalicylic acid preparations, coticosteroid enemas, sucralfate (oral, enemas), formalin, short chain fatty acid enemas, oestrogen/progesterone, hyperbaric oxygen, antioxidants, sodium pentosan polysulphate and misoprostol rectal suppositories. Of these, sucralfate and formalin therapy appear to be effective for bleeding control. Misoprostol rectal suppositories and oral sucralfate may be useful in the prevention of acute and chronic symptoms of radiation proctopathy. Endoscopic cautery techniques have included the use of Nd:YAG laser and argon laser for coagulation of bleeding neovascular telangiectasias. Argon plasma coagulation offers a safe non-contact method of delivering haemostasis which has proven to be particularly useful in targeting difficult to reach lesions tangentially. Surgery is generally reserved for severe refractory cases involving ongoing haemorrhage, obstruction, stricture formation, fistulas and perforation. Given that formal randomized placebo-controlled studies are lacking for most treatments, the management of these patients is often challenging and unclear. Hence, there is a need for more research and education on radiation proctopathy.

Improving the serum D-xylose test for the identification of patients with small intestinal malabsorption.

BACKGROUND: D-Xylose absorption testing is a simple, low-cost method of screening for small intestinal malabsorption. The optimum method to measure D-xylose absorption (serum vs. urine testing) is uncertain. GOALS: We present a method of improving the accuracy of D-xylose testing. STUDY: Fifty-one consecutive patients (40 with chronic diarrhea and 5 asymptomatic patients with renal insufficiency) and 6 volunteers with normal renal function were recruited. All received D-xylose, 10 g intravenously and 25 mg orally, on two separate occasions. Serum concentration was determined at baseline and at frequent times thereafter. Area under the curve was calculated to infinity, and D-xylose bioavailability (F) was calculated. A nonlinear model used to derive the relationship between 3-hour D-xylose concentrations and F showed that a value of less than 22.5 mg/dL correlated with an F of less than 60% (malabsorption of D-xylose). A 1-hour D-xylose of less than 20 mg/dL was considered abnormal. RESULTS: Using these indexes for normal 1-and 3-hour D-xylose levels, 90% of patients with D-xylose malabsorption were identified (sensitivity, 90%; specificity, 95%), which represents a marked improvement within the conventional 1-hour D-xylose of less than 20 mg/dL alone (sensitivity, 71%; specificity, 100%). The model was applied prospectively to 15 additional patients with chronic diarrhea. Of these, 12 patients with an F of less than 60% were identified, including 2 patients with normal 1-hour D-xylose levels. CONCLUSIONS: Thus, the addition of a 3-hour D-xylose serum level of less than 22.5 mg/dL to conventional 1-hour D-xylose determination greatly improves the D-xylose test for malabsorption screening.

Treatment of anal fissures with topical nitroglycerin.

Anal fissure is a painful condition that is caused by anodermal tearing after the passage of hard stool. Severe cases result in involuntary internal anal sphincter spasm and have traditionally been treated surgically with a lateral sphincterotomy. Investigators have demonstrated that nitric oxide causes relaxation of the smooth muscle of the anal canal, so topical nitroglycerin ointment preparations have recently been studied as an efficacious alternative to surgery. Despite the fact that there are a number of trials examining topical nitroglycerin for the treatment of anal fissures, there remains no consensus about concentrations, compositions and applications necessary to obtain good results. This review summarises current literature regarding topical nitroglycerin pharmacotherapy for anal fissure.

Malabsorption testing: a review.

Malabsorption syndromes often present diagnostic dilemmas to even the most experienced clinicians. Several malabsorption screening tests are available, but d-xylose testing is our initial screening method of choice. Recent innovations such as serum assays for antibodies associated with celiac sprue are improving the work-up of patients with suspected malabsorption. In addition, physicians are applying technological advances in imaging to determine the underlying pathologies responsible for the occurrence of malabsorption and maldigestion. Breath testing remains a controversial modality in the work-up of patients with malabsorption. Tubeless tests of pancreatic function are also the subject of debate due to a lack of sensitivity for diagnosing mild to moderate chronic pancreatic insufficiency. This review identifies and provides critical analysis of new developments in the field of malabsorption testing. The authors also provide a clinical algorithm for diagnosing malabsorption.

D-xylose kinetics and hydrogen breath tests in functionally anephric patients using the 15-gram dose.

Malabsorptive evaluation in renal failure is difficult because most absorptive testing requires urinary collections. Kinetic analysis of d-xylose absorption and d-xylose breath testing were performed in an effort to establish an effective absorption test in functionally anephric patients. We studied 13 fasting renal failure patients with no diarrhea or symptoms suggesting malabsorption on two separate nondialysis days after they received 15 g oral d-xylose on day 1 and 10 g IV on day 2. Serum collections were used to calculate the kinetic rate constants and extent of d-xylose absorption. After the oral d-xylose, end expiratory breaths were collected every 15 minutes for 3 hours and were analyzed for H2 with gas chromatography. Five subjects also allowed upper endoscopy and duodenal biopsy. The mean absorption rate constant (Ka) and bioavailability (F) were similar to published values for normal subjects using the 15-g dose (0.936 min(-1); range, 0.227-1.96; and 74%, range 46-99, respectively). Of the patients, 12 had normal 1-hour serum d-xylose concentrations (>20 mg/dL). There was no clear inverse correlation between the rate constant for absorption or bioavailability and peak breath hydrogen or the area under the curve for breath H2 versus time. Using 15 g oral d-xylose, mean bioavailability and absorption rate constants are normal in functionally anephric patients with no clinical evidence of malabsorption. Three patients had elevated breath peak H2 concentrations, but there was no clear inverse correlation between bioavailability and the breath H2 values. A 1-hour serum dxylose concentration >20 mg/dL may be considered normal in this patient group, similar to patients with normal renal function.

Thalidomide therapy for patients with refractory Crohn's disease: an open-label trial.

BACKGROUND & AIMS: Inhibition of tumor necrosis factor is a proposed mechanism for the anti-inflammatory properties of thalidomide. We performed an open-label trial of thalidomide in refractory Crohn's disease. METHODS: Twenty-two patients with refractory Crohn's disease (Crohn's Disease Activity Index [CDAI] > 200 and/or draining perianal disease) initiated therapy with thalidomide, 200 mg at bedtime (18 patients), or 300 mg at bedtime (4 patients). CDAI and goal interval scores (GIS) were assessed at weeks 0, 4, and 12. Clinical response for patients with luminal disease was defined as reduction in CDAI score of >150 points and for fistula patients was 2 scores of >/=1+ in 3 parameters of the GIS. Clinical remission was defined as a total CDAI < 150 (luminal patients) or >/=2+ for all parameters of the GIS (fistula patients). RESULTS: Nine patients with luminal disease and 13 with fistulas (16 male, 6 female) were enrolled. The median CDAI score at entry was 371 (95-468). Sixteen patients completed 4 weeks of treatment (12 clinical responses, 4 clinical remissions). All 14 patients completing 12 weeks met criteria for clinical response. Nine achieved clinical remission (3 luminal, 6 fistula patients). The median CDAI score was 175 (30-468; P < 0.001 vs. baseline). CONCLUSIONS: Thalidomide is efficacious in some patients with refractory Crohn's disease.

D-xylose testing.

The literature on D-xylose testing has been reviewed, stressing advances in our understanding of absorption in general (including D-xylose absorption), the relationship of D-xylose testing to the development of excellent serologic tests for the diagnosis of celiac disease, the use of D-xylose testing in the evaluation of diarrhea in acquired immunodeficiency syndrome, new information on breath testing for the evaluation of malabsorption, and recent information on the understanding of D-xylose absorption compared with transcellular vs. paracellular transport. The authors suggest ways in which D-xylose testing might be employed in malabsorption or diarrhea evaluations, including some algorithms.

Colonoscopy in octogenarians: a review of 428 cases.

Studies on the use of colonoscopy in the octogenarian are few. Therefore this study evaluated the results and cost-effectiveness of colonoscopy in octogenarians. A total of 403 patients 80 years of age or older who underwent colonoscopy from May 1994 to May 1996 were reviewed (median 84, range 80-95). Parameters evaluated were indications for colonoscopy, significant endoscopic findings (biopsy-confirmed adenocarcinoma and adenomatous polyps >/=1 cm), complications, colonoscopy completion rate, and mean charge per procedure. Postpolypectomy bleeding occurred in one patient. The cecal intubation rate was 94%. The calculated cost per procedure was U.S. $2,342. Indications for colonoscopy/number of cancers detected include: change in bowel habits, 78/2; blood/hemoccult positive, 69/8; abdominal pain, 12/0; constipation, 9/0; diarrhea, 8/0; surveillance for history of polyps, 159/3; surveillance for history of cancer, 51/1; cancer or polyp on sigmoidoscopy, 42/4. The cancer detection rate in patients with bleeding was 11.5%, compared with 1. 9% for all other symptoms. Colonoscopy can be safely performed in the octogenarian population. Our data suggest that more stringent selection criteria for colonoscopy in the octogenarian could result in significant cost savings.