A new amino acid derivative of ursodeoxycholate, (N-L-Glutamyl)-UDCA (UDCA-Glu), to selectively release UDCA in the colon.

BACKGROUND: Ursodeoxycholic acid (UDCA) is chemoprotective in animal models of colon cancer but results from clinical trials have been less impressive probably because UDCA is rapidly absorbed in the small intestine and little reaches the colon. UDCA-glutamate (Glu), a novel bile acid, was synthesized with the objective of utilizing peptide bond cleavage by brush border enzymes to enhance delivery of UDCA to the colon. MATERIALS AND METHODS: Qualitative and quantitative intestinal intraluminal and fecal bile acid composition measured by mass spectrometry was determined in Fisher rats after intragastric administration of UDCA, or UDCA-Glu for 5 days. The effect of UDCA and UDCA-Glu on bile flow was studied after bile duct canulation. RESULTS: In the small intestine, UDCA was found in higher amounts when UDCA was administered compared with UDCA-Glu (1.50 + or - 0.32 vs. 0.75 + or - 0.12 mg). By contrast, UDCA-Glu administration resulted in a greater delivery of UDCA to the colon. The fecal bile acid composition resembled that of the intraluminal colonic composition and a higher mass of UDCA (unconjugated 3.39 + or - 0.30 mg; conjugated 6.40 + or - 1.03 mg) was found in rats treated with UDCA-Glu compared to those treated with UDCA (2.27 + or - 0.11 and. 0.04 + or - 0.01 mg, respectively), establishing increased delivery of UDCA to the colon. Both bile acids similarly increased bile flow but the initial effect of UDCA was greater than that of UDCA-Glu. CONCLUSION: Conjugation of UDCA to glutamic acid reduces its intestinal absorption and biotransformation resulting in increased colonic delivery of UDCA. UDCA-Glu may have potential application as a pro-drug for enhancing the action of UDCA in the treatment of colonic diseases.

Noncardiac chest pain of esophageal origin in patients with and without coronary artery disease.

BACKGROUND/AIMS: Non-cardiac chest pain is a frequent finding in patients admitted to emergency departments, and it has been shown that many of these patients may have an esophageal cause for their pain. However, little data are available on patients primarily referred to the cardiology unit, and especially those with coronary artery disease. The purpose of this study was to assess the role of esophageal dysfunction in chest pain patients with and without coronary artery disease. METHODOLOGY: Eighty-one patients referred from a cardiology unit for chest pain and no myocardial infarction entered the study. Sixty-one patients had no evidence of coronary artery disease, whereas 20 had coronary artery disease with chest pain at rest. After the cardiological evaluation, the patients underwent esophageal function testing by means of upper endoscopy, manometry, and 24-hour pH-monitoring. RESULTS: Overall, 10% of patients (2.5% in the coronary artery disease group) had evidence of endoscopic esophagitis, 46% of esophageal motor disorders (12% in the coronary artery disease group), and 10% abnormal pH-monitoring (1% in the coronary artery disease group). CONCLUSIONS: We report that the esophagus might be responsible for non-cardiac chest pain in patients with and without coronary artery disease. In our experience, esophageal motor disorders, and not an increased acid reflux, are the abnormalities most commonly found in these patients.

Empirical antibiotic treatment with piperacillin-tazobactam in patients with microbiologically-documented biliary tract infections.

AIM: To report our experience with empiric antimicrobial monotherapy (piperacillin/tazobactam, of which no data are available in such specific circumstances) in microbiologically-documented infections in patients with benign and malignant conditions of the biliary tract. METHODS: Twenty-three patients, 10 with benign and 13 with malignant conditions affecting the biliary tree and microbiologically-documented infections were recruited and the efficacy of empirical antibiotic therapy was assessed. RESULTS: The two groups featured similar demographic and clinical data. Overall, the infective episodes were most due to Gram negative agents, more than 60% of such episodes (mostly in malignant conditions) were preceded by invasive instrumental maneuvers. Empirical antibiotic therapy with a single agent (piperacillin/tazobactam) was effective in more than 80% of cases. No deaths were reported following infections. CONCLUSION: An empiric therapeutic approach with piperacillin/tazobactam is highly effective in biliary tract infections due to benign or malignant conditions.

Colonic regular contractile frequency patterns in irritable bowel syndrome: the 'spastic colon' revisited.

BACKGROUND: Irritable bowel syndrome is a frequent gastrointestinal disorder of which the pathophysiological basis is still not completely understood. Among the various proposed mechanisms, colonic motility may play a role, at least in a subset of patients. AIMS: To investigate the regular colonic contractile patterns in patients with irritable bowel syndrome. Our working hypothesis was that an increase of these patterns in such condition might represent a motility equivalent of the so-called 'spastic colon'. PATIENTS AND METHODS: Twelve patients of both genders were investigated by means of 24 h colonic manometry, and the results were compared to those from 20 healthy controls. Regular contractile patterns (with frequencies ranging from 2 to 8 per min) were calculated for the entire recording period and in single colonic segments. RESULTS: Overall, colonic frequency patterns were significantly more frequent in patients than controls (12.6% vs 6.4% of the total contractile activity, P < 0.001); in both groups, the 3 cycles/min frequency was predominant, especially in the sigmoid colon. More than 40% patients displayed a correlation between abdominal pain and occurrence of regular contractile frequencies. CONCLUSIONS: Abnormal colonic motility may play some role in the pathogenesis of symptoms related to irritable bowel syndrome, with an excess of regular contractile activity related to the so-called 'spastic colon'.

Twenty-four-hour manometric study of colonic propulsive activity in patients with diarrhea due to inflammatory (ulcerative colitis) and non-inflammatory (irritable bowel syndrome) conditions.

BACKGROUND: Little is known concerning colonic motility and almost nothing is known concerning propulsive activity in pathological conditions characterized by diarrhea of both inflammatory and non-inflammatory origin. AIMS: The purpose of the present study was to investigate colonic propulsive activity in ulcerative colitis and diarrhea-predominant irritable bowel syndrome (IBS) patients. PATIENTS AND METHODS: Seven patients with active, moderate ulcerative colitis and nine diarrhea-predominant IBS patients entered the study. Sixteen healthy volunteers were recruited as a control group. In all subjects, 24-h colonic motility was recorded by a colonoscopically positioned manometric catheter. Both high- (mass movements) and low-amplitude propagated contractions were analyzed. RESULTS: High-amplitude propagated contractions were significantly increased in ulcerative colitis with respect to controls; no significant differences were found with respect to IBS patients, and between IBS and controls. Concerning amplitude, no significant difference was found between groups, although IBS patients approached the statistical difference with respect to controls. Low-amplitude propagated contractions were significantly increased in ulcerative colitis with respect to controls; no significant differences were found compared with IBS patients. The latter, however, displayed a trend toward an increase with respect to controls that approached but did not reach statistical significance. CONCLUSIONS: Both inflammatory and non-inflammatory diarrheal conditions are characterized by an overall increase of colonic propulsive activity. This observation may be useful for a better understanding of the pathophysiologic mechanisms of these disorders.

One-year follow-up study on the effects of electrogalvanic stimulation in chronic idiopathic constipation with pelvic floor dyssynergia.

BACKGROUND: Constipation is a commonly reported symptom, and pelvic floor dyssynergia is frequently documented in constipated patients. The standard therapeutic approach for pelvic floor dyssynergia is biofeedback training, but long-term studies show that a significant percentage of patients remain symptomatic. Alternative or adjunctive therapeutic options are needed. AIMS: The purpose of this study was to evaluate the long-term effects of electrogalvanic stimulation in patients with pelvic floor dyssynergia and severe constipation, to see whether this treatment may be of some benefit. PATIENTS AND METHODS: Thirty consecutive constipated patients with clinical and instrumental evidence of pelvic floor dyssynergia entered the study and were treated with a standard high-frequency galvanic electrostimulation protocol. Clinical and instrumental (colon transit time, anorectal manometry, defecography, rectal balloon expulsion) assessment evaluations were performed basally and one year after the treatment. RESULTS: Overall, approximately 50 percent of patients showed significant improvement after electrogalvanic treatment, from both a clinical and an instrumental point of view, as shown by the objective measurements obtained through manometry, defecography, and the balloon expulsion test. The benefit was limited to normal transit constipation patients. CONCLUSIONS: Because of the relatively simple, painless and effective nature of electrogalvanic stimulation, we concluded that it may represent a useful adjunct to the therapeutic armamentarium for pelvic floor dyssynergia in normal transit constipation.

Long-term study on the effects of visual biofeedback and muscle training as a therapeutic modality in pelvic floor dyssynergia and slow-transit constipation.

PURPOSE: Biofeedback training has been shown as an effective therapeutic measure in patients with pelvic floor dyssynergia, at least in the short term. Long-term effects have received less attention. Moreover, its effects in patients with slow-transit constipation have been scarcely investigated. This study was designed to assess in an objective way the medium- and long-term effects of biofeedback and muscle training in patients with pelvic floor dyssynergia and slow-transit constipation. METHODS: Twenty-four patients (14 with pelvic floor dyssynergia and 10 with slow transit) meeting the Rome II criteria for constipation, and unresponsive to conventional treatments, entered the study. Clinical evaluation and anorectal manometry were performed basally and three months after a cycle of electromyographic biofeedback and muscle training; moreover, a clinical interview was obtained one year after biofeedback. Patients with slow-transit constipation also had colonic transit time reassessed at one year. RESULTS: Clinical variables (abdominal pain, straining, number of evacuations/week, use of laxatives) all significantly improved in both groups at three-month assessment; anorectal manometric variables remained unchanged, apart from a significant decrease of sensation threshold in the pelvic floor dyssynergia group and of the maximum rectal tolerable volume in the slow-transit constipation group. At one-year control, 50 percent of patients with pelvic floor dyssynergia still maintained a beneficial effect from biofeedback, whereas only 20 percent of those complaining of slow-transit constipation did so. Moreover, the latter displayed no improvement in colonic transit time. CONCLUSIONS: In our experience, patients with pelvic floor dyssynergia are likely to have continued benefit from biofeedback training in the time course, whereas its effects on slow-transit constipation seems to be maximal in the short-term course.

Colonic propulsive impairment in intractable slow-transit constipation.

HYPOTHESIS: Intractable constipation, especially of the slow-transit subtype, may represent several pathophysiologic entities with a common final symptomatic appearance. An overall impairment of colonic propulsive activity may represent a major disease mechanism. DESIGN: Case series. SETTING: Tertiary university hospital. SUBJECTS: Twenty-nine severely constipated patients with clinical and homogeneous features of slow-transit constipation that were unresponsive to conventional medical measures and 16 age-matched healthy volunteers. INTERVENTIONS: Twenty-four-hour manometric recordings obtained in patients and controls to assess high- and low-amplitude colonic propulsive activity. RESULTS: Compared with controls, patients showed heavily reduced high-amplitude propagated activity (average, <1 event per subject per day). No differences were found in low-amplitude propagated activity. CONCLUSIONS: Patients with severe constipation that is refractory to medical treatment may display an important reduction of colonic forceful propulsive activity. This may justify a surgical approach, which may offer the best results in such patients. It is, however, important to obtain thorough physiologic documentation before such a drastic approach is considered. The residual low-amplitude propulsive activity might represent a partially compensatory mechanism in these patients. Studies in more homogeneous groups of such patients are needed.

Abnormal colonic propagated activity in patients with slow transit constipation and constipation-predominant irritable bowel syndrome.

BACKGROUND: The pathophysiological basis of constipation is still unclear, and the role of colonic dysfunction is debated, especially in irritable bowel syndrome. Objective data are quite scarce, especially concerning colonic propulsive activity. AIMS: To evaluate high- and low-amplitude colonic propulsive activity in constipated patients (slow-transit type and irritable bowel syndrome) in comparison with normal controls. PATIENTS AND METHODS: Forty-five constipated patients (35 with slow-transit constipation and 10 with constipation-predominant irritable bowel syndrome) were recruited, and their data compared to those of 18 healthy subjects. Twenty-four-hour colonic manometric recordings were obtained in the three groups of subjects, and data concerning high- and low-amplitude colonic propulsive activity were then compared. RESULTS: High-amplitude propagated contractions were significantly (p < 0.05) decreased in patients with slow-transit constipation and constipation-predominant irritable bowel syndrome with respect to controls (1.5 +/- 0.4, 3.7 +/- 2, and 6 +/- 1 events/subject/day, respectively). In slow-transit constipation, a significant decrease of contractions' amplitude was also observed. Concerning low-amplitude propagated contractions, patients with slow-transit constipation had significantly less events with respect to patients with constipation-predominant irritable bowel syndrome (46 +/- 7 vs. 87.4 +/- 19, p = 0.015); no differences were found between patients with slow-transit constipation and controls and between patients with constipation-predominant irritable bowel syndrome and controls. All three groups displayed a significant increase of low-amplitude propagated contractions after meals (6.3 +/- 2 vs. 18.2 +/- 5 for controls, p < 0.005; 6.4 +/- 1.4 vs. 16.3 +/- 2.4 for slow-transit constipation, p < 0.005; 10.5 +/- 3.2 vs. 32.6 +/- 7 for constipation-predominant irritable bowel syndrome, p = 0.001). CONCLUSIONS: Low-amplitude propagated contractions may represent an important physiologic motor event in constipated patients, reducing the severity of constipation in patients with irritable bowel syndrome and preserving a residual colonic propulsive activity in patients with slow-transit constipation.

Pathophysiological aspects of diverticular disease of colon and role of large bowel motility.

Colonic diverticular disease (diverticulosis) is one of the most common gastrointestinal disorders in Western countries. This disorder is strictly related to aging and fibre intake, and still bears a discrete amount of morbidity. Numerous etiological co-factors have to date been implicated in the pathogenesis of the disease, yet the supporting evidence is still far from absolute. The present review considers the pathophysiology of colonic diverticular disease, with a special emphasis on factors related to abnormal colonic motility.