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At least 19 recordsLinked to original sources

Metabolism and transport of the macrolide immunosuppressant sirolimus in the small intestine.

Small intestinal metabolism and transport of sirolimus, a macrolide immunosuppressant with a low and highly variable oral bioavailability, were investigated using small intestinal microsomes and intestinal mucosa in the Ussing chamber. After incubation of sirolimus with human and pig small intestinal microsomes, five metabolites were detected using high performance liquid chromatography/electrospray-mass spectrometry: hydroxy, dihydroxy, trihydroxy, desmethyl and didesmethyl sirolimus. The same metabolites were generated by human liver microsomes and pig small intestinal mucosa in the Ussing chamber. Anti-CYP3A antibodies, as well as the specific CYP3A inhibitors troleandomycin and erythromycin, inhibited small intestinal metabolism of sirolimus, confirming that, as in the liver, CYP3A enzymes are responsible for sirolimus metabolism in the small intestine. Of 32 drugs tested, only known CYP3A substrates inhibited sirolimus intestinal metabolism with inhibitor constants (Ki) equal to those in human liver microsomes. The formation of hydroxy sirolimus by small intestinal microsomes isolated from 14 different patients ranged from 28 to 220 pmol.min-1.mg-1 microsomal protein. In the Ussing chamber, >99% of the sirolimus metabolites reentered the mucosa chamber against a sirolimus gradient, indicating active countertransport. Intestinal drug metabolism and countertransport into the gut lumen, drug interactions with CYP3A substrates and inhibitors in the small intestine and an 8-fold interindividual variability of the intestinal metabolite formation rate significantly contribute to the low and highly variable bioavailability of sirolimus.

Animals↗

The continuing clinical dilemma of primary tumors of the small intestine.

Small intestinal tumors are relatively rare, notoriously difficult to diagnose, and often advanced at the time of definitive treatment. The purpose of this study is to compare the differences between benign and malignant tumors of the small intestine and between symptomatic and asymptomatic tumors with respect to their clinical presentation, efficacy of diagnostic procedures, and surgical management with correlation to pathologic findings. Forty-nine patients with primary small intestinal tumors between 1981-1993 had 17 benign and 32 malignant tumors. Benign tumors more commonly presented with acute gastrointestinal hemorrhage (29% versus 6%, P < 0.05), and were often asymptomatic (47% versus 6%, P < 0.05). Malignant tumors more commonly presented with abdominal pain (63% versus 24%, P < 0.05) and weight loss (38% versus 0%, P < 0.05). The total number of diagnostic tests/patient averaged 2.3 +/- 0.3, and the average time from onset of symptoms to resection was 30.2 +/- 6.6 weeks. Upper endoscopy, angiography, and upper gastrointestinal contrast studies had the most useful sensitivity rates. Surgical treatment of tumors included biopsy/excision, limited bowel resection, segmental resection with regional lymphadenectomy, or a bypass procedure. The most common types of benign and malignant tumors were leiomyoma (41%) and adenocarcinoma (53%), respectively. Histologically, tumors were evenly distributed throughout the small intestine. Small intestinal tumors remain difficult to diagnose because of an atypical presentation and renew the need for appropriate suspicion when treating patients with vague abdominal symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdominal Pain↗

A novel cytochrome P450 enzyme responsible for the metabolism of ebastine in monkey small intestine.

Small intestinal microsomes of cynomolgus monkeys were found to catalyze hydroxylation and dealkylation of an H(1)-antihistamine prodrug, ebastine. To identify the main enzyme responsible for ebastine hydroxylation, which has been hitherto unknown, we purified two cytochrome P450 isoforms, named P450 MI-2 and P450 MI-3, from the intestinal microsomes on the basis of the hydroxylation activity. P450 MI-2 and P450 MI-3 showed the respective apparent molecular weights of 56,000 and 53,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The internal amino acid sequence of P450 MI-2 had high similarity with those of human CYP4F2, CYP4F3, and CYP4F8. The first 27 amino acid residues of P450 MI-3 were highly homologous with those of monkey CYP3A8 and human CYP3A4/5/7. Furthermore, P450 MI-2 and P450 MI-3 were recognized by anti-CYP4F and anti-CYP3A antibodies, respectively, in immunoblot analysis and catalyzed leukotriene B(4) omega-hydroxylation and testosterone 6beta-hydroxylation, which are known to be mediated by CYP4F and CYP3A, respectively. Although both enzymes had ebastine hydroxylation activity, the V(max) value of P450 MI-2 was much higher than that of P450 MI-3 (37.0 versus 0.406 nmol/min/nmol of P450), and the former K(M) (5.1 microM) was smaller than the latter K(M) (10 microM). Anti-CYP4F antibody inhibited the hydroxylation in small intestinal microsomes strongly (70%), but anti-CYP3A antibody did not. These results indicate that P450 MI-2 belongs to the CYP4F subfamily and is mainly responsible for hydroxylation of ebastine in monkey small intestinal microsomes. This suggests that the small intestinal CYP4F enzyme, P450 MI-2, can play an important role in the metabolism of drugs given orally.

Amino Acid Sequence↗

Postprandial concentrations of free and conjugated bile acids down the length of the normal human small intestine.

Small intestinal samples were obtained by intubation from multiple sites along the small intestine in 11 subjects with no known gastrointestinal disease eating a normal diet and at laparotomy in a further three subjects. Free (unconjugated) bile acids were consistently demonstrated in ileal samples, and occasionally in lower jejunal samples, by thin-layer chromatography, supplemented in some cases by gas/liquid chromatography and by infrared spectroscopy. The free bile acid concentration, measured enzymically following thin-layer chromatography, reached a maximum (1 mM) in the lower ileum, where it represented half the total bile acid concentration. Following ampicillin, the concentration of free bile acids decreased markedly, suggesting that they resulted from bacterial deconjugation; at the same time the total bile acid concentration increased, suggesting impaired absorption due to the reduced concentration of the more rapidly absorbed free bile acids. Our results indicate that the presence of free bile acids in lower jejunal and ileal samples is a normal finding, and cannot be taken as evidence of abnormal bacterial overgrowth. They also suggest that bacterial deconjugation at these sites may be a factor contributing to the remarkable efficiency of bile salt reabsorption.

Adult↗

Optimising oral rehydration solution composition in model systems: studies in normal mammalian small intestine.

Small intestinal perfusion studies have been carried out in animals to evaluate the role of the individual constituents of oral rehydration solution (ORS), in order to draw some conclusions relating to the optimal composition of ORS. Two commercially available ORS, Dioralyte and Rehidrat have also been compared to the World Health Organisation (WHO) standard solution. Maximum rate of water absorption occurred with the WHO solution and least with Rehidrat. The findings of the perfusion studies suggest that in the normal small intestine, optimal water absorption occurs from a solution containing 60 mmol/l of sodium and 80-120 mmol/l of glucose. The addition of bicarbonate and citrate at concentrations present in ORS does not appear to have a significant effect on water absorption. The addition of glycine and diglycine to the standard ORS reduced the net rate of absorption of sodium and water, probably because of the effect of increased osmoality.

Animals↗

[Small intestine adenocarcinoma. Cause of mechanic obstruction through slide of intestine into the small intestine (clinical case)].

It's present the case of a patient from nineteen years with acute abdominal pain with debut in the day of presentation. Biological investigations is negative, with exception VSH = 40 mm/h. The gynecological examination raise the doubt of a strangled and floating ovary balloon. It's operate in emergency--it's about a mechanic obstacle from the small intestine (adenocarcinoma) with slide the small intestine into the small intestine with three cylinders. Reduction the small intestine slide-segmental enterectomy. Recovery. The mechanic obstacle from the small intestine with slide the small intestine into the small intestine through a cancer, to young patients, is a rare disease. The small intestine adenocarcinoma is meeting particularly at grown-up and old patients (3-4% from the digestive cancers) (2). The case in face is alone in personal statistics.

Adenocarcinoma↗

Severed nerve stumps around a laser-irradiated locus in the deep muscular plexus of the guinea-pig small intestine.

Small foci of photocoagulation necrosis (diameter about 0.5 mm) were produced in the wall of the guinea-pig small intestine by argon laser irradiation applied to the serosal surface. Features of the nerve elements around the necrotic masses were examined by immunocytochemistry, scanning electron microscopy, and transmission electron microscopy. The severed ends of nerve strands were examined at various intervals from 10 to 60 h after the laser irradiation, and the acute cytological responses of the nerve terminals, glial cells and connective tissue cells were studied. The laser irradiated foci in the deep muscular plexus (plexus muscularis profundus: CAJAL, 1911) had concentric configuration: 1) central necrotic area, 2) inner transitional zone, 3) outer transitional zone, and 4) normal area. In the necrotic area, there were inflammatory cells such as neutrophile leukocytes and macrophages. Contours of the smooth muscle cells and nerve strands were well preserved in spite of the damage to their subcellular structures. In the inner transitional area, individual nerve fibers gathered to form bundles. Some of these nerve bundles were devoid of a glial cell framework. In the outer transitional zone, there were swollen nerve terminals with a strong immunoreactivity for methionine-enkephalin-Arg6-Gly7-Leu6. In transmission electron microscopy, some of these swollen nerve fibers contained many large cored vesicles. Glial cells in the outer transitional zone exhibited an S-100b protein-like immunoreactivity. Scanning electron microscopy revealed gatherings of fibroblast-like (FBL) cells in the outer transitional zone. Two subtypes of these were distinguished: the first subtype (FBL I) was characterized by short, blunt cytoplasmic processes; the second subtype (FBL II), possessing long, slender dendritic processes, assembled to form a dense network which intermeshed with that of the nerve strands. The enteric nerve plexuses severed by laser-irradiation affords a unique experimental model in the cytological investigation of the plasticity of the peripheral autonomic nervous system.

Animals↗

Assessment of blood flow in the small intestine by laser Doppler flowmetry: comparison of healthy small intestine and small intestine in Crohn's disease.

Blood flow and blood distribution were investigated in 40 patients with normal small intestine and the relation between blood flow and the morphological features of Crohn's disease was examined in 11 patients with Crohn's disease by laser Doppler flowmetry from the serosal side during surgery. In normal small intestine, blood flow was measured at six points: upper, middle, and lower small intestine, each of the mesenteric borders, and the antimesenteric surface. In Crohn's disease, macroscopically normal tissue and affected lesions were observed in detail by intraoperative endoscopy after blood flow measurement. The blood flow values in the normal small intestine gradually decreased from the upper to the lower small intestine. As the level of inflammation progressed in Crohn's disease the blood flow values gradually decreased; the exudative stage of Crohn's disease (aphthoid ulcer) showed blood flow values that were slightly below those in macroscopically normal tissue. These results are the first to demonstrate decreased blood flow in affected lesions in Crohn's disease and changes in blood flow according to the degree of inflammation in vivo.

Adolescent↗

Interposed colon between remnants of the small intestine exhibits small bowel features in a patient with short bowel syndrome.

We describe herein the case of a 48-year-old man who underwent emergency massive resection of the small intestine due to a strangulated ileus, which led to short bowel syndrome (SBS), as he was left with only 7 cm of jejunum and 8 cm of ileum with ileocecal valve. He then received interposition of a colon segment between the jejunum and ileum remnants isoperistaltically. For 24 months after the operation, he has been able to tolerate oral intake, but still requires partial home parenteral nutritional support during the night on a bimonthly basis. Biochemical and nutritional parameters, including the analysis of minerals and trace elements, indicated that the patient was in relatively good health. Histological examination revealed that the mucosa of the interposed colon showed hypertrophy and hyperplasia of the crypt glands, and cells resembling Paneth cells which are usually seen in the small intestine, suggesting that the colon segment exhibits adaptive changes to the small intestine. Colon interposition may be a useful technique in patients with SBS when the small bowel is too short for the other surgical considerations.

Anastomosis, Surgical↗

The value of double-contrast study of the small intestine in immunoproliferative small intestinal disease.

Radiological findings of 2 patients with immunoproliferative small intestinal disease were studied. One of the cases was associated with alpha-chain disease. Both patients complained of severe diarrhea, and diagnosis was made by endoscopic biopsy of the duodenum and jejunum. Double-contrast studies of the small intestine and hypotonic duodenographies in these patients revealed thickened folds and innumerable fine granular elevations without ulcerations or luminal narrowings. Double-contrast studies are one of the most important examinations in the diagnosis of this disorder.

Adult↗

[Influence of small intestine shunt and small intestine resection on gastrin secretion].

In 10 healthy controls, in 3 patients with subtotal resection of the small intestine and in 7 patients with jejuno-ileal bypass gastric ackd secretion and serum gastrin were determined in the basal state and after stimulation. The patients with short bowel revealed basal and pentagastrin stimulated gastric acid secretion in the lower normal range. Hypergastrinaemia, however, was present in these patients in the basal state and after food stimulation of gastrin release, while in patients with jejuno-ileal bypass basal and postprandial serum gastrin concentrations were within the normal range. These data suggest, that hypergastrinaemia in patients with short bowel is due to dimished gastrin catabolism and that the small intestine plays a significant role in gastrin inactivation.

Gastrins↗

Primary small-intestinal lymphomas in Taiwan: immunoproliferative small-intestinal disease and nonimmunoproliferative small-intestinal disease.

PURPOSE: The clinicopathologic findings in 45 adult Chinese patients with primary small-intestinal lymphoma (PSIL) are described and compared with those in Western countries and in underdeveloped nations. The efficacy of combination chemotherapy is also assessed. PATIENTS AND METHOD: Six patients had immunoproliferative small-intestinal disease (IPSID) indicated by the presence of alpha-heavy chain protein (alpha-CP) in body fluids or tumor tissues. Thirty-nine patients had non-IPSID, including one with postrenal transplant lymphoma. Thirty-three non-IPSID patients received a minimum of four cycles of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). RESULTS: All IPSID patients presented with the clinical and laboratory features of severe intestinal malabsorption, and all had diffuse lymphoplasmacytic infiltration in the mucosa of the small bowel. Lymphomas were localized mainly in the jejunum and mesenteric nodes. The histologic subtypes were diffuse large cell in two, immunoblastic in three, and diffuse mixed in one. All patients responded poorly to chemotherapy, with a median survival duration of 10.5 months. The common presenting symptoms of the 39 non-IPSID patients included abdominal pain (90%), weight loss (31%), abdominal mass (26%), obstruction (26%), and perforation (23%). Diffuse large-cell and immunoblastic lymphomas constituted 82% of cases. Four patients had stage IE, 19 stage II 1E, and 16 stage 112E disease according to the Musshoff's criteria; 22 had bulky tumors and 19 had multiple tumors. The tumors were completely resected in 14 patients. Of 33 patients treated with combination chemotherapy, 73% achieved a complete remission. With a median follow-up duration of 90 months, there have been four relapses, with only one at the primary tumor site. The overall 5-year survival and disease-free survival rates for non-IPSID patients who were treated with chemotherapy were 59% and 54%, respectively. CONCLUSION: Intensive chemotherapy produces long-term disease-free survival in locally advanced non-IPSID PSIL.

Adult↗

[Apoptosis of small intestinal epithelial cells in small intestinal allograft rejection].

OBJECTIVE: To investigate apoptosis of epithelial cells during small intestinal allograft rejection in rats. METHODS: Heterotopic small intestinal transplantation was performed with inbred rat F344/N (RT1(l)) and inbred rat Wistar/A (RT1-A(k), RT1-E(d)). All recipients were divided into four groups: group I, nonoperative control (Wistar); group II, isograft control (Wistar-->Wistar); group III, allograft (F344-->Wistar); group IV, treatment control [F344-->Wistar + Cyclosporine A (6 mg x kg(-1) x d(-1))]. The grafts were harvested on day 3, 5, 7 after operation. All graft samples were subjected to histological examination and apoptotic cells of graft epithelial cells with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). RESULTS: Histologically mild acute rejection occurred on day 3 after operation in group III, moderate acute rejection on day 5 after operation, severe acute rejection on day 7 after operation. But none of group II had the histological evidence of acute rejection and the histological evidence of group IV indicated that Cyclosporine A could effectively controlled small intestinal acute allograft rejection. The TUNEL showed that the number of apoptotic cells per crypt in group III was significantly higher than that of the other three control groups on day 3 and day 5 after operation (P < 0.01). The epithelial mucosa in group III completely sloughed on day 7 after operation. CONCLUSIONS: Apoptosis plays an important role in small intestinal allograft rejection. Detection of apoptotic cells with TUNEL could be a valuable tool for the diagnosis of small intestinal allograft rejection.

Animals↗

[Diverticulosis of the small intestine].

Small bowel diverticulosis is a rare disease of gastrointestinal tract that occurs most frequently in older patients. Since this disease can be asymptomatic, for a long time, the diagnosis rarely is made in the preoperative period. In 40% of cases there are acute or chronic complications, most frequently diverticulitis either with or without perforation, bowel obstruction and massive haemorrhage clinically manifested as bleeding from the lower part of the gastrointestinal tract. Abdominal pain, pseudoobstructive and malabsorption syndrome, expressive weight loss, steatorrhea and anemia are common chronic complications. In these cases a surgical treatment is necessary. Resection of the affected part of the small bowel is usually performed with end-to-end anastomosis. The authors present 4 cases with diverticulosis of the small bowel, two cases of which were manifested by diverticulitis and one of them was perforated. Pseudoobstructive syndrome, malabsorption and expressive weight loss were presented in other two cases. All four cases were dominated by severe abdominal pain. The surgical treatment was based upon radical resection of the small bowel with end-to-end anastomosis. (Fig. 4, Ref. 28.)

Adolescent↗