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Colon delivery efficiencies of intestinal pressure-controlled colon delivery capsules prepared by a coating machine in human subjects.

Large quantities of pressure-controlled colon delivery capsules (PCDCs) were prepared by a Hicoater-mini pharmaceutical coating machine and colon delivery efficiencies were evaluated in man. Caffeine powder as a model drug was suspended with a polyethylene glycol (PEG) 1000 suppository base at 50 degrees C, and was hardened in no. 0- and no. 2-sized capsular shapes. The capsule-shaped suppositories were coated with 5% w/v ethanolic ethylcellulose (7G grade) solution using the coating machine. By increasing the coating weight of ethylcellulose from 28.6 +/- 1.1 mg to 45.3 +/- 0.2 mg, the mean coating thickness of no. 0 PCDCs increased from 56 +/- 1 microm to 64 +/- 1 microm. With no. 2 PCDCs, the mean coating thickness increased from 50 micro +/- 1 microm to 57 +/- 1 microm by increasing the coating weight of ethylcellulose from 8.1 +/- 0.5 mg to 11.2 +/- 0.3 mg. The no. 0 PCDCs, having a mean ethylcellulose coating membrane thicknesses of 56 +/- 1 microm (type 1) and 64 +/- 1 microm (type 2), as well as no. 2 PCDCs, having thicknesses of 50 +/- 1 microm (type 3) and 57 +/- 1 microm (type 4), were used for in-vivo evaluation in man. After oral administration of test preparations containing 75 mg of caffeine, saliva samples were obtained and salivary caffeine levels were measured by an HPLC method. The first appearance time, Ti, of caffeine in the saliva was used as a parameter for the estimation of the release time of caffeine from PCDCs in the gastrointestinal tract. The mean Ti values of no. 0 PCDCs were 3.3 +/- 0.3 h for type- 1 and 5.3 +/- 0.3 h for type-2 preparations while the mean Ti values of no. 2 PCDCs were 4.3 +/- 0.5 h for type 3 and 5.3 +/- 0.3 h for type 4. There were good correlations between ethylcellulose coating membrane thicknesses and in-vivo Ti values. A colon arrival time of 5 h was reported in our subjects by gastrointestinal magnetomarkergraphy. PCDCs having a mean coating thickness of 64 +/- 1 microm for no. 0 capsules and of 57 +/- 1 microm for no. 2 capsules were thought to deliver caffeine to the human colon efficiently.

Adult↗

The effects of distention of the colon during air-contrast barium enema on colonic morphology: anatomic correlation.

Radiologic and pathologic findings are snapshots of disease processes that may vary with a host of dynamic variables. This pictorial essay shows how the presence and visibility of the innominate grooves of the colon are a function of colonic distention. This article also shows how each layer of the colonic wall, including the epithelium, muscularis mucosae, and muscularis propria, changes dramatically in thickness with varying degrees of colonic distension. These anatomic changes are documented by barium enema radiography, specimen radiography, dissecting photomicrography, and histology. These observations have important implications for the interpretation of radiologic and pathologic findings in both normal and diseased states.

Barium Sulfate↗

'The fat-encrusted colon'. A radiological abnormality of colonic mucosa occurring in patients with steatorrhoea.

The clinical and radiological features of six cases of fat-encrusted colon are described. In patients with steatorrhoea, despite standard colonic preparation, fat may adhere to colonic mucosa and produce a radiological appearance that simulates the changes of inflammatory bowel disease. Steatorrhoea was due to coeliac disease in five patients, the sixth being a case of primary sclerosing cholangitis. The initial radiological diagnosis at barium enema in all six patients was of inflammatory bowel disease. On the basis of this appearance surgery was advised in three patients, one of whom proceeded to laparotomy with a view to colectomy. The correct diagnosis can be established by familiarity with the radiological appearance and confirmed by repeating the barium enema examination after 5 days of a fat-free diet, when the colonic mucosal pattern returns to normal.

Adult↗

An endogenous colon mitosis inhibitor and dietary calcium inhibit the increased colonic cell proliferation induced by cholic acid.

We have previously reported that a single intraperitoneal injection of the tripeptide pGlu-His-GlyOH (colon mitosis inhibitor (CMI] is followed by a transient reduction of cell proliferation in the colonic epithelium in mice. The effect of the tripeptide on accelerated cell proliferation in the colonic epithelium was tested during the acute response of the epithelial cells to a diet supplemented with cholic acid. The kinetics of this response was first examined with different amounts of calcium in the feed. We found an increased labeling index (LI) and mitotic rate 2 days after changing the diet, and this response was stronger in animals with a low-calcium cholic acid diet than in animals with cholic acid diet with a standard amount of calcium or a high-calcium cholic acid diet. After 2 weeks of treatment cell proliferation remained significantly elevated only in the animals with low-calcium cholic acid diet. The effect of CMI was tested 7 days after the change to a low-calcium cholic acid diet. Under these conditions a single dose of CMI (10(-12) mol per animal) was still followed by a transient reduction in the proliferative indices in the colonic epithelium. However, the decreases in LI was observed earlier after CMI treatment (at 2 h) in the animals fed a low-calcium cholic acid than in animals with a standard diet.

Animals↗

Localized absence of colonic musculature: an unusual cause of perforation in a colonic esophageal transplant.

A 4 1/2-year-old boy underwent subtotal esophageal substitution by left colon for caustic soda stricture. The transposed colon had to be removed for perforation 9 days later, and pathological examination showed several tiny perforations in an area 1.8 cm in diameter where the colonic wall was thin and devoid of muscularis. Arguments are presented to show that this absence of muscle coat is congenital. The perforations are thought to be the result of minimal ischemia in a colonic wall weakened by the defect.

Child, Preschool↗

Influence of erythromycin on the normal human flora and colonization of the oral cavity, throat and colon.

Erythromycin stearate was given orally in doses of 500 mg twice daily for 7 days to 10 volunteers. Saliva, throat and faecal specimens were taken up to 16 days for cultivation of aerobic and anaerobic bacteria. In specimens from saliva and throat only minor changes in the numbers of bacteria were detected during the antibiotic administration period, while pronounced changes in the aerobic and anaerobic faecal flora occurred. Thus among aerobes the number of enterobacteria significantly decreased and also the numbers of most anaerobes. During the erythromycin administration period, 8 subjects were colonized by erythromycin-resistant enterobacteria in the oral cavity and throat. All subjects were colonized by erythromycin-resistant enterobacteria, clostridia or yeasts in the colon. Many of the colonizing microorganisms were potential pathogens.

Adult↗

Cdk2/cdc2 expression in colon carcinogenesis and effects of cdk2/cdc2 inhibitor in colon cancer cells.

Cyclin dependent kinases propel the cell cycle in collaboration with cyclins. We have examined the expression of cdk2/cdc2 in adenoma and focal carcinoma in adenomatous tissue to explore their role in tumorigenesis of colorectum. Immunohistochemical study revealed that cdk2/cdc2 was overexpressed in a subsets of adenoma (14/50; 28.0%) but this overexpression was much more obvious in focal carcinoma (13/15; 86.7%). These results suggest that cdk2/cdc2 is remarkably upregulated together with a malignant change. In an effort to demonstrate a significant role for cdk2/cdc2 in colon cancer, we investigated growth and apoptosis with butyrolactone I, a specific inhibitor for cdk2/cdc2, using 4 colon carcinoma cell lines (HCT116, LoVo, HT29, Colo 320DM). Butyrolactone I inhibited proliferation of all colon carcinoma cell lines at 100 microM and it induced apoptosis in LoVo cell line with induction of p53. Our findings suggest that inhibition of cdk2/cdc2 may be a useful strategy against colon cancer.

4-Butyrolactone↗

Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators.

PURPOSE: The goal of this analysis was to determine whether fluorouracil (FU) and folinic acid (leucovorin, LV) is an effective adjuvant therapy for patients after potentially curative resection of colon cancer in patients with B2 tumors. PATIENTS AND METHODS: One thousand sixteen patients with B2 colon cancer entered onto five separate trials were randomized to FU + LV or observation. A pooled analysis for event-free (EFS) and overall survival (OS) using a stratified log-rank and Cox model was performed. RESULTS: The median follow-up duration was 5.75 years. Patients receiving FU + LV did not experience a significant increase in EFS or OS. The hazards ratio at 5 years was 0.83 (90% confidence interval, 0.72 to 1.07) for EFS and 0.86 (90% confidence interval, 0.68 to 1.07) for OS. The 5-year EFS was 73% for controls and 76% for FU + LV. The 5-year OS was 80% for controls and 82% for FU + LV. Increasing age and poorly differentiated tumors were significant indicators of poor prognosis (P < .02). CONCLUSION: This data set does not support the routine use of FU + LV in all patients with B2 colon cancer. Longer follow-up may identify a small benefit. At present, studies in B2 colon cancer designed with a no-treatment control arm should be considered appropriate.

Age Factors↗

Early and late effects of wound healing on development of colon tumours in a model of colon carcinogenesis by 1,2-dimethylhydrazine in the rat.

The early and late effects of wound healing on tumour development at a distant site were evaluated morphologically in an experimental model of colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH). Random bred male Wistar rats were given subcutaneous injections of DMH (20 mg/kg) or saline, once a week, for eight weeks. One week after the last DMH injection the animals received a full thickness skin wound in their dorsal skin and the wound was left open to heal by second intention. Control and DMH treated rats, with or without skin wounds were sacrificed at the twelfth and twentieth weeks. The colons were removed and the incidence, distribution and morphology of any tumours were recorded. Tumours induced by DMH in the colonic mucosa increased in size during the experiment. At the twelfth week, just after healing of the skin wound was complete, the total number of tumours in the colonic mucosa and the number of tumours per rat was significantly higher in the skin-wounding DMH-treated group than in the unwounded group. No differences on tumour incidence and multiplicity were observed among the groups at the twentieth week. Histologically the number of poorly differentiated mucin-secreting carcinomas was increased in the skin-wounding DMH-treated group than in the unwounded group at the twelfth week. This effect was not observed at the twentieth week. The present results suggest that wound healing enhances tumour development at a distant site. This effect coincides with the period of repair and does not have a marked impact on later stages of tumour progression.

1,2-Dimethylhydrazine↗

The colon mitosis inhibitor pyroglutamyl-histidyl-glycine inhibits growth of non-tumorigenic colonic epithelial cells.

BACKGROUND: The colon mitosis inhibiting peptide pyroglutamyl-histidyl-glycine (pEHG) increases the expression of c-fos, fosB and egr-1 genes in the colon carcinoma cell line HT-29. However, the effect on non-tumorigenic colonic cells has not been investigated. MATERIALS AND METHODS: After exposure of the cell lines YAMC (from colon mucosa of Immorto mice) and IMCE (fromn Immorto-Min mouse hybrid) to pEHG, DNA-synthesis was analysed by H3-thymidine incorporation, apoptosis and necrosis by fluorescence microscopy, and cell cycle distribution by flow cytometry. RESULTS: pEHG inhibited DNA-synthesis with a maximal effect at 10(-8)-10(-9) M, but stimulated at 10(-4) M. It blocked cell flow through the cell cycle at GC/M after 8 h of treatment, but had no effect on apoptosis or necrosis at any concentration. A low concentration of ascorbic acid stabilised the cells, maybe as a free radical scavanger. CONCLUSION: pEHG inhibits flux at the G2/M transition, but has no effect on cell death.

Animals↗

Colon interposition for esophageal disease: histologic finding of colonic mucosa after a follow-up of 5 months to 15 years.

Thirty-six patients, subjected to colon interposition for benign esophageal disease or carcinoma of the esophagus or gastric cardia, were studied by endoscopy for signs of mucosal disease in the interposed colon. Five months to 15 yr (mean 57 months) after the operation, endoscopic finding of the interposed colon was macroscopically normal in 28 patients. Signs of inflammation, including hyperemia or hyperemia and friability, were observed in seven patients. Histologic specimens obtained at endoscopy were examined microscopically, and the findings were compared with those seen in the preoperative graft. In two patients, chronic inflammatory changes were observed in the graft mucosa, consisting of mononuclear cell infiltration of the lamina propria accompanied by crypt dilatation and deformation. In one of these patients, the inflammation was in the proximal third of the graft, and it was also seen at the endoscopy. In the remaining 34 patients, the graft mucosa was microscopically comparable to normal. The alterations were unexpectedly few and mild considering the marked change in the location and function of the colonic segment.

Adult↗

Expression of VLA-alpha 2, VLA-alpha 6, and VLA-beta 1 chains in normal mucosa and adenomas of the colon, and in colon carcinomas and their liver metastases.

'Very late antigen' (VLA) proteins are members of the integrin superfamily with cell-surface receptor function and are involved in the cell-cell matrix interaction. They are heterodimers with a common beta 1 chain and different alpha chains counted through VLA-1 to VLA-6. The VLA-2 complex (alpha 2/beta 1) was found to act as collagen receptor on platelets and the VLA-6 complex (alpha 6/beta 1) as laminin receptor. Using monoclonal antibodies and an indirect immunoperoxidase method, we investigated the expression of VLA-alpha 2, VLA-alpha 6, and VLA-beta 1 chains in 20 normal colonic mucosa samples, in 20 colonic adenomas, and in 96 carcinomas together with 10 accompanying liver metastases. All three proteins were expressed throughout the colonic epithelium, except for VLA-alpha 2, which was present in the cryptic gland but was absent on the mucosal surface in some cases. In general, adenomas were strongly positive for the VLA proteins but 3 of 20 cases showed focal VLA-alpha 2-negative areas. The carcinomas revealed considerable heterogeneity of VLA-alpha 2 expression; ie, 59 tumors were completely positive, 35 tumors revealed a focal loss of antigen, and 2 cases were negative. This reduced antigen expression was statistically associated with Dukes' stage C/D (P = 0.003). VLA-alpha 6 was expressed throughout in all tumors. VLA-beta 1 was found extensively expressed in 77 carcinomas, partially expressed in 17 carcinomas, and was absent in 2 carcinomas. As compared to their primary tumors, liver metastases showed roughly corresponding patterns of antigen expression. The down regulation/loss of VLA proteins in a subset of epithelial colon tumors might cause a disturbed cell-cell/cell-matrix interaction that might augment the invasive property of their cells.

Adenoma↗

[Da cheng qi tang on 45Ca content of the isolated colon smooth muscle from experimental colon obstruction rats].

Da Cheng Qi Tang (DCQT) is a classical prescription of Chinese medicine for treatment of acute intestinal obstruction. In this paper, the isolated colon smooth muscle from normal and experimental colon obstruction (CO) rats were used to study the effect of DCQT on 45Ca content. The results showed that the 45Ca content on isolated colon smooth muscle (microns/g wet tissue, mean +/- S) was 0.043 +/- 0.009 in the normal and 0.057 +/- 0.012 in those treated by DCQT respectively. The content of 45Ca in CO was higher than the normal, DCQT can reduce the content of 45Ca in CO. It is known that the higher level of intracellular CA++ is related to the formation and the development of acute intestinal obstruction. The inhibitory effect of DCQT on 45Ca content may play an important role in the treatment of acute colon obstruction.

Animals↗

The association of multiple colonic adenomatous polyps with cancer of the colon.

We reviewed our colonoscopy data for the past 10 yr for patients with five or more polyps to determine the association of multiple adenomatous polyps and colon cancer. During that period, 3,834 patients underwent colonoscopy. Fifty-two patients with five or more polyps at the initial colonoscopy were found. In 25 patients (group I) there were at least five synchronous adenomas, and in 27 patients (group II) a combination of adenomas and hyperplastic polyps totaling five or more. The number of polyps ranged from five to 30 (median, six). There was no significant difference in the location of polyps between groups I and II. Eight of 52 patients (15%) were found to have colon cancer at the initial colonoscopy. In group I, there were six cancers (24%), five of which were in the cecum. Two of 27 patients (7%) in group II had cancer, one of which was located in the cecum. Patients with five or more adenomas at the index colonoscopy are at high risk of having colon cancer that is particularly prone to arise from the right side of the colon.

Adenoma↗

[Phase II study with cisplatin in advanced stomach and colon carcinoma. Cooperative Study Group of Cisplatin for Stomach and Colon Carcinoma].

A multicenter phase II study was performed to evaluate cisplatin (CDDP) in patients with gastric carcinoma or colon carcinoma. Ninety-nine cases of gastric carcinoma and 25 cases of colon carcinoma were entered into the study. According to the eligibility criteria prepared for the study protocol, 28 and 5 patients were excluded from the stomach and colon group, respectively. CDDP, 70-100 mg/m2, was administered intravenously with sufficient hydration. The efficacy rates evaluated by the UICC tumor reduction criteria were 19.1% (13/68 cases) in gastric carcinoma and 5.0% (1/20 cases) in colon carcinoma. Lymph node metastasis and metastatic abdominal tumor were effective targets for CDDP treatment. As side-effects of CDDP, nausea/vomiting (69.2%) and general malaise (35.2%) were observed. CDDP was thus considered to be one of the effective chemotherapeutic agents for treatment of gastric carcinoma.

Adult↗

Monoclonal antibody against human colonic sulfomucin: immunochemical detection of its binding sites in colonic mucosa, colorectal primary carcinoma, and metastases.

Previous studies using metabolic labeling of fresh colonic mucosa and colorectal carcinoma with [35S]sulfate followed by biochemical analysis demonstrated that the amount of a sulfated high-molecular-weight glycoprotein expressed in primary colorectal carcinoma was lower than that in normal mucosa, and that the amount further decreased in liver metastases. This suggested that this sulfated molecule represented a sulfomucin previously defined by histochemical reactivity with a cationic dye. We have extracted and partially purified this high-molecular-weight sulfated glycoprotein from normal human colonic mucosa. We immunized mice with the partially purified sulfomucin and generated hybridomas. One cloned hybridoma, designated as 91.9H, produced a monoclonal antibody strongly reactive with a component which migrated at an identical position as the metabolically [35S]sulfate-labeled high-molecular-weight glycoprotein after polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The reactive molecules appeared to have a polydisperse nature with a molecular weight ranging between 400,000 and 900,000. The [35S]sulfate-labeled high-molecular-weight glycoprotein was bound to Staphylococcus Protein A-agarose coated with this monoclonal antibody but did not bind to unconjugated Protein A-agarose. The immunoprecipitated substance also migrated at an apparent molecular weight range of 400,000 to 900,000. The reactivity of monoclonal antibody 91.9H with the extracts of normal mucosa, colorectal primary carcinoma, and metastasis was compared by dot blot assay on a nitrocellulose membrane. This antibody was more reactive with the extracts of mucosa adjacent to carcinoma tissues than with the carcinoma extracts. Primary tumors showed higher reactivity than metastases in most of the cases. These results strongly suggest that this antibody is specific to colonic sulfomucins or at least to mucins closely related to colonic mucins previously identified by metabolic labeling with [35S]sulfate.

Antibodies, Monoclonal↗

[A metachronous and synchronous multiple colonic cancer appearing 15 years and 3 months after resection of a synchronous multiple colonic cancer].

A case of multiple colonic cancer appearing 15 years and 3 months after the resection of a synchronous multiple colonic cancer is reported. A 65-year-old man complained of abdominal pain, abdominal fullness, and diarrhea. A barium enema revealed a so-called "apple core lesion" and a filling defect, and he was diagnosed as having a multiple colonic cancer. A subtotal colectomy was performed and he has been free of any sign of recurrence since this operation. In this case, the interval between the first and the second cancer is longer than most reported cases. Thus, as a precaution, a longer follow-up is recommended for patients with a synchronous multiple colonic cancer.

Adenocarcinoma↗

Relationship of in vitro cell motility and colonization potential in a mouse colon adenocarcinoma (MCA-38) cell line.

Cell motility is an important factor in the metastatic process that can be affected by environmental conditions. A quantitative study was made of the relationship between cell motility and the colonization potential of a mouse colon adenocarcinoma cell line (MCA-38). MCA-38 cells grown in culture did not produce hepatic or pulmonary colonies following ileocolic or tail vein injection, respectively. In contrast, MCA-38 cells adapted to grow in the mouse produced colonies in both organs. The motility of the MCA-38 cells that did not produce colonies, as determined by the depth of penetration into cellulose nitrate filters (8 micron pore size), was significantly less than that of MCA-38 cells with colony-forming potential. Return to in vitro growth resulted in both a loss of colonization potential and a reduction in motility. In this system, secondary organ colonization and in vitro cell motility are positively correlated, suggesting an association between cell motility and metastatic potential.

Adenocarcinoma↗