Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021390 (inflammatory bowel disease)
 23,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the beginning of the 1940s salazosulfapyridine (SASP) has been used in the treatment of chronic inflammatory bowel disease (CIBD). Almost 40 years later 5-aminosalicylic acid (5-ASA), which is split off by azo-reducing enzymes in the colon, was identified as the therapeutically active moiety of SASP. Thus different 5-ASA containing drugs were produced from which 5-ASA is released in the small and large intestine in a pH-dependent manner. Since there is a firm clinical indication that the 5-ASA concentration in the gut lumen is decisive for the therapeutic effect, a method was developed to evaluate the 5-ASA concentration at different levels in the intestine. The method was subsequently used to clarify factors of importance for the release of 5-ASA from the preparations. Ileostomy patients and healthy volunteers were investigated during continuous treatment with the three 5-ASA containing drugs with pH-dependent 5-ASA release: Asacol, Mesasal (Salofalk, Claversal), and Pentasa. The study confirmed release of 5-ASA in the small intestine from all preparations, but at different levels and speeds. Despite similar peroral dosage, very different 5-ASA concentration profiles were found in the ileostomy effluents, reflecting not only the difference in the release pattern of the preparations, but also the influence of the gastric residence time for larger sized tablets. The 5-ASA concentrations increased in the faeces of healthy volunteers. Furthermore the systemically absorbed fraction of 5-ASA was larger than previously found after SASP. The 5-ASA release from the preparation with the most proximal release, Pentasa, was less influenced by acceleration of the intestinal transit time than previously demonstrated after SASP in a similar study design. A comparative study of children given SASP and Pentasa showed similar results as in adults: a tendency for smaller 5-ASA concentration at rectal level after Pentasa than after SASP, and also larger systemic absorption. Despite higher 5-ASA dose per kg body weight, lower 5-ASA concentrations were seen in the faeces after both preparations, compared with adults. A peroral dose increase of Pentasa in healthy adults resulted in higher intraluminal 5-ASA concentration in the gut lumen, but also in saturation of the local and probably also systemic acetylation capacity, demonstrated by higher plasma concentrations and larger urinary excretion of 5-ASA. Similar faecal water concentrations were found after Pentasa 4 g and the azo-bond preparation with colonic 5-ASA release, Dipentum (olsalazine) 2 g, confirming the substantial 5-ASA release from Pentasa in the small intestine. Investigation of pregnant patients treated with different 5-ASA containing drugs showed a similar pattern to SASP treatment: small amounts of 5-ASA cross the placenta, whereas the concentration of the metabolite Ac-5-ASA is similar in the maternal and fetal circulations. Only minute amounts of 5-ASA were found in milk from nursing mothers, while the concentrations of Ac-5-ASA were considerably higher. The decrease in the semen quality during SASP treatment was improved by changing to a controlled-release 5-ASA drug. The concentrations of 5-ASA in seminal plasma were similar during the two treatment periods, but higher of its metabolite Ac-5-ASA during treatment with the controlled-release preparation. That indicates that the toxic effect after SASP is not caused by the 5-ASA or Ac-5-ASA moiety. All the preparations have proved effective in the treatment of ulcerative colitis, but data concerning the 5-ASA treatment of Crohn's disease are conflicting. Knowledge of the demonstrated differences in the release profiles of the 5-ASA containing drugs is therefore important when designing future clinical trials.
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PMID:5-Aminosalicylic acid containing drugs. Delivery, fate, and possible clinical implications in man. 1070 42

Tissue antioxidant status is altered as a response to oxidative stress. This oxidative stress, caused by reactive oxygen species, is associated with inflammatory bowel disease (IBD). Our aim was to examine the relationship between total tissue low-molecular-weight antioxidant (LMWA) profile and inflammation severity in dinitrobenzene sulfonic acid (DNBS) experimental colitis in the rat. Rats were treated with three doses of DNBS: 1, 10, and 20 mg. Inflammation severity was assessed by tissue colonic wet weight, macroscopic evaluation, and tissue myeloperoxidase (MPO) activity. The capacity of water-soluble LMWA was assessed by measuring the reducing power of the tissues with cyclic voltammetry (CV) and by measuring tissue levels of reduced glutathione. While typical markers of inflammation (MPO, macroscopic examination, and colonic wet weight) indicated DNBS dose dependency, such dependency could not be demonstrated for the tissue LMWA as measured by reduced glutathione levels and by the tissues' reducing power. Mild colonic inflammation (induced by ethanol or by 1 mg of DNBS) caused an increase in the overall capacity of water-soluble LMWA. However, severe inflammation (induced by 20 mg of DNBS) caused a reduction in the tissue LMWA capacity. An intermediate dose of DNBS (10 mg) caused moderate inflammation, but did not cause a significant change in the tissue LMWA compared with a saline control treatment. In conclusion, LMWA changed in a biphasic pattern reflective of the severity of mucosal colonic inflammation. It is suggested that: low dose of DNBS (1 mg) and topical alcohol (25% v/v) caused an adaptation effect to the mild oxidative stress associated with mild inflammation. This resulted in an increase in the LMWA. A higher dose of DNBS (20 mg) caused more severe inflammation with an overall reduction in LMWA. The increased efflux of reactive oxygen species, associated with severe inflammation, led to an overall consumption of the tissue LMWA, which masked the increase in LMWA caused by the mild oxidative stress.
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PMID:Relation between colonic inflammation severity and total low-molecular-weight antioxidant profiles in experimental colitis. 1087 35

The symptom of diarrhoea is defined as an abnormally frequent discharge from the bowel (more than 3 times a day) and a semisolid or fluid consistency of the faecal matter. Diarrhoea is termed chronic when it lasts more than four weeks. Diarrhoea is the result of disturbances in enteral water and electrolyte balance. Increased intestinal motility is usually not the cause but the result of diarrhoea. Transport of water through the gut is dependent on the osmotic gradient between interstitium and gut lumen. The secretion of chloride ions by the cells of the intestinal glands plays a major role in water secretion into the gut lumen, while sodium and potassium absorption in the villous zone of the enterocytes is crucial for enteral water absorption. Enteral water and electrolyte balance is regulated by the autonomic and enteral nervous system, by gastrointestinal hormones and signal messengers of mesenchymal cells. Pathogenetically, one distinguishes between secretory and osmotic diarrhoea. Furthermore, mixed forms of both pathogenic types can occur. The various types can be differentiated clinically and by the "osmotic gap". Diarrhoea can be a symptom of various diseases. Its pathogenesis is illustrated using examples of diarrhoea in pathological bile acid absorption, bacterial infections, carbohydrate malabsorption or disaccharidase insufficiency and in chronic inflammatory bowel disease.
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PMID:[Pathophysiology of chronic diarrhea]. 1108 64

Megacolon refers to cecal dilatation above the dimension of 12 cm and above 6.5 cm of the sigmoid colon, measured at the pelvic brim. Dilatation of the colon can be broadly categorized into three clinical entities: In acute megacolon (Ogilvie's syndrome), colonic dilatation is attributed to a sympathetically mediated reflex response to a number of serious medical or surgical conditions in elderly patients. The initial tasks are to exclude mechanical obstruction (with a hypaque enema), to discontinue enabling medications, and to correct metabolic disturbances. Dilatation of the cecum to greater than 12 cm diameter is a cause for grave concern. The rectum should be decompressed with an indwelling tube and tap water enemas. Intravenous neostigmine is generally effective and safe for patients with colonic distention unresponsive to such conservative therapies. Endoscopic decompression is necessary for patients who do not respond to, or relapse after neostigmine, or in whom neostigmine is contraindicated. Signs of peritonitis may imply colonic perforation, and surgery will be needed, often on an emergent basis. Toxic megacolon is secondary to an identifiable inflammation of the colon. Therapy is directed toward specific treatment for the underlying disorder, inflammatory bowel disease, or infectious colitis. Bowel rest and close monitoring of the clinical status is vital. Colectomy may be needed under emergency circumstances. Chronic megacolon may be congenital (due to Hirschsprung's disease) or may represent the end-stage of any form of refractory constipation (slow transit constipation or pelvic floor dysfunction). The initial treatment for Hirschsprung's disease is surgery, while pelvic floor dysfunction and encopresis respond to biofeedback therapy. In chronic idiopathic megacolon, medical measures, such as colonic evacuation with enemas, fiber supplementation, and laxatives may suffice. If severe motor dysfunction is confined to the colon, a subtotal colectomy with an ileorectal anastomosis, or an ileostomy may occasionally be necessary.
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PMID:Megacolon: Acute, Toxic, and Chronic. 1109 35

A multiple unit dosage form for oral delivery based on the microencapsulation of anti-inflammatory drugs using different biodegradable polymers, poly(epsilon-caprolactone), polylactic acid and poly(lactic-co-glycolic acid), prepared either by the water-in-oil-in-water (w/o/w) or the solid-in-oil-in-water (s/o/w) solvent evaporation method was developed. Microparticles were characterized for their size, morphology, encapsulation efficiency and drug release. The physical state of drugs and polymers was determined by differential scanning calorimetry (DSC), imaging of the particles was performed by scanning electron microscopy and confocal laser scanning microscopy. Sulfasalazine and betamethasone used for the treatment of inflammatory bowel disease, were chosen as model drugs. The microparticles were spherical with diameters in the range of 91 to 258 microm by the w/o/w-method, and in the range of 102 to 277 microm by the s/o/w-method. The encapsulation efficiency (EE) varied between 11 and 16% for sulfasalazine and 50 and 67% for betamethasone with the w/o/w-method, and between 73 and 79% for sulfasalazine and 60 and 70% for betamethasone with the s/o/w-method. DSC showed no interaction between polymers and drugs, while the drugs were dispersed in the polymer. In vitro release studies showed a controlled release of sulfasalazine and betamethasone from microparticles prepared by the s/o/w-method; a pronounced burst release of sulfasalazine was observed from microparticles prepared by the w/o/w-method.
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PMID:Biodegradable microparticles as a two-drug controlled release formulation: a potential treatment of inflammatory bowel disease. 1110 84

Adenosine is a potent anti-inflammatory mediator. Through elevation of endogenous adenosine concentrations the adenosine kinase inhibitor GP515 might serve to down-regulate local inflammatory responses. In the present study we investigated the effect of systemic GP515 in the nonacute model of dextran sulfate sodium (DSS)-induced colitis. The clinical score, colon length, histologic score, colon cytokine production, and spleen weight from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving GP515 treatment were determined and compared with untreated control mice. Splenocytes were analyzed for phenotype, interferon-gamma (IFNgamma) production, and CD69 expression. First, GP515 treatment resulted in a significant improvement of clinical score (weight loss, stool consistency, and bleeding) and of histologic score. Second, colon shortening, an indirect parameter for the degree of inflammation, was decreased, consistent with a decreased IFNgamma concentration in the colonic tissue. Third, spleen weight was reduced in GP515-treated DSS mice. And fourth, IFNgamma synthesis and CD69 expression, as a marker for early cell activation, of ex vivo-stimulated splenocytes were suppressed in the GP515-treated DSS mice. These studies show that GP515 is effective in the therapy of DSS-induced colitis. One potential mechanism of action is the suppression of IFNgamma synthesis and CD69 expression. Adenosine kinase inhibition forms a pharmacologic target that should be further investigated for chronic inflammatory bowel disease.
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PMID:Adenosine kinase inhibitor GP515 improves experimental colitis in mice. 1112 68

During acute attacks of inflammatory bowel disease, the luminal pH of the colon decreases significantly. This drop in pH can be exploited by developing coated dosage forms with acid-soluble coating polymers to achieve topical drug delivery to the colon. Two batches of minitablets, a conventional and a swellable formulation, were prepared by direct compression and coated with different amounts of either Eudragit E or AEA in a small coating pan. The release of the model drug dexamethasone from the coated tablets was measured spectrophotometrically at pH 2.0, 4.0, 5.0, and 6.8 and different stirring rates (100-200 rpm) to simulate the influence of pH and hydrodynamic stress on drug release. In general, lag times of drug release, determined as the time points of a 5% drug release, were longer with AEA-coated cores compared to those coated with Eudragit E, resulting from a lower polymer dissolution rate and water permeability of this film. In low pH media, drug release was dependent on the stirring rate because the onset of drug release is determined by the time required for dissolution of the basic polymer films. At pH 6.8, lag times from nonswelling tablets coated with Eudragit E, for which drug release only begins after complete erosion of the polymer film, are not significantly affected by hydrodynamic stress. Drug release from AEA-coated cores is determined by the slow drug diffusion through the polymer film. Lag times from tablets with swelling properties, for which drug release is induced by disruption of the basic polymer films due to water penetration and subsequent core swelling, are not significantly affected by hydrodynamic stress. Additional coating layers such as an intermediate hydroxypropylcellulose (HPC) layer and an enteric outer layer do not influence the lag times of drug release, nor does a 2-hr pretreatment of the entire dosage form in acidic media.
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PMID:Basic coating polymers for the colon-specific drug delivery in inflammatory bowel disease. 1114 24

Infrequently, clusterings of Crohn's disease (CD) occur that suggest it is transmissible. We studied such a clustering. Graduates of the Mankato West High School Class of 1980 were contacted by mail and asked to respond, by self-addressed postcard, to a six-item questionnaire about inflammatory bowel disease and CD. Responses were followed-up by telephone contact and additional mailings. Two visits were made to Mankato, Minnesota, to interview individuals with CD, to obtain medical records, radiographs, and sera, and to study environmental risk factors. Of the 320 graduates of the class of 1980, 285 were contacted. Seven cases of CD were identified, the equivalent of a prevalence of 2,400/100,000. Concerns were discovered that CD may have emanated from recreational swimming. Fecal coliform counts in excess of 200/dL, the standard above which water is regarded as unsafe for recreational use, had been recorded year after year for the Blue Earth River at Mankato and for the Minnesota River. Recent fecal coliform counts (1993-1995) of Lake Washington, Lake German/Jefferson, and Lake Shetek were greater than 200/dL in 57%, 65%, and 62% of water samples. This clustering, in unrelated individuals, argues against a genetic cause for CD and suggests that environmental transmission occurred.
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PMID:A clustering of Crohn's disease in Mankato, Minnesota. 1123 57

Smoking has a dichotomous effect on inflammatory bowel disease, ameliorating disease activity in ulcerative colitis but having a deleterious effect on Crohn's disease. This effect is thought to be due to nicotine. We investigated the effect of chronic nicotine administration on the small and large bowel in iodoacetamide-induced jejunitis and colitis. Jejunitis was induced in Sprague-Dawley rats by intrajejunal administration of 0.1 ml 2% iodoacetamide and colitis by intrarectal administration of 0.1 ml 3% iodoacetamide. Nicotine was dissolved in drinking water (12.5 or 250 micrograms/ml), rats drinking ad libitum. Nicotine administration started 10 days prior to damage induction and throughout the experiment and had no effect on weight gain or daily food intake of rats. Rats were killed 5 days after iodoacetamide-induced colitis and 7 days after induction of jejunitis. The jejunum and colon were resected, rinsed, weighed, damage assessed macroscopically and microscopically and tissue processed for myeloperoxidase and nitric oxide synthase (NOS) activities and prostaglandin E2 (PGE2) generation. Effects of nicotine on gut microcirculation were also assessed. Nicotine by itself caused no damage to the colon. Nicotine had a dichotomous effect on jejunitis and colitis. At a dose of 12.5 micrograms/ml nicotine improved the macroscopic damage of colitis from 252 +/- 66 to 70 +/- 31 mm2, and segmental weight also declined significantly in the colon (from 1.7 +/- 0.2 to 1.2 +/- 0.1 g/10 cm). In contrast, the same dose of nicotine had a deleterious effect on iodoacetamide-induced jejunitis, increasing the macroscopic damage from 368 +/- 38 to 460 +/- 97 mm2 in rats treated with injury escalating to 970 +/- 147 in rats treated with 250 micrograms/ml nicotine. Nicotine treatment also significantly increased jejunal segmental weight. By itself nicotine did not change NOS activity or PGE2 generation compared to control rats, but it enhanced microcirculation in the colon, whereas in the jejunum nicotine decreased PGE2 generation and increased NOS activity but not jejunal microcirculation. Nicotine has opposite effects on iodoacetamide-induced colitis and jejunitis, which may be partly explained by decreased PGE2 generation and increased NOS activity in the jejunum and an increase in the colonic microcirculation.
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PMID:Dual effect of chronic nicotine administration: augmentation of jejunitis and amelioration of colitis induced by iodoacetamide in rats. 1131 92

The objective of this study was to determine the effectiveness of an iodine based disinfectant (IBD, Iocide, Biomedical Development Corporation, San Antonio, TX) on Salmonella enteritidis and S. typhimurium inoculated on egg shell surfaces under simulated industry egg processing conditions with a commercial egg washer used as the sanitizer delivery system. Re-circulated egg washer water containing 1.40-2.85 g/l total dissolved solids was obtained from a commercial egg processing. Sanitizing treatments consisted of distilled deionized water (DDW), IBD, and chlorine (CL; 200 ppm). All treatments (DDW, IBD and CL) significantly (p < 0.05) decreased Salmonella spp. populations on the shell compared to dry (no spray) egg controls. However, efficacy of egg sanitizers appeared to be dependent on the level of total dissolved solids in the egg wash water.
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PMID:Response of foodborne Salmonella spp. marker strains inoculated on egg shell surfaces to disinfectants in a commercial egg washer. 1140


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