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PubMed2001

Neuropathology of paediatric chronic intestinal pseudo-obstruction and related animal models.

Chronic intestinal pseudo-obstruction (CIP) in paediatric patients is due to heterogeneous aetiologies that include primary disorders of the enteric nervous system. These conditions are poorly delineated by contemporary diagnostic approaches, in part because the complex nature of the enteric nervous system may shelter significant physiological defects behind subtle or quantitative anatomical changes. Until recently, relatively few experimental animal models existed for paediatric CIP. However, the availability of rodent models, particularly novel mutants created in the last few years by genetic manipulations, has brought unprecedented opportunities to investigate molecular, cellular, physiological, and histological details of enteric neuropathology. Information gleaned from studies of these animals is likely to change diagnostic and therapeutic approaches to paediatric CIP and related conditions.

Animals↗
PubMed2001

Apoptosis induction by sennoside laxatives in man; escape from a protective mechanism during chronic sennoside use?

Chronic sennoside use induces melanosis coli (MC) and possibly increases colorectal cancer risk. Sennosides alter colonic crypt length, proliferative activity, and bcl-2 expression 18 h after administration. To investigate possible mechanisms for carcinogenesis, the effects of acute sennoside use and the presence of MC on colorectal epithelium were studied. Colorectal biopsies from 15 subjects receiving sennosides 6 h before sigmoidoscopy (Sen), 15 controls (NSen), and 27 with MC [11 moderate (MMC) and 16 severe (SMC)]. were analysed for degree of apoptosis (H&E staining), immunohistochemical p53, p21/WAF and bcl-2 expression, and proliferative activity (labelling index, LI). Apoptosis (p=0.0004), intensity of p53 staining (p=0.01), and p21/WAF expression (p=0.008) were increased in Sen and SMC compared with NSen and MMC. p53 expression was increased in Sen (p=0.004). No difference in bcl-2 expression or LI was observed. Crypts were shorter in Sen (p=0.05) and longer in SMC (p=0.04) than in NSen. It is concluded that sennosides acutely induce apoptosis of colonic epithelial cells, presumably by a p53, p21/WAF-mediated pathway, resulting in shorter crypts. In severe melanosis coli, apoptosis seems to be delayed, causing longer crypts without a rise in proliferative activity or bcl-2 expression. This escape from a presumably protective mechanism may enhance the risk of carcinogenesis during chronic sennoside use.

Adolescent↗
PubMed2004

Ovarian cancer risk and use of phenolphthalein-containing laxatives.

PURPOSE: Experimental studies in rodents demonstrated the carcinogenic potential of phenolphthalein, the active ingredient in some laxatives, administered at doses similar to the dose that could be used by humans. Ovarian cancer was one of the cancers observed in these studies. We examined the association between epithelial ovarian cancer and use of phenolphthalein-containing laxatives in a population-based case-control study. METHODS: The study includes 356 epithelial ovarian cancer cases (256 invasive, 100 borderline) and 424 controls. Cases were identified through a population-based registry in Los Angeles County in 1992-1998, and controls were matched to cases by age, race/ethnicity and neighborhood. Data on laxative use (specific brands, frequency of use, usual dose) were obtained by structured in-person interview. RESULTS: Compared to women who never used a laxative, ever use of a phenolphthalein-containing laxative was not associated with an increased risk of invasive ovarian cancer (odds ratio (OR) 1.1, 95% confidence interval (CI) 0.75, 1.5) or of borderline ovarian cancer (OR 0.75, 95%CI 0.37, 1.5). Total days used, mean number of pills per day and cumulative dose were also unrelated to risk. CONCLUSIONS: This study provides some assurance that phenolphthalein-containing laxatives do not increase the risk of ovarian cancer in humans. These findings are of particular importance to those countries in which phenolphthalein is still used in over-the-counter medications.

Adult↗
PubMed2004

Treatment patterns and health care costs of mebeverine-treated IBS patients: a case-control study.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional disorder affecting the quality of life of patients. In the Netherlands, mebeverine is currently the only medical treatment registered for IBS, although its efficacy is considered disputable. OBJECTIVE: To assess treatment patterns and associated health care cost in mebeverine users relative to matched controls. METHODS: A matched case-control study was performed using pharmacy data. Cases were mebeverine users as proxy for IBS patients. Controls were non-mebeverine users and matched to cases by age, gender and pharmacy. Prevalence and incidence of mebeverine use, concomitant drug use and hospitalizations were assessed in 3431 cases and 3431 controls. Concomitant drug use and hospitalizations was also assessed in a subgroup of 1222 users of mebeverine and laxatives (proxy for constipation-IBS) and their controls. RESULTS: Twelve per 1000 residents were ever-dispensed mebeverine in 1998. One-third of these mebeverine users used laxatives concomitantly. Concomitant drug use and hospitalizations were increased in mebeverine users. The odds ratio for hospitalizations for gastrointestinal reasons was increased predominantly in mebeverine users with concomitant laxative use (OR:8.7; 95%CI [4.3-17.3]). Excess yearly costs for all concomitant medications were 94 Euros [95%CI 79 Euros-109 Euros] and for hospital admissions 120 Euros [74 Euros-166 Euros] per mebeverine user. In mebeverine users with concomitant laxative use these costs were 136 Euros and 251 Euros respectively. CONCLUSIONS: In treated IBS patients, concomitant drug use and hospitalizations are increased relative to matched controls. Medical resource use and associated health care costs are particularly increased in mebeverine users using laxatives. The total mean excess cost per patient per year is 482 Euros.

Adolescent↗
PubMed2001

Kinetics of chemical degradation of isoxaflutole: influence of the nature of aqueous buffers (alkanoic acid/sodium salt vs phosphate).

A kinetic study of the chemical degradation of isoxaflutole (5-cyclopropyl-1,2-oxazol-4-yl alpha alpha alpha-trifluoro-2-mesyl-p-tolyl ketone) into its diketonitrile derivative (DKN), which is its active herbicide principle, in organic buffers at different pH values was carried out using a HPLC/UV detection method. The values of the pseudo-first-order rate constants Kobs for the reaction were calculated and compared with those previously obtained in inorganic buffers. In both cases, Kobs was found to be dependent on pH and temperature, but at pH 5.2 the degradation of isoxaflutole in CH3COOH/CH3COONa buffers was considerably faster than in KH2PO4/Na2HPO4 buffers, indicating that the compound was sensitive to the nature of the reagents used to prepare buffered solutions. The influence of phosphate and acetate concentrations and the influence of the R-substituent in RCOOH/RCOONa buffers were investigated. For the HA/A- buffers studied, the values of Kobs were linearly dependent on HA and A- concentrations, which meant that the degradation of isoxaflutole was subject to general catalysis. The values of Kobs were also found to be dependent on the number and the position of the CH3 groups of the R-substituent. The known degradation product of DKN (a benzoic acid derivative) was not detected throughout this study.

Biodegradation, Environmental↗
PubMed2006

Bulk agent Plantago ovata after Milligan-Morgan hemorrhoidectomy with Ligasure.

The aim of this study was to determine usefulness of the bulk agent Plantago ovata in reducing postoperative pain and tenesmus after open hemorrhoidectomy (Milligan-Morgan with Ligasure). Ninety-eight patients were randomized into two groups of 49 patients each. In both groups Milligan-Morgan open hemorrhoidectomy with Ligasure was performed. The first group received postoperatively two sachets daily of 3.26 g of the bulk agent, Plantago ovata, for 20 days. The control group was treated postoperatively with glycerin oil. There was no statistically significant difference in age, gender distribution and hemorrhoid grading, between the two groups. The pain score after first defecation (p < 0.001) and after 10 days (p < 0.01) and the global pain score (p < 0.001) was statistically significantly lower in the group treated with Plantago ovata, while there was no statistically significant difference in the pain level after 20 days (p > 0.05). The hospital stay was statistically significantly shorter in the group receiving Plantago ovata (2.6 +/- 0.6 vs 3.9 +/- 0.7 days, p < 0.001). The incidence of tenesmus was higher in the control group (40.8% vs 10.2%, p < 0.01). Treating patients with Plantago ovata after open hemorrhoidectomy, reduces pain, tenesmus rate and shortens postoperative hospital stay.

Cathartics↗
PubMed1999

Prospective trial of aggressive postoperative bowel stimulation following radical hysterectomy.

INTRODUCTION: Postoperative traditional feeding protocols are not based on scientific studies, but rather on anecdotal evidence. We present the first prospective trial of aggressive postoperative bowel stimulation following radical hysterectomy in an attempt to determine its effect on the length of hospital stay. METHODS: Twenty consecutive patients undergoing radical hysterectomy were entered onto a prospective trial of aggressive postoperative bowel stimulation, which consisted of 30 cc milk of magnesia p.o. b.i.d. starting on postoperative day 1 and biscolic suppositories q.d. starting on day 2. A clear liquid diet was begun following flatus or bowel movement and patients were discharged 12 h after tolerating a clear liquid diet. Diet was slowly advanced at home. RESULTS: Median time to flatus was 3 days, bowel movement 3 days, and clear liquid diet 3 days. Median time to discharge was 4 days. No patients developed ileus or bowel obstructions and there were no readmissions for bowel complications. Our median time to discharge of 4 days represents a 50% reduction in hospital stay compared to our previous prospective study using traditional postoperative bowel management (8 days), which was statistically significant at P = 0.001. CONCLUSION: Aggressive bowel stimulation with milk of magnesia and biscolic suppositories resulted in early return of bowel function and early discharge with no noticeable complications.

Adult↗
PubMed1996

Different mechanism of saturation of acetaminophen sulfate conjugation in mice and rats.

Sulfation of acetaminophen is a high-affinity and low-capacity conjugation pathway in rats. It is thought that sulfation becomes saturated in rats at high doses of acetaminophen because of limited availability of the active sulfate donor, 3'-phosphoadenosine 5'-phosphosulfate (PAPS), the supply of which is, in turn, limited by the availability of its precursor, inorganic sulfate. The present study was designed to determine whether a similar mechanism is responsible for capacity-limited sulfation in mice. Saturation of acetaminophen sulfation occurs in both species; however, at the maximal rate of sulfation, sulfate and PAPS concentrations were markedly decreased in rats but not in mice. Administration of sodium sulfate and the sulfate precursor N-acetylcysteine enhanced the formation of acetaminophen sulfate in rats, but not in mice. Mice exhibited lower activities of hepatic PAPS synthetic enzymes (i.e., ATP sulfurylase and APS kinase) and sulfotransferase than rats, which may in part be responsible for their lower capacity to sulfate acetaminophen. In addition, administration of acetaminophen further decreased phenolsulfotransferase activity in mice. In rats, administration of acetaminophen did not influence hepatic sulfotransferase activity. These observations suggest that while the capacity of rats to sulfate acetaminophen is limited by the availability of PAPS, in mice it is limited by sulfotransferase activity.

Acetaminophen↗
PubMed2000

Phenolphthalein metabolite inhibits catechol-O-methyltransferase-mediated metabolism of catechol estrogens: a possible mechanism for carcinogenicity.

Phenolphthalein (PT), used in over-the-counter laxatives, has recently been identified as a multisite carcinogen in rodents, but the molecular species responsible for the carcinogenicity is not known. A catechol metabolite of PT, hydroxyphenolphthalein (PT-CAT), was recently identified and may be the molecular species responsible for at least part of the toxicity/carcinogenicity of PT. We hypothesize that PT-CAT inhibits the enzyme catechol-O-methyltransferase (COMT) and therefore potentiates genotoxicity by either PT-CAT itself or the endogenous catechol estrogens (CEs) in susceptible tissues. The present studies were conducted to determine the effects of PT treatment and PT-CAT itself on the COMT-mediated metabolism of 4- and 2-hydroxyestradiol both in vitro and in vivo. Female mice were treated with PT (50 mg/kg/d) for 21 days and then euthanized. PT-CAT concentration in urine reached plateau levels by 7 days of exposure. An O-methylated metabolite of PT-CAT was detected in feces. In vitro experiments demonstrated that PT treatment resulted in an increase in free CEs, which are normally cleared by COMT and a concurrent decrease in the capacity of hepatic catechol clearance by COMT. In vitro, PT-CAT was a substrate of COMT, with kinetic properties within the range measured with endogenous substrates. PT-CAT was an extremely potent mixed-type inhibitor of the O-methylation of the catechol estrogens, with 90-300 nM IC50s. The above data, when taken together, suggest that chronic administration of PT may enhance metabolic redox cycling of both PT-CAT and the catechol estrogens and this, in turn, may contribute to PT-induced tumorigenesis.

Animals↗
PubMed1980

Therapy of acute oral poisoning by organic solvents: treatment by activated charcoal in combination with laxatives.

High doses of activated charcoal effectively decrease enteral absorption of organic solvents. Insufficiently large amounts of liquid paraffin or castor oil showed no protective effect. On the contrary, blood levels of some solvents were increased, especially by paraffin. Therefore, the use of paraffin in the therapy of solvent intoxications prior to the application of activated charcoal cannot be generally recommended.

Animals↗
PubMed1996

Relationship between nitric oxide and platelet-activating factor in castor-oil induced mucosal injury in the rat duodenum.

The modulation of platelet activating factor (PAF) formation in duodenal tissue by nitric oxide (NO) released in response to castor oil was studied in rats pretreated with NG-nitro-L-arginine methyl ester (L-NAME, 6.25-25 mg/kg, i.p.), an inhibitor of NO synthase, NG-nitro-D-arginine methyl ester (D-NAME, 25 mg/kg, i.p.), the inactive enantiomer of L-NAME or isosorbide-5-mononitrate (IMN, 30-90 mg/kg, p.o.), a NO donating compound. Castor oil (2 ml/rat orally) increased PAF production in the rat duodenum 3 h after challenge. L-NAME, but not D-NAME, enhanced the amount of PAF formed by duodenal tissue, while IMN (30-90 mg/kg) counteracted the effects of L-NAME (12.5 mg/kg) and also reduced PAF release in the tissue of rats treated with castor oil. L-NAME 12.5 mg/kg, but not D-NAME, enhanced both macroscopic damage and acid phosphatase release induced by castor oil. These effects were reduced by a PAF antagonist BN 52021 (3-t-Butyl-hexahydro-4, 7b, 11-trihydroxy-8-methyl-9H-1, 7a-epoxymethano-1H, 6aH-cyclopenta [c] furo [2, 3b] furo [3'2':3,4] cyclopenta [1.2-d]furan-5,9,12(4H)trione) 10 and 20 mg/kg i.p. Such findings suggest that endogenous nitric oxide could reduce PAF biosynthesis in castor oil-treated rats.

Acid Phosphatase↗
PubMed1996

[Effect of orthograde intestinal irrigation with Prepacol and polyethyleneglycol solution on duration of postoperative ileus after colorectal resections].

In a prospective randomized study in 100 patients undergoing conventional (n = 66) or laparoscopic (n = 34) colorectal resection, mechanical lavage with 2 l of a polyethylene glycol (PEG) solution (group A, n = 50) combined with a laxative was compared with lavage with 4 l of PEG alone (group B, n = 50). The influence of bowel preparation on postoperative ileus was investigated. The efficacy of bowel preparation was determined intraoperatively by a surgeon blind to the type of preparation. The time interval between the end of the operation an first flatus or bowel movement was recorded. The efficacy of preparation was no different between the groups (group A: 94%, group B: 84%; P = 0.5). The time lapse before first flatus (A: 3.1 +/- 1.2 days, B: 3.2 +/- 1.3 days; P = 0.6) or bowel movement (A: 3.9 +/- 1.3 days, B: 4.1 +/- 1.3 days; P = 0.5) also did not differ between the groups. The only factor found in multivariate analysis (age, sex, operation, duration and type of surgery, bowel preparation) to prolong the duration of postoperative ileus was the type of surgery. The first bowel movement occurred 3.2 +/- 1.1 days after conventional surgery and 4.3 +/- 1.2 days (P < 0.001) after laparoscopic surgery. The type of preoperative bowel preparation had no influence on the duration of postoperative ileus. The postoperative interval before the first bowel movement was shorter after laparoscopic surgery.

Aged↗