Severity in irritable bowel syndrome: a Rome Foundation Working Team report.

OBJECTIVES: The concept of severity in irritable bowel syndrome (IBS) is clinically recognized and operative in diagnostic decision making and treatment planning. Yet, there is no consensus on its definition, and there are limited data on the prevalence of severity subgroups, its medical and psychosocial determinants, and its association with other health status measures. The aims of the Rome Foundation Working Team Committee were to summarize current research, to develop a consensus of understanding on this concept, and to make recommendations for its use in research and clinical care. METHODS: In 2006, a multinational committee of clinical investigators with expertise in IBS and/or psychometric research methods undertook a systematic review of the literature relating to severity in IBS. Owing to limited data, the Foundation commissioned three clinical studies to better characterize the concept of severity in IBS, and summary information and recommendations for future research and clinical care were developed. RESULTS: The main findings were: (i) severity in IBS is defined as a biopsychosocial composite of patient-reported gastrointestinal and extraintestinal symptoms, degree of disability, and illness-related perceptions and behaviors; (ii) both visceral and central nervous system physiological factors affect severity; as severity increases, the central nervous system provides a greater contribution; (iii) severity is related to and influences health-related quality of life and health behaviors and also guides diagnostic and therapeutic clinical decision making; (iv) severity can be subcategorized into clinically meaningful subgroups as mild (∼40%), moderate (∼35%), and severe (∼25%), and this provides a working model for use in future research and clinical care. CONCLUSIONS: Future work is required to understand more precisely the factors contributing to severity and to develop a valid patient-reported instrument to measure severity in IBS.

Trimoprostil plasma concentration--gastric acid inhibition relationships: potentiation by food.

A single, oral, 1.5-mg dose of trimoprostil was taken before a standard meal and a matching placebo was taken after a standard meal by 10 subjects (group A). A second group of 10 subjects took placebo before a meal and trimoprostil after the meal (group B), while a third group took placebo both before and after the standard meal (group C). Food-stimulated gastric acid production was measured by intragastric titration for 6.5 hr after dosing. Trimoprostil taken after the meal had a greater effect on gastric acid secretion than when taken before the meal: Duration of effect was 5 to 5.5 hr in group B and 2 to 2.5 hr in group A. Blood samples were drawn and assayed for trimoprostil by gas chromatography-mass spectrometry. Mean trimoprostil plasma concentration and mean inhibition of gastric acid secretion data were fit to two models by the Hill equation. The mean plasma concentration associated with 50% inhibition of gastric acid secretion was 1.25 ng/ml. Trimoprostil plasma concentrations between 3 and 4 ng/ml were associated with 70% to 80% gastric acid inhibition. Overall, there appears to be a pharmacokinetic-pharmacologic correlation between trimoprostil plasma concentrations and inhibition of gastric acid secretion. Trimoprostil (1.5 mg) in the presence of food appears to have a therapeutic advantage, in that it decreases acid secretion longer than when taken without food and suffers no loss of bioavailability.

Some effects of deoxycholate administration on the metabolism of cholesterol in man.

Hypercholesterolemic subjects in a metabolic ward were kept under uniform dietary conditions until constant levels of serum cholesterol were observed. Oral dosage with deoxycholate (1.5 to 3 g daily for a period of 4 to 10 weeks) resulted in a marked reduction of serum cholesterol concentration. Studies with 14C-labeled cholesterol demonstrated that deoxycholate administration decreased absorption of cholesterol from the human intestinal tract. In these subjects, the turnover rate of serum cholesterol was more rapid during therapy with deoxycholate than during control periods. Deoxycholate appeared to influence the intestinal flora as assessed indirectly by analysis of the types of neutral sterols eliminated with the feces. Decreased synthesis of cholesterol during deoxycholate administration uas demonstrated in a study with 14C-mevalonate. It is concluded that deoxycholic acid can have an important role in the regulation of cholesterol metabolism in humans.

Phagocytosis of alpha-tocopheryl nicotinate by the reticuloendothelial system: a microautoradiographic study.

The cellular distribution of labelled alpha-tocopheryl nicotinate after intravenous administration to normal rats was examined by light microscopic autoradiography. The compound was found to have accumulated in cells of the reticuloendothelial system.

The effect of medium-chain triglycerides on the bioavailability of vitamin E.

Overnight fasted, normal rats were fed a single dose of isotopically labeled vitamin E emulsified in either medium-chain or long-chain triglyceride (MCT or LCT). The animals were sacrificed at various time intervals of up to 72 hours. Levels of radioactivity in the small intestinal wall, liver, plasma, skeletal muscle and adipose tissue were higher in animals in which tocopherol was administered in MCT rather than LCT. Thus, the intestinal absorption of vitamin E was enhanced by solubilization in MCT. These findings are consistent with the theory that the gastrointestinal absorption of dietary tocopherol is dependent upon the simultaneous digestion and absorption of the fat in which the vitamin is solubilized.

Methodology for the determination of bioavailability of labeled residues.

Methods are described for the determination of bioavailability of lipo- and hydro- soluble compounds in the rat. These procedures involve catheterization of the portal vein and/or intestinal lymphatics to study absorption in unanesthetized animals. Catheterization of the common bile duct prevents recycling of materials through the entero-porto-hepato-biliary circulation (EPHBC). Steady-state conditions are ensured by constant infusion of bile or a solution of bile acids into the stomach or duodenum. The techniques and physiological considerations discussed in detail here have resulted in new proposed animal preparations, of value in the accurate determination of the bioavailability of labeled residues ingested by the second species. Since intake must be adequate to permit meaningful conclusions, the concentration of radioactivity in the harvested homogenized tissue is increased by lyophilization. The lyophilized material is compressed into pellets of adequate size. The animals, kept in restraining cages to prevent coprophagy, are allowed to eat the labeled residue spontaneously, if necessary, for 48 and even 72 hr. Bile, urine, and feces are collected for a sufficient length of time to allow quantitative excretion of the labeled residue, if no absorption takes place. Collection of these excreta must be complete. It is essential to account for most-if not all-of the radioactivity administered. Data so obtained allow an accurate balance between intake and excretion of the labeled residue. The presence of radioactivity in the intestinal wall, carcass, liver, and urine is indicative of absorption. The appearance of radioactivity in the bile also indicates absorption, in addition to suggesting that the compound(s) may undergo EPHBC. The extent of recovery of the administered radioactivity in the luminal contents and feces indicates the extent to which the labeled residue is not bioavailable. Evaluation of data obtained with these new animal models should permit corresponding upward adjustments of the minimum levels of residues allowable in the tissue of animals intended for human consumption.

A method for the bioassay of intestinal secretory activity in the conscious rat: studies with arachidonic acid and prostaglandin E2.

A method to study the kinetics of intestinal absorption and secretion in the unanesthetized rat is described. This procedure consists of the perfusion of the small intestine with isotonic NaCl-KCl-[36Cl]NaCl and polyethylene glycol-6000 as a nonabsorbable marker. Secretagogues [arachidonic acid (AA) or PGE2] were administered by continuous infusion via the superior mesenteric artery. Samples of perfusate, taken every 15 min, were analyzed for Na, Cl, 36Cl, K, and PEG-6000 to calculate solute and volume movement. In control rats, net absorption of water and electrolytes increased steadily throughout the 2-hr duration of the perfusion. Water, Na, and Cl moved across the intestine in parallel proportions. Net absorption of K was lower than that of the other electrolytes. AA, at the intraarterial dose of 1 mg/kg/hr did not produce a significant effect; at 4 mg/kg/hr it impaired net absorption, and at 8 mg/kg/hr it gradually enhanced net secretion of both water and electrolytes, especially K. Secretion was also demonstrated with the intraarterial infusion of PGE2 (312 microgram/kg). It is concluded that this new rat model is suitable for the bioassay of intestinal secretory stimulants and can be used for the search of intestinal antisecretory drugs.

Biliary, fecal and urinary excretion of [3H]-prostaglandins in the rat.

The profiles of biliary, fecal and urinary excretion of tritium labeled prostaglandins (PG's) of differing biological activity were investigated in the rat. The PG's (10 micrograms/kg: 2 to 50 microCi/rat, in 1 ml polyethylene glycol-400) were administered intragastrically. Excretion data were expressed as a percentage of the total administered radioactivity. For the orally administered PG's 11R-methyl-16R-fluoro-15R-hydroxy-9-oxoprosta-ci s-5-trans-13-dienoic acid and its methyl ester, excretion was equally divided between urine and feces. The fecal and urinary profile of excretion of 3H after prostacyclin (PGI2) was similar to that following administration of 11R, 16, 16-trimethyl-15R-hydroxy-9-oxoprosta-cis-5-trans-13-dienoic acid (trimoprostil), a PG with antisecretory-antiulcer potential. However, PGI2 was very poorly absorbed from the intestine, while the absorption of trimoprostil was very efficient. Biliary excretion, with little entero-porto-hepatic biliary circulation, was the main route of elimination of trimoprostil, thereby resulting in rapid elimination of drug-related products and diminishing the potential for systemic liability in the rat.

Pharmacokinetics and antisecretory activity of trimoprostil in Heidenhain-pouch dogs.

Trimoprostil, a prostaglandin E2 analog, was evaluated to determine if there was a relationship between plasma concentrations and inhibition of histamine-stimulated gastric acid secretion in dogs prepared with Heidenhain pouches. Trimoprostil was given p.o. followed by collection (drainage) of gastric juice from the pouch to determine acid output. In addition, serial blood samples were withdrawn to determine trimoprostil plasma concentrations. Trimoprostil was absorbed rapidly and eliminated with T1/2 ranging from 25 to 37 min. Trimoprostil was effective in inhibiting acid output compared with control. The maximal response and duration of activity were dependent on the concentration-time profile of trimoprostil. Trimoprostil produced a maximum inhibition of 98% and suppressed acid output for at least 3 hr. When plasma concentrations were related to the antisecretory response using a modified Hill equation, the response was found to lag behind plasma concentrations as evidenced by hysteresis loops. The predicted plasma concentration associated with a 50% inhibition of acid secretion (IC50) ranged from 0.58 to 0.79 ng/ml.