Biomedical subjects
S F Phillips
Publications and source records attributed to S F Phillips.
Role of oxygen free radicals in the etiology of pouchitis.
Transient mucosal ischemia may cause oxygen-derived free radical production by xanthine oxidase, precipitating pouchitis after ileal pouch-anal anastomosis. Our aim, therefore, was to determine the effect of allopurinol, a xanthine oxidase inhibitor, in patients with acute and chronic pouchitis. Acute pouchitis was characterized clinically by sporadic episodes of increased frequency and decreased viscosity of stools, hematochezia, fever, malaise, and pelvic pain, which resolved promptly with treatment. Chronic pouchitis patients required continuous treatment to remain asymptomatic and invariably developed the signs and symptoms of pouchitis within one week following cessation of therapy. Eight patients with acute pouchitis were treated with allopurinol (300 mg p.o. b.i.d.) during the episode. Fourteen patients with chronic pouchitis had their standard antibiotic therapy discontinued while still asymptomatic; they were then given allopurinol (300 mg p.o. b.i.d.) for 28 days. Acute pouchitis resolved promptly in four of eight patients. Seven of the 14 patients with chronic pouchitis responded completely with no recurrence of symptoms during treatment. Allopurinol either terminated an episode of acute pouchitis or prevented pouchitis from recurring in 50 percent of patients. These data support a role for mucosal ischemia and oxygen free radical production in the etiology of pouchitis.
Ileocolonic transit does not change after right hemicolectomy.
The role of the human ileocolonic junction in the transit of solid contents through the entire gut was evaluated. Eight patients, well compensated after right hemicolectomy for localized colon cancer, and eight age-matched healthy controls were enrolled. Scintigraphic transit was quantified after subjects ingested a mixed meal containing 111In-labeled Amberlite beads (average diameter, 1 mm; Sigma Chemical Co., St. Louis, MO). Gastric emptying was initially faster in the postoperative group, but overall emptying was not different from controls; small bowel transit also did not differ between the groups. In patients in whom the distal ileum, ileocolonic sphincter, and proximal colon were absent, isotopes moved from small to large bowel in a manner that was qualitatively and quantitatively no different from that of controls. Major episodes of coloileal reflux could not be identified in either group. After hemicolectomy, the residual transverse colon, and to a lesser degree the descending colon, were able to store solid residue, although in lesser amounts than the unoperated large bowel. The ileocolonic sphincter in humans appears to play only a minor role, at most, in ileocolonic transit, and the colon remaining after right hemicolectomy stores residue so that bowel habits are not greatly disturbed.
Transit through the proximal colon influences stool weight in the irritable bowel syndrome.
The inherent variability of symptoms and motor abnormalities in patients with the irritable bowel syndrome has hampered the demonstration of motor abnormalities that could underlie symptoms. The aim in the current study was to evaluate whether altered regional capacitance or transit of solid residue through the unprepared human gut were factors in the diarrhea of patients with the irritable bowel syndrome. In 10 such patients and in 5 healthy controls, gastric and small bowel transits were evaluated scintigraphically by means of a mixed meal containing 99mTc-labeled resin pellets. Regional colonic transit was quantitated by 111In-labeled pellets delivered to the ileocecal region by a pH-sensitive, methacrylate-coated capsule. Symptomatic patients did not have significantly altered gastric or small bowel transits, but colonic transit was accelerated in 7 of 10 persons with the irritable bowel syndrome (P less than 0.02), in the proximal colon of five patients and in the left colon of two patients. The 24-hour stool weight was positively correlated with the rate at which solid residue emptied from the ascending and transverse colons (r = 0.78; P less than 0.01). There was also an inverse relationship between emptying rates and maximal volumes accommodated by the proximal colon (r = -0.58; P less than 0.05), although the maximum volume of the proximal colon was not significantly different in patients and healthy subjects. Thus, accelerated transit through the proximal colon is a factor in the pathophysiology of the irritable bowel syndrome and influences the stool weight of such patients. The capacitance of the proximal colon presumably influences its storage capacity and, hence, the rate at which it empties.
Distribution of mesalamine enemas in patients with active distal ulcerative colitis.
Mesalamine (5-aminosalicylic acid), a topically administered anti-inflammatory agent, is effective treatment by enema for distal ulcerative colitis; it lacks many of the side effects of orally administered sulfasalazine. In this study, we determined the colonic distribution of a 60-ml mesalamine enema in eight patients (five women and three men, 18 to 48 years old) with active distal ulcerative colitis that ranged from 12 to 40 cm proximal to the anal verge. On 3 consecutive days, each patient self-administered a 4-g (60-ml) 5-aminosalicylic acid enema that contained 3.7 MBq of [99mTc]technetium-sulfur colloid. Anterior and posterior images were obtained at 0, 30, 60, 120, and 240 minutes. During the 4-hour study period, all patients retained the enemas. The enemas spread to the sigmoid region in 24 of 24 studies, to the splenic flexure region in 22 of 24, and to the transverse colon in 1 of 24. Most of the enema was retained in the sigmoid colon. Therefore, we conclude that a 60-ml enema, when administered as recommended clinically, routinely flows retrograde as far as the splenic flexure but rarely spreads beyond this point. These results support the use of intrarectally administered 5-aminosalicylic acid for segmental colitis of the descending colon.
Colonic tone and motility in patients with irritable bowel syndrome.
In this study, our aim was to test the hypothesis that colonic tone is abnormal in patients with irritable bowel syndrome (IBS). We studied eight patients with IBS and eight age-matched asymptomatic control subjects, in whom tone and motility were measured by an electronic barostat and by pneumohydraulic perfusion manometry, respectively. Tone and motility were recorded from the descending colon for a 14-hour period--3 hours awake, 7 hours asleep, 2 hours fasting after awakening, and 2 hours postprandially. In patients with IBS and in healthy subjects, colonic tone decreased by up to 50% during sleep and increased promptly on awakening. Fasting colonic tone (as quantified by the volume in the barostat balloon) in the awake state was not significantly higher in patients with IBS than it was in healthy subjects (125 +/- 13 versus 152 +/- 15 ml; P = 0.19). Tone increased postprandially in both study groups, and the increase was greater in healthy subjects than it was in patients with IBS (P < 0.05). The motility index during fasting was greater in patients with IBS than it was in healthy control subjects (3.2 +/- 0.6 versus 1.6 +/- 0.4; P = 0.05), and the postprandial increase in motility index was greater in the healthy subjects. Preprandially and postprandially, we noted a trend for high-amplitude prolonged contractions to be more frequent in patients with IBS than in healthy subjects. We conclude that colonic tone in patients with IBS showed the same nocturnal and postprandial variations as it did in healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Selective 5-hydroxytryptamine type 3 receptor antagonism with ondansetron as treatment for diarrhea-predominant irritable bowel syndrome: a pilot study.
Serotoninergic innervation may contribute to the control of colonic motility and to visceral sensation from the large bowel. Indeed, ondansetron hydrochloride, a selective 5-hydroxytryptamine type 3 receptor antagonist, has been shown to slow colonic transit in healthy volunteers. Thus, we wished to determine whether 5-hydroxytryptamine type 3 receptor blockade slows colonic and small bowel transit in patients with diarrhea-predominant irritable bowel syndrome (IBS) and whether symptoms would be ameliorated with drug therapy. Of 14 patients with well-established IBS who entered a randomized, double-blind, placebo-controlled crossover pilot trial of 4 weeks of treatment with ondansetron, 16 mg three times daily, 11 completed the study. A minimal "washout period" of 4 weeks (median, 7 weeks) separated the two phases of the trial because patients were required to have similar symptoms before both periods of the study. Colonic transit tended to be longer during drug therapy than during the placebo trial, but this difference was not significant. Small intestinal transit and orocecal transit were unchanged by the drug. The integrated and peak postprandial increases in neurotensin, peptide YY, and human pancreatic polypeptide in serum were not significantly different in the drug and placebo periods. After treatment with ondansetron, stool consistency improved significantly; however, stool frequency, stool weight, abdominal pain, and the symptom criteria for IBS were not significantly altered by the drug. The results of this pilot study suggest that the motor effects expected with 5-hydroxytryptamine type 3 receptor blockade (namely, slowed colonic transit) may be diminished in some patients with IBS. The subjective improvement in stool consistency may reflect changes in the perception of defecation.(ABSTRACT TRUNCATED AT 250 WORDS)
Control of muscle tone in the human colon.
Human colonic muscle tone varies diurnally and postprandially in predictable ways. Increased tone reduces the capacity of the colon to store contents after a meal, whereas increased distensibility (lesser tone) during sleep enlarges the storage capabilities and may slow transit. We tested the hypothesis that antidiarrhoeal drugs would also alter tone which, in turn, might reduce diarrhoea by facilitating the storage and salvage of fluids. Using a colonic barostat to create low pressure, isobaric colonic distension in healthy volunteers, we found that intravenous atropine (0.01 mg/kg) relaxed the colon during fasting, reduced the postprandial increase in tone, and enhanced relaxation in the late (1-2 hour) postprandial period. Intravenous morphine (0.1 mg/kg) caused variable effects soon after injection but, in fasting subjects, the descending colon relaxed 70-90 minutes after morphine. These changes in colonic motility were not always obvious by conventional manometric recording. Colonic distensibility is increased by antidiarrhoeal drugs and this effect may contribute to their efficacy in slowing colonic transit and augmenting absorption.
[Transit of solids through the human colon: simplification of a technique].
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Absorption from the jejunum is increased by forward and backward pacing.
In 4 dogs a 75-cm segment of jejunum was isolated from the intestinal stream. Stimulating electrodes were implanted at each end of the segment and recording electrodes at intervals between. The two ends of the segment were fashioned as stomas on the anterior abdominal wall. After recovery, the electrical activity of the segment was continuously recorded, whilst a solution of 100 mmol/l glucose and 90 mmol/l NaCl was infused into the proximal stoma at 2.9 ml/min. Effluent from the distal stoma was collected in 5-min aliquots for three consecutive 30-min periods. In the second period electrical stimuli were given via either the proximal or the distal bipolar electrodes to entrain pacesetter potentials. Both forward and backward electrical pacing decreased the output of water, glucose and sodium from the jejunal segment, but the decrease was significantly greater with backward pacing. We conclude that pacing a segment of jejunum backwards with electrical stimuli produces a greater increase in absorption from the segment than pacing it forwards, a finding which has therapeutic implications in patients with the short bowel syndrome.
Absorption of nutrients in lactase deficiency.
The influence of malabsorption of lactose, as a result of primary lactase deficiency, on the absorption of the nutrients in milk was tested in four healthy controls and four subjects with lactase deficiency. An ileal perfusion technique was used to quantify arrival in the ileum of nutrients and a nonabsorbable marker (polyethylene glycol, PEG 4000) ingested as a test meal of milk. The meal was 250 ml of whole milk or milk in which the lactose had been hydrolyzed to glucose and galactose. In the fasting state, ileal flow of volume, protein, carbohydrate, and electrolytes was small and not different in controls and lactase-deficient subjects. Ileal flow increased in all subjects after the test meal of milk; more fluid and nutrient was recovered from the ileum in lactase-deficient subjects after whole milk than in control subjects or in lactase deficiency after hydrolyzed milk. Two deficient subjects showed marked malabsorption of lactose (35 and 50%); two did not. Protein, calcium, magnesium, and phosphorus were also recovered from the ileum in greater quantities in lactase deficients after whole milk. However, apart from decreased absorption of lactose, the nutritional consequences of malabsorption in association with primary lactase deficiency in adults are probably minimal.
Colonic absorption of unconjugated bile acids: perfusion studies in man.
Colonic absorption of three major unconjugated bile acids--cholate, chenodeoxycholate, and deoxycholate--was measured under steady-state conditions using a technique of colonic perfusion in healthy volunteers. Aqueous solutions at pH 8.0 and varying in concentration from 1 mM to 10 mM were used. The rate of chenodeoxycholate absorption averaged nine times that of cholate absorption; deoxycholate absorption was somewhat less than that of chenodeoxycholate absorption, averaging six times that of cholate. At concentrations below 5 mM, the rate of absorption of bile acids was directly proportional to concentration, so that "clearance" could be calculated. Clearance values for a 1-mM solution (ml/min/colon, mean +/- SE) were: chenodeoxycholate, 9.84 +/- 1.0; deoxycholate, 7.0 +/- 1; and cholate, 0.82 +/- 0.10. Since absorption was proportional to concentration in the lumen, and was more rapid for the dihydroxy acids, the major mechanism of absorption was thought to be passive nonionic diffusion. Maximal rates of bile acid absorption were calculated from a 1-mM solution and found to be as high as 4.2 g/day for chenodeoxycholate, 3.2 g/day for deoxycholate, and 0.5 g/day for cholate, and the rate would be still greater for more concentrated solutions. Colonic absorption may contribute significantly to conservation of the dihydroxy bile acid pool, especially in conditions of bile acid malabsorption.
Gastric emptying of lipids after ingestion of an homogenized meal.
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Fluid and electrolyte fluxes in the gut.
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Functions of the large intestine.
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Enhancement of absorption from the intact and transected canine small intestine by electrical pacing.
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Effect of molecular structure on bile acid-induced alterations in absorptive function, permeability, and morphology in the perfused rabbit colon.
An in vivo intestinal perfusion system was used to study the effects of different bile acids on fluid secretion, mucosal permeability, and mucosal morphology in the rabbit colon. To define the structure-activity relationships of the bile acids, nine unconjugated bile acids were used, varying only in the number (two or three) or position (3, 7, or 12 or various combinations) of hydroxy or keto nuclear substituents. Results showed that bile acids with two hydroxy groups in the alpha configuration at the 3,7 position, 3,12 position, or 7,12 position induced fluid secretion, increased mucosal permeability, and produced mucosal damage as assessed by light and scanning electron microscopy and quantitated by DNA loss during perfusion. Replacement of hydroxy groups by keto groups or a change from alpha to beta configuration for the hydroxylic substituent in the 7 position abolished all three activities. Trisubstituted derivatives, whether hydroxy or keto, did not affect fluid secretion permeability or cause mucosal damage. These studies indicate that of the major primary and secondary bile acids in man, only deoxycholic and chenodeoxycholic acids alter colonic structure and function in the rabbit. They show further that the cathartic effects of bile acids have specific structural requirements; and they show that bile acid-induced secretion was invariably associated with increased mucosal permeability and epitheliolysis.
Pancreatic insufficiency and Ménétrier's disease. Report of a case with clinical response to pancreatic enzyme replacement.
A patient with exocrine pancreatic insufficiency and hypoalbuminemic edema was shown also to have a protein-losing gastropathy secondary to giant hypertrophic gastritis (Ménétrier's disease). Despite continuation of excessive gastric protein loss, the manifestations of hypoproteinemia were reversed by oral pancreatic enzyme replacement therapy. We speculate that impaired intraluminal proteolysis exaggerated the consequences of gastric protein loss.