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One of the surprises of the flood of placebocontrolled, endoscopic, double-blind studies of duodenal ulcer healing in the last 10 yr has been the realization that placebo therapy results in healing in up to 50% of patients treated for 4-6 wk and may approach the rate of healing noted with active therapy* after this time (;1,2). For example, in a large American multicenter double-blind study of cimetidine versus placebo for duodenal ulcer (3), a significant difference in healing rates was evident only at 2 wk but not at 4 or 6 wk. Even more striking is the similarity in symptom relief between placebo and active agents: no statistically significant differences are demonstrable in most studies (4-6). These observations have led some to conclude that ulcer therapy with currently available drugs such as antacids, antisecretory agents, or sucralfate may not be truly efficacious (7) and others to conclude that placebo treatment for peptic ulcer might be the ideal therapy: safe, cheap, and effective (8). These conclusions, however, may be wrong. Because of the relatively small size of each individual study, the good overall results with placebo might mask rare but important complications or problems that might be avoided by using active agents. To evaluate this, we examined the results of 48 double

To determine whether the antidiarrheal effect of loperamide is due to an effect on intestinal motor function or to an acceleration of the rate of absorption by the intestine (as has been suggested recently), we studied absorption during experimental diarrhea produced by the rapid intragastric infusion of electrolyte solution. In studies in which a 2700-m1 bolus of electrolyte solution was infused into the stomach over 90 min, loperamide delayed the appearance of rectal effluent in each of 5 subjects and decreased the volume of rectal effluent from 1090 ± 118 to 770 ± 73 ml (p = 0.05). When intragastric infusion was continued for 5 h, producing steadystate total gut perfusion, the volume of effluent produced per unit time and the concentration of a nonabsorbable polyethylene glycol marker in rectal effluent was not different with or without loperamide, indicating that loperamide did not alter the rate of absorption by intestinal mucosal cells. Loperamide also had no effect during steady-state perfusion when absorption rates were reduced by intravenous infusion of vasoactive intestinal polypeptide. Loperamide did substantially increase the intraluminal volume of the total gut, from 985 ± 131 to 1764 ± 195 ml (p

There is limited information on the effect of cholinergic agonists on gastric acid secretion in humans. In the present study we found that a large intravenous dose of bethanechol (50 µ/kg · h) significantly increased gastric juice output and salivary flow but did not significantly affect gastric acid output or acid concentration in healthy subjects. Gastric juice osmolality decreased significantly during bethanechol infusion, suggesting neutralization of gastric acid by bicarbonate. Assuming that parietal (acid) secretion contains 160 mM of H+ and that nonparietal (alkaline) secretion contains 25 mM of bicarbonate we calculated that bethanechol increased both parietal and nonparietal secretion in each of 6 healthy subjects and also in 9 of 10 patients with duodenal ulcer. Thus the increase in gastric juice output in response to bethanechol was due to stimulation of both acid and alkaline secretion. Parietal secretion during bethanechol infusion averaged 27% ± 4% of maximal pentagastrin-stimulated parietal secretion in healthy subjects and averaged 44% ± 8% of maximal pentagastrin- or histamine-stimulated secretion in duodenal ulcer patients. Unlike bethanechol, neither pentagastrin- nor histaminestimulated nonparietal secretion. Atropine (2.3 µg/ kg) also did not affect basal nonparietal secretion, although this dose of atropine significantly reduced basal parietal (acid) secretion.

Clonidine, an alpha 2-adrenergic agonist, has been reported to stimulate the rate of electrolyte absorption in vitro, to alter intestinal motility in vivo, and to have antidiarrheal effects in animals. Experiments were performed in 8 healthy volunteers in order to evaluate the antidiarrheal effect of clonidine in humans. When diarrhea was induced by intragastric infusion of 2700 ml of balanced electrolyte solution over 90 min, oral administration of 0.3 mg of clonidine reduced the volume of rectal effluent by 48% (from 1233 +/- 62 to 640 +/- 77 ml, p less than 0.001), a clear-cut antidiarrheal effect. Clonidine increased total gut volume significantly (from 987 +/- 91 to 1830 +/- 142 ml, p less than 0.001), suggesting that clonidine exerted its antidiarrheal effect by altering gut motility, i.e., increasing the capacity of the gut and slowing the transit of fluid through the intestine. In other experiments, the net absorption rate of the whole gut during steady state total gut perfusion was measured. The rate of absorption of fluid was transiently stimulated by clonidine by 15% (from 696 +/- 77 to 799 +/- 55 ml/h, p less than 0.02), indicating an additional effect on mucosal cell function. These studies indicate that in this experimental diarrhea model, clonidine has antidiarrheal properties that are due largely to effects on motility of the gut but that clonidine also modestly stimulates the net rate of absorption by intestinal mucosa.

Chez 31 malades atteints de diarrhee chronique, l'observation du comportement au cours du jeune et l'etude de l'absorption au cours de la perfusion de l'intestin entier ou de segments separes permet de preciser les differences entre diarrhee secretoire, diarrhee par colite microscopique et diarrhee idiopathique

In vitrostudies under short-circuited conditions suggest that amiloride, a diuretic agent which is thought to block apical membrane sodium entry, has significant effects on sodium absorption by the human colon. To evaluate this in vivo,we studied the effect of amiloride applied in concentrations of 10−5and 10−4M on sodium transport and potential difference (PD) in human colon during steadystate perfusion. Net sodium absorption was reduced 25% by amiloride and chloride absorption by 15%; potassium and bicarbonate secretion rates were enhanced. In other studies the colon was divided into a proximal and distal test segment by endoscopic introduction of a collection channel to the descending colonsigmoid junction. Comparison of tritiated water absorption by the two segments indicated that the distal segment comprised approximately 20% of the total colon surface area. However, the distal test segment only accounted for 5–7% of total sodium, chloride, or water absorption; in contrast, 17–20% of total potassium or bicarbonate secretion occurred there. In the proximal test segment, amiloride reduced net sodium absorption by almost one third from 21.0 to 14.4 mmollhr (P

We studied the effect of vagal stimulation by sham feeding on gastric emptying in normal human subjects. When a saline test meal was infused into the stomach, simultaneous sham feeding did not alter the emptying of a nonabsorbable marker added to the meal or the volume of fluid emptied from the stomach. When a homogenized steak meal was infused, sham feeding caused a slight acceleration of emptying (47 ± 2 vs. 53 ± 2% marker recovered from the stomach 45 min after the meal, P

We measured net calcium absorption and the calcium content of the digestive glands secretions in people with widely different serum concentrations of 1,25 dihydroxy vitamin D (hereafter referred to a 1,25-D). Patients with end stage renal disease on hemodialysis served as a model of human 1,25-D deficiency; they were also studied when they had abnormally high serum 1,25-D concentrations as a result of short periods of treatment with exogenous 1,25-D. Normal subjects were studied for comparison. The amount of calcium secreted into the duodenum by the digestive glands was found to be trivial compared to the calcium content of normal or even low calcium meals; therefore, values for net and true net calcium absorption differed only slightly. There was a linear correlation between true net calcium absorption and serum 1,25-D concentration. By extrapolating the short distance to a zero value for serum 1,25-D, D-independent true net calcium absorption was estimated. By subtracting D independent from true net calcium absorption, values for D-dependent absorption were obtained. For a given level of meal calcium intake, D-dependent calcium absorption was found to be directly proportional to serum 1,25-D concentration. At any given value for serum 1,25-D, absorption via the D-dependent mechanism was approximately the same with a low (120 mg) calcium meal as it was when meal calcium intake was increased to 300 mg. We interpret this to mean that the D-dependent mechanism is saturated or nearly saturated by low calcium meals. The D-independent absorption/secretion mechanism resulted in secretion (a loss of body calcium in the feces) when intake was low (120 mg per meal) and absorption when intake was normal. All of the increment in calcium absorption that occurs when low or normal calcium meals are supplemented with extra calcium is mediated by the D-independent mechanism.

Patients with chronic diarrhea and fecal in continence are unable to retain as much rectally infused saline as patients without incontinence. We explored the effect of training such a patient to retain rectally infused saline. The patient was a 31-yr-old female with chronic diarrhea of obscure etiology who had daily episodes of fecal incontinence which markedly restricted her lifestyle. Training was accomplished by urging the patient to retain as much of a 25-min rectal infusion of 1500 ml saline as possible. After 10 training sessions, the patient increased her ability to hold rectally infused saline almost sevenfold. This increase was well maintained over 10 wk. In spite of continued diarrhea, the patient's incontinence did not recur after the first week of training, and she was able to resume a normal life. Anal sphincter pressure and a test of continence for a solid sphere did not change during or after training. This simple training technique has potential as a treatment for disabling fecal incontinence in patients with chronic diarrhea.

Antacids used to decrease phosphorus absorption in patients with renal failure may be toxic. To find more efficient or less toxic binders, a three-part study was conducted. First, theoretical calculations showed that phosphorus binding occurs in the following order of avidity: Al3+ greater than H+ greater than Ca2+ greater than Mg2+. In the presence of acid (as in the stomach), aluminum can therefore bind phosphorus better than calcium or magnesium. Second, in vitro studies showed that the time required to reach equilibrium varied from 10 min to 3 wk among different compounds, depending upon solubility in acid and neutral solutions. Third, the relative order of effectiveness of binders in vivo was accurately predicted from theoretical and in vitro results; specifically, calcium acetate and aluminum carbonate gel were superior to calcium carbonate or calcium citrate in inhibiting dietary phosphorus absorption in normal subjects. We concluded that: (a) inhibition of phosphorus absorption by binders involves a complex interplay between chemical reactions and ion transport processes in the stomach and small intestine; (b) theoretical and in vitro studies can identify potentially better in vivo phosphorus binders; and (c) calcium acetate, not previously used for medical purposes, is approximately as efficient as aluminum carbonate gel and more efficient as a phosphorus binder than other currently used calcium salts.

Previous studies have emphasized the role of bile acid and fat malabsorption as the cause of the diarrhea that may follow ileal and right colon resection; unabsorbed bile acids and fat are believed to reduce sodium chloride and water absorption in the remaining colon. In this paper we report studies in eight patients with severe postresection diarrhea, in search of a more basic defect in sodium chloride absorption, ie, a loss of sodium chloride absorptive capacity as a direct consequence of resection of sodium chloride absorption sites. First, we determined whether or not diarrhea persisted during a 48-hr fast; in all patients diarrhea and large fecal electrolyte losses continued during a fast. Second, we measured sodium chloride and water absorption rates during total gut perfusion with a balanced electrolyte solution; compared to normal controls, the patients absorbed 23–31% less water, sodium, and chloride. In three patients who could be studied further, the absorptive defect was markedly accentuated when the perfusing solution was such that sodium chloride absorption had to take place against a concentration gradient. These observations indicate that postresection diarrhea patients have a reduced capacity to absorb sodium chloride, particularly when there is a concentration gradient between lumen and plasma. Although all of these patients had malabsorption of radiolabeled taurocholic acid, there was only a modest and statistically insignificant reduction in daily stool weight during treatment with large doses of cholestyramine, suggesting that bile acid malabsorption was not responsible for a major part of their diarrhea. We postulate that a loss of ileal and colonic absorptive capacity for sodium chloride rather than a cathartic effect of unabsorbed bile acids or fat is the major cause of diarrhea in these patients.

Phosphorus binders are given to patients with renal failure to increase gastrointestinal excretion of phosphorus. To determine the relative importance of the binding of dietary as compared with endogenous phosphorus and to determine the optimal dose schedule, we gave either 4.4 g of calcium acetate (25 mmol of calcium) or a placebo to six normal subjects on each of seven different schedules in a randomized sequence. The net gastrointestinal balance of phosphorus and calcium was determined by a one-day lavage technique. After a meal containing approximately 12 mmol of phosphorus, the mean phosphorus absorption (+/- SE) measured 9.17 +/- 0.36 mmol (78 percent) with placebo but decreased to 3.81 +/- 0.58 mmol (31 percent) when calcium acetate was given immediately before the meal (representing binding of 5.36 +/- 0.77 mmol of phosphorus). Similar binding was observed when calcium acetate was given immediately after the meal and when half the dose was given before and half after the meal. In contrast, when calcium acetate was given two hours after the meal or while the subject was fasting, phosphorus binding was reduced to 2.00 +/- 0.52 mmol and 1.81 +/- 0.84 mmol, respectively. Calcium absorption from calcium acetate averaged 21 +/- 1 percent when the binder was given with a meal; absorption from calcium acetate averaged 40 +/- 4 percent when the binder was given while the subject was fasting. We conclude that calcium acetate increases fecal excretion of phosphorus by binding both dietary and endogenous phosphorus, but the binding of dietary phosphorus is quantitatively much more important. For the most efficient phosphorus binding, calcium (and presumably other phosphorus-binding cations) should be given with meals.

The purpose of these studies was to gain insight into the pathophysiology of pure osmotic diarrhea and the osmotic diarrhea caused by carbohydrate malabsorption. Diarrhea was induced in normal volunteers by ingestion of polyethylene glycol (PEG), which is nonabsorbable, not metabolized by colonic bacteria, and carries no electrical charge. In PEG-induced diarrhea, (a) stool weight was directly correlated with the total mass of PEG ingested; (b) PEG contributed 40-60% of the osmolality of the fecal fluid, the remainder being contributed by other solutes either of dietary, endogenous, or bacterial origin; and (c) fecal sodium, potassium, and chloride were avidly conserved by the intestine, in spite of stool water losses exceeding 1,200 g/d. Diarrhea was also induced in normal subjects by ingestion of lactulose, a disaccharide that is not absorbed by the small intestine but is metabolized by colonic bacteria. In lactulose-induced diarrhea, (a) a maximum of approximate 80 g/d of lactulose was metabolized by colonic bacteria to noncarbohydrate moieties such as organic acids; (b) the organic acids were partially absorbed in the colon; (c) unabsorbed organic acids obligated the accumulation of inorganic cations (Na greater than Ca greater than K greater than Mg) in the diarrheal fluid; (d) diarrhea associated with low doses of lactulose was mainly due to unabsorbed organic acids and associated cations, whereas with larger doses of lactulose unmetabolized carbohydrates also played a major role; and (e) the net effect of bacterial metabolism of lactulose and partial absorption of organic acids on stool water output was done dependent. With low or moderate doses of lactulose, stool water losses were reduced by as much as 600 g/d (compared with equimolar osmotic loads of PEG); with large dose, the increment in osmotically active solutes within the lumen exceeded the increment of the ingested osmotic load, and the severity of diarrhea was augmented.

Various nonelectrolyte meal components such as glucose and lysine enhance gastrointestinal calcium absorption under experimental conditions. The effect of a mixed meal on Ca absorption from Ca supplements is unknown. The effect of glucose polymer on Ca absorption when ingested with food also is unknown. Using a single-day method, we measured net Ca absorption from Ca carbonate when ingested in fasting state, with a steak and potatoes meal, and with the meal and 50 g glucose polymer. Eight healthy human subjects were studied after a 500-mg elemental Ca dose. Mean net Ca absorption was 195 +/- 18 mg (4.87 +/- 0.45 mmol) fasting, 213 +/- 21 mg (5.31 +/- 0.52 mmol) with a meal, and 179 +/- 16 mg (4.47 +/- 0.40 mmol) with a meal plus glucose polymer. The differences are not statistically significant. In normal people Ca absorption from Ca carbonate was not significantly enhanced by a meal or by 50 g glucose polymer ingested with food.

We studied 16 patients with diabetes and fecal incontinence. The onset of incontinence coincided with the onset of chronic diarrhea in most patients. Episodes of incontinence occurred when stools were frequent and loose; however, 24-hour stool weights were usually within normal limits. All patients had evidence of autonomic neuropathy, and one third had steatorrhea. Incontinent diabetics had a lower mean basal anal-sphincter pressure than 35 normal subjects (63 +/- 4 vs. 37 +/- 4 mm Hg; P less than 0.001), reflecting abnormal internal-anal-sphincter function. The increment in sphincter pressure with voluntary contraction (external-sphincter function) was not significantly different from normal. Incontinent diabetics also had impaired continence for a solid sphere and for rectally infused saline. In contrast, 14 diabetics without diarrhea or incontinence had normal sphincter pressures and normal results on tests of continence, even though 79 per cent had evidence of autonomic neuropathy and nearly half had steatorrhea. We conclude that incontinence in diabetic patients is related to abnormal internal-anal-sphincter function, and that as a group, diabetics without diarrhea do not have latent defects in continence.

To determine whether the antidiarrheal action of opiate drugs in humans is due to enhanced intestinal absorption rates, as suggested by recent experiments in animals, or is due to altered intestinal motility, as traditionally thought, we studied the effect of therapeutic doses of codeine on experimental diarrhea and on the rate of intestinal absorption of water and electrolytes in normal human subjects. Our results show that codeine (30-60 mg i.m.) markedly reduced stool volume during experimental diarrhea induced by rapid intragastric infusion of a balanced electrolyte solution. There was, however, no evidence that codeine stimulated the rate of intestinal absorption in the gut as a whole or in any segment of the gastrointestinal tract, either in the basal state or when absorption rates were reduced by intravenous infusion of vasoactive intestinal polypeptide. We also measured segmental transit times to determine whether and where codeine delayed the passage of fluid through the intestine. Codeine caused a marked slowing of fluid movement through the jejunum, but had no effect on the movement of fluid through the ileum or colon. In other studies, we found that the opiate antagonist naloxone did not significantly affect water or electrolyte absorption rates in the jejunum or ileum. We conclude (a) that therapeutic doses of codeine increase net intestinal absorption (and thereby reduce stool volume) by increasing the contact time of luminal fluid with mucosal cells, not by increasing the rate of absorption by the mucosal cells; and (b) that endogenous opiates do not regulate intestinal absorption in humans.

The intravenous secretin test is widely used to distinguish gastrinoma (Zollinger-Ellison syndrome) from other causes of fasting hypergastrinemia. We report 2 patients with fasting hypergastrinemia and a rise of greater than 200 pg/ml in serum gastrin concentration after intravenous injection of 2 CU/kg body wt of pure natural secretin. Both patients had pentagastrin-fast achlorhydria. Thus, the intravenous secretin test may be positive in patients with achlorhydria-related hypergastrinemia. Gastric acid secretion should be measured in hypergastrinemic patients before embarking on a secretin test.

Gastrointestinal symptoms such as vomiting, constipation, diarrhea, and fecal incontinence occur frequently in patients with diabetes mellitus. In a survey of 136 diabetic outpatients, 76% had one or more gastrointestinal symptoms, the commonest symptom being constipation (found in 60%). In many cases these symptoms are thought to be due to abnormal gastrointestinal motility that, in turn, may be a manifestation of diabetic autonomic neuropathy involving the gastrointestinal tract. The pathophysiology of these gastrointestinal symptoms, clarified in recent studies, and the clinical features and treatment of these problems in diabetic patients are reviewed.