Twenty-seven patients with chronic diarrhea due to Crohn's disease, ulcerative colitis, short bowel syndrome, and idiopathic (functional) causes participated in a multiphase study (open, double blind, and long term open) of loperamide HCl, a new single entity, oral antidiarrheal agent. In the open phase of the study, loperamide effectively relieved symptoms of diarrhea in 21 of 27 patients. The average number of stools dropped from eight in the initial relapse period to two stools after 1 month of treatment (P = 0.0001). Efficacy was confirmed in the double blind and long term open phases of the study. Four patients who were not relieved while on therapy had discontinued the drug because of abdominal cramping. No other side effects attributable to the drug were observed. Loperamide has been found to be a safe and effective agent for the treatment of chronic diarrhea.

In 32 healthy male volunteers the effects on gastric secretion of three methyl analogues of prostaglandin (PG) E2 have been studied, namel, 15 (R) -15-methyl PGE2 methyl ester, 15 (S) -15-methyl PGE2 methyl ester, and 16, 16-dimethyl PGE2. Secretion was measured for 30 min and a PG analogue at doses ranging from 1.25 to 2.5 mug per kg or a placebo was administered. Gastric secretion was then stimulated either by an intravenous infusion of pentagastrin (2 mug per kg-hr) or by a peptone meal with acid secretion determined by intragastric titration technique. The tests were randomized and double blind. All three methyl PG analogues exhibited a profound and prolonged inhibitory action on gastric acid and pepsin secretion induced by pentagastrin. PG analogues caused almost complete inhibition of gastric acid response to a peptone meal accompanied by a significant reduction in the serum concentration of immunoassayable gastrin. Except with the highest dose of PG (S) -15-methyl PGE2 methyl ester, which caused abdominal discomfort and single episodes of diarrhea in some subjects, no symptoms or untoward biochemical effects were observed. It is concluded that these methylated PG analogues are very potent inhibitors of gastric acid and pepsin secretion stimulated by pentagastrin or a meal and may have clinical potential in the treatment of peptic ulcer.

Between 1968 and 1974, azathioprine has been used in a controlled prospective trial to treat patients with symptomatic but precirrhotic primary cirrhosis. Forty-five patients were admitted, of whom 22 were given azathioprine in a dose of 2 mg per kg of body weight. During the 1st year, serum aspartate transaminase levels showed a significant change in favor of the treated group, but improvement did not continue. Throughout the trial, serum alkaline phosphatase, bilirubin, cholesterol, albumin and immunoglobulin M values showed no significant change. Titers of serum mitochondrial antibodies tended to become negative more often in the treated than the untreated. Pruritus cannot be assessed objectively, but seemed less in the treated than in controls. Serial hepatic biopsy specimens showed the development of cirrhosis equally in the two groups. Survival, as judged by the life table method, was similar for the first 5 years of the trial. There was, however, a significant difference in favor of the treated group in the 6th year, although the number of patients available for assessment at that time was extremely small.

Lower esophageal sphincter (LES) pressure was evaluated in response to oral or intravenous metoclopramide in normal subjects and in patients with symptomatic gastroesophageal reflux. Both the oral and intravenous administration of metoclopramide gave a dose-related increase in LES pressure. Complete dose-response curves to the oral compound showed greater absolute responsiveness in normals as compared to patients with LES incompetence. The generally accepted oral dose of 10.0 mg of metoclopramide gave a slight increase in LES pressure which was not consistent in all symptomatic patients. These studies suggest that higher doses of metoclopramide may be required for treating symptomatic gastroesophageal reflux secondary to LES incompetence.

The effect of oral metoclopramide (15 mg), AlMgOH (30 ml), and placebo on the cumulative duration of gastroesophageal reflux induced by a protein-rich meal was compared in 15 patients with reflux esophagitis. Oral metoclopramide was found to be more effective than AlMgOH in reducing the cumulative duration of reflux after placebo over a 3-hr period. The same dose of oral metoclopramide increased resting lower esophageal sphincter pressures in all 15 patients for at least 1 hr and prevented gastroesophageal reflux after an intragastric acid load (300 ml of O.1 N HCl) in 8 of 10 of these patients. Oral metoclopramide, however, failed to increase the amplitude of esophageal contractions and acid clearing of the distal esophagus. These findings suggest that oral metoclopramide in the dose of 15 mg may be potentially valuable in the management of reflux esophagitis.

The standard preparation for cleansing the gastrointestinal tract for diagnostic studies such as barium enema usually involves dietary restrictions, purgatives, and cleansing enemas. This preparation is time consuming, often uncomfortable for the patient, and frequently unsuccessful. In this study, we examined the efficacy of saline lavage (without dietary restrictions or cleansing enemas) as a gentle, alternative method for cleansing the bowel, and compared lavage to the standard castor oil method of bowel preparation. Lavage cleansing was preferred by 75% of patients who had previously experienced a castor oil preparation. Although 11% of patients could not consume an adequate (4-liter) lavage volume, there was no significant difference in preparation success rate between the remaining lavage patients and the castor oil patients. Total preparation time for lavage (3 +/- 1 hr) was 60% less than for castor oil. The anticipated dehydration produced by castor oil and the hydration produced by lavage were confirmed. No significant changes were noted, however, in serum electrolytes with either method of preparation. Additional early studies are promising for the lavage method when used in inflammatory bowel disease patients and as a cleansing preparation for colonoscopy.

Ampicillin was tested with regards to its capacity to reduce gastric ammonia production in basal and betazole-stimulated gastric secretion. A 7-day course of oral ampicillin (4 g per day) reduced basal gastric ammonia concentration from 5.5 +/- 1.4 to 1.8 +/- 0.3 mM and postbetazole ammonia from 4.7 +/- 0.9 to 1.3 +/- 0.3 mM (P less than 0.01) in 7 control subjects. Similar results were obtained after oral neomycin (4 g per day) or intramuscular ampicillin (4 g per day), each given to a separate group of 7 control subjects. In 5 azotemic patients, oral ampicillin treatment resulted in a reduction of ammonia concentration from 16.3 +/- 4.7 to 3.1 +/- 0.7 mM in basal secretion and from 18.3 +/- 8.1 to 2.3 +/- 0.6 mM in betazole-stimulated gastric juice (P less than 0.01). Antibiotic therapy did not alter volume of gastric secretion. Gastric acidity appeared lower in azotemic patients and increased significantly after treatment, indicating that the higher ammonia content could account for at least part of the hypoacidity. Because ampicillin is active orally as well as parenterally and can be readily used in renal failure, it may be of value for the treatment of hepatic encephalopathy, especially in the azotemic patient in whom neomycin is toxic.

Older work in man with meals of carbohydrates in water has indicated that such meals slow gastric emptying in proportion to their osomolarities. Nevertheless, different carbohydrates have been found to have differing efficacies per milliosmole. One possibility which would explain such discrepancies among carbohydrates is that hyperglycemia induced by carbohydrate absorption itself contributes to the slowing of gastric emptying. To test this possibility, normal subjects were made acutely hyperglycemic with intravenous loads of glucose during the ingestion of various liquid test meals, and rates of gastric emptying of these meals were compared in the same subjects during periods of induced hyperglycemia with rates of gastric emptying under euglycemia conditions. Induced hyperglycemia significantly slowed the rate of emptying of meals containing fat + protein, or protein, but did not significantly alter emptying of meals containing only NaCl. It is concluded that hyperglycemia does exert some effect on gastric emptying, but that these effects of hyperglycemia are variably expressed, depending on the presence of other factors which themselves slow gastric emptying.

Bile acid kinetics were measured by isotope dilution, and hourly outputs of bile acid, cholesterol, and phospholipid were quantified by duodenal perfusion over 24 hr including three liquid meals and an overnight fast in 6 gallstone patients during a pretreatment period and two randomized treatment periods with chenodeoxycholic (chenic) acid or cholic acid. During chenic acid ingestion, bile contained predominantly chenyl conjugates. During cholic acid ingestion, bile was composed of about equal amounts of cholyl and deoxycholyl conjugates; chenyl conjugates decreased markedly due in part to a 50% decrease in chenic acid synthesis. Total bile acid pool size doubled in half the patients receiving either bile acid and was not different during treatment with chenic or cholic acid. Compared to cholic acid, chenic acid caused decreased cholesterol output with no difference in bile acid or phospholipid output. Therefore, bile unsaturated with cholesterol entered the duodenum for more hours per day during chenic acid ingestion than during the cholic or pretreatment periods. There was no relationship among bile acid pool size, bile acid output, and hours per day of supersaturated bile; there was an inverse relationship between total pool size and recycling frequency such that bile acid output remained stable over a wide range of pool sizes. Fasting-state gallbladder bile was supersaturated during the cholic and pretreatment periods, but became unsaturated during chenic acid ingestion. However, hours per day of supersaturated bile could not be reliably predicted from the degree of saturation of fasting-state gallbladder bile (r = 0.62). The efficacy of chenic acid and the lack of efficacy of cholic acid for gallstone dissolution appear related to their different specific effects on biliary cholesterol secretion and not to any effect on bile acid and phospholipid secretion or bile acid pool size.

This study was conducted to determine the effectiveness of transcranial electrotherapy (TCE) in reducing gastric secretion in man. TCE has been proposed as a therapeutic modality which induces a relaxed psychological state by the application of low intensity diffuse electrical current and has been purported by Soviet investigators to be beneficial in the treatment of peptic ulcers. Secretion rates were monitored in adult male volunteers by a method of intragastric titration utilizing a pH-sensitive telemetry capsule. In one study 5 subjects had their basal secretion rates monitored before, during, and after the application of TCE at graduated current intensities. A threshold of inhibition was observed for currents of 0.9 ma and greater. In a second study, 12 subjects had histamine-stimulated maximum acid output determined for control and during TCE application. Gastric acid secretion was reduced by an average of 30% when 1-ma TCE was applied, with individual reductions ranging from 5.7% to 53.2%. Since the application of relatively high TCE currents may produce discomfort in some subjects, a third study was conducted to determine whether the inhibition might not merely be the result of nonspecific noxious stimuli. For this study the electrical connections to the TCE electrodes were altered so that the same uncomfortable sensation was produced on the forehead, but no current was actually applied transcranially. This "placebo" TCE produced no reduction in the maximal acid output of 6 volunteers, but when the currents were applied transcranially, the gastric acid secretion was reduced by an average of 27% below control values.

The cause of pseudomembraneous colitis is not known but has been attributed to an alteration in the microbial flora of the colon. To test this hypothesis, a blind, prospective study was undertaken in which fecal samples were cultured quantitatively for aerobic and anaerobic organisms. The patients from which these samples were taken were all receiving clindamycin and had diarrhea secondary to the use of the drug. We were able to show definite differences in the colonic microflora which correlated with the presence of pseudomembranes on biopsy. Those patients who had diarrhea and pseudomembranous colitis showed a striking decrease, both quantitatively and qualitatively, in the number of anaerobes present. Those patients who had diarrhea but no pseudomembranes had large numbers of anaerobes which qualitatively approximated normal fecal cultures but quantitatively were fewer in number. A third group of patients, which had resolving pseudomembranous colitis, and were no longer symptomatic, had large numbers of anaerobic organisms which approximated those found in normal fecal cultures. There were no differences among the three groups with regard to facultative anaerobic microflora. Thus, the presence of pseudomembranous colitis correlated directly with a striking quantitative and qualitative decrease in the anaerobic microflora of the colon. The symptom of diarrhea alone appeared to have no meaning with regard to changes in the bacterial flora. Resolution of pseudomembranous colitis was associated with a return of the anaerobic microflora.

To determine the efficacy of azathioprine in the treatment of ulcerative colitis, a 6-month double blind trial was carried out. Thirty patients with chronic ulcerative colitis who required the equivalent of at least 10 mg of prednisone per day over the 3 months prior to entering the study were randomized into placebo and azathioprine (1.5 mg per kg) treatment groups. Reduction of steriods was a major objective of the trial. Age and sex distribution, number of bowel movements, sense of well being, steroid dosage, and findings on proctoscopy, rectal biopsy, and colon X-ray initially were similar in the two groups. No side effects were associated with azathioprine. Although steroid dose was lower (p less than 0.05) in the azathioprine group at the termination of the study, no difference between the two groups could be detected in the number of bowel movements, sense of well being, and findings on proctoscopy during the first 3 weeks compared with the last 3 and during the first 3 months compared with the last 3. Although azathioprine does not confer dramatic benefit upon patients with chronic ulcerative colitis who require steroids, it does permit reduction of steroid dosage without apparent worsening of the disease. Its major value in ulcerative colitis may be in facilitating significant decreases or complete discontinuance of steroids.

This study compares the efficacy of intravenous adrenocorticotropic hormone (ACTH) with intravenous hydrocortisone in the treatment of patients with symptomatic inflammatory bowel disease. Drug doses were pharmacologically equivalent on the basis of achieved plasma cortisol levels and continuously monitored urinary corticoid excretion rates. Drug selection and patient evaluation were accomplished with a random double blind technique. Evaluation of 22 consecutive hospital patients indicates that ACTH and hydrocortisone, when administered intravenously in pharmacologically equivalent dosage, are therapeutically equivalent, that response to ACTH is rapid, with no therapeutic lag, and that differences in therapeutic responses cannont be corrrelated with differences in systemic steroid levels.

Chloroquine and metronidazole were compared in a randomized trial for the treatment of amoebic liver abscess in 36 patients. An additional 30 patients were treated without randomization. Chloroquine was given according to the standard protocol at Los tangeles County-University of Southern California Medical Center, which is 500 mg daily for 10 weeks, whereas metronidazole was given in a dose of 750 mg three times daily for 10 days. Criteria for the diagnosis of amoebic abscess included (a) a suitable clinical picture, (b) filling defect on hepatic scan, (c) high titer of antibody to Entamoeba histolytica by indirect hemagglutination, and (d) eventual complete recovery with treatment or appropriate findings on autopsy examination. Treatment failure, defined as illness that persisted beyond 10 days or recurred after that time, occurred in 1 of 28 patients treated with chloroquine and in 2 of 36 treated with metronidazole. In 2 patients who died it was difficult to assess the result of drug therapy. We conclude that both drugs are highly effective. Metronidazole has the advantage of effectiveness against intestinal amoebiasis and the probability of cure with a shorter course of treatment. Speed of response was slightly greater with metronidazole and was somewhat related to abscess size.

The colonic concentrations of the combustible gases, H2 and CH4, were well below hazardous levels in 60 consecutive patients at the time of colonoscopy. Independent analysis of the effect of a low residue liquid diet, a 12-hr fast, and bowel cleansing on the pulmonary excretion of these gases suggest that the low colonic concentrations encountered were largely the result of our patient preparation procedure. Both ingestion of the liquid diet and fasting decreased the pulmonary excretion of H2 markedly but caused only a slight fall in CH4 excretion. Thus H2, but not CH4, production appears to depend on the delivery to the colonic bacteria of exogenous fermentable substrate. Bulk removal of bacteria from the colon resulted in about a 10-fold reduction in the excretion of both gases. The results of these studies do not support the need for routine CO2 insufflation prior to colonoscopic electrosurgical polypectomy.

A major criterion for the selection of patients with gallstones for treatment with chenodeoxycholic acid is the radiographic demonstration of lucent gallstones. In this study, we sought to evaluate the degree of selectivity of that criterion for distinguishing patients with cholesterol stones from those with pigment stones and to define the determinants of stone lucency or opaqueness. Of 92 lucent stones, 14% were pigment stones; and of 18 of opaque stones, 33% were cholesterol. Thus, the criterion of stone lucency allows inclusion of a significant number of subjects (14%) with lucent pigment stones, which may account for about one-half of the reported 33% incidence of treatment failures with chenodeoxycholic acid. Conversely, of patients with opaque stones, the one-third with cholesterol stones would be excluded from chenodeoxycholic acid treatment. Calcium is the major metal of both types of stones. However, opaque stones contain 6 times more calcium than lucent stones, which accounts for the difference in radiographic appearance.

The serum alkaline phosphatase was fractionated by polyacrylamide gel electrophoresis in 317 patients with elevated serum alkaline phosphatase activity. In 253 patients the source of the elevation was the isoenzyme of presumed liver origin, band L. In 87 of these patients, there was either no obvious liver disease or the alkaline phosphatase elevation was inappropriately high. In 19 of the 87, liver disease was further excluded by liver biopsy or by laparotomy. Because of this, biochemical studies were done to verify the hepatic origin of band L. Band L and alkaline phosphatase extracted from human liver migrated together on polyacrylamide gel electrophoresis before and after digestion with Vibrio cholerae neuraminidase. They had identical pH optima, sedimentation coefficients, Michaelis constants, and rates of inactivation at 55.5 degrees C. They had different rates of inactivation in 3 M urea. Over-all, the data indicate that band L is of liver origin, and that elevation of the hepatic alkaline phosphatase isoenzyme may be a nonspecific finding in certain patients.

The effects of oral metoclopramide, 10 and 20 mg, bethanechol, 25 mg, and placebo on lower esophageal sphincter pressure (LESP) were studied in 15 men with symptoms of gastroesophageal reflux and basal LESP less than 11 mm Hg. Each drug produced a significant increase in LESP when compared to placebo. Metoclopramide, 20 mg, produced a greater increase than either metoclopramide, 10 mg, or bethanechol, 25 mg. Serum gastrin concentrations were not altered by any of the drugs. Side effects were unremarkable. The LESP increasing effect of metoclopramide might be useful in treatment of gastro-esophageal reflux.

The purpose of this study was to measure the effect of alkaline intragastric pH on lower esophageal sphincter pressure (LESP) and on serum gastrin concentration in man. One hundred ten milliliters each of 0.1 N NaHCO3 and control solution were instilled into the stomach for 30 min in random order. Neither LESP nor serum gastrin were higher during the alkali instillation than during the control instillation. Individual subject's peak gastrin and peak LESP during the alkali period were not significantly higher than the corresponding basal values. We conclude that intragastric alkalinization did not increase total radioimmunoassayable serum gastrin concentration or LESP.