Measurement of the postprandial rate of acid delivery into the duodenum directly assessed the efficacy of two radically different acid-reducing therapies for duodenal ulcer disease. Cimetidine, 400 mg, with an ordinary solid meal decreased the 4-hr delivery of titratable acid and hydrogen ion into the duodenum by 63 and 86%, respectively (P less than 0.01 versus control). Liquid Maalox, 30 ml, 1 and 3 hr after an identical meal reduced 4-hr delivery of acid by 47 and 74%, respectively (P less than 0.01 versus control). During the study period, the H2 receptor antagonist effected a continuous reduction in gastric acidity and the delivery of acid into the duodenum. The liquid neutralizing antacid produced a more fluctuating decrease in these parameters. However, given in these dosages, the magnitude and duration of the acid-reducing effect were similar for both treatments.

To determine whether laxatives alter the proctoscopic and morphological appearances of the human rectum, 10 normal subjects were studied prospectively, and the following manipulations were assessed in a randomized, blinded manner: no treatment; oral mannitol to induce diarrhea; isotonic saline enema; Fleet's Phospho-Soda enema; and bisacodyl (Dulcolax), 10 mg, by enema or suppository. The rectal mucosa after mannitol-induced diarrhea, or after saline enema could not be distinguished from untreated rectum by proctoscopy, light microscopy, or scanning electron microscopy. Fleet's enema, and bisacodyl invariably changed proctoscopic appearances, and frequently altered light and scanning microscopic aspects. Both Fleet's enema and bisacodyl caused sloughing of surface epithelium. In addition, bisacodyl decreased the uptake of hematoxylin and eosin by crypt epithelial cells so that the affected cells had a partially erased appearance (16 of 25 biopsies examined by light microscopy). The lamina propria of 3 of these 25 biopsies contained polymorphonuclear cells. Transmission electron microscopy revealed that the abnormal crypt epithelial cells contained fewer cytoplasmic organelles and less nuclear chromatin. All lesions resolved within 7 days. Fleet's enema and bisacodyl by rectum may mislead the proctologist and the pathologist by altering normal rectal mucosa.

As part of a double blind, randomized trial evaluating D-penicillamine in primary biliary cirrhosis, we monitored urinary copper excretion and hepatic copper concentration during the 1st year of therapy in 46 patients with this disease. The retention of copper in primary biliary cirrhosis was confirmed by finding abnormally high levels of standard copper measurements in almost all patients before treatment. The hepatic copper was elevated in 43 of 45 patients, the urinary copper in 42 of 46, and the ceruloplasmin in 46 of 46. Urinary copper excretion correlated with the hepatic copper concentration (r = 0.68, P less than or equal to 0.001). No significant correlation occurred between hepatic copper and ceruloplasmin. Hepatic copper concentrations greater than 400 microng per g of dry weight were found almost exclusively in patients with advanced histological disease (P less than or equal to 0.01). Therapy with D-penicillamine and a low copper diet sustained increased urinary copper excretion for 1 year in almost all patients (P less than or equal to 0.001). Among patients taking placebo, the median hepatic copper concentration increased 13 microng per g of dry weight after 1 year. In contrast, among the patients taking D-penicillamine, the median hepatic copper concentration decreased 99 microng per g of dry weight (P less than or equal to 0.02). Continued observation of this therapeutic trial may help to clarify the relationship of copper retention and liver injury in primary biliary cirrhosis.

Progression of acute type B hepatitis to chronic liver disease and cirrhosis is well recognized, whereas no progression of acute type A hepatitis has as yet been documented. The natural history of acute non-A, non-B hepatitis has not been previously characterized. Ten cases of chronic liver disease were identified in 44 cases of acute non-A, non-B post-transfusion hepatitis. Age, sex, severity of acute illness, and prevalence of preoperative antibodies to known hepatitis-producing agents did not differ between the group whose hepatitis progressed to chronicity and the group whose hepatitis resolved. Less progression of acute hepatitis to chronic liver disease was seen in those patients receiving immune serum globulin preoperatively than in those receiving an albumin placebo (P = 0.009). Only 3 patients had clinical symptoms of hepatitis at the time of liver biopsy, and elevations of liver enzymes and gamma-globulin were mild. However, liver biopsy specimens in 8 of 10 patients showed chronic active hepatitis and an additional biopsy specimen showed cirrhosis. Acute non-A, non-B post-transfusion hepatitis often progresses to chronic active hepatitis. Preoperative gamma-globulin prophylaxis significantly reduces this progression. Identification and characterization of this viral agent(s) will further aid in the prevention of this undesirable complication of blood transfusion.

A randomized double blind clinical comparison of neomycin and lactulose was performed in 33 cirrhotic patients with chronic portal-systemic encephalopathy (PSE) at seven cooperating hospitals. In order to maintain double blindness, sorbitol syrup was used as a control solution along with neomycin and was compared with lactulose syrup and placebo tablets in a double drug protocol. Twenty-nine patients were studied in a crossover investigation in which each received both therapeutic regimens preceded and followed by control periods. Four additional patients received one or the other agent, but did not receive both. Serial, semiquantitative assessments were made in all patients of mental status, asterixis, and the trailmaking test (TMT) and electroencephalograms (EEG) and arterial ammonia levels. Both neomycin-sorbitol and lactulose were effective in the majority of patients (83 and 90%, respectively). Each of these parameters (mental state, asterixis, TMT, EEG, and NH3) was improved significantly by neomycin-sorbitol and lactulose. The post-treatment levels for each of these measures were similar in the neomycin and lactulose-treated groups. Mean stool pH was reduced by neomycinsorbitol to 6.1 and by lactulose to 5.5. This difference was highly significant statistically. Bowel activity was similar in the two groups. Both drugs were free of toxicity. These investigations demonstrate that both lactulose and neomycin-sorbitol are effective in the treatment of chronic portal-systemic encephalopathy.

The effect of nitroglycerine and long acting nitrites was studied in a group of 8 normal control subjects and 12 patients with esophageal spasm. The objective response of the esophagus to these drugs was recorded by obtaining esophageal manometric studies and was correlated with response in clinical symptoms. In 7 patients who had significant gastroesophageal reflux associated with spasm, the response to nitroglycerine was unpredictable. But in the group of 5 patients with diffuse esophageal spasm without gastroesophageal reflux, the response was uniformly good. All of the patients who responded to nitroglycerine also responded to long acting nitrites. These 5 patients, who were placed on long term management with long acting nitrites, remained symptom-free from 6 months to 4 years. None of them had recurrence of symptoms while they were on long acting nitrite therapy. The study suggests that if esophageal spasm is associated with reflux, the use of nitrites is less effective in controlling spasm than it is in those who do not show this association, and that diffuse esophageal spasm can be effectively managed with long acting nitrites on a long term basis in the absence of reflux. If there is esophageal spasm associated with reflux esophagitis, nitrites may be beneficial as an adjunct to antireflux therapy.

Pancreatic bicarbonate secretion and plasma secretin were measured in response to graded amounts of hydrochloric acid (0.94, 1.88, 3.75, and 7.5 mEq per 5 min) instilled directly into the duodenum in duodenal ulcer patients and in normal subjects. These graded amounts of acid produced graded increases in pancreatic bicarbonate in both groups. Mean bicarbonate secretion was significantly greater in the duodenal ulcer patients than in the normal subjects basally and after the lowest dose of hydrochloric acid. Mean (+/- SE) peak 30-min bicarbonate output (in milliequivalents) after duodenal acidification was 3.0 +/- 1.0 in the duodenal ulcer patients and 2.1 +/- 0.6 in the normal subjects (P less than 0.5). A significant (P less than 0.05) increase in plasma secretin occurred after duodenal acidification, but the increase in the duodenal ulcer and normal subjects was not significantly different (P less than 0.2). These results indicate that pancreatic bicarbonate secretion and increase in plasma secretin in response to graded amounts of duodenal acid are at least as great in patients with duodenal ulcer as in normal subjects.

Crude preparations of hog gastric intrinsic factor or their own previously collected gastric juices administered with labeled vitamin B12 did not enhance vitamin B12 absorption in patients with vitamin B12 malabsorption secondary to pancreatic insufficiency. However, when these sources of gastric intrinsic factor were incubated with three times crystallized preparations of insolubilized bovine trypsin or chymotrypsin, the proteolytic enzymes were removed by centrifugation, and the preparations of gastric intrinsic factor were readministered to these patients, the absorption of vitamin B12 was markedly enhanced. Studies of hog gastric intrinsic factor before and after exposure to proteolytic enzymes failed to show any difference on Sephadex chromatography or polyacrylamide gel electrophoresis or on its affinity for vitamin B12 or the ileal receptor in guinea pigs. These investigations demonstrate that: (1) gastric intrinsic factor as secreted by subjects with pancreatic insufficiency or obtained from hog pyloric mucosal extracts is ineffective in promoting vitamin B12 absorption in patients with pancreatic insufficiency, (2) incubation of crude preparations of gastric intrinsic factor with insolubilized pancreatic proteases modified these preparations of gastric intrinsic factor in an as yet undefined manner, allowing them to enhance vitamin B12 absorption, and (3) in vitro studies using gut sacs or brush border preparations do not reflect the abnormality in vitamin B12 absorption associated with pancreatic dysfunction.

The effect of deoxycholate ingestion, 750 mg per day, on bile acid kinetics, biliary bile acid composition, and biliary lipid secretion was studied in 7 healthy volunteers. Bile acid kinetics were measured by isotope dilution, and hourly outputs of bile acid, cholesterol, and phospholipid were quantitated by a duodenal perfusion technique during a 24-hr period which included three liquid meals and an overnight fast. Biliary bile acid composition was assessed by coupled gas chromatography-mass spectrometry. After deoxycholic acid ingestion, biliary bile acids became composed of predominantly deoxycholyl conjugates, and deoxycholic acid pools increased 4-fold. Both chenodeoxycholic and cholic acid pools decreased, and daily synthesis of each of the primary bile acids was inhibited by 50%. Total bile acid pools did not change in any consistent manner. Daily bile acid secretion increased slightly during deoxycholic acid ingestion, and recycling frequency varied reciprocally with the total bile acid pool both before and during deoxycholic acid treatment. Deoxycholic acid ingestion caused no change in either the daily secretion of cholesterol or lecithin, or the cholesterol saturation of fasting-state bile, which remained unsaturated throughout the study. SGOT levels increased to 4 times the upper limits of normal in 2 of 7 subjects, but these levels promptly returned to normal when deoxycholate feeding was stopped. Serum cholesterol levels decreased in every subject (average 15%) during deoxycholic acid administration. No evidence for a direct role of deoxycholate in the pathogenesis of cholesterol cholelithiasis was obtained in these studies.

In 5 patients with portal hypertension caused by schistosomiasis, the sinusoidal pressure (wedged hepatic pressure) varied from 20.7 to 35.4 mm Hg. While the catheter was in an occluded position within the hepatic vein and the patients were undergoing splenectomy, the main trunk of the hepatic artery was clamped. The sinusoidal pressures then fell to levels that varied from 3.7 to 7.4 mm Hg but returned to previous levels when the clamping was released. Wedged hepatic venous pressure levels, which were significantly greater than portal venous pressure values, decreased minimally after splenectomy. Portal venous pressure levels, however, fell to 63% of presplenectomy levels. In a control case with an enlarged spleen (cavernous hemangioma, but with a normal liver, the wedged hepatic pressure was 7.4 mm Hg and showed no alteration after clamping of hepatic artery. These data point out the importance of hepatic artery hypertrophy, that has already been demonstrated in other studies, in causing elevation of the wedged hepatic pressure in advanced hepatic schistosomiasis.

A double blind, randomized, controlled trial has been conducted in 11 Veterans Administration hospitals during a 49-month period to compare the relative efficacies of immune serum globulin (ISG) and an albumin placebo for the prevention of post-transfusion hepatitis (PTH). A total of 2204 patients, of whom 1094 received ISG, participated in the study. The results indicate that ISG significantly reduced the incidence of icteric type non-B hepatitis only (inferred to be also type non-A hepatitis). Adverse reactions were rare, and the ISG did not significantly alter the incubation period or duration of the disease. The data suggest, however, that a similar reduction in type non-A, non-B hepatitis would have occurred had commercial blood been excluded from use. Analysis of the 241 patients who developed hepatitis indicates that type B hepatitis constituted less than 20% of the cases each year of the study. Furthermore, the efficacy of the ISG, manufactured in 1944, against apparent type non-A, non-B hepatitis suggests that this overlooked disease has existed from at least that time. Host- and transfusion-related factors that might have modified the development of PTH were examined. The use of commercial blood was observed to be the most important risk factor. It is concluded that the PTH incidence can be most effectively reduced by eliminating commercial donor blood, and continuing to screen volunteer donors for hepatitis B surface antigen (HBsAg) by sensitive procedures. Of prime importance is the need to define the agent(s) responsible for type non-A, non-B hepatitis.

The effectiveness of antacid and placebo in relieving single episodes of spontaneous duodenal ulcer pain were compared in two double blind, controlled, randomized trials. The trials compared the effects on ulcer pain of individual doses of a liquid antacid and placebo, rather than the effects of therapeutic regimens with antacid or placebo. Thirty patients were studied. There were no significant differences between antacid and placebo in time to onset, degree, or duration of pain relief. These results suggest that factors other than gastric acid neutralization are important in acute relief of spontaneous duodenal ulcer pain.

Histamine H2-receptor antagonists are potentially useful agents in duodenal ulcer and knowledge of their effect on postprandial digestive events will contribute to their clinical application. We studied the effect of 200- and 300-mg doses of cimetidine, an H2-receptor antagonist, taken with an ordinary meal, on gastric, pancreatic, and biliary function. Both doses significantly reduced acid output and its delivery into the duodenum. Gastric secretory volume and pepsin output were less affected. Acid inhibition was related to blood drug levels and was less than that previously found at night in nocturnal fasting studies. As the stomach emptied the food, the gastric pH rose. The fractional gastric emptying rate, pancreatic enzyme, and bile acid outputs were unaltered. Cimetidine taken orally with meals at these doses is a potent gastric antisecretory agent without affecting other postprandial gastric, pancreatic, or biliary functions.

Anithistamines that specifically block the gastric and secretory action of histamine have recently been developed. One of these H2-receptor blockers, metiamide, has been found to increase lower esophageal sphincter (LES) pressure in the opossum. Because of reported agranulocytosis with metiamide, another H2-receptor blocking agent, cimetidine, was developed. To determine its effect on LES pressure, 8 normal volunteers received placebo or oral doses of cimetidine (50, 100, 200, and 400 mg) in a random, blinded manner. Indicative of adequate absorption, significant serum levels were achieved with all doses of cimetidine (50 mg = 0.17 mug per ml; 100 mg = 0.33 mug per ml; 200 mg = 0.76 mug per ml; and 400 mg = 1.61 mug per ml). Although these serum levels have been found to produce marked inhibition of gastric acid secretion, no discernible effect was found on LES pressure when compared to placebo. Thus cimetidine does not increase LES pressure. It does not decrease sphincter pressure either and is therefore not contraindicated in patients with reflux esophagitis.

Intravenous metoclopramide (M) was compared to placebo (P) by a double blind crossover design to determine whether M was superior to P in difficult cases of intubation of the small intestine, using a multipurpose biopsy tube and capsule. Metoclopramide decreased intubation time in 20 volunteers successfully intubated with M and P (P less than 0.05). Of 9 subjects, 8 were intubated to ligament of Treitz with M but not with P (P less than 0.01). Of 29 volunteers, 22 were successfully intubated by 15 min when M was given, but only 9 of the 29 could be intubated in 15 min with P (P less then 0.001). Of 29 volunteers receiving M, 9 experienced side effects but none were serious. This study demonstrated that M is superior to P in decreasing intubation time of a small intestinal biopsy capsule and is particularly useful in patients who may not otherwise be sucessfully intubated.

Thirty-five patients with active duodenal ulceration were included in a double blind randomized trial, the antiulcer agent sodium amylosulfate (Depepsen), being compared with placebo. Diagnosis and healing were determined by duodenoscopy. Results showed, in the whole series, 13 of 18 patients treated with Depepsen healed, whereas 10 of 17 healed on placebo (P = 0.04). In the group of 23 outpatients, 6 of 11 healed on Depepsen, and 5 of 12 healed on placebo (P = 0.55). It was concluded that Depepsen did not accelerate the healing of duodenal ulcer.

A double blind study of 111 consecutive elective upper gastrointestinal endoscopies performed with a flexible fiberoptic esophagogastroduodenoscope was made to determine the efficacy of topical pharyngeal anesthesia with lidocaine as an adjunct to intramuscular meperidine, intramuscular atropine, and intravenous diazepam. Patients who received lidocaine rated the over-all endoscopy and passage of the endoscope significantly easier than did those receiving placebo. The endoscopist found that patients who received lidocaine tolerated endoscopy significantly better, although gagging was not affected.

Sixty consecutive patients, who were deeply jaundiced or in whom intravenous cholangiography had failed, were randomized to retrograde endoscopic cholangiography or percutaneous transheptic cholangiograhy with the "skinny" Chiba needle technique. Twenty-eight patients were assigned to retrograde cholangiography, which succeeded in 17 (65%). Percutaneous cholangiography was successful in 16 (50%) of the remaining 32 patients. When patients in whom the first procedure was unsuccessful were reinvestigated by the alternative technique, retrograde cholangiograms were obtained in 13 (81%) of 16, and percutaneous cholangiograms in 8 (73%) of 11. Thus, one or the other technique was successful in 54 (90%) of 60 patients. When the results were analyzed separately for extrahepatic (29 patients) or intrahepatic (31 patients) cholestasis, percutaneous cholangiography was successful in 95% of patients with extrahepatic cholestasis but in only 25% with intrahepatic cholestasis. Endoscopic retrograde cholangiography successded in 63% of patients with extrahepatic and 76% with intrahepatic causes of cholestasis. Complications occurred only in patients with extrahepatic cholestasis. Cholangitis and septicemia occurred in 1 patient after retrograde cholangiography and in 2 after the percutaneous technique. An intraperitoneal bile leak occurred in one other patient after percutaneous cholangiography. Percutaneous cholangiography with the narrow needle is a simple, inexpensive, and reliable method for demonstrating the biliary system and is usually successful when an extrahepatic cause of cholestasis is present. The occurrence of serious complications in patients with extrahepatic cholestasis, despite prophylactic antibiotics, makes provision for early surgery mandatory after both techniques.

Meal-stimulated acid secretion, measured by in vivo intragastric titration, was progressively inhibited by increasing oral doses of cimetidine (25 to 400 mg). Four hundred milligrams suppressed acid secretion by 73% for the first 3 hr after the meal, whereas it inhibited acid secretion by 94% during the 30-min period of maximal inhibition. The dose of cimetidine required to suppress acid secretion by 50% during the 30-min period of maximal inhibition was 25 mg. The duration of action of a 300-mg dose was at least 7 hr. Cimetidine was equally effective in inhibiting meal-stimulated acid secretion at two physiological intragastric pH levels (5.0 and 2.5). Cimetidine had no effect on serum gastrin concentration when intragastric pH was maintained at 5.0, but when pH was allowed to seek its own level, serum gastrin concentration was higher after cimetidine than after placebo. Cimetidine had no effect on gastric emptying. No side effects were noted in any patients.

Loperamide, a novel antidiarrheal agent, was compared with diphenoxylate in a double blind crossover study of 23 patients with chronic diarrhea of various etiologies. Both agents were found to be capable of controlling or greatly reducing chronic diarrhea. Loperamide was superior to diphenoxylate in its abiltiy to decrease the frequency and improve the consistency of the stools, even at a 2.5-fold lower dose level.