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.

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.