Sixty-six outpatients with active ulcerative colitis who were intolerant of sulfasalazine were treated in a double-blind randomized trial. They received placebo or olsalazine sodium in daily doses of 0.75, 1.5, or 3 g. Overall, 35% of patients receiving olsalazine improved clinically, compared to 16% of patients receiving placebo. When the colitis activity at study entry was compared with that observed at the completion of the study period, statistically significant or nearly significant improvement was demonstrated within the combined olsalazine group (p = 0.01) and within patient groups receiving olsalazine at daily doses of 1.5 g (p = 0.04) and 3 g (p = 0.055). A dose-response relationship was suggested because 16%, 29%, 27%, and 50% of patients improved in the placebo and 0.75-, 1.5-, and 3-g olsalazine groups, respectively, (p = 0.04). A similar pattern of improvement was seen when sigmoidoscopic criteria were used, although a dose-response relationship was not demonstrated. There were no differences between the treatment and placebo groups for any of the adverse effects or laboratory variables reported at baseline or during the trial period. Four patients were withdrawn because of adverse reactions: 2 developed a skin rash while receiving olsalazine and 2 had diarrhea, one while on olsalazine and the other while on placebo. The data suggest that olsalazine is effective for the treatment of ulcerative colitis and is well tolerated among patients intolerant to sulfasalazine.

In this review, we compared the outcome of 25 studies of experimentally induced pancreatitis in animals with 13 studies of human acute pancreatitis in which the same therapeutic agents were used (aprotinin, glucagon, 5-fluorouracil, somatostatin, peritoneal lavage). Whereas 81% of the animal studies had a positive outcome (improvement in survival), only 7.7% of the human studies showed a positive outcome on survival. Most animal studies suffered from a protocol in which treatment was not significantly delayed after induction of acute pancreatitis. Of the 12 human studies that showed no effect of treatment on survival, none had sufficient statistical power (1 - beta error) for the investigators to have confidence in the negative outcomes. This was due to the fact that the studies had too few patients or that the event rates in the untreated populations were too low. Only five of the human studies reported the complication rates of acute pancreatitis in patients who did not die of their disease. Treatment (by any agent) did not improve the complication rate in these studies, but only one of the five reports had sufficient statistical power for the investigators to have confidence in these negative results. Large multicenter studies with sufficient numbers of patients with severe pancreatitis (high mortality and complication rates) are needed to evaluate new therapies in this disease.

In a prospective controlled study, 68 patients undergoing maintenance sclerotherapy were randomized to have intravariceal sclerotherapy based on either manometric assessment (n = 35) or visual assessment (controls, n = 33) of varix patency. For manometric assessment, a perfused variceal needle punctured each variceal column and, if low pressures fluctuating with respiration were obtained, the varix was injected. Control patients had patent varices injected based on visual assessment alone. During a mean follow-up of 13 mo (range 4-16 mo), 1 manometrically assessed patient bled once (0.002 bleeds/patient month) and 7 visually assessed patients bled 14 times from varices (0.03 bleeds/patient-month) (p less than 0.05). Two and nine episodes of ulceration occurred in manometric and visually assessed patients, respectively, (p less than 0.05). Varices were obliterated (i.e., disappeared) in 11 patients undergoing manometric assessment and in 2 patients undergoing visual assessment (p less than 0.01). Comparing results of visual and manometric assessment within "manometric" patients showed a consistent 25% error rate in diagnosing patency or thrombosis by visual assessment. Manometric assessment of varices during maintenance sclerotherapy reduces rebleeding and ulceration to very low levels.

The combination of laser with endoluminal 192-iridium radiation for the palliation of malignancies of the oesophagus and the cardia has been introduced to overcome the short-lived effect of laser treatment alone. Concluding from early experience, this method seems to prolong the effect of laser treatment alone, with a low risk of complications. However the initial optimistic results, claiming a permanent relief of dysphagia in 80% of the patients, cannot be reproduced under prospective conditions. The combination of laser and 192-iridium radiation with other palliative methods, such as external radiation and/or chemotherapy is feasible and remains to be studied in a comparative way.

Isosorbide dinitrate, a long-acting organic nitrate, has been shown to decrease portal pressure in the experimental animal and humans. We conducted a double-blind randomized hemodynamic evaluation of the effects of placebo and 10 mg and 20 mg isosorbide dinitrate in stable individuals with alcoholic cirrhosis. Baseline values for all three groups were similar. Isosorbide dinitrate resulted in a peak reduction of the hepatic venous gradient of 24.7% +/- 3.0%, with significantly decreased values 4 h after the administration of the 20-mg dose. A reduction of arterial pressure and cardiac index (peak decrease of 25.7% +/- 1.5%) was well tolerated by 13 of 15 patients. Changes in mean arterial pressure were not predictive of modifications in the hepatic vein wedge pressure. There was no relation between the area under the plasma isosorbide dinitrate concentration curve and hemodynamic changes. Levels of isosorbide-5-mononitrate, a vasoactive metabolite, were detectable for an 8-h period. Isosorbide dinitrate significantly reduced portal pressure in stable cirrhotics, in association with systemic hemodynamic changes. Thus, titration of isosorbide dinitrate is required to maximize hemodynamic benefits in individual patients. As the decrease in portal pressure is more predictable than the effect of previously tested pharmacologic agents, isosorbide dinitrate should be evaluated for its efficacy in the management of portal hypertension.

The effects of cisapride on gastric emptying, esophageal emptying, and gastrointestinal symptoms were evaluated in 8 patients with progressive systemic sclerosis who had delayed gastric emptying of the solid or liquid component of a meal, or both. A double-isotope technique was used to measure gastric emptying, and esophageal emptying was measured as the time for a bolus of the solid meal to enter the stomach. Gastrointestinal symptoms were assessed by a questionnaire. On 2 days each patient received cisapride (10 mg) or placebo intravenously, 5 min before an esophageal and gastric emptying test. After these 2 days each subject took cisapride (10 mg q.i.d., p.o.) for 1 mo. Cisapride improved solid and liquid gastric emptying (p less than 0.001), but had no significant effect on esophageal emptying (p less than 0.1). Upper gastrointestinal symptoms were reduced after cisapride (p less than 0.001), and no side effects were reported. These results indicate that gastroparesis is a treatable cause of morbidity in progressive systemic sclerosis.

To investigate whether paracentesis could be an alternative therapy for ascites, 117 cirrhotics with tense ascites were randomly allocated into two groups. Fifty-eight patients (group 1) were treated with paracentesis (4-6 L/day until disappearance of ascites) and intravenous albumin infusion (40 g after each tap). Fifty-nine patients (group 2) were treated with spironolactone (200-400 mg/day) plus furosemide (40-240 mg/day). Patients from group 2 not responding to diuretics were treated with a LeVeen shunt. After disappearance of ascites, patients from both groups were discharged from hospital and were instructed to take diuretics. Patients developing tense ascites during follow-up were readmitted to hospital and treated according to their initial schedule. Paracentesis was effective in eliminating the ascites in 56 patients from group 1 (96.5%) and did not induce significant changes in renal and hepatic function, plasma volume, cardiac index, peripheral resistance, plasma renin activity, plasma norepinephrine and antidiuretic hormone concentration, and urinary excretion of prostaglandin E2 and 6-keto-prostaglandin F1 alpha. Diuretics were effective in eliminating the ascites in 43 patients from group 2 (72.8%) (p less than 0.05). Ten patients in group 1 and 36 in group 2 developed complications during their first hospital stay (p less than 0.001). This difference was due to the significantly higher incidence of hepatic encephalopathy, renal impairment, and electrolyte disturbances occurring in patients treated with diuretics. The duration of hospital stay was 11.7 +/- 1.5 days for patients from group 1 and 31 +/- 2.8 days for patients from group 2 (p less than 0.001). The two groups did not differ significantly with respect to the probability of requiring readmission to hospital during follow-up, reasons for readmission, survival probability after entry into the study, and causes of death. These results indicate that paracentesis associated with intravenous albumin infusion is a fast, effective, and safe therapy for ascites in patients with cirrhosis.

Placebo-controlled trials are not available to assess the efficacy of smooth muscle relaxants in the treatment of painful esophageal motility disorders. Therefore, we compared the effects of oral nifedipine (10-30 mg t.i.d.) and placebo in 20 patients (mean age 50 yr) with chronic noncardiac chest pain and the nutcracker esophagus in a 14-week double-blind crossover study. Compared to placebo, nifedipine significantly decreased distal esophageal contraction amplitude (mean +/- SEM, 198 +/- 11 mmHg to 123 +/- 9 mmHg; p less than 0.005), as well as duration and lower esophageal sphincter pressure. Nifedipine, however, was no better than placebo in the relief of daily chest pain frequency, severity, or index (frequency X severity) as assessed by patient diaries. Despite these disappointing results, long-term follow-up (mean, 16.6 mo) suggests these patients do improve. Mean daily chest pain index significantly (p less than 0.005) decreased from 10.3 +/- 2.0 at the beginning of the study to 3.2 +/- 0.8 at follow-up. Prescription drug use and physician visits for chest pain also significantly decreased. Distal esophageal contraction pressures significantly fell during the long-term follow-up but there was poor correlation with chest pain improvement. This study suggests that identification of the esophagus as the cause of chest pain coupled with supportive intervention may be more effective than drug therapy in improving these patients' chest pain.

The effect of the metenkephalin analogue Hoe 825 on esophageal motility, fundic accommodation to distention, and migrating myoelectric complex was studied in 17 healthy volunteers. The metenkephalin analogue (40 micrograms i.v.) significantly increased the duration, amplitude, and propagation velocity of the postdeglutitive esophageal peristaltic contraction waves. It had no effect on the basal lower esophageal sphincter pressure but significantly decreased the completeness of the sphincteric relaxation from 85% +/- 5% on placebo to 70% +/- 7% (p less than 0.01). The metenkephalin analogue (40 micrograms i.v.) significantly decreased the fundic accommodation to distention. In doses ranging from 20 to 60 micrograms i.v. it induced a premature phase III of the migrating motor complex that started ectopically in the duodenum (without a gastric component) and migrated distally at a significantly higher velocity than a spontaneous phase III. It is hypothesized that the metenkephalin analogue induces these effects via an inhibition of the inhibitory nervous system.

The effects of cyclooxygenase inhibition by indomethacin on gastric acid secretion were studied in 8 healthy men. Oral doses of indomethacin (200 mg), administered 15 and 2 h before testing, were known to inhibit prostaglandin synthesis by 90% in 3 of the subjects as determined by prostaglandin E2 generation assay on endoscopically obtained gastric mucosal biopsy specimens. Acid-induced inhibition of gastric acid secretion was evaluated in a randomized and blinded study in which acid output was measured for 2 h during basal conditions by aspiration, for the next 2 h by intragastric titration during distention with isotonic glucose, and for the following 2 h by intragastric titration during meal stimulation with peptone. The studies were done on separate days, and intragastric pH was maintained at either 2.5 or 5.5 after administration of indomethacin or placebo. Basal acid output was not altered by indomethacin treatment. Distention of the stomach stimulated acid output significantly to a similar degree in all groups, without affecting plasma gastrin. Meal stimulation increased plasma gastrin and acid output significantly more at pH 5.5 (47 +/- 12 pM, 13 +/- 2 mmol/30 min) than at pH 2.5 (30 +/- 8 pM, 6 +/- 2 mmol/30 min). No effect of indomethacin treatment was observed. It is concluded that the participation of cyclooxygenase products in the mechanisms by which acid inhibits the gastric phase of acid secretion in humans is likely to be minor. These results also cast doubt on an important physiologic role for cyclooxygenase products in the regulation of basal acid secretion or of acid secretion stimulated by distention or a peptone meal.

The effects of cisapride on gastric emptying, esophageal emptying, gastrointestinal symptoms, and glycemic control were evaluated in 20 insulin-dependent diabetics who had delayed gastric emptying of the solid or liquid component of a meal, or both. A double-isotope technique was used to measure gastric emptying, and esophageal emptying was measured as the time for a bolus of the solid meal to enter the stomach. On 2 days each patient received cisapride (20 mg) or placebo orally, 60 min before an esophageal and gastric emptying test. A third gastric and esophageal emptying test was performed after each patient had orally taken 10 mg of cisapride or placebo q.i.d. for 4 wk. Single-dose cisapride increased esophageal emptying (p less than 0.01) and both solid and liquid gastric emptying (p less than 0.001). The response to cisapride was most marked in patients with the greatest delay in esophageal and gastric emptying (p less than 0.05). After administration of cisapride for 4 wk, gastric emptying of solid and liquid were faster (p less than 0.001), but esophageal emptying was not significantly different from the placebo test. Upper gastrointestinal symptoms were less after cisapride (p less than 0.05), whereas there was no change on placebo (p greater than 0.2). Plasma glucose and glycosylated hemoglobin concentrations were not different after cisapride compared with placebo. These results indicate that single-dose cisapride increases esophageal emptying in insulin-dependent diabetics and that chronic administration of cisapride is effective in the treatment of diabetic gastroparesis.

The efficacy and safety of 4-g 5-aminosalicylic acid enemas were assessed in 153 patients with ulcerative colitis involving up to 50 cm of distal colon. Seventy-six patients received active medication and 77 received a placebo. There were 20 dropouts (6 in the active group and 14 in the placebo group) during the study because of insufficient efficacy. After 6 wk of therapy, 48 of the 76 patients (63%) receiving 5-aminosalicylic acid were considered to be "much improved" by the study physician compared to 22 of the 77 patients (29%) on placebo (p = 0.001). A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mean disease activity index declined 55% for patients on 5-aminosalicylic acid and 24% for patients on placebo (p = 0.0001). Analysis of subgroups indicated that patients most likely to respond were those with disease confined to the 20-40 cm from the anus. Response was not affected by concurrent sulfasalazine, but patients requiring concurrent oral steroids had a diminished response. Rapid onset of efficacy was shown by a significant reduction in rectal bleeding within 3 days of treatment initiation. 5-Aminosalicylic acid enemas are well tolerated and are of benefit in the treatment of ulcerative colitis confined to the distal colon.

The metabolism of synthetic human sulfated heptadecapeptide gastrin (G-17) was studied in normal human volunteers. Plasma concentrations were measured by radioimmunoassay using antibodies specific for intact G-17, and for the C- and N- terminus of G-17, during and after infusion of both sulfated and unsulfated G-17. With all three antibodies, plasma concentrations at a steady state were higher during infusion of sulfated compared with unsulfated G-17. In addition, the half-life in plasma measured by the three antibodies was two to five times higher for sulfated G-17 compared with unsulfated G-17. The half-life measured by N-terminal-specific antibodies was greater than that with antibodies specific for C-terminal or intact G-17. The difference was accounted for by the production during infusion of N-terminal fragments of relatively long half-life. The pattern of fragments generated during infusion of sulfated G-17 resembled that during unsulfated G-17 infusion, but there was no evidence of desulfation in the systemic circulation. The results indicate that in humans, sulfation protects G-17 from metabolism.

A unicenter, single-blind, randomized study was conducted on 283 patients with active duodenal ulcer to compare possible factors that may affect healing and relapse in patients treated with a potent antisecretory agent, cimetidine, or a site-protective and cytoprotective agent, sucralfate. The endoscopic healing rates at 4 wk were 76% and 79%, respectively, and cross-over treatment of the failures for a further 4 wk resulted in 68% healing with cimetidine and 69% healing with sucralfate, both differences being not statistically different. Unlike cimetidine, healing by sucralfate was unaffected by cigarette smoking, reluctance to give up smoking, habitual use of alcohol, high maximal acid output, and large ulcer diameter. In particular, the healing rate of smokers treated with sucralfate (82%) was significantly greater than that of smokers treated with cimetidine (63%). Duodenal bulb deformity significantly affected healing in both groups, and was the only offsetting factor identifiable for sucralfate out of 46 factors examined. Of the patients with healed ulcers, 238 participated in a 24-mo follow-up study consisting of interviews at 2-mo intervals and endoscopy at 4-mo intervals or whenever symptoms recurred. The cumulative relapse rate was significantly (p less than 0.007) greater in patients healed with cimetidine than with sucralfate, 50% relapse occurring at 6 and 12 mo, respectively. In both, the cumulative relapse rate was significantly greater in cigarette smokers than in nonsmokers, but smokers and nonsmokers treated with cimetidine relapsed (50% at 4 and 8 mo, respectively) faster than the corresponding smokers and nonsmokers treated with sucralfate (50% at 8 and 18 mo, respectively). Furthermore, in cimetidine- but not sucralfate-healed patients, early ulcer relapse (within 6 mo) was associated with short duration of illness, short remission period, long symptomatic spell, and reluctance to give up smoking. We conclude that smoking adversely affects duodenal ulcer healing by cimetidine and hastens subsequent relapse, and that sucralfate overcomes the adverse effect of smoking on healing as encountered with cimetidine, and results in a subsequent remission period double that of cimetidine.

We evaluated in healthy human beings the effect of indomethacin on gastric mucosal prostaglandin concentration and on gastric mucosal damage in a placebo-controlled study. Prostaglandin E2, prostaglandin F2 alpha, and 6-keto prostaglandin F1 alpha concentrations of gastric mucosal biopsy specimens, obtained endoscopically, were measured by radioimmunoassay. Mean prostaglandin concentration of the antrum and fundus was similar. In both regions there was considerable intersubject variability in prostaglandin concentration. Repeated 50-mg oral doses of indomethacin for 4 days reduced mean prostaglandin F2 alpha and E2 concentration by 50.2% and 69.4%, respectively, in the fundus and by 40.0% and 49.7% in the antrum, but this led to no significant mucosal damage when assessed endoscopically or histologically. A single 100-mg oral dose of indomethacin reduced mean prostaglandin F2 alpha and prostaglandin E2 concentration by 81.4% and 60.9% in the fundus and by 64.2% and 57.5% in the antrum and also induced significant mucosal injury in both regions when assessed endoscopically. However, there was no correlation between degree of suppression of prostaglandin concentration by indomethacin and endoscopic evidence of mucosal damage.

Delayed gastric emptying is common in primary anorexia nervosa. We investigated in 12 patients whether gastric emptying could be accelerated by the prokinetic drug cisapride. Patients were studied on two occasions 1 wk apart and received, under random double-blind conditions, 8 mg of cisapride and placebo intravenously. Gastric emptying of an isotopically labeled semisolid meal and antral motor activity were measured using a dual-headed gamma-camera for 50 min. Emptying was significantly slower (half-emptying time, 50-191 min; median, 121 min) than in 24 healthy volunteers (half-emptying times, 21-119 min; median, 47 min). Cisapride accelerated emptying significantly (p less than 0.001; half-emptying time after cisapride, 22-80 min; median, 42 min). Antral contraction amplitude increased and contraction frequency decreased significantly (p less than 0.001), whereas the propagation velocity of contractions remained unchanged. We concluded that intravenous cisapride accelerates gastric emptying and increases antral contraction amplitude in patients with anorexia nervosa. Whether or not these effects can prove beneficial in diminishing the patients' symptoms and in helping them to gain weight can only be answered from studies involving long-term treatment with cisapride.

Twenty-nine patients with esophageal symptoms and contraction abnormalities of the esophageal body completed a 6-wk, double-blind, placebo-controlled trial of trazodone (100-150 mg/day). Measures of esophageal and psychologic symptoms were completed at entry and at each follow-up visit. Esophageal manometry was repeated at the termination of the trial. Upon completion of the treatment, patients receiving trazodone (n = 15) reported a significantly greater global improvement than those receiving placebo (n = 14; p = 0.02). Although a variable clinical response was observed, the trazodone group had less residual distress over esophageal symptoms compared with the placebo group (59% +/- 9% vs. 108% +/- 19%, p = 0.03). Manometric changes observed during the course of the trial were not influenced by treatment nor by clinical response. Remarkable reductions in ratings of chest pain were reported by both treatment groups, emphasizing the importance of controlled trials when studying this patient population. We conclude that low-dose trazodone therapy can be of benefit in the management of symptomatic patients with esophageal contraction abnormalities. In addition, our findings support recent observations that manometric abnormalities characterizing this patient group may not be solely responsible for symptoms.

Previous therapeutic trials with prostaglandins have shown them to be effective in healing duodenal ulcers when used at doses that are highly effective suppressors of gastric acid secretion. We undertook this trial to determine if a cytoprotective dose of arbaprostil (10 micrograms q.i.d. for 4 wk) would also be efficacious in this disease state. Eighty-two patients between the ages of 19 and 72 yr with endoscopically documented duodenal ulcers were entered into this randomized double-blind placebo-controlled trial. The patients were monitored with biweekly endoscopies and laboratory examinations, weekly interviews during the period when drug was administered, and a follow-up interview plus laboratory examinations 1 wk after drug administration was completed. No statistically significant differences between the arbaprostil and placebo treatment groups were found for ulcer healing rates, pain relief, antacid consumption, side effects, or laboratory examinations. It is presumed that this prostaglandin may not have sufficient duodenal cytoprotective capacity to effectively heal duodenal ulcers, or that some suppression of gastric acid secretion may be required to achieve significant clinical efficacy.