Misoprostol in the treatment of duodenal ulcer refractory to H2-blocker therapy. A placebo-controlled, multicenter, double-blind, randomized trial.

A multicenter, double-blind, randomized study compared 200 micrograms of misoprostol and placebo four times daily for four weeks in the treatment of 225 patients with duodenal ulcer (0.7 cm to 2.0 cm in size) persisting after at least four weeks of adequate, conventional therapy with cimetidine or ranitidine. Misoprostol was significantly superior to placebo in healing duodenal ulcers (achieving a healing rate of 37 percent versus 22 percent in the placebo group [p = 0.02], and in relieving ulcer pain [p = 0.01]). Healing also occurred more frequently with misoprostol than with placebo in patients with subgroups of particularly resistant ulcers. In the treatment of ulcers refractory to at least eight weeks of histamine H2-blocker therapy, misoprostol achieved a healing rate of 42 percent versus 20 percent with placebo. In the treatment of pyloric channel ulcers, 28 percent of patients in the misoprostol group showed healing as compared with 20 percent in the placebo group. Diarrhea was reported by 15.4 percent and 3.4 percent of patients receiving misoprostol and placebo, respectively, and was usually mild and transient. Misoprostol is safe and effective therapy for duodenal ulcers that have not healed during the course of H2-blocker therapy.

Overview of misoprostol clinical experience.

Misoprostol is an E1 prostaglandin analog. Most of the other synthetic prostaglandins that are being studied in advanced clinical trials for gastrointestinal diseases are E2 derivatives. Misoprostol has shown a dose-related antisecretory effect that lasted 3-5.5 hr. In addition, animal studies have shown cytoprotective properties that are being confirmed in clinical studies. Ulcer-healing trials using four times daily dosing appear to parallel the antisecretory dose-response curve up to a dose of 200 micrograms qid. Evidence presented in this supplement suggests a further increase in healing-rate response at 300 micrograms misoprostol qid. The misoprostol healing rates obtained in duodenal ulcer and gastric ulcer therapy at 200 micrograms qid are not significantly different from those seen in the same studies with cimetidine at a dose of 300 mg qid. No significant rebound in recurrence has been observed during follow-up for 12 months after short-term 100- and 200-micrograms qid misoprostol treatment. The most frequent adverse effects are dose-related diarrhea and abdominal cramping, which are transient in most patients and have not caused a significant problem in clinical use. There is also a tropic effect on the pregnant uterus, which was observed in a special pharmacologic clinical study. No significant abnormalities have been detected in clinical laboratory tests or gastric biopsies. There have also been no adverse effects noted on blood pressure, pulse, platelets, the immune system, pulmonary function, gastrointestinal hormones, or the endocrine system. These previously discussed characteristics of misoprostol, and current data, suggest that this prostaglandin E1 derivative may be an important addition to the treatment of peptic ulcer disease.

Gastrointestinal cytoprotective effects of misoprostol. Clinical efficacy overview.

The cytoprotective effects of misoprostol, a synthetic analog of prostaglandin E1, were investigated in healthy human subjects using randomized and placebo-controlled studies. Misoprostol significantly inhibited established aspirin (975 mg q.i.d.)-induced gastric microbleeding at 50 micrograms q.i.d., and to some extent, but not significantly, at 25 micrograms q.i.d. Misoprostol also reduced acid and chloride secretion significantly at 50 micrograms q.i.d., but not at 25 micrograms q.i.d. When administered concurrently with aspirin 650 mg q.i.d., misoprostol 25 micrograms q.i.d. significantly inhibited aspirin-induced fecal blood loss without affecting plasma salicylate concentration. The fact that misoprostol was tested at a sub-therapeutic gastric antisecretory dose (25 micrograms) indicates that the inhibition of fecal blood loss was not due to its gastric antisecretory property. Misoprostol tended to reduce antral erosion and DNA content of gastric fluid, but increased mucus concentrations in subjects with ethanol-induced damage. However, the dose of ethanol used produced gastric damage in only six of the 10 subjects and did not provide a satisfactory baseline. Misoprostol attenuated the drop in transmucosal potential difference induced by sodium taurocholate. It is concluded that misoprostol has cytoprotective activity in man. These effects may be of great importance in the treatment of acid peptic disease of the gastrointestinal tract.

A randomized, double-blind, parallel group comparison of disopyramide phosphate and quinidine in patients with cardiac arrhythmias.

This report summarizes the results of a randomized, double-blind, parallel group, multicenter study which compared the antiarrhythmic activity and safety of oral disopyramide phosphate and oral quinidine sulfate. A total of 124 outpatients, whose pretreatment rates of ventricular and/or supraventricular arrhythmias were documented by ambulatory ECG recordings, were randomly assigned to receive either oral disopyramide or oral quinidine for the eight-week course of the study. Every two weeks, ten-hour ambulatory ECG recordings were obtained from each patient and blood was drawn to determine serum concentrations of assigned drug.