Role of interleukin-1 and the therapeutic potential of interleukin-1 receptor antagonist in sepsis.

Clinical trials of anticytokines in sepsis have not been as straightforward as had been anticipated from results in animal models of sepsis and the role of cytokines in sepsis is now in question. Retrospective analysis of the results of a phase III trial of interleukin-1 (IL-1) receptor antagonist suggests that sepsis-induced adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), renal dysfunction, and shock are valuable markers of patients in whom IL-1 is a pathogenic mediator and in whom IL-1ra can reduce mortality. A re-examination of the effects of IL-1ra in animal models of sepsis supports the validity of this analysis. A new phase III clinical trial will confirm or disprove the hypothesis that IL-1 is a mediator of pathology, and IL-1ra is a valuable therapy for sepsis complicated by ARDS, DIC, renal dysfunction, or shock.

A multiclinic trial evaluating arbaprostil [15(R)-15-methyl prostaglandin E2] as a therapeutic agent for gastric ulcer.

A randomized, double-blind, placebo-controlled, multiclinic trial evaluated arbaprostil [15(R)-15 methyl prostaglandin E2] for the treatment of acute gastric ulcer, achieving an overall enrollment of 124 patients (of which 113 were considered evaluable). This 6-wk trial used an arbaprostil dose of 10 micrograms q.i.d., which has little gastric acid antisecretory activity. Endoscopies were performed after 21 and 42 days of treatment, at which times the arbaprostil and placebo healing rates, respectively, were 6/59 (10.2%) and 4/53 (7.6%) on day 21 and 25/59 (42.4%) and 16/50 (32.0%) on day 42. No significant differences between the treatment groups were found for pain relief, antacid consumption, and mucosal healing. This trial documents that a 10-micrograms dose of arbaprostil (which may be considered cytoprotective because of its small effect on gastric acid secretion), although safe and associated with no side effects, is not efficacious in healing acute gastric ulcers.

Failure of a cytoprotective dose of arbaprostil to heal acute duodenal ulcers. Results of a multiclinic trial.

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.

Lack of effect of arbaprostil on the human non-pregnant uterus.

Arbaprostil ((15R)-15-methyl Prostaglandin E2) is being studied for the treatment of gastrointestinal illness. To determine its effect on the human uterus, eight sterilized pre-menopausal women were studied during the proliferative phase of their menstrual cycle. Using a microtransducer catheter, intra-uterine pressures were recorded for at least 30 minutes prior to and 2 hours after arbaprostil administration. Each subject was studied four times, at 48-hour intervals, receiving in a double-blind manner; 0, 10, 25, and 50 micrograms. Arbaprostil at does up to 50 micrograms was found not to have any clinically significant effects on the non-pregnant human uterus.