Stress ulcers and organ failure in intubated patients in surgical intensive care units.

This study compared prophylactic administration of either intragastric misoprostol (200 micrograms four times a day), a prostaglandin E1 analog, or bolus intravenous cimetidine (300 mg every 6 hours) in preventing stress lesions and stress bleeding in 127 adult postoperative patients who required mechanical ventilation and also had developed hypotension or sepsis. Both drug treatments were equally effective in preventing the development of diffuse gastritis (greater than 10 gastric hemorrhagic lesions) and in preventing upper gastrointestinal hemorrhage (UGIH). The combined data from both groups showed that for the 44 (35%) patients who died, death was significantly associated with the presence at study entry of renal failure (64% of 25 patients with renal failure died), hepatic failure (57% of 23 patients) or coagulopathy (62% of 29 patients) (p less than 0.02 for each), and with the number of organ system failures at study entry (48% of 69 patients with multiple organ system failures died, p less than 0.001). Death was also significantly associated with the presence of adult respiratory distress syndrome (ARDS) at study entry or the development of ARDS (63% of 24 patients with ARDS died, p less than 0.001), and the development of UGIH (5% of 93 patients with known bleeding outcome died, p less than 0.05). The number of stress lesions that developed was significantly associated with subsequent UGIH (p less than 0.001). Additional organ system failure developed during the study in 31% of the 127 patients, as did diffuse gastritis in 20% of 111 patients who had a follow-up endoscopy. These results demonstrate that postoperative patients who require mechanical ventilation and have hypotension or sepsis are at significant risk for the development of stress gastric lesions and multiple organ system failure even when prophylaxis for stress ulcers is provided. Furthermore, the presence of ARDS, renal failure, hepatic failure, coagulopathy, and UGIH are significantly associated with death.

A double-blind, placebo-controlled, 6-day evaluation of two doses of misoprostol in gastroduodenal mucosal protection against damage from aspirin and effect on bowel habits.

Ninety-one normal, healthy volunteers participated in a single-center, double-blind, placebo-controlled, randomized, parallel group study: 1) to compare the prostaglandin E1 analog, misoprostol, given at a dose of 200 micrograms bid, with the recommended dose of 200 micrograms qid in protecting the gastroduodenal mucosa against injury due to anti-inflammatory doses of aspirin (3900 mg/day); and 2) to determine whether the reduced dose was associated with a lesser incidence of gastrointestinal (GI) side effects, particularly diarrhea. All subjects received 975 mg of aspirin qid with meals and at bedtime. They were concurrently administered either misoprostol 200 micrograms qid, misoprostol 200 micrograms bid and placebo bid, or placebo qid. All subjects were endoscopically normal at the onset of the study and were re-endoscoped on the morning of the 7th day of therapy, 2 h after the morning dose of medications. Gastric and duodenal mucosa were assessed separately on a 0-7 scale which gave a greater weight to erosions than to hemorrhages. GI symptoms, especially bowel habits, were assessed by means of diary cards. Subjects in both misoprostol groups had significantly less gastric and duodenal mucosal injury than subjects who received placebo (p less than 0.007 for each pairwise comparison). There was no statistically significant difference between the two misoprostol groups (p less than 0.093). Subjects in the misoprostol 200 micrograms qid group had significantly more loose and watery bowel movements than the subjects in the misoprostol 200 micrograms bid group (p less than 0.013), whereas there were no significant differences in bowel habits between the misoprostol 200 micrograms bid and placebo groups (p less than 0.122). More subjects in the misoprostol 200 micrograms qid group reported abdominal pain, loose stools, watery stools, flatulence, dyspepsia, and nausea than in the misoprostol 200 micrograms bid and placebo groups. In conclusion, the adverse events in the misoprostol 200 micrograms bid group were not significantly different from those in the placebo group, and were significantly better than in the misoprostol 200 micrograms qid group. The lower dose retained mucosal protective activity that was statistically indistinguishable from that of misoprostol 200 micrograms qid.

Aging does not alter the sensitivity of benzodiazepine receptors to GABA modulation.

The effects of GABA on benzodiazepine receptor binding in cerebral cortical, hippocampal, and cerebellar membranes from 2-3 months old and 28-32 months old rats were studied. GABA modulation of agonist, antagonist, and inverse agonist binding to the receptor was examined using the displacement of 3H-Ro15-1788 by diazepam, Ro15-1788, and beta-carboline-3-carboxylate methyl ester, respectively, in the absence and presence of 100 microM GABA and 150 mM sodium chloride. GABA modulation was alike in old and young rats, with respect to the particular ligand and brain region. The results support the hypothesis that, in the brain regions studied, the allosteric modulation of benzodiazepine receptor binding by GABA remains intact as a function of aging.

Cholecystokinin in vivo reduces binding to rat hypothalamic beta-adrenergic sites.

Intraperitoneal injection of sulfated cholecystokinin octapeptide (CCK-8; 10 micrograms/kg) resulted in an increase in the IC50 for isoproterenol (4.2 microM to 23.3 microM) in displacing 1 nM 3H-dihydroalprenolol binding to rat hypothalamic membranes. 3H-p-Aminoclonidine binding was also lower in membranes prepared from CCK-treated rats, but the decrease was not statistically significant. In vitro, CCK(1-100 nM) had no effect on either alpha- or beta-adrenergic binding or on the 5'-guanylylimidodiphosphate modulation of binding. The results indicate that CCK does not act directly upon adrenergic receptors, but may reduce beta-adrenergic affinity through indirect means.

Calcium alters divalent cation modulation of brain benzodiazepine receptors.

Nickel (Ni+2) ions enhance the binding of 3H-diazepam, but decrease the binding of 3H-propyl beta-carboline-3-carboxylate to benzodiazepine receptors in mouse brain. Our experiments were performed to determine the locus for this action. In both control and Ca+2-depleted membranes, Ca+2 blocked the stimulatory effect of Ni+2 on 3H-diazepam binding in a concentration-dependent manner. In Ca+2-depleted membranes, physiological Ca+2 concentrations blocked this effect of Ni+2. In control membranes, Ca+2 did not reverse Ni+2 inhibition of 3H-propyl beta-carboline-3-carboxylate binding, but was effective at physiological concentrations in reversing Ni+2 inhibition in Ca+2-depleted membranes. The effects of Cd+2 ions on 3H-diazepam binding were similar to Ni+2 and were also reversed by Ca+2. The effects of Ni+2 were blocked by La+3 ions but not by Mg+2 ions, and were not due to interactions with the GABA receptor or Cl- ionophore. These data suggest that a Ca+2 binding site is associated with the brain benzodiazepine receptor.

The binding of [3H]diazepam to rat brain homogenates.

A technique is described for the measurement of specific [3H]diazepam binding to subcellular fractions of rat brain. Binding occurred in fresh or hypotonically shocked, frozen and thawed preparations; was independent of the buffer used; and was concentrated in the synaptosomal fraction. The total binding capacity of crude brain homogenate was entirely recovered in the particulate fractions (P1, P2 and P3). Binding was saturable and reached 34 pmol/g of tissue; half-maximal binding (KD) occurred at 3.2 nM. Hill and Scatchard analysis indicated that the binding was noncooperative and to a single class of sites. Binding was time dependent and reversible; the bimolecular association constant (K1) was 1.13 . 10(6) sec-1 M-1 and the first order dissociation constant (K-1) was 2.69 . 10(-3) sec-1. Binding was highest in cerebral cortex, hippocampus and cerebellum; intermediate in midbrain, hypothalamus, corpus striatum and medulla oblongata/pons; and lowest in spinal cord. Benzodiazepines inhibited binding of [3H]diazepam in a manner correlated with pharmacological activity in vivo, and binding was not inhibited by non-benzodiazepine anxiolytics, muscle relaxants, anticonvulsants or by strychnine and glycine. Distribution of [3H]diazepam binding in several regions of the rat central nervous system correlated with Na+-independent binding of gamma-aminobutyric acid in the same regions. The results may be in accord with the possible involvement of gamma-aminobutyric acid in the mechanism of action of the benzodiazepines but provide no support for a mechanism based on the interaction of benzodiazepines with central glycine receptors.

Synthesis of beta-spiro[pyrrolidinoindolines], their binding to the glycine receptor, and in vivo biological acitivity.

A series of beta-spiro[pyrrolidinoindolines], 3a-d, was prepared and evaluated for their ability to bind to the glycine receptor. These compounds were also tested in vivo to determine if they would produce convulsant or anxiolytic effects. The target indolines were chosen because they represent rings A, B, E, and a portion of ring C of strychnine. Results of this study indicate that, in this series, an acetylindoline in the endo configuration and a tertiary amine, such as that of the pyrrolidine ring nitrogen, are required for biological activity. In all of the cases studied, the activity was of a convulsant rather than a relaxant nature. Excellent correlation was found to exist between the binding affinities to the strychnine site of the glycine receptor and clonic convulsions (ED50) and death (LD50) in the mouse.

The binding of strychnine and strychnine analogs to synaptic membranes of rat brainstem and spinal cord.

Crude synaptic membranes were isolated from rat pons, medulla and spinal cord by differential centrifugation. The specific binding of [3H]strychnine, obtained by subtracting from the bound radioactivity the amount not displaced by 50 micronm unlabeled strychnine, was saturable with a KD value of 12 nM. The dissociation constants (KD values) for the binding of several strychnine analogs to the strychnine site in vitro were determined and found to be highly correlated with the convulsant and lethal effects in the mouse. However, neither the biological activities in the mouse nor the binding activity in vitro correlated with the n-octanol-water distribution coefficients. The results are in accord with the concept that the [3H]strychnine binding site detected in vitro is the site of pharmacological activity in vivo.