K. V. Speeg

Cimetidine impairs elimination of chlordiazepoxide (librium) in man

We have studied chlordiazepoxide (Librium) disposition and elimination in eight normal subjects before and after 1 week of cimetidine therapy, 300 mg orally four times a day. Cimetidine strikingly impaired the clearance of chlordiazepoxide from plasma, and this was, at least in part, due to decreased demethylation of the drug to N-desmethylchlordiazepoxide. Since the volume of distribution of chlordiazepoxide was not altered by cimetidine, the elimination half-life of chlordiazepoxide was also significantly prolonged by cimetidine therapy.

Cimetidine protects against acetaminophen hepatotoxicity in rats

Acetaminophen hepatotoxicity is believed to result from the metabolic conversion of acetaminophen to a highly reactive intermediate by cytochrome P 450. Cimetidine has been shown to be a potent inhibitor of cytochrome P 450-mediated drug metabolism in humans and in laboratory animals, -both in vivo and in vitro. Therefore, this study was undertaken to examine the possible protective effects of cimetidine administration on acetaminophen-induced hepatic necrosis in rats. We observed a striking protection against acetaminophen hepatotoxicity in cimetixad dine-treated rats (120 mg/kg) up to 4 h after i.p. administration of 500 mg/kg of acetaminophen. Cixad metidine-treated animals had less histologic damxad age when examined by light microscopy. and they had lower serum aminotransferases than those treatxad ed with acetaminophen alone. Furthermore. there was less functional hepatic impairment. e.g .. imxad proved survival and improved ability to metabolize aminopyrine in vivo in rats receiving cimetidine compared with those receiving acetaminophen withxad out cimetidine. Comparison of cjmetidine treatment with N-acetylcysteine treatment of acetaminophen overdose in rats showed cimetidine as effective as Nxad acetylcysteine, even though the dose of cimetidine given was only isth that of N-acetylcysteine on a molar basis. Cimetidine also inhibited the covalent binding of [3H]acetaminophen to hepatic microxad somes in vitro, both in the presence and absence of reduced glutathione. Cimetidine did not, however,

Effect of Cimetidine and other antihistaminics on the elimination of aminopyrine, phenacetin and caffein

Abstract Cimetidine is widely prescribed for the treatment of peptic ulcer disease and has recently been shown to inhibit the metabolism of warfarin, antipyrine and diazepam. To further examine this phenomenon we investigated the effect of various doses of cimetidine and other related drugs on 14C-aminopyrine, 14C-phenacetin and 14C-caffeine breath tests. Cimetidine caused a dose-related inhibition of the metabolism of aminopyrine and caffeine but had no effect on the phenacetin breath test. Metiamide, H1-antihistamines, phenothiazines and local anesthetics also inhibited the aminopyrine breath test. Cyproheptadine had no effect on either phenacetin or caffeine elimination. This study demonstrates a complex drug-drug interaction which may have widespread clinical implications.

ISOLATION OF FUNCTIONAL HUMAN TROPHOBLAST CELLS AND THEIR PARTIAL CHARACTERIZATION IN PRIMARY CELL CULTURE

SummaryHuman trophoblast isolation and cell culture procedures were examined to identify variables that enhance secretion of chorionic gonadotropin (HCG) in primary culture. Brief exposure of unminced first-trimester placental specimens to a solution of trypsin-EDTA-DNAse, and isolation of the dispersed cells after Ficoll-hypaque centrifugation yielded primary cultures that were high in HCG secretion and content of epithelial-like cells. The gradual decline in HCG level with time in monolayer culture in these presumptive trophoblast cells was retarded by treatment with theophylline and cyclic adenosine monophosphate. Exposure to methotrexate (MTX) did not increase HCG secretion in normal trophoblast cells, in contrast to a 5-fold stimulation by MTX in the JAR line of choriocarcinoma cells. Clusters of polygonal cells in primary culture progressively lost their capacity to secrete HCG and their epithelial-like morphology. However, they could be maintained as cell strains through approximately 15 passages over a period of 13 to 16 weeks.

Aging and benzodiazepine binding in the rat cerebral cortex

The specific binding of 3H-diazepam in the cerebral cortex was investigated in membrane preparations from 6 and 30 month old Fisher-344 rats. No age-related differences in the association, equilibrium, or dissociation, binding characteristics were observed. The increased sensitivity of the elderly to the central sedative effects of the benzodiazepines does not, therefore, appear to involve changes in binding to the receptor site located in the cortex.

Cerebral acetylcholine in thiamine deficiency.

Summary This study assesses the hypothesis that severe thiamine deficiency may lead to a depletion of cerebral ACh, which, in turn, may be responsible for the cerebral dysfunction seen in this condition. Acetylcholine assays were carried out in rats with diet-induced thiamine deficiency resulting in overt neurologic signs and in asymptomatic pair-fed and normally fed controls. The brainstem and cerebellum were assayed, in addition to the cortex, since the former sites exhibit the most significant biochemical alterations in thiamine deficiency. Acetylcholine was assayed by a modification of a specific and accurate fluorometric procedure. For every brain area studied the cerebral ACh concentrations in thiamine-deficient rats exhibiting overt neurologic signs were comparable to values seen in asymptomatic pair-fed controls. This study indicates that thiamine deficiency does not cause an alteration in cerebral regional ACh stores and that alternate mechanisms for the neurologic dysfunction will have to be sought.

Physostigmine reversal of diazepam-induced hypnosis. A study in human volunteers

Under randomized double-blind conditions, 1.00 to 1.67 mg of intravenous physostigmine (Antilirium) reversed sleep induced by administration of 0.102 to 0.238 mg/kg body weight of intravenous diazepam in eight healthy human volunteers. Awakening occurred 330 to 740s after initiation of the physostigmine infusion at a rate of 0.5 mg/min every 4 min. Diazepam plasma levels were not significantly different at the start of either the physostigmine or placebo infusion. Physostigmine did not effect plasma binding of diazepam. Six subjects experienced nausea, and one subject developed an arrhythmia. Physostigmine reverses diazepam-induced hypnosis but causes side-effects requiring cautious administration.

Characteristics of alkaline phosphatase from two continuous lines of human choriocarcinoma cells

Abstract Several characteristics of human choriocarcinoma alkaline phosphatase have been studied. BeWo and Jar choriocarcinoma lines each contain heat-stable alkaline phosphatase activity with characteristics similar to the D-variant term placental isoenzyme. The activity is also similar to the Nagao enzyme found in many malignancies. Each choriocarcinoma also has heat-labile alkaline phosphatase activity with characteristics similar to the enzyme found in normal first-trimester placenta. Neither BeWo alkaline phosphatase could be stimulated with cortisol. Both BeWo alkaline phosphatase activities could be stimulated with methotrexate and actinomycin D.

Cerebral Acetylcholine, Serotonin, and Norepinephrine in Acute Ammonia Intoxication

Summary The primary purpose of this study was to assess the hypothesis that a depletion of cerebral acetylcholine (ACh) may be responsible for the coma induced with ammonia. An ancillary aim was to determine the effect of ammonia on cerebral levels of two other likely neurotransmitters, serotonin and norepinephrine. Acetylcholine, serotonin, and norepinephrine were measured in the brain of rats with NH4Ac-induced stupor and in asympotomatic NaAc-injected and uninjected controls. Studies were carried out during and after the development of stupor; and both cortex and brainstem were assayed separately since these areas are believed to be primarily responsible for the maintenance of consciousness. Acetylcholine was measured by a specific and accurate fluorometric procedure. In rats with ammonia-induced precoma and coma, the ACh and norepinephrine levels in the cerebral cortex and brainstem were comparable to values seen in control animals. Cerebral serotonin likewise was normal during the development of stupor but fell modestly in both cortex and brainstem of animals with established coma. This study indicates that cerebral regional stores of ACh, serotonin, and norepinephrine are normal during the development of acute ammonia-induced coma and that other mechanisms for this neurologic dysfunction will have to be considered.

Antagonism of benzodiazepine binding in rat and human brain by antiliriumR

Abstract Physostigmine (Antilirium R ) has been reported to reverse benzodiazepine- induced sleep or coma in man and prevent death in animals. Accordingly, we investigated the effect of Antilirium upon benzodiazepine binding to both rat and human brain. We report that Antilirium inhibits 3 H-diazepam and 3 H-flunitrazepam binding in a dose-dependent manner. The degree of inhibition of binding by Antilirium correlates with the affinity of benzodiazepine for its “receptor” such that diazepam is more affected than flunitrazepam. The inhibition is rapid but the kinetics are complex with only doses of Antilirium showing competitive inhibition when studied at equilibrium. These results may explain, at least in part, the effectiveness of Antilirium at reversing benzodiazepine-induced hypnosis without necessarily implicating a cholinergic mechanism.