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Biomedical subjects

S Schenker

Publications and source records attributed to S Schenker.

At least 127 records · Page 7Linked to original sources
PubMed1981

Effect of acute ammonia intoxication on energy stores in the cerebral reticular activating system.

Ammonia intoxication causes loss of consciousness. One postulated mechanism for this stipulates impaired energy metabolism in critical brain sites. The ascending reticular activating system in the brainstem may modulate consciousness. Accordingly, the present study, using micromethods, assessed energy stores in cells from the reticular activating system of mice acutely intoxicated with ammonia. In the early coma period (3.5 min after ammonia) phosphocreatine, adenosine triphosphate and glucose fell significantly while glycogen decreased later. Subsequently during coma, the high energy phosphates returned to normal and supranormal. The maximal fall in these metabolites was not accompanied by a rise in lactate, implying lack of local hypoxia or acidosis. The cells of the posterior coliculus in the same animals failed to show a significant fall in energy stores. These data suggest a selective effect of ammonia on energy metabolism in the cells of the reticular activating system of the brainstem.

Adenosine Triphosphate↗
PubMed1981

In vitro antagonism of benzodiazepine binding to cerebral receptors by H1 and H2 antihistamines.

Antihistamines directed at either the H1 or H2 histamine receptor have the well-known side effect of sedation. The mechanism for the CNS depressant action of antihistamines is unknown. We examine here the possibility that the mechanism may involve modulation of the cerebral benzodiazepine receptor. We demonstrate that cimetidine and pyrilamine are competitive antagonists of 3H-benzodiazepine binding to human cerebral receptor in vitro. The inhibition of radioligand binding was not specific for benzodiazepine receptor, however, since antihistamines also antagonized binding to GABA, opiate, and muscarinic acetylcholine receptor. The interaction of antihistamine with CNS receptors other than histamine receptor may explain, at least in part, the side effect of sedation.

Binding, Competitive↗
PubMed1981

Fetal alcohol syndrome: overview of pathogenesis.

The pathogenesis of Fetal Alcohol Syndrome (FAS) has been reviewed briefly in terms of factors which can influence its development and specific mechanisms. FAS was defined arbitrarily to include a wide spectrum ranging from the fully expressed clinical syndrome to growth and developmental impairment seen in fetal and neonatal animals exposed to ethanol. The available evidence suggests that ethanol per se in the absence of nutritional deficit can cause some from of FAS. Acetaldehyde may contribute to the FAS, but there is lack of knowledge concerning the levels of acetaldehyde needed to achieve fetal damage and the effect of this agent on the placenta and its placental transfer to the fetal organs. There is no specific data at this time to incriminate nutritional impairment, although further studies in animal models and man of the role of possible deficiencies of certain vitamins (i.e., folate) and of trace minerals (i.e., zinc) are needed. There is some evidence that alcohol or its metabolites may alter placental transport function. The relevance of this to FAS needs further investigation. The possible additive roles of caffeine, nicotine and other drugs on fetal development and viability deserve more consideration. The specific mechanism(s) of FAS are unknown. Of those considered--mutagenic (paternal) effect, abnormal protein synthesis, altered cerebral neurotransmitter balance, hormonal and other effects--impairment of protein synthesis at present seems best documented, but all clearly require further evaluation. When specific mechanisms are investigated it will be essential also to determine the dose-response relationship and the effects of a given dose of alcohol at various stages of gestation.

Animals↗
PubMed1981

The differential localization of various drug metabolizing systems within the rat liver lobule as determined by the hepatotoxins allyl alcohol, carbon tetrachloride and bromobenzene.

Rats were pretreated with allyl alcohol, carbon tetrachloride or bromobenzene to induce histopathological evidence of periportal, midzonal to centrilobular, and centrilobular hepatic necrosis. The amount of various drug metabolizing enzyme systems present after necrosis was determined indirectly by measuring the rate of metabolism for specific substrates in vitro. The chemically induced hepatocellular injury of these toxins produced variable but significant alterations in hepatic drug metabolism. The changes in enzymatic activity related well with the area of the lesion produced by each toxin. Thus, these hepatotoxins appear to be useful as probes to determine the hepatolobular distribution of the various drug metabolizing enzyme systems studied. Aniline hydroxylase and p-nitroanisole o-demethylase were concentrated in the midzonal and periportal zones, while aminopyrine N-demethylase was more uniformly distributed along the cytochrome P-450 gradient. Glucuronyltransferase was more heavily concentrated in the periportal-midzonal area, acetyltransferase was centrilobular-midzonal and glutathionetransferase was concentrated in the midzonal region. Thus, as is the case for cytochrome P-450, there appears to be a high degree of regional organization for all of the drug metabolizing enzymes within the hepatic lobule.

1-Propanol↗
PubMed1981

Lack of tolerance and rapid recovery of cimetidine-inhibited chlordiazepoxide (Librium) elimination.

Cimetidine has been shown to inhibit oxidative metabolism of several drugs while sparing the glucuronidation pathways of drug metabolism. We studied the time-course of inhibition and recovery of cimetidine-inhibited chlordiazepoxide elimination in 7 healthy subjects. Chlordiazepoxide elimination was studied after cimetidine treatment for 1 and 30 days, and after withdrawing cimetidine for 48 h. The plasma clearance of chlordiazepoxide was reduced by 54% (p less than 0.001) after 24 h of cimetidine, by 57% (p less than 0.001) after 30 days of cimetidine and returned to normal after cimetidine was stopped for 48 h. In the absence of changes in volume of distribution, these changes resulted in proportional increases in the elimination half-life (t 1/2 beta) after 24 h and 30 days cimetidine treatment, and returned to pretreatment values after stopping cimetidine. In addition, the impaired chlordiazepoxide elimination was accompanied by inhibition of generation and subsequent elimination of N-desmethylchlordiazepoxide, the first metabolite of chlordiazepoxide metabolism. This study demonstrates a rapid inhibitory effect on chlordiazepoxide elimination, an absence of tolerance to this effect and a rapid reversal of this effect upon stopping cimetidine. These findings may have important therapeutic implications for patients receiving both drugs simultaneously.

Adult↗
PubMed1981

Short-term and long-term ethanol administration inhibits the placental uptake and transport of valine in rats.

Ethanol ingestion during pregnancy causes a pattern of fetal/neonatal dysfunction called the FAS. The effects of short- and long-term ethanol ingestion on the placental uptake and maternal-fetal transfer of valine were studied in rats. The in vivo placental uptake and fetal uptake were estimated after injection of 0.04 micromol of 14C-valine intravenously on day 20 of gestation in Sprague-Dawley rats. Short-term ethanol ingestion (4 gm/kg) caused a significant reduction in the placental uptake of 14C-valine by 33%, 60%, and 30%, and 31% at 2.5, 5, 10, and 15 min after valine administration, respectively (p less than 0.01), and a similar significant reduction occurred in the fetal uptake of 14C-valine (p less than 0.01). Long-term ethanol ingestion prior to and throughout gestation resulted in a 47% reduction in placental valine uptake (p less than 0.01) and a 46% reduction in fetal valine uptake (p less than 0.01). Long-term ethanol feeding from day 4 to day 20 of gestation caused a 32% reduction in placental valine uptake (p less than 0.01) and a 26% reduction in fetal valine uptake (p less than 0.01). We conclude that both short- and long-term ingestion of ethanol inhibit the placental uptake and maternal-fetal transfer of an essential amino acid--valine. An alteration of placental function may contribute to the pathogenesis of the FAS.

Animals↗
PubMed1981

Normal metabolism of morphine in cirrhosis.

Morphine disposition and elimination was studied in 6 healthy male subject s and 6 male patients with cirrhosis, to assess the role of differences, if any, on the reported intolerance of morphine in cirrhosis. In addition the elimination of indocyanine green was studied in the same subjects on a separate occasion. The elimination half-life of indocyanine green was increased and its plasma clearance was markedly reduced in patients with cirrhosis as compared with controls (p less than 0.05). In contrast the disposition and elimination of morphine were unaffected by moderate to severe cirrhosis. Furthermore, while marked sedation was observed in normal subjects, the cirrhotics demonstrated mild sedation with no clinical evidence of hepatic coma. The normal elimination of morphine in cirrhosis is in contrast to the decreased elimination of high clearance drugs metabolized by oxidation, such as lidocaine and meperidine. Morphine is also normally a high clearance drug that is detoxified by conjugation with glucuronic acid. Since intra- or extrahepatic shunting, or both, in cirrhosis do not significantly impair morphine clearance, we postulate that significant extrahepatic morphine conjugation may occur in both normal subjects and in patients with cirrhosis. Furthermore, the reported morphine intolerance to the central effects of morphine cannot be explained by impaired drug elimination and increased availability of morphine to cerebral receptors.

Adult↗
PubMed1980

Short-term ethanol administration impairs the elimination of chlordiazepoxide (Librium) in man.

Ethanol may enhance the sedative effect of benzodiazepines leading to greater psychomotor impairment, but the mechanism is not clear. The present study was carried out to determine the effect of acute ethanol ingestion on the disposition and elimination of chlordiazepoxide (Librium), a widely used benzodiazepine. Five healthy, 22-39-year-old, male volunteers ingested ethanol 0.8 g/kg as 25% in orange juice 1 h before chlordiazepoxide 0.6 mg/kg was injected intravenously. To maintain plasma ethanol concentrations of 50-150 mg!100 ml for 32 h additional ethanol 0.5 g/kg was given orally every 5 h. Plasma clearance of chlordiazepoxide fell from 26.6 +/- 2.6 ml/min (mean +/- SD) without ethanol to 16.6 +/- 3.1 ml/min (P less than 0.05) after ethanol. There was no change in the volume of distribution and therefore the elimination half-life was prolonged from 7.1 +/- 1.9 h to 11.8 +/- 6.0 h (P less than 0.05) after ethanol. Ethanol also lowered the plasma binding of chlordiazepoxide from 94.7 +/- 0.6% to 93.4 +/- 1.3% (P less than 0.05). The plasma clearance of unbound chlordiazepoxide fell from 468 +/- 51 ml/min to 264 +/- 98 ml/min (P less than 0.05) after ethanol. The plasma level of the metabolite desmethylchlordiazepoxide was higher and its elimination slower after ethanol. Thus using a pharmacokinetic approach this study has demonstrated that short-term ethanol ingestion in moderate doses impairs the elimination of chlordiazepoxide and accounts, at least partly, for the greater sedation that results when ethanol is taken concomitantly.

Adult↗
PubMed1980

Impaired elimination of caffeine in cirrhosis.

The effect of cirrhosis on the disposition and elimination of caffeine was examined. Caffeine (250 mg) was administered orally to 15 healthy controls and eight patients with cirrhosis. The elimination half-life was prolonged from 5.2 +/- 2.4 hr (mean +/- SD) in controls to 6.1 +/- 1.9 hr in cirrhotics, although this did not reach statistical significance. The plasma clearance, however, was significantly higher (1.4 +/- 0.5 ml/min/kg) in controls as compared to cirrhotics (0.9 +/- 0.3 ml/min/kg) (P less than 0.05). The plasma binding of caffeine was also lower in cirrhotics (31.3 +/- 1.8% vs 25.5 +/- 4.0%, P less than 0.01). The plasma clearance of unbound caffeine therefore was reduced from 2.0 +/- 0.7 ml/min/kg in controls to 1.2 +/- 0.4 ml/min/kg (P less than 0.01) in cirrhotics, demonstrating impaired elimination of caffeine in cirrhosis.

Adolescent↗
PubMed1980

Effects of caffeine on plasma free fatty acids, urinary catecholamines, and drug binding.

The effects of caffeine (250 mg orally) on plasma free fatty acids (FFA), urinary catecholamines, and drug binding were studied in 16 normal subjects (six men, five women on oral contraceptives, and five women not on oral contraceptives). FFA doubled 1 hr after caffeine, and remained elevated for at least 4 hr. with elevation of each FFA. Urinary excretion of epinephrine and dopamine increased (p<0.05) in the first 2 hr. returning to baseline in the next 2 hr. Plasma binding of chlordiazepoxide, diaxepam, and propranolol was estimated in each of the hourly plasma samples after caffeine; there was no change in percent unbound drug in any of the samples. In vitro addition of oleic acid to plasma samples of four subjects caused a step-wise increase in percent unbound fraction of all three drugs whereas in vitro addition of caffeine did not further alter drug binding. In our study circulating plasma FFA and urinary catecholamine levels were elevated after caffeine ingestion. In spite of a rise in FFA, there was, however, no change in plasma binding of chlordiazepoxide, diazepam, or propranolol.

Blood Proteins↗
PubMed1980

Effect of heparin administration on plasma binding of benzodiazepines.

1 The effect of intravenous administration of 100 units of heparin on plasma of diazepam, chlordiazepoxide, oxazepam and lorazepam was examined in fourteen normal subjects and five patients with cirrhosis. 2 In normal non-fasted subjects heparin caused a rapid 150--250% rise in the free fraction of diazepam, chlordiazepoxide and oxazepam but no change of lorazepam. The changes in free fraction were slightly smaller, but still significant, when the subjects were fasted. 3 These change in free fraction occurred within 90 s of administration of heparin and binding had returned to baseline by 30 to 45 min. 4 In the cirrhotic subjects the response to heparin was variable. 5 The use of heparin during drug disposition studies may affect the estimation of pharmacokinetic parameters and possibly pharmacological effects which are dependent on the circulating unbound drug level.

Anti-Anxiety Agents↗