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C V Smith

Publications and source records attributed to C V Smith.

At least 181 records · Page 10Linked to original sources
PubMed1985

Effects of N-acetylcysteine on acetaminophen covalent binding and hepatic necrosis in mice.

Experiments were designed to test whether the protective effect of N-acetylcysteine against acetaminophen hepatotoxicity precedes arylation of tissue or whether protection occurs after arylation of tissue. Investigation of potential postarylation actions showed that N-acetylcysteine was unable to attenuate the liver necrosis caused by acetaminophen or several other hepatotoxins that act through chemically reactive metabolites. Furthermore, varying the time and route of N-acetylcysteine treatment indicated that the late protection against acetaminophen mortality probably was a consequence of pharmacokinetic factors rather than postarylation intervention in the process of cell death. The antidote was found to inhibit covalent binding of acetaminophen by about 70% when N-acetylcysteine protected against liver necrosis. Treatment regimens that had no effect upon covalent binding also had no effect on acetaminophen hepatotoxicity. Previous failures to detect this relationship apparently occurred because of a failure to consider biological events important in the pathophysiology of acetaminophen-induced necrosis, particularly the marked intrahepatic hemorrhage and vascular congestion with liver engorgement by protein and fluid. These results support the hypothesis that sulfhydryl nucleophiles such as N-acetylcysteine act primarily through prearylation mechanisms to decrease the amount of reactive metabolite available for initiation of hepatic injury.

Acetaminophen↗
PubMed1985

Pharmacokinetics of the toxic hydrazino metabolites formed from isoniazid in humans.

The plasma concentrations of isoniazid and its hydrazino metabolites, acetylisoniazid, acetylhydrazine and diacetylhydrazine, were measured by gas chromatography-mass spectrometry in 12 healthy subjects after the ingestion of 300 mg of isoniazid. The area under the plasma concentration-time curve of acetylisoniazid and diacetylhydrazine increased with increasing rate of acetylation of isoniazid. In contrast, the area under the plasma concentration-time curve of acetylhydrazine, the postulated precursor of a toxic metabolite formed from isoniazid, was greater in slow acetylators. This occurred even though rapid acetylators generated more acetylisoniazid and thus more acetylhydrazine from isoniazid, because the rapid acetylators also acetylated acetylhydrazine faster to diacetylhydrazine than did the slow acetylators. Due to this complex relationship between area under the plasma concentration-time curve of acetylhydrazine and the rate of isoniazid acetylation (i.e., a faster rate of formation of acetylhydrazine is accompanied by a faster clearance to diacetylhydrazine), the rate of acetylation of isoniazid minimally influences the exposure of most patients to acetylhydrazine. This pharmacokinetic analysis, however, also shows that the apparent plasma half-life of acetylhydrazine is about five times longer than the plasma half-life of isoniazid, and thus repeated doses of isoniazid should lead to an accumulation of acetylhydrazine in the slowest acetylators in which the plasma half-life of acetylhydrazine is 20-plus hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1984

Biliary excretion of glutathione and glutathione disulfide in the rat. Regulation and response to oxidative stress.

Regulation of the biliary excretion of reduced glutathione (GSH) and glutathione disulfide (GSSG) and responses to selected model toxins were examined in male Sprague-Dawley rats. In control and phenobarbital-pretreated rats in which the intrahepatic concentration of GSH was modulated by the administration of diethyl maleate or acetaminophen, the biliary concentration of GSH was consistently lower than, but directly proportional to, the intrahepatic concentration of GSH. Furthermore, increments in bile flow produced by the infusion of sulfobromophthalein (BSP)-glutathione were associated with proportional increases in the biliary excretion of GSH, suggesting that GSH passes into bile passively along a concentration gradient. In contrast, GSSG appears to be secreted into bile against a steep concentration gradient. An increased hepatic production and biliary excretion of GSSG resulted from the administration of t-butyl hydroperoxide. Measurement of biliary GSSG and BSP during a constant infusion of the GSH adduct of BSP indicated that GSSG shares a common excretory mechanism with GSH adducts. Diquat, nitrofurantoin, and paraquat also markedly stimulated the biliary excretion of GSSG. On a molar basis, these compounds generated much more GSSG than a direct substrate for glutathione peroxidase such as t-butyl hydroperoxide, indicating that the compounds undergo redox-cycling with concomitant production of hydrogen peroxide. Aminopyrine (0.8 mmol/kg) also significantly increased biliary GSSG. This increase, however, was associated with a proportional increase in bile flow and in the biliary excretion of GSH such that the GSSG/GSH ratio in bile did not change. Acetaminophen and chloroform, two compounds generating electrophilic metabolites that deplete intrahepatic GSH, led to a progressive decrease in the biliary excretion of GSH and GSSG. Furosemide and dimethylnitrosamine, the electrophilic metabolites of which do not deplete hepatic GSH, minimally altered biliary GSH and GSSG. Similarly, carbon tetrachloride and iproniazid, which yield organic radical metabolites that can peroxidize membrane lipids, did not increase the biliary excretion of GSSG. This finding indicates that membrane-bound lipid hydroperoxides may not be good substrates for glutathione peroxidases. The measurement of the biliary excretion of GSSG and of the GSSG/GSH ratio in bile is a sensitive index of oxidative stress in vivo and thus complements other in vivo parameters for the study of reactive intermediates of xenobiotics such as the determination of covalent binding, the formation of lipid hydroxy acids, and the depletion of intracellular GSH.

Acetaminophen↗
PubMed1984

Free radicals in vivo. Covalent binding to lipids.

As one means of determining the extent to which free radical metabolites are involved in the interaction of hepatotoxic drugs with target tissues, we have measured the covalent binding to hepatic lipids of carbon tetrachloride, acetaminophen, 2-furamide, furosemide, dimethylnitrosamine, and bromobenzene. Transesterification of the Folch lipid fraction was required to distinguish radioactive label present but not covalently bound to alkyl residues through radical addition or combination reactions. Although all hepatotoxins were covalently bound to hepatic protein in the range of 1-2 nmoles/mg, thereby confirming tissue alkylation by reactive metabolites under the present experimental conditions, only carbon tetrachloride gave significant covalent binding to the alkyl residues of hepatic lipids (4.34 nmoles/mg). Thus, although these data further support the already well-documented role of a free radical in the reaction of carbon tetrachloride with target tissue molecules, none of the other hepatotoxins gave similar indications. Dimethylnitrosamine did give significant covalent binding to lipids, but the removal of the binding by transesterification indicates that the binding apparently resulted from electrophilic attack on nucleophilic centers present in phospholipids rather than from radical attack on electroneutral alkyl residues of the lipids.

Acetaminophen↗
PubMed1983

High-performance liquid chromatography and gas chromatography-mass spectrometry determination of specific lipid peroxidation products in vivo.

Peroxidation of membrane lipids has been implicated in the toxicity of reactive oxygen intermediates and of several hepatotoxins, but the specific products of this peroxidation in vivo have not been chemically identified. A method for the isolation, identification, and quantitation of specific lipid hydroperoxy and hydroxy acids formed in vivo has been developed. Hydroxylated derivatives of linoleic, arachidonic, and docosahexaenoic acids formed in mouse liver phosphatidylcholines following carbon tetrachloride administration were isolated by high-pressure liquid chromatography and identified as the trimethylsilyl ether methyl ester derivatives by gas chromatography-mass spectrometry. This methodology should be important for the investigation of the role of lipid peroxidation in a variety of normal physiologic and pathologic processes.

Animals↗
PubMed1982

The nonstress test: the false negative test.

The nonstress test (NST) has been shown to be a reliable technique for the evaluation of fetal status. As a rule, a reactive NST, as opposed to a nonreactive NST, has been associated with a good pregnancy outcome. Nonetheless, fetal death has followed a reactive test. Because of the uncommon occurrence of a false negative NST, a retrospective investigation of the 2,226 patients who had undergone 4,500 NSTs was undertaken. Of these high-risk pregnancies, 1,564 women were delivered within 7 days of a reactive NST and there were four fetal deaths (0.026%). The presumed etiology for the four deaths was cord accident in three cases and abruptio placentae in one case. As with the false negative contraction stress test, the false negative NST appears to be associated with cord accidents, congenital anomalies, and abruptio placentae. Even though a reactive NST is associated with a low incidence of fetal death, close attention to the presence of fetal heart rate decelerations on the NST may be helpful in identifying those patients at risk for a cord accident and, theoretically, in reducing the incidence of fetal death. Even then, certain unavoidable situations can occur soon after a reactive NST, and, at present, no test of fetal well-being offers complete reassurance.

False Negative Reactions↗
PubMed1976

Flammability of disposable surgical drapes.

We discuss the high degree of flammability of disposable surgical drapes. The results of two separate tests and corresponding photographs are presented to verify the flammability. We stress the importance of the flame spread rate.

Disposable Equipment↗
PubMedDate not supplied

Influence of intravenous fentanyl on fetal biophysical parameters during labor.

The short-acting opioid fentanyl has been shown to be a useful analgesic during labor. The purpose of this prospective, comparative investigation was to determine whether fentanyl influenced fetal biophysical parameters during labor. Twenty-four uncomplicated pregnancies at 37-41 weeks were studied during the early active phase of labor. Those patients who requested analgesia (study group) were given a standard 50-micrograms dose of fentanyl intravenously. The study (N = 12) and control (N = 12) groups were similar in maternal age, parity, and gestational age distribution. Fetal body and breathing movements and heart rate patterns were evaluated continuously for 80 min at 10-min epochs. Unlike the control group, fetuses exposed to fentanyl had fewer body movements between contractions (P < 0.03) and spent less overall time moving (P < 0.02). Breathing was abolished at 10 min postdosing in all fetuses exposed to fentanyl but not in the control group. The FHR beat-to-beat variability was reduced between contractions for the first 30 min in 8 (66%) of study cases and none of the control cases (P < 0.01). A sine wave-like FHR pattern was observed for 30 min in two fetuses exposed to fentanyl. All infants had 1- and 5-minute Apgar scores > 6, an umbilical artery pH > 7.20, and no need for resuscitation. In conclusion, an intravenous dose of fentanyl during early active labor was associated with temporary depressant effects on many fetal biophysical parameters without apparent harm being observed at delivery.

Analgesics, Opioid↗
PubMedDate not supplied

Cimetidine inhibits the formation of the reactive, toxic metabolite of isoniazid in rats but not in man.

The hepatotoxicity of isoniazid in rats results from the metabolic activation of acetylhydrazine, a metabolite of isoniazid, by the cytochrome P450 monooxygenase system. Inhibition of the drug-metabolizing enzyme system with a compound suitable for clinical use such as cimetidine might therefore prevent liver injury in experimental animals and in patients on isoniazid without interfering with the antituberculous activity of the drug. To test this hypothesis, we studied the effect of cimetidine on acetylhydrazine-induced hepatocellular necrosis in rats and the formation of 14CO2 from [14C]acetylisoniazid, which provides an indirect assessment of the fraction of a dose of isoniazid metabolized via the toxifying pathway. Pretreatment of rats with 150 mg per kg of cimetidine significantly decreased the extent of hepatocellular necrosis produced by 100 mg per kg of acetylhydrazine and the formation of 14CO2 from [14C]acetylisoniazid. In man, however, 300 mg of cimetidine administered every 6 hr did not decrease the formation of 14CO2 from [14C] acetylisoniazid administered concomitantly with 300 mg of isoniazid; similarly, cimetidine did not affect the urinary excretion of isoniazid, acetylisoniazid, acetylhydrazine and diacetylhydrazine. These data demonstrate that the mechanistic information obtained in animal models cannot be applied readily in clinical practice and that measurable inhibition of acetylhydrazine metabolism to prevent isoniazid liver injury does not occur after administration of therapeutic doses of cimetidine to patients.

Animals↗