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Biomedical subjects

R G Knodell

Publications and source records attributed to R G Knodell.

At least 37 records · Page 2Linked to original sources
PubMed1984

Budd-Chiari syndrome in a patient with the lupus anticoagulant.

Lupus anticoagulant is an immunoglobulin that interferes with prothrombin conversion to thrombin and is manifested biochemically by prolongation of the partial thromboplastin time. Paradoxically, bleeding is rare in association with this anticoagulant, and deep leg vein thromboses, pulmonary emboli, and cerebrovascular accidents have been described in patients with this clotting inhibitor. This report describes the first case of Budd-Chiari syndrome associated with the lupus anticoagulant. The patient presented with abdominal pain and massive ascites. The Budd-Chiari syndrome was confirmed by liver biopsy and venography. No medical condition known to predispose to an increased thrombotic tendency could be identified, and the presence of the lupus anticoagulant in the patient's plasma may provide an explanation for his hypercoagulability and development of the Budd-Chiari syndrome.

Adult↗
PubMed1984

Effects of parenteral and enteral hyperalimentation on hepatic drug metabolism in the rat.

Whereas patients receiving parenteral hyperalimentation frequently have abnormalities in serum liver enzymes, the influence of i.v. administration of hypertonic glucose-protein solutions on hepatic function has received little attention. Recent data from this laboratory indicated that in vivo clearance of pentobarbital was significantly decreased in rats receiving total parenteral hyperalimentation (TPN) vs. animals receiving the same hyperalimentation solution enterally (total enteral hyperalimentation; TEN). To determine the cause of this decreased clearance, we have analyzed mixed-function oxidase activity in hepatic microsomes prepared from livers of rats receiving 7 day continuous i.v. or i.g. infusions of hypertonic glucose (25%) combined with fibrin hydrolysate or crystalline amino acids. Hepatic microsomal cytochrome P-450 and capacity for demethylation of meperidine and hydroxylation of pentobarbital were significantly reduced in TPN animals as compared to TEN and ad libitum chow-fed control rats. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of microsomal protein revealed increased staining of a 46,500 molecular weight band and decreased intensity of a 52,700 molecular weight band in TPN experiments as compared to TEN studies. Increasing amino acid concentration in infusions to 4.25% from the standard 2.75% resulted in marked reductions in hepatic microsomal drug metabolism in enterally hyperalimented animals. These studies show that the route of alimentation delivery has an important influence on hepatic drug metabolic function in rats and suggest that quantitative and/or qualitative differences in hepatic delivery of protein may be responsible for the quantitative and qualitative differences in hepatic microsomal mixed-function oxidases observed between TPN and TEN animals. If similar changes occur in humans receiving TPN, major alterations in drug regimens may be required.

Amino Acids↗
PubMed1984

Effect of cholestasis on hepatic transport of 99mtechnetium p-isopropyl-iminodiacetic acid.

Hepatobiliary imaging with 99mTc-p-isopropyl-iminodiacetic acid (PIPIDA) and other acetanilidoiminodiacetic acid derivatives is a frequently used clinical tool in evaluating patients with jaundice. However, there has been little objective assessment of the effects of cholestasis on hepatic transport of acetanilioiminodiacetic acid derivatives. In our studies, transport of 99mTc-PIPIDA by isolated rat hepatocytes obtained from animals with extrahepatic obstruction secondary to bile duct ligation or intrahepatic cholestasis induced by ethinyl estradiol therapy was determined. Uptake constants for 99mTc-PIPIDA by hepatocytes isolated from livers of animals with ligated bile ducts were significantly decreased compared with uptake by liver cells from sham-operated controls (0.0030 +/- 0.0003 vs. 0.0089 +/- 0.0010 femtomole X 10(6) cells-1 X min-1 X pmol/L-1; p less than 0.001). Hepatocytes isolated from livers of animals given ethinyl estradiol also demonstrated significantly reduced 99mTc-PIPIDA uptake compared with controls given propylene glycol (0.0034 +/- 0.0002 vs. 0.0060 +/- 0.0004 fmol X 10(6) cells-1 X min-1 X pmol/L-1; p less than 0.001). Fractional rates of efflux of the study compound from hepatocytes preincubated with 99mTc-PIPIDA were significantly decreased in experiments using ethinyl estradiol (p less than 0.005) but did not differ significantly from controls in studies of bile duct ligation. 99mTc-PIPIDA uptake was significantly decreased in the presence of high bile salt concentrations (100 to 200 mumol/L), but unconjugated bilirubin concentrations as high as 200 mumol/L (approximately 12 mg/dl) had no effect on hepatocyte uptake of the ligand. The finding that cholestasis significantly impairs hepatocyte uptake of 99mTc-PIPIDA provides a possible explanation for the clinical observation that a patent biliary tree and normal serum bilirubin level are not always sufficient to ensure normal hepatobiliary imaging. These data also suggest that elevation of bile acid levels during cholestasis may either contribute to impaired uptake of hepatobiliary imaging agents or serve as a marker of cholestasis-induced abnormalities in the liver functions responsible for hepatic transport of these compounds.

Alkaline Phosphatase↗
PubMed1984

Ascorbic acid protects against acetaminophen- and cocaine-induced hepatic damage in mice.

Administration of large doses of acetaminophen or cocaine to male CD-1 mice produces significant hepatic injury with marked elevation in serum glutamate-pyruvate transaminase activity and severe hepatocellular necrosis. The proposed mechanism for this phenomenon is activation of both parent compounds to hepatotoxic metabolites. Ascorbic acid, 1 g/kg, given to mice 1 hour before and 1 hour after either acetaminophen or cocaine treatment prevented development of the severe hepatocellular damage observed with administration of either drug alone. Plasma disappearance of acetaminophen was less rapid in ascorbic acid-treated animals, suggesting that in vivo metabolism of acetaminophen was altered by ascorbic acid treatment. However, ascorbic acid treatment alone produced a modest decrease in hepatic glutathione content and did not prevent marked hepatic glutathione depletion when administered concomitantly with acetaminophen. Furthermore, a 2-mM ascorbic acid concentration did not alter in vitro hepatic microsomal metabolism of cocaine as measured by formaldehyde formation. While the mechanism(s) for its protective effect remains to be elucidated, these results raise the possibility that ascorbic acid may be useful in preventing hepatic injury caused by some hepatotoxic drugs.

Acetaminophen↗
PubMed1983

Acute effects of nicotinic acid on hepatic transport of 99mTc-PIPIDA.

Hepatic injury has been associated with nicotinic acid treatment of schizophrenia and hypercholesterolemia. This association was implicated when the liver and biliary tract were not visualized after 99mTc-HIDA in a patient taking 3 g daily of nicotinic acid. We studied hepatic transport of 99mTc-PIPIDA both in vitro in isolated hepatocytes and in vivo in rabbits pretreated with nicotinic acid to further examine this association. Nicotinic acid increased uptake of PIPIDA by isolated hepatocytes and 7 days of nicotinic acid treatment in rabbits produced no abnormalities in hepatic uptake, gallbladder visualization, or biliary excretion of PIPIDA. We conclude that nicotinic acid does not have an inhibitory effect on uptake of biliary imaging agents and actually may be useful in enhancing hepatic imaging in patients with reduced liver function.

Animals↗
PubMed1983

Prevention of acetaminophen and cocaine hepatotoxicity in mice by cimetidine treatment.

Hepatotoxicity occurs in animals after administration of large doses of acetaminophen and cocaine and is thought to result from production of reactive metabolites of these parent drugs by cytochrome P450. Because cimetidine binds to cytochrome P450 and inhibits hepatic drug metabolism in both humans and animals, we determined the effects of cimetidine coadministration on acetaminophen and cocaine hepatotoxicity in mice. Marked elevations of serum glutamic pyruvic transaminase and severe pericentral hepatocellular necrosis occurred in animals receiving intraperitoneal doses of 350 mg/kg acetaminophen or 35 mg/kg cocaine, while minimal serum glutamic pyruvic transaminase elevations and liver necrosis were seen in animals who also received 100 mg/kg cimetidine 1 h before and 1 h after administration of either acetaminophen or cocaine. Consistent with the hypothesis that these in vivo protective effects resulted from interaction with cytochrome P450, cimetidine inhibited in vitro hepatic microsomal metabolism of cocaine. However, despite its protective effect against acetaminophen-induced hepatic injury, concomitant administration of cimetidine did not significantly affect plasma pharmacokinetics of acetaminophen, prevent depletion of hepatic glutathione after acetaminophen administration, or alter in vivo covalent binding of [3H]acetaminophen to hepatic proteins. These studies suggest that current theories regarding production of acetaminophen-induced liver damage require reexamination. The possibility that cimetidine treatment might be useful in preventing hepatic damage due to acetaminophen and other hepatotoxins in humans is intriguing and also warrants consideration.

Acetaminophen↗
PubMed1982

Drug metabolism by rat and human hepatic microsomes in response to interaction with H2-receptor antagonists.

Cimetidine has been reported to decrease plasma clearance of drugs in humans and animals. This reduction in hepatic drug metabolism could be due to cimetidine's intrinsic H2-receptor blocking activity. Alternatively, the imidazole ring structure of cimetidine could explain these observations because imidazole derivatives have been reported to be potent inhibitors of hepatic microsomal drug metabolism. Rat and human hepatic microsomal drug metabolism in the presence of cimetidine and ranitidine, a nonimidazole H2-receptor antagonist, have been studied. High binding affinity of cimetidine for cytochrome P 450(Ks = 31 micro M) was seen, while no evidence for ranitidine binding to cytochrome P450- was observed. Cimetidine inhibited meperidine and pentobarbital metabolism by both rat and human hepatic microsomes while ranitidine did not affect these two cytochrome P450-medicated biotransformation reactions. Conjugation of morphine, a reaction not mediated by cytochrome P450, was unaffected by either cimetidine or ranitidine. The imidazole structure of cimetidine rather than its H2-receptor blocking activity is primarily responsible for cimetidine-induced inhibition of hepatic drug metabolism.

Animals↗
PubMed1982

Effects of ethinyl estradiol on pharmacokinetics of meperidine and pentobarbital in the rat.

Effects of estrogen administration on in vivo hepatic microsomal drug metabolism have been frequently assessed, but there has been little study of the effects of estrogen treatment on in vivo drug pharmacokinetics. After administration of ethinyl estradiol (5 mg/kg daily for 5 days), meperidine and pentobarbital pharmacokinetics were determined both in vivo and in the isolated perfused rat liver. Estrogen pretreatment caused a 45% reduction in systemic meperidine clearance in vivo and perfusate disappearance of both meperidine and its major metabolite, normeperidine, was slower in isolated liver experiments from ethinyl estradiol-treated animals as compared with propylene glycol-treated controls. In contrast to meperidine, clearance of pentobarbital was not decreased by estrogen treatment. These studies demonstrate that estrogen treatment singularly can alter drug pharmacokinetics in the rat and raise the question as to whether clinically important alterations in drug pharmacokinetics occur in humans receiving estrogen therapy.

Animals↗
PubMed1982

Effects of liver congestion on hepatic drug metabolism in the rat.

Pharmacokinetic alterations in drug disposition have been demonstrated for a variety of hepatic disease states, but there is little information concerning the effects of elevated hepatic venous pressure on hepatic drug metabolism. A rat model of hepatic congestion which was characterized by significantly elevated hepatic venous pressure, marked prolongation of prothrombin time, reduced total hepatic blood flow and histological changes of marked pericentral fibrosis and central vein dilation was used to study the effects of liver congestion on hepatic microsomal biotransformation and in vivo disposition of morphine and pentobarbital. No significant differences in levels of microsomal cytochrome P-450 or NADPH-dependent cytochrome c reductase were seen between the two groups. Total hepatic microsomal capacity for glucuronidation of morphine and hydroxylation of pentobarbital was not altered by elevated hepatic vein pressure and no change in in vivo systemic clearance was seen for either drug in response to hepatic venous congestion. These animal data demonstrate that hepatic congestion produces minimal alterations in hepatic metabolism of morphine and pentobarbital and may not have the severe detrimental effects on drug biotransformation and disposition which would be predicted.

Animals↗
PubMed1981

Vitamin C prophylaxis for posttransfusion hepatitis: lack of effect in a controlled trial.

In vitro data suggest that vitamin C alters numerous parameters of immune function and might have potential as an agent which prevents infection. When an uncontrolled Japanese trial claimed efficacy of vitamin C in preventing posttransfusion hepatitis, a randomized double-blind controlled trial was initiated to determine if this claim of vitamin C efficacy could be confirmed. For 2 days before surgery and 2 wk after operation, cardiac surgery patients received orally either a lactose placebo or 800 mg of vitamin C four times daily. One hundred seventy-five patients completed the study. Highly significant elevations of plasma vitamin C were seen in the vitamin C treatment group as compared to the placebo group (p < 0.0005), but no significant difference in the incidence of posttransfusion hepatitis (p < 0.50) or the clinical course of hepatitis was seen between the two treatment groups.

Alanine Transaminase↗
PubMed1981

HLA antigen frequencies in cirrhotic and noncirrhotic male alcoholics: a controlled study.

Although epidemiological data suggest that the development of cirrhosis in alcohol abusers is related to the duration and amount of ethanol intake, the fact that only a small percentage of alcohol abusers develop cirrhosis remains unexplained and suggests a possible predisposing genetic factor. Several previous studies have reported an association between various human leucocyte antigens (HLA) and alcoholic cirrhosis. In this study HLA antigen frequencies were determined in Anglo- and Spanish-American cirrhotic and noncirrhotic alcoholics and in a control group of nonalcoholic patients without liver disease. No statistically significant differences in HLA frequencies among the groups were found. Our comparisons of HLA frequencies between cirrhotic and noncirrhotic alcoholic patients do not support the hypothesis that individual susceptibility to the development of alcoholic cirrhosis is genetically determined.

Alcohol Drinking↗
PubMed1980

Alterations in pentobarbital pharmacokinetics in response to parenteral and enteral alimentation in the rat.

Recent in vitro observations suggest that the intestine, in addition to the liver, may be an important organ of first-pass drug metabolism. While a variety of changes in intestinal morphology and function in response to continuous parenteral and enteral nutrition have been documented, the effect of different routes of alimentation on intestinal drug metabolism has not been previously investigated. Objectives of this study were to assess the contribution of intestinal pentobarbital metabolism to overall in vivo pentobarbital pharmacokinetics in the rat and to determine if differences in pentobarbital pharmacokinetics were seen between parenterally and enterally nourished animals. After 7 days of continuous infusion of amino acid-glucose mixture via a gastric or jugular vein catheter, pharmacokinetic parameters were determined after 40 mg/kg of pentobarbital was given orally or into the portal or femoral vein. Reduced systemic availability of pentobarbital after oral administration as compared to portal vein injection was seen in both alimentation groups indicating that significant intestinal metabolism of pentobarbital occurred in vivo. Total area under the pentobarbital plasma concentration-time curve was significantly greater in parenterally nourished animals as compared with enterally alimented animals after oral, portal vein and systemic vein drug administration. Differences in pentobarbital, pharmacokinetics between the two alimentation groups appeared to be primarly due to effects on hepatic pentobarbital metabolism. While the mechanism producing these changes has not been defined, differences in gut hormones release and/or pancreatic secretion in response to the two routes of alimentation may be contributory. The widespread use of enteral and parenteral alimentation in clinical medicine suggests that studies to determine if nutrition route of administration similarly influences drug metabolism in humans may be indicated.

Administration, Oral↗
PubMed1980

Alterations in pentobarbital and meperidine pharmacokinetics induced by bile duct ligation in the rat.

Although impaired microsomal drug metabolism has been demonstrated in response to bile duct ligation, there has been little previous assessment of the effects of extrahepatic biliary obstruction on drug pharmacokinetics in vivo. In this study, the effects of bile duct ligation on overall disposition on pentobarbital and meperidine in the rat have been assessed in vivo and in isolated perfused rat livers. A significant reduction in clearance of both compounds was seen in response to bile duct ligation. No change in protein binding of either drug was demonstrated, but alterations in initial volume of distribution of both drugs occurred in response to extrahepatic biliary tract obstruction. A significant reduction in the rate of perfusate flow was also seen in perfused liver experiments using livers from animals with previous bile duct ligation. Reduction in clearance of both a high extraction drug (meperidine) and a lower extraction drug (pentobrbital) in response to bile duct ligation suggests that both hepatic blood flow and drug metabolizing enzyme activity may be altered by extrahepatic biliary tract obstruction.

Animals↗