Interferenz von Diazepam und Pentobarbital an der Ratte und am Menschen

Heubel, Friedrich

doi:10.1007/bf02431442

Cited by 8 publications

(5 citation statements)

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“…more significant with mevalonate than with acetate reticulum. Diazepam is a highly lipid-soluble drug, metabolized in animals by liver microsomal enzymes (Heubel, 1969) and is able to lower serum bilirubin in newborn hyperbilirubinaemia (Heubel and Muehlberger, 1972). In Wistar rats, the administration of Diazepam (from 5 to 20 mg per kg i.p.…”

Section: Discussionmentioning

confidence: 99%

“…In man, N-demethylation, 3hydroxylation and glucuro-conjugation of derivative oxazepam are the main metabolic steps (Schwartz et aZ., 1965). Diazepam accelerates pentobarbital metabolism in man (Heubel, 1969) and is able to lower serum bilirubin in newborn hyperbilirubinaemia (Heubel and Muehlberger, 1972). In Wistar rats, the administration of Diazepam (from 5 to 20 mg per kg i.p.…”

Section: Phenobarbital and Othermentioning

confidence: 99%

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Hepatic Cholesterol Synthesis in Man: Effect of Diazepam and Other Drugs†

Orlandi

Bamonti

Dini

et al. 1975

Eur J Clin Investigation

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The hepatic synthesis of cholesterol-measured as incorporation of 14C-acetate into digitonin-precipitable sterols-has been evaluated in needle biopsy material of normal untreated patients and patients under short-term treatment with Diazepam, Phenobarbital, Chlorpromazine or Diphenylhydantoin. A significant increase of cholesterol synthesis was observed in the first two groups with much higher levels of incorporation in the Diazepam-treated patients. Moreover in this group the levels were still elevated from 4 to 7 days after drug withdrawl. Ultrastructural and morphometric studies performed on the same biopsy material showed a significant increase of smooth endoplasmic reticulum in hepatocytes of Diazepam-treated patients; in addition, there seemed to be a positive correlation between the increased cholesterol synthesis and the formation of areas of non vesicular, type 2, smooth endoplasmic reticulum. These findings suggest an early stimulation of the liver cell microsomal system by Diazepam in man; they also point to side effects of some drugs, which are not predictable from studies in Wistar rats.

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Section: Discussionmentioning

confidence: 99%

Section: Phenobarbital and Othermentioning

confidence: 99%

Hepatic Cholesterol Synthesis in Man: Effect of Diazepam and Other Drugs†

Orlandi

Bamonti

Dini

et al. 1975

Eur J Clin Investigation

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“…Further studies would be needed to metabolism (Marcucci et al, 1970). In rat, it has been claimed that diazepam reduces sleeping time and increases liver weight (Heubel, 1969) but no changes in liver weight, hepatic cholesterol synthesis, cytochrome P-450 levels, or hepatic ultrastructure have followed the administration of diazepam (10 mg/kg ip) for six days to rats or guinea-pigs (unpublished observations). In man, diazepam seems to affect the bilirubin levels in newborn and interfere with phenobarbital metabolism (Heubel, 1969;Heubel and Muhlberger, 1972).…”

Section: Discussionmentioning

confidence: 99%

“…In rat, it has been claimed that diazepam reduces sleeping time and increases liver weight (Heubel, 1969) but no changes in liver weight, hepatic cholesterol synthesis, cytochrome P-450 levels, or hepatic ultrastructure have followed the administration of diazepam (10 mg/kg ip) for six days to rats or guinea-pigs (unpublished observations). In man, diazepam seems to affect the bilirubin levels in newborn and interfere with phenobarbital metabolism (Heubel, 1969;Heubel and Muhlberger, 1972). In addition, and contrary to rats or guinea-pigs, the administration of diazepam to human subjects is followed by ultrastructural changes in hepatocytes together with increased hepatic cholesterol synthesis, as shown in the present study.…”

Section: Discussionmentioning

confidence: 99%

A morphometric study of the endoplasmic reticulum in human hepatocytes : Correlation between morphological and biochemical data in subjects under treatment with certain drugs

Jézéquel¹,

Koch²,

Orlandi³

1974

Gut

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SUMMARYThe distribution of the endoplasmic reticulum in human hepatocytes is defined in quantitative terms using the techniques of morphometry. The subjects of the study are liver biopsies from normal, untreated subjects and patients being treated with various drugs. In contrast to rat hepatocytes, the amount of smooth endoplasmic reticulum (SER) in man exceeds that of the rough endoplasmic reticulum (RER) and accounts for 76.3 % of the total endoplasmic reticulum. This is to be taken into consideration in pharmacological or toxicological studies. In addition, two components of the SER have been identified: more prominent is the type 1 or vesicular which has a regular honeycomb pattern, made up ofcisternae with patent lumina and a mean width of 1500 A; the type 2, or non-vesicular, occurs in discrete foci of densely packed smooth membranes with a spacing of about 140 A. In subjects under short-term treatment with Benzodiazepin (diazepam) the RER remained unchanged but the SER membranes were significantly increased with a remarkable, twoto threefold increase of the SER type 2 in three out of four patients. A rise in incorporation of 14C-acetate into digitonin-precipitable sterols as measured in liver biopsy material was also noted in these three patients. The suggestion is made that the SER 2 represents the newly formed membranes whereas the SER 1 would represent 'adult' membranes. No changes were observed in two patients under short-term treatment with phenobarbital or Dilantin.A few morphometric studies have already been conducted on animal liver in normal (Loud, 1968;

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“…Different effects in different subjects are not unexpected because surgery under general anaesthesia is associated both with factors known to increase, and with factors known to decrease drug metabolism. (1) Many drugs used for premedication or anaesthesia in these patients (Table 2), including diazepam (Heubel, 1969), halothane (Cascorbi, Blake & Helrich, 1970;Linde & Berman, 1971), hydroxyzine (Kato, Chiesara &Vassanelli, 1964), nitrous oxide (Remmer, 1962), phenobarbital and thiopental (loannides & Parke, 1965;Valerino, Vesell, Aurori & Johnson, 1974) have been shown to induce the activity of hepatic drug-metabolizing enzymes; trimeprazine is likely to be an inducer as are a number of phenothiazine derivatives (Conney, 1967); in addition, it cannot be excluded that some of the drugs administered after surgery in these patients (Table 3), albeit not listed as drugs inducing drug metabolism (Conney, 1967;Thebault-Lucas & Tillement, 1977), might nevertheless be yet unknown inducers. (2) Surgery may be followed by inflammation, fever and nitrogenfree infusions, all factors that are known to depress the activity of drug-metabolizing enzymes (Perrey, Jonen, Kahl & Jihnchen, 1976;Whitehouse & Beck, 1973;Elin, Vesell & Wolff, 1975;Trenholme, Williams, Rieckmann, Frischer & Carson, 1976;Alvares, Anderson, Conney & Kappas, 1976;Kappas, Anderson, Conney & Alvares, 1976).…”

Section: Discussionmentioning

confidence: 99%

Effect of surgery under general anaesthesia on antipyrine clearance.

Pessayre¹,

Allemand²,

Benoist³

et al. 1978

Brit J Clinical Pharma

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1 The effect of surgery under general anaesthesia on drug metabolism was investigated in man. The activity of hepatic drug‐metabolizing enzymes was evaluated by measurement of antipyrine clearance, before surgery and 3 days after surgery, in eighteen patients. 2 In those patients in whom the operation lasted 2 h or less, the postoperative clearance of antipyrine was significantly (P less than 0.05) increased by 48%; in those patients in whom the operation lasted 2–4 h, it was non‐significantly decreased by 36%; in those patients in whom the operation lasted more than 4 h, it was significantly decreased by 47% (P less than 0.01). 3 It is concluded (a) that short operations are followed by increased activity of hepatic drug‐metabolizing enzymes, whereas (b) protracted operations are followed by decreased activity. It is suggested (a) that the former effect may be a consequence of enzyme induction by drugs used for premedication and anaesthesia, whereas (b) the latter effect may be the result of major surgical trauma.

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Interferenz von Diazepam und Pentobarbital an der Ratte und am Menschen

Cited by 8 publications

References 0 publications

Hepatic Cholesterol Synthesis in Man: Effect of Diazepam and Other Drugs†

Hepatic Cholesterol Synthesis in Man: Effect of Diazepam and Other Drugs†

A morphometric study of the endoplasmic reticulum in human hepatocytes : Correlation between morphological and biochemical data in subjects under treatment with certain drugs

Effect of surgery under general anaesthesia on antipyrine clearance.

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