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  • 1
    ISSN: 1432-8798
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Application of 50–100 μg/ml of compound 48/80 induces vacuolation of the cytoplasma of rabbit kidney cell cultures. These vacuoles originate from activated lysosomes. Comparison of structure analoges of the monomer of compound 48/80 with compound 48/80 and Resochin® in respect to the inhibition of giant cell formation, activation of lysosomes and release of histamine indicate that induction of these phenomena depend on the drug concentration used: Resochin® activates lysosomes already at a concentration of 1 μg/ml, whereas 50 μg/ml are necessary to inhibit the formation of giant cells. Resochin never stimulates the release of histamine. With compound 48/80, however, release of histamine has been demonstrated at a concentration of 0.1 μg/ml, inhibition of giant cell formation at 10 μg/ml and activation of lysosomes at 50 μg/ml. These data suggest that in respect to the three phenomena the compounds probably are characterized by different reaction mechanisms. Lysosomal enzymes do not induce the herpesvirus-induced giant cell formation.
    Notes: Zusammenfassung Nach Anwendung von 50 bis 100 μg Compound 48/80 pro ml treten im Zytoplasma von Kaninchennierenzellen Vacuolen auf. Sie gehen durch Autolyse aus den aktivierten Lysosomen hervor. Vergleichsuntersuchungen mit Strukturverwandten des Monomers von Compound 48/80 und mit Resochin® hinsichtlich der Hemmung der Riesenzellbildung, der Aktivierung der Lysosomen und der histaminfreisetzenden Wirkung haben ergeben, daß die drei genannten Phänomene bei unterschiedlichen Schwellenkonzentrationen ausgelöst werden. Resochin® aktiviert die Lysosomen schon in einer Konzentration von 1 μg/ml, während die Riesenzellbildung erst bei 50 μg/ml blockiert wird. Histamin wird nicht freigesetzt. Demgegenüber setzt Compound 48/80 Histamin schon in einer Konzentration von 0,1 μg/ml frei, die Riesenzellbildung wird mit 10 μg/ml blockiert, und die Lysosomen werden mit 50 μg/ml aktiviert. Aus den Befunden wird gefolgert, daß die drei genannten Phänomene auf unterschiedlichen Wirkungen der jeweils angewandten Substanz beruhen. Die herpesbedingte Riesenzellbildung wird nicht durch lysosomale Enzyme hervorgerufen.
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  • 2
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The kinetics of melphalan leakage into the peripheral blood were studied in 21 patients undergoing hyperthermic isolation perfusion of the upper or lower limb as an adjuvant treatment in high-risk melanoma; in 5 patients cisplatin was added. The melphalan concentrations in the peripheral blood rose predominantly during the first 20 min of perfusion and levelled out to an apparent steady state of about 0.28 μg/ml in upper extremity perfusions, and 0.34 (without cisplatin) and 0.37 μg/ml (with cisplatin) in lower extremity perfusions. Erythrocytes labelled with technetium Tc 99m, which were added concomitantly with melphalan to the perfusion medium, appeared in the systemic circulation of the patients at an almost constant rate of 0.32% (lower and upper limb perfusions without cisplatin and 0.37% (with cisplatin) of total tracer/min. This perfusate flow rate indicated by labelled erythrocytes completely explained the leakage of melphalan from the perfusion circuit into the peripheral blood. Peak concentrations of melphalan in the peripheral blood were observed immediately after reconstitution of normal hemodynamic conditions once isolation perfusion had been teminated. This fraction of melphalan might originate from tissue-binding sites, but also from vascular compartments; therefore, a thorough washing-out procedure might minimize this effect.
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  • 3
    ISSN: 1432-1440
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Wirksamkeit und Wirkungsdauer eines Arzneimittels können beeinflußt werden durch Veränderung seiner Abbaugeschwindigkeit. Alternative Substrate der arzneimittelabbauenden Enzymsysteme in den Lebermikrosomen, zu denen neben anderen Arzneimitteln auch Steroide und Umweltgifte wie Insecticide und carcinogene Kohlenwasserstoffe gehören, können den Stoffwechsel eines Arzneimittels einerseits durch Enzyminduktion beschleunigen, anderseits durch Konkurrenz um die Abbaureaktion hemmen. Fremdstoffe, deren induzierende bzw. hemmende Wirkung auf den Arzneimittelabbau beim Menschen nachgewiesen ist, werden aufgezählt. Besondere Beachtung erfordern Induktions- und Hemmvorgänge bei der Therapie mit Arzneimitteln geringer therapeutischer Breite, wie Anticoagulantien, Antikonvulsiva und oralen Antidiabetica. Alkoholzufuhr kann ebenfalls auf das Tempo des Arzneimittelstoffwechsels einwirken. Wechselwirkungen zwischen Steroidinaktivierung und Fremdstoffabbau in der Leber sind vielfach beschrieben; ihre mögliche Bedeutung bei der Anwendung von Ovulationshemmern wird diskutiert. Eine therapeutische Ausnutzung hat die Induktion der mikrosomalen Enzymsysteme bei der Entgiftung körpereigener Substanzen gefunden, z. B. bei der Prophylaxe des Neugeborenenikterus und beim Cushingsyndrom. Zu den endogenen Faktoren, deren Bedeutung für die Geschwindigkeit des Arzneimittelabbaus tierexperimentell und z. T. auch beim Menschen gezeigt wurde, gehören die genetische Ausstattung des Organismus, das Lebensalter, endokrine Einflüsse von seiten der Gonaden, der Nebenniere und der Schilddrüse und die Stoffwechsellage der Leber z. B. in der Hypoxie und beim Diabetes. Lebererkrankungen führen nur selten zur Beeinträchtigung der Entgiftungsfunktion der Leber.
    Notes: Summary Intensity and duration of drug action can be modified by altering the rate of drug metabolism. Alternative substrates of the hepatic drug metabolizing enzymes such as other drugs, steroids, and environmental chemicals, including insecticides and carcinogenic hydrocarbons, may either accelerate the biotransformation of a drug by enzyme induction or inhibit its breakdown by competing for the hydroxylation reaction. Xenobiotics known to stimulate or to inhibit drug metabolism in man are listed. Attention must be paid to induction and inhibition processes when drugs of a low therapeutic index are applied, e. g. coumarin anticoagulants, anti-convulsants, and oral antidiabetics. Administration of ethanol can also interfere with the rate of drug hydroxylation. Interactions between steroid inactivation and drug metabolism in the liver have frequently been demonstrated; their possible role in the treatment with contraceptive agents is discussed. Induction of the hepatic drug metabolizing enzymes has therapeutical implications for the detoxication of some physiological substances, e. g. bilirubin inicterus neonatorum or steroids in Cushing's syndrome. Among the endogenous factors which have been shown to determine the rate of drug metabolism in animals and in man, genetic patterns, age, and endocrine influences from the adrenals, the gonades, and the thyroid as well as the metabolic situation of the liver in a hypoxic or diabetic state have to be mentioned. Liver diseases rarely impair the velocity of detoxication processes in the liver.
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  • 4
    ISSN: 1432-1440
    Keywords: Nicotine ; Metabolism ; Lung ; Liver ; Phenobarbital ; Cytochrome P-450
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The metabolic fate of cotinine, the major metabolite of nicotine, was studied in phenobarbital-induced and non-induced isolated perfused rat lung and liver and in isolated hepatocytes of rats and mice. The non-induced lung tissue showed low cotinine metabolizing capacity while the perfused liver was approximately four times more active. After phenobarbital pretreatment the metabolism of cotinine was increased eight-fold in the intact liver. A substantial increase in cotinine metabolism was also found in isolated hepatocytes from PB-induced rats and in cultured mouse hepatocytes grown in a medium supplemented with PB. This was paralleled by an increased formation of cotinine-N-oxide which could be inhibited by 100 μM metyrapone. In contrast, the pulmonary elimination of cotinine was not affected by PB. A dominant role of primary N-oxidation of nicotine compared to C-oxidation was apparent in non-induced rat liver. After PB treatment the rate of nicotine-N′-oxide formation dropped markedly while the cotinine related pathways were increased causing an inversion of the N- to C-oxidation ratio. In the lung, cotinine formation was the preferred metabolic pathway of nicotine already in non-induced organs. The pattern of nicotine metabolites was not altered by PB induction. In conscious PB-induced rats receiving nicotine orally or intravenously, 3′-hydroxycotinine was found as the main urinary metabolite of nicotine while only a small fraction was excreted as cotinine-N-oxide. This discrepancy between the profile of nicotine metabolites in perfused liver and lung and in the urine in vivo indicates that extrahepatic organs other than the lung may be important sites of cotinine metabolism.
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  • 5
    ISSN: 1432-1912
    Keywords: Biphenyl metabolism ; Conjugation ; Induction ; Differential inhibition ; Isolated rat liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A differential inhibition of biphenyl hydroxylation by α-naphthoflavone and metyrapone was observed in isolated pefused rat liver. α-Naphthoflavone inhibited 2- and 4-hydroxylation in livers from β-naphthoflavone-pretreated animals but had no effect on both reactions in livers from phenobarbital-pretreated animals. Metyrapone inhibited 2- and 4-hydroxylation in phenobarbital-stimulated livers, but only insignificant inhibition of 2-hydroxylation and a slight enhancement of 4-hydroxylation by metyrapone was observed in β-naphthoflavone-stimulated livers. Conjugation of 2-hydroxybiphenyl and 4-hydroxybiphenyl by isolated perfused livers was also studied. 4-Hydroxybiphenyl preferentially formed sulphates in livers from untreated animals but after induction glucuronidation was as effective as sulphation or even exceeded sulphation. Only glucuronic acid conjugates of 2-hydroxybiphenyl were detected.
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  • 6
    ISSN: 1432-1912
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary For the understanding of the mechanism of histamine liberation from mast cells it is instrumental to know if this process requires cellular energy. For this reason the oxygen uptake of histamine liberating rat peritoneal mast cells was measured. Cells were prepared and purified by density gradient centrifugation in Ficoll solution. Oxygen consumption was measured polarographically with the aid of a micro platinum electrode under carefully controlled conditions. For the recording of oxygen tensions in a volume of 0.1 ml a U-shaped reaction vessel was used. The oxygen uptake was found to be 0.066 ± 0.009 millimicromoles/min per 105 cells. It is not changed when histamine is released by compound 48/80. This result has been substantiated by statistical methods. From these findings the conclusion is drawn that the release of histamine is not accompanied by an increase of oxygen consumption of the mast cells, although presently available evidence suggests it to be an endergonic process.
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  • 7
    ISSN: 1432-1912
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
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  • 8
    ISSN: 1432-1912
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
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  • 9
    ISSN: 1432-1912
    Keywords: O-, N-demethylation ; Liver Microsomes ; Drug Metabolism ; Metyrapone ; Binding Kinetics ; O-, N-Demethylierung ; Lebermikrosomen ; Arzneimittelstoffwechsel ; Metyrapon ; Bindungskinetik
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Kinetic experiments on the inhibition of oxidative microsomal O- and N-demethylations by metyrapone (2-methyl-1,2-bis(3-pyridyl)-1-propanone, Su 4885) were carried out using mouse liver microsomes as the enzyme source. The model substrates were p-nitroanisole and N-monomethyl-p-nitroaniline. It was shown that the inhibition is competitive. Thek i for metyrapone is 0.42 × 10−4 M and for the reduced metabolite of metyrapone 1.15×10−4M. Their spectral dissociation constants as determined from difference spectra, have almost the same values. From this it is concluded that the degree of inhibition is correlated to the amount of metyrapone bound to cytochrome P-450. Metyrapone does not seem to displace naphthalene from its binding to cytochrome P-450. Assuming the simultaneous binding of substrate and inhibitor to different binding sites of the same enzyme, possible mechanisms for explaining competitive inhibition are discussed.
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  • 10
    ISSN: 1432-1912
    Keywords: Metyrapone Metabolism ; Rat Liver Supernatant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The formation of a metabolite of metyrapone by an oxygen sensitive soluble enzyme system in rat liver 105,000×g supernatant has been demonstrated. Enzyme activity requires the intact keto function of metyrapone.
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