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  • 1
    ISSN: 1432-1041
    Keywords: Liver cirrhosis ; Spirapril ; ACE inhibitor ; pharmacokinetics ; haemodynamic effects ; liver function tests
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensinconverting enzyme (ACE) inhibitor, have been investigated in patients with liver cirrhosis (n=10), in patients with chronic, non-cirrhotic liver disease (n=8) and in a control group of healthy subjects (n=16). The absorption and elimination of spirapril did not differ between patients with liver disease and control subjects. In contrast, the bioavailability of spiraprilat, the metabolite responsible for the pharmacological action of spirapril, was significantly reduced in patients (AUC 820 μg·h·l−1, 923 μg·h·l−1 and 1300 μg·h·l−1 in patients with cirrhosis, patients with non-cirrhotic liver disease and in healthy subjects, respectively. Compared to healthy subjects, cirrhotic patients had a reduced rate constant of spiraprilat formation (1.10 h−1 in patients vs. 2.00 h−1 in control subjects) while the elimination half-life of spiraprilat was not different. The effect of spirapril on diastolic blood pressure was decreased in patients with chronic liver disease as compared to the controls. Thus, the pharmacokinetics of spirapril was unchanged in patients with different types of liver disease, including cirrhosis. However, the bioavailability of spiraprilat and hypotensive effect of spirapril were reduced in patients.
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  • 2
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract We used a strategy based on long PCR (polymerase chain reaction) for detection and characterization of mitochondrial DNA (mtDNA) rearrangements in two patients with clinical signs suggesting Pearson syndrome and Kearns-Sayre syndrome (KSS), respectively, and one patient with myopathic symptoms of unidentified origin. Mitochondrial DNA rearrangements were detected by amplification of the complete mitochondrial genome (16.6 kb) using long PCR with primers located in essential regions of the mitochondrial genome and quantified by three-primer PCR. Long PCR with deletion-specific primers was used for identification and quantitative estimation of the different forms of rearranged molecules, such as deletions and duplications. We detected significant amounts of a common 7.4-kb deletion flanked by a 12-bp direct repeat in all tissues tested from the patient with Pearson syndrome. In skeletal muscle from the patient with clinical signs of KSS we found significant amounts of a novel 3.7-kb rearrangement flanked by a 4-bp inverted repeat that was present in the form of deletions as well as duplications. In the patient suffering from myopathic symptoms of unidentified origin we did not detect rearranged mtDNA in blood but found low levels of two rearranged mtDNA populations in skeletal muscle, a previously described 7-kb deletion flanked by a 7-bp direct repeat and a novel 6.6-kb deletion with no repeat. These two populations, however, were unlikely to be the cause of the myopathic symptoms as they were present at low levels (10–40 ppm). Using a strategy based on screening with long PCR we were able to detect and characterize high as well as low levels of mtDNA rearrangements in three patients.
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  • 3
    ISSN: 1432-1041
    Keywords: albendazole ; albendazole sulphoxide ; absorption ; elimination ; benzimidazole ; pharmacokinetics ; echinococcosis ; cholestasis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of albendazole and its main metabolite, albendazole sulphoxide, have been examined after giving a single oral dose of 200 mg albendazole to 19 patients with either Echinococcus multilocularis or E. granulosus, 5 of whom had significant extrahepatic obstruction due to the underlying disease. The AUC of albendazole sulphoxide was increased in the latter patients (mean 122 μmol · h · l−1 compared to 17 μmol · h · l−1 in the non-obstructed group). Obstructed patients had delayed absorption, ka averaging 0.39 compared to 1.41 h−1 in non-obstructed patients. The corresponding elimination rate constant, ke was also prolonged, averaging 0.041 and 0.13 h−1 in the two groups, respectively. Four patients were restudied after complete or partial resolution of the cholestasis. The pharmacokinetic parameters in them had returned towards values comparable to those in the non-obstructed patients.
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  • 4
    ISSN: 1432-1041
    Keywords: Isradipine ; cirrhosis ; systemic ; calcium antagonist ; aminopyrine breath test ; serum bile acids ; galactose elimination ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the dihydropyridine calcium antagonist isradipine has been examined in 8 healthy volunteers, 7 patients with non-cirrhotic chronic liver disease (CLD), and 8 patients with biopsy-proven cirrhosis (CIR). Isradipine was simultaneously given orally (12C 5 mg) and i.v. (13C 1 mg). Systemic availability was significantly increased from 17% and 16% in controls and CLD, respectively, to 37% in CIR. The corresponding systemic clearances averaged 1.1, 0.9 and 0.61 · min−1, the reduction in cirrhotics being significant. Both aminopyrine demethylation capcity, a measure of hepatic microsomal function, and indocyanine green disappearance, a measure of hepatic perfusion, were correlated with the reduction in systemic clearance, and the reduction in oral clearance was correlated with the reciprocal of the serum bile acid concentration. The loss of first-pass extraction should be considered when this calcium antagonist is given perorally in patients with hepatic cirrhosis.
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  • 5
    ISSN: 1432-2307
    Keywords: Key words Apoptosis ; Programmed cell death ; Ductular proliferation ; Biliary decompression ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A complex molecular network controls cell homeostasis by inducing apoptosis or proliferation. The balance of Bcl-2 and Bax, members of a protein family, determines whether a cell will become immortal (Bcl-2) or will undergo apoptosis (Bax). To determine the role of Bcl-2 and Bax during proliferation of biliary epithelial cells (BEC) after bile duct ligation (BDL) and their regression after biliary decompression we induced hyperplasia of BEC by BDL in male rats. Regression of hyperplastic BEC by way of apoptosis was induced by biliary decompression through a Roux-en-Y biliodigestive anastomosis. To quantify apoptosis a modified TUNEL assay was used. Expression of Bcl-2 and Bax was visualized by immunohistochemistry and quantified stereologically. BEC increased from 〈1% to 〉20% after BDL; this increase was associated with overexpression of Bcl-2 in up to 30% of hyperplastic BEC. After biliodigestive anastomosis, apoptotic BEC increased from 〈0.1% to a peak of 5.4% after 1 day to reach baseline again 1 week after decompression. This was associated with de novo appearance of Bax. The interaction between Bcl-2 and Bax triggers apoptosis in BEC and acts as a cell rheostat in BEC hyperplasia and its involution after biliary decompression.
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  • 6
    ISSN: 1432-2277
    Keywords: Liver transplantation ; leishmaniasis-Leishmaniasis ; liver transplantation-Splenomegaly ; liver transplantation ; leishmaniasis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Visceral leishmaniasis was observed in a 50-year-old female liver transplant recipient 1 year following transplantation. Signs of active infection were low-grade fever, pancytopenia, persistent splenomegaly, positive cultures for leishmania in liver and bone marrow biopsy specimens, and newly positive leishmania serology. Following sequential therapy with pentavalent antimony and amphotericin B, blood values improved massively, bone marrow cultures became negative, and leishmania serology decreased. Secondary prophylaxis with fluconazole was instituted and the patient remains without signs of active infection 1 year after successful therapy.
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  • 7
    ISSN: 1433-0385
    Keywords: Key words: Liver transplantation ; Quality ; Results ; Small centre. ; Schlüsselwörter: Orthotope Lebertransplantation ; Qualität im kleinen Zentrum ; Langzeitergebnisse.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung. Die orthotope Lebertransplantation ist heute zur Therapie der Wahl der Endstadien verschiedener Lebererkrankungen geworden. International beträgt das perioperative Überleben 80 % und die 5-Jahres-Überlebensrate liegt bei elektiv operierten nicht malignen Erkrankungen über 70 %. Das Lebertransplantationsprogramm in Bern ist im internationalen Vergleich klein und basiert auf dem Routinebetrieb einer Universitätsklinik. Es stellt sich daher die Frage nach den Resultaten und der Daseinsberechtigung eines solchen Programms. Im Zeitraum von 66 Monaten wurden am Inselspital in Bern 62 Lebertransplantationen bei 60 Patienten durchgeführt. Die perioperative Letalität betrug 3,3 %, die 30-Monats-Überlebensrate 92 % (elektive Patienten mit benignen Erkrankungen). 68 % der Patienten sind im Median 30 Monate nach der Transplantation arbeitsfähig und 83 % unabhängig von fremder Hilfe. Diese Resultate über einen 5-Jahres-Zeitraum sind vergleichbar mit den Ergebnissen internationaler Transplantationszentren. Aus unserer Sicht hat ein solches kleines Programm daher, wenn es interdisziplinär im Konzept einer Universitätsklinik eingepaßt ist, Daseinsberechtigung und Perspektive.
    Notes: Summary. Today, orthotopic liver transplantation is the treatment of choice for the end-stage of various liver diseases, and a 1-year survival rate of 80 % and a 5-year survival rate of 70 % in elective patients without tumor are reported in international surveys. The liver transplant programme of the Inselspital in Bern is small compared with international centres, which may raise questions about the results and the justification for such a programme. Over a period of 66 months, 62 liver transplantations were performed in 60 patients at the Inselspital. The hospital mortality was 3.3 %, and the 2.5-year overall survival rate was 92 % for elective cases without tumor. After a median follow-up of 30 months, 68 % of all patients were re-integrated in housework or full- or part-time in their profession, and 83 % were independent from the help of others. We conclude that a small liver transplant programme based only on routine resources can achieve results comparable to the international standards.
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  • 8
    ISSN: 1420-9071
    Keywords: Cimetidine ; heme ; heme oxygenase ; cytochromes ; breath test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Cimetidine inhibits oxidative drug metabolism; it is not known whether this drug alters the catabolic fate of hepatic heme. We therefore investigated hepatic heme turnover both by a14CO breath test and directly by labeling the heme pool. Neither acute (150 mg/kg i.p.) nor chronic (150 mg/kg i.p. bid for 3 days) cimetidine administration significantly affected hepatic heme turnover. Chronic, but not acute, cimetidine significantly (p〈0.025) increased heme oxygenase activity. Cimetidine inhibited heme oxygenase activity in vitro at concentrations achieved in vivo.
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  • 9
    ISSN: 1420-9071
    Keywords: Taurocholate ; acinus ; liver perfusion ; extraction ; excretion ; periportal ; bile flow ; oxygen consumption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary We investigated whether acinar differences in taurocholate transport are responsible for the increased maximal secretory rate observed after expansion of the bile acid pool. The bile acid pool was expanded by cholate feeding for four days. Periportal and centrizonal hepatocytes were then probed by ante- and retrograde liver perfusion, respectively. In control animals, secretory rate constant α1 averaged 0.439±0.123 and 0.104±0.035 min−1 during ante- and retrograde perfusion, respectively, in the absence of exogenous taurocholate. These value did not significantly change when taurocholate was infused. In cholate-fed animals, α1 was comparable during antegrade perfusion but was significantly reduced (0.038±0.035, p〈0.05) during retrograde perfusion in the absence of exogenous taurocholate, presumably owing to induction of cytosolic bile acid binding proteins. During loading with exogenous taurocholate, by contrast, α1 was significantly accelerated (0.252±0.026; p〈0.01) in centrizonal hepatocytes from bile-acid fed rats. Expansion of the bile acid pool is able to change the bile salt secretory characteristics of centrizonal hepatocytes toward those of periportal ones.
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  • 10
    ISSN: 1420-9071
    Keywords: Cytochrome P-450 ; heme oxygenase ; cytochrome c reductase ; hemoproteins ; liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary We evaluated the effect of hypoxia (7% v/v) on hepatic heme turnover in vivo and microsomal heme protein content in male Sprague-Dawley rats. Hepatic heme protein turnover, measured as14CO-production during continuous infusion of 5-14C-aminolevulinic acid, a precursor of nonerythrogenic heme, was decreased 60% during hypoxia and returned to control levels promptly after reoxygenation. Hepatic cytochrome P-450 content was decreased in hypoxic and 24-h reoxygenated animals. We conclude that normobaric hypoxia decreases hepatic cytochrome P-450 which could contribute to decreased drug metabolism in hypoxia. This decrease is probably due to heme oxygenase-independent breakdown of hepatic heme.
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