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Biomedical subjects

J Reichen

Publications and source records attributed to J Reichen.

At least 91 records · Page 5Linked to original sources
PubMed1994

Ursodeoxycholate-induced hypercholeresis in cirrhotic rats: further evidence for cholehepatic shunting.

The aim of the investigation was to explore whether ursodeoxycholate, a tertiary bile acid with potential for treatment of chronic cholestasis in cirrhotic liver disease, has the same physiological effects in cirrhotic as in normal rats. Furthermore, we wanted to investigate whether ductular proliferation, as it occurred in this situation, increases the bicarbonate stimulatory effect of ursodeoxycholate. Rats (n = 16) were rendered cirrhotic by continuous exposure to phenobarbital-carbon tetrachloride; untreated animals (n = 13) served as controls. In cirrhotic rats in vivo, ursodeoxycholate (20 mumoles/min/kg) stimulated bile salt secretion and bile flow less than in controls. Nevertheless, the increment in ursodeoxycholate-induced biliary bicarbonate--the bicarbonate stimulatory potency--was increased by 29% in cirrhotic animals (0.55 +/- 0.08 mmol vs. 0.71 +/- 0.11 mmol; p < 0.05). This finding could be related to ductular proliferation because the volume fraction of bile ductules, determined stereologically, increased from 0.3% +/- 0.1% to 2.7% +/- 0.6% in cirrhotic rats (p < 0.005). To explore further the behavior of ductules during ursodeoxycholate stimulation, we carried out experiments in the in situ perfused rat liver. In the portally perfused organ, replacement of bicarbonate by tricine-acetate abolished ursodeoxycholate-induced hypercholeresis. In the dually perfused organ (perfusion of both portal vein and hepatic artery) perfusion of the hepatic artery with bicarbonate-containing buffer, ursodeoxycholate had a similar stimulatory effect as in vivo in both control and cirrhotic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Ursodeoxycholate protects oxidative mitochondrial metabolism from bile acid toxicity: dose-response study in isolated rat liver mitochondria.

The effect of ursodeoxycholate and tauroursodeoxycholate on the toxicity of lipophilic bile acids (chenodeoxycholate and lithocholate) on the function of the electron transport chain was investigated in isolated rat liver mitochondria. At a concentration of 30 mumol/L, both chenodeoxycholate and lithocholate reduced state 3 oxidation rates and respiratory control ratios of L-glutamate, succinate and duroquinol. In contrast, ADP/O ratios of these substrates and oxidative metabolism of ascorbate were not significantly affected. Ursodeoxycholate did not impair mitochondrial oxidative metabolism up to concentrations of 100 mumol/L; at 300 mumol/L, however, it decreased state 3 oxidation rates and respiratory control ratios of L-glutamate, succinate and duroquinol. Tauroursodeoxycholate had no significant inhibitory effect on state 3 oxidation rates of L-glutamate and succinate at concentrations up to 300 mumol/L. When ursodeoxycholate (final concentration, 30 mumol/L or 100 mumol/L) was added to mitochondrial incubations containing chenodeoxycholate or lithocholate, the toxic effects of lipophilic bile acids on mitochondrial oxidative metabolism were partially reversed. However, 300 mumol/L ursodeoxycholate, in combination with chenodeoxycholate or lithocholate, exhibited greater toxicity compared with incubations containing only the individual bile acids. In contrast to ursodeoxycholate, tauroursodeoxycholate did not reduce the toxic effects of chenodeoxycholate or lithocholate on mitochondrial metabolism. Ursodeoxycholate (100 mumol/L) significantly decreased the incorporation of chenodeoxycholate into mitochondrial membranes, whereas the decrease in lithocholate incorporation was not statistically significant. These studies demonstrate that ursodeoxycholate, but not tauroursodeoxycholate, decreases the toxicity of lipophilic bile acids on the function of the electron but increases bile acid-induced mitochondrial toxicity at higher concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Hepatocellular Na+/H+ exchange is activated at transcriptional and posttranscriptional levels in rat biliary cirrhosis.

BACKGROUND/AIMS: Rat hepatocyte Na+/H+ exchange is activated in vitro by growth factors and in vivo following partial hepatectomy. This study explored by which mechanism(s) it is activated in a cirrhosis model characterized by chronic stimulation of hepatocyte proliferation. METHODS: Rat hepatocytes were isolated 4 weeks after bile duct ligation or sham operation. Intracellular pH (pHi) was fluorimetrically determined, and plasma membranes and messenger RNA (mRNA) were prepared from isolated hepatocytes by standard methods. RESULTS: Resting pHi was higher in bile duct-ligated than in control rats (7.42 +/- 0.03 vs. 7.06 +/- 0.04; P < 0.001). Although plasma membrane lipid composition and intracellular buffering capacity were similar, initial Na+/H+ exchange-mediated rates of pHi recovery following acid loading were higher in bile duct-ligated than in control rats (0.098 +/- 0.011 vs. 0.055 +/- 0.005 pH units/min; P < 0.05). The antiporter's set point was shifted approximately 0.3 pH units towards more alkaline values and its steady-state mRNA levels were doubled after bile duct ligation. CONCLUSIONS: Hepatocellular Na+/H+ exchange is transcriptionally and posttranscriptionally activated in rat biliary cirrhosis further supporting a relationship between hepatocyte proliferation and Na+/H+ exchange activation.

Animals↗
PubMed1994

Efficacy of steroid withdrawal and low-dose interferon treatment in chronic active hepatitis B. Results of a randomized multicenter trial. Swiss Association for the Study of the Liver.

Fifty-six patients with biopsy-proven, chronic active hepatitis B were included in a multi-center, randomized trial comparing steroid withdrawal followed by 1.5 MU recombinant interferon alpha 2b (Intron) with placebo withdrawal followed by either 1.5 or 5 MU interferon. The patients were equally distributed between the treatment groups with respect to biochemical and histologic activity as well as with respect to DNA levels and quantitative liver function tests. One patient was lost to follow up. After 1 year of treatment, 10/18, 13/19 and 11/18 patients had lost hepatitis B virus DNA in the three groups, respectively (non-significant). Transaminase levels were normal in 27/34 of the responders but in only 4/21 of the non-responders (p < 0.0001). Both galactose elimination capacity and aminopyrine breath test improved significantly in responders, but either did not change (aminopyrine breath test) or deteriorated in non-responders (galactose elimination capacity). Biopsy score improved in both groups but this reached statistical significance only in responders. This effect was due to improvements in both inflammatory and fibrotic activity. Side effects included almost universally a flu-like syndrome, granulocytopenia (1), depression (3) and thyroid dysfunction (2). Two deaths occurred, one due to hepatocellular cancer, and the other to hepatorenal syndrome after spontaneous bacterial peritonitis. A severe cytolytic episode was observed in three patients in the steroid withdrawal group. We conclude that in patients with marked histologic activity, lower doses of interferon may be as effective as the standard dose of 5 MU.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Effect of development on the functional and histological changes induced by bile-duct ligation in the rat.

Secondary biliary cirrhosis in the rat can be induced by bile duct ligation; the aim of the present study was to investigate whether susceptibility to this injury depends on development. Rats aged 4, 7, 14 and 22 weeks were bile-duct ligated or sham operated. Four weeks later, stereologic analysis of the liver was performed and the volume fraction of parenchyma, bile ducts and connective tissue was determined. Microsomal function was assessed in vivo by the aminopyrine breath test and in vitro by determining the microsomal cytochrome P450 content and microsomal lipid composition. In addition, portal pressure was measured. The volume fraction of parenchyma decreased in an age-dependent fashion in bile-duct ligated rats from 64.0 +/- 11.2% in the youngest to 46.4 +/- 8.4% in the oldest age group. This decrease was compensated by an age-dependent increase in both ductular proliferation and fibrosis. Microsomal function both in vivo and in vitro showed an age-dependent deterioration. Microsomal cholesterol and some individual phospholipids showed age-dependent changes. Portal hypertension developed in all bile-duct ligated groups, but portal pressure was significantly lower in the oldest bile-duct ligated groups (16.0 +/- 2.6 cmH2O) compared with other bile-duct ligated groups (around 21 cmH2O). We conclude that susceptibility to the sequelae of chronic cholestasis depends on the stage of development in rats. In experiments using this model, the age of the rats should be explicitly stated.

Age Factors↗
PubMed1994

Increased hepatic lysosomal activity in biliary cirrhosis originates from hepatocytes rather than from macrophages.

To investigate the potential role of lysosomes in cirrhosis, the activity of lysosomal enzymes was analyzed in rats with cirrhosis induced by bile-duct ligation. Twenty-eight days after surgery, the activity of lysosomal enzymes was markedly increased in the homogenate of cirrhotic livers (e.g. arylsulfatase 7 +/- SD 1 vs 17 +/- 3 nmol.min-1.mg-1 in controls and cirrhotics, respectively; p < 0.001). The corresponding plasma levels were also increased (arylsulfatase: 10 +/- 1 vs 25 +/- 9 pmol.min-1.mg-1; p < 0.01). In contrast, the activities of these enzymes in lysosomal fractions did not differ, suggesting an increase in number of lysosomes. The increased lysosomal activity correlated with severity of cirrhosis as assessed by the aminopyrine breath test and with cholestatic parameters but less with transaminases. Since macrophages, cells which are rich in lysosomes, could contribute to the increase in lysosomal enzyme content, these cells were estimated stereologically after being marked immunohistochemically with a monoclonal antibody against the rat macrophage membrane antigen ED2. ED2 positive cells were increased 2.7-fold in cirrhotic livers. This increase cannot account for the observed increase in hepatic lysosomal enzyme content. Furthermore, 1 week after bile-duct ligation, when there was cholestasis but not yet cirrhosis, lysosomal enzyme activities were already increased. These data support the idea that the increased hepatic lysosomal activity in biliary cirrhosis is of hepatocyte rather than of macrophage origin, and is presumably related to cholestasis.

Animals↗
PubMed1994

Differential effect of micronodular and biliary cirrhosis on epidermal growth factor receptor expression in the rat.

Cirrhosis is characterized by fibrogenesis, hepatocyte necrosis and the formation of regenerative nodules. Modulation of the epidermal growth factor receptor is an early event during regeneration. We have recently demonstrated alterations in the epidermal growth factor receptor during the development of biliary cirrhosis. The aim of the present study was to compare epidermal growth factor receptor distribution, expression and binding in biliary cirrhosis to that occurring in micronodular cirrhosis induced by phenobarbital/CCl4 exposition. Biliary cirrhosis and micronodular cirrhosis had similar functional impairment as assessed by the aminopyrine breath test. Epidermal growth factor receptor binding capacity was reduced in both models (control vs micronodular cirrhosis vs biliary cirrhosis: (mean +/- 1 SD) 60 +/- 22 vs 16 +/- 12 vs 27 +/- 9 fmol/mg protein, p < 0.05), while the binding constant was increased in biliary cirrhosis only. The receptor mass in plasma membrane, determined by Western blotting, was not changed. Distribution of epidermal growth factor receptor was assessed immunohistochemically on tissue sections. In both models, cytoplasmic staining was decreased and basolateral plasma membrane labeling was maintained. Nuclear localization was found in biliary cirrhosis only. In conclusion, in both models, cirrhosis induces an alteration in the binding properties, but not in the number of epidermal growth factor receptors in the plasma membrane. The loss of cytoplasmic epidermal growth factor receptor could reflect alterations in expression and/or in intracellular trafficking. This is supported by the reduced mRNA steady state levels for epidermal growth factor receptor which were found in both models, presumably representing down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Intraindividual variability of the bioavailability of low dose methotrexate after oral administration in rheumatoid arthritis.

OBJECTIVES: To analyse whether the intraindividual variability of the bioavailability of oral methotrexate in rheumatoid arthritis (RA) is as high as the interindividual variability and whether the bioavailability testing can be simplified. METHODS: Fifteen mg methotrexate was given orally after an overnight fast to 10 patients with RA on two occasions, one week (n = 4) or two years (n = 6) apart, respectively. Plasma samples were taken at specific time intervals and analysed by fluorescence polarisation immunoassay. The areas under the plasma concentration versus time curves from 0 to infinity (AUC) were calculated after fitting to a two-compartment extravascular model with lag time. RESULTS: The interindividual variability of the AUCs showed a more than five fold range from 77 to 471 min x mumol/l. In contrast, the intraindividual differences of AUCs between the two visits ranged from 3 to 100 min x mumol/l, reflecting a 3-30% change in nine of 10 patients. Close correlations were found between the AUCs and the plasma concentrations with a most pronounced correlation eight hours after methotrexate intake (r = 0.975; p < 0.001). CONCLUSIONS: The high interindividual variability of the AUCs was confirmed. Conversely, only a modest intraindividual variability was disclosed. Plasma sample analysis at a single time point four to eight hours after methotrexate application could simplify estimation of the bioavailability.

Administration, Oral↗
PubMed1994

Changes in distribution and activity of glutamine synthetase in carbon tetrachloride-induced cirrhosis in the rat: potential role in hyperammonemia.

Cirrhosis induced in rats by carbon tetrachloride was used to study alterations in the activities and lobular distribution of carbamoylphosphate synthetase and glutamine synthetase. Specific activity of carbamoylphosphate synthetase in cirrhotic subjects was decreased to 70% of controls. Staining was homogeneous within micronodular areas, but varied from area to area and generally showed a decreased intensity. Specific activity of glutamine synthetase and the size of the glutamine synthetase-positive area were decreased to 20% and less of controls. Glutamine synthetase-positive hepatocytes were rare and scattered at the periphery of nodular areas and within fibrous septa, the normal association with the central veins being widely lost. Rarely, complete micronodules showed a slight homogeneous staining for glutamine synthetase. Arginase activity was not affected, whereas glutaminase activity was enhanced by 50%. Serum levels of ammonia were elevated more than 2-fold and those of glutamine by 30%. In contrast, urea levels tended to be slightly diminished. Serum ammonia levels showed a clear negative correlation with the specific activity of glutamine synthetase and the size of the glutamine synthetase-positive area. Furthermore, blood urea levels correlated with the sum of ammonia and glutamine concentrations, but not with each of these substrate concentrations alone. These data suggest that the changes in activity and distribution of glutamine synthetase contribute to hyperammonemia in cirrhosis. Despite a reduced activity of the initial enzyme of the urea cycle, urea synthesis is not diminished accordingly. This may be due to an enhanced flux caused by the elevated blood level of ammonia and an increased hydrolysis of glutamine, because of higher levels of glutaminase.

Ammonia↗
PubMed1993

Metabolism of antipyrine in vivo in two rat models of liver cirrhosis. Its relationship to intrinsic clearance in vitro and microsomal membrane lipid composition.

Antipyrine metabolism depends on at least three isoenzymes of cytochrome P450 forming the main metabolites 3-OH-, 4-OH- and norantipyrine. We investigated to what extent antipyrine clearance and metabolite formation are impaired in two models of liver cirrhosis in the rat, namely micronodular cirrhosis induced by chronic exposure to phenobarbital/CCl4 and biliary cirrhosis induced by bile duct ligation. Salivary antipyrine clearance was decreased to a similar extent in cirrhosis induced by CCl4 and bile duct ligation (-35%). Clearance for production of 3-OH-antipyrine was decreased in both models, while 4-hydroxylation was maintained. Metabolic clearance of both 3-OH-antipyrine and 4-OH-antipyrine in vivo correlated with their clearance in vitro (r = 0.658 and r = 0.583) but not with that of norantipyrine. The microsomal cholesterol content was increased by 16% and 90% in CCl4 and bile duct-ligated cirrhotic rats (P < 0.001), respectively. Membrane fluidity, expressed as the ratio of phospholipids to cholesterol, correlated with the in vivo clearance for production of norantipyrine (r = 0.841) but not of 3-OH- or 4-OH-antipyrine, while clearance in vitro was not related to altered lipid composition. Our results demonstrate that the cytochrome P450 isoenzymes responsible for the different pathways of antipyrine metabolism are affected to different extents by cirrhosis. Alterations in intrinsic clearance explain only part of the loss of hepatocellular function. Altered lipid composition contributes to this loss of function but other factors, among them loss of hepatocytes and changes in microcirculation, could be more important determinants of the decrease in xenobiotic metabolism in cirrhosis.

Animals↗
PubMed1993

[Liver biopsy in ambulatory patients. Diagnostic value in comparison to conventional and quantitative liver function tests].

In this retrospective analysis we investigated the diagnostic yield of 148 consecutive liver biopsies performed as an outpatient procedure. In 144 patients, adequate specimens for histologic analysis were obtained. In these patients, 226 diagnoses were entertained. Clinical diagnosis was confirmed in 49.3%, modified in 43.8% and altered in 6.9%. Liver biopsy was particularly helpful in patients where an alcoholic etiology was suspected, since this could be confirmed in only 59.4% while in the others different, often treatable, causes of chronic liver disease were found. Neither conventional nor quantitative liver tests (galactose elimination capacity, aminopyrine breath test) served to differentiate reliably between severe and mild lesions. We conclude that liver biopsy remains an important diagnostic tool in patients with chronic liver disease, and that it can be safely performed on an outpatient basis in appropriately selected patients.

Ambulatory Care↗
PubMed1993

Low-dose interferon in chronic hepatitis non-A/non-B: effects on quantitative liver function and structure in a randomized, controlled multicenter trial.

In this randomized, controlled multicenter trial we evaluated the effects of recombinant interferon-alpha 2b on galactose elimination capacity and histological activity index in 88 patients with chronic active hepatitis non-A/non-B. Forty-five patients were randomly assigned to treatment with interferon at 1.5 x 10(6) U three times per for 1 year; 43 patients were assigned to no treatment. A complete response (normalization of alanine aminotransferase) was observed, respectively, in 47% and 5% of the two groups (P < 0.006); 47% of these patients suffered a relapse. Thus 22% of patients had a sustained response. Histological activity decreased significantly in responders (P < 0.04) while the biopsy score did not change significantly in nonresponders. In contrast, galactose elimination capacity--a surrogate marker for survival in chronic active hepatitis--was not affected by response to treatment. None of the parameters evaluated, including hepatitis C virus RNA, was able to predict response or relapse. We conclude that low-dose interferon treatment for 1 year is as effective as the recommended treatment schedule.

Adolescent↗
PubMed1993

Pharmacokinetics and haemodynamic effects of a single oral dose of the novel ACE inhibitor spirapril in patients with chronic liver disease.

The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensin-converting 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 micrograms.h.l-1, 923 micrograms.h.l-1 and 1300 micrograms.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.

Administration, Oral↗
PubMed1993

Visceral leishmaniasis after orthotopic liver transplantation: impact of persistent splenomegaly.

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.

Female↗
PubMed1993

Structure-function relationship in secondary biliary cirrhosis in the rat. Stereologic and hemodynamic characterization of a model.

Secondary biliary cirrhosis in the rat is an attractive model since unlike other models it does not rely on exogenous toxic compounds to induce cirrhosis. However, because little is known about the microcirculatory abnormalities of this model, this study investigated hemodynamics in rats with predefined functional impairment and related them to different aspects of stereologically quantified structure. All animals with at least 50% reduction in microsomal function, assessed by the aminopyrine breath test, had portal hypertension. The sinusoidal space, as assessed by multiple indicator dilution in the perfused liver, was reduced whereas large vessel space was increased. This reduction in sinusoidal space could contribute to increased portal resistance. The degree of intrahepatic shunting varied as assessed by a microsphere technique (13.9 vs. 0.5% in controls). These alterations were confirmed by stereological analysis. Numerically, there was excellent agreement between functional indicator dilution data and anatomic quantitation. Microvascular exchange was impaired as in other models of cirrhosis as shown by a reduced extravascular albumin space (4.5 vs. 2.2%, p < 0.01). In contrast to alterations in vascular space, this functional impairment was not reflected in the stereologically assessed space of Disse which averaged 5% of liver volume in both groups. Finally, in spite of reduced microsomal function in vivo (aminopyrine breath test) and in vitro (aminopyrine N-demethylase activity), the smooth endoplasmic reticulum was maintained (4.3 vs. 3.5 m2/ml cytosol, n.s.), which demonstrates that microsomal function in this model is reduced per unit hepatocyte. This suggests that the sick-cell hypothesis applies to secondary biliary cirrhosis in the rat.

Aminopyrine↗