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Biomedical subjects

J Reichen

Publications and source records attributed to J Reichen.

At least 127 records · Page 7Linked to original sources
PubMed1991

Accurate prediction of death by serial determination of galactose elimination capacity in primary biliary cirrhosis: a comparison with the Mayo model.

We retrospectively analyzed the predictive accuracy of serial determinations of galactose elimination capacity in 61 patients with primary biliary cirrhosis. Death was predicted from the time that the regression line describing the decline in galactose elimination capacity vs. time intersected a value of 4 mg.min-1.kg-1. Thirty-one patients exhibited decreasing galactose elimination capacity; in 11 patients it remained stable and in 19 patients only one value was available. Among those patients with decreasing galactose elimination capacity, 10 died and three underwent liver transplantation; prediction of death was accurate to 7 +/- 19 mo. This criterion incorrectly predicted death in two patients with portal-vein thrombosis; otherwise, it did better than or as well as the Mayo clinic score. The latter was also tested on our patients and was found to adequately describe risk in yet another independent population of patients with primary biliary cirrhosis. Cox regression analysis selected only bilirubin and galactose elimination capacity, however, as independent predictors of death. We submit that serial determination of galactose elimination capacity in patients with primary biliary cirrhosis may be a useful adjunct to optimize the timing of liver transplantation and to evaluate new pharmacological treatment modalities of this disease.

Adult↗
PubMed1990

Sex difference in antipyrine 3-hydroxylation. An in vivo-in vitro correlation of antipyrine metabolism in two rat strains.

Antipyrine metabolism depends on at least three isoenzymes of cytochrome P450 forming the main metabolites 3-OH-, 4-OH- and norantipyrine. We investigated to which extent antipyrine clearance and metabolite formation in vivo correlate with metabolite formation by microsomal fractions in vitro. The influence of sex was investigated in two rat strains. Antipyrine clearance in saliva was determined in 10-month-old Sprague-Dawley and Dark Agouti rats of either sex. Antipyrine and its metabolites in urine and microsomes were measured by a new HPLC method after solid phase or liquid extraction. Antipyrine clearance was 46% higher in males than in female rats. This was associated with a 40% higher urinary excretion of 3-OH-antipyrine in the male rats, the other metabolites being excreted to a similar extent. This higher production of 3-OH-antipyrine in vivo was paralleled by a higher intrinsic clearance in vitro while no sex difference in intrinsic clearance for the formation of the other metabolites was seen. The correlation between in vivo and in vitro metabolic clearance for 3-OH-antipyrine was good (r = 0.75) but unconvincing for 4-OH- (r = 0.49) and norantipyrine (r = 0.01). This could be due to further metabolism of 4-OH- and norantipyrine.

Animals↗
PubMed1990

[Is a pharmacological treatment of liver cirrhosis possible?].

Loss of hepatic function is the limiting factor in survival of patients with cirrhosis. Fibrogenesis, cytolysis/necrosis and sinusoidal capillarization, altered composition of biomembranes, and hyporegeneration are identified as major factors in loss of hepatic function. Fibrogenesis has been successfully treated with colchicine. Cytolysis/necrosis in autoimmune hepatitis has for years been treated successfully with steroids: in postviral chronic hepatitis the interferons are showing high promise. Treatment of the other factors is the subject of intensive basic and clinical research.

Drug Therapy, Combination↗
PubMed1990

Cholate uptake in basolateral rat liver plasma membrane vesicles and in liposomes.

The mechanism(s) and driving force(s) for hepatocellular uptake of the unconjugated bile acid cholate were investigated in isolated basolateral (sinusoidal) rat liver plasma membrane (blLPM) vesicles and in protein free liposomes. In blLPM vesicles both an inwardly directed Na+ gradient and a transmembrane pH difference (8.0 in/6.0 out) stimulated cholate uptake 2-3-fold above equilibrium uptake values (overshoot). While Na+ gradient driven cholate uptake could be inhibited by the anion transport inhibitor 4,4'-diisothiocyanato-2,2'-disulfonic acid stilbene (DIDS), the pH gradient dependent portion of cholate uptake was insensitive to DIDS, but could be inhibited by furosemide. Furthermore, initial rates (1-s values) of the pH gradient stimulated cholate uptake were linear with increasing substrate concentrations (no saturability). In liposomes a similar inside alkaline pH gradient also induced a transient DIDS insensitive/furosemide inhibitable intravesicular accumulation (approx. 2-fold) of cholate (overshoot). These findings confirm that hepatocellular uptake of cholate occurs in part via the common Na+/bile acid cotransport system. In addition, the data strongly indicate that in isolated membrane vesicles pH gradient driven cholate uptake represents nonionic diffusion rather than a carrier mediated process (Blitzer, B.L., Terzakis, C. and Scott, K.A. (1986) J. Biol. Chem. 261, 12042-12046). Since in the perfused liver DIDS inhibited uptake of both cholate and taurocholate to a similar extent, DIDS-insensitive pH gradient dependent membrane diffusion appears to be of minor significance for cholate uptake in the intact organ.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1990

Mitochondrial structure and function in CCl4-induced cirrhosis in the rat.

To investigate whether the impairment of mitochondrial function in cirrhosis is due to a reduction in liver cell mass or whether mitochondrial function is altered specifically, we analyzed mitochondrial volume and surface density of mitochondrial membranes in control and cirrhotic rats by stereological means. Cirrhosis was induced by long-term exposure to phenobarbital and CCl4. Hepatocellular and mitochondrial volumes were reduced to a similar extent, by 39% and 40%, respectively, in cirrhotic animals (p less than 0.01). Thus the fraction of hepatocytes occupied by mitochondria did not differ between the two groups. Both total outer (31 +/- 3 vs. 19 +/- 6 m2; p less than 0.01) and inner (87 +/- 24 vs. 45 +/- 12 m2; p less than 0.01) mitochondrial membranes were significantly reduced. Membrane surface was normal per unit of mitochondrial volume, however, suggesting intact mitochondrial structure. Matrix and outer membrane enzyme activities expressed per compartment did not differ between control and cirrhotic animals. Inner membrane, in contrast, had an increased enzyme content per unit area both for cytochrome oxidase (10.3 +/- 2.9 vs. 13.0 +/- 1.6; p less than 0.05) and ATPase (13.7 +/- 1.4 vs. 21.2 +/- 2.9; p less than 0.01). Basal oxygen consumption measured in the perfused liver in situ was significantly reduced in cirrhotic livers (1.6 +/- 0.1 vs. 1.1 +/- 0.4 mumol/min-1/gm-1) but was unchanged when expressed per square meter of inner membrane. Our results demonstrate that impaired mitochondrial function is mainly due to loss of hepatocellular mass. Increased enzyme activity per unit surface area of inner mitochondrial membrane may be important to maintain mitochondrial function of the cirrhotic liver.

Animals↗
PubMed1990

Pharmacokinetics of isradipine in patients with chronic liver disease.

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% to 16% in controls and CLD, respectively, to 37% in CIR. The corresponding systemic clearances averaged 1.1, 0.9 and 0.6 l.min-1, the reduction in cirrhotics being significant. Both aminopyrine demethylation capacity, 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.

Administration, Oral↗
PubMed1990

Albendazole kinetics in patients with echinococcosis: delayed absorption and impaired elimination in cholestasis.

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 mumols.h.l-1 compared to 17 mumols.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.

Adult↗
PubMed1990

Decreased hepatocellular volume and intact morphology of tight junctions in calcium deprivation-induced cholestasis. Stereological and multiple indicator dilution analysis.

Cholestasis induced by perfusion of the liver with hypocalcemic media has been ascribed to several defects in bile secretion including increased biliary permeability. To investigate this model of cholestasis further, livers perfused with hypo- and normocalcemic media were examined stereologically using thin sections and freeze-fracture replicas. Organization of tight junctions was not altered by hypocalcemia; neither the number of strands nor the junctional depth were significantly affected. By contrast, the volume of hepatocytes decreased by 11% (p less than 0.001), compensated for by an increase in the space of Dissé and of the sinusoids. The canalicular length decreased by 25% (p less than 0.01), while the canalicular membrane surface was not altered. Multiple indicator dilution studies confirmed a decrease in hepatocellular volume, measured as the water space by 14% (p less than 0.03). This was compensated for by an increase in the extravascular sucrose, but not the albumin space. Immediately after switching from normo- to hypocalcemic perfusate a K+ efflux of 62 mumol/g liver was observed corresponding to approx. 8% of the hepatocellular water space. Our results suggest that hypocalcemia-induced cholestasis is due, at least in part, to a disturbance of the osmotic equilibrium, possibly caused by impairment of an ion transport system involved in hepatocellular volume control.

Animals↗
PubMed1990

Albendazole treatment of echinococcosis in humans: effects on microsomal metabolism and drug tolerance.

We prospectively studied the effect of albendazole on microsomal reserve and on first-pass activation to albendazole sulfoxide in patients with hydatid disease. An aminopyrine breath test was performed in 12 patients while they were receiving albendazole treatment and while they were not. Excretion of 14CO2 in breath averaged 0.70%.kg.mmol-1 +/- 0.20%.kg.mmol-1 without treatment and 0.54%.kg.mmol-1 +/- 0.14%.kg.mmol-1 with treatment (p less than 0.005). Plasma levels of albendazole sulfoxide were measured 4 hours after the morning dose during the first and second half of the 4-week treatment cycles. In nine of the 12 patients albendazole sulfoxide levels decreased during the second half of the cycle by an average of 0.84 +/- 0.76 mumol/L (p less than 0.02). Transaminase levels increased in 10 of the 12 patients during long-term albendazole treatment, and major side effects, including hepatotoxicity, neutropenia, and alopecia, were observed in three patients. We conclude that albendazole partially inhibits microsomal enzyme function but induces its own metabolism. Hepatotoxicity and other possible severe side effects necessitate close therapeutic monitoring of patients who are given albendazole.

Adult↗
PubMed1990

Effects of ursodeoxycholic acid treatment on nutrition and liver function in patients with cystic fibrosis and longstanding cholestasis.

The prevalence of biliary and hepatic diseases is increasing in patients with cystic fibrosis as more of them reach adult life. There is no effective treatment or method of preventing cholestasis in cystic fibrosis, although beneficial effects have been ascribed to the tertiary bile acid, ursodeoxycholate, in other forms of chronic cholestasis. We evaluated prospectively the effects of a six month course of ursodeoxycholate (15-20 mg/kg per day) in eight, mostly adult, patients with cystic fibrosis and chronic cholestasis. Bile acid treatment improved inflammatory activity (average decrease in alanine aminotransferase, 60%, p less than 0.005) and cholestasis (alkaline phosphatase, 47%; p less than 0.01) in all patients. Quantitative liver function, measured by 45 minute sulphobromophthalein retention and by the 14C-aminopyrine breath test, improved in all patients while galactose elimination capacity showed a slight decrease. Patients' nutritional state improved as evidenced by a 1.8 kg weight gain and an increase in muscle mass suggested by a 26% increase in 24 hour urinary creatinine excretion. Steatorrhea was not affected by bile acid treatment. Ursodeoxycholic acid may be beneficial in the treatment of chronic cholestasis in cystic fibrosis by improving liver function and also the patient's nutritional state.

Adolescent↗
PubMed1989

Mitochondrial function in carbon tetrachloride-induced cirrhosis in the rat. Qualitative and quantitative defects.

Mitochondrial function is impaired in patients and experimental animals with liver cirrhosis. The relationship between mitochondrial impairment and severity of cirrhosis is unknown, however. We therefore characterized the severity of cirrhosis in rats with phenobarbital/CCl4-induced cirrhosis by the aminopyrine breath test, a microsomal function test reflecting hepatocellular mass. Mitochondrial function was evaluated by measuring oxygen consumption, enzyme activities and ATP production in mitochondria isolated from cirrhotic (N = 8) and control livers (N = 4). Oxygen consumption and mitochondrial enzyme activities calculated per liver were significantly reduced in the presence of cirrhosis. This decrease corresponded to the loss of hepatocytes calculated from the reduction in aminopyrine breath test. The effect of atractylate, oligomycin and dinitrophenol on state 3 respiration was equal between the two groups. The respiratory control ratio was significantly reduced in mitochondria from cirrhotic livers with beta-hydroxybutyrate (4.01 +/- 0.94 vs 5.45 +/- 0.40), but not with succinate as substrate. The rate of ATP production was significantly decreased in mitochondria from cirrhotic rats for both substrates. In contrast, the static head (state 4) phosphate potential was fully developed after 10 min and was equal between the two groups. We conclude that cirrhosis of the liver leads to a loss of hepatocytes which is paralleled by reduced oxygen uptake and reduced mitochondrial enzyme activities.

Adenosine Triphosphate↗
PubMed1989

Expansion of the bile acid pool changes the biliary transport characteristics of centrizonal hepatocytes.

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 (alpha 1) 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 values did not significantly change when taurocholate was infused. In cholate-fed animals, alpha 1 was comparable during antegrade perfusion but was significantly reduced (0.038 +/- 0.035, p less than 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, alpha 1 was significantly accelerated (0.252 +/- 0.026; p less than 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.

Animals↗
PubMed1989

Non-micelle forming bile acids increase biliary gentamicin excretion in the rat.

To investigate whether non-micelle forming bile acids are able to increase biliary gentamicin excretion, male Sprague-Dawley rats were anesthetized with pentobarbital and fitted with a biliary fistula. After a control period of 30 min, dehydrocholate, taurodehydrocholate, or norursodeoxycholate were administered iv at doses of 2 or 10 mumol.min-1.kg-1. Taurodehydrocholate increased bile flow and biliary gentamicin clearance similarly in a dose-dependent fashion. Its unconjugated analogue, in contrast, increased gentamicin clearance fourfold, while increasing bile flow only 1.6-fold. This suggests that other than purely osmotic phenomena were involved. This effect was even more marked for the short-chain bile acid, norursodeoxycholate. At a dose of 2 mumol.min-1.kg-1 it increased bile flow by 30%, but gentamicin clearance by 210%; a similar discrepancy between choleresis and gentamicin clearance was observed at the higher dose tested. It may be concluded that conjugated triketo bile acids increase biliary gentamicin clearance by osmotic choleresis. Unconjugated triketo bile acids and nor-bile acids, to an even greater extent, increase gentamicin clearance much more markedly than bile flow; other effects, such as the putative cholahepatic shunt pathway, are responsible for this phenomenon. This novel therapeutic principle might be useful in achieving therapeutic biliary antibiotic concentrations or in treating gentamicin intoxication in patients with renal insufficiency.

Animals↗
PubMed1989

Effect of secretin on bile formation in rats with cirrhosis of the liver: structure-function relationship.

To investigate whether the hypercholeresis seen in cirrhotic humans and animals is due to ductular proliferation or altered inactivation of secretin, or both, we studied the response of bile flow and biliary erythritol clearance to synthetic porcine secretin in rats rendered cirrhotic by chronic exposure to phenobarbital/carbon tetrachloride (n = 11) and untreated control rats (n = 5). Bile duct mass was determined morphometrically. Furthermore, plasma disappearance of secretin was measured by radioimmunoassay. Basal bile flow did not differ between the two groups. Whereas secretin had no effect in the control group, it stimulated bile flow by 49% +/- 33% in the cirrhotic group (p less than 0.001). Erythritol bile-to-plasma ratio was lower and biliary bicarbonate concentration higher in the cirrhotic rats, suggesting some ductular contribution to bile flow even in the absence of secretin. Biliary bicarbonate concentration did not increase further during secretin administration, whereas bile salt concentration decreased from 27 +/- 6 to 18 +/- 4 mM. The elimination half-life of secretin was not affected by cirrhosis, averaging 5 +/- 2 min in both groups. Bile duct volume was increased in cirrhotics (2.9% +/- 1.4% vs. 0.2% +/- 0.1%; p less than 0.01) and showed an excellent correlation with the maximal secretin-induced increment of bile flow. Our results suggest that the proliferating ductules contribute to bile flow and that increased secretin responsiveness is not due to altered pharmacokinetics in cirrhotic rat liver.

Animals↗
PubMed1989

Taurocholate transport by liver plasma membrane vesicles is not altered in cirrhotic rats.

Recently, we have shown that taurocholate transport is impaired in hepatocytes isolated from CCl4 cirrhotic rats. Na+,K+-ATPase activity depends on the lipid composition of the surrounding membrane. Therefore, we performed this study in order to detect differences in plasma membrane composition and membrane functions between livers of CCl4 cirrhotic (n = 17) and of control rats (n = 15). After biochemical characterization of the animals we isolated basolateral and canalicular membrane vesicles and determined membrane enzyme activities, transport functions and lipid composition. We found no differences in the isolation characteristics of the plasma membranes between the two groups. The lipid composition of the membrane fractions was not altered, except for a lower cholesterol content in the canalicular membranes of the cirrhotic group (200 +/- 15 vs. 246 +/- 18 micrograms/mg protein, P less than 0.05). Taurocholate transport into basolateral membrane vesicles and marker enzyme activities of the membrane fractions were also equal in control and cirrhotic animals. We conclude that the plasma membrane composition and membrane enzyme/transport activities have returned to normal in CCl4 cirrhotic rats 14 days after cessation of exposure to CCl4. Thus, a disturbed transport system is not the cause for the observed decreased taurocholate transport into hepatocytes from cirrhotic rats. Even a cirrhotic liver has a high potential for recovery after acute CCl4 intoxication.

Animals↗
PubMed1989

Bile salts and hydrodynamics of bile formation.

We report a novel method to assess bile secretory pressure using a Statham pressure transducer. The studies were performed in vivo in male Sprague-Dawley rats under pentobarbital anesthesia. Maximal secretory pressure averaged 21.8 +/- 1.1 (S.D.) cmH2O. The bile accumulated after 10 min of obstruction was 7.7 +/- 2.8 microliters.g-1; assuming a basal biliary dead space of 2.3 microliters.g-1, the distended capacity of the biliary tree averaged 10 microliters.g-1. The small volume of the strain gauge permitted calculation of compliance of the biliary tree which averaged 0.35 +/- 0.12 microliters.cmH2O-1.g-1. Stimulation of bile flow by bile salts reduced the time required to reach maximal bile secretory pressure. Taurocholate but not taurodehydrocholate decreased maximal secretory pressure within minutes, the pressure-time curves showing a new equilibrium between bile formation and regurgitation forces. Both bile flow and bile salt recoveries were decreased by taurocholate but not by taurodehydrocholate. Taurocholate decreased biliary compliance while taurodehydrocholate had no effect. This provides further evidence that taurocholate increases the biliary permeability and suggests that this bile salt also affects the elastic properties of the biliary tree.

Animals↗
PubMed1989

Effect of intravenous fructose on the P-31 MR spectrum of the liver: dose response in healthy volunteers.

Dynamic phosphorus-31 magnetic resonance (MR) spectroscopy of the liver after intravenous administration of fructose has been suggested as a test of liver function. To establish dose-response curves of the phosphorus metabolites in the normal human liver, each of four healthy volunteers was given two to four different fructose doses on separate days: 62.5, 125, 250, 375, or 500 mg per kilogram of body weight. P-31 MR spectra of the liver were acquired with a 2-T whole-body magnetic, both before and after fructose administration, at 2.5-minute intervals over at least 30 minutes. The fructose load caused a significant, linearly dose-dependent accumulation of phosphomonoesters (r = .72, P less than .01) and a decrease in inorganic phosphate (r = .78, P less than .005) and adenosine triphosphate (r = .73, P less than .01). On the basis of these experiments, dynamic P-31 MR spectroscopy seems promising in the assessment of liver function.

Adult↗