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P Sauer

Publications and source records attributed to P Sauer.

At least 37 records · Page 2Linked to original sources
PubMed2000

Downregulation of ileal bile acid absorption in bile-duct-ligated rats.

BACKGROUND/AIMS: Accumulation of toxic bile acids in cholestasis contributes to liver injury and depends on their synthesis, secretion and intestinal absorption. In the present study, we investigated the effect of cholestasis on the active ileal absorption of bile acids in vivo and the adaptation of transporters involved in ileal bile acid absorption. METHODS: Male Wistar rats underwent ligation of the common bile duct or biliary diversion. Sham-operated rats served as controls. Active ileal bile acid absorption of taurocholate was measured by an intestinal perfusion technique. Transporter mRNA levels of the Na+/bile acid cotransporting protein (IBAT), ileal lipid binding protein (ILBP) and organic anion transporter subtype 3 (Oatp3) and protein expression of IBAT and ILBP were determined in the distal ileum. RESULTS: After bile duct ligation the intestinal absorption rates of taurocholate were lower (p<0.05) and after biliary diversion absorption rates were higher compared to sham-operated animals (p<0.05). The absorption rates were inversely correlated to serum bile acid concentrations. Levels of IBAT-, ILBP- and Oatp3- mRNA were not different between the groups. However, in cholestatic rats, the expression of the 99-kDa dimer of IBAT was decreased compared to controls (p<0.05), whereas the 46-kDa monomeric protein of IBAT and the expression of ILBP was unchanged. After biliary diversion a similar pattern of protein expression was observed, despite an increased absorption rate. CONCLUSIONS: Cholestasis leads to a decreased active ileal absorption of taurocholate. The changes in protein expression may not account for the different absorption rates. The intestinal absorption of bile acids seems to be regulated by their systemic concentration.

Animals↗
PubMed2000

Drug use of children in the community assessed through pharmacy dispensing data.

AIMS: : To determine the extent of drug use in children and the types of drugs that children use. METHODS Cross-sectional study and cohort study, using computerized pharmacy dispensing records for all children aged 0-16 years in the northern part of The Netherlands in 1998. The main outcome measures were proportion of children that used drugs (per sex and age group), mean number of drugs per child, 10 most widely used drug groups and cumulative proportions of drugs users (per drug group) during the first 2 years of life. RESULTS: Drug use was the highest among infants, decreased till adolescence and increased from there. Overall, approximately 60% of all children used at least one drug in 1998. At younger ages, boys used more drugs than girls and at older ages girls used more drugs than boys. Systemic antibiotics were used by 21% of the children and were by far the most widely used drugs. Other frequently used drugs were analgesics (10%), corticosteroids for dermatologic use (9%), anthistamines (8%) and antiasthmatics (7%). Approximately 10% of the children had used at least one drug at the age of 1 month and at the age of 2 years this proportion was 81%. CONCLUSIONS: The majority of children was exposed to one or more drugs and this exposure started at very young age. This shows the importance of good guidelines for drug use in children and emphasizes the necessity of research of pharmacokinetic and pharmacodynamic properties in children to obtain safety, efficacy and quality evidence of these drugs.

Adolescent↗
PubMed2000

Effect of tauroursodeoxycholic acid on bile acid-induced apoptosis in primary human hepatocytes.

BACKGROUND/AIMS: The accumulation of endogenous bile acids contributes to hepatocellular damage during cholestatic liver disease. To evaluate the potential role of apoptotic cell death due to increased concentrations of bile acids, primary human hepatocytes were treated with hydrophobic and hydrophilic bile acids. Because the Fas receptor-ligand system may mediate apoptosis in human liver cells, the effect of toxic bile acids on hepatocellular Fas receptor expression was evaluated. MATERIALS AND METHODS: Primary human hepatocytes were incubated with 50 and 100 microM glycochenodeoxycholic acid (GCDCA) and co-incubated with equimolar concentrations of tauroursodeoxycholic acid (TUDCA). To evaluate cytolytic and apoptotic effects, morphological alterations, hepatocellular enzyme release, nuclear DNA fragmentation and hepatocellular Fas receptor expression were evaluated. RESULTS: Apoptotic cell death was significantly increased after exposure to 50 microM GCDCA. Bile acid-induced apoptosis was not accompanied by hepatocellular Fas receptor overexpression. Tauroursodeoxycholic acid reduced apoptosis, as indicated by a significant reduction of oligonucleosomal DNA cleavage. Fas receptor expression was not significantly affected by tauroursodeoxycholic acid. At higher concentrations, direct cytolytic cell destruction was observed. CONCLUSION: Primary human hepatocytes represent a suitable model to study bile acid-induced apoptotic cell death. In these hepatocytes, already low bile acid concentrations might induce apoptotic cell death, which is not triggered by hepatocellular Fas receptor overexpression. Apoptotic DNA fragmentation was significantly reduced by co-incubation with tauroursodeoxycholic acid. The reduction of bile acid-induced apoptosis by ursodeoxycholic acid and its conjugates may contribute to the beneficial effects of these hydrophilic bile acids used for medical treatment of several cholestatic liver diseases.

Apoptosis↗
PubMed2000

Primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibrosing inflammation and obliteration of intra- and/or extrahepatic bile ducts. The disease is one of the most common cholestatic diseases in adults and is diagnosed with increasing frequency. It is very often associated with ulcerative colitis. Patients with PSC have an increased incidence of bile duct carcinomas, and those with ulcerative colitis also have an increased incidence of colonic carcinomas. In end-stage disease, liver transplantation is the treatment of choice. Immunosuppressive treatment has little effect. Ursodeoxycholic acid (UDCA), which has been shown to improve liver histology and survival in patients with primary biliary cirrhosis, has a beneficial effect in PSC, provided that patients who develop major duct stenoses are treated endoscopically. The aim is to treat patients as early as possible to prevent progression to the advanced stages of the disease. During treatment with UDCA, stenoses of major ducts may develop, and early endoscopic dilation is highly effective. Because UDCA treatment improves but does not cure cholestatic liver diseases, permanent treatment seems to be necessary. Such prolonged treatment with UDCA may be recommended because, until now, no side effects have been reported. In patients with end-stage disease, UDCA is not effective and liver transplantation is indicated.

Bile Duct Neoplasms↗
PubMed1999

Mechanism of hepatoprotective action of bile salts in liver disease.

Ursodeoxycholic acid (UDCA) improves liver enzymes and in many instances liver histology in cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis. Besides classic cholestatic diseases, UDCA also improves liver biochemistry in alcoholic liver disease and in chronic viral hepatitis C. The main target of UDCA treatment, however, is cholestasis, and consequently the mechanisms responsible for the beneficial effects in these diseases are of interest, and are discussed in detail in this article.

Animals↗
PubMed1999

Influence of cholestasis on absorption of ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA) has beneficial effects in cholestatic liver diseases. Absorption of UDCA is slow and incomplete. In the present study the effect of cholestasis on absorption was evaluated in 10 patients with pancreatic carcinoma and extrahepatic biliary drainage. At days 3 and 10 after insertion of the biliary drain, all patients received 750 mg UDCA in three divided doses. On both occasions intestinal absorption of UDCA was determined to evaluate the influence of cholestasis. Serum bilirubin was used as indicator of cholestasis. Biliary output of UDCA served as measure of absorption and was determined by gas-liquid chromatography. At days 4 and 11 bile consisted of less than 2% of UDCA, indicating that UDCA excretion was complete within 24 hr and no accumulation of UDCA had occurred. After insertion of the drain, serum bilirubin decreased from 12.2 +/- 2.4 mg/dl at day 3 to 5.4 +/- 0.9 mg/dl at day 10. Biliary secretion of bile acids increased from 2.0 +/- 0.3 to 3.1 +/- 0.4 mmol/day, whereas percentage of ursodeoxycholic acid in bile did not significantly increase (41.1% vs 42.1%). Absorption of UDCA increased from 39.8 +/- 5.0% to 61.1 +/- 6.2% of the administered dose, indicating an improvement of the absorption rate after decrease of cholestasis by 53.65% (P < 0.05). In conclusion, in severe cholestasis absorption of orally administered UDCA is markedly reduced. This may have implications in the treatment of patients with cholestatic disease.

Administration, Oral↗
PubMed1999

Cold face test demonstrates parasympathetic cardiac dysfunction in familial dysautonomia.

In familial dysautonomia (FD), i.e., Riley-Day syndrome, parasympathetic dysfunction has not been sufficiently evaluated. The cold face test is a noninvasive method of activating trigeminal brain stem cardiovagal and sympathetic pathways and can be performed in patients with limited cooperation. We performed cold face tests in 11 FD patients and 15 controls. For 60 s, cold compresses (0-1 degrees C) were applied to the cheeks and forehead while we monitored heart rate, respiration, beat-to-beat radial artery blood pressure, and laser-Doppler skin blood flow at the first toe pulp. From these measurements heart rate variability parameters were calculated: root mean square of successive differences (RMSSD), coefficient of variation (CV), low- and high-frequency (LF and HF, respectively) power spectra of the electrocardiogram, and the LF transfer function gain between blood pressure and heart rate. All patients perceived cold stimulation and acknowledged discomfort. In controls, heart rate and skin blood flow decreased significantly during cold face test; in patients, both parameters decreased only briefly and not significantly. In controls, blood pressure, RMSSD, CV, and heart rate HF-power spectra increased but remained unchanged in patients. Respiration, as well as heart rate LF power spectra, did not change in either group. In controls, LF transfer function gain between blood pressure and heart rate indicated that bradycardia was not secondary to blood pressure increase. We conclude that the cold face test demonstrated that patients with FD have a reduced cardiac parasympathetic response, which implies efferent parasympathetic dysfunction.

Adolescent↗
PubMed1998

Effect of tauroursodeoxycholic acid on bile-acid-induced apoptosis and cytolysis in rat hepatocytes.

BACKGROUND/AIMS: In cholestatic liver disease, bile acids may initiate or aggravate hepatocellular damage. Cellular necrosis and cell death may be due to detergent effects of bile acids, but apoptosis may also play a role. In cholestasis, the conditions determining either apoptotic or cytolytic cell death are still unclear. Primary rat hepatocytes in culture represent a suitable model to study bile-acid-induced liver damage. METHODS: Glycochenodeoxycholic acid, a hydrophobic bile acid, was used to induce cell damage. Tauroursodeoxycholic acid, a hydrophilic bile acid, served as substrate to study possible protective effects of such compounds. To study the time and concentration dependency of bile-acid-induced cytolysis and apoptosis, morphologic alterations, hepatocellular enzyme release and nucleosomal DNA fragmentation were evaluated. RESULTS: Bile-acid-induced cytolysis, as indicated by hepatocellular enzyme release and by morphologic signs of membrane destruction, increased with concentration and time. Addition of tauroursodeoxycholic acid to the incubation medium reduced cytolysis significantly, indicating a direct hepatoprotective effect of this bile acid against the detergent action of hydrophobic bile acids. In contrast to cytolysis, apoptosis with DNA fragmentation was induced by low concentrations of glycochenodeoxycholic acid a few hours after incubation. Coincubation with tauroursodeoxycholic acid in equimolar concentrations significantly reduced apoptosis, indicating another direct hepatoprotective effect of tauroursodeoxycholic acid. CONCLUSIONS: It seems likely that in severe cholestasis, bile-acid-induced injury of hepatocytes is due mainly to cytolysis, whereas in moderately severe cholestasis apoptosis represents the predominant mechanism of bile acid toxicity. Tauroursodeoxycholic acid may reduce both bile-acid-induced apoptosis and cytolysis.

Animals↗
PubMed1998

Effect of S-adenosylmethionine versus tauroursodeoxycholic acid on bile acid-induced apoptosis and cytolysis in rat hepatocytes.

BACKGROUND: S-adenosylmethionine (SAMe) increases survival in alcoholic liver cirrhosis and may have a beneficial effect in cholestatic liver disease. SAMe repletes glutathione stores and protects tissue from oxygen free radicals. The effect of SAMe on bile acid-induced apoptosis is unknown. In the present study the possible hepatoprotective effect of SAMe was evaluated and compared with that of tauroursodeoxycholic acid (TUDCA). METHODS: Primary rat hepatocytes treated with glycochenodeoxycholic acid (GCDCA) were used as a model for cholestasis-induced hepatocellular damage, which served to study the effects of SAMe and TUDCA on bile acid-induced apoptosis and cytolysis. RESULTS: SAMe reduced bile acid-induced apoptosis but did not prevent bile acid-induced cytolysis. Compared with SAMe, TUDCA was more efficient in reducing apoptosis due to toxic bile acids. The combination of SAMe and TUDCA had additive effects in reducing apoptosis. CONCLUSION: The reduction in bile acid-induced apoptosis by SAMe may represent one of the factors responsible for its beneficial effects in the treatment of liver diseases.

Animals↗
PubMed1997

MRI findings in chronic hepatic encephalopathy depend on portosystemic shunt: results of a controlled prospective clinical investigation.

BACKGROUND/AIMS: Deterioration of hepatic encephalopathy is a major concern with the transjugular intrahepatic portosystemic shunt procedure. Symmetric hyperintense globus pallidus on T1-weighted cranial magnetic resonance imaging in patients with liver cirrhosis anticipates hepatocerebral disease. It is hypothesized that hepatic encephalopathy and basal ganglia signal intensity progress in patients with cirrhosis of the liver undergoing transjugular intrahepatic portosystemic shunt. METHODS: Twenty-four patients were randomized to undergo either transjugular intrahepatic portosystemic shunt or elective sclerotherapy. At study entry and 6 months after randomization, neurologic assessment, psychometric tests, standard EEG, and magnetic resonance imaging were performed. The severity of liver failure was graded using Child-Pugh's classification. The signal intensity of the globus pallidus was determined on sagittal T1-weighted magnetic resonance imaging. RESULTS: The T1-weighted signal intensity of the globus pallidus on magnetic resonance imaging significantly increased after transjugular intrahepatic portosystemic shunt placement (p<0.01), but not with elective sclerotherapy. At follow-up, neurological symptoms indicating decline of mental status and motor performance were somewhat more prevalent in transjugular intrahepatic portosystemic shunt patients. Significant deterioration of EEG abnormalities occurred in patients treated with transjugular intrahepatic portosystemic shunt as opposed to elective sclerotherapy (p<0.01). CONCLUSIONS: Transjugular intrahepatic portosystemic shunt procedure increases hyperresonant globus pallidus on magnetic resonance imaging. Neuropsychiatric evaluation shows advancing hepatic encephalopathy, in particular with transjugular intrahepatic portosystemic shunt; however, it does not parallel the augmentation of pallidal signal intensity on magnetic resonance imaging.

Adult↗
PubMed1997

Efficacy of ursodeoxycholic acid treatment and endoscopic dilation of major duct stenoses in primary sclerosing cholangitis. An 8-year prospective study.

BACKGROUND/AIMS: Primary sclerosing cholangitis is characterized by progressive fibrotic inflammation and obliteration of intra- and extrahepatic bile ducts. Ursodeoxycholic acid treatment leads to improvement of biochemical parameters of cholestasis and in part also of liver histology. During treatment, obstruction of major ducts may lead to deterioration of liver function, which may be prevented by endoscopic dilation of the stenoses. Controlled trials for evaluation of the beneficial effects of ursodeoxycholic acid treatment and of endoscopic measures in patients with major duct stenoses have become clinically difficult. Estimation of survival probabilities without treatment allows comparison of actuarial survival with the estimated survival probabilities. METHODS/RESULTS: We studied survival in 65 patients with PSC treated with ursodeoxycholic acid (750 mg/day) and by endoscopic measures whenever necessary. Patients with decompensated cirrhosis in whom transplantation was foreseen were excluded. The study was started in May 1987 and the mean follow-up period was 45.0+/-3.5 (mean+/-SEM) months. Liver histology was performed in each of the patients before entry into the study and revealed that 21% were in stage 1, 37% in stage 2, 21% in stage 3 and 20% in stage 4. Of 65 patients, 12 had major duct stenosis at entry and another 11 developed major duct stenosis during ursodeoxycholic acid treatment, which was successfully treated by repeated endoscopic balloon dilations. The actuarial Kaplan-Meier survival probabilities without liver transplantation after treatment with ursodeoxycholic acid and dilation of major duct stenoses were significantly improved compared to the predicted survival rates with p=0.001. CONCLUSIONS: Ursodeoxycholic acid does not prevent major bile duct occlusion. When ursodeoxycholic acid treatment and endoscopic opening of duct stenoses are combined, survival may be significantly improved.

Adolescent↗
PubMed1997

Transjugular intrahepatic portosystemic stent shunt versus sclerotherapy plus propranolol for variceal rebleeding.

BACKGROUND & AIMS: In patients with cirrhosis of the liver, after the first variceal bleeding episode, transjugular intrahepatic portosystemic stent shunting (TIPS) and endoscopic sclerotherapy plus propranolol (ES) were compared regarding prevention of variceal rebleeding and mortality. METHODS: Eighty-three patients with cirrhosis of the liver were randomized to undergo TIPS (n = 42) or ES (n = 41). RESULTS: Median observation time was in 1.6 years in the TIPS group and 1.45 years in the ES group. Cumulative rates of rebleeding were 23% in the TIPS group and 57% in the ES group (P = 0.0001). Hepatic encephalopathy was observed in 29% of the patients in the TIPS group and in 13% of those in the ES group (P = 0.041). Cumulative rates of survival were 69% in the TIPS group and 67% in the ES group (P = 0.62). Mortality rates in both groups were positively correlated with a higher Child's classification. CONCLUSIONS: Although TIPS significantly reduced the rate of rebleeding, survival rates were not improved. Because TIPS is associated with an increased risk of encephalopathy and high rates of shunt dysfunction, which requires reintervention, the procedure cannot be recommended for elective treatment after the first variceal bleeding episode, but it is an effective therapy in patients in whom endoscopic sclerotherapy fails to control bleeding.

Adult↗
PubMed1997

[Changes in liver perfusion caused by transjugular intrahepatic stent shunt (TIPSS)].

PURPOSE: to demonstrate and document TIPSS-induced changes of the perfusion pattern of the liver with special reference to several rheologic, morphologic, functional and biochemical parameters. Our analysis was based on a study in 100 consecutive cases. PATIENTS AND METHODS: Evaluation and assessment of the following parameters before and within a 30-day post TIPSS period: portosystemic gradient; morphologic delineation of the portal circulation; invasive scintigraphic determination of the portal perfusion fraction (PPF) and the total liver perfusion (GLP); transcatheter intraarterial flow change measurement; serum levels of albumin and bilirubin; assessment of hepatic encephalopathy by appropriate testing; assessment of recurrent variceal bleeding RESULTS: by TIPSS variceal filling was widely reduced; as assessed morphologically and rheologically portal liver perfusion was significantly reduced. However, there was immediate onset of compensated liver perfusion by increased arterial inflow. Total liver perfusion was not significantly altered. In TIPSS portal decompression was readily achieved with reduction of the portosystemic gradient from an average of 24 mmHg to 10.5 mmHg. In our series we could not demonstrate an increased incidence of hepatic encephalopathy during the 30-day post TIPSS period. Bilirubin levels were significantly increased after TIPSS from 2.45 to 2.61 mg/dl (p = 0.0067), while albumin levels were not altered. Early mortality was 4% and early re-bleeding rate 3%, respectively. CONCLUSION: the concept of TIPSS represents an individually calibrated H-shunt. The significant reduction of post TIPSS portal perfusion appears to be compensated by increased arterial inflow. This is reflected by invasive flow measurement results and by the clinical results. Letality of TIPSS is low.

Blood Flow Velocity↗
PubMed1996

Phenprocoumon for prevention of shunt occlusion after transjugular intrahepatic portosystemic stent shunt: a randomized trial.

Development of stenosis or occlusion of the transjugular intrahepatic portosystemic stent shunt (TIPSS) is one of the major limiting factors in the long-term viability of this procedure. The efficacy of anticoagulation with heparin which is used in different centers is still unclear. In the present study, we evaluated the effect of phenprocoumon on shunt patency after TIPSS placement using Palmaz stents; 49 patients with Child's A and B cirrhosis, who underwent successful TIPSS placement were randomized into the treatment group (n = 24) who received phenprocoumon and a control group (n = 25). After 11 to 13 weeks, all patients were admitted and had a reevaluation that included control angiography by transjugular approach. Phenprocoumon treatment was stopped after the first reevaluation and both groups were followed for 1 year after randomization. During the 3-month treatment period 11 of 22 patients of the treatment group and 12 of 23 patients of the control group required reintervention because of an increased portosystemic gradient. Five of the 12 patients in the control group showed complete occlusion of the shunt, whereas no occlusion in the treatment group was observed (P < .05). During the mean follow-up of 8 months after the treatment was stopped, in both groups stenosis occurred in 50% of patients, but no further occlusion of the stent was observed. These data indicate that occlusion of the stent is related to thrombosis, whereas stenosis does not appear to be dependent on blood coagulation. In patients with preserved liver function occlusion of the shunt may be prevented by phenprocoumon treatment in the first 3 months after TIPSS placement. Thereafter shunt occlusion was not observed and further phenprocoumon treatment seemed unnecessary.

Anticoagulants↗
PubMed1996

Kinetics of primary bile acids in patients after orthotopic liver transplantation.

Administration of cyclosporin A (CsA) may induce cholestasis, and this effect has been attributed to impaired hepatocellular uptake, transport, secretion and intestinal absorption of bile acids. Disturbances of the enterohepatic circulation may affect metabolism of bile acids. To test whether liver transplantation and treatment with CsA alters pool sizes or synthesis and turnover rates, we determined kinetics of primary bile acids in patients after orthotopic liver transplantation on CsA. Two male and four female patients were studied 6-20 months after transplantation. They had no overt signs of cholestasis, graft dysfunction or rejection. Kinetics of cholic acid (CA) and chenodeoxycholic acid (CDCA) were simultaneously determined after oral administration of [24-13C]-CA and [24-13C]-CDCA on the basis of isotope dilution in a single pool of bile acids. Ten healthy volunteers served as controls. After orthotopic liver transplantation, pool sizes, fractional turnover rates and synthesis rates of both primary bile acids, CA and CDCA were not significantly different from control subjects. In spite of the known interference of CsA with the enterohepatic circulation of bile acids, in the majority of patients after orthotopic liver transplantation without cholestasis, graft dysfunction of rejection, treatment with CsA does not disturb kinetics of primary bile acids.

Adult↗