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Volkhard Kaever - One of the best experts on this subject based on the ideXlab platform.
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everolimus cyclosporine interactions on Bile Flow and biliary excretion of Bile salts and cholesterol in rats
Digestive Diseases and Sciences, 2004Co-Authors: Michael Deters, G Kirchner, Klaus Resch, Therese Koal, Volkhard KaeverAbstract:As a possible explanation for everolimus/cyclosporine-induced hypercholesterolemia seen in transplant recipients, we investigated the interactions of the immunosuppressants everolimus and cyclosporine on Bile Flow and biliary excretion of Bile salts and cholesterol in a subchronic Bile fistula model in rats because biliary excretion is a main elimination route of cholesterol. After 2 weeks of daily treatment, everolimus (1 mg/kg i.p.) and cyclosporine (5 mg/kg i.p) decreased Bile Flow (-45 and -36%) and biliary excretion of Bile salts (-34 and -54%) and cholesterol (-25 and -39%) and increased serum concentrations of cholesterol (+40 and +17%) and triglycerides (+220 and +110%). Bile salt serum concentration was elevated only by cyclosporine (+100%), and not by everolimus. Everolimus/cyclosporine slightly enforced the cyclosporine-induced hyperlipidemia but not reduction of Bile parameters, while the cyclosporine-induced increase in Bile salts in serum was totally prevented. From these results we conclude that Bile salt synthesis could be impaired by everolimus, which could be one reason for everolimus-induced hypercholesterolemia.
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sirolimus cyclosporine tacrolimus interactions on Bile Flow and biliary excretion of immunosuppressants in a subchronic Bile fistula rat model
British Journal of Pharmacology, 2002Co-Authors: Michael Deters, Til Klabunde, G Kirchner, Klaus Resch, Volkhard KaeverAbstract:The new immunosuppressive agent sirolimus generally is combined in transplant patients with cyclosporine and tacrolimus which both exhibit cholestatic effects. Nothing is known about possible cholestatic effects of these combinations which might be important for biliary excretion of endogenous compounds as well as of immunosuppressants. Rats were daily treated with sirolimus (1 mg kg(-1) p.o.), cyclosporine (10 mg kg(-1) i.p.), tacrolimus (1 mg kg(-1) i.p.), or a combination of sirolimus with cyclosporine or tacrolimus. After 14 days a Bile fistula was installed to investigate the effects of the immunosuppressants and their combinations on Bile Flow and on biliary excretion of Bile salts, cholesterol, and immunosuppressants. Cyclosporine as well as tacrolimus reduced Bile Flow (-22%; -18%), biliary excretion of Bile salts (-15%;-36%) and cholesterol (-15%; -47%). Sirolimus decreased Bile Flow by 10%, but had no effect on cholesterol or Bile salt excretion. Combination of sirolimus/cyclosporine decreased Bile Flow and biliary Bile salt excretion to the same extent as cyclosporine alone, but led to a 2 fold increase of biliary cholesterol excretion. Combination of sirolimus/tacrolimus reduced Bile Flow only by 7.5% and did not change biliary Bile salt and cholesterol excretion. Sirolimus enhanced blood concentrations of cyclosporine (+40%) and tacrolimus (+57%). Sirolimus blood concentration was increased by cyclosporine (+400%), but was not affected by tacrolimus. We conclude that a combination of sirolimus/tacrolimus could be the better alternative to the cotreatment of sirolimus/cyclosporine in cholestatic patients and in those facing difficulties in reaching therapeutic ranges of sirolimus blood concentration.
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sirolimus cyclosporine tacrolimus interactions on Bile Flow and biliary excretion of immunosuppressants in a subchronic Bile fistula rat model
British Journal of Pharmacology, 2002Co-Authors: Michael Deters, Til Klabunde, G Kirchner, Klaus Resch, Volkhard KaeverAbstract:The new immunosuppressive agent sirolimus generally is combined in transplant patients with cyclosporine and tacrolimus which both exhibit cholestatic effects. Nothing is known about possible cholestatic effects of these combinations which might be important for biliary excretion of endogenous compounds as well as of immunosuppressants. Rats were daily treated with sirolimus (1 mg kg−1 p.o.), cyclosporine (10 mg kg−1 i.p.), tacrolimus (1 mg kg−1 i.p.), or a combination of sirolimus with cyclosporine or tacrolimus. After 14 days a Bile fistula was installed to investigate the effects of the immunosuppressants and their combinations on Bile Flow and on biliary excretion of Bile salts, cholesterol, and immunosuppressants. Cyclosporine as well as tacrolimus reduced Bile Flow (−22%; −18%), biliary excretion of Bile salts (−15%;−36%) and cholesterol (−15%; −47%). Sirolimus decreased Bile Flow by 10%, but had no effect on cholesterol or Bile salt excretion. Combination of sirolimus/cyclosporine decreased Bile Flow and biliary Bile salt excretion to the same extent as cyclosporine alone, but led to a 2 fold increase of biliary cholesterol excretion. Combination of sirolimus/tacrolimus reduced Bile Flow only by 7.5% and did not change biliary Bile salt and cholesterol excretion. Sirolimus enhanced blood concentrations of cyclosporine (+40%) and tacrolimus (+57%). Sirolimus blood concentration was increased by cyclosporine (+400%), but was not affected by tacrolimus. We conclude that a combination of sirolimus/tacrolimus could be the better alternative to the cotreatment of sirolimus/cyclosporine in cholestatic patients and in those facing difficulties in reaching therapeutic ranges of sirolimus blood concentration. Keywords: Cyclosporine, sirolimus, tacrolimus, cholestasis, rat Introduction Sirolimus (rapamycin, RAPAMUNE®) is a macrocyclic lactone isolated from Streptomyces hygroscopicus. Whereas cyclosporine (CyA) and tacrolimus (TRL), the two base therapy agents currently used in organ transplantation, achieve their effects principally by blocking calcineurin and thereby inhibiting interleukin-2 production, sirolimus (SRL) has no effect on calcineurin. Sirolimus reduces T-lymphocyte activation by inhibiting the interleukin-2-mediated signal transduction pathway (Seghal, 1995; Liu et al., 1991). As the significant nephrotoxicity, neurotoxicity, and hypertension associated with CyA and TRL can be partly attributed to calcineurin blockade (Mayer et al., 1997; Bennett et al., 1996; Andoh et al., 1997), SRL would be expected to have a different toxicity profile. In preclinical studies, SRL has been shown to be as effective as CyA in maintaining survival of renal and cardiac allografts without causing nephrotoxicity (Granger et al., 1995). When SRL was added to CyA-therapy in phase I (Murgia et al., 1996) and phase II studies (Kahan et al., 1999), no deleterious effects on renal function were observed, and the incidences of neurotoxicity and hypertension were unchanged. The most notable side-effects were hyperlipidaemia (both hypercholesterolaemia and hypertriglyceridaemia), thrombocytopenia, and leukopenia. The exact mechanisms of CyA- and SRL-induced hyperlipidaemia are not known yet. In the case of CyA, drug-induced cholestasis could be one important reason of hypercholesterolaemia, because CyA is known to cause cholestasis by inhibiting both basal and canalicular hepatocellular Bile salt transporters (Stacey & Kotecka, 1988; Bohme et al., 1994). In experiments with α-naphthylisothiocyanate-treated mice, cholestasis was induced and increased levels of free cholesterol in the plasma were observed (Chisholm et al., 1999). Because experimental transplantation studies suggest a synergism between SRL and TRL (Vu et al., 1997), the combination of SRL/TRL is of increasing interest in clinical trials, too (Mcalister et al., 2000). The first results of these studies indicate that the incidence of hypercholesterolaemia is lower in SRL/TRL-treated patients than in patients under SRL/CyA therapy. In studies with rats TRL was shown to reduce Bile Flow, as well (Sanchez-Campos et al., 1998), but was less effective on cholestasis than CyA (Mizuta et al., 1999). In a previous study in an acute Bile fistula model in rats we could show that SRL/CyA reduced Bile Flow and biliary excretion of Bile salts and cholesterol (Deters et al., 2001). On the other hand, these parameters were not attenuated by SRL/TRL. To augment the clinical impact of these observations we investigated the effects of SRL, CyA, TRL, and the combination of either SRL/CyA or SRL/TRL on Bile Flow after treatment with these immunosuppressants in a subchronic rat Bile fistula model over 2 weeks. Additionally, we measured the concentrations of these immunosuppressants and the main CyA metabolites in Bile and blood to explore the role of biliary excretion of them for possible pharmacokinetic interactions that are of clinical importance, as well.
Katsuyoshi Ito - One of the best experts on this subject based on the ideXlab platform.
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pancreatobiliary Flow dynamics association between Bile and pancreatic juice evaluated with cine dynamic magnetic resonance cholangiopancreatography using spatially selective inversion recovery pulse
Journal of Magnetic Resonance Imaging, 2021Co-Authors: Mayumi Higashi, Masahiro Tanabe, Kenichiro Ihara, Etsushi Iida, Matakazu Furukawa, Munemasa Okada, Katsuyoshi ItoAbstract:BACKGROUND The physiological Flow patterns and the reciprocal relationship between pancreatic juice and Bile excretion dynamics have not been clearly elucidated by imaging. PURPOSE To assess the physiological Flow patterns of Bile and pancreatic juice simultaneously in order to clarify the pancreatobiliary Flow dynamics using cine-dynamic magnetic resonance cholangiopancreatography (MRCP) with a spatial selective inversion recovery (IR) pulse. STUDY TYPE Retrospective. POPULATION A total of 85 patients with physiologically normal pancreatobiliary Flow without ductal dilatation (normal group) and 19 patients with dilated pancreatic duct. FIELD STRENGTH/SEQUENCE A 3 T, fast spin echo sequence with IR pulse to nullify the signal of static pancreatic juice and Bile. ASSESSMENT The frequency and secretion grade of the antegrade and reverse Flow of the pancreatic juice and Bile on cine-dynamic MRCP were visually evaluated. Additionally, the reciprocal relationship between pancreatic juice and Bile Flow was evaluated based on its Flow patterns. STATISTICAL TESTS Spearman's rank correlation coefficient analysis and the Kruskal-Wallis and Mann-Whitney U tests were used. P values of <0.05 were considered to indicate statistical significance. RESULTS In the normal group, the antegrade pancreatic juice Flow and no Bile Flow pattern was most frequently observed (29%), followed by the no pancreatic juice Flow and no Bile Flow pattern (23%), the antegrade pancreatic juice Flow and antegrade Bile Flow pattern (22%), and the no pancreatic juice Flow and reverse Bile Flow pattern (9%). The Flow of the pancreatic juice and Bile were synchronized with each other in 47%, while they were not in 53%. In the dilated pancreatic duct group, the mean secretion grade of the antegrade Bile and pancreatic juice Flow was significantly lower than in the normal group. DATA CONCLUSION Cine-dynamic MRCP with a spatially selective IR pulse can visualize the variations of the physiological Flow patterns of Bile and pancreatic juice including 53% of unsynchronized patterns. LEVEL OF EVIDENCE 4 TECHNICAL EFFICACY: Stage 5.
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influence of cholecystectomy on the Flow dynamic pattern of Bile in the extrahepatic Bile duct assessment by cine dynamic mrcp with spatially selective ir pulse
Magnetic Resonance Imaging, 2020Co-Authors: Hidemitsu Sotozono, Akihiko Kanki, Akira Yamamoto, Tsutomu Tamada, Kazuya Yasokawa, Takeshi Fukunaga, Katsuyoshi ItoAbstract:Abstract Purpose To evaluate the influence of cholecystectomy on the Flow dynamic pattern of Bile in the extrahepatic Bile duct by using cine-dynamic MRCP with spatially-selective inversion-recovery (IR) pulse non-invasively. Materials and methods 56 patients with cholecystectomy and 48 control subjects without cholecystectomy who underwent cine-dynamic MRCP with spatially-selective IR pulse at 1.5 T or 3 T (TR/TE, 4000 msec/500 msec; echo train spacing, 6.5 msec; echo train length, 172; section thickness, 50 mm; matrix, 320 × 320; field of view, 320 × 320 mm; bandwidth, 488 Hz; and inversion time, 2200 msec). In cine-dynamic MRCP, IR pulse with 20 mm width was placed on the common Bile duct (CBD) to evaluate the movement of Bile (antegrade and reversed Bile Flow). Cine-dynamic MRCP imaging was scanned every 15 s (imaging, 4 s; rest, 11 s) during 5 min to acquire a series of single-shot images (a total of 20 images). The frequency that antegrade or reversed Bile Flow was observed in the extrahepatic Bile duct, and 5-point grading score based on the moving distance of antegrade or reversed Bile Flow were compared between the groups. Both groups were compared using the χ2 and Mann-Whitney U tests (P Results Antegrade Bile Flow was observed more frequently in the cholecystectomy group than in the non-cholecystectomy group (5.1 times vs. 2.8 times, P = 0.008). Mean grading score of antegrade Bile Flow was significantly greater in the cholecystectomy group than in the non-cholecystectomy group (mean grade, 0.33 vs 0.21; P = 0.014). Regarding reversed Bile Flow, there were no significant differences in the frequency and grading score between cholecystectomy group and non-cholecystectomy group. Conclusion Antegrade Bile Flow was observed more frequently and predominantly in patients after cholecystectomy in cine-dynamic MRCP with spatially-selective IR pulse while reversed Bile Flow was observed equivalently.
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assessment of physiologic Bile Flow in the extrahepatic Bile duct with cine dynamic mr cholangiopancreatography and a spatially selective inversion recovery pulse
Radiology, 2014Co-Authors: Katsuyoshi Ito, Akihiko Kanki, Akira Yamamoto, Tsutomu Tamada, Kazuya Yasokawa, Daigo Tanimoto, Tomohiro Sato, Atsushi Higaki, Yasufumi Noda, Koji YoshidaAbstract:Nonpharmacologic cine-dynamic MR cholangiopancreatography with a spatially selective inversion-recovery pulse allows direct and noninvasive visualization of Bile Flow in the extrahepatic Bile duct, demonstrating that reversed Bile Flow is a physiologic phenomenon.
Michael Deters - One of the best experts on this subject based on the ideXlab platform.
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everolimus cyclosporine interactions on Bile Flow and biliary excretion of Bile salts and cholesterol in rats
Digestive Diseases and Sciences, 2004Co-Authors: Michael Deters, G Kirchner, Klaus Resch, Therese Koal, Volkhard KaeverAbstract:As a possible explanation for everolimus/cyclosporine-induced hypercholesterolemia seen in transplant recipients, we investigated the interactions of the immunosuppressants everolimus and cyclosporine on Bile Flow and biliary excretion of Bile salts and cholesterol in a subchronic Bile fistula model in rats because biliary excretion is a main elimination route of cholesterol. After 2 weeks of daily treatment, everolimus (1 mg/kg i.p.) and cyclosporine (5 mg/kg i.p) decreased Bile Flow (-45 and -36%) and biliary excretion of Bile salts (-34 and -54%) and cholesterol (-25 and -39%) and increased serum concentrations of cholesterol (+40 and +17%) and triglycerides (+220 and +110%). Bile salt serum concentration was elevated only by cyclosporine (+100%), and not by everolimus. Everolimus/cyclosporine slightly enforced the cyclosporine-induced hyperlipidemia but not reduction of Bile parameters, while the cyclosporine-induced increase in Bile salts in serum was totally prevented. From these results we conclude that Bile salt synthesis could be impaired by everolimus, which could be one reason for everolimus-induced hypercholesterolemia.
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sirolimus cyclosporine tacrolimus interactions on Bile Flow and biliary excretion of immunosuppressants in a subchronic Bile fistula rat model
British Journal of Pharmacology, 2002Co-Authors: Michael Deters, Til Klabunde, G Kirchner, Klaus Resch, Volkhard KaeverAbstract:The new immunosuppressive agent sirolimus generally is combined in transplant patients with cyclosporine and tacrolimus which both exhibit cholestatic effects. Nothing is known about possible cholestatic effects of these combinations which might be important for biliary excretion of endogenous compounds as well as of immunosuppressants. Rats were daily treated with sirolimus (1 mg kg(-1) p.o.), cyclosporine (10 mg kg(-1) i.p.), tacrolimus (1 mg kg(-1) i.p.), or a combination of sirolimus with cyclosporine or tacrolimus. After 14 days a Bile fistula was installed to investigate the effects of the immunosuppressants and their combinations on Bile Flow and on biliary excretion of Bile salts, cholesterol, and immunosuppressants. Cyclosporine as well as tacrolimus reduced Bile Flow (-22%; -18%), biliary excretion of Bile salts (-15%;-36%) and cholesterol (-15%; -47%). Sirolimus decreased Bile Flow by 10%, but had no effect on cholesterol or Bile salt excretion. Combination of sirolimus/cyclosporine decreased Bile Flow and biliary Bile salt excretion to the same extent as cyclosporine alone, but led to a 2 fold increase of biliary cholesterol excretion. Combination of sirolimus/tacrolimus reduced Bile Flow only by 7.5% and did not change biliary Bile salt and cholesterol excretion. Sirolimus enhanced blood concentrations of cyclosporine (+40%) and tacrolimus (+57%). Sirolimus blood concentration was increased by cyclosporine (+400%), but was not affected by tacrolimus. We conclude that a combination of sirolimus/tacrolimus could be the better alternative to the cotreatment of sirolimus/cyclosporine in cholestatic patients and in those facing difficulties in reaching therapeutic ranges of sirolimus blood concentration.
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sirolimus cyclosporine tacrolimus interactions on Bile Flow and biliary excretion of immunosuppressants in a subchronic Bile fistula rat model
British Journal of Pharmacology, 2002Co-Authors: Michael Deters, Til Klabunde, G Kirchner, Klaus Resch, Volkhard KaeverAbstract:The new immunosuppressive agent sirolimus generally is combined in transplant patients with cyclosporine and tacrolimus which both exhibit cholestatic effects. Nothing is known about possible cholestatic effects of these combinations which might be important for biliary excretion of endogenous compounds as well as of immunosuppressants. Rats were daily treated with sirolimus (1 mg kg−1 p.o.), cyclosporine (10 mg kg−1 i.p.), tacrolimus (1 mg kg−1 i.p.), or a combination of sirolimus with cyclosporine or tacrolimus. After 14 days a Bile fistula was installed to investigate the effects of the immunosuppressants and their combinations on Bile Flow and on biliary excretion of Bile salts, cholesterol, and immunosuppressants. Cyclosporine as well as tacrolimus reduced Bile Flow (−22%; −18%), biliary excretion of Bile salts (−15%;−36%) and cholesterol (−15%; −47%). Sirolimus decreased Bile Flow by 10%, but had no effect on cholesterol or Bile salt excretion. Combination of sirolimus/cyclosporine decreased Bile Flow and biliary Bile salt excretion to the same extent as cyclosporine alone, but led to a 2 fold increase of biliary cholesterol excretion. Combination of sirolimus/tacrolimus reduced Bile Flow only by 7.5% and did not change biliary Bile salt and cholesterol excretion. Sirolimus enhanced blood concentrations of cyclosporine (+40%) and tacrolimus (+57%). Sirolimus blood concentration was increased by cyclosporine (+400%), but was not affected by tacrolimus. We conclude that a combination of sirolimus/tacrolimus could be the better alternative to the cotreatment of sirolimus/cyclosporine in cholestatic patients and in those facing difficulties in reaching therapeutic ranges of sirolimus blood concentration. Keywords: Cyclosporine, sirolimus, tacrolimus, cholestasis, rat Introduction Sirolimus (rapamycin, RAPAMUNE®) is a macrocyclic lactone isolated from Streptomyces hygroscopicus. Whereas cyclosporine (CyA) and tacrolimus (TRL), the two base therapy agents currently used in organ transplantation, achieve their effects principally by blocking calcineurin and thereby inhibiting interleukin-2 production, sirolimus (SRL) has no effect on calcineurin. Sirolimus reduces T-lymphocyte activation by inhibiting the interleukin-2-mediated signal transduction pathway (Seghal, 1995; Liu et al., 1991). As the significant nephrotoxicity, neurotoxicity, and hypertension associated with CyA and TRL can be partly attributed to calcineurin blockade (Mayer et al., 1997; Bennett et al., 1996; Andoh et al., 1997), SRL would be expected to have a different toxicity profile. In preclinical studies, SRL has been shown to be as effective as CyA in maintaining survival of renal and cardiac allografts without causing nephrotoxicity (Granger et al., 1995). When SRL was added to CyA-therapy in phase I (Murgia et al., 1996) and phase II studies (Kahan et al., 1999), no deleterious effects on renal function were observed, and the incidences of neurotoxicity and hypertension were unchanged. The most notable side-effects were hyperlipidaemia (both hypercholesterolaemia and hypertriglyceridaemia), thrombocytopenia, and leukopenia. The exact mechanisms of CyA- and SRL-induced hyperlipidaemia are not known yet. In the case of CyA, drug-induced cholestasis could be one important reason of hypercholesterolaemia, because CyA is known to cause cholestasis by inhibiting both basal and canalicular hepatocellular Bile salt transporters (Stacey & Kotecka, 1988; Bohme et al., 1994). In experiments with α-naphthylisothiocyanate-treated mice, cholestasis was induced and increased levels of free cholesterol in the plasma were observed (Chisholm et al., 1999). Because experimental transplantation studies suggest a synergism between SRL and TRL (Vu et al., 1997), the combination of SRL/TRL is of increasing interest in clinical trials, too (Mcalister et al., 2000). The first results of these studies indicate that the incidence of hypercholesterolaemia is lower in SRL/TRL-treated patients than in patients under SRL/CyA therapy. In studies with rats TRL was shown to reduce Bile Flow, as well (Sanchez-Campos et al., 1998), but was less effective on cholestasis than CyA (Mizuta et al., 1999). In a previous study in an acute Bile fistula model in rats we could show that SRL/CyA reduced Bile Flow and biliary excretion of Bile salts and cholesterol (Deters et al., 2001). On the other hand, these parameters were not attenuated by SRL/TRL. To augment the clinical impact of these observations we investigated the effects of SRL, CyA, TRL, and the combination of either SRL/CyA or SRL/TRL on Bile Flow after treatment with these immunosuppressants in a subchronic rat Bile fistula model over 2 weeks. Additionally, we measured the concentrations of these immunosuppressants and the main CyA metabolites in Bile and blood to explore the role of biliary excretion of them for possible pharmacokinetic interactions that are of clinical importance, as well.
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Choleretic effects of curcuminoids on an acute cyclosporin-induced cholestasis in the rat.
Planta medica, 1999Co-Authors: Michael Deters, Claudia Siegers, Philipp Muhl, Wolfram HänselAbstract:Former studies have shown that curcumin, which can be extracted from different Curcuma species, is able to stimulate Bile Flow in rats, whereas bisdemethoxycurcumin, which is mainly found in rhizomes of Curcuma longa, is believed to inhibit Bile Flow. To reevaluate this observation we investigated the influence of both curcuminoids on Bile Flow, Bile acid concentration and excretion over a time period of 180 min in the Bile fistula model in rats. Furthermore, we tested the ability of both curcuminoids to reduce cyclosporin-induced cholestasis. 30 min after intravenous injection of 25 mg/kg of curcumin and bisdemethoxycurcumin Bile Flow was enhanced from 500 microliters/kg/15 min (100%) to 180% and to 220%, respectively. The choleretic effect of bisdemethoxycurcumin lasted longer than that of curcumin. Following intravenous injection of 30 mg/kg of cyclosporin, which reduced Bile Flow, Bile acid concentration (15 mmol/l) and excretion (12.5 mumol/kg/15 min) to 40% of the initial value, administration of curcumin and bisdemethoxycurcumin transiently increased Bile Flow to 100% and to 125% of the starting value, respectively. However, only bisdemethoxycurcumin statistically significantly attenuated cyclosporin-induced reduction of Bile acid excretion. We conclude that the beneficial properties of curcuminoids for the therapy of cyclosporin-induced cholestasis still remain to be proven.
Greg J. Barritt - One of the best experts on this subject based on the ideXlab platform.
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evidence that estrogen receptors play a limited role in mediating enhanced recovery of Bile Flow in female rats in the acute phase of liver ischemia reperfusion injury
Annals of Hepatology, 2013Co-Authors: Heleen A H De Vries, Vincent B. Nieuwenhuijs, Arthur Morphett, Robert Padbury, Fraukje A M Ponds, Greg J. BarrittAbstract:Introduction. Female patients exhibit better survival and less hepatic damage from ischemia reperfusion (IR) injury following surgery. However, the effects of sex and estrogens on liver function in the acute phase of IR are not well understood. Objective. The aim was to investigate this question. Material and methods. A rat model of segmental hepatic ischemia was employed. Rats were pre-treated with the estrogen receptor antagonist ICI182,780 and/or the estrogen receptor agonist 17β-estradiol. Bile Flow, blood concentrations of bilirubin and liver enzymes were measured, and liver histology was assessed. Results. Bile Flow recovery immediately after the initiation of reperfusion was faster in females than in males. ICI182,780 reduced the rate of Bile Flow recovery in females but this reduction was not reversed by co-administration of 17 β-estradiol. In males, 17 β-estradiol alone did not enhance Bile Flow recovery. The changes in Bile Flow recovery observed under a given condition were correlated with small changes in blood liver enzymes and liver histology. Conclusions. Sex has a significant influence on the early recovery of liver function in the acute phase of IR injury. However, in female rats estrogen receptors play only a limited role in mediating enhanced recovery of liver function.
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rapamycin induces heme oxygenase 1 in liver but inhibits Bile Flow recovery after ischemia
Journal of Surgical Research, 2012Co-Authors: Alwine Kist, Vincent B. Nieuwenhuijs, Joris Wakkie, Max Madu, Ruth I Versteeg, Judith Ten Berge, Andrej Nikolic, Robert J Porte, Robert Padbury, Greg J. BarrittAbstract:Background/Aims Rapamycin, which is employed in the management of patients undergoing liver surgery, induces the synthesis of heme oxygenase-1 (HO-1) in some non-liver cell types. The aim was to investigate whether rapamycin can induce HO-1 expression in the liver, and to test the effects of rapamycin on liver function in the early phase of ischemia reperfusion (IR) injury. Methods Isolated rat hepatocytes and a rat model of segmental hepatic ischemia and reperfusion were employed. Bile Flow was measured gravimetrically or by using indocyanine green. mRNA and protein (by quantitative PCR and Western blot, respectively) and blood concentrations of rapamycin, bilirubin, and liver marker enzymes were measured. Results In isolated hepatocytes, rapamycin induced a 6-fold increase in HO-1, comparable to that induced by cobalt proporphyrin (CoPP), and a 2-fold increase in peroxiredoxin-1. Pretreatment of rats with rapamycin resulted in a small increase in liver HO-1 expression, a 20% inhibition of the basal rate of Bile Flow, and a 50% inhibition in the rate of Bile Flow recovery after ischemia. CoPP increased basal Bile Flow by 20% and inhibited Bile Flow recovery by 50%. These effects were associated with small increases in the blood concentrations of bilirubin and liver marker enzymes. Conclusions Rapamycin, through HO-1 induction, has the potential to protect the liver against damage in the late phase of IR. The inhibition by rapamycin of Bile Flow indicates that its actions on liver function in the acute phase of IR injury are complex.
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intermittent ischemia but not ischemic preconditioning is effective in restoring Bile Flow after ischemia reperfusion injury in the livers of aged rats
Journal of Surgical Research, 2009Co-Authors: Marc Schiesser, Vincent B. Nieuwenhuijs, Arthur Morphett, Robert Padbury, Anna Wittert, Greg J. BarrittAbstract:Background/Aims Ischemic preconditioning (IPC) and intermittent ischemia (INT) reduce liver injury following ischemia reperfusion in liver resections. Aged livers are at higher risk for ischemia reperfusion injury, but little is known of the effectiveness of IPC and INT in aged livers. The aim of this study was to investigate the effects of IPC and INT on ischemia reperfusion injury in aged livers. Methods A rat model of segmental hepatic ischemia (45 min) and reperfusion (60 min) was used. Bile Flow, as an indicator of early hepatocyte damage and dynamic liver function, plasma concentrations of bilirubin, liver marker enzymes, and liver histology were assessed. Results In young rats (8–13 weeks), IPC regimes of 10 min clamping and 10 min reperfusion, and 5 min clamping and 30 min reperfusion, restored Bile Flow to 23 and 42%, respectively, of the initial value, compared to 14 and 88% for continuous clamping and controls, respectively. An INT regime of three cycles of alternating 15 min perfusion and 15 min clamping gave a substantially greater (70%) restoration of Bile Flow. In aged rats (20–24 months), the IPC regimes did not give any restoration of Bile Flow. By contrast, the INT regime restored Bile Flow to 68%. Plasma bilirubin concentrations were lowest in the INT groups, whereas alanine transaminase concentrations for the IPC and INT groups compared with the continuous clamping groups showed no significant differences. Conclusions In young rats, INT is more effective than IPC in restoring the immediate consequences of IP-induced damage to hepatocytes and liver function after ischemia-reperfusion. In aged rats INT, but not IPC, reverses hepatocyte damage and restores liver function. INT may promote better hepatocyte and liver function than IPC following the surgical resection of aged livers.
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Ischemic Preconditioning and Intermittent Ischemia Preserve Bile Flow in a Rat Model of Ischemia Reperfusion Injury
Digestive Diseases and Sciences, 2007Co-Authors: Vincent B. Nieuwenhuijs, Menno T. Bruijn, Marc Schiesser, Arthur Morphett, Robert T. A. Padbury, Greg J. BarrittAbstract:Ischemia and reperfusion (IR) injury of the liver is associated with impaired Bile secretion, but the effects of ischemic preconditioning (IPC) and intermittent ischemia (INT) on Bile Flow are unknown. A rat model of segmental (60%–70%) hepatic ischemia and reperfusion was employed to test the effects of IPC and INT on Bile Flow. Continuous clamping for 45 min (CC) substantially reduced Bile Flow, and this did not recover after 60 min of reperfusion. IPC and INT caused a significant recovery of Bile Flow. The elevation in plasma liver marker enzymes induced by CC was not reduced by IPC and INT. Light microscopy showed mild hepatocyte damage in all groups. In the CC group, the amount of F-actin localized around the Bile canaliculi in the ischemic lobes was less than that in the nonischemic lobes, but this difference was not observed in the IPC and INT groups. It is concluded that IPC and INT substantially alleviate the decrease in Bile Flow induced by ischemia. Bile Flow may be useful in the assessment of IR injury.
Vincent B. Nieuwenhuijs - One of the best experts on this subject based on the ideXlab platform.
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evidence that estrogen receptors play a limited role in mediating enhanced recovery of Bile Flow in female rats in the acute phase of liver ischemia reperfusion injury
Annals of Hepatology, 2013Co-Authors: Heleen A H De Vries, Vincent B. Nieuwenhuijs, Arthur Morphett, Robert Padbury, Fraukje A M Ponds, Greg J. BarrittAbstract:Introduction. Female patients exhibit better survival and less hepatic damage from ischemia reperfusion (IR) injury following surgery. However, the effects of sex and estrogens on liver function in the acute phase of IR are not well understood. Objective. The aim was to investigate this question. Material and methods. A rat model of segmental hepatic ischemia was employed. Rats were pre-treated with the estrogen receptor antagonist ICI182,780 and/or the estrogen receptor agonist 17β-estradiol. Bile Flow, blood concentrations of bilirubin and liver enzymes were measured, and liver histology was assessed. Results. Bile Flow recovery immediately after the initiation of reperfusion was faster in females than in males. ICI182,780 reduced the rate of Bile Flow recovery in females but this reduction was not reversed by co-administration of 17 β-estradiol. In males, 17 β-estradiol alone did not enhance Bile Flow recovery. The changes in Bile Flow recovery observed under a given condition were correlated with small changes in blood liver enzymes and liver histology. Conclusions. Sex has a significant influence on the early recovery of liver function in the acute phase of IR injury. However, in female rats estrogen receptors play only a limited role in mediating enhanced recovery of liver function.
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rapamycin induces heme oxygenase 1 in liver but inhibits Bile Flow recovery after ischemia
Journal of Surgical Research, 2012Co-Authors: Alwine Kist, Vincent B. Nieuwenhuijs, Joris Wakkie, Max Madu, Ruth I Versteeg, Judith Ten Berge, Andrej Nikolic, Robert J Porte, Robert Padbury, Greg J. BarrittAbstract:Background/Aims Rapamycin, which is employed in the management of patients undergoing liver surgery, induces the synthesis of heme oxygenase-1 (HO-1) in some non-liver cell types. The aim was to investigate whether rapamycin can induce HO-1 expression in the liver, and to test the effects of rapamycin on liver function in the early phase of ischemia reperfusion (IR) injury. Methods Isolated rat hepatocytes and a rat model of segmental hepatic ischemia and reperfusion were employed. Bile Flow was measured gravimetrically or by using indocyanine green. mRNA and protein (by quantitative PCR and Western blot, respectively) and blood concentrations of rapamycin, bilirubin, and liver marker enzymes were measured. Results In isolated hepatocytes, rapamycin induced a 6-fold increase in HO-1, comparable to that induced by cobalt proporphyrin (CoPP), and a 2-fold increase in peroxiredoxin-1. Pretreatment of rats with rapamycin resulted in a small increase in liver HO-1 expression, a 20% inhibition of the basal rate of Bile Flow, and a 50% inhibition in the rate of Bile Flow recovery after ischemia. CoPP increased basal Bile Flow by 20% and inhibited Bile Flow recovery by 50%. These effects were associated with small increases in the blood concentrations of bilirubin and liver marker enzymes. Conclusions Rapamycin, through HO-1 induction, has the potential to protect the liver against damage in the late phase of IR. The inhibition by rapamycin of Bile Flow indicates that its actions on liver function in the acute phase of IR injury are complex.
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intermittent ischemia but not ischemic preconditioning is effective in restoring Bile Flow after ischemia reperfusion injury in the livers of aged rats
Journal of Surgical Research, 2009Co-Authors: Marc Schiesser, Vincent B. Nieuwenhuijs, Arthur Morphett, Robert Padbury, Anna Wittert, Greg J. BarrittAbstract:Background/Aims Ischemic preconditioning (IPC) and intermittent ischemia (INT) reduce liver injury following ischemia reperfusion in liver resections. Aged livers are at higher risk for ischemia reperfusion injury, but little is known of the effectiveness of IPC and INT in aged livers. The aim of this study was to investigate the effects of IPC and INT on ischemia reperfusion injury in aged livers. Methods A rat model of segmental hepatic ischemia (45 min) and reperfusion (60 min) was used. Bile Flow, as an indicator of early hepatocyte damage and dynamic liver function, plasma concentrations of bilirubin, liver marker enzymes, and liver histology were assessed. Results In young rats (8–13 weeks), IPC regimes of 10 min clamping and 10 min reperfusion, and 5 min clamping and 30 min reperfusion, restored Bile Flow to 23 and 42%, respectively, of the initial value, compared to 14 and 88% for continuous clamping and controls, respectively. An INT regime of three cycles of alternating 15 min perfusion and 15 min clamping gave a substantially greater (70%) restoration of Bile Flow. In aged rats (20–24 months), the IPC regimes did not give any restoration of Bile Flow. By contrast, the INT regime restored Bile Flow to 68%. Plasma bilirubin concentrations were lowest in the INT groups, whereas alanine transaminase concentrations for the IPC and INT groups compared with the continuous clamping groups showed no significant differences. Conclusions In young rats, INT is more effective than IPC in restoring the immediate consequences of IP-induced damage to hepatocytes and liver function after ischemia-reperfusion. In aged rats INT, but not IPC, reverses hepatocyte damage and restores liver function. INT may promote better hepatocyte and liver function than IPC following the surgical resection of aged livers.
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Ischemic Preconditioning and Intermittent Ischemia Preserve Bile Flow in a Rat Model of Ischemia Reperfusion Injury
Digestive Diseases and Sciences, 2007Co-Authors: Vincent B. Nieuwenhuijs, Menno T. Bruijn, Marc Schiesser, Arthur Morphett, Robert T. A. Padbury, Greg J. BarrittAbstract:Ischemia and reperfusion (IR) injury of the liver is associated with impaired Bile secretion, but the effects of ischemic preconditioning (IPC) and intermittent ischemia (INT) on Bile Flow are unknown. A rat model of segmental (60%–70%) hepatic ischemia and reperfusion was employed to test the effects of IPC and INT on Bile Flow. Continuous clamping for 45 min (CC) substantially reduced Bile Flow, and this did not recover after 60 min of reperfusion. IPC and INT caused a significant recovery of Bile Flow. The elevation in plasma liver marker enzymes induced by CC was not reduced by IPC and INT. Light microscopy showed mild hepatocyte damage in all groups. In the CC group, the amount of F-actin localized around the Bile canaliculi in the ischemic lobes was less than that in the nonischemic lobes, but this difference was not observed in the IPC and INT groups. It is concluded that IPC and INT substantially alleviate the decrease in Bile Flow induced by ischemia. Bile Flow may be useful in the assessment of IR injury.
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hepatic ischemia reperfusion injury roles of ca2 and other intracellular mediators of impaired Bile Flow and hepatocyte damage
Digestive Diseases and Sciences, 2006Co-Authors: Vincent B. Nieuwenhuijs, Menno T. Bruijn, Robert Padbury, Gregory J BarrittAbstract:Liver resection and liver transplantation have been successful in the treatment of liver tumors and end-stage liver disease. This success has led to an expansion in the pool of patients potentially treatable by liver surgery and, in the case of transplantation, to a shortage of liver donors. At present, there are significant numbers of potential candidates for liver resection and liver donation who have fatty livers, are aged, or have livers damaged by chemotherapy. All of these are at high risk for ischemic reperfusion (IR) injury. The aims of this review are to assess current knowledge of the clinical effectiveness of ischemic preconditioning and intermittent ischemia in reducing IR damage in liver surgery; to evaluate the use of Bile Flow as a sensitive indicator of IR liver damage; and to analyze the molecular mechanisms, especially intracellular Ca2 +, involved in IR injury and ischemic preconditioning. It is concluded that Bile Flow is a sensitive indicator of IR injury. Together with reactive oxygen species (ROS) and other extracellular and intracellular signaling molecules, intracellular Ca2 + in hepatocytes plays a key role in the normal regulation of Bile Flow and in IR-induced injury and cell death. Ischemic preconditioning is an effective strategy to reduce IR injury but there is considerable scope for improvement, especially in patients with fatty and aged livers. The development of effective new strategies to reduce IR injury will depend on improved understanding of the molecular mechanisms involved, especially by gaining a better perspective of the relative importance of the various intrahepatocyte signaling pathways involved.