Bile secretion is dependent on the coordinated functions of a number of hepatobiliary transport systems. Cholestasis may be caused by an impairment of bile secretion, an obstruction of bile flow or a combination of th...Bile secretion is dependent on the coordinated functions of a number of hepatobiliary transport systems. Cholestasis may be caused by an impairment of bile secretion, an obstruction of bile flow or a combination of the two. The common consequence of all forms of cholestasis is retention of bile acids and other potentially toxic compounds in the hepatooltes leading to apoptosis or necrosis of hepatocytes and eventually to chronic cholestatic liver disease. In certain cholestatic disorders there is also leakage of bile acids into the peribiliary space causing portal inflammation and fibrosis. The following pharmacological targets for treatment of intrahepatic cholestasis can be identified： stimulation of orthograde biliary secretion and retrograde secretion of bile acids and other toxic cholephils into the systemic circulation for excretion via the kidneys to reduce their retention in the hepatocytes; stimulation of the metabolism of hydrophobic bile acids and other toxic compounds to more hydrophilic, less toxic metabolites; protection of injured cholangiocytes against toxic effects of bile; inhibition of apoptosis caused by elevated levels of cytotoxic bile acids; inhibition of fibrosis caused by leakage of bile acids into the peribiliary space. The clinical results of ursodeoxcholic acid therapy of primary biliary cirrhosis may be regarded as the first success of this strategy.展开更多
AIM： To evaluate the protective effects of preconditioning by α-lipoic acid （LA） in patients undergoing hepatic resection under inflow occlusion of the liver. METHODS： Twenty-four patients undergoing liver resect...AIM： To evaluate the protective effects of preconditioning by α-lipoic acid （LA） in patients undergoing hepatic resection under inflow occlusion of the liver. METHODS： Twenty-four patients undergoing liver resection for various reasons either received 600 mg LA or NaCI 15 min before transection performed under inflow occlusion of the liver. Blood samples and liver wedge biopsy samples were obtained after opening of the abdomen immediately after inflow occlusion of the liver, and 30 min after the end of inflow occlusion of the liver. RESULTS： Serum levels of aspartate transferase and alanine transferase were reduced at all time points in patients who received LA in comparison to those who received NaCL. This was accompanied by reduced histomorphological features of oncosis. We observed TUNEL-positive hepatocytes in the livers of the untreated patients, especially after 30 min of ischemia. LA attenuated this increase of TUNEL-positive hepatocytes. Under preconditioning with LA, ATP content was significantly enhanced after 30 min of ischemia and after 30 min of reperfusion. CONCLUSION： This is the first report on the potential for LA reducing ischemia/reperfusion injury （IRI） of the liver in humans who were undergoing liver surgery. Beside its simple and rapid application, side effects did not occur. LA might therefore represent a new strategy against hepatic IRI in humans.展开更多
1 Introduction Although older adults are generally among the highest users of cardiovascular medications, they are typically underrepresented or excluded from most efficacy and safety trials. Drug developers are usual...1 Introduction Although older adults are generally among the highest users of cardiovascular medications, they are typically underrepresented or excluded from most efficacy and safety trials. Drug developers are usually reluctant to include many senior adults in randomized controlled clinical trials in part due to their high prevalence of multiple comorbidities, frailty, and polypharmacy; and to age-related pharmacokinetic and pharmacodynamic complexities. Consequently, there is often insufficient high quality evidence-based data to inform pharmacologic management of common cardiovascular conditions on older adults. In the absence of data, clinicians often rely on conceptual principles regarding metabolism and drug-drug interactions to minimize adverse drug events, but this is often not well-substantiated or standardized. A related challenge is poor cardiovascular medication adherence among older adults, and its detrimental impact on their health outcomes. In this brief review we highlight some aspects of these topics.展开更多
AIM： To study an inherent effect of insulin on small intestinal transit and to explore involvement of various systems/mechanisms in normal mice. METHODS： Insulin at the doses of 2 μU/kg, 2 mU/kg, 2 U/kg or vehicle ...AIM： To study an inherent effect of insulin on small intestinal transit and to explore involvement of various systems/mechanisms in normal mice. METHODS： Insulin at the doses of 2 μU/kg, 2 mU/kg, 2 U/kg or vehicle was subcutaneously administered to four groups of overnight fasted normal male mice. Blood glucose （BG） levels were measured 2 min before insulin administration and 2 min before sacrificing the animals for the measurement of small intestinal transit （SIT）. Charcoal meal was administered （0.3 mL） intragastrically 20 min after insulin administration and animals were sacrificed after 20 min and SIT was determined. For exploration of the various mechanisms involved in insulin-induced effect on SIT, the dose of insulin which can produce a significant acceleration of SIT without altering BG levels was determined. The following drugs, atropine （1 mg/kg）, clonidine （0.1 mg/kg）, ondansetron （1 mg/kg）, naloxone （5 mg/kg）, verapamil （8 mg/kg） and glibenclamide （10 mg/kg）, were administered intravenously 10 min prior to the administration of insulin （2 μU/kg）. RESULTS： The lower doses of insulin （2 μU/kg and 2 mU/kg） produced a significant acceleration of SIT from 52.0% to 70.7% and 73.5% without lowering blood glucose levels （P〈0.01）, while the highest dose of insulin （2 U/kg） produced a fall in blood glucose levels which was also associated with significant acceleration of SIT （P〈0.01）. After pretreatment of insulin （2 μU/kg） group with atropine, insulin could reverse 50% of the inhibition produced by atropine. In clonidine-pretreated group, insulin administration could reverse only 37% of the inhibition produced by clonidine and inhibition of SIT was significant compared with vehicle ＋ insulintreated group, i.e. from 74.7% to 27.7% （P〈0.01）. In ondansetron-pretreated group, insulin administration could produce only mild acceleration of SIT （23.5%）. In naloxone-pretreated group, insulin administration could significantly reverse the inhibition of SIT produced by naloxone when compared with naloxoneperse group, i.e. from 32.3% to 53.9% （P〈0.01）. In verapamil-pretreated group, insulin administration could only partially reverse the inhibition （65%）. In glibenclamide-pretreated group, insulin administration produced further acceleration of SIT （12.2%）. CONCLUSION： Insulin inherently possesses an acceleratory effect on SIT in normal mice. Adrenergic and cholinergic systems can play a significant role. Calcium channels and opioidergic system can play a supportive role; in addition, enhancement of endogenous insulin release can augment the effect of exogenously administered insulin on SIT.展开更多
文摘Bile secretion is dependent on the coordinated functions of a number of hepatobiliary transport systems. Cholestasis may be caused by an impairment of bile secretion, an obstruction of bile flow or a combination of the two. The common consequence of all forms of cholestasis is retention of bile acids and other potentially toxic compounds in the hepatooltes leading to apoptosis or necrosis of hepatocytes and eventually to chronic cholestatic liver disease. In certain cholestatic disorders there is also leakage of bile acids into the peribiliary space causing portal inflammation and fibrosis. The following pharmacological targets for treatment of intrahepatic cholestasis can be identified： stimulation of orthograde biliary secretion and retrograde secretion of bile acids and other toxic cholephils into the systemic circulation for excretion via the kidneys to reduce their retention in the hepatocytes; stimulation of the metabolism of hydrophobic bile acids and other toxic compounds to more hydrophilic, less toxic metabolites; protection of injured cholangiocytes against toxic effects of bile; inhibition of apoptosis caused by elevated levels of cytotoxic bile acids; inhibition of fibrosis caused by leakage of bile acids into the peribiliary space. The clinical results of ursodeoxcholic acid therapy of primary biliary cirrhosis may be regarded as the first success of this strategy.
文摘AIM： To evaluate the protective effects of preconditioning by α-lipoic acid （LA） in patients undergoing hepatic resection under inflow occlusion of the liver. METHODS： Twenty-four patients undergoing liver resection for various reasons either received 600 mg LA or NaCI 15 min before transection performed under inflow occlusion of the liver. Blood samples and liver wedge biopsy samples were obtained after opening of the abdomen immediately after inflow occlusion of the liver, and 30 min after the end of inflow occlusion of the liver. RESULTS： Serum levels of aspartate transferase and alanine transferase were reduced at all time points in patients who received LA in comparison to those who received NaCL. This was accompanied by reduced histomorphological features of oncosis. We observed TUNEL-positive hepatocytes in the livers of the untreated patients, especially after 30 min of ischemia. LA attenuated this increase of TUNEL-positive hepatocytes. Under preconditioning with LA, ATP content was significantly enhanced after 30 min of ischemia and after 30 min of reperfusion. CONCLUSION： This is the first report on the potential for LA reducing ischemia/reperfusion injury （IRI） of the liver in humans who were undergoing liver surgery. Beside its simple and rapid application, side effects did not occur. LA might therefore represent a new strategy against hepatic IRI in humans.
文摘1 Introduction Although older adults are generally among the highest users of cardiovascular medications, they are typically underrepresented or excluded from most efficacy and safety trials. Drug developers are usually reluctant to include many senior adults in randomized controlled clinical trials in part due to their high prevalence of multiple comorbidities, frailty, and polypharmacy; and to age-related pharmacokinetic and pharmacodynamic complexities. Consequently, there is often insufficient high quality evidence-based data to inform pharmacologic management of common cardiovascular conditions on older adults. In the absence of data, clinicians often rely on conceptual principles regarding metabolism and drug-drug interactions to minimize adverse drug events, but this is often not well-substantiated or standardized. A related challenge is poor cardiovascular medication adherence among older adults, and its detrimental impact on their health outcomes. In this brief review we highlight some aspects of these topics.
文摘AIM： To study an inherent effect of insulin on small intestinal transit and to explore involvement of various systems/mechanisms in normal mice. METHODS： Insulin at the doses of 2 μU/kg, 2 mU/kg, 2 U/kg or vehicle was subcutaneously administered to four groups of overnight fasted normal male mice. Blood glucose （BG） levels were measured 2 min before insulin administration and 2 min before sacrificing the animals for the measurement of small intestinal transit （SIT）. Charcoal meal was administered （0.3 mL） intragastrically 20 min after insulin administration and animals were sacrificed after 20 min and SIT was determined. For exploration of the various mechanisms involved in insulin-induced effect on SIT, the dose of insulin which can produce a significant acceleration of SIT without altering BG levels was determined. The following drugs, atropine （1 mg/kg）, clonidine （0.1 mg/kg）, ondansetron （1 mg/kg）, naloxone （5 mg/kg）, verapamil （8 mg/kg） and glibenclamide （10 mg/kg）, were administered intravenously 10 min prior to the administration of insulin （2 μU/kg）. RESULTS： The lower doses of insulin （2 μU/kg and 2 mU/kg） produced a significant acceleration of SIT from 52.0% to 70.7% and 73.5% without lowering blood glucose levels （P〈0.01）, while the highest dose of insulin （2 U/kg） produced a fall in blood glucose levels which was also associated with significant acceleration of SIT （P〈0.01）. After pretreatment of insulin （2 μU/kg） group with atropine, insulin could reverse 50% of the inhibition produced by atropine. In clonidine-pretreated group, insulin administration could reverse only 37% of the inhibition produced by clonidine and inhibition of SIT was significant compared with vehicle ＋ insulintreated group, i.e. from 74.7% to 27.7% （P〈0.01）. In ondansetron-pretreated group, insulin administration could produce only mild acceleration of SIT （23.5%）. In naloxone-pretreated group, insulin administration could significantly reverse the inhibition of SIT produced by naloxone when compared with naloxoneperse group, i.e. from 32.3% to 53.9% （P〈0.01）. In verapamil-pretreated group, insulin administration could only partially reverse the inhibition （65%）. In glibenclamide-pretreated group, insulin administration produced further acceleration of SIT （12.2%）. CONCLUSION： Insulin inherently possesses an acceleratory effect on SIT in normal mice. Adrenergic and cholinergic systems can play a significant role. Calcium channels and opioidergic system can play a supportive role; in addition, enhancement of endogenous insulin release can augment the effect of exogenously administered insulin on SIT.
