Alanine Transaminase ; blood ; Antiviral Agents ; administration & dosage ; Drug Therapy, Combination ; Hepatitis C, Chronic ; blood ; drug therapy ; pathology ; Humans ; Interferon-alpha ; administration & dosage ; Polyethylene Glycols ; administration & dosage ; Recombinant Proteins

Atropine (2.5 mg/kg), hexamethonium (1 mg/kg), Trasylol (1,000 u/kg), acetazolamide (100 mg/kg), cortisone (5 mg /kg) or procaine (5 mg/kg) were injected intraperitoneally once a day for 21 days into rats (both sexes) fed a low protein diet. The rats were fasted and sacrificed 24 hr after the last injection. Atropine and cortisone, but not the other agents, cause a significant increase in both pancreatic weight and enzymes. Serum amylase increased markedly in the cortisone group and serum GOT and GPT increased but slightly in the atropine group. Enlargement of the pancreatic acini, cellular hypertrophy and increases of zymogen granules were observed in all the groups except the procaine and normal control group. The hypertrophy of acini was more prominent in the atropine and cortisone groups. None of drugs used could induce decrease or depress the enzyme formation and weight of pancreas. This data indicates that long-term administration of these drugs, particularly atropine, cortisone or even other Ragents may induce preferential formation of pancreatic enzymes to exocrine secretions and consequently may cause enlargement of the pancreatic acini.
Acetazolamide/administration & dosage* ; Alanine Transaminase/blood ; Amylases/blood ; Animal ; Aprotinin/administration & dosage* ; Aspartate Aminotransferases/blood ; Atropine/administration & dosage* ; Cortisone/administration & dosage* ; Female ; Hexamethonium Compounds* ; Lipase/blood ; Male ; Organ Weight ; Pancreas/drug effects* ; Pancreas/enzymology ; Procaine/administration & dosage* ; Rats ; Time Factors

Some polymers and bioactive compounds derived from Styela clava tunic (SCT) have been reported as traditional medicine for the treatment of inflammation, oxidative stress and surgical wounds although there is little scientific evidence of their liver and kidney toxicity. To investigate the toxicity of ethanol extracts of SCT (EtSCT) in the liver and kidney of ICR mice, alterations in related markers including body weight, organ weight, urine composition, liver pathology and kidney pathology were analyzed following oral administration of 50 and 100 mg/kg body weight/day of EtSCT for 14 days. EtSCT showed a high level of free radical scavenging activity for DPPH (93.1%) and NO (16.2%) as well as the presence of 14.8 mg/mL of flavonoids and 36.2 mg/mL of phenolics, while EtSCT treated groups did not show any significant alterations in the body and organ weight, clinical phenotypes, urine parameters or mice mortality when compared with the vehicle treated group. In addition, constant levels of serum biochemical markers including alanine phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and serum creatinine (CRE) were maintained. Moreover, no specific histopathological features induced by most toxic compounds were observed in liver and kidney sections stained with hematoxilin and eosin. Therefore, the present results indicate that EtSCT with strong antioxidant activity cannot induce any specific toxicity in liver and kidney organs of ICR at doses of 100 mg/kg body weight/day.
Administration, Oral ; Alanine ; Alanine Transaminase ; Animals ; Aspartate Aminotransferases ; Biomarkers ; Blood Urea Nitrogen ; Body Weight ; Creatinine ; Eosine Yellowish-(YS) ; Ethanol ; Flavonoids ; Inflammation ; Kidney ; Liver ; Medicine, Traditional ; Mice ; Mice, Inbred ICR* ; Mortality ; Organ Size ; Oxidative Stress ; Pathology ; Phenol ; Phenotype ; Polymers ; Wounds and Injuries

The primary objective of this study was to compare thepharmacokinetics of a new anti-human immunodeficiencyvirus agent 1-(2-amino-pyridin-4-ylmethyl)-6-(3,5-dimethyl-benzoyl)-5-isopropyl-1H-pyrimidine-2,4-dione (VP-0502)with its amino acid prodrug alanine amide of VP-0502(VP-0502AL), following intravenous and oral administrationsto rats. The plasma concentrations of both analytes wereanalyzed via high-performance liquid chromatographycoupled with photodiode-array detection (HPLC-DAD).When VP-0502 was intravenously administered at 20mg/kg, the analyte appeared in low levels with an AUC of 0.3microg.h/ml, and C0 of 0.2microg/ml in plasma. However, boththe prodrug VP-0502AL and its metabolite VP-0502 appearedat comparatively higher levels following intravenousinjection of VP-0502AL at the same dose. VP-0502AL'spharmacokinetic parameters were Vd: 4.6 l/kg; AUC:3microg.h/ml; t1/2: 0.5h; C0: 6microg/ml; CLtot: 7l/h/kg; andMRT: 0.6h. Following oral administration of VP-0502(100mg/kg), it was not detectable in plasma (<50ng/ml),while after the oral administration of VP-0502AL, VP-0502 was quantitatively detected as an active metabolite forthe first 7h, with a maximum plasma concentration(Cmax) of 0.8microg/ml, and an area under the concentration-time curve (AUC) of 2microg.h/ml. The oral pharmacokineticparameters of VP-0502AL were calculated to be: maximumconcentration time (tmax) 2.7h; Cmax 0.2microg/ml; eliminationhalf-life (t1/2): 0.8h; and AUC 0.5microg.h/ml. Overall thefindings indicate that VP-0502AL has a favorable pharmaco-kinetic profile as a prodrug with rapid transformationinto the active metabolite, and that the attachment of theamino acid alanine to VP-0502 is an effective approach toimprove its oral bioavailability. VP-0502AL is predictedto become a new highly bioavailable anti-AIDS drugcandidate and/or lead compound.
Administration, Oral ; Alanine/*analogs & derivatives/pharmacokinetics ; Aminopyridines/*pharmacokinetics ; Animals ; Anti-HIV Agents/administration & dosage/blood/*pharmacokinetics ; Area Under Curve ; Biological Availability ; Half-Life ; Injections, Intravenous ; Male ; Prodrugs/administration & dosage/*pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Uracil/*analogs & derivatives/pharmacokinetics

OBJECTIVETo study the toxicity of water extracts from the fruits of Evodia Fructus in different producing areas.

METHODCompare the toxicity of the extracts from different Evodia Fructus on mice by the methods of acute and subacute toxicity test. The mice were given the extracts for 1 d to test the maximal tolerance dose (MTD) or maximal dose and observe the acute toxic symptoms; The mice were given the extracts for 15 d and then detected the level of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride (TG). The liver index was calculated, and the liver histological changes were investigated.

RESULTThe MTD of water extracts from the fruits of Evodia Fructus is 62, 44.8, 35.84 g x kg(-1); the MTD of Evodia Fructus is 56, 44. 8, 35.84 g x kg(-1); the maximal dose of Evodia Fructus is 60, 54, 45 g x kg(-1). The toxic symptoms of the mice which had been given the nine samples were almost consistent. Compared with the control group in subacute toxicity test, the level of serum ALT and the liver index were all increased. The liver histological were changed.

CONCLUSIONWhen water extracts from the fruits of Evodia Fructus are given to mice one or more times. It may be toxic and induce liver damage. There is no significant correlation between the toxicity and Evodia orgins, while the toxicity seems to be more closely related to the producing area.

Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; China ; Drugs, Chinese Herbal ; administration & dosage ; metabolism ; toxicity ; Evodia ; chemistry ; Female ; Fruit ; chemistry ; Liver ; drug effects ; metabolism ; Male ; Mice ; Triglycerides ; blood

OBJECTIVETo screen out effective ingredients of Huangqi Decoction (HQD) on dimethylnitrosamine (DMN) induced liver fibrosis and its assembling actions.

METHODS(1) DMN solution (0. 5%) was peritoneally injected to rats to prepare the liver fibrosis model for 12 times, starting from the 1st day of modeling to the end of the 4th week. Uniform design method with 4-factor 8-level table was used to optimize the proportion of four ingredients from HQD, including astragaloside (AS), astragalus flavonoids (AF), glycyrrhizae acid (GA), and glycyrrhizae flavonoids (GF). Moreover, the changes of hydroxyproline (Hyp) content in the liver issue and the level of alanine aminotransferase (ALT) in serum were observed as screen indices, and the method of regression analysis was used to find out an optimal combination. (2) A further study for comparing and verifying the efficacy of the obtained optimized prescription was conducted by observing the changes of fibrosis pathology, the content of Hyp in the liver tissue and serum enzyme activity after medication.

RESULTSThe optimal proportion of AS and GA was 164:48. Compared with the model group, the content of Hyp in the liver tissue and the levels of ALT, aspartate aminotransferase (AST), and alkaline phosphatase (ALP) in serum decreased significantly, indicating the inhibiting effect of HQD and the AS/GA combination group on hepatic fibrosis formation (P<0.05). The AS/GA combination group was better than AS/GA used alone group in reducing the content of Hyp in the liver tissue and the level of ALT in serum. Furthermore, the AS/GA combination group was better than the HQD group in reducing the level of ALT in serum.

CONCLUSIONSAS and GA were effective ingredients of HQD, and the combination of AS and GA had obvious synergistic effect in reducing liver collagen deposition and decreasing serum ALT activity in DMN-induced liver fibrosis.

Alanine Transaminase ; blood ; Animals ; Dimethylnitrosamine ; adverse effects ; Drug Interactions ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; Hydroxyproline ; analysis ; Liver Cirrhosis, Experimental ; blood ; chemically induced ; pathology ; Male ; Rats ; Rats, Wistar

BACKGROUND: Ischemia reperfusion (IR) injury is a complex phenomenon that leads to organ dysfunction and causes primary liver failure following liver transplantation. We investigated whether an intravenous administration of magnesium before reperfusion can prevent or reduce IR injury. METHODS: Fifty-nine living donor liver transplant recipients were randomly assigned to an MG group (n = 31) or an NS group (n = 28). Each group was also divided in two groups based on the preoperative magnesium levels (normal: > or = 0.70 mmol/L, low: < 0.70 mmol/L). The MG groups received 25 mg/kg of MgSO4 mixed in 100 ml normal saline intravenously before reperfusion and the NS groups received an equal volume of normal saline. The levels of lactate, pH, arterial oxygen tension, and base excess were measured to assess reperfusion injury at five specific times, which were 10 min after the beginning of anhepatic phase, and 10, 30, 60 and 120 min after reperfusion. To evaluate postoperative organ function, the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin and creatinine levels were measured at preoperative day 1, postoperative day 1 and 5. RESULTS: The blood lactate levels were significantly lower at 10, 30, 60 and 120 min after reperfusion in the MG groups compared to the NS groups. In addition, significantly higher blood lactate levels were observed in the NS group with preoperative hypomagnesemia than in MG groups. CONCLUSIONS: Magnesium administration before reperfusion of liver transplantation significantly reduces blood lactate levels. These findings suggest that magnesium treatment may have protective effects on IR injury during living donor liver transplantation.
Administration, Intravenous ; Alanine Transaminase ; Aspartate Aminotransferases ; Bilirubin ; Creatinine ; Humans ; Hydrogen-Ion Concentration ; Ischemia ; Lactic Acid ; Liver ; Liver Failure ; Liver Transplantation ; Living Donors ; Magnesium ; Oxygen ; Reperfusion ; Reperfusion Injury

OBJECTIVETo study the toxic effects of aqueous extract of Crotalariae Assamicae Semen (CAS), one of the pyrrolizidine alkaloid-containing Chinese herbal medicines, in rats and the possible mechanism in association with liver damage.

METHODThe aqueous extract of CAS (CASE) was prepared by the conventional water extracting-alcohol precipitating method. The LD50 value of CASE in rats was determined by Kärber method. Rats were randomly divided into four groups in which three groups were orally administered with different doses of the CASE and one group with distilled water as control. Toxic effects were assessed by morphological, biochemical and histopathological changes. Moreover, in vitro metabolism using rat liver microsomes was also conducted and applied for the exploration of the underlying mechanism of liver damage.

RESULTThe LD50 value of CASE in Wistar rats was (2.36 +/- 0.26) g x kg(-1). The toxic effects were found in all groups of rats dosed with CASE, in which serum levels of ALT and AST were significantly elevated, and the obvious and dose-dependent damages in liver and lung were observed by histopathological examination. Moreover, the liver tissue-bound pyrroles were detected and generated in a dose-dependent manner, and the pyrrole metabolites observed in the in vitro microsomal metabolism. All the evidences suggested a strong correlation between metabolism and toxicity of CASE in rats.

CONCLUSIONCASE could induce the acute toxicity in rats, of which liver and lung were the major targets. Toxic effects were strongly correlated with pyrrolizidine alkaloids in CAS. The possible mechanism for its liver toxicity may be related to the formation of pyrrole metabolites as well as the corresponding tissue-binding products.

Alanine Transaminase ; metabolism ; Animals ; Crotalaria ; chemistry ; Drugs, Chinese Herbal ; administration & dosage ; toxicity ; Lethal Dose 50 ; Liver ; drug effects ; enzymology ; injuries ; Male ; Microsomes, Liver ; drug effects ; enzymology ; Pyrrolizidine Alkaloids ; administration & dosage ; toxicity ; Rats ; Rats, Wistar

OBJECTIVETo investigate the effect of acupoint injection of oxymatrine (OM) on experimental hepatocellular carcinoma and the mechanism.

METHODSThe rats of hepatocellular carcinoma induced by 2-acetoaminoflurence (2-AAF) were randomly divided into a normal control group (group N), a model group (group M), a control group of oxymatrine intraperitoneal injection (OM ip group) and a treatment group of small dose oxymatrine injection into Zusanli (OM ZSL group). At the end of 12h week, the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (gamma-GT) were determined. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expressions of cyclin D1 and cyclin-dependent kinase 4 (CDK4) mRNA in hepatocellular carcinoma tissues.

RESULTSThe number of cancer nodes on the surface of liver in th Om ip group and the Om ZSL group was lower than in the group M, with the serum ALT, AST, and gamma-GT levels significantly decreased (P<0. 01), and significantly inhibited expressions of cyclin D1, CDK4 mRNA (P<0. 01).

CONCLUSIONOM ip and small dose oxymatrine injection into ZSL can treat or delay hepatocarcinogenisis of hepatocellular carcinoma induced by 2-AAF. Partial mechanism of this anti-carcinoma is protecting hepatocytes possibly through improving hepatic functions, and inhibiting excessive proliferation of liver cancer cells via inhibiting the expressions of cyclin Dl, CDK4 mRNA.

Acupuncture Points ; Alanine Transaminase ; blood ; Alkaloids ; administration & dosage ; Animals ; Aspartate Aminotransferases ; blood ; Cyclin D1 ; genetics ; Cyclin-Dependent Kinase 4 ; genetics ; Injections ; Liver Neoplasms, Experimental ; drug therapy ; Male ; Quinolizines ; administration & dosage ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; gamma-Glutamyltransferase ; blood

OBJECTIVETo investigate the protective effect of emodin in young rats with intrahepatic cholestasis.

METHODSA total of 120 young Sprague-Dawley rats were randomly divided into control, model, and high-, medium-, and low-dose emodin groups, with 24 rats in each group. The rats in the control and model groups were given sodium carboxymethyl cellulose solution by gavage, while the other groups were given different doses of emodin solution by gavage. On the 5th day of experiment, alpha-naphthylisothiocyanate (ANIT, 50 mg/kg) was applied by gavage to establish the model of intrahepatic cholestasis in all groups except the control group. At 24, 48, and 72 hours after gavage, 8 rats in each group were sacrificed. Colorimetry was used to measure the serum levels of total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in each group, and hematoxylin-eosin staining was applied to observe the morphological changes of the liver under a light microscope at different time points.

RESULTSCompared with the control group, the model group had significantly increased serum levels of TBIL, DBIL, TBA, ALP, GGT, ALT, and AST at the 24-hour, 48-hour, and 72-hour time points (P<0.01). In the model group, the serum levels of TBIL, DBIL, TBA, ALT, and AST showed varying degrees of increase at 48 hours after establishment of model, compared with the values at 24 and 72 hours (P<0.05). At 24, 48, and 72 hours, the high-, medium-, and low-dose emodin groups had varying degrees of reductions in the serum levels of TBIL and TBA compared with the model group (P<0.05); the high- and low-dose emodin groups had significantly increased serum levels of TBA compared with the medium-dose emodin group (P<0.05). The model group had the most severe pathological changes at 48 hours. Compared with the model group, the high-, medium-, and low-dose emodin groups showed certain improvement in pathological changes of the liver at each time point, and the medium-dose emodin group had better improvement compared with the high- and low-dose emodin groups.

CONCLUSIONSEmodin can effectively improve ANIT-induced intrahepatic cholestasis in young rats, and medium-dose emodin shows the best effect.

Alanine Transaminase ; genetics ; metabolism ; Animals ; Aspartate Aminotransferases ; genetics ; metabolism ; Bilirubin ; metabolism ; Cholestasis, Intrahepatic ; drug therapy ; genetics ; metabolism ; pathology ; Drugs, Chinese Herbal ; administration & dosage ; Emodin ; administration & dosage ; Female ; Humans ; Liver ; enzymology ; pathology ; Male ; Rats ; Rats, Sprague-Dawley