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At least 343 records · Page 19Linked to original sources
PubMed1984

Proliferative response and renewal of hepatic function following cocaine administration in mice.

Experiments were undertaken to investigate the hepatic, temporal and spatial sequence of events following a single injection of cocaine, a known hepatotoxin. Centrilobular necrosis was induced in male mice (DBA/2Ha) 24 hr post-injection (PI). The time course of hepatic damage was monitored by assaying microsomal cytochrome P450 content, the activity of microsomal FAD-containing monooxygenase (FAD-M) and by determining the levels of serum glutamic pyruvic transaminase (SGPT). Kinetics of the onset of DNA synthesis were determined by autoradiography of thin liver sections and the incorporation of 3H-methyl thymidine into perchloric-acid-precipitable material. There was no increase in the labelling index (LI) and thymidine (TdR) incorporation in the first 24 hr PI. The LI rose to 14.6% and TdR incorporation showed a 5-fold increase over control values 48 hr PI. Both indices declined slightly at 72 hr PI and returned to control values by 96 hr PI. In contrast, the cytochrome P450 content declined by 69%, the FAD-M activity dropped by 40% and the SGPT levels showed an 18-fold increase at 24 hr PI, coincident with cytological signs of necrosis. Although the patterns of recovery differed between these selected enzymes, normal values were attained by 96 hr PI. These results demonstrate that cell damage and hepatic dysfunction precede the onset of DNA synthesis and subsequent proliferation.

Alanine Transaminase↗
PubMed2000

Single-dose pharmacokinetics of amprenavir, a human immunodeficiency virus type 1 protease inhibitor, in subjects with normal or impaired hepatic function.

Amprenavir (141W94) is extensively metabolized by P450 cytochromes, specifically, CYP3A4. Because hepatic insufficiency reduces P450-mediated metabolism, the concentrations in plasma of drugs metabolized through this pathway are often increased in subjects with liver disease. Following administration of a single, oral dose of 600 mg of amprenavir, pharmacokinetic parameters were determined for 10 subjects with severe cirrhosis, 10 subjects with moderate cirrhosis, and 10 healthy volunteers. Model-independent methods for determining the area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC(0-infinity)) showed an increase in amprenavir AUC(0-infinity) of 2.5-fold in the group with moderate cirrhosis and 4.5-fold in the group with severe cirrhosis compared with that in the control group of healthy volunteers (P < 0.05). AUC(0-infinity) was linearly related to the severity of liver disease, as assessed by the Child-Pugh score. Of the laboratory data used to calculate the Child-Pugh score, only the mean total bilirubin concentration showed a significant relationship with AUC(0-infinity). The relationship between the total bilirubin concentration and the AUC(0-infinity) of amprenavir was well characterized by a simple E(max) model, suggesting that the total bilirubin concentration may be a useful parameter for predicting the amprenavir AUC in subjects with hepatic insufficiency. Finally, the sera of cirrhotic subjects showed significant decreases in the levels of alpha(1)-acid glycoprotein, the primary plasma binding protein for amprenavir. On the basis of the results of this study, for an exposure equivalent to a clinical dose of 1,200 mg twice daily in subjects without cirrhosis, subjects with Child-Pugh scores of 5 to 8 should receive a twice-daily 450-mg dose of amprenavir, and subjects with Child-Pugh scores of 9 to 15 should receive a twice-daily 300-mg dose of amprenavir.

Adult↗
PubMed1998

Hepatic function as assessed by lidocaine metabolism in sickle cell disease.

OBJECTIVE: To evaluate hepatic drug metabolism, as determined by the formation of monoethylglycinexylidide (MEGX) after lidocaine injection and indocyanine green (ICG) clearance, in patients with sickle cell disease. STUDY DESIGN: A case-control study including 19 patients with homozygous hemoglobin S, and 13 age- and sex-matched black control subjects. Serum MEGX concentration was measured after intravenous injection of 1 mg/kg (maximum 50 mg) lidocaine. ICG (0.5 mg/kg) was injected concomitantly and absorbance (805 nm) of serum was measured over time to determine its volume of distribution, serum half-life, and hepatic blood flow. RESULTS: MEGX formation at 15 minutes was decreased in patients with sickle cell disease compared with formation in the control subjects (39.9 +/- 18.0 vs 65.6 +/- 50.0 micrograms/L, respectively, p < 0.02). The volume of distribution of ICG was increased in patients with sickle cell disease compared with that in the control subjects (0.21 +/- 0.09 vs 0.11 +/- 0.03 L/kg, p < 0.01). This partly accounts for the decreased MEGX formation. The ICG half-life was similar in both groups (3.8 +/- 1.5 vs 3.1 +/- 1.0 min). Hepatic blood flow, derived from ICG clearance, was increased in sickle cell patients compared with that of the control subjects (12.2 +/- 4.5 vs 8.1 +/- 2.1 ml/kg/min, p < 0.01). CONCLUSION: Hepatic drug metabolism, as assessed by MEGX formation after lidocaine injection, is impaired in patients with sickle cell disease. This impairment may have clinical implications when using hepatically metabolized medications in patients with sickle cell disease.

Adult↗
PubMedDate not supplied

Radiolabeled constructs for evaluation of the asialoglycoprotein receptor status and hepatic functional reserves.

Transplantation of isolated hepatocytes may eventually replace a whole liver transplantation for the treatment of selected liver metabolic disorders and acute hepatic failure. To understand the behavior of transplanted hepatocytes, methods for longitudinal assessment of functional activity and survival of hepatocyte transplants must be developed. Targeting of asialoglycoprotein receptor (ASGPr) with various radiolabeled or Gd-labeled constructs of asialofetuin (AF) is expected to allow noninvasive and quantitative assessments of the ASGPr status in functioning hepatocytes before and after the transplant. Six new constructs of (125)I-, (99m)Tc-, (153)Gd-, and (111)In-radiolabeled AF with distinct stabilities and clearance rates were prepared and evaluated in vitro in mice, rat, porcine, and human hepatocytes, and in vivo in mice and rats. The blood and organ clearance rates, as well as liver and spleen uptake, were measured. Even extensive chemical modifications of AF with poly-l-lysine and various chelating agents do not appear to diminish AF's binding to ASGPr. Binding to isolated hepatocytes and the in vivo liver uptake studies indicate unimpaired functional activity of AF as evidenced by the rapid (<10 min) and nearly complete hepatic extraction of AF constructs from the systemic circulation. The catabolic processing and elimination of AF constructs from liver depend on the chemical modification used in the preparation of a given reagent. Radioiodinated AF has by far the shortest postabsorption (5.1 min +/- 0.05 min) and elimination half-lives (2.8 +/- 0.06 h) in liver. In comparison, the AF construct prepared by conjugation of DTPA- and 2-iminothiolane-substituted p-Lys with N-sulfosuccinimidyl 4-(p-maleimidophenyl)butyrate (SMPB)-modified AF (AF-SMPB-Traut-p-Lys-((111)In-DTPA)(20)(-)(30)) has a hepatic postabsorption time of 9.1 +/- 0.1 min and an elimination half-life of 44.3 +/- 3.08 h, whereas [(99m)Tc]technetium-labeled AF appears to be permanently retained in liver. These differences in rates of liver uptake and clearance of catabolized radiolabeled AF can be used to determine functional activity of liver and transplanted hepatocytes.

Animals↗
PubMed1983

Relations between thyroid function, hepatic and lipoprotein lipase activities, and plasma lipoprotein concentrations.

Lipoprotein concentrations and activities of lipoprotein lipase (LPL) and hepatic lipase (HL) were measured in 70 subjects with thyroid function ranging from overt hypothyroidism over subclinical hypothyroidism and euthyroidism to hyperthyroidism. In parallel with serum T3 (S-T3) concentrations increasing from low in hypothyroidism to high in hyperthyroidism there were gradually higher HL activities over the full spectrum of thyroid function, accompanied by decreasing levels of total and low density lipoprotein (LDL) cholesterol. High density lipoprotein (HDL) cholesterol was lower (P less than 0.05) in hyperthyroidism than in euthyroidism but not significantly changed in the hypothyroid groups. HL was correlated to S-T3 (r = 0.77, P less than 0.001), LDL cholesterol to log S-T3 (r = -0.76, P less than 0.001), and LDL cholesterol to log HL (r = -0.55, P less than 0.001). The activity of LPL was decreased (P less than 0.001) in overt hypothyroidism compared to euthyroidism but, in contrast to HL, the activity of LPL was not increased in hyperthyroidism. The plasma triglyceride (P-TG) concentration was elevated (P less than 0.01) in overt hypothyroidism but not significantly changed in subclinical hypothyroidism or in hyperthyroidism. The LPL activity was correlated to log S-T3 (r = 0.45, P less than 0.001), P-TG to log S-T3 (r = -0.37, P less than 0.01) and P-TG to log LPL activity (r = -0.71, P less than 0.001). Our results demonstrate that thyroid hormones influence HL and LPL activities in different ways, suggesting different mechanisms of action. Changes in HL activity seem to be an important mechanism for the disturbance of cholesterol metabolism in thyroid dysfunction while the thyroid hormone influence on LPL seems to be of importance mainly for the disturbance in triglyceride metabolism.

Adult↗
PubMed2006

[Preconditioning of the liver for protecting the hepatic functional reserve].

Ischemia reperfusion (I/R) injury of the liver is a major cause of post-surgical hepatic failure. The liver produced heat shock protein 72 (HSP72) 24 approximately 48 hours after heat shock preconditioning. We have found that these livers were provided with ischemic tolerance. The animal survival after I/R injury was improved, and the release of hepatic enzymes during reperfusion was significantly suppressed. As one of the mechanisms of this tolerance, the integrity of hepatic mitochondria was well maintained during I/R in the liver after heat shock preconditioning. In addition, the production of denatured proteins during I/R was significantly reduced in the heat shock group. This fact was well corroborated with the theoretical function of HSP72 as a molecular chaperon. Intra-vital microscopy showed that sinusoidal perfusion failure as well as leukocyte stagnation after ischemia were well suppressed. These beneficial effects of heat shock preconditioning on the hepatic microcirculation seemed to be related with the effective suppression of NF-kappaB activation and subsequent TNF-alpha production during I/R injury. We further studied the effects of geranyl-geranylacetone(GGA) in inducing HSP72 protein. Although GGA could not induce HSP72 by itself, GGA of 200mg/kg facilitated the production of HSP72 after heat shock preconditioning. With the preadministration of GGA, the heat stress to induce HSP72 (stress for preconditioning) could be minimized to one third. Although further investigation is necessary before the use of this strategy in the clinical setting of liver surgery, preconditioning and ischemic tolerance is a promising field of surgical research.

Animals↗
PubMed1991

[Primary risk of hemorrhage due to esophageal varices in cirrhotic patients: significance of the associated endoscopic signs and hepatic functional reserve].

Significance of endoscopic findings associated to esophageal varices (Japanese Research Society for Portal Hypertension) and hepatic dysfunction (Child-Pough classification) as predictive factors of variceal bleeding in cirrhotic patients is analyzed. In a cooperative prospective experience 137 cirrhotic patients with esophageal varices were examined in the period May 1987/89: 83 out of them had never bled from their varices (VENS group) while 54 recently had (VES group). A highly significative association was found between variceal size over 3 mm (grade II-III) and bleeding: 96.3% vs. 34.9% in VENS group (p = 0.01); similar association was found with regard to endoscopic detection of "red signs": 92.6% in bleeding group vs. 20.5% in VENS one (p = 0.01). "Red signs" were found on grade II-III varices in 98.5% of cases, and this association were related to variceal bleeding in 75.5%. Hepatic dysfunction was not directly related to bleeding episodes but "red signs" endoscopic detection in VENS group increased with liver function deterioration: 9.1% in Child A class, 27.3% in Child B, and 41.2% in Child C (p = 0.01). The strong association founded between bleeding and both grade II-III variceal size and "red signs" detection, suggest the possibility to identify a high risk group of cirrhotic patients candidate to prophylactic methodologies.

Adult↗
PubMed1993

[Evaluation of clinical usefulness of 99mTc-GSA, a functional hepatic imaging agent--correlation with per-rectal portal scintigraphy].

Liver scintigraphy using 99mTc-GSA, which binds specifically to the asialoglycoprotein receptors on the surface of the hepatocytes, was performed in 41 patients with chronic liver disease (11 chronic hepatitis cases and 30 liver cirrhosis) to investigate the correlations between the images and the various liver function tests. Two liver functional indexes, HH15 for plasma clearance of 99mTc-GSA and LHL15 for liver accumulation of 99mTc-GSA, showed significant differences between the chronic hepatitis group and the decompensated liver cirrhosis group. These indexes also showed significant correlations with the liver function tests such as serum albumin level and prothrombin time. HH15 and LHL15 correlated with the per-rectal portal shunt index obtained in 10 patients by 99mTcO4- per-rectal portal scintigraphy. These results suggest that HH15 and LHL15 have value as new liver functional indexes.

Adult↗
PubMed1987

A review of new approaches to assessing hepatic function in animals.

Although a multitude of effective liver function tests are available for use in animals, a variety of modifications of currently used tests have been recently reported. In addition, newer procedures now used in human medicine may also provide unique insights into assessing and detecting acquired hepatic disorders in animals. Examples of new procedures are: assessing microsomal mixed function oxidase activity by plasma caffeine clearance; estimating the extent of active hepatic fibrogenesis through serum procollagen-III peptide levels; determining hepatic blood flow and functional mass by the galactose elimination capacity; detecting primary hepatocellular cancer through serum or urinary ligandin levels; and to estimate the liver's maximal capacity to excrete indocyanine green independent of blood flow. In evaluating drugs as to their hepatotoxicity, function tests should be included in the liver profile which measure specific metabolic alterations unique to the compound under study.

Animals↗
PubMed1990

Nitrous oxide does not impair hepatic function in young or old surgical patients.

We investigated whether anesthesia including nitrous oxide (N2O) caused hepatic injury, and whether any adverse effect of N2O was affected by patient age. One hundred patients having total hip replacements were randomly assigned to a regimen that included or excluded N2O (50%-60%) during regional anesthesia supplemented with isoflurane and intravenous adjuvants. Using postoperative plasma levels of alanine aminotransferase, bilirubin, and alkaline phosphatase 1 and 3 days after surgery as indicators of hepatic impairment, we found no evidence that N2O causes hepatic injury in either young or old patients.

Aged↗
PubMed1994

Vecuronium neuromuscular blockade reflects liver function during hepatic autotransplantation in pigs.

BACKGROUND: Rapid assessment of hepatic function early after reperfusion of the liver graft is of great importance, because it may allow for prompt detection of incipient hepatic graft failure. The current study was undertaken to determine whether the continuous recording of neuromuscular transmission could be used as an on-line assessment of hepatic function during liver transplantation when a muscle relaxant with high hepatic uptake is used. METHODS: We quantified and compared the effect of liver exclusion and graft reperfusion on the level of vecuronium-induced neuromuscular blockade in nine pigs studied twice within 3 days. During the 1st day (control session), an intravenous infusion of vecuronium was administered to maintain a constant 90-95% twitch depression during 180 min. The twitch response was then allowed to recover spontaneously to 75% of its prerelaxant value. Neuromuscular transmission was continuously measured on the right anterior leg using an acceleration transducer. During the same time period, the metabolic rate of 14C-labeled aminopyrine (a well-established quantitative test of the liver microsomal function) was determined by measuring the excretion of 14CO2 in expired air after administration of an intravenous bolus of 14C-labeled aminopyrine. Two days later, the pigs underwent a hepatic autotransplantation, during which vecuronium was administered to maintain a constant 90-95% twitch depression. After reperfusion of the liver graft, the vecuronium infusion rate was maintained at its anhepatic level, and the recovery index of the neuromuscular blockade (the time from 25% to 75% recovery of twitch height) was calculated. The aminopyrine breath test was performed during the last 30 min of the anhepatic phase, and during 3 h after reperfusion of the liver graft. RESULTS: During control studies, the mean infusion rate of vecuronium was 1.30 +/- 0.33 mg.kg-1.h-1 and the recovery index was 3.4 +/- 0.5 min. During liver dissection, the infusion rate of vecuronium was similar to the control value (1.18 +/- 0.16 mg.kg-1.h-1), then considerably decreased to 0.05 +/- 0.03 mg.kg-1.h-1 during the anhepatic phase. After reperfusion of the liver graft, the recovery index was markedly prolonged to 35.5 +/- 15.8 min, indicating a prolongation of the recovery of neuromuscular blockade by a factor of 10.4. Excretion of 14CO2 was equal to zero during the anhepatic phase and then increased to 0.19 +/- 0.11% during the 1st h after reperfusion of the liver graft, an excretion rate corresponding to 11.2% of control conditions. The relationship between individual changes in the recovery index of the neuromuscular blockade and 14CO2 excretion in expired air after reperfusion of the liver graft showed a strong significant correlation (r2 = 0.71). CONCLUSIONS: These results indicate that, compared with the control studies, there is a similar decrease in the recovery rate of vecuronium-induced neuromuscular blockade and in the metabolic rate of 14C-labeled aminopyrine during the progressive recovery of hepatic function immediately after unclamping of the liver vessels. Metabolism of 14C-labeled aminopyrine increased progressively during the reperfusion phase. Therefore, recording of neuromuscular transmission during liver transplantation could serve as a continuous and easy to perform assessment of liver graft function provided that a muscle relaxant with a high hepatic uptake is used for neuromuscular blockade.

Aminopyrine↗
PubMed1992

[Hepatic function in circulatory insufficiency. Mathematical modeling of 137I-labelled rose bengal transport in the body].

131I-labelled bengali pink was used to perform radiohepatography in patients with circulatory failure. Both amplitude-time parameters of blood clearance curves and hepatograms and the generalized index of parameters of the linear 3-chambered reversible model of this tracer transport in the body indicate that the decrease of hepatic absorptive and excretory function in the presence of 131I-labelled bengali pink occurs in a direct relationship to the degree of circulatory insufficiency and developed in parallel with bilirubin metabolic disturbances. In some patients, hepatic lesion in the presence of Stages IIB-III circulatory insufficiency with signs of hepatocellular failure and cholestasis was accompanied only by moderate hepatic absorptive and excretory dysfunction against 131I-labelled bengali pink and by an increase in blood total bilirubin levels no more than that in Stage IIA circulatory insufficiency.

Bile↗
PubMed1979

[Hepatic function in vivo and in the isolated liver of rats poisoned with parathion].

Enzyme determinations and hepatic histological studies were carried out in normal rats and in rats intoxicated with the organophosphorus pesticide parathion. No significative evidence of hepatocellular damage was seen in parathion -- intoxicated rats as responsible of the impaired bile flow and sulfobromophthalein biliary excretion that were previously reported. On the contrary, the isolated perfused rat liver from normal and intoxicated rats showed a similar behavior when the perfusate flow through the liver was maintained at a similar rate. We conclude that altered hepatic blood flow may be a factor determinant of an impairment of bile flow and of biliary excretion of several organic anions like sulphobromopthalein that were observed in parathion -- intoxicated rats.

Alanine Transaminase↗