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G Molino

Publications and source records attributed to G Molino.

At least 55 records · Page 3Linked to original sources
PubMed1989

Relationship between the intrahepatic expression of 'e' and 'c' epitopes of the nucleocapsid protein of hepatitis B virus and viraemia.

The relationship between hepatitis B viraemia and intrahepatic HBV nucleocapsid proteins (HBcAg and HBeAg) was studied in 18 patients with chronic hepatitis B. Monoclonal antibodies (MoABs) were obtained in BALB/c mice primed with recombinant HBV nucleocapsid proteins. Four MoABs reacting with recombinant proteins gave positive results in competitive assays. Two reacted as anti-HBc and two as anti-HBe. One of them showed a strong affinity for the cytoplasmic, membrane-bound antigen (P23e) of infected hepatocytes while the latter showed a higher specificity for serum HBeAg than for the intrahepatic antigen. Anti-HBc MoABs had a staining capacity for liver cell nuclei comparable with that of polyclonal antibodies. Overall the anti-HBc MoABs stained the liver cell nuclei in 86% of cases, while anti-HBe MoABs stained in 58% of cases. The hepatocyte cytoplasm was stained by anti-HBc MoABs and anti-HBe MoABs in 64% and 72% of cases respectively. Not one of 12 control liver biopsies was stained. Viraemia (HBV-DNA) was measured by dot blot hybridization and was correlated with the number of hepatocytes containing the nucleocapsid antigen. The highest levels of HBV-DNA (greater than 10(8) genomes/ml) were detected in patients with prevalent nuclear staining while the lowest ones were observed in those with prevalent cytoplasmic expression of this antigen. The application of anti-HBV-nucleocapsid MoABs in diagnostics requires careful scrutiny since some are specific for the circulating antigen while others show a higher affinity for the intrahepatic antigen.

Antibodies, Monoclonal↗
PubMed1987

Hepatic clearance of D-sorbitol. Noninvasive test for evaluating functional liver plasma flow.

The hepatic clearance of D-sorbitol, a natural polyol which is metabolized by the liver, was studied in normal and cirrhotic subjects after bolus intravenous injection (2 g) and during constant infusion (54 mg/min) with the aim of providing a noninvasive and simple measure of functional liver plasma flow. The high hepatic extraction of D-sorbitol and the dose-independence of its clearance pointed to a flow-dependent clearance regimen. The renal excretion was taken into account when computing the hepatic clearance. Day-to-day reproducibility of the test was good. No significant difference was found when the hepatic clearance was measured by bolus injection or constant infusion methods. As measured by the bolus injection method, the mean (+/- SD) hepatic clearance in the normal subjects (911 +/- 137 ml/min) was significantly greater (P less than 0.001) than that of the cirrhotics (456 +/- 181 ml/min).

Humans↗
PubMed1987

Simulation of the metabolism and enterohepatic circulation of endogenous deoxycholic acid in humans using a physiologic pharmacokinetic model for bile acid metabolism.

The metabolism and enterohepatic circulation of deoxycholic acid (DCA), a major secondary bile acid in humans, was simulated using a linear multicompartmental physiologic pharmacokinetic model. The model was similar to that previously reported and used to simulate the metabolism of cholic acid and chenodeoxycholic acid, but differed in two respects: (a) the input of newly formed DCA molecules originated from colonic absorption rather than from de novo hepatic biosynthesis and (b) a new type of transfer coefficient was proposed to describe the movement of DCA molecules from an insoluble, bound compartment to a soluble compartment. Simulations were performed to define the effect of varying fractional colonic absorption (from 0.1 to 0.6) as well as varying fractional formation of DCA from cholic acid (from 0.3 to 1). The simulations indicated that the exchangeable total DCA pool expanded up to 12-fold as fractional colonic absorption was increased from 0.1 to 0.6. The fractional turnover rate of the DCA pool showed a corresponding decrease. Increased conversion of cholic acid to DCA had an effect on DCA pool size that was similar to that resulting from increased colonic fractional absorption. So long as ileal absorption was efficient, the "soluble" colonic pool of DCA remained small relative to other organ pools, and the absorption of unconjugated DCA from the colon was less than 10% of the total DCA absorption from the ileum. It is proposed that the relatively large proportion of DCA in the biliary bile acids of white adults in the Western world as compared with that of most other mammals is attributable to (a) a high fractional absorption of DCA because of a diet relatively low in fiber, (b) the absence of hepatic 7-hydroxylation of DCA, and (c) effective competition by DCA conjugates for active transport by the terminal ileum.

Biliary Tract↗
PubMed1987

Non-invasive evaluation of portal-systemic shunting in man by D-sorbitol bioavailability.

Portal-systemic shunting is an important circulatory abnormality in patients with cirrhosis. This study explores the potential of the natural polyol D-sorbitol as test compound for non-invasive assessment of shunting. Ten normal subjects, 10 patients with cirrhosis and 12 cirrhotics with surgical portacaval shunts were studied after oral and intravenous administration of a 2 g dose of sorbitol. As measured by the H2 breath test, removal from the intestinal lumen was complete in both groups. Bioavailability of sorbitol, calculated as ratio of the areas under the plasma concentration/time curve after p.o. and i.v. administration, was zero in normal subjects, 0.29 +/- 0.15 in cirrhotic patients, and 0.38 +/- 0.11 in patients with portacaval shunts. Calculation of bioavailability on the basis of urinary outputs of sorbitol gave similar results. It is concluded that the bioavailability of sorbitol reflects portal-systemic shunting, although the relatively low figures suggest some degree of sorbitol metabolism by enterocytes.

Adult↗
PubMed1986

Simulation of the metabolism and enterohepatic circulation of endogenous chenodeoxycholic acid in man using a physiological pharmacokinetic model.

The metabolism and enterohepatic circulation of chenodeoxycholic acid (CDC), a major primary bile acid in man, has been stimulated using a multicompartmental physiological pharmacokinetic model which was previously reported and used to simulate the metabolism of cholic acid. The model features compartments and linear transfer coefficients. Compartments, which are defined as the pools of single chemical species in well defined anatomical volumes, are aggregated into nine 'spaces' based on anatomical and physiological considerations (liver, gall-bladder, bile ducts, duodeno-jejunum, ileum, colon, portal blood, sinusoidal blood, and general circulation). Each space contains several compartments which correspond to the compounds present in that space, for example, the compound in question and its biotransformation products. For CDC (as for cholic acid in the previous simulation) each space contains three compartments corresponding to the unconjugated bile acid, its glycine amidate, and its taurine amidate. Transfer coefficients, which denote the fractional amount of the compartment's contents exiting per unit time, are categorized according to function: flow, for example gall-bladder contraction (which involves transfer of all substances contained in the space at the same fractional rate); biotransformation (which transfers the substrate from one compartment to another within the same space); or transport (which denotes movements between contiguous compartments, belonging to different spaces across a diffusion membrane or a cellular barrier). The model is made time-dependent by incorporating meals which trigger gall-bladder emptying and modify intestinal flow. The transfer coefficients in the cholic acid model were modified for the CDC model since there is indirect evidence that CDC amidates (probably chenodeoxycholylglycine) are absorbed from the duodeno-jejunum and the first pass hepatic clearance of CDC species differs from that of cholyl species. The model was then used with all existing experimental data to simulate CDC metabolism in healthy humans over a 24-h period during which three meals were ingested. Satisfactory agreement was obtained between simulated and experimental data indicating that this model continues to be useful for describing the metabolism of bile acids and may also be of value for describing the metabolism of drugs whose metabolism is similar to that of bile acids.

Bile Acids and Salts↗
PubMed1986

Insulin resistance in human liver cirrhosis is not modified by porto-systemic surgical shunt.

Cirrhosis of the liver is characterized by glucose intolerance and hyperinsulinaemia. It is considered an insulin resistant state with both a receptor and a post-receptor defect of insulin activity. It would appear that reduced hepatic degradation rather than increased B-cell production is responsible for hyperinsulinaemia. The effect of surgical portosystemic shunt on insulin resistance was studied in 18 cirrhotics with impaired glucose tolerance (12 males, 6 females; mean age 46.9 +/- 0.7 years) by measuring: glucose production (3H-glucose infusion), glucose utilisation (euglycaemic clamp at approximately 100, approximately 1000 and approximately 10,000 microU/1), plasma insulin and C-peptide levels, and liver function indices (serum bilirubin, albumin, ALT, GGT) before and 2 months after surgery. Liver sorbitol clearance was also employed to measure variations in the functional liver plasma flow induced by the shunt. No significant changes were noted in: glucose production (1.94 +/- 0.17 SEM vs 1.96 +/- 0.17 mg/kg/min), glucose utilisation (metabolic clearance rate: 3.32 +/- 0.48 vs 3.42 +/- 0.43 at approximately microU/ml; 9.70 +/- 1.0 vs 9.16 +/- 0.9 at approximately 1000 microU/ml; 10.92 +/- 1.1 vs 11.07 +/- 0.8 ml/kg/min at approximately 10 000 microU/ml), fasting plasma insulin, C-peptide and C-peptide/insulin molar ratio (4.66 +/- 0.47 vs 5.50 +/- 0.54), and the liver function indices. By contrast, there was a significant decrease in functional liver plasma flow (813 +/- 34 vs 604 +/- 34 ml/min, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Sorbitol clearance: a parameter reflecting liver plasma flow in the rat.

According to the clearance concepts, the functional liver plasma flow may be directly measured from the plasma kinetics of any substance whose hepatic intrinsic clearance largely exceeds liver perfusion. The present study was designed to ascertain the requirements for the reliability of D-sorbitol plasma clearance in evaluating changes of liver perfusion in the male Wistar rat. The plasma disappearance curve of D-sorbitol (3 mg/100 g b.w. by bolus i.v. injection) followed a first order kinetics and fitted a two-compartment model. Very similar estimates of D-sorbitol plasma clearance were obtained by applying the area under the curve method to data obtained by the trapezoidal rule and by compartmental analysis. D-sorbitol hepatic extraction was almost complete in controls and in rats submitted to porta-caval shunt and hepatic artery ligation, while significantly decreased after partial hepatectomy. Renal output never exceeded 10% of the administered amount. No in-vivo diffusion into red cells was observed. In controls, the functional liver plasma flow, as measured by D-sorbitol clearance was 2.83 +/- 0.68 ml/min/100 g (mean +/- SD). Significantly lower values were found in rats submitted to porta-caval shunt (1.19 +/- 0.38), hepatic artery ligation (2.06 +/- 0.53), and partial hepatectomy (1.03 +/- 0.44).

Animals↗
PubMed1985

Evaluation of the diagnostic value of serum bile acid in the detection and functional assessment of liver diseases.

The diagnostic usefulness of fasting total serum bile acids (SBA/F) in the detection of liver diseases and assessment of different aspects of hepatic function alteration was evaluated in 61 healthy subjects and 186 patients with liver disease. The value of SBA/F was compared with other routine tests. In 49 healthy subjects and 92 patients, serum bile acids were also measured after the im administration of Ceruletide as a cholecystokinetic agent (SBA/C). The diagnostic efficacy for the detection of disease states was better with aspartate-aminotransferase (EC 2.6.1.1) and alanine-aminotransferase (EC 2.6.1.2) than with SBA/F. When SBA/C was also determined the diagnostic efficacy was not substantially better than the SBA/F test. In the assessment of hepatocellular necrosis SBA/F showed a higher rate of misclassification errors compared to alanine-aminotransferase (mean error 45% vs 17%), whereas SBA/F gave similar results with direct bilirubin and pseudocholinesterase (EC 3.1.1.8) in the evaluation of cholestasis (mean error 40% vs 41%) and impaired biosynthesis (mean error 39% vs 40%), respectively. Serum bile acid determination did not show any significant diagnostic advantage with respect to the other routine liver tests.

Adolescent↗
PubMed1984

A sequential protocol for the optimization of diagnostic procedures in hepatology.

The aim of this paper is to present a sequential protocol to be used in clinical practice for the detection of liver diseases, based on clinical history, physical examination, and laboratory investigation. The evaluation of the protocol efficacy was carried out on a sample of 288 subjects (92 normal, and 196 affected by various liver alterations) by comparing the obtained results with reference classifications independently performed on the basis of all available subject records (including many more laboratory tests than the ones used in the protocol). A cost-benefit analysis was also carried out, based on the resident population of Regione Piemonte, comparing the protocol with two other simpler ones. Results show that the proposed protocol allows a considerable reduction of costs, showing a high estimated efficacy for clinical use.

Adolescent↗
PubMed1984

An expert system for the evaluation of liver functional assessment.

The paper describes an expert system for the assessment of the liver function. Since the system must act as an intelligent assistant for a general physician, a major emphasis has been laid upon its interactive capabilities. In particular, the user can ask the system how a given conclusion has been reached (explanation facilities) and can alter the normal operation flow. In the design of the system, the different significance and availability of the clinical data and the laboratory tests have been taken into account: The investigations about a given patient start from the clinical data, and only when there is some evidence of hepatopathy are the results of some laboratory tests requested. The final result of the investigations consists of the assessment of the liver function in terms of four aspects (biosynthesis, cholestasis, cytolysis, reactivity), each of which is assigned a linguistic value describing its impairment degree. The techniques adopted in the system are based on Artificial Intelligence methodologies augmented with linguistic terms handled according to the fuzzy set theory.

Diagnosis, Computer-Assisted↗
PubMed1984

Should blood transport kinetics be modeled in metabolic processes?

We analyze the interaction between blood transport phenomena and uptake processes when drug kinetics are studied with compartmental models. Relevant advantages in the physiological interpretation of the model parameters are obtained when blood transport is explicitly included in the model. This is done by aggregating into a single compartment all the blood spaces where no exchange with extravascular spaces takes place and separating into different blood compartments those spaces where some uptake and/or return occurs. The proposed strategy extensively uses all available a priori information about the physiological system, instead of considering only the information available in the measurements. This modeling approach has three main advantages: it provides greater insight into the identified quantities; it allows the introduction of quantitative a priori information; and it facilitates the experiment design task.

Animals↗
PubMed1983

Qualitative and quantitative evaluation of liver diseases: functional classifications.

The problem of the best use of experimental data for qualitative and quantitative evaluation of liver disfunction is analysed. Only statistical procedures for classification are considered. Emphasis is placed on a complete description of the most important steps that must be performed (degree of clustering of the data, validity of the hypotheses underlying the statistical methods used, meaning and adequate use of the reference classification, reliability of the different statistical methods used, information content of the laboratory tests studied) since the omission of any of them may contribute to a misleading interpretation of the overall results or may prevent significant practical utilization. An application to BSP tests is carried out: results obtained from 350 subjects are presented and discussed. A classification related to the main functional aspects of liver impairment was chosen. Different combinations of the parameters obtained from BSP blood disappearance curve--initial disappearance rate (K1), 45 min-retention of total (RT45) and conjugated (RC45) BSP- and different mathematical algorithms are compared. Five classes (N, normal subjects; PN, paranormal subjects; H, prevalent hepatocellular damage; C, prevalent cholestatic damage; HC, heavy combined damages) can be satisfactorily discriminated with all three parameters (K1 + RT45 + RC45); however K1 + RC45 give almost the same results and represent an interesting compromise between data information content and laboratory complexity.

Diagnosis, Computer-Assisted↗
PubMed1983

Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.

A multicompartmental pharmacokinetic model based on physiological principles, experimental data, and the standard mathematical principles of compartmental analysis has been constructed that fully describes the metabolism and enterohepatic cycling in man of cholic acid, a major bile acid. The model features compartments and linear transfer coefficients. The compartments are aggregated into nine spaces based on physiological considerations (liver, gallbladder, bile ducts, jejunum, ileum, colon, portal blood sinusoidal blood, and general circulation). The transfer coefficients are also categorized according to function: flow, i.e., emptying of gallbladder or intestinal spaces, and circulation of the blood; biotransformation, i.e., conjugation, deconjugation, or dehydroxylation; and transport, i.e., active or passive transport. The model is made time dependent by introducing meals, which trigger discrete increases in gallbladder emptying and intestinal flow. Each space contains three compartments. For cholic acid, these are unconjugated cholic acid, cholylglycine, and cholyltaurine. The model was then used with all existing experimental data to simulate cholic acid metabolism in healthy man over a 24-h period. Satisfactory agreement was obtained between simulated and experimental results for serum bile acid levels, hepatic bile acid secretion, and bile acid secretion into the intestine. The model was also used to classify 16 clinical instances in which the enterohepatic circulation of bile acids is altered by drugs or disease. The model can be extended to describe completely the metabolism and enterohepatic circulation of any bile acids in man in health and digestive disease. The model should also be broadly applicable to the description of the pharmacokinetics of all other drugs whose metabolism is similar to that of bile acids, i.e., drugs for which there are tissue and bacterial biotransformations, enterohepatic cycling, and appreciable first-pass clearance.

Bile Acids and Salts↗
PubMed1983

Pirenzepine does not impair liver blood flow in the rat.

The present study was performed with the aim of establishing whether the muscarinic-receptor antagonist pirenzepine impairs liver blood flow, as previously observed for H2-blockers. For this purpose, two different doses of pirenzepine (0.3 and 0.6 mg/100 g b.w. respectively) were administered to two groups of rats. Liver plasma flow was measured 30 min after treatment by the new sorbitol clearance test which is simple and does not require hepatic vein catheterization. The results were compared with those obtained in a control group and in a group treated with cimetidine. It was shown that, compared to the control group in which the observed functional liver plasma flow was 5.0 +/- 1.3 ml/min/100 g b.w. (MV +/- SD), rats treated with either dose of pirenzepine showed no significant impairment of liver perfusion. On the other hand, cimetidine treatment produced a significant reduction (p less than 0.001) of functional liver plasma flow. Our results show that pirenzepine treatment does not significantly impair liver functional activity through reduced liver perfusion. They also suggest that muscarinic receptors are probably not involved in the control of splanchnic blood flow.

Animals↗
PubMed1982

Bromsulphalein (BSP) kinetics in the rat: a new approach in evaluating experimental hepatotoxicity.

An animal model for the identification and definition of toxic liver damage, based on the investigation of the BSP metabolism in the rat is proposed. Different hepatotoxins can induce specific functional alteration on the different steps of the BSP hepatobiliary transport, mainly the uptake by hepatocytes and the biliary excretion. Removal curves of BSP from the plasma compartment as well as the biliary secretion were evaluated in rats treated with either alpha-naphthylisothiocyanate (ANIT) for metabolic cholestasis, or with carbon tetrachloride (CCl4) for fatty infiltration and necrosis of the liver. The data were compared with those obtained with untreated rats and with animals submitted either to complete or incomplete mechanically induced cholestasis. Our results lead to the conclusion that a satisfactory discrimination among different types of liver damage may be obtained when only two plasma parameters of BSP metabolism are considered: the disappearance rate for the early 5 min (K), and 15-min plasma BSP retention (R15). The model is proposed as a suitable tool for the evaluation of experimental hepatotoxicity in living rats giving a characterisation of the functional alteration and a measure of liver impairment.

1-Naphthylisothiocyanate↗
PubMed1981

[Changes in plasma lipids and lipoproteins in chronic liver diseases].

In 214 patients with different chronic liver diseases and in 31 controls the plasma lipids (total and esterified cholesterol, HDL cholesterol, triglycerides) and lipoproteins have been evaluated. The liver patients were classified not only according to traditional diagnostic criteria, but also using a functional classification based on the evaluation of biosynthetic alteration and cholestatic damage, separately assessed in all patients. Parenchimal liver diseases and cholestatic diseases show different and specific plasma lipids and lipoprotein abnormalities. In parenchimal diseases (notably cirrhosis) a reduction of the plasmatic level of total, esterified and HDL cholesterol, without significant changes of triglycerides and lipoproteins was observed. As documented by functional classification, the reduction of total and esterified cholesterol correlates significantly with the degree of biosynthetic alteration. This finding may be related to the reduced hepatic cholesterol synthesis, probably associated with a decreased serum activity of the lecithin cholesterol acyl transferase (LCAT), due to impaired hepatic enzyme synthesis.

Adult↗