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Biomedical subjects

R Poupon

Publications and source records attributed to R Poupon.

At least 163 records · Page 9Linked to original sources
PubMed1989

Effect of vasodilators on hepatic microcirculation in cirrhosis: a study in the isolated perfused rat liver.

We studied the effects of a series of vasodilators on intrahepatic vascular resistance of isolated perfused cirrhotic rat livers in basal conditions and during norepinephrine-induced vasoconstriction. Cirrhosis was induced by repeated intraperitoneal injections of carbon tetrachloride. The vasodilators were a nonselective beta-adrenergic antagonist (propranolol), an alpha 1-adrenergic antagonist (prazosin), a nonselective beta-adrenergic agonist (isoproterenol), an alpha 2-agonist (clonidine), nitrovasodilators (nitroglycerin and nitroprusside), calcium channel blockers (verapamil, diltiazem, nifedipine), papaverine, diazoxide and pentoxifylline. In basal conditions, isoproterenol, nitroglycerin, papaverine, pentoxifylline and nitroprusside demonstrated significant vasodilatory activity. However, the response was weak and isoproterenol was the only drug active in the therapeutic range of concentrations. Propranolol, prazosin, verapamil, diltiazem, nifedipine and diazoxide were ineffective. Prazosin, papaverine and pentoxifylline reduced norepinephrine-induced vasoconstriction, whereas isoproterenol, clonidine and propranolol were ineffective. We conclude that several vasodilators can reduce resistance in the cirrhotic rat liver, but their potency is low and few are effective at therapeutic concentrations. Furthermore, their activity may be blunted when resistance is increased by norepinephrine.

Animals↗
PubMed1989

Protective effect of vasodilators on liver function after long hypothermic preservation: a study in the isolated perfused rat liver.

The effects of two vasodilators, papaverine and pentoxifylline (a methylxanthine derivative), on liver function after 19 hr hypothermic preservation were investigated. Hypothermic preservation was performed according to the standard technique, and liver hemodynamics and function were studied during 70 min immediately after reperfusion in an isolated perfused rat liver system. No significant changes occurred after hypothermic storage for 5 hr. However, when the storage was prolonged to 19 hr, bile flow and taurocholate intrinsic clearance were significantly reduced; transaminase release was markedly increased and histological studies demonstrated centrilobular necrosis. Concomitantly, liver blood flow was significantly reduced and intrahepatic vascular resistance was increased. Papaverine and pentoxifylline administered during preservation and at the time of reperfusion significantly improved all parameters. The improvement was more pronounced after pentoxifylline, and this group showed no significant difference in any of the studied parameters from the control livers. The results show that two vasodilators significantly protect the liver during long hypothermic preservation. The data suggest that abnormalities of liver microcirculation are of major importance in the pathogenesis of liver injury after hypothermic storage.

Animals↗
PubMed1989

Effect of D-tryptophan-6-luteinizing hormone-releasing hormone on the tumoral growth and plasma sex steroid levels in cirrhotic patients with hepatocellular carcinoma.

Certain evidence suggests androgen dependence of hepatocellular carcinoma in cirrhotic patients. Consequently, it was postulated that antiandrogen therapy might be effective in the treatment of hepatocellular carcinoma. D-Tryptophan-6-luteinizing hormone-releasing hormone is a potent agonist analog of luteinizing hormone-releasing hormone which, when chronically administered, inhibits the pituitary gonadal axis and testicular androgen secretion in man. We studied the effects of D-tryptophan-6-luteinizing hormone-releasing hormone on tumoral growth in 17 male cirrhotic patients with hepatocellular carcinoma. After 3 to 6 months of therapy, no tumoral response was observed. Furthermore, measurements of plasma levels of testosterone, dihydrotestosterone, androstenedione, estradiol, estrone and sex hormone-binding globulin were performed before and 3 months after initiation of the antiandrogenic treatment. Before treatment, hypoandrogenism and hyperestrogenism were present; D-tryptophan-6-luteinizing hormone-releasing hormone induced a fall in plasma testosterone and dihydrotestosterone levels. Only a moderate decrease in estradiol and no modification of plasma estrone and sex hormone-binding globulin were found, indicating that the hyperestrogenemia of cirrhotic patients could be attributed to an increase in peripheral aromatization of androgens of adrenal origin. The inability of D-tryptophan-6-luteinizing hormone-releasing hormone to reduce the growth of hepatocellular carcinoma is not totally in disagreement with the concept of androgen dependence of hepatocellular carcinoma since D-tryptophan-6-luteinizing hormone-releasing hormone does not inhibit the production of androgens of adrenal origin.

Aged↗
PubMed1989

Bile acid glycine and taurine conjugates in serum of patients with primary biliary cirrhosis: effect of ursodeoxycholic treatment.

We have applied a specific and accurate high pressure liquid chromatographic technique to determine fasting serum glycine and taurine conjugates of individual bile acids in patients with primary biliary cirrhosis before and during ursodeoxycholic acid therapy. The study was carried out in nine patients in whom the diagnosis of primary biliary cirrhosis was established according to accepted criteria. After one year of UDCA therapy liver function tests significantly improved. Total serum bile acid concentration did not change significantly (29.2 (31.5) v 28.3 (26.4) microM). Total UDCA (1.7 (2.2) v 13.3 (14.5) microM) and glyco UDCA (0.8 (1.6) v 10.9 (11.4 microM) but not tauro UDCA levels increased significantly (p less than 0.01); UDCA (7.7 (12.6) v 40.2 (12.7)%) became the major species of the circulating bile acids. Primary bile acids (23 (28.3) v 11.2 (10.5) and their glycoconjugates fell significantly (p less than 0.01). There were no significant changes in the concentrations of conjugates of the secondary bile acids (4.5 (3.8) v 3.9 (3.0]. Our study shows that oral administration of UDCA to patients with primary biliary cirrhosis induced marked changes in the circulating pool of endogenous bile acids together with improvement in liver function test values. The data also suggest that the beneficial effect of longterm administration of UDCA in these patients might be mediated through changes in the circulating primary bile acids and UDCA rather than through changes in the circulating secondary bile acids, deoxycholate and lithocholate.

Bile Acids and Salts↗
PubMed1989

Pharmacological effect of somatostatin on bile secretion in man.

Somatostatin (SST) has been shown to induce cholestasis in the dog and in the rat. In man, it is still unknown whether SST modifies bile formation. The present study was undertaken to examine the influence of SST on bile secretion in man. Two volunteers who had a total external biliary fistula received 1-hour SST infusions (3.5 micrograms/kg/h). Bile flow, bile acid, phospholipid and cholesterol biliary outputs were measured before, during and 1 h after the infusion. The SST infusion was associated with a pronounced decrease in bile flow and in bile acid secretion and with an increase in bile cholesterol saturation. These findings suggest that SST has cholestatic properties in man as in other species. This may provide a rational explanation for the formation of gallstones and for the steatorrhea observed in patients with somatostatinomas or during therapeutic SST administration.

Adult↗
PubMed1989

Effect of protein binding on testosterone extraction by human cirrhotic liver: evidence for a dissociation-limited uptake.

Testosterone (T) is a protein-bound substance, the hepatic extraction of which largely exceeds the free plasma fraction. In this study we attempted to determine if the dissociation of T from plasma proteins is the limiting factor for testosterone hepatic uptake in patients with cirrhosis. For this purpose we measured the hepatic uptake of T and the peripheral plasma concentrations of the different fractions of the hormone (total, free, albumin-bound, and sex hormone-binding globulin (SHBG)-bound) in 12 men with alcoholic cirrhosis. The hepatic extraction of T (mean = 42%) greatly exceeded the non-SHBG-bound fraction of T (free T plus albumin-bound T: mean = 13%). Thus, a substantial amount of SHBG-bound T must have entered the liver. A theoretical extraction ratio was calculated based upon the dissociation rate constants of T from albumin and SHBG and upon an estimate of sinusoidal transit time of plasma through the liver. The similarity between the measured and expected values indicates that the limiting step in hepatic uptake of T might be SHBG binding.

Adult↗
PubMed1989

A randomised controlled study of propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis.

74 cirrhotic patients with a history of variceal or gastric bleeding were randomly assigned to treatment with propranolol (40 to 360 mg/day) or placebo. The patients were all in good condition and doses of propranolol were titrated until a 25% reduction in heart rate was achieved. After 2 years, the cumulative percentage of patients free from rebleeding was significantly greater among the patients receiving propranolol (79%) than in the placebo group (32%; p less than 0.0001). Similarly, the percentage of surviving patients was significantly greater with propranolol (90%) than with placebo (57%; p less than 0.02) after 2 years. It was concluded that in cirrhotic patients in good condition, propranolol reduced both the risk of recurrent gastrointestinal haemorrhage and the mortality rate during a 2-year period of continuous administration of the drug.

Adult↗
PubMed1989

Evidence of the intact hepatocyte theory in alcoholic cirrhosis.

To improve our understanding of the predominant operational model involved in the decreased clearance in cirrhosis, hepatic clearance, the extraction ratio of indocyanine green, and liver plasma flow were estimated in cirrhosis, either with a method based on the Fick principle or with a pharmacokinetic method assuming a bicompartmental plasma elimination of the dye. The two methods gave similar values for clearance. In contrast, the pharmacokinetic analysis gave significantly (p less than 0.01) lower hepatic plasma flow values and significantly (p less than 0.01) higher extraction values than those obtained with the reference (Fick principle) method. The main finding of this work is that in these cirrhotic patients, as in normal subjects, 'cellular' extraction estimated by the pharmacokinetic method is in the range of 0.60-0.80, whereas the extraction by the entire liver, assessed by the reference method, is low. In chronic liver diseases such as cirrhosis these data support the predominance of the intact hepatocyte theory, which assumes the existence of intrahepatic shunts associated with normally perfused and normally extracting hepatocytes. In acute liver disease, a cellular damage could be superadded.

Adult↗
PubMed1988

Sex hormone imbalance in male alcoholic cirrhotic patients with and without hepatocellular carcinoma.

To investigate the possible role of sex-hormone imbalance in hepatocellular carcinogenesis in male alcoholic cirrhotic patients, we determined plasma levels of testosterone (T), dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone (DHA), estrone (E1), estradiol (E2), and sex-hormone-binding globulin (SHBG) in 15 men with alcoholic cirrhosis alone and in 15 similar men with alcoholic cirrhosis and hepatocellular carcinoma (HCC). The groups were matched for age and severity of liver disease using Child-Pugh scoring. Patients of both groups had evidence of hypogonadism with a decrease in plasma T levels (P less than 0.02) and of hyperestrogenemia with an increase in E1 (P less than 0.001), E2 (P less than 0.01), and SHBG (P less than 0.01) plasma levels compared with ten healthy age-matched controls. Cirrhotic patients with HCC had significantly lower plasma concentrations of T (P less than 0.02), DHT (P less than 0.01), and DHA (P less than 0.001) than patients with cirrhosis alone. However, the plasma concentrations of A, E1, E2, and SHBG did not significantly differ between these two groups. These results suggest a possible alteration of the estrogen-to-androgen ratio during carcinogenesis of the cirrhotic liver. This is shown by a greater reduction of circulating androgens and a similar elevation of estrogens in the group of cirrhotics with HCC.

Aged↗
PubMed1988

Hepatic transport of bile acids in the isolated perfused rat liver. Structure-kinetic relationship.

We studied the transport kinetics of a series of bile acids from blood to bile in the isolated perfused rat liver in order to define better the relationship between chemical structure of bile acid molecules and efficiency of the overall hepatic transport process. BA studied were taurocholate (TC), glycocholate (GC), cholate (C), tauroursodeoxycholate (TUDC), ursodeoxycholate (UDC) and hyodeoxycholate (HDC). Estimates of intrinsic hepatic clearance (Cl(int)), maximal secretory rate (Vmax) were provided from the analysis of the relationship between bile acid removal rates and sinusoidal concentration under steady-state conditions. TC and TUDC had the highest Cl(int) (about 5 ml/min/g liver) and Vmax (about 800 nmol/min/g liver) followed in order by GC (1.71 ml/min/g liver; 442 nmol/min/g liver); C (1.25 ml/min/g liver; 252 nmol/min/g liver); HDC (0.86 ml/min/g liver; 238 nmol/min/g liver); UDC (0.72 ml/min/g liver; 176 nmol/min/g liver). The findings suggest that the efficiency of the overall hepatic transport of bile acids is highly dependent on their molecular structure and that conjugation has a more important effect on both Cl(int) and Vmax that the number or position of hydroxyl groups.

Animals↗
PubMed1988

Relationship among beta-adrenergic blockade, propranolol concentration, and liver function in patients with cirrhosis.

In 20 patients with cirrhosis we studied the relationship among the efficiency of beta-adrenergic blockade induced by oral administration of 40 mg propranolol, the plasma level of propranolol, and the liver function. The beta-adrenergic blockade was studied 2 h and 8 h after propranolol administration and assessed by the cardiac chronotropic response to isoprenaline. Liver function was evaluated by a standard liver function test and the Child-Turcotte or Pugh score. The beta-adrenergic blockade and propranolol plasma concentration were higher 2 h than 8 h after propranolol administration. The beta-adrenergic blockade and the propranolol plasma concentration varied widely among patients. No significant correlation was found between the efficiency of beta-blockade and propranolol concentration. The beta-adrenergic response before propranolol administration was correlated with bilirubin level and Child scores, but no significant correlation was found between the beta-blockade and the severity of liver disease. These results suggest that in patients with cirrhosis, differences in response to propranolol are not related to differences in the severity of the liver disease or to differences in propranolol concentration.

Female↗
PubMed1988

Differential response of normal and cirrhotic liver to vasoactive agents. A study in the isolated perfused rat liver.

In cirrhosis, endogenous vasoactive agents could act as modulators of intrahepatic resistance and thus portal pressure. The aim of this work was to study the effects of norepinephrine, angiotensin II and arg8-vasopressin on intrahepatic portal resistance in isolated perfused livers from normal rats and rats with carbon tetrachloride-induced cirrhosis. Livers were perfused at a constant pressure and the measured variable was portal blood flow. Dose-response curves were obtained by cumulative addition of agonists to the perfusate. The three vasoactive agents increased resistance in normal and cirrhotic livers. The maximal amplitude of response was similar in normal and cirrhotic livers. The cirrhotic livers exhibited an increased sensitivity to norepinephrine, a decreased sensitivity to angiotensin II but an unchanged sensitivity to arg8-vasopressin. The shape of the dose-response curve for norepinephrine and arg8-vasopressin, but not for angiotensin II, was modified in cirrhotic livers. We conclude that the cirrhotic liver retains a strong vascular reactivity to vasoactive agents and particularly to norepinephrine.

Algorithms↗