Pharmacokinetics and safety of single oral doses of amlodipine in patients with and without hepatic impairment: an open study.

An open study was conducted to assess the pharmacokinetics, cardiovascular effects and safety of a single oral dose of amlodipine 5 mg in 12 patients with hepatic impairment and eight healthy convalescing subjects. Cmax values were found to be similar in both groups although Tmax was shorter, and T1/2 was longer, in patients with hepatic insufficiency. AUCs were also higher in hepatic patients although these differences were not significantly different. No side-effects or cardiovascular/ECG changes were observed in either group. Three patients with hepatic failure experienced mild laboratory abnormalities which were of doubtful clinical significance.

[Current etiological problems, in France, posed by primary liver cancer after cirrhosis. Personal observations of 130 cases]. / Problèmes étiologiques actuels posés, en France, par le cancer primitif du foie développé sur cirrhose. A propos de 130 observations personnelles.

The etiological problems concerning, in France, hepatocellular carcinoma (HCC) developed on liver cirrhosis, are studied in this work through 130 personal cases followed up during the last decade. These 130 cases of HCC are divided in five groups according to apparent etiology: alcoholic (63 p. cent), B virus, (15.3 p. cent), cryptogenetic (11.5 p. cent), hemochromatosic (7.6 p. cent), autoimmune (2.3 p. cent). A review of these cases according to recent publications shows an evidence underestimated for years: we mean the important role played in France by HBV (and probably HCV) not only in chronic cirrhogen hepatitis, but even more in cancerisation of cirrhosis in general whatever is the apparent etiology. This role, unsuspected when biological investigations are limited to serological markers of HBV, is demonstrated by implementing more sophistical technics (molecular hybridation and genic amplification). But it is very unlikely that this role is exclusive and one must recognize that viral "focalisation" of recent publications has a tendancy to hide other causes of HCC and primarily the toxicological etiology in a wide sense. This etiology is in fact indubitable, already in tropical areas, where the role of mycotoxins and particularly of aflatoxin B1 is very well demonstrated, even in areas of very high incidence of HBV. In low incidence areas, such as France, the specific carcinogenic role of alcohol cannot be excluded, neither the role of numerous experimental hepato-carcinogens, very much studied 15 years ago and may be incorrectly forgotten in our days.(ABSTRACT TRUNCATED AT 250 WORDS)

[Current etiological problems, in France, related to primary liver cancer in cirrhosis (personal observation of 130 cases)]. / Problèmes étiologiques actuels posés, en France, par le cancer primitif du foie développé sur cirrhose (à propos de 130 observations personnelles).

The etiological problems concerning, in France, hepatocellular carcinoma (H C C) developed on liver cirrhosis, are studied in this work through 130 personal cases followed up during the last decade. These 130 cases of H C C are divided in five groups according to apparent etiology: alcoholic (63%), B virus (15.3%), cryptogenetic (11,5%), hemochromatic (7.6%), autoimmune (2.3%). A review of these cases according to recent publications shows an evidence underestimated for years: we mean the important role played in France by H B V (and probably H C V) not only in chronic cirrhotic hepatitis, but even more in cancerization of cirrhosis in general whatever is the apparent etiology. This role, unsuspected when biological investigations are limited to serological markers of H B V, is demonstrated by implementing more sophisticated+ technics (molecular hybridization+ and gene amplification). But it is very unlikely that this role is exclusive++ and one must recognize that viral "focalization" of recent publications has a tendency to hide other causes of H C C and primarily the toxicological etiology in a wide sense. This etiology is in fact indubitable, already in tropical areas, where the role of mycotoxins and particularly of aflatoxin B l is very well demonstrated, even in areas of very high incidence of H B V. In low incidence areas, such as France, the specific carcinogenic role of alcohol cannot be excluded, neither the role of numerous experimental hepato-carcinogen, very much studied 15 years ago and may be incorrectly forgotten in our days. If the accidents of research lead to privilege temporarily one or the other factor, one must not forget that the genesis of H C C is most probably multifactorial, as for the majority of human cancers.

Rioprostil in the short-term treatment of duodenal ulcer: a multicentre double-blind trial vs. cimetidine.

The efficacy and safety of the new prostaglandin E1 (PGE1) synthetic analogue, rioprostil, 300 micrograms b.d. and cimetidine, 400 mg b.d., on duodenal ulcer healing are compared in an international, multicentre, double-blind study. A total of 257 patients have entered the study; 243 are considered eligible for efficacy analysis and 207 for safety analysis. After 4 and 6 weeks of treatment, the endoscopic healing rates do not significantly differ between the two groups, being 55% and 83% respectively with rioprostil vs. 60% and 78% respectively with cimetidine. The major adverse effect attributable to rioprostil is diarrhoea, which was documented in 11% of patients compared with 1% of patients taking cimetidine. However, central nervous system complaints are twice as frequent in the cimetidine group. Monitoring of clinical laboratory tests show no significant abnormalities when compared with the baseline values during the administration of either drug. This study documents that rioprostil, at the dosage of 300 micrograms b.d., is as effective and safe as cimetidine in the short-term therapy of duodenal ulcer.

Liver adenoma and focal nodular hyperplasia in a man with high endogenous sex steroids.

The authors report the case of a 29-yr-old man presenting with both hepatocellular adenoma and focal nodular hyperplasia. The patient had never been treated with androgens or estrogens. Investigations revealed the existence of high plasma levels of androgens and estrogens. In addition, the patient presented features compatible with the syndrome of partial androgen resistance. We propose that the hepatic lesions could be secondary to an abnormally high secretion of sex steroids. We suggest that in the absence of known intake of either estrogens or androgens, the existence of hepatocellular adenoma or focal nodular hyperplasia, or both, should indicate a search for abnormal secretion of sex steroids.

Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of "autoimmune" hepatitis.

Sixty-five patients with histologically proven chronic active hepatitis of unknown cause but associated with the antiliver/kidney microsome antibody type 1, confirmed by immunofluorescence and immunoprecipitation, were selected as forming a special entity. This disease was found to be rare with a prevalence of 5/1,000,000. The female to male ratio was 8:1. The condition occurred at all ages but was most common between the ages of 2 and 14 years. In 22 of the 65 cases, the hepatitis was associated with an autoimmune disease, most commonly insulin-dependent diabetes, autoimmune thyroid disease and vitiligo. The same autoimmune diseases were present in first-degree relatives from seven families. In 36 cases, the onset of disease resembled acute viral hepatitis. Serum biochemical tests showed marked elevation in aminotransaminases and hypergammaglobulinemia. Paradoxically, serum and salivary IgA levels were often normal or low. Histologic findings were multifocal hepatic necrosis with bridging in the acute stage, and aggressive hepatitis with mononuclear cell infiltration or macronodular cirrhosis in the late stages. Serologically, apart from the presence of antiliver/kidney microsome antibody type 1, the disease was characterized by the absence of antiactin, antimitochondria and antinucleus antibodies; however, organ-specific autoantibodies were often present. The clinical course was usually severe: six patients in the acute stage presented with fulminant hepatitis, and all, except two, other patients progressed to cirrhosis. Prolonged treatment with corticosteroids and immunosuppressants was usually effective in rendering the cirrhosis inactive. The cumulative survival rate was 51% at 14 years. We propose to call this entity "anti-LKM1 chronic active hepatitis" or "autoimmune hepatitis type II" to differentiate it from classical "lupoid hepatitis" or autoimmune hepatitis type I.

Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis?

The effects of ursodeoxycholic acid (UDCA, 13-15 mg/kg body weight daily) were prospectively evaluated in fifteen patients with primary biliary cirrhosis (PBC). The mean concentration of UDCA in serum expressed as the percentage of total bile acids rose from 0% at baseline to 58% (SEM 9%) after 2 years' treatment, whereas total serum bile acid levels did not change significantly. The proportion of patients with pruritus necessitating the use of cholestyramine was significantly lower at 2 years than at baseline. Standard liver function tests improved in all the patients. At 2 years the average activities of gamma-glutamyltranspeptidase, alkaline phosphatases, and alanine aminotransferase and bilirubin levels were reduced (respectively 78%, 65%, 68%, and 36% of pretreatment values). In three patients who agreed to interrupt the ingestion of UDCA for 3 months after 2 years' treatment there was clear deterioration in liver function tests, which again improved after reinstitution of UDCA. These results suggest that long-term UDCA might be a safe and effective treatment for PBC, but a randomised, controlled, double-blind trial is urgently needed.

[Does the size of esophageal varices have a prognostic significance in alcoholic cirrhosis?]. / La taille des varices oesophagiennes a-t-elle une signification pronostique au cours des cirrhoses alcooliques?

This study was designed to determine whether the size of esophageal varices were of prognostic value in patients with alcoholic cirrhosis. Esophageal varices were classified into 2 groups according to whether their size was larger or smaller than 4 mm. There was a total of 99 patients; 56 had small varices and 43 had large varices. Of the clinical and biological data collected at the time of determination of the size of the esophageal varices, only the duration of cirrhosis and the prevalence of gastrointestinal bleeding were significantly greater in patients with large esophageal varices. The one- and two-year cumulative rates of patients with large esophageal varices were 63 +/- 7 p. 100 and 42 +/- 8 p. 100, respectively; these results were not significantly different from those in patients with small esophageal varices, i.e. 68 +/- 6 p. 100 and 61 p. 100 respectively (p less than 0.5 for one-year survival; p less than 0.08 for two-year survival). Serum bilirubin and albumin as well as the presence of ascite were of significant prognostic value concerning death at two years while the presence of esophageal varices did not significantly increase the prognostic value of the above-mentioned variables (using Cox's regression model). In conclusion, the results of our study suggest that large esophageal varices, in spite of their association with a high incidence of gastrointestinal bleeding, do not influence prognosis at two years for patients with alcoholic liver cirrhosis.

Hepatic uptake of sex steroids in men with alcoholic cirrhosis.

We attempted to determine to what extent the degree of liver function impairment might affect the hepatic uptake and, as a consequence, alter the systemic plasma levels of endogenous sex steroids in male patients with alcoholic cirrhosis. The plasma levels and hepatic uptake of the steroids dehydroepiandrosterone, androstenedione, testosterone, dihydrotestosterone, estrone, estradiol, progesterone, and 17-hydroxyprogesterone were assessed. Systemic plasma levels of testosterone and dehydroepiandrosterone were significantly (p less than 0.05) reduced, whereas those of androstenedione, estrone, and estradiol were significantly (p less than 0.05) elevated in men with alcoholic cirrhosis when compared to controls. Sex hormone binding globulin levels were also significantly elevated (p less than 0.01). The hepatic uptake of sex steroids depended on the degree of liver function impairment as shown by the linear significant relationship between their hepatic extractions and that of indocyanine green (r = 0.74-0.92, p less than 0.05; except for dihydrotestosterone, r = 0.17, not significant). In addition, the hepatic uptake of sex steroids depended on the binding affinity to sex hormone binding globulin. The higher the affinity for sex hormone binding globulin, the lower the hepatic uptake influenced by liver function impairment. It was estimated that hepatic clearances accounted for only 20%-50% of the metabolic clearance of sex steroids. No significant relationship between plasma levels of sex steroids and their hepatic clearance was found. We show here that in alcoholic cirrhosis the extent of hepatic uptake of sex steroids depends partly on the degree of liver function impairment and partly on the degree to which they are bound to sex hormone binding globulin. Production rate or peripheral metabolism, or both, rather than hepatic uptake alone may account for the altered circulating levels of sex steroids.

[Ascites disclosing systemic lupus erythematosus]. / Ascite révélatrice d'un lupus érythémateux disséminé.

We report the case of a 38-year old woman with massive ascites. No cause could be demonstrated despite multiple investigations. The patient was febrile and had an elevated erythrocyte sedimentation rate. Systemic lupus erythematosus was subsequently diagnosed, when malar rash, arthritis, leucopenia, anti-native DNA and anti-Sm antibodies appeared. Ascites and lupus manifestations resolved simultaneously on steroid therapy. This unusual cause of ascites should be recognized, since it responds favorably to steroid therapy.

[Nodular regenerative hyperplasia of the liver and primary biliary cirrhosis. A fortuitous association?]. / Hyperplasie nodulaire régénérative du foie et cirrhose biliaire primitive. Une association fortuite?

We report here in a case of primary biliary cirrhosis associated with nodular regenerative hyperplasia of the liver in a white woman revealed by digestive hemorrhage due to ruptured esophageal varices. The diagnosis of primary biliary cirrhosis was based on the following: elevated serum IgM, high titer of antimitochondrial antibody (anti M2), typical histopathological picture of stage I/II disease. The diagnosis of nodular regenerative hyperplasia was supported by the demonstration of disseminated small hepatic nodules without perinodular fibrosis. This association may be a supplementary argument in favor of a possible autoimmune origin of nodular regenerative hyperplasia of the liver.

[Drug hepatotoxicity. Description of a microcomputerized file of hepatic attacks and the responsible drugs]. / Hépatotoxicité médicamenteuse. Description d'un fichier micro-informatisé des atteintes hépatiques et des médicaments responsables.

The very large number of medications recognized as hepatotoxic has required the establishment of microcomputerized data file. This file presently indexes 347 active principles contained in more than 1000 patent medications. It may be rapidly examined with microcomputer.

Expression of blood group antigens including HLA markers in human adult liver.

The localisation of the principal blood group antigens has been studied in human liver. These blood group antigens included the erythrocyte antigens and the antigen of the major histocompatibility complex. This study was performed by the indirect immunofluorescence technique using polyclonal antibodies of human or animal origin and monoclonal antibodies from hybridomas. This study has shown that the normal hepatocyte is lacking in blood group antigens. On the contrary, the biliary cell was rich in antigenic markers: the main antigens expressed were Lewis, Pr, HLA-A and B antigens. In Kupffer cells, only i and HLA-DR antigens were clearly expressed. The endothelial cells of blood vessels mainly show A, B, H, HLA-A and B antigens; HLA-DR and Pr are slightly expressed. HLA-DR antigens were more strongly expressed on veins than on arteries. Dendritic cells have been identified in the portal space of human liver. They bore i and HLA-DR antigens.