salicylates and Liver-Cirrhosis

Transjugular intrahepatic portosystemic shunt (TIPS) is nowadays the benchmark treatment of severe portal hypertension complications. However, besides usual contraindication to the procedure (namely recurrent hepatic encephalopathy, severe liver dysfunction, right heart failure and/or pulmonary hypertension), TIPS appears regularly unfeasible due to abnormal and/or distorted anatomy. In this situation, the only non-surgical approaches to treat severe portal hypertension consist in the creation of an intrahepatic portocaval shunt from percutaneous (direct intrahepatic portocaval shunt - DIPS) or transjugular route (transjugular transcaval intrahepatic portosystemic shunt - TTIPS). These procedures have been rapidly adopted in patients with Budd-Chiari syndrome but are only poorly reported in patients with cirrhosis and without BCS. Considering the broadening landscape of TIPS indication in patients with cirrhosis within the last ten years, we aimed to describe the techniques, safety and efficacy of DIPS and TTIPS procedures as an alternative to TIPS in case of unfavourable anatomy.

Topics: Budd-Chiari Syndrome; Humans; Hypertension, Portal; Liver Cirrhosis; Portasystemic Shunt, Transjugular Intrahepatic; Salicylates; Treatment Outcome

Imidazole-salicylate is a non-steroidal anti-inflammatory drug with limited inhibitory effects on prostaglandin synthesis. The renal effects of this drug were investigated by a double-blind cross-over study in 10 patients with cirrhosis and ascites. Two therapeutic doses of imidazole-salicylate (750 mg each) were given at midnight and 08:00 h and 80 mg of furosemide were injected intravenously at 09:00 h. The same procedure was followed on another day but a placebo replaced imidazole-salicylate. Renal function (creatinine clearance, free water and electrolyte excretions) and urinary excretion of prostaglandin E, 6-keto-prostaglandin F1 alpha and thromboxane B2 were evaluated for 8 h after the first dose of the drug and for 2 h after furosemide injection. Platelet thromboxane production was also determined 9 h after the first administration of drug or placebo. Imidazole-salicylate did not affect renal function or inhibit kidney prostanoid production either under basal conditions or after the stimulating effect of furosemide. On the contrary, imidazole-salicylate significantly inhibited platelet thromboxane production (45.8 +/- 9 vs. 69.4 +/- 7.5 ng/ml, P < 0.05). These results suggest that imidazole-salicylate is an anti-inflammatory drug that can be given to patients with decompensated cirrhosis without risk of inhibiting kidney prostaglandin synthesis or the renal response to furosemide.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Ascites; Blood Platelets; Diuretics; Double-Blind Method; Female; Furosemide; Glomerular Filtration Rate; Humans; Imidazoles; Kidney; Liver Cirrhosis; Male; Middle Aged; Prostaglandins F; Salicylates; Thromboxane B2; Time Factors

A double-blind crossover study versus placebo of the renal effects of the nonsteroidal anti-inflammatory drug imidazole 2-hydroxybenzoate was conducted in 10 patients with compensated liver cirrhosis. The administration of the drug (750 mg, t.i.d., for three days) did not affect renal plasma flow, glomerular filtration rate, free water clearance nor the urinary excretion of sodium or potassium. Values of plasma renin activity also did not change after drug administration. Direct tubular damage from imidazole 2-hydroxybenzoate was also excluded by normal excretion of beta-2-microglobulin and N-acetyl-beta-D-glucosaminidase. Urinary 6-keto-PGF1 alpha output were comparable during imidazole 2-hydroxybenzoate and placebo administration. These data indicate that this nonsteroidal antiinflammatory drug does not affect the renal function in patients with compensated liver cirrhosis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Double-Blind Method; Female; Humans; Imidazoles; Kidney; Kidney Function Tests; Liver Cirrhosis; Male; Metabolic Clearance Rate; Middle Aged; p-Aminohippuric Acid; Pilot Projects; Renal Circulation; Salicylates

Bismuth subsalicylate (BSS) is the active ingredient in over-the-counter antacid and antidiarrheal medications. Coagulopathy in the setting of acetylsalicylic acid toxicity is well documented but not in setting of bismuth subsalicylate overuse. We present a case report of coagulopathy from BSS poisoning in a patient with underlying cirrhosis. The patient's high prothrombin time suggests inhibition of vitamin K-dependent coagulation factors. The patient had decreased factor V activity, which is responsible for converting prothrombin to thrombin. Patients with cirrhosis often have hypoprothrombinemia which may be exacerbated by salicylate-induced coagulopathy. Given the widespread use of BSS products, physicians should recognize coagulopathy as a possible manifestation of toxicity especially in patients with underlying liver disease.

Topics: Bismuth; Blood Coagulation Disorders; Chronic Disease; Female; Humans; International Normalized Ratio; Liver Cirrhosis; Middle Aged; Organometallic Compounds; Salicylates

Portal hypertension resulting from increased intrahepatic resistance is a common complication of chronic liver diseases and a leading cause of death in patients with liver cirrhosis, a scarring process of the liver that includes components of both increased fibrogenesis and wound contraction. A reduced production of nitric oxide (NO) resulting from an impaired enzymatic function of endothelial NO synthase and an increased contraction of hepatic stellate cells (HSCs) have been demonstrated to contribute to high intrahepatic resistance in the cirrhotic liver. 2-(Acetyloxy) benzoic acid 3-(nitrooxymethyl) phenyl ester (NCX-1000) is a chemical entity obtained by adding an NO-releasing moiety to ursodeoxycholic acid (UDCA), a compound that is selectively metabolized by hepatocytes. In this study we have examined the effect of NCX-1000 and UDCA on liver fibrosis and portal hypertension induced by i.p. injection of carbon tetrachloride in rats. Our results demonstrated that although both treatments reduced liver collagen deposition, NCX-1000, but not UDCA, prevented ascite formation and reduced intrahepatic resistance in carbon tetrachloride-treated rats as measured by assessing portal perfusion pressure. In contrast to UDCA, NCX-1000 inhibited HSC contraction and exerted a relaxing effect similar to the NO donor S-nitroso-N-acetylpenicillamine. HSCs were able to metabolize NCX-1000 and release nitrite/nitrate in cell supernatants. In aggregate these data indicate that NCX-1000, releasing NO into the liver microcirculation, may provide a novel therapy for the treatment of patients with portal hypertension.

Topics: Animals; Carbon Tetrachloride; Collagen; Hypertension, Portal; Liver; Liver Cirrhosis; Male; Nitrates; Nitric Oxide; Nitric Oxide Donors; Rats; Rats, Wistar; Salicylates; Ursodeoxycholic Acid

The gastric toxic effects of aspirin (ASA) and NCX-4016, a nitric oxide (NO)-releasing ASA, were compared in normal, cirrhotic, and arthritic rats. Oral administration of ASA (100 mg/kg) produced hemorrhagic lesions on the gastric mucosa in normal rats. The gastric ulcerogenic response to ASA was significantly worsened in both cirrhotic rats induced by N-nitrosodiethylamine and in arthritic rats induced by Freund's complete adjuvant. By contrast, NCX-4016 at 190 mg/kg (a dose equimolar to 100 mg/kg of ASA) did not induce damage in normal rat stomachs but caused slight lesions in the gastric mucosa of both cirrhotic and arthritic rats. Plasma salicylate levels following administration of ASA or NCX-4016 were not different between normal, cirrhotic, and arthritic rats, although the latter drug gave significantly lower values in any group of rats as compared to the former. Acid secretion was significantly increased in both cirrhotic and arthritic rats. ASA with 150 mM HCl caused severe gastric lesions in normal rats, the degree of damage being significantly greater than that induced by ASA alone. Coadministration of NOR-3, a NO donor, significantly prevented the development of gastric lesions induced by ASA, irrespective of whether or not ASA was given together with HCl. Gastric mucosal application of ASA (100 mg/kg) for 30 min caused a marked reduction of transmucosal potential difference (PD) with a minimal effect on gastric mucosal blood flow in both normal and cirrhotic rats, while that of NCX-4016 did not cause a PD reduction and produced a marked increase in the mucosal blood flow in both groups of rats. These results suggest that gastric mucosal susceptibility to ASA-induced damage is increased in both cirrhotic and arthritic rats (the process being partly accounted for by acid hypersecretion in these animals), NCX-4016 has even less gastric toxicity in both cirrhotic and arthritic rats, and the gastric-sparing effect of NCX-4016 is due, at least partly, to an increase of gastric mucosal blood flow, mediated by NO released from this drug.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Aspirin; Blood Flow Velocity; Gastric Acid; Gastric Mucosa; Hydrochloric Acid; Liver Cirrhosis; Male; Membrane Potentials; Nitric Oxide Donors; Nitro Compounds; Rats; Rats, Sprague-Dawley; Salicylates; Stomach Ulcer

Topics: Adult; Aged; Cortisone; Endoscopy; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Male; Middle Aged; Peptic Ulcer Hemorrhage; Phenylbutazone; Renal Dialysis; Salicylates; Sepsis

Topics: Adult; Aged; Binding Sites; Circular Dichroism; Dialysis; Diazepam; Female; Humans; In Vitro Techniques; Kinetics; Liver Cirrhosis; Male; Middle Aged; Protein Binding; Salicylates; Serum Albumin; Warfarin

In patients with severe hepatic parenchymal damage drug metabolism is presumably impaired. The reduced detoxification can not be sufficiently described in the postulated multicompartment model by determination of plasma half-life, because it depends on the physicochemical properties of the drugs. An increase of dihydroxybilic acids inhibits drug metabolism. Some drugs and also its metabolites formed in the liver induce hepatic cell injury including necrosis and therefore they are contraindicated in patients suffering from liver disease.

Topics: Aminopyrine; Biotransformation; Chloramphenicol; Coumarins; Half-Life; Humans; Kinetics; Liver Cirrhosis; Pharmaceutical Preparations; Phenylbutazone; Salicylates; Tolbutamide

Topics: Alcoholic Beverages; Anticoagulants; Blood Transfusion; Cortisone; Drug Therapy, Combination; Gastrointestinal Hemorrhage; Hip Joint; Humans; Indomethacin; Joint Diseases; Kidney Diseases; Liver Cirrhosis; Neoplasms; Phenylbutazone; Postoperative Complications; Prospective Studies; Salicylates; Stomach Diseases

Topics: Adult; Age Factors; Aged; California; Esophageal and Gastric Varices; Ethanol; Gastritis; Gastrointestinal Hemorrhage; Gastroscopy; Hematemesis; Hematocrit; Hospitalization; Humans; Liver Cirrhosis; Melena; Middle Aged; Peptic Ulcer; Recurrence; Salicylates; Shock, Hemorrhagic

In 8 out of 32 juvenile patients suffering from chronic polyarthritis and in one patient with dermatomyositis, raised transaminase levels were found; the salicylate level was above 35 mg/100 ml in all except one. Reduction in the salicylate level led to a prompt fall in the serum transaminases. Despite a rise in alkaline phosphatase in three cases there was no other evidence of liver dysfunction in the children. Only one of the adults showed a rise in transaminase levels, and she had mild cirrhosis.

Topics: Adolescent; Adult; Age Factors; Aged; Alanine Transaminase; Alkaline Phosphatase; Arthritis, Juvenile; Aspartate Aminotransferases; Aspirin; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Dermatomyositis; Female; Humans; Liver Cirrhosis; Male; Middle Aged; Salicylates

Topics: Barbiturates; Bilirubin; Binding Sites; Blood Pressure; Blood Volume; Edema; Exchange Transfusion, Whole Blood; Humans; Infant, Newborn; Kernicterus; Liver Cirrhosis; Nephrosis; Salicylates; Serum Albumin

Topics: Amylases; Blood Chemical Analysis; Chromatography; Clinical Enzyme Tests; Colorimetry; Diabetes Mellitus; Electrophoresis; gamma-Globulins; Glucose; Humans; Intestinal Obstruction; Liver Cirrhosis; Maltose; Pancreatitis; Salicylates; Starch

Topics: Adhesives; Ascites; Hepatitis; Humans; Liver Cirrhosis; Phenols; Salicylates; Tissue Adhesions

Topics: Benzenesulfonates; Hepatitis A; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Salicylates