vitamin-k-semiquinone-radical and Ascites

We report here the final analysis of a multicentre randomized, single-blind trial of propranolol for prophylaxis of first bleeding in cirrhosis. One hundred and seventy-four consecutive patients with large esophageal varices were randomly assigned to either propranolol in doses reducing the resting heart rate by 25% (85 patients) or to a placebo (vitamin K: 89 patients). Three were lost to follow-up and 26 had to be withdrawn from propranolol because of side effects (n = 23) or low compliance (n = 3). The cumulative value over 42 months of patients free of bleeding was 74% (95% confidence interval = 85%-63%) in the propranolol and 59% (95% CI = 79%-43%) in the control group and the corresponding survival figures were 51% (95% CI = 63%-39%) and 59% (95% CI = 75%-43%): neither of the differences was significant. A retrospective analysis according to the presence of ascites at randomization showed that in the subset without ascites the proportion of patients free of bleeding was significantly higher in the propranolol group than in the control group (83% vs. 61%; 95% CI = 97%-69% and 78%-44%, respectively; P = 0.028); this difference was even more evident in the ascites-free period (94% vs. 58%; 95% CI = 100%-86% and 76%-40%, respectively; P = 0.002). No differences were found in patients with ascites at randomization. Survival was not significantly affected by treatment in any subgroup, although it was shorter in the ascitic patients given propranolol than in controls (33% vs. 49%; 95% CI = 51%-15% and 71%-27%, respectively; P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Ascites; Clinical Trials as Topic; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Liver Cirrhosis; Male; Meta-Analysis as Topic; Middle Aged; Multicenter Studies as Topic; Prognosis; Propranolol; Random Allocation; Retrospective Studies; Risk Factors; Vitamin K

Experiments with cultured cells showed that most cellular stress resistance components are specialized for certain types of damage. For example, superoxide dismutase protects from oxidative damage; DNA repair enzymes guard against mutagens and other DNA-damaging agents. On the other hand, the major inducible heat shock protein Hsp72 protects cells from a large variety of stresses and thus represents a generalized repair/stress resistance component. Hsp72 not only refolds damaged proteins but also interferes with programmed cell death signaling pathways, thus providing cells with time to repair the damage, hence its universality as a stress protector. In the present study we demonstrate the occurrence in murine and human ascites fluids (AF) of a natural nontoxic extracellular factor (ascites Hsp72-inducing factor, AHIF) capable of activating Hsp72 expression in different types of cells via a pathway distinct from the heat shock response pathway. AHIF is unique in that it is the first physiological factor capable of inducing synthesis of Hsp72 not only in young cells but, remarkably, also in aged human cells that largely have lost the ability to express Hsp72 in response to stresses, a manifestation at the cellular level of a progressive impairment in the ability to adapt to environmental changes which characterizes aging. Pretreatment of aged human cells with AF triggers Hsp72 expression at levels seen in young stressed cells and protects cells from a variety of otherwise lethal stressful treatments such as heat shock, TNF, UV irradiation, etoposide, and menadione. Activation of Hsp72 expression is essential for antiapoptotic action of AHIF because specific inhibition of Hsp72 expression by antisense RNA abolishes the cytoprotective effect of AF. In view of an important link between stress resistance and longevity in different organisms, the abilities of AHIF make it a unique candidate for the role of a systemic regulator of the aging process. While a cell-autonomous stress response diminishes with aging, aged cells retain the ability to respond to an extracellular factor which induces the expression of Hsp72. This finding opens up exciting possibilities for using AF factor to restore stress resistance to old cells and organisms and the possibility of interfering with the aging process. The ability to induce stress resistance in young cells and to restore it in aged cells could serve as a basis for developing effective antiapoptotic therapies.

Topics: Adenoviridae; Animals; Antisense Elements (Genetics); Apoptosis; Ascites; Cellular Senescence; Fibroblasts; Genetic Vectors; Heat-Shock Proteins; Heat-Shock Response; Hot Temperature; HSP72 Heat-Shock Proteins; Humans; Hybridomas; JNK Mitogen-Activated Protein Kinases; Lymphoma; MAP Kinase Kinase 4; Mice; Mitogen-Activated Protein Kinase Kinases; Oxidative Stress; Tumor Cells, Cultured; Ultraviolet Rays; Vitamin K

To study the metabolism of K Vitamins (VK) in the liver, two types of natural VK, phylloquinone (K1) and menaquinone-4 (MK-4), were administered to male Wistar rats orally (P.O.), intravenously (I.V.) and intraperitoneally (I.P.). Blood and a small portion of the liver (and ascites by I.P.) were collected 8 times up to 72 h (P.O.) or 24 h (I.V. and I.P.). A modified assay procedure followed by high performance liquid chromatography (HPLC) was developed to detect VK from small amounts of liver tissue. After oral administration of both K1 and MK-4 (10 mumol/kg-P.O.), their concentrations in the liver increased from 1 h then reached a maximum at 6 h (10 nmol/g v.s. 0.35 nmol/g). After intravenous or intraperitoneal administration of K1 and MK-4 (0.5 mumol/kg-I.V. and I.P.), MK-4 concentrations in the liver reached a maximum faster than those of K1 (1.2 nmol/g -3 h vs. 1.3 nmol/g -0.5 h I.V. and 0.97 nmol/g -6 h vs. 0.47 nmol/g -1 h I.P.). MK-4 also increased in the liver from 6 h to 12 h (0.11 nmol/g -12 h) after oral administration of K1 (P.O.). These results indicate that K1 stays in plasma and liver longer than MK-4 and orally administered K1 might be transformed partially into MK-4 in the liver.

Topics: Animals; Ascites; Injections, Intraperitoneal; Injections, Intravenous; Kinetics; Liver; Male; Rats; Rats, Wistar; Vitamin K; Vitamin K 1; Vitamin K 2

Topics: Alkaloids; Animals; Antifungal Agents; Antineoplastic Agents; Ascites; Colchicine; Demecolcine; Hydrazines; Indicators and Reagents; Iron; Leukemia; Mice; Radiation-Sensitizing Agents; Riboflavin; Triacetin; Triglycerides; Urethane; Vitamin K

Topics: Acute Disease; Ascites; Ascorbic Acid; Blood Protein Disorders; Diet Therapy; Diuretics; Glucocorticoids; Hemorrhagic Disorders; Hepatic Encephalopathy; Hepatitis A; Humans; Mineralocorticoid Receptor Antagonists; Rest; Rutin; Serum Albumin; Vitamin K

Topics: Animals; Ascites; Body Temperature Regulation; Carcinoma, Ehrlich Tumor; Depression, Chemical; Diethylstilbestrol; Dimethyl Sulfoxide; Ethanol; Fever; Glucose; Mice; Rabbits; Stimulation, Chemical; Surface-Active Agents; Vitamin K

Topics: Animals; Ascites; Biochemical Phenomena; Biochemistry; Carcinoma; Carcinoma, Ehrlich Tumor; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Radiation-Protective Agents; Radiation-Sensitizing Agents; Research; Sulfhydryl Compounds; Tritium; Vitamin K

Topics: Ascites; Diet; Diet Therapy; Diuretics; Drainage; Humans; Liver Cirrhosis; Rest; Vitamin K; Vitamins

Topics: Ascites; Bilirubin; Esophageal and Gastric Varices; Humans; Liver Function Tests; Portacaval Shunt, Surgical; Prothrombin; Radiography, Thoracic; Serum Albumin; Vitamin K

Topics: Animals; Ascites; Carbohydrate Metabolism; Cell Respiration; Glycolysis; Lymphoma; Metabolism; Mice; Naphthoquinones; Neoplasms, Experimental; Vitamin K

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Antibiotics, Antitubercular; Antineoplastic Agents; Antitubercular Agents; Ascites; Cardiac Glycosides; Diagnosis, Differential; Diet; Diet Therapy; Diuretics; Humans; Vitamin K; Vitamins

Topics: Anticoagulants; Ascites; Diet, Sodium-Restricted; Diuretics; Edema; Humans; Hydroflumethiazide; Liver Cirrhosis; Neomycin; Organomercury Compounds; Spironolactone; Vitamin K; Vitamins

Topics: Animals; Antifibrinolytic Agents; Ascites; Carcinoma; Glycolysis; Lymphoma; Metabolism; Mice; Naphthoquinones; Neoplasms, Experimental; Vitamin K; Vitamin K 1; Vitamins

Topics: Adenosine Triphosphate; Animals; Ascites; Carcinoma; Carcinoma, Ehrlich Tumor; Diphosphates; Mice; Radiation-Sensitizing Agents; Vitamin K

Topics: Animals; Ascites; Carcinoma, Hepatocellular; Coenzymes; Electron Transport Complex II; Liver Neoplasms; Liver Neoplasms, Experimental; Mechlorethamine; Naphthoquinones; Neoplasms, Experimental; Oxidoreductases; Rats; Succinate Dehydrogenase; Succinates; Succinic Acid; Tetrazolium Salts; Ubiquinone; Vitamin K; Vitamin K 3

Topics: Animals; Ascites; Carcinoma, Ehrlich Tumor; Diphosphates; Mice; Neoplasms, Experimental; Radiation-Sensitizing Agents; Vitamin K

Topics: Antifibrinolytic Agents; Ascites; Hemostatics; Humans; Liver Cirrhosis; Vitamin K