ABSTRACT
Renal failure is a serious complication in patients with advanced cirrhosis. It occurs in about 20 % of patients hospitalized with cirrhosis. In about 70 % it is caused by prerenal failure, and in 30 % it is due to intrarenal causes. In about 70 % of patients with rperenal failure, renal function can be restored with fluid replacement, but the remaining 30 % are unresponsive to volume expansion. Minor increase in serum creatinine have been shown to be clinically relevant and can adversely affect survival. Therefore early efforts should be made to avoid precipitation of renal failure.Hepatorenal syndrome (HRS) is a fully reversible impairment of renal function in patients with cirrhosis unresponsive to volume expansion characterized by an acute progressive decrease in kidney function (serumcreatinin > 1,5 mg/dl) - type 1 HRS, whereas type 2 HRS features a decrease in kidney function over a long time, mostly in patients with refractory ascites. Therapy with vasoconstrictors like terlipressin to reverse splanchnic vasodilation, together with albumin is effective in 30-50 % of patients with HRS 1 and improves survival. The only effective longterm therapy is livertransplantation. An improvement of kidney fuction before transplantation is associated with a better outcome and posttransplant kidney function.
Subject(s)
Critical Care , Hepatorenal Syndrome/diagnosis , Liver Cirrhosis/complications , Liver Cirrhosis/diagnosis , Liver Failure/diagnosis , Liver Failure/therapy , Fluid Therapy , Hepatorenal Syndrome/etiology , Hepatorenal Syndrome/therapy , Humans , Kidney Function Tests , Liver Cirrhosis/therapy , Liver Transplantation , Lypressin/analogs & derivatives , Lypressin/therapeutic use , Prognosis , Serum Albumin/administration & dosage , Terlipressin , Vasoconstrictor Agents/therapeutic useABSTRACT
In a 63-year-old cirrhotic patient, recanalisation of a partial portal vein thrombosis was achieved by a low dose of rivaroxaban (10âmg daily). After anticoagulant therapy was stopped, partial vein thrombosis recurred. Restarting rivaroxaban at a dose of 10âmg led to recanalisation. The patient did not suffer any complications; in particular no bleeding occurred during 8 months of treatment.
Subject(s)
Morpholines/administration & dosage , Portal Vein/drug effects , Thiophenes/administration & dosage , Venous Thrombosis/diagnostic imaging , Venous Thrombosis/drug therapy , Anticoagulants/administration & dosage , Dose-Response Relationship, Drug , Factor Xa Inhibitors/administration & dosage , Female , Humans , Middle Aged , Radiography , Rivaroxaban , Treatment OutcomeABSTRACT
BACKGROUND: Renal dysfunction is a common complication of cirrhosis, occurring in approximately 20 % of all hospitalized patients with cirrhosis and associated with increased mortality. In about two thirds of the patients, renal dysfunction is caused by prerenal disorders (e.g. gastrointestinal bleeding, diuretics, bacterial infection); one third is caused by intrarenal diseases (e.g. hepatitis associated glomerulonephritis). In most patients, prerenal failure can be successfully handled by volume therapy. In one third, volume replacement is not effective any more to improve kidney function. This kind of prerenal failure is called hepatorenal syndrome (HRS). PATHOPHYSIOLOGY: The pathophysiology is based on an increased splanchic vasodilation, which cannot be compensated any more by an increased cardiac output. Therefore, patients with cardiac insufficiency are more at risk of developing HRS. The decompensation leads to a stimulation of the baroreceptors with consecutive activation of the sympathetic nerve system, the renin-angiotensin-aldosteron system (RAAS), and nonosmotic release of vasopressin. This results in renal vasoconstriction, which is strengthened by the activation of hepatorenal reflex secondary to an increase in intrahepatic pressure and/or decrease in sinusoidal blood flow. THERAPY: Several studies have shown that the vasopressin analogue terlipressin combined with albumin can reverse HRS in up to 50 % of patients. Long-term survival can only be achieved by liver transplantation. Improving kidney function before transplantation improves outcome after transplantation.
Subject(s)
Critical Care/methods , Hepatorenal Syndrome/therapy , Liver Cirrhosis/complications , Multiple Organ Failure/therapy , Hemodynamics/physiology , Hepatorenal Syndrome/diagnosis , Hepatorenal Syndrome/physiopathology , Humans , Kidney/physiopathology , Liver/physiopathology , Liver Cirrhosis/physiopathology , Liver Cirrhosis/therapy , Multiple Organ Failure/diagnosis , Multiple Organ Failure/physiopathology , Renin-Angiotensin System/physiologyABSTRACT
BACKGROUND: Sorafenib is the new reference standard for patients with advanced hepatocellular carcinoma (HCC). AIM: To identify prognostic factors in sorafenib-treated HCC patients and to evaluate outcomes with respect to liver function. METHODS: In this retrospective study, 148 HCC patients received sorafenib 400 mg b.d. across 11 Austrian institutions. Seventy-eight HCC patients who received best supportive care (BSC) in the pre-sorafenib era served as a control. RESULTS: In sorafenib-treated patients, low baseline α-fetoprotein, low Child-Pugh (CP) score, compensated cirrhosis, and low baseline aspartate aminotransferase (AST) were associated with significantly longer overall survival (OS) on univariate analysis. CP score and baseline AST remained independent prognostic factors on multivariate analysis. In patients with Barcelona Clinic liver Cancer (BCLC) stage B or C HCC (sorafenib: n = 139; BSC: n = 39), CP-A patients had a median OS of 11.3 (sorafenib [n = 76]) vs. 6.4 (BSC [n = 17]) months (P = 0.010), and CP-B patients had a median OS of 5.5 (sorafenib [n = 55]) vs. 1.9 (BSC [n = 22]) months (P = 0.021). In the sorafenib group, median OS according to baseline AST was 11.8 (<100 U/L [n = 58]) vs. 3.9 (≥100 U/L [n = 15]) months for CP-A patients (P = 0.127), and 6.5 (<100 U/L [n = 33]) vs. 2.1 (≥100 U/L [n = 21]) months for CP-B patients (P = 0.011). There was no survival difference between sorafenib and BSC in patients with BCLC stage D HCC (1.5 vs. 1.4 months; P = 0.116). CONCLUSIONS: Sorafenib was associated with improved survival in both CP-A and CP-B patients. In CP-B patients, baseline AST may be helpful in determining which patients are most likely to benefit from sorafenib.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzenesulfonates/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Pyridines/therapeutic use , Administration, Oral , Aged , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/physiopathology , Female , Humans , Liver Neoplasms/mortality , Liver Neoplasms/physiopathology , Magnetic Resonance Imaging , Male , Middle Aged , Niacinamide/analogs & derivatives , Phenylurea Compounds , Prognosis , Retrospective Studies , Severity of Illness Index , Sorafenib , Statistics as Topic , Survival Rate , Tomography, X-Ray ComputedABSTRACT
This multicenter randomized phase III study was designed to compare the efficacy and toxicity of IFN alpha-2c (3.5 MU/d) in combination with either araC (10 mg/m(2) d1-10) or hydroxyurea (HU: 25 mg/kg per day) in newly diagnosed CML patients. A total of 114 patients were randomized. Following a median observation period of 36 (range 1-73) months the major cytogenetic response rates were 25 and 27% and the 4-year survival probabilities 62.5 and 63% for the araC and HU group, respectively. While the overall toxicity profile was comparable between both groups, patients in the HU arm exhibited a slightly higher degree of WHO grades 3 and 4 non-hematological toxicities.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Chronic-Phase/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cytarabine/administration & dosage , Cytarabine/adverse effects , Female , Gastrointestinal Diseases/chemically induced , Hematologic Diseases/chemically induced , Humans , Hydroxyurea/administration & dosage , Hydroxyurea/adverse effects , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Leukemia, Myeloid, Chronic-Phase/mortality , Life Tables , Male , Middle Aged , Nervous System Diseases/chemically induced , Recombinant Proteins , Treatment OutcomeABSTRACT
Prostaglandin E ( 1 ) (PGE ( 1 ) ) is a naturally occurring paracrine hormone that is used pharmacologically for treatment of peripheral occlusive arterial disease and to maintain ductus-arteriosus patency in neonates with congenital heart disease until the primary condition is operable. PGE ( 1 ) treatment also has been associated with reduction in pulmonary arterial pressure and increase in cardiac output in patients with left ventricular failure. In contrast, in isolated cases, patients with heart failure reportedly have developed pulmonary edema while receiving PGE ( 1 ). Therefore, to better define the effect of PGE ( 1 ) in heart failure, this double-blind study investigated the effect of PGE ( 1 ) on extravascular lung water in intensive-care patients with severe heart failure (New York Heart Association [NYHA] classes III and IV) and slightly above-normal extravascular lung water. Intravenous infusion of 60 microg PGE ( 1 ) (Prostavasin; Schwarz Pharma, Monheim, Germany) over a period of 2 hours caused no significant change in lung water relative to the baseline values (9.8 +/- 4.3 mL/kg before the infusion, 9.3 +/- 3.2 mL/kg after 1 hour, and 9.4 +/- 3.5 mL/kg after 2 hours) or to values observed in placebo-treated patients (6.5 +/- 3.3 mL/kg before the infusion, 7.1 +/- 2.7 mL/kg after 1 hour, and 7.0 +/- 3.2 mL/kg after 2 hours). Thus, administration of PGE ( 1 ) is unlikely to cause or worsen pulmonary edema in patients with severe heart failure (NYHA classes III and IV).
Subject(s)
Alprostadil/adverse effects , Extravascular Lung Water/drug effects , Heart Failure/complications , Pulmonary Edema/chemically induced , Adult , Aged , Double-Blind Method , Female , Humans , Male , Middle AgedABSTRACT
Prostaglandin E1 (PGE1) is a physiologic vasodilator, which is broadly used in the therapy of peripheral arterial occlusive disease. In addition, the successful use of PGE1 in patients with severe heart failure has been described in several studies, where a decrease in pulmonary artery pressure and an increase in cardiac output were observed. In contrast to these positive effects, the development of lung edema was reported in individual cases after the infusion of PGE1 in patients with heart disease. We therefore conducted a double-blind study to evaluate the effect of PGE1 on extravascular lung water (EVLW) in patients with heart failure (NYHA III-IV) and borderline increased EVLW. Seven patients received an infusion of PGE1 (Prostavasin) at a dosage of 60 micrograms over 2 hours, while in 6 patients (control group) isotonic saline was given as placebo. EVLW was measured using a double indicator method at time points -15 h, -9 h before and at the start of the infusion, 1 h and 2 h during infusion, as well as +1 h, +4 h, +7 h, and +22 h after termination of the infusion. Infusion of PGE1 did not alter EVLW both in comparison to pre-study values (9.8 +/- 4.3 ml/kg bw preinfusion. 9.3 +/- 3.2 ml/kg bw after 1 hour and 9.4 +/- 3.5 ml/kg bw after 2 hours) or to the control group (6.5 +/- 3.3 ml/kg bw preinfusion, 7.1 +/- 2.7 ml/kg bw after 1 hour and 7.0 +/- 3.2 ml/kg bw after 2 hours). We conclude that there is no evidence that PGE1 might contribute to the development, or worsening of lung edema by inducing extravascular lung water accumulation and can, thus, be savely given to patients with even a severe degree of heart failure (NYHA III-IV).
Subject(s)
Alprostadil/administration & dosage , Extravascular Lung Water/drug effects , Heart Failure/drug therapy , Pulmonary Edema/drug therapy , Vasodilator Agents/administration & dosage , Alprostadil/adverse effects , Blood Pressure/drug effects , Cardiac Output/drug effects , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Heart Rate/drug effects , Humans , Male , Middle Aged , Pulmonary Wedge Pressure/drug effects , Vasodilator Agents/adverse effectsABSTRACT
In a previous report we have described some properties of a novel flavoenzyme from a denitrifying Pseudomonas species which catalyzes the oxygen- and NAD(P)H-dependent conversion of 2-aminobenzoyl-CoA [Buder, R., Ziegler, K., Fuchs, G., Langkau, B. & Ghisla, S. (1989) Eur. J. Biochem. 185, 637-634]. In this paper, we report on the identification of the three products formed from 2-aminobenzoyl-CoA in this reaction. The spectroscopic data and the chemical properties of these compounds and those of their degradation products are compatible with the structures of 2-amino-5-hydroxybenzoyl-CoA, 2-amino-5-hydroxycyclohex-1-enecarboxyl-CoA and of 2-amino-5-oxocyclohex-1-enecarboxyl-CoA. The latter is the main product and was found to be rather unstable since it hydrolyzes and decarboxylates readily at pH less than 5. Ammonia is released from the decarboxylation product in the neutral pH range to yield 1,4-cyclohexanedione. Conditions were optimized such that the CoA thioester of 2-amino-5-hydroxybenzoate is the product obtained at greater than 98% yield. 2-amino-5-hydroxycyclohex-1-enecarboxyl-CoA is the product which is formed when the mixture of the reaction products is treated with sodium borohydride before separation.
Subject(s)
Mixed Function Oxygenases/metabolism , Chemical Phenomena , Chemistry , Chromatography, Thin Layer , Hydrogen-Ion Concentration , Hydrogenation , Hydroxylation , Magnetic Resonance Spectroscopy , SpectrophotometryABSTRACT
The reaction catalyzed by 2-aminobenzoyl-coenzyme-A monooxygenase/reductase from a denitrifying Pseudomonas sp. has been investigated. 2-Aminobenzoyl-CoA and 2-amino[carboxy-14C]benzoyl-CoA were synthesized enzymatically using 2-aminobenzoyl-CoA synthetase from the same organism. The product was purified by chromatography and characterized by ultraviolet/visible and 1H-NMR spectroscopy. The conversion of 2-aminobenzoyl-CoA catalyzed by the monooxygenase/reductase requires NADH and oxygen, and yields at least two different products depending on the relative concentration of NADH. At [NADH] less than Km (40 microM), i.e. [NADH]/[2-aminobenzoyl-CoA] approximately 0.02-0.05, the main product is probably a hydroxylated derivative of 2-aminobenzoyl-CoA, which is characterized by an absorbance maximum around 375 nm. When [NADH]/[2-aminobenzoyl-CoA] approximately 2-5, the predominant product is a non-aromatic coenzyme A thioester (lambda max approximately 320 nm). The stoichiometry in this case is 2.1-2.4 mol NADH oxidized (mol oxygen consumed)-1 (mol 2-aminobenzoyl-CoA metabolized)-1. The product is extremely unstable in the acidic pH range and undergoes decarboxylation in a few minutes at pH less than 5. Some degree of stabilisation is obtained upon reduction with sodium borohydride, probably resulting in a further reduced non-aromatic coenzyme-A thioester.
Subject(s)
Mixed Function Oxygenases/metabolism , Oxidoreductases/metabolism , Pseudomonas/enzymology , Catalysis , Chemical Phenomena , Chemistry , Chromatography, High Pressure Liquid , Enzyme Stability , Hydrogen-Ion Concentration , Hydroxylation , Magnetic Resonance Spectroscopy , NAD/pharmacology , Oxygen Consumption , SpectrophotometryABSTRACT
A novel aerobic mechanism of 2-aminobenzoate metabolism was proposed in a denitrifying Pseudomonas species. 2-Aminobenzoic acid is activated in a coenzyme-A-ligase reaction to 2-aminobenzoyl-CoA and this intermediate is dearomatized by a unique enzyme, tentatively named 2-aminobenzoyl-CoA monooxygenase/reductase. This paper describes the purification and some molecular, kinetic and spectral properties of this flavoenzyme which catalyzes the hydroxylation and reduction of 2-aminobenzoyl-CoA to an unknown non-aromatic compound. 2-Aminobenzoyl-CoA monooxygenase/reductase was purified 25-fold to a specific activity of 25 mumol.min-1.mg-1 protein using ammonium sulfate precipitation, DEAE-cellulose anion-exchange, hydroxylapatite and Mono Q FPLC anion-exchange chromatography. Superose 6 gel filtration for estimation of molecular mass resulted in one symmetrical protein peak corresponding to a molecular mass of 170 kDa. Several experimental data suggest that the protein is probably an alpha 2 dimer; however, it may exist in three dimeric forms, alpha alpha, alpha alpha' and alpha' alpha', where alpha' may be a subunit with a different conformation. Approximately 2 mol noncovalently bound FAD/mol enzyme was found, which in the absence of O2 was reduced by NADH. The enzyme was specific for the substrates 2-aminobenzoyl-CoA (Km less than or equal to 25 microM) and O2 (Km less than or equal to 5 microM), but less specific for the reduced pyridine nucleotides NADH (Km = 42 microM) or NADPH [Km = 500 microM; Vmax (NADH)/Vmax (NADPH) = 1.7:1]. The turnover number was 4250 min-1. The enzyme also reduced N-ethylmaleimide and maleimide with NAD(P)H. The substrate, the products and the reaction stoichiometry are described in two following papers.
Subject(s)
Mixed Function Oxygenases/isolation & purification , Oxidoreductases/isolation & purification , Pseudomonas/enzymology , ortho-Aminobenzoates/metabolism , Catalysis , Chromatography/methods , Electrophoresis, Polyacrylamide Gel , Flavoproteins/analysis , Hydroxylation , Kinetics , Oxidation-ReductionSubject(s)
Chronic Kidney Disease-Mineral and Bone Disorder/prevention & control , Kidney Failure, Chronic/complications , Bone and Bones/metabolism , Calcium/administration & dosage , Chronic Kidney Disease-Mineral and Bone Disorder/diet therapy , Chronic Kidney Disease-Mineral and Bone Disorder/etiology , Chronic Kidney Disease-Mineral and Bone Disorder/metabolism , Ergocalciferols/therapeutic use , Humans , Minerals/metabolism , Phosphates/administration & dosageABSTRACT
A total of 60 patients with chronic urinary tract infections were included in this comparative study. 29 patients received cinoxacin and 31 nalidixic acid for a period of ten days. There were five therapy failures in the cinoxacin group and nine in the nalidixic acid group. Drug-related side-effects were reported by 11 patients in the cinoxacin group and by 13 patients in the nalidixic acid group. Gastrointestinal and central nervous disturbances were the adverse reactions which occurred most frequently. In all cases side-effects disappeared quickly after therapy was discontinued.