deoxycholic-acid and Leukemia--Myeloid

Continuous administration of amphotericin B deoxycholate over 24 hours (24 h-D-AmB) is better tolerated than rapid infusions. However, toxicity and outcome have not been assessed in a homogenous patient population with acute myeloid leukaemia (AML). We retrospectively analysed renal function and outcome in all adult patients with AML undergoing intensive chemotherapy between 2007 and 2012 at our institution. We compared a patient group with exposure to 24 h-D-AmB to a patient group without exposure to 24 h-D-AmB. One hundred and eighty-one consecutive patients were analysed, 133 (73.5%) received at least 1 dose of 24 h-D-AmB, and 48 (26.5%) did not. Reasons for 24 h-D-AmB initiation were invasive fungal disease (IFD) in 63.5% and empirical treatment for febrile neutropenia in 36.5% of the cases. Most patients with IFD received an oral triazole drug at hospital discharge. Baseline characteristics were well matched. Amphotericin B deoxycholate over 24 hours was given for a median 7 days (interquartile range 3-13). Peak creatinine concentration was higher in the 24 h-D-AmB-group (104.5 vs. 76 μmol/L, P < .001) but normalized within 1 month after therapy (65.5 vs. 65 μmol/L, P = .979). In neither of the 2 groups, end-stage renal disease occurred. There was no difference in 60-day survival (90% vs. 90%) and 2-year survival (58% vs. 58%). Invasive fungal disease partial response or better was observed in 68% of the patients. We conclude that antifungal therapy with continuously infused amphotericin B deoxycholate is safe in patients with AML. An antiinfective strategy based on 24 h-D-AmB in first line followed by an oral triazole compound represents an economically attractive treatment option.

Topics: Acute Disease; Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Deoxycholic Acid; Drug Combinations; Female; Humans; Infusion Pumps; Leukemia, Myeloid; Male; Middle Aged; Mycoses; Neutropenia; Retrospective Studies; Survival Analysis; Treatment Outcome

Meningitis is a common evolution in progressive disseminated histoplasmosis in children, and is asymptomatic in many cases. In leukemia, the impaired of the T cells function can predispose to the disseminated form. The attributed mortality rate in this case is 20%-40% and the relapse rate is as high as 50%; therefore, prolonged treatment may be emphasized. We have described a child with acute myeloid leukemia (AML), that developed skin lesions and asymptomatic chronic meningitis, with a good evolution after prolonged treatment with amphotericin B deoxycholate followed by fluconazole.

Topics: Acute Disease; Adolescent; Amphotericin B; Antifungal Agents; Chronic Disease; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Fluconazole; Histoplasmosis; Humans; Immunocompromised Host; Leukemia, Myeloid; Male; Meningitis, Fungal; Treatment Outcome

Myeloid differentiated human leukaemia (HL-60) cells contain a soluble phospholipase C that hydrolysed phosphatidylinositol 4.5-bisphosphate and was markedly stimulated by the metabolically stable GTP analogue guanosine 5'-[gamma-thio]triphosphate (GTP[S]). Half-maximal and maximal (up to 5-fold) stimulation of inositol phosphate formation by GTP[S] occurred at 1.5 microM and 30 microM respectively. Other nucleotides (GTP, GDP, GMP, guanosine 5'-[beta-thio]diphosphate. ATP, adenosine 5'-[gamma-thio]triphosphate, UTP) did not affect phospholipase C activity, GTP[S] stimulation of inositol phosphate accumulation was inhibited by excess GDP, but not by ADP. The effect of GTP[S] on inositol phosphate formation was absolutely dependent on and markedly stimulated by free Ca2+ (median effective concn. approximately 100 nM). Analysis of inositol phosphates by anion-exchange chromatography revealed InsP3 as the major product of GTP[S]-stimulated phospholipase C activity. In the absence of GTP[S], specific phospholipase C activity was markedly decreased when tested at high protein concentrations, whereas GTP[S] stimulation of the enzyme was markedly enhanced under these conditions. As both basal and GTP[S]-stimulated inositol phosphate formation were linear with time whether studied at low or high protein concentration, these results suggest that (a) phospholipase C is under an inhibitory constraint and (b) GTP[S] relieves this inhibition, most likely by activating a soluble GTP-binding protein.

Topics: Cytosol; Deoxycholic Acid; Enzyme Activation; Granulocytes; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Diphosphate; Humans; Hydrogen-Ion Concentration; Hydrolysis; Inositol Phosphates; Kinetics; Leukemia, Experimental; Leukemia, Myeloid; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipids; Stimulation, Chemical; Tumor Cells, Cultured; Type C Phospholipases

Complement receptor activity for cell bound C3b and C3d was detected on plasma membrane fragments prepared by nitrogen cavitation from cultured human lymphoid cells. The activity of the membrane fragments reflected the activity of the whole cells in that cells which did not form rosettes (P3J and RPMI 4098) resulted in inactive membranes and cells with high rosette formation (NC37 and Raji) yielded highly active membrane fragments. Two test systems were devised to detect these receptor activities, namely a rosette inhibition and a hemagglutination assay. Solubilization of C3 receptors was accomplished by extraction of active plasma membrane fragments with 2 MKBr. Dissociation and reassociation experiments suggest C3b and C3d receptors to be highly complex molecular structures. It appears that these complement receptors on plasma membranes rely on both protein and lipid moieties for the expression of their activity.

Topics: Binding Sites; Burkitt Lymphoma; Butanols; Cell Fractionation; Cell Line; Cell Membrane; Cells, Cultured; Complement C3; Complement System Proteins; Deoxycholic Acid; Electrophoresis, Polyacrylamide Gel; Erythrocytes; Ethanol; Hemagglutination Tests; HEPES; Humans; Immune Adherence Reaction; Leukemia, Myeloid; Lipids; Lymphocytes; Neoplasm Proteins; Polyethylene Glycols; Sodium Dodecyl Sulfate; Sucrose