Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have evaluated a method to simultaneously assess three major processes involved in hepatic drug clearance using three model substrates administered simultaneously as a 5-minute intravenous injection. Lorazepam, indocyanine green, and antipyrine are used to assess conjugation, liver blood flow, and microsomal oxidative metabolism, respectively. These substrates were administered individually and as a mixture to 10 healthy adult male volunteers to determine if clearances of any of the compounds were affected by simultaneous administration. Mean clearances of the substrates were not different when administered alone (9.97, 0.78, and 0.53 ml/min/kg) vs. together (11.5, 0.89, and 0.52 ml/min/kg), using a paired t test. Since we were using this method to assess hepatic drug clearance in children with leukemia, the effect of short-term allopurinol was assessed. The three model substrates were administered to the volunteers after 0, 1, 8, and 22 days of treatment with allopurinol, 200 mg t.i.d. There was no change in mean clearance of any of the three compounds at any point during allopurinol treatment (repeated-measures ANOVA). We conclude that this technique is a simple and valid method to simultaneously assess three major processes involved in hepatic drug clearance and is not affected by up to 22 days of oral allopurinol treatment. This simple technique, requiring a single set of blood samples, has potential applications in the assessment of developmental changes in hepatic drug clearance, as well as the effects of environmental, therapeutic, and pathophysiologic factors on three major processes involved in hepatic drug clearance.
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PMID:Simultaneous administration of multiple model substrates to assess hepatic drug clearance. 358 48

This report presents the results of a randomized parallel design comparative study of the serum concentrations of fluconazole and itraconazole after administration of 100 mg orally to patients with leukaemia. Each group consisted of ten patients. The antimycotic drugs were administered with a standard breakfast immediately before the start of chemotherapy (day one) and on days eight and fifteen. No significant differences (p > 0.05; ANOVA) in the pharmacokinetic parameters of fluconazole (AUC, Cmax, Tmax) were found during the three days of the trial. It is concluded that there is no clinically important pharmacokinetic interaction between fluconazole and the chemotherapeutic agents given to this group of patients. A pharmacokinetic interaction between fluconazole and the fever suffered by some of the patients also seems unlikely. No significant differences (p < 0.05; ANOVA) in the pharmacokinetic parameters of itraconazole (AUC, Cmax, Tmax) were found during the three days of the trial, although the statistical power of the data was low. The significantly greater variability of all pharmacokinetic parameters for itraconazole than for fluconazole and the sharp increases and decreases in AUC during the course of the trial found for some patients in the itraconazole group suggest the need for caution in this group of patients.
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PMID:Administration of the antimycotic agents fluconazole and itraconazole to leukaemia patients: a comparative pharmacokinetic study. 792 99

Body wasting (cachexia) is a common feature of cancer and a major cause of morbidity and mortality. The mechanisms underlying cachexia are largely unknown, and studies in experimental animals have focused mainly on solid tumors. Therefore, the objective of the present study was to quantify and investigate cachexia in experimentally induced T-cell leukemia in the rat. Induction of leukemia by serial passage (injection of cervical lymph node suspension) resulted in a rapid increase in white blood cell (WBC count, hypertrophy of the spleen (by day 11), and severe morbidity within 17 to 18 days. Body weight gain and food intake declined steadily in leukemic animals from day 12, although weight loss was significantly greater in pair-fed, nonleukemic animals. However, leukemic rats had a lower body fat content and higher water content than pair-fed animals on day 18, so the measurement of body weight significantly underestimated the severity of cachexia. Resting oxygen consumption (VO2), measured during the light phase, declined in pair-fed animals from day 13, but was elevated in leukemic rats on days 12 to 18 by 25% (P < .05, one-way ANOVA) compared with pair-fed rats and by 7% (P < .05, one-way ANOVA) relative to free-feeding controls. Hypermetabolism was associated with an increase in brown adipose tissue (BAT) activity (74% and 89%, respectively, P < .05, one-way ANOVA) in leukemic rats compared with control and pair-fed groups. Effects of leukemia on VO2 and BAT were prevented by administration of the adrenergic antagonist, propranolol. These results indicate that T-cell leukemia in the rat results in rapid and severe cachexia, which is largely due to marked hypophagia, but is also accompanied by inappropriately high rates of energy expenditure that are mediated by sympathetic activation of BAT thermogenesis.
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PMID:Mechanisms of cachexia induced by T-cell leukemia in the rat. 862 10

The type and ability to differentiate in vitro of cells found in blastocysts of two marsupials were examined. Thirteen unilaminar blastocysts on Day 7 to Day 12 of gestation and 24 bilaminar blastocysts on Day 16 and Day 18 of gestation were collected from 11 brown antechinus, Antechinus stuartii. A total of of 77 unilaminar blastocysts on Day 5 and Day 6 of gestation and a total of 61 bilaminar blastocysts on Day 6 and Day 7 of gestation were collected from 40 stripe-faced dunnarts, Sminthopsis macroura. Pluriblast and trophoblast cells, confined to separate hemispheres, were found in unilaminar and bilaminar blastocysts, establishing that the blastocyst epithelium was not a protoderm. Hypoblast cells were found only in bilaminar blastocysts. Pluriblast and hypoblast cells did not differentiate or proliferate in up to eight weeks in culture. A small number of trophoblast cells transformed to a multinucleate state but the remainder did not proliferate or differentiate further. The presence of murine leukaemia inhibitory factor or medium conditioned by exposure to marsupial fibroblast feeder layer was not required for the maintenance of an undifferentiated state. Differentiation, proliferation and attachment of cells were not influenced by the presence of the yolk mass or the egg coats in culture. The time taken for attachment of dissociated cells varied significantly between cultures with no substrate and with collagen, fibronectin or laminin (P = 0.001, ANOVA) but did not vary significantly between substrates. The substrates did not influence the state of differentiation of the cells.
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PMID:The type and differentiation of cells in vitro from unilaminar and bilaminar blastocysts of two marsupials, Antechinus stuartii and Sminthopsis macroura. 887 95

Cranial irradiation (CI) is an effective way to prevent central nervous system (CNS) leukemia in children with acute leukemia (AL). However, it is still unclear whether the antileukemic effect of CI is mediated by alteration of blood-brain barrier (BBB) permeability and consequent increased levels of systemically administered drugs or whether it simply results from a direct cytolytic effect on leukemic cells in the meninges at diagnosis. We evaluated the influence of CI on BBB permeability to 1-beta-D-arabinofuranosylcytosine (ara-C) in 23 children with AL undergoing CI for CNS leukemia prophylaxis. CI was administered at 18 Gy (16 patients) and 24 Gy (7 patients). ara-C levels were measured in cerebrospinal fluid (CSF) and plasma before, during, and after CI. Two doses were evaluated: 75 mg/m2/day (12 patients) and 480 mg/m2/day (11 patients). CSF and plasma ara-C levels were measured when steady state was achieved. CSF:plasma ratios, obtained before, during, and after CI, were compared by an ANOVA model for repeated measures and by Tukey's test. At the 75-mg/m2/day dose, the mean values of ara-C CSF:plasma ratios before, during, and after CI were 0.20, 0.27, and 0.27, respectively. At the 480-mg/m2/day dose, the mean CSF:plasma ratios before, during, and after CI were 0.09, 0.12, and 0.13, respectively. No significant differences were observed when CSF:plasma ratios were compared before and during, during and after, and before and after CI. Our results indicate that CI at the doses used for CNS prophylaxis in AL does not significantly alter the BBB as far as ara-C is concerned.
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PMID:Cranial irradiation and permeability of blood-brain barrier to cytosine arabinoside in children with acute leukemia. 951 54

The relevance of chronopharmacology for improving tolerability and antitumor efficacy of the antimitotic drug vinorelbine was investigated in female B6D2F1 mice standardized with 12 h of light and 12 h of darkness. A single i.v. vinorelbine dose (26 mg/kg) was given to 279 mice at 7, 11, 19, or 23 hours after light onset (HALO). Bone marrow necrosis and leukopenia were nearly twice as large in the mice injected at 7 HALO as compared with those treated at 19 HALO (ANOVA: p <.001 and p = 0.004, respectively). The relevance of vinorelbine dosing time for antitumor efficacy was assessed in 672 P388 leukemia-bearing mice. Vinorelbine was injected as a single dose (20, 24, 26, or 30 mg/kg) or weekly (20, 24, 26, or 28 mg/kg/injection x 3) at one of six circadian times, 4 h apart. A significant correlation between single dose and median survival time was limited to vinorelbine administration at 19 or 23 HALO. An increase in the vinorelbine weekly dose shortened median survival time in the mice treated at 7 HALO (20 mg/kg: 29 days; 24 mg/kg: 17 days; and 26 mg/kg: 6 days) but significantly improved it in those treated at 19 HALO (20 mg/kg: 28.5 days; 24 mg/kg: 32 days; and 26 mg/kg: 36 days). The study demonstrates the circadian rhythm dependence of maximum tolerated dose and the need to deliver maximum tolerated dose at the least toxic time to achieve survival improvement through chronotherapy. This may be obtained with an evening administration of vinorelbine in cancer patients.
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PMID:Relationship between circadian rhythm of vinorelbine toxicity and efficacy in P388-bearing mice. 1008 9

Elevated plasma concentrations of endogenous thrombin generation markers and thrombotic events have been reported in children with leukemia. The aim of this study was to evaluate the effects of cancer and its treatment on thrombin generation (TAT levels) in children with acute lymphoblastic leukemia (ALL). The authors evaluated 32 children (23 M, 9 F) aged between 1 and 15 years (mean 6) affected by ALL (immunophenotypic subgroups: 16 common, 7 T, and 9 pre-B type). In all patients TAT levels at onset and after 5-6 doses of L-asparaginase were evaluated. TAT levels were higher in patients both at onset (13.04 +/- 10.90 ng/L) and after the 5-6 doses of L-asp (19.41 +/- 11.05 ng/L) with respect to controls (4 +/- 1 ng/L) (p < .001 and p < .001). TAT levels after 5-6 doses of L-asp were higher than those at onset (p < .001). Factorial ANOVA showed that at onset there was a significant effect of leukemia immunophenotypic subgroups upon TAT levels (p < .05) and no effect of inherited thrombotic risk factors. These results indicate that in children with ALL an important role is played by acquired thrombotic risk factors, among which the indirect cancer procoagulant activity has its importance.
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PMID:Thrombin generation in children with acute lymphoblastic leukemia: effect of leukemia immunophenotypic subgroups. 1112 98

The objective of this study was to investigate whether folinic acid supplementation would protect young mice against suppression of growth by methotrexate (MTX). Four equal groups of Balb/c young male mice (5 animals in each group; mean+/-SD body weight 9.64+/-0.85 g, in their rapid growth phase) were subjected to the following drug treatment: One group was given MTX (3.5 mg/kg body weight) intraperitoneally on every 2nd day, another received folinic acid (7.0 mg/kg body weight) intraperitoneally every 2nd day. The third group was given both of these drugs (MTX on every 2nd day and folinic acid 8 h post-MTX injection). The fourth group was injected with physiological saline every other day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 3 weeks. After this period mice were sacrificed and liver, spleen and kidneys were excised, weighed and analyzed for MTX and dihydrofolate reductase activity. A small segment of the proximal part of small intestine and small pieces of liver and kidney were also removed to study morphological changes. Compared to the groups, which received folinic acid alone, folinic acid plus MTX or physiological saline, mean increase in body weight (6.8+/-0.8 g) of mice over a period of 3 weeks was minimal in the group receiving MTX alone (one-way ANOVA p=0.0001). The mean weights of liver and kidney in this group receiving MTX alone were also found to be significantly less than the mean weights of these organs in the 3 groups (p<0.001). The negative effect on growth of animals appears not only due to malabsorption but inhibition of pathway of de novo DNA synthesis may also be involved. This is supported by loss of villous pattern in small intestine of mice treated with MTX alone and increased accumulation of free MTX and decreased dihydrofolate reductase in the liver of the group receiving MTX alone as compared with the group receiving MTX plus folinic acid. The data indicate that the administration of folinic acid protects mice against suppression of growth by MTX. On the basis of these observations it can be deduced that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving MTX over a long period of time might be at a risk of experiencing short-term suppression of growth, however they could benefit from supplementation with folinic acid.
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PMID:Folinic acid protects against suppression of growth by methotrexate in mice. 1174 19

Few large demographic studies of acute myeloid leukemia (AML) are derived from population-based registries. Demographic and karyotypic data were provided for AML cases from two regional leukemia registry databases in Scotland and the Northern Region of England. A population-based dataset was compiled, comprising 1709 patients aged >16 years (1235 North England/474 Scotland patients). The most common cytogenetic abnormalities involved chromosomes 5 and/or 7 (17%). Patients with the following abnormal chromosome 5/7 combinations: -5, del(5q), -5/-7 and del(5q)/-7 represented a significantly older population (P < 0.01, ANOVA). t(8;21) was the only 'favourable' karyotype found in older age. Karyotypic complexity varied within chromosome 5/7 combination groups; those containing -5, -5/-7, -5/del(7q), del(5q)/-7 or del(5q)/del(7q) combinations were significantly more frequently complex than those containing -7 and del(7q) (P < 0.01, chi2 test). Additional recurring cytogenetic abnormalities within complex karyotypes containing chromosome 5/7 combinations included (in order of frequency), abnormalities of chromosomes 17, 12, 3 and 18. Complex karyotypes not involving chromosomes 5 or 7 represented 30% of all complex karyotypes, occurred in younger patients than those involving chromosomes 5 and 7, and frequently included additional trisomy 8 (26%). In conclusion, we describe subgroups within adverse karyotypes, with different demographics, degree of complexity and additional chromosome abnormalities.
Leukemia 2006 Mar
PMID:Population-based demographic study of karyotypes in 1709 patients with adult acute myeloid leukemia. 1642 77

To date, there is scant information on in vivo induction of chromosomal damage by heavy ions found in space (i.e. 56Fe ions). For radiation-induced response to be useful for risk assessment, it must be established in in vivo systems especially in cells that are known to be at risk for health problems associated with radiation exposure (such as hematopoietic cells, the known target tissue for radiation-induced leukemia). In this study, the whole genome multicolor fluorescence in situ hybridization (mFISH) technique was used to examine the in vivo induction of chromosomal damage in hematopoietic tissues, i.e. bone marrow cells. These cells were collected from CBA/CaJ mice at day 7 following whole-body exposure to different doses of 1 GeV/amu 56Fe ions (0, 0.1, 0.5 and 1.0 Gy) or (137)Cs gamma rays as the reference radiation (0, 0.5, 1.0 and 3.0 Gy, at the dose rate of 0.72 Gy/min using a GammaCell40). These radiation doses were the average total-body doses. For each radiation type, there were four mice per dose. Several types of aberrations in bone marrow cells collected from mice exposed to either type of radiation were found. These were exchanges and breaks (both chromatid- and chromosome-types). Chromosomal exchanges included translocations (Robertsonian or centric fusion, reciprocal and incomplete types), and dicentrics. No evidence of a non-random involvement of specific chromosomes in any type of aberrations observed in mice exposed to 56Fe ions or 137Cs gamma rays was found. At the radiation dose range used in our in vivo study, the majority of exchanges were simple. Complex exchanges were detected in bone marrow cells collected from mice exposed to 1 Gy of 56Fe ions or 3 Gy of 137Cs gamma rays only, but their frequencies were low. Overall, our in vivo data indicate that the frequency of complex chromosome exchanges was not significantly different between bone marrow cells collected from mice exposed to 56Fe ions or 137Cs gamma rays. Each type of radiation induced significant dose-dependent increases (ANOVA, P < 0.01) in the frequencies of chromosomal damage, including the numbers of abnormal cells. Based upon the linear-terms of dose-response curves, 56Fe ions were 1.6 (all types of exchanges), 4.3 (abnormal cells) and 4.2 (breaks, both chromatid- and chromosome-types) times more effective than 137Cs gamma rays in inducing chromosomal damage.
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PMID:mFISH analysis of chromosomal damage in bone marrow cells collected from CBA/CaJ mice following whole body exposure to heavy ions (56Fe ions). 1748 87


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