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S Just

Publications and source records attributed to S Just.

32 records · Page 2Linked to original sources
PubMed1994

A lupus anticoagulant neutralization procedure using the patient's own platelets.

An auto platelet neutralization procedure (APNP) which assists identification of lupus anticoagulants (LA) is described. Patient platelet-rich plasma is frozen then thawed (PRPF) and an activated partial thromboplastin time (aPTT) is performed on both platelet-poor plasma and PRPF. The degree of correction between the two plasmas is calculated and the percentage APNP is obtained. A lupus anticoagulant was suspected if a sample had a prolonged aPTT and at least two out of three of the following characteristics: (1) aPTT resistant to correction with equal parts normal plasma, (2) prolonged kaolin clotting time mixing test (delta KCT), (3) prolonged dilute Russell's Viper Venom Time that did not correct with normal plasma (DRVVR). Ten normal volunteers had mean (+/- SD) APNP of 7.7 +/- 4.3%. Fifty LA negative patients with normal aPTT, delta KCT and DRVVR, had a mean APNP of 10.0 +/- 6.3%. Twenty-eight patients suspected as LA positive had APNP > 25% with a mean of 39.0 +/- 7.5%. Twenty-one patients with prolonged aPTT attributed to factor deficiency had APNP < 25% with a mean of 6.3 +/- 12.0%. LA was also suspected in two other patients with prolonged aPTT that did not meet the above criterion but had APNP > 25%. In three patients with normal aPTT, LA was suspected and APNP ranged from 21 to 28%. An intermediate APNP range of 20-25% may be suggestive of LA in patients with normal aPTT. The APNP did not appear to be effected by platelet count in the samples tested unless the platelet count in PRP was less than 175 x 10(9)/1.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Platelets↗
PubMed1993

Duplex ultrasonography of superior mesenteric artery: interobserver variability.

The aim of this study was to evaluate the interobserver variability during duplex ultrasonographic investigation of the SMA. Eleven healthy volunteers were examined twice under the same conditions by two independent observers. Three basic Doppler wave parameters were assessed for the SMA: pV, edV, and rT. The tD was recorded for SMA and abdominal aorta (AotD) with B-mode imaging. The interobserver variability was very low for all parameters: pV = 13.5 cm/s; edV = 3.4 cm/s; rT = 0.01 s; tD = 0.3 mm; AotD = 0.5 mm, with corresponding 95% confidence intervals as follows: pV = 19 cm/s; edV = 4.7 cm/s; rT = 0.015 s; tD = 0.4 mm; and AotD = 0.75 mm. Coefficients of variation also showed very low dispersion for results obtained. Under the appropriate standard conditions for duplex sonographic examination of the mesenteric artery, assessments of basic Doppler wave parameters do not differ significantly between independent investigators. Reliable evaluation of B-mode distances can be obtained by replication of measurements.

Adult↗
PubMed1987

Clinical pharmacokinetics of the antitumor drug navelbine (5'-noranhydrovinblastine).

Eleven patients with advanced cancer received navelbine (15 mg/m2) as a single i.v. bolus injection. At least 1 week later, the patients were given a 2-fold increased dose of navelbine (30 mg/m2) and, for seven of them, the 30-mg/m2 dose was repeated after a delay longer than a week. After each administration, plasma and urine were collected for 72 h and monitored for navelbine concentration by radioimmunoassay. The comparison of dose-normalized plasma level profiles showed significant time dependence (P less than 0.05) in four of the seven assessable patients. Some patients also exhibited significant (P less than 0.05) nonlinear (dose dependent) kinetic profiles. Only 3 of the 10 appreciable patients were characterized by both time independent and linear profiles. However, the plasma concentration decay curves presented a triphasic shape similar to that obtained with other antitumor Vinca alkaloids and the data were consistent with a three-compartment pharmacokinetic model. The dose and/or time dependence evidenced for most of the patients did not result in marked changes in pharmacokinetic parameters among courses. The pharmacokinetics of navelbine were characterized by a high plasma clearance (0.27 to 1.49 liter.h-1.kg-1), a large distribution volume (8.2 to 48.2 liter.kg-1), and a long terminal half-life (22.1 to 67.8 h). Urine excretion was low (less than 7.9%). Thus, navelbine pharmacokinetics resembles that of other antitumor Vinca alkaloids.

Adult↗
PubMed1987

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate after methotrexate infusions.

Methotrexate was administered by IV infusion, 2g (1.19 +/- 0.05 g/m2) over 24 hours, to a homogeneous group of patients undergoing treatment for breast cancer. Three courses were given at three week intervals. Methotrexate and 7-hydroxy-methotrexate plasma and urine pharmacokinetics were investigated. The average terminal half-lives of methotrexate and 7-hydroxy-methotrexate in plasma were 15.02 and 15.19 hours respectively. The area under concentration-time curve was 723.8 +/- 196.4 microM x h for methotrexate and 598.1 +/- 212.5 microM x h for 7-hydroxy-methotrexate. The total average urinary excretions of methotrexate and 7-hydroxy-methotrexate over a 96 hour period were 52% and 5.4% respectively. Urinary clearance of methotrexate was 3.46 +/- 1.4 1/h. In contrast, urinary excretion of 7-hydroxy-methotrexate was not linear. These results confirm the protein binding of metabolite to serum albumin and may suggest that distribution of 7-hydroxy-methotrexate is different from unchanged drug or that the metabolite can be eliminated by another route, such as bile.

Aged↗
PubMed1986

Comparative pharmacokinetics of antitumor Vinca alkaloids: intravenous bolus injections of navelbine and related alkaloids to cancer patients and rats.

The kinetics of distribution and elimination in rats of the antitumor drug navelbine and of two of its analogues, Na-formyl navelbine and deacetyl navelbine amide, have been studied by radioimmunoassay and compared with the kinetics obtained with vinblastine and vincristine. Fitting to two-exponential curves was used to derive pharmacokinetic parameters. Clearance was found to parallel toxicity for all drugs: it increases from 0.19 1 h-1 kg-1 for vincristine to 0.41 for Na-formyl navelbine, 1.4 for vinblastine, 2.3 for navelbine, and 2.6 for deacetyl navelbine amide. Terminal half-lives were longer for the Na-formyl-substituted alkaloids (around 13 h) than for the others (8-10 h). We have also studied navelbine kinetics in cancer patients entered in recent navelbine clinical trials and found that navelbine pharmacokinetics are characterized by fast and extensive distribution, high clearance (0.92 +/- 0.27 1 h-1 kg-1), and a relatively long terminal half-life (31.2 +/- 4.4 h). Relationships between chemical structure, pharmacokinetic properties, and toxicity or therapeutic efficiency within the Vinca alkaloid series are discussed, together with the relevance of animal models such as the rat in the screening of new antitumor drugs.

Animals↗
PubMed1984

Radioimmunoassays of 7-hydroxymethotrexate and methotrexate.

Antisera against 7-hydroxymethotrexate were raised in rabbits by injection of 7-hydroxymethotrexate coupled to bovine serum albumin. A 125I-radiolabelled probe was synthesised by radioiodination of 7-hydroxymethotrexate conjugated to tyrosine methyl ester. We developed with these reagents a liquid phase radioimmunoassay for 7-hydroxymethotrexate in which methotrexate did not interfere significantly (cross-reactivity factor = 2.5 X 10(-4]. Similar techniques were used also for the development of a specific radioimmunoassay for methotrexate, which minimally cross-reacted with 7-hydroxymethotrexate. The assessment of the specificity of these assays showed that parallel monitoring of methotrexate and 7-hydroxymethotrexate in human plasma was possible. Coefficients of variation for duplicate determinations were less than 15% between 0.06 and 1.2 nmol/l for methotrexate and between 0.08 and 9 nmol/l for 7-hydroxymethotrexate. Methotrexate and its oxidative metabolite, 7-hydroxymethotrexate, were quantified in plasma of patients following high-dose infusion (2 g over 24 h) by radioimmunoassay and high performance liquid chromatography. The agreement between the two techniques was found satisfactory, as evaluated by least square regression analysis (slopes 1.007 +/- 0.046 for 7-hydroxymethotrexate and 0.937 +/- 0.046 for methotrexate with y-axis intercept not significantly different from zero). These radioimmunoassays permitted also the evaluation of the concentrations of methotrexate and 7-hydroxymethotrexate in plasma after intravenous bolus injection (50 mg/m2), and large inter-individual difference in both methotrexate and 7-hydroxymethotrexate kinetic behaviour could be observed.

Animals↗
PubMed1983

High-performance liquid chromatographic analysis of MTX, 7-OH-MTX and MTX derivatives: application to intracellular metabolism in tumor cells (HT 29).

In order to study the intracellular metabolism of Methotrexate (MTX) and the cytotoxicity of the antifolates, a specific paired-ion HPLC method has been developed which permits the simultaneous determination of DAMPA, MTX, 7-OH-MTX, MTX-G1, MTX-G2 and MTX-G3. Cells were incubated with 3H-MTX. The MTX metabolites were extracted, purified on SEP-PAK cartridges and further analysed by high-performance liquid chromatography (HPLC). The stationary phase was constituted by a C18 muBondapak and the mobile phase by 5 mM phosphate buffer (pH 7.4) containing 2.5 mM tetrabutylammonium nitrate. The elution was performed with a linear methanol gradient (20--30%). HPLC fractions were collected and radioactivity evaluated by beta counting (retention times: DAMPA = 12.93 min; MTX = 18.29 min; 7-OH-MTX = 21.13 min; MTX-G1 = 22.69 min; MTX-G2 = 26.81 min; MTX-G3 = 30.61 min). This analytical procedure was applied to separate and characterize multiple forms of MTX polyglutamate derivatives in HT 29, a human adenocarcinoma cell line varying the incubation time (4--18 h) and MTX concentration (0.6--10.6 micrometer). The incorporation process seems to be characteristic of a cell line resistant to MTX. The incorporation were very low and after a 4-h exposure time only 5% of the MTX was converted to polyglutamates. Between 1.6 and 10.6 microM MTX, no difference was observed in the polyglutamization. The defect in the incorporation of the drug and in the metabolization process in vitro could partially explain the failure of the MTX treatment in colorectal cancer.

Adenocarcinoma↗
PubMed1983

In vitro approach to 7-hydroxymethotrexate interaction on methotrexate metabolism as tool of pharmacokinetic study.

Methotrexate (MTX), a widely used antineoplastic agent, is metabolized to a non-active derivative, 7-OH-MTX, and to some active poly-gamma-glutamyl derivatives (MTX-Gn) which are retained within cells. Pharmacokinetic studies in humans indicate (i) a higher concentration of 7-OH-MTX than of MTX in plasma after a 24-h infusion and (ii) a time-dependent relationship for MTX and 7-OH-MTX kinetics in plasma and urine which might be explained by the variation of MTX metabolism. The intracellular metabolism of MTX and 7-OH-MTX has been investigated using a specific ion-paired method of high-performance liquid chromatography (HPLC) which permits the simultaneous determination of DAMPA, MTX, 7-OH-MTX and their respective polyglutamate derivatives. The formation of 7-OH-MTX polyglutamates and the possible effect of 7-OH-MTX on the transport and/or metabolism of the unchanged MTX in a human acute lymphoblastic leukaemia cell line (Molt 4) have been studied. After incubation of the cells to 1 microM (3H) 7-OH-MTX, four radiolabelled peaks, representing 75% of the intracellular 3H, were converted to 7-OH-MTX upon exposure to hog kidney conjugase indicating the formation of 7-OH-MTX polyglutamyl derivatives. The effects of 7-OH-MTX on MTX-PG formation were analysed after simultaneous incubation of the cells to 1 microM (3H) MTX and 10 microM 7-OH-MTX. The formation of the higher glutamyl derivatives, MTX-G3 and MTX-G4 was completely inhibited and the total intracellular accumulation of the MTX-PG's decreased by 35% compared to control. These data suggest that the 7-OH-MTX and the 7-OH-MTX-PG might modify the chemotherapeutic activity of this agent in vivo.

Cell Line↗
PubMedDate not supplied

Metabolism of cyclosporin A. I. Study in freshly isolated rabbit hepatocytes.

The metabolism of cyclosporin A (CsA), a widely used immunosuppressive agent, was evaluated in freshly isolated rabbit hepatocytes by HPLC which separated CsA from its major group of derivatives, e.g. "first generation" metabolites (monohydroxylated and N-demethylated) and "second generation" derivatives (dihydroxylated and dihydroxy-N-demethylated). After exposure of hepatocytes to radiolabeled CsA (0.5 mg/liter), CsA was rapidly accumulated inside the cells and metabolized. The dihydroxylated metabolites represent the major intracellular forms after 1 hr. CsA metabolites synthesized inside the cells are then rapidly detected in the extracellular compartment. Unchanged drug and the various metabolites are concentrated inside the cells with transmembrane chemical gradients ranging between 20:1 and 40:1. Transport and metabolic processes for CsA have been evaluated over the following CsA extracellular concentration range, 0.1-10 mg/liter. Metabolism appears to be the rate-limiting step. The apparent affinity constant of CsA for the enzyme system involved in its metabolism is approximately 15 microM. Besides the lipophilicity of the molecule, which is responsible for the retention of CsA and its metabolites in the intracellular compartment, the presence of a binding component(s) in the hepatocytes was also demonstrated. CsA and its metabolites seem to have similar affinities for this binding site. These studies demonstrate that CsA is rapidly transformed inside the hepatocytes to various metabolites which may play an important role in the pharmacological activity of the drug and/or in its clinical toxicity.

Animals↗
PubMedDate not supplied

Metabolism of cyclosporin A. II. Implication of the macrolide antibiotic inducible cytochrome P-450 3c from rabbit liver microsomes.

The in vitro metabolism of cyclosporin A (CsA) was investigated by rabbit liver microsomes in order to identify the form(s) of cytochrome P-450 responsible for its biotransformation. Metabolites including monohydroxy-, N-demethylated, dihydroxy- and dihydroxy-N-demethylated derivatives were detected and quantified by HPLC from incubates of liver microsomes, CsA, and NADPH. Kinetic data indicated that monohydroxy- and N-demethylated derivatives were first generated and then served as substrates for production of dihydroxylated derivatives. Liver microsomes from phenobarbital-, beta-naphthoflavone-, triacetyloleandomycin-, erythromycin-, or rifampicin-treated and untreated rabbits were investigated, but only microsomes from animals treated with macrolide antibiotics (specific inducers of form P-450 3c) exhibited a type I binding spectrum upon CsA addition (Ks = 1.5 +/- 0.5 microM) and extensively metabolized the drug to all groups of derivatives (Km = 5.0 +/- 0.5 microM, Vmax = 1.0 +/- 0.2 nmol/mg/min). A linear correlation existed between CsA oxidase activity and P-450 3c specific content. Antibodies to P-450 3c strongly inhibited CsA oxidase activity of microsomes from macrolide antibiotic-induced animals, whereas antibodies to other forms, including P-450 2, 3b, 4, and 6, did not. When highly purified forms of P-450, including P-450 2, 3b, 3c, and 4, were assayed in a reconstituted system, only P-450 3c exhibited type I binding spectrum upon CsA addition (Ks = 1.4 +/- 0.5 microM) and extensively metabolized the drug to all derivatives. We conclude that the macrolide antibiotic-inducible form P-450 3c (or P-450 3c related from(s)) is responsible for the major part of CsA metabolism by rabbit liver microsomes.

Animals↗
PubMedDate not supplied

Chest radiography after minor chest trauma.

The results of chest radiography in 581 patients with blunt minor thoracic trauma were reviewed. Frontal and lateral views of the chest indicated pathology in 72 patients (12.4%). Pneumothorax was present in 16 patients; 4 had hemothorax. The physical examination and the results of chest radiography were not in accordance because in 6 (30%) of the 20 patients with hemo/pneumothorax the physical examination was normal. Consequently there is wide indication for chest radiography after minor blunt chest trauma.

Adolescent↗