Search PubMed⌕ Search

Biomedical subjects

P Sie

Publications and source records attributed to P Sie.

At least 37 records · Page 2Linked to original sources
PubMed1992

[Biological reference values in the human fetus. 106 cord blood sampling in utero].

The authors give biological reference figures obtained from 106 fetuses that were sampled in utero between the 20th and 34th week of amenorrhoea. These fetuses were considered to be normal because there was no clinical or ultrasound evidence of an abnormality. Furthermore the biological values sought in antenatal testing and the absence of all pathology in the first year of life, confirmed that these were normal fetuses. The result has been expressed as a global figure for all 106 fetuses; then they have been divided up according to the gestational age groups (20-23, 24-27, and 28-34 weeks of amenorrhoea). These biological reference values and their changes as the age of the fetuses advanced are discussed and compared with the figures reported in the literature.

Age Factors↗
PubMed1992

Pharmacologic properties of an unfractionated heparin butyryl derivative with long-lasting effects.

This article reports on the pharmacologic properties of an O-acylated butyryl derivative (C4-UH) of unfractionated heparin (UH). In a purified system, the ability of C4-UH to catalyze the inhibition of thrombin and of factor Xa in the presence of antithrombin III was similar to that of UH. Addition of albumin (10 mg/ml) to the reagents reduced the antithrombin and antifactor Xa catalytic potency of C4-UH 68-fold and 20-fold, respectively, and did not alter those of UH. As judged from the prolongation of the activated partial thromboplastin time and the thrombin clotting time, the anticoagulant activities of C4-UH were two times weaker than those of UH. After calibration against UH, the antifactor Xa-specific and antithrombin-specific activities were two and 6.6 times lower, respectively. After bolus intravenous injection into rabbits, the apparent clearances of C4-UH were reduced 2.4 (antifactor Xa activity) and 3.2 times (antithrombin activity) in comparison with those of UH. This property accounted for the higher plasma concentrations generated during a constant infusion of the same dose. In the Wessler thromboplastin model, the minimum doses providing the maximum antithrombotic effect after bolus injection were equivalent for both compounds when expressed as antifactor Xa units; the duration of the antithrombotic effect of this derivative was prolonged, whereas the hemorrhagic potential was unaffected. This study opens a new concept for heparin derivatives having lower clearances and long-lasting effects. These properties could be linked to nonspecific binding of C4-UH to plasma proteins, thereby reducing the amount of free compound available to interact with antithrombin III.

Animals↗
PubMed1991

[Influence of protein S deficiency on the arterial thrombosis risk].

Protein S is the cofactor of activated protein C which, together with the antithrombin system, is a major regulator of coagulation. Congenital protein S deficiency is an important risk factor for venous thrombosis. In this study of 105 patients with protein S deficiency, 64 had one of several thromboembolic accidents, including 14 arterial thrombotic accidents involving the central nervous system or the myocardium. These accidents occurred in young subjects (mean age: 25 +/- 13 years) only one-third of whom had another risk factor. This high frequency of arterial thrombosis associated with protein S deficiency calls for a prospective study in young subject with cerebral vascular accident or myocardial infarction.

Adolescent↗
PubMed1991

Prothrombin fragment 1 + 2, thrombin-antithrombin III complexes and D-dimers in acute deep vein thrombosis: effects of heparin treatment.

Plasma levels of prothrombin fragment 1 + 2 (F 1 + 2), of thrombin-antithrombin III complexes (TAT) and of D-dimers were evaluated at several time intervals in 15 patients affected by acute proximal deep vein thrombosis, complicated or not by pulmonary embolism, and treated by conventional heparin therapy for 9 d. The mean levels of the three markers remained significantly increased throughout the period of observation, except for F 1 + 2 on day 9, when compared to normal values established in a population of normal healthy blood donors. However, whereas heparin significantly decreased the plasma levels of F 1 + 2 and of TAT complexes in less than 3 d. D-dimer levels were not significantly altered. Significant correlations were observed between the plasma levels of the three markers but they were not correlated to the actual intensity of heparin treatment evaluated as the activated partial thromboplastin time prolongation. These results indicate that heparin improves the hypercoagulable state associated with a deep vein thrombosis within the first days of treatment as indicated by TAT and F 1 + 2. They also account for the performances of D-dimer assay for the diagnosis of deep vein thrombosis in patients already receiving heparin, a common situation in routine hospital practice.

Acute Disease↗
PubMed1991

Pharmacokinetics of a low molecular weight heparin (Fraxiparine) in various stages of chronic renal failure.

This study investigates the pharmacokinetics of a low molecular weight heparin (Fraxiparine) after a single bolus intravenous injection of 100 antifactor Xa IC U.kg-1 in 3 groups of patients affected by chronic renal insufficiency of various severity: group A (n = 7) was composed of hemodialyzed patients; groups; B (n = 7) had a creatinine clearance ranging from 10 to 20 ml.min-1 and group C (n = 5) from 30 to 50 ml.min-1. There was no significant difference between the pharmacokinetic parameters determined in the 3 groups of patients and no correlation between these parameters and the creatinine clearance. However, when compared to the values established in a group of 12 healthy volunteers, the half-life of disappearance of the antifactor Xa activity was significantly prolonged. Therefore it is advised to monitor antifactor Xa activity in patients affected by chronic renal insufficiency of any severity to avoid a possible accumulation phenomenon.

Adult↗
PubMed1990

Leishmania donovani: cell-surface heparin receptors of promastigotes are recruited from an internal pool after trypsinization.

With the use of [3H]heparin, we recently demonstrated that Leishmania donovani promastigotes express a cell-surface receptor that is specific for the glycosaminoglycan heparin (Mukhopadhyay et al. 1989, The Biochemical Journal, 264, 517-525.). Treatment of the parasite with trypsin abolishes 75-90% of this [3H]heparin-binding activity. When trypsinized promastigotes were resuspended in fresh culture medium in the absence and presence of cycloheximide (10 micrograms/ml), approximately 25-30% of the original heparin-binding capacity was restored within 1 hr, indicating that recruitment of receptors from an internal pool occurred without de novo protein synthesis. Scatchard analysis of the regenerated receptor revealed that the number of regenerated binding sites per cell was 2.3 x 10(5); these sites have a binding affinity of 6.7 x 10(-7) M. Like the native heparin receptors on the surface of freshly isolated cells, the receptors recruited after trypsinization are also highly specific for heparin, as a 25-fold excess of four other glycosaminoglycans displaced less than 10% of bound [3H]heparin from the trypsinized cells. The structural requirements of the ligand heparin, namely the number of monosaccharide units and degree of sulfation, were compared for both the native and regenerated receptor: for both receptors, oversulfated polysaccharide heparin fragments of at least six to eight sugar residues were most efficient at displacing [3H]heparin. The concentrations of oligosaccharide fragments required to displace 50% of [3H]heparin were 0.32 and 0.035 microM for the hexa- and octasaccharides, respectively. Colloidal gold-labeled heparin was bound to promastigotes and visualized by electron microscopy. This analysis revealed that the heparin bound almost exclusively to the flagella of control cells (not subjected to trypsin) and those which had regenerated receptor after trypsinization. The physiological significance of this heparin-binding activity on the surface of promastigotes is discussed.

Animals↗
PubMed1990

Pharmacokinetics of heparin and low molecular weight heparin.

After parenteral injection, heparin is removed from the blood via two mechanisms, saturable and non-saturable. The saturable mechanism represents clearance by the reticuloendothelial system and endothelial cells, to which heparin binds with a high affinity. The non-saturable mechanism is represented by renal excretion. The contribution of the two mechanisms to the clearance of heparin varies according to the dose delivered and the molecular weight of the heparin preparation. At low doses, unfractionated heparin (UH) is removed mainly via the saturable mechanism, while at higher doses the contribution of the non-saturable mechanism to its clearance becomes pre-eminent. This model accounts for the major pharmacokinetic properties of UH. After bolus intravenous injection of low doses, UH disappears from the blood exponentially with a dose-dependent half-life; at higher doses, UH disappears with a concave-convex pattern. Under continuous intravenous infusion there is a non-linear relationship between the dose of UH injected and the steady-state plasma concentration. After subcutaneous injection, the bioavailability of the anti-factor Xa activity increases with the dose delivered and tends toward 100% at high doses. In contrast, low molecular weight heparins (LMWH) are mainly removed by non-saturable renal excretion. This explains the dose independence of the pharmacokinetic parameters of LMWH, the excellent bioavailability of the subcutaneous route at any dose, and the prolongation of LMWH half-life in cases of chronic renal insufficiency. However, the model does not explain the large interindividual variability of the pharmacokinetic parameters of both UH and LMWH.

Animals↗
PubMed1990

Antithrombotic potencies of heparins in relation to their antifactor Xa and antithrombin activities: an experimental study in two models of thrombosis in the rabbit.

Our purpose was to determine the relative contribution of the antifactor Xa and antithrombin activities of heparin to its antithrombotic potency. The antithrombotic activities of unfractionated heparin (UH), two low molecular weight heparins (LMWH, CY 216 and CY 222) with increasing anti-factor Xa/antithrombin ratio and a synthetic pentasaccharide (PS) with high affinity to antithrombin III and no antithrombin activity were evaluated. In the Wessler-thromboplastin model, the most potent antithrombotic agent, on a weight basis, was UH followed by CY 216, CY 222 and the PS which was 40 times less potent than UH. On an antithrombin unit basis, the antithrombotic potencies of UH, CY 216 and of CY 222 were equivalent. Thus, in this model, the antithrombotic effect results from the catalytic action of UH or LMWH on thrombin inhibition. In the Wessler-serum model, on a weight basis, the antithrombotic effectiveness of UH was unchanged, those of CY 216 and CY 222 were doubled, and that of the PS was increased 10 times. On an anti-factor Xa unit basis, CY 216 was as effective as UH, and PS as effective as CY 222. On an antithrombin unit basis, CY 216 and CY 222 were equivalent and more potent than UH. Thus, in this model, the antifactor Xa activity of heparin becomes important for its antithrombotic property. After a single subcutaneous injection of 1000 antifactor Xa U/kg, the antithrombotic effects of UH were maintained for more than 14 h in the two models. After injection of the same dose of CY 216 significant antithrombotic effects were observed only for 9 h, in the Wessler-thromboplastin model but for 18 h in the Wessler-serum model. At that time, no detectable antithrombin activity was measurable in the plasma while 0.11 units of antifactor Xa activity/ml was detected. Thus, the relative contribution of the anti-factor Xa and antithrombin activities to the antithrombotic effect of a LMWH differs according to the nature of the thrombogenic stimulus.

Animals↗
PubMed1990

Distribution of 16 hemostatic laboratory variables assayed in 100 blood donors.

The aim of the present study was to establish the normal range of 16 hemostatic variables routinely assayed in our laboratory. We therefore measured the activated partial thromboplastin time, the prothrombin time, and the plasma levels of fibrinogen (Fg), factors II, V, VII + X, VIII, IX, XI, XII, von Willebrand factor-antigen (vWf), protein C (PC), total (tPS) and free (fPS) protein S-antigen, C4b binding protein (C4bBP) and fibrin degradation products (FDP), in 100 unselected adult blood donors (58 males, 42 females). We further examined the influence of age and sex on these variables. Age was shown to affect the plasma level of free PS: in comparison with a normal reference plasma, the levels of measured fPS in subjects less than or equal to 40 years (n = 67) and greater than 40 years (n = 33) were 86% (normal range: 52-143%) and 99% (60-162%), respectively (P = 0.01). The plasma levels of factors VIII, vWf, C4bBP and PS were significantly influenced by sex. This finding was particularly marked for fPS: in males (n = 31) and females (n = 36) less than or equal to 40 years, plasma levels of fPS were 94% (59-150%) and 80% (49-132%), respectively (P = 0.008). Finally, we studied the relationships existing between these factors. We found that plasma levels of most coagulation factors were interrelated. In addition, FDP values were positively correlated with plasma level of Fg (r = 0.26); P = 0.008).

Adult↗
PubMed1990

Pharmacologic properties of a low molecular weight dermatan sulfate: comparison with unfractionated dermatan sulfate.

The anticoagulant, pharmacodynamic, and antithrombotic properties of a low molecular weight dermatan sulfate (molecular weight range 1600 to 8000, peak 4000) were compared with those of unfractionated dermatan sulfate (molecular weight range 12,000 to 45,000, peak 25,000). Anticoagulant activities were evaluated as the ability of the compounds to catalyze the inhibition of thrombin in the presence of heparin cofactor II in a purified system and to prolong the activated partial thromboplastin time or the thrombin clotting time of human and rabbit plasmas. On the basis of weight, low molecular weight dermatan sulfate was two times less potent than unfractionated dermatan sulfate. After bolus intravenous injection into rabbits, the volume of distribution of low molecular weight dermatan sulfate was 10 times larger than that of unfractionated compound, and the half-life of disappearance was two to four times longer despite a 1.4 to 2.3 times higher total clearance. The bioavailability of low molecular weight dermatan sulfate from its subcutaneous depot was 100%; it was absorbed faster from that depot than unfractionated dermatan sulfate. The antithrombotic activities of unfractionated and of low molecular weight dermatan sulfate were also examined with a Wessler-type model with tissue factor as the thrombogenic stimulus. When evaluated 3 minutes after a bolus intravenous injection, unfractionated dermatan sulfate was twice as active as low molecular weight dermatan sulfate on the basis of weight. With subcutaneous injection, 10 mg/kg of low molecular weight dermatan sulfate generated an activity in plasma equivalent to 5.6 micrograms/ml 1 hour later. This concentration was associated with a significant antithrombotic effect that lasted for less than 6 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Pharmacokinetics of heparin and related polysaccharides.

The pharmacodynamic profile of standard heparin (SH), a low molecular weight derivative (CY 216) and of dermatan sulfate (DS), a new potential antithrombotic drug, was investigated in the rabbit over a large range of doses. After bolus i.v. injection of low doses, the biological activity of SH disappeared exponentially; however, its half-life was prolonged when the dose injected increased, and over 158 micrograms/kg (100 anti-factor Xa U/kg) the biological activity disappeared as a concave-convex curve. CY 216 disappeared more slowly than SH at low doses but faster than SH at higher doses. More than 90% of the DS biological activity present 1 minute after the i.v. injection disappeared exponentially without dose-dependent effects. Increasing doses of the three drugs were then delivered for 5 h under continuous infusions. Below 500 micrograms/kg/h the DS and CY 216 plateau concentrations were higher than that of SH while above this dose the SH concentration was higher than that of DS and CY 216. These observations may be explained by the results of pharmacokinetics experiments where 125I-labeled compounds were delivered by bolus i.v. injection in association with increasing doses of their unlabeled counterparts. For SH there was a 10-fold difference between the half-life of the lower dose (32 micrograms/kg or 5 anti-factor Xa U/kg) and that of the higher dose (3200 micrograms/kg); it was demonstrated that the half-life of SH continuously shortened as its plasma concentration decreased. In contrast the CY 216 and DS half-lives were very close, independent of the dose delivered, and therefore longer than that of SH at low doses and shorter than that of SH at higher doses. The renal contribution to the clearance of SH, CY 216, and DS was also investigated by injecting a low dose (150-200 micrograms/kg) and a 10 times higher dose to sham-operated or binephrectomized animals: renal function is critical for the elimination of the three compounds from the blood except for SH at low doses. These observations are promising for the development of DS and may have clinical implications.

Animals↗
PubMed1989

Pharmacological properties of dermatan sulfate, of a low molecular weight dermatan sulfate and of two oversulfated derivatives.

The pharmacological properties of unfractionated dermatan sulfate (U-DS, mean MW 25 kd, range 12-45 kd) of a low molecular weight fraction (LMW-DS, mean MW 4 kd range 1.6-8 kd), and of 2 oversulfated derivatives (S-DS1 and S-DS2, 2 and 3.8 sulfate groups per disaccharide units) were investigated. In a purified system, LMW-DS, S-DS1 and S-DS2 were respectively 0.5, 10 and 17 times more potent than U-DS to catalyse thrombin inhibition by heparin cofactor II. Identical differences were observed for the respective anticoagulant activities (activated partial thromboplastin time and thrombin clotting time). After bolus IV injection of increasing doses the pharmacokinetic parameters of U-DS were slightly dose dependent, and the total clearance of LMW-DS was, on the average, 2 times higher. The patterns of disappearance of S-DS1 and S-DS2 were strongly dose dependent and became concave-convex, suggesting different mechanisms of clearance. After SC injection, the bioavailability was less than 50% for U-DS and at least 100% for LMW-DS. The antithrombotic activity (Wessler-thromboplastin model) of LMW-DS was 2 timer lower than that of U-DS. In contrast to their in vitro (and ex vivo) enhanced anticoagulant activities, the antithrombotic potency of S-DS1 was identical to that of U-DS, while, at the same doses S-DS2 was devoid of any activity.

Animals↗
PubMed1989

Pharmacodynamics and pharmacokinetics of dermatan sulfate in humans.

Dermatan sulfate (DS), a catalyst of the thrombin-heparin cofactor II interaction, has antithrombotic activity and is devoid of significant hemorrhagic risk in several animal models. We investigated the pharmacodynamic and pharmacokinetic properties of DS in humans. DS was injected in single bolus intravenous injections of four increasing doses (0.5, 1, 1.5, 2 mg/kg) to six healthy volunteers. The resulting anticoagulant activities were assessed by the activated partial thromboplastin time (APTT) and the thrombin clotting time (TCT). There were dose-dependent prolongations of the APTT and TCT, and the anticoagulant activities disappeared in less than three hours. The pharmacokinetic parameters were calculated from the plasma concentrations of DS measured with a new chromogenic assay. The volume of distribution was approximately 1.8 times greater than the theoretical plasma volume and was independent of dose. In contrast, the clearance decreased with dose and the terminal half-life ranged from 0.45 +/- 0.08 hours at 0.5 mg/kg to 0.72 +/- 0.11 hours (mean +/- SD) at 2 mg/kg. The bioavailabilities of subcutaneous (SC) and intramuscular (IM) administration relative to those of intravenous administration were determined in 12 other volunteers. The respective bioavailabilities were 24.7% +/- 12.9% and 12.4% +/- 9.2% for SC and IM administration. There was no detectable change in the APTT and the TCT when the volunteers were injected with 1.5 mg/kg SC or IM. In addition, the pharmacokinetic parameters derived from plasma concentrations of DS showed considerable interindividual variations by the two later routes of administration. Peak concentrations were noted 2.7 +/- 1.3 hours after SC injection and 4.3 +/- 4.9 hours after IM injection. The average peak concentrations were 0.7 +/- 0.3 and 0.4 +/- 0.2 mg/L after SC and IM injections, respectively. The half-lives of DS were 7.9 +/- 6.5 hours (SC) and 6.3 +/- 7.4 hours (IM). No adverse reaction to DS was recorded during this study.

Adult↗
PubMed1987

Inactivation of heparin cofactor II by polymorphonuclear leukocytes.

Inactivation of purified human heparin cofactor II by polymorphonuclear leukocytes was investigated. A proteolytic mechanism of inactivation was demonstrated by SDS-polyacrylamide gel electrophoresis. Inactivation and related proteolysis did not occur in the presence of unstimulated leukocytes and were prevented by various protease inhibitors. Heparin cofactor II was inactivated more rapidly than antithrombin III. However, heparin (1-10 ug/ml) strongly accelerated the rate of antithrombin III inactivation and slightly protected heparin cofactor II, thus reversing the order of inactivation. Dermatan sulfate had no effect on this process.

Antithrombin III↗
PubMed1987

Evidence for a saturable mechanism of disappearance of standard heparin in rabbits.

This work demonstrates that after bolus intravenous injection standard heparin (SH) disappearance results from the combination of a saturable and a non saturable mechanism. Pharmacokinetics and pharmacodynamics of SH were studied by measuring the disappearance of increasing doses (5 - 500 anti-factor Xa U/kg) of 125I-heparin and of its biological effects. CPM curves allowed to determine the half lives of heparin according to the dose injected. The half lives were clearly dose dependent and reached a plateau over 100 anti-factor Xa U/kg. The complex curve which describes the amount of heparin cleared per time unit after any given dose has been resolved into its two components reflecting a saturable and a non saturable mechanism of disappearance. For the doses less than 100 anti-factor Xa U/kg the saturable mechanism was preeminent and the anti-factor Xa activity disappearance followed an exponential pattern; for the doses less than 100 anti-factor Xa U/kg the contribution of the non saturable mechanism becomes more important and the anti-factor Xa activity disappearance followed a concave-convex pattern. Further experiments showed that the heparin half life shortened as the circulating anti-factor Xa activity decreased; this phenomenon may explain the concave-convex pattern of the curve of the anticoagulant effect observed after injection of large doses of SH.

Animals↗