Pharmacokinetic of a very low molecular weight heparin in chronic renal failure.

The pharmacokinetic characteristics of a low molecular weight heparin (LMWH) (Cy 222; mean mw: 2500 daltons) are studied in 24 patients with 3 degrees of chronic renal failure (CRF) stage I (creatinine clearance between 50 and 30 ml/mn), stage 2 (creatine clearance between 30 and 10 ml/mn), stage 3 (creatinine clearance below 10 ml/mn). Patients with CRF have significantly higher values of anti Xa activity at 3 hours (p less than 0.05), 5 hours (p less than 0.05), and at 8 hours (p less than 0.03) after injection than controls, CMAX values, VDSS and AUC do not differ, whereas patients with the highest stage of CRF are characterised by the most important t1/2 a (p less than 0.001) and the smallest total body clearance (p less than 0.01). Consequences of these disturbances of pharmacokinetic characteristics have to be evaluated before adequate posology of heparin fragments could be determined in patients with CRF.

[Parameters of hemostasis during treatments associating fractionated heparin administered subcutaneously to standard and fractionated heparin administered intravenously in the chronic hemodialysis patient]. / Etude des paramètres de l'hémostase au cours de traitements associant l'héparine fractionnée par voie sous-cutanée aux héparines standard et fractionnée par voie intraveineuse chez l'hémodialysé chronique.

The hemorrhagic risk of an association of fractioned heparin (Fraxiparine) injected intravenously at the dose of 7500 AXaICU or of unfractionned heparin (UFH) injected intravenously at the usual dose used for a priming dose for hemodialysis (3750 +/- 1280 IU + 1000 IU after 2 hours of dialysis) to the subcutaneous administration of a thrombo-embolism preventive dose of Fraxiparine (7500 AXaICU) was evaluated on the modifications of the following hemostasis parameters: thrombin time, Activated Partial Thrombin Time (APTT), prothrombin time, anti Xa activity in 13 uremic patients on hemodialysis. The association of intravenous and subcutaneous Fraxiparine prevents efficiently the clotting of the extracorporeal circulation without inducing a detectable antithrombinic activity. In contrast, the association of I.V. UFH to subcutaneous Fraxiparine induces a significant increase of the thrombin time and of the APTT. This latter is exclusively explained by the activity of UFH. It is concluded that subcutaneous Fraxiparine at the thromboembolism preventive dose can be associated as well to I.V. Fraxiparine as to UFH without increasing the antithrombinic activity of the plasma.

Pharmacodynamics of CY 216 in healthy volunteers: inter-individual variations.

The pharmacodynamic parameters of a low molecular weight heparin (LMWH, CY 216) and their inter-individual variations were investigated. In a cross over study 100 anti-factor Xa IC U/kg were injected, one week apart, to 12 healthy volunteers by intravenous (IV) or subcutaneous (SC) route. The pharmacological effects were followed by performing activated partial thromboplastin time (APTT), thrombin clotting time (TCT) and a chromogenic anti-factor Xa assay. The main pharmacodynamic parameters were calculated from the anti-factor Xa activity disappearance curves. Five to ten min after IV injection, the APTT ranged between 56 and 98 sec (baseline 40 sec), the TCT between 28 and 99 sec (baseline 19 sec) and the anti-factor Xa activity between 1.58 and 2.28 IC U/ml. The anti-factor Xa activity half-life ranged between 1.5 and 2.9 h. After SC injection, there were no detectable APTT and TCT prolongations; the maximum anti-factor Xa activity ranged between 0.36 and 0.88 IC U/ml and the half life between 1.5 and 6.4 h. These results indicate that, as for standard heparin, there are large inter-individual variations in the anticoagulant responses to a given dose of CY 216 an observation which may have clinical implications.

[Prevention of deep venous thrombosis of the leg by a very low molecular weight heparin fraction (CY 222) in patients with hemiplegia following cerebral infarction: a randomized pilot study (30 patients)]. / Prévention des thromboses veineuses profondes des membres inférieurs par une fraction d'héparine de très bas poids moléculaire (CY 222) chez des patients porteurs d'une hémiplégie secondaire à un infarctus cérébral: étude pilote randomisée (30 patients).

The effectiveness and safety of a very low molecular weight heparin fraction were evaluated in the prevention of deep-vein thrombosis in patients confined to bed due to hemiplegia consecutive to a recent cerebral infarction. CY 222 was administered within 48 hours of the stroke by one single daily subcutaneous injection of 0.6 ml (= 15,000 U AXa IC) during 14 days. This randomized pilot study involved 30 patients. The effects of CY 222 were assessed in a group of 15 patients compared with a control group of 15 untreated patients. No deep-vein thrombosis was detected by the labelled fibrinogen test in the treated group, as against 12 patients in the control group. Six patients (3 in each group) died during the study. One case of lethal pulmonary embolism was observed and confirmed at autopsy in the control group. In the remaining 5 patients, no systematic autopsy which would have asserted the absence of pulmonary embolism or drug-induced haemorrhage was performed. Numerous standard laboratory tests confirmed that CY 222 was well tolerated.

Unfractionated heparin and CY 216: pharmacokinetics and bioavailabilities of the antifactor Xa and IIa effects after intravenous and subcutaneous injection in the rabbit.

This report compares the pharmacokinetics and the bioavailabilities of the antifactor Xa and of the antifactor IIa activities generated by intravenous (IV) and subcutaneous (SC) injections of increasing doses of unfractionated heparin (UH) and of a low molecular weight heparin (CY 216). Rabbits were injected with 500, 1,000, 2,500, and 5,000 antifactor Xa u/kg of both heparins and their biological activities were followed at various time intervals. After IV injection the clearance of the antifactor Xa activities was independent of the dose and the clearance of UH was significantly higher than that of CY 216; after SC injection the bioavailability estimated from the antifactor Xa effect was consistently over 100% for CY 216 while that of UH increased from 27% at the lowest dose to 93% at the highest dose. The pharmacokinetic parameters estimated by the antifactor IIa activity of UH were superimposable to those calculated with the antifactor Xa activity. For CY 216 no direct comparison between the two activities was made since the dose injected expressed in antifactor IIa units was 3.4 times lower. UH and CY 216 were therefore injected intravenously to other animals at equivalent and increasing doses expressed in antifactor IIa units (50-5,000 u/kg). The pharmacokinetic parameters calculated from the curves of the antifactor IIa activities were basically identical except at the two lower doses (50 and 100 u/kg) for which UH was cleared faster than CY 216.(ABSTRACT TRUNCATED AT 250 WORDS)

Low-molecular-weight heparin Fraxiparin in chronic hemodialysis. A dose-finding study.

A two-step dose-ranging study was undertaken with CY216 (Fraxiparin) in 8 patients on 7 sessions each. The different doses were administered each time as a single bolus injection at the start of hemodialysis without heparinized priming nor further administration during the 4-hour session. In the first step, the clinical efficacy of 4 different doses of Fraxiparin was compared with that of standard heparin on the percentage of sessions free of clot formation in the extracorporeal circulation (ECC). Safety was evaluated by the compression time for hemostasis at the puncture sites. The second step was a randomized comparison of 3 Fraxiparin dosages. In addition to the clinical assessment of efficacy, the following biological parameters were measured: fibrinopeptide A (FPA), anti-Xa (AXa) activity calibrated against Fraxiparin, thrombin time (TT), activated partial thromboplastin time, blood counts, hemoglobin, hematocrit, plasma creatinine and urea, and residual blood volume in the dialyzer. A 'standard' dosage of 10,000 AXa Institut Choay units of Fraxiparin was shown to prevent clot formation in the ECC. It resulted in a marked increase in TT, without any lengthening of the puncture site compression time. After 4 h, AXa and FPA levels in the venous line were related to the doses used (p less than 0.05). After 48 h AXa activity was very low. Dialysance and tolerance were excellent. Thus, a single dose of Fraxiparin unrelated to body weight and not determined by the measurement of the whole-blood activated clotting time appeared to be a safe and effective means for preventing fibrin formation in 4-hour dialysis sessions.

[Plasma exchange with very low molecular weight heparin CY 222. Biological profile and therapeutic value]. / Echanges plasmatiques sous héparine de très faible masse moléculaire CY 222. Profil biologique et intérêt thérapeutique.

In a clinical, between-patient study we investigated the effects of a VLMW Heparin fragment (CY 222) versus standard heparin (SH) in plasma exchanges (n = 10) on coagulation factors (CF). Fibrinogen (FGN), II, V, VIIF + X, IX, XI, XII, VIIIc, VIIIRag, VIIIvwf and ATIII, ProtC, ProtS, Plasminogen (PGN), Activated Thromboplastin time (APTT), Prothrombin time (PT), Thrombin time (TT), anti factor Xa (Axa), DDimer, Platelet count. Heparin was administered as a bolus and by infusion during the session, CY 222 as a bolus dose only; 1 to 1.5 plasma volume was exchanged with substitution by 5% albumin. Results (mean, s.d.) at the end of the session (End) and 4 hours later (T4) were analyzed and showed no differences between groups (with CY 222 and with SH) for technical and clinical findings. Biologically, CF were similar in both groups except for Factor XII levels at the end of the session, and Factors II, V, XII at T4. Prolonged APTT in all samples appear related to low FGN. Significant differences in Axa activities were found for each treatment when compared with its own standard, suggesting different ranges of activities of both drugs. Changes in D-dimer levels differed during the session and four hours after the session with the drug tested, and could be related to their mode of administration. Clinical efficiency and tolerance were excellent both with CY 222 and SH.

[Comparative study of heparin and a very low molecular-weight heparin in hemodialysis in chronic renal insufficiency]. / Etude comparative de l'héparine et d'une héparine de très faible masse moléculaire en hémodialyse dans l'insuffisance rénale chronique.

In the course of dialysis sessions, we have compared the antithrombotic effect of two heparinization regimens: low molecular weight heparin (CY 222, mean molecular weight: 2,500, Institute Choay, France): 90 anti-Xa units/kg bodyweight as a bolus injection followed by a continuous infusion of 1,000 anti-Xa units/hour (regimen 1); or 300 anti-Xa units/kg as a bolus injection (regimen 3), with a standard heparinization regimen (100 IU/kg regimen 2). Eight patients received the 3 regimens successively. Factor IIa and factor Xa inactivation was measured by a method that uses chromogenic substrates. The frequency of adverse effects, ultrafiltration rates, creatinine and BUN clearances of the 3 regimens were similar, whereas dialyser blood loss was higher in the first regimen. At the dose of 300 anti-Xa units of CY 222 (regimen 3), inactivation of factor Xa was similar to Xa inhibition reached through the conventional treatment (regimen 2) but IIa inhibition was less pronounced.

Comparative study on the effects of a low molecular weight heparin (CY 216) and standard heparin in low dosage on experimental venous thrombosis.

In a venous thrombosis model in the rat obtained by ligation of the inferior vena cava, the effects of standard heparin and CY 216, a low molecular weight heparin fraction, are compared. At a dosage of less than 2 mg/kg b.w. CY 216 is an effective antithrombotic, whereas standard heparin is not.

[Anticoagulation in hemodialysis sessions with a low molecular weight heparin (CY 222, Choay). Dosage studies in chronic hemodialysis. Its use in patients at high risk of hemorrhage]. / Anticoagulation des séances d'hémodialyse par une héparine de bas poids moléculaire (CY 222, Choay). Etudes de posologies en hémodialyse chronique (HDC). Utilisation chez les patients à haut risque hémorragique.

Efficacy of CY 222 for providing anticoagulation during hemodialysis was evaluated in three successive trials by rating quality of blood restitution (degree of coagulum formation in extracorporeal circulation) and by assay of fibrinopeptide A. Its safety was assessed by measurement of manual compression time necessary to ensure hemostasis of puncture points at end of session. Details of the first preliminary study were: 60 sessions in 11 chronic uremia patients; CY 222: 75, 150 and 300 A-Xa IC U/kg + 1,000 A-Xa IC U/h, then 150 and 300 A-Xa IC U/kg without continuous injection, compared with standard heparin (SH) at the usual dosage for each patient (60 +/- 13 IU/kg). Results showed CY 222 at 150 U/kg + 1,000 U/h to possess the same efficacy as SH and to give a shorter compression test time: for 150 U/kg the efficacy was satisfactory, although less than with SH, and compression times were shorter (interest in patients at risk of hemorrhage). For 300 U/kg, efficacy was superior (improved restitution and lower FPA level at end of seance: 6 ng/ml instead of 15 ng/ml.p less than 0.002) and compression times were identical. The second study to evaluate optimal dosage of CY 222 in chronic hemodialysis (CHD) involved: 10 patients; CY 222: 200 A-Xa IC U/kg and 250 A-Xa IC U/kg by single-dose injection. Results failed to demonstrate any significant difference in evolution of FPA levels, but restitution was better at 250 U/kg. In addition, investigation of the effect of rinsing of ECC with standard heparin before the session showed that its suppression did not alter effectiveness but improved tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

[Low molecular weight heparin (CY 222) levels during hemodialysis sessions. Comparison of various chromogenic and chronometric methods. Problem of standardization]. / Dosage d'une héparine de bas poids moléculaire (CY 222) au cours des séances d'hémodialyse. Comparaison de différentes méthodes chromogéniques et chronométriques. Problème de l'étalonnage.

Current evaluation of biological activity of low molecular weight heparins (LMWH) is dependent solely on technics determining Xa inhibition. Comparison of these technics was carried out during 2 studies of the use of CY 222 during hemodialysis. In the first study, 66 plasma samples from 11 patients treated with 200 or 250 U A Xa IC kg/i.v. at start of session (sample collections at 2-4 h) were tested using a chronometric technic (Hepaclot Stago-plasma diluted to 1/3) and 2 chromogenic technics on microplates using C.B.S. 31-39 substrates (Stachrom-modified Stago: incubation time 90" for a wide range) and S 2222 (Coatest-modified Kabi: incubation time 180"). In the second, 28 plasma samples from 7 patients (sample collection 2-4 h, TO following session; anticoagulation CY 222 10,000-15,000-20,000 U A Xa IC) were studied by 2 chronometric methods: Hepaclot (Stago) and Heptest (Hemachem). Standardization was with CY 222 in each case (results expressed as U A Xa IC). Mean blood heparin in the first study was 2.39 +/- 0.7 with Hepaclot, 2.50 +/- 0.55 with Stachrom and 1.94 +/- 0.37 with Coatest. Student's test failed to show any difference between results with Strachrom and Hepaclot (t = 1.48 NS) whereas the difference was very significant between Hepaclot and Coatest and Stachrom and Coatest (p less than 10(-9).(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo neutralization of low-molecular weight heparin fraction CY 216 by protamine.

The neutralization in vivo of a low molecular weight heparin by protamine was investigated. Large doses and excessive doses of intravenously administered CY 216 were studied. An intravenous injection of protamine given 10 minutes after the administration of CY 216 did not cause the studied biologic parameters to return to normal levels, but merely attenuated them, whatever the protamine dosage tested. In contrast, the bleeding time and the volume of blood loss resumed normal values that were close to those observed in the controls. This dissociation of actions cannot be explained at present. The ratio of protamine to CY 216 dosage that produced the best results was 1 antiheparin U of protamine to 2 anti-Xa U of CY 216. Nevertheless CY 216 appeared to have a small hemorrhagic potential.