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L Bara

Publications and source records attributed to L Bara.

At least 73 records · Page 4Linked to original sources
PubMed1988

Pharmacokinetics of low molecular weight heparins.

Low molecular weight heparin (LMWH) fragments have recently been proposed as antithrombotic drugs. Several fractions and fragments have been studied in human healthy volunteers: Enoxaparin (Lovenox) from Pharmuka, Fraxiparin from Choay, Fragmin from Kabi, LHN1 from Novo laboratories. The pharmacokinetics of LMWH are clearly different from those of unfractionated heparin as demonstrated by a small group of studies. In our laboratory, we undertook one study with enoxaparin. After intravenous and sub-cutaneous injection the clearance half-life of the different LMW heparins is about 3 to 4 hours. It is significantly longer for LMW heparin than for unfractionated heparin. The half-life of anti-IIa activity is similar for LMW heparins and for unfractionated heparin. However, contrary to unfractionated heparin, there is, for Enoxaparin, a difference between the two activity half-life. The anti-IIa activity half-life is smaller than that of anti-Xa activity. After intravenous and sub-cutaneous injection of 30 to 40 mg of the different fragments and fractions the biodisponibility of LMWH S.C.(A.U.C.) I.V.(A.U.C.) was about 4 times higher when compared to unfractionated heparin injected at a dose of 29 mg. In a recent study with 12 volunteers, using S.C. administration of 20, 40, 60, and 80 mg of Enoxaparin, we were able to demonstrate a good linearity between the area under the curves and the injected doses. Standard heparin is mainly cleared by a cellular mechanism while LMWH is essentially cleared by a renal mechanism. Anti-Xa activities obtained by the chromogenic technique are higher than those obtained in human plasmas with a competitive binding assay and with labelled Enoxaparin in the dog and in the rat. The persistent anti-Xa activity may be mediated by some compounds released by Enoxaparin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Laboratory monitoring of a low molecular weight heparin (enoxaparin) with a new clotting test (Heptest).

A new simple clotting test (Heptest) for low molecular weight heparins was compared to anti-Xa determination by an amidolytic assay in volunteers and in patients receiving standard calcium heparin or low molecular weight (LMW) heparin (Enoxaparin) by subcutaneous administration. The results obtained with both methods are in very good agreement. It seems that the Heptest, although influenced by various other clotting parameters, is nevertheless relatively specific for anti-Xa activity. Despite our positive first impression, we object to expressing the results in micrograms of heparin per milliliter or anti-Xa units. Until rigorous standardization is possible, we prefer to express the results as clotting times. Preliminary results warrant a more extensive study in order to assess the clinical relevance of Heptest in patients receiving unfractionated or LMW heparins.

Blood Coagulation Tests↗
PubMed1987

[Biological modifications induced by 3 low molecular weight heparins, PK 10169, Kabi 2165 and CY 216, compared to unfractionated heparin injected subcutaneously in healthy subjects in general surgery and in aged subjects in internal medicine].

Activities of anti-Xaam, anti-IIaam, Heptest and calcium thrombin time (Ca TT) were compared in: 12 male healthy volunteers after increasing doses of 20, 40, 60 and 80 mg/day of Enoxaparine; 76 patients after gynecological surgery treated with 20 mg (12 cases), 40 mg (15 cases) or 60 mg (10 cases) per day of Enoxaparine versus calcium heparin as 5,000 IU x 3/day (39 cases); 68 patients after general surgery treated with 2,500 units Fragmine/day (34 cases) versus calcium heparin 5,000 IU x 2/day (34 cases); 27 patients in a medical ward treated with either 7,500 Choay Institute units/day of Fraxiparine (14 cases) or Cutheparine (magnesium heparinate) (13 cases). In this latter case results of Heptest only are reported. In healthy volunteers and patients after gynecological operations, the Ca TT and anti-IIaam activity were significantly modified after doses greater than or equal to 40 mg. Values for anti-Xaam and anti-IIaam were dose-related but higher in healthy volunteers. The anti-Xa/anti-IIa ratio was 3-4. Correlation between Heptest, a simple test, and anti-Xa activity--both very good markers of low molecular weight heparins (LMWH)--was very good (r = 0.93, p less than 0.02 in healthy volunteers; r = 0.87, p less than 0.01 in operated patients). Peak activity was at about 3 to 4 hours after injection, the half-life of anti-Xa and anti-IIa activities being 4 and 2 hours respectively. After heparin injection, the anti-Xa/anti-IIa ratio was 1 but activities were weak (5,000 IU x 2 = 0.02 +/- 0.02), a little higher with 5,000 IU x 3 (0.05 +/- 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

[Lipolytic and anticoagulant activities of heparin and one of its low molecular weight derivatives].

The plasma lipolytic and anticoagulant activities following i.v. injection of either standard heparin or low molecular weight heparin (PK 10169) were compared in a study involving 10 healthy volunteers. The total lipolytic activity (lipoprotein lipase + hepatic lipase) released by PK 10169 was similar to that released by standard heparin when low molecular weight heparin was administered in doses 3- to 5-fold higher (by weight) than standard heparin. There was a dose-response relationship between the amount of PK 10169 injected and the level of plasma lipolytic activity. With doses of PK 10169 lower than 20 mg or heparin lower than 6 mg, lipolytic but not anticoagulant activity was observed. With doses higher than 20 mg with PK 10169 and 6 mg with heparin, both lipolytic and anticoagulant activities appeared. In doses where the lipoprotein lipase activities released by the 2 heparins were similar, the hepatic lipase released with low molecular weight heparin was significantly higher than with standard heparin.

Adult↗
PubMed1986

Relationship between biological activity and concentration of a low-molecular-weight heparin (PK 10169) and unfractionated heparin after intravenous and subcutaneous administration.

The pharmacokinetics of unfractionated heparin and the low-molecular-weight (LMW) heparin PK 10169 after intravenous and subcutaneous injection were compared by crossover study in 8 healthy volunteers. The heparin concentrations in plasma were measured by a competitive binding assay, and anti-IIa and anti-Xa activities were also assayed. Unfractionated heparin was cleared after intravenous administration with a half-life of 35 min irrespective of assay method. However, the concentration of PK 10169 declined with the longer half-life of 60 min, and its anti-IIa and anti-Xa activities had half-lives of 40 and 275 min, respectively. Some of this anti-Xa activity may be mediated by a compound released by PK 10169 rather than by the LMW heparin itself. The bioavailability of PK 10169 was 3-fold greater than that of unfractionated heparin, due to more effective absorption after subcutaneous administration.

Adult↗
PubMed1986

Partial reversal of low molecular weight heparin (PK 10169) anti-Xa activity by protamine sulfate: in vitro and in vivo study during cardiac surgery with extracorporeal circulation.

Neutralization of a low molecular weight (LMW) heparin fraction by protamine sulfate was evaluated in vitro and in vivo. Anti-Xa and anti-IIa activities were measured by amidolytic and coagulation methods (activated partial thromboplastin time, APTT). Fifteen patients (4 males and 11 females) underwent surgery with extracorporeal circulation. In vitro, anti-Xa and anti-IIa activities and APTT of unfractionated heparin were neutralized with a protamine/heparin (P/H) gravimetric ratio of 1.6, 1.33 and about 2, respectively. Anti-IIa activity and APTT induced by PK 10169 were completely corrected at a P/H ratio of 1 and 2, respectively, while anti-Xa activity was incompletely neutralized at a ratio of 5. In vivo, in 9 patients who did not receive intravenous protamine sulfate, a good correlation was found between doses of PK 10169 infused, anti-IIa plasma level and blood loss. In 3 patients who were treated prophylactically with protamine, bleeding was normal or only slightly increased. In 3 patients who received protamine because of hemorrhage, mean anti-Xa and anti-IIa were 2.3 and 0.54 U before and 1.32-0.06 U after neutralization. Bleeding was stopped by a second dose of protamine in 1 patient, but blood loss was abnormal in the other patients. However, a correlation between bleeding and anti-Xa or anti-IIa activities was not clearly evident.

Adolescent↗
PubMed1986

[Low molecular weight heparins].

Heparin is a heterogeneous component consisting of anionic polysaccharides chains of variable molecular weight ranging from 3 000 to 40 000 daltons. It is by potentiating antithrombin III (AT III) a natural inhibitor of coagulation, that heparin exerts its anticoagulant effect. Actually, it has been demonstrated that only 30% of the molecule in commercial heparin preparations are capable of binding to AT III: moreover, several procedures were used to prepare low molecular weight heparin fractions or fragments. These preparations were lacking in ability to prolong the clotting time (APTT) and to inhibit thrombin, but were capable of potentiating the inhibition of factor Xa. The hypothesis that low molecular weight heparins may exhibit antithrombotic effect by inhibition the coagulation cascade system at the initial stages is very attractive. Moreover, on animal models, heparin fractions with molecular weight less than 3 000 had limited ability to prevent experimental thrombosis despite good anti-Xa activity. Thus, the anti-Xa activity did not alone reflect the antithrombotic effect. Experimental studies have shown less bleeding with low molecular weight heparins compared to standard heparin. Some data have suggested other properties of low molecular weight heparins such as enhancement of fibrinolysis and a slighter effect on platelets. The risk of thrombocytopenia induced heparin could be reduced by the use of low molecular weight heparins. The pharmacokinetics of low molecular weight heparins have been studied in human subjects. A higher bioavailability and a longer duration of action were reported compared to heparin. Preliminary clinical trials have shown that one daily injection is sufficient to protect against post-operative thrombosis.

Animals↗
PubMed1986

Comparison of antithrombotic activity of two heparin fragments PK 10169 (mol. wt. 5,000) and EMT 680 (mol. wt. 2,500) and unfractionated heparin in a rabbit experimental thrombosis model: relative importance of systemic anti-Xa and anti-IIa activities.

Two fragments obtained by chemical depolymerization of heparin from porcine mucosal origin PK 10169 (mol. wt. 5,000) and EMT 680 (mol. wt. 2,500) were compared to the original heparin in a rabbit experimental thrombosis model. Thrombosis was induced either by human serum or by bovine Xa. Various doses of heparins (6 animals per dose and per inducer) were injected in order to find the lowest systemic levels of anti-Xa and anti-IIa activities able to inhibit venous-induced thrombogenesis. The systemic activities associated with an inhibition of 50% of the generated thrombi were as follows: 0.17 +/- 0.02 anti-Xa and 0.16 +/- 0.03 anti-IIa units obtained after injection of 97 micrograms/kg (14 anti-Xa and anti-IIa units/kg) of unfractionated heparin, 0.28 +/- 0.04 anti-Xa and 0.14 +/- 0.03 anti-IIa units obtained after injection of 250 micrograms/kg (15 anti-Xa and 7.5 anti-IIa units/kg of PK 10169, and 2.6 +/- 0.2 anti-Xa and 0.06 +/- 0.01 anti-IIa units obtained after injection of 5000 micrograms/kg (260 anti-Xa and 5 anti-IIa units/kg) of EMT 680. These results suggest that the presence of an anti-IIa activity associated with the anti-Xa activity strongly increases the thrombogenesis inhibition in the serum and Xa-induced thrombosis for the heparin fragments of low and very low molecular weight used in this study.

Animals↗
PubMed1982

Interactions of anticoagulant insoluble modified polystyrene resins with plasmatic proteins.

In previous papers, we have described the preparation and heparin-like properties of insoluble modified polystyrene resins. We now report results about the interactions of several coagulation factors with some of these materials. Most of the non-activated factors are neither adsorbed nor modified, except factor V and prekallikrein. In contrast thrombin, antithrombin III and factor Xa adsorb on the surface of such insoluble polymers. Thrombin can be desorbed by addition of a polycationic compound. The inactivation of thrombin or factor Xa by antithrombin is catalysed by the presence in the mixture of these insoluble materials as it is with soluble heparin. The initial velocity of these reactions is second order for both types of catalysis-homogeneous or heterogeneous - as previously reported for soluble heparin. In the case of these insoluble materials, the inhibition of protease by antiprotease seems to be accelerated when complexes are formed between the polymer and the proteins.

Adsorption↗
PubMed1981

Ultrastructure of a model of thrombogenesis induced by mechanical injury.

Injured cortical arteries were observed by electron microscopy. Haemostasis was brought about by both platelets and fibrin, but the intravascular thrombus contained only platelets. Some platelets adhered to the exposed subendothelium but did not form a continuous layer. Such platelet adhesion does not provoke a thrombus, which appears only at the opening in the artery. There was a gap of 7 micrometers between the thrombus and the intact arterial wall. The thrombus was built up progressively by concentric accumulation around the main injury. Central platelets were closely packed and the more distal ones loosely gathered but not touching and not activated. This structure was very different from that observed in in vitro aggregates which formed rapidly and whose platelets are all at the same stage of development and disposed radially. This implies a different sequence in the physiological evolution of platelets submitted to either mode of activation. The results obtained with the present model differ in several respects from those obtained with other models.

Animals↗