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Biomedical subjects

J Fareed

Publications and source records attributed to J Fareed.

At least 199 records · Page 11Linked to original sources
PubMed1993

Pharmacological profile of reviparin-sodium.

Clivarin (reviparin-sodium) is a homogeneous low molecular weight heparin (LMWH) as determined by the data obtained in molecular profiling studies. The limited biochemical studies carried out indicate that this LMWH has a specific potency of 124 anti-XA IU/mg and a weaker aPTT activity of approximately 30 U/mg. Assay-dependent neutralization of the in vitro effects of reviparin-sodium were noted. Protamine preparations at equigravimetric concentrations effectively neutralized the aPTT and TT effects; however, Heptest and anti-Xa effects were only partially neutralized. In contrast, heparin's effects were completely neutralized by this agent. PF 4 only partially neutralized the effects of reviparin-sodium. Assay-dependent variations were noted in this study. In comparison with heparin, the haemorrhagic effects of reviparin-sodium were much weaker. Reviparin-sodium produced a dose-dependent antithrombotic action in both the intravenous and subcutaneous studies. This agent also showed sustained activity and better bioavailability characteristics than heparin. Reviparin-sodium exhibited a distinct biochemical and pharmacological profile that may be useful in the optimization of LMWH.

Animals↗
PubMed1993

Antithrombin III- and heparin cofactor II-mediated anticoagulant and antiprotease actions of heparin and its synthetic analogues.

A chemically synthesized pentasaccharide, a specific ligand for AT III, and a synthetic, sulfated bis-lactobionic acid amide, a ligand for HC-II, were studied along with heparin to determine the relative contribution of AT III and HC II in the inhibition of protease activation in plasma. The global clotting assays (PT, APTT, Heptest, TT), amidolytic anti-IIa and anti-Xa assays, and defined biochemical systems supplemented with purified AT III and HC II were used in this study. In the plasma-based assays, heparin exhibited strong inhibition in both thrombin and Factor Xa-based assays, whereas pentasaccharide was only active in Factor Xa-based assays and lactobionic acid was only active in thrombin-based assays. In the AT III supplemented systems, heparin was able to inhibit strongly both Factor Xa and thrombin, while pentasaccharide could only inhibit Factor Xa. Lactobionic acid was ineffective at mediating its actions through AT III. In the HC II-mediated inhibition of thrombin, heparin and lactobionic acid both had strong inhibitory actions. Pentasaccharide was ineffective in this assay. All three agents failed to inhibit Factor Xa via HC II. These studies suggest that specific synthetic analogues of heparin such as the pentasaccharide and lactobionic acid can be used to study the relative contributions of AT III and HC II in the control of protease activation during thrombogenesis.

Antithrombin III↗
PubMed1993

Biochemical and pharmacologic profile of low molecular weight heparin (LU 47311, Clivarin).

1. Clivarin is a homogeneous LMWH as determined by the data obtained in molecular profiling studies. 2. The limited biochemical studies carried out indicated that this LMWH has a specific potency of 124 anti-Xa IU/mg and a weaker APTT activity of approximately 30 U/mg. 3. Assay-dependent neutralization of the in vitro effects of Clivarin was noted. Protamine preparations at equigravimetric concentrations effectively neutralized the APTT and TT effects; however, Heptest and anti-Xa effects were only partially neutralized. In contrast, heparin's effects were completely neutralized by this agent. 4. PF 4 only partially neutralized the effects of Clivarin. Assay-dependent variations were noted in this study. 5. In comparison to heparin, the hemorrhagic effects of Clivarin were much weaker. 6. Clivarin produced a dosage-dependent antithrombotic action in both the intravenous and subcutaneous studies. This agent also showed sustained activity and better bioavailability characteristics than heparin. 7. Clivarin exhibited a distinct biochemical and pharmacologic profile that may be useful in the optimization of this agent.

Animals↗
PubMed1993

Evaluation of hematologic alterations associated with daily administration of low molecular weight heparin (Mono-Embolex) for a 12-week period.

The long-term success rate of coronary angioplasty is only 50 to 70% due to restenosis. The pathophysiologic mechanism of this event is mainly mediated by smooth muscle cell proliferation. To some extent, it can be inhibited by heparin. The introduction of LMWHs allows for prophylaxis against restenosis on an outpatient basis, but no data are available on the long-term usage of LMWH. To investigate possible side effects, nonhuman primates received daily injections of LMWH (Mono-Embolex) over a 12-week period and the hematologic profile was assessed. There were no significant alterations of the red blood cell system. The overall WBC profile did not change, although a significant increase of granulocytes with a corresponding decrease of lymphocytes and monocytes occurred. Data from a control group suggest that these alterations are caused by chronic stress and are not drug related. Platelet count as well as platelet function tests were unaffected by this treatment. In conclusion, the long-term administration of Mono-Embolex as projected for the use in the prophylaxis of restenosis following angioplasty appears to be safe regarding hematologic parameters.

Animals↗
PubMed1993

Postoperative monitoring of low molecular weight heparin prophylaxis in high-risk patients.

The alterations of the laboratory assays described for heparin monitoring in low molecular weight and unfractionated heparin prophylaxis groups did not correlate with the clinical outcome. Current laboratory techniques failed to detect an increased need for a higher dose of unfractionated or low molecular weight heparin to prevent DVT in these high-risk patients. The parameters commonly associated with thrombosis, that is, decreases in protein C and AT III were correlated with an increased incidence of DVT, but there was no difference in the assay values between the low molecular weight heparin and unfractionated heparin groups. Fibrinolysis activation is known to be associated with surgery; however, our data suggest an additional activation due to low molecular weight heparin compared with the unfractionated heparin group. Most interestingly, elevated PAI levels appear to correlate with thrombosis.

Double-Blind Method↗
PubMed1992

Isolation and characterization of human heparin.

Heparin was isolated from an unusually large human hemangioma that contained an elevated level of mast cells. Purification of multimilligram quantities of heparin from this tissue sample permitted a thorough examination of its structure and activity. Characterization of this human heparin included the following: one-dimensional and two-dimensional 1H-nuclear magnetic resonance spectral analysis; oligosaccharide mapping; saccharide compositional analysis; and in vitro assessment and anticoagulant activity. Oligosaccharide mapping and nuclear magnetic resonance spectroscopy showed that this human heparin is structurally similar to porcine intestinal mucosal heparin but distinctly different from bovine lung heparin. This human heparin also has substantially more in vitro anticoagulant activity than either of these pharmaceutical heparins.

Animals↗
PubMed1992

Neutralization of the antithrombotic effects of heparin and Fraxiparin by protamine sulfate.

In general, the in vitro anti Xa activity of low molecular weight heparins is neutralized to a lesser degree than the anti Xa activity of unfractionated heparin. To determine whether these differences occur in vivo, a rabbit stasis thrombosis model and a rat laser-induced thrombosis model were utilized. In the laser model, a similar degree of neutralization of the antithrombotic activity of heparin and Fraxiparin was obtained. However, in the stasis thrombosis model, significant antithrombotic activity of Fraxiparin remained after equigravimetric protamine administration. Ex vivo APTT, thrombin time, Heptest, amidolytic anti Xa and anti IIa assays were performed. A coefficient (r = .806) was obtained for the correlation of Heptest activity to antithrombotic effect in the stasis thrombosis model, while the coefficients obtained for the other tests ranged from .152-.570. However, after neutralization by protamine, the thrombin time exhibited the highest correlation coefficient (r = .685) between ex vivo activity and residual antithrombotic effect. Since Fraxiparin retains antithrombotic activity after protamine administration, clinical benefit may be observed for this low molecular weight heparin as compared to unfractionated heparin after neutralization.

Animals↗
PubMed1992

Ex vivo activity of heparin is not predictive of blood loss after neutralization by protamine.

To study whether the ex vivo activity of heparin and Fraxiparin correlates to and predicts the extent of blood loss induced by the heparins (pre- and post neutralization by protamine), a rat tail transection model and a rabbit ear bleeding model were used. In the rat model heparin (2 mg/kg i.v.) significantly prolonged the bleeding time, while this dose of Fraxiparin had no effect. In the rabbit ear blood loss model, heparin (2 mg/kg i.v.) produced significant increases in blood loss while Fraxiparin (2 mg/kg i.v.) produced approximately 30% of the blood loss induced by heparin. Equigravimetric protamine reduced the heparin-induced blood loss by approximately 50%, however, significant blood loss, thrombin time and Heptest activity remained. Heparin and Fraxiparin (3 mg/kg s.c.) did not cause any increased bleeding. While, all activities of heparin were completely neutralized by protamine, the Heptest activity of Fraxiparin was resistant to neutralization. The ex vivo activity of heparins after neutralization by protamine does not correlate to the extent of blood loss which suggests it may not be necessary to neutralize all ex vivo activities of the heparins to baseline values to be assured that blood loss is reversed.

Animals↗
PubMed1992

The thrombolytic potency of LMW-heparin compared to urokinase in a rabbit jugular vein clot lysis model.

Since the beginning of the clinical use of low molecular weight (LMW) heparins their thrombolytic or profibrinolytic potency has been a matter of controversial discussions. Regarding this problem, the aim of our study was to test a LMW-heparin (Sandoparin) in an in vivo model comparing its lytic activity to unfractionated heparin and urokinase at different doses. For this purpose a newly developed short-term rabbit jugular vein clot lysis model was developed. Urokinase infused at doses of 3300, 6600 and 10,000 U/kg to control animals for one hour showed a clear dose-dependent clot lysis. Test animals were injected with a bolus of 0.5 mg/kg of LMW-heparin followed by a constant infusion of either 0.5, 1.0 or 2.0 mg/kg for one hour. A similar dose-dependent effect was observed for LMW-heparin as for urokinase. Unfractionated heparin did not exhibit a dose-dependent lytic activity in this model. No lysis was found in rabbits treated with saline. These findings suggest that the LMW-heparin tested exhibits a dose-dependent in vivo lytic activity which can be compared to clinically effective doses of urokinase, and that this activity is not present with unfractionated heparin.

Animals↗
PubMed1992

Influence of recombinant hirudin and unfractionated heparin on thrombin and factor Xa generation in extrinsic and intrinsic activated systems.

Using biochemically defined conditions on a fast kinetic centrifugal analyzer the effect of recombinant hirudin (rH) and unfractionated heparin (UH) on thrombin and factor Xa generation was investigated. Diluted fibrinogen deficient human plasma was incubated with increasing concentrations of the anticoagulants and protease generation was initiated either by extrinsic (EA; thromboplastin/calcium chloride) or intrinsic (IA; ellagic acid/cephaloplastin/calcium chloride) activation of the coagulation process. Generation of thrombin or factor Xa was measured continuously by amidolytic assays using the specific chromogenic substrates Spectrozyme TH and Spectrozyme FXa. By means of calibration curves for thrombin and factor Xa the IC50 values for the inhibition of the proteases were calculated. It was found that rH and UH were nearly equally effective in inhibiting both the thrombin and factor Xa formation after IA, whereas in EA system rH produced a stronger inhibition on thrombin generation than UH, which in general showed a more pronounced effect after intrinsic than after extrinsic activation. The results suggest that, with regards to thrombin and factor Xa generation, rH does not exhibit a much higher activity than UH. This may be an expression that thrombin-mediated positive feedback-reactions are not influenced by rH as strongly as expected when using a highly specific and selective thrombin inhibitor. Furthermore, it can be concluded that protease generation assays may be useful in the characterization of anticoagulants/antithrombotics.

Blood Coagulation↗