Generic Versions of Low Molecular Weight Heparin May Not Have the Same Safety-Efficacy Profile as the Branded Low Molecular Weight Heparins In Acute Coronary Syndrome.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1098-1098
Author(s):  
Debra Hoppensteadt ◽  
Walter Jeske ◽  
Evangelos Litinas ◽  
Omer Iqbal ◽  
Jeanine M. Walenga ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Animal Studies ◽  
Conflicts Of Interest ◽  
Low Molecular Weight ◽  
South American ◽  
Primate Model ◽  
Coronary Syndrome ◽  
Molecular Weight Distributions ◽  
Branded Product ◽  
Aggregation Of Platelets

Abstract Abstract 1098 LMWHs lp;&5q;1such as enoxaparin and dalteparin are widely used for the management of ACS. Recently, several generic versions of enoxaparin and dalteparin have been approved in Asian and South American countries for all of the branded product's indications. However, no data on their clinical equivalence in ACS is available. Since generic versions of enoxaparin and dalteparin are manufactured by different processes and may use starting material from different sources, these drugs may differ in their pharmacological profile in simulated ACS settings. A branded version of enoxaparin was compared with three of the generic versions in a primate model at a dosages of 1 mg/kg IV. Such pharmacodynamic parameters such as TFPI release, TAFI modulation, vWF release, and TF mediated platelet activation. In addition, the anticoagulant effects of these drugs were also measured after IV administration using iSTAT ACT and aPTT. Simulated catheter related thrombosis studies were also carried out to differentiate each agent in contact, intrinsic and extrinsic clotting systems. The generic versions of enoxaparin namely, Cutenox (Gland Pharma, India), Fibrinox (Sandoz, Argentina), Versa (EuroPharma, Brazil) exhibited product based pharmacodynamic differences compared with the branded product and the results are provided in the following table. Drug TFPI (ng/ml) TAFI (% NHP) VWF (% NHP) Enoxaparin 210+10 65+4.8 138+12 Fibrinox 160+10 74+8 175+16 Versa 205+16 59+7 148+12 Cutenox 180+11 60+4 110+12 Each of the generic products exhibited its own specific pharmacologic profile despite comparable molecular weight distributions and anti-Xa potencies. The ACT values at a 10 ug/ml varied from 172–200 seconds among the four products. The ED 50 values in the catheter related thrombogenesis model varied considerably. Significant differences were noted in the anticoagulant effects of each of these agents as compared with the branded products. Differences were also noted in HIT antibody mediated aggregation studies. The HIT antibody mediated aggregation of platelets varied from 17–28%. The pharmacodynamic differences between the branded and generic versions of LMWHs may be due to the higher dosages used and the potential IV administration which leads to higher circulating levels of these agents. These observations suggest the need for additional animal studies and clinical trials to validate the use of generic versions of LMWHs in ACS. Disclosures: No relevant conflicts of interest to declare.

Generic Low Molecular Weight Heparins May Not Have the Same Safety –Efficacy Profile As the Branded Low Molecular Weight Heparins in Acute Coronary Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2308-2308
Author(s):  
Debra Hoppensteadt ◽  
Walter Jeske ◽  
Jeanine M. Walenga ◽  
Bruce E Lewis ◽  
Jawed Fareed
Keyword(s):  
Molecular Weight ◽  
Acute Coronary Syndrome ◽  
Animal Studies ◽  
Conflicts Of Interest ◽  
Pharmacokinetic Parameters ◽  
Low Molecular Weight ◽  
Low Molecular Weight Heparins ◽  
Primate Model ◽  
Coronary Syndrome ◽  
Molecular Weight Distributions

Abstract Abstract 2308 Low molecular weight heparins such as enoxaparin and dalteparin are widely used for the management of Acute Coronary Syndrome (ACS). Recently, several generic versions of enoxaparin and dalteparin have been approved in various countries for all of the branded product's indications. However, no data on their clinical equivalence in ACS is available. Since generic versions of enoxaparin and dalteparin are manufactured by different processes and may use starting material from different sources, these drugs may differ in their pharmacological profile in simulated ACS settings. To compare the pharmacodynamic effects, a branded version of enoxaparin was compared with three generic versions in a primate model at a dosage of 1 mg/kg IV. Such pharmacokinetic parameters as TFPI release, TAFI modulation, vWF release, and TF mediated platelet activation were measured. Anticoagulant effects of these drugs were also measured after IV administration using iSTAT ACT and aPTT. Simulated catheter related thrombosis studies were carried out to differentiate each agent in contact, intrinsic and extrinsic clotting systems. The generic versions of enoxaparin namely, Cutenox (Gland Pharma), Fibrinox (Sandoz AG) and Versa (EuroPharma) exhibited product based pharmacodynamic differences compared with the branded product and the results are provided in the following table. Each of the generic products exhibited its own specific pharmacologic profile despite comparable molecular weight distributions and anti-Xa potencies. Significant differences were noted in the anticoagulant effects of each of these agents as compared with the branded products. Some differences were also noted in HIT antibody mediated aggregation studies. The differences between the branded and generic versions of LMWHs may be due to the higher dosages used and the IV administration which leads to higher circulating levels of these agents. These observations suggest the need for additional animal studies and clinical trials to validate the use of generic versions of LMWHs in such critical indications as ACS and related syndromes. Disclosures: No relevant conflicts of interest to declare.

Tertiary amine catalyzed photo-induced controlled radical polymerization of methacrylates

2015 ◽  
Vol 6 (30) ◽  
pp. 5362-5368 ◽  
Author(s):  
Qiang Fu ◽  
Thomas G. McKenzie ◽  
Shereen Tan ◽  
Eunhyung Nam ◽  
Greg G. Qiao
Keyword(s):  
Molecular Weight ◽  
Radical Polymerization ◽  
Uv Irradiation ◽  
Tertiary Amine ◽  
Controlled Radical Polymerization ◽  
Low Molecular Weight ◽  
Molecular Weight Distributions ◽  
Weight Distributions ◽  
End Group

A novel tertiary amine catalyst and trithiocarbonate synergistic photo-induced controlled radical polymerization of methacrylates has been realized under mild UV irradiation, yielding polymethacrylates with low molecular weight distributions and excellent end-group fidelity.

scholarly journals Inhibition of Plasmin Generation in Plasma By Heparin, Low Molecular Weight Heparin and a Covalent Antithrombin-Heparin Complex (ATH)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4217-4217
Author(s):  
Gabriela Chang ◽  
Helen M. Atkinson ◽  
Leslie R. Berry ◽  
Anthony K.C. Chan
Keyword(s):  
Molecular Weight ◽  
Plasminogen Activator ◽  
Low Molecular Weight Heparin ◽  
Conflicts Of Interest ◽  
Area Under The Curve ◽  
Low Molecular Weight ◽  
Plasminogen Activator Inhibitor 1 ◽  
Significant Difference

Abstract Introduction: Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are widely used anticoagulants for thrombosis treatment. However, these anticoagulants have limitations such as increased bleeding, variable dose response, required frequent monitoring, and, in the case of LMWH, inability to inhibit thrombin. This has led to the development of a covalent complex of antithrombin and heparin (ATH), which has been shown to overcome many of these shortcomings. ATH has faster rates of inhibition of many coagulation factors, is able to inhibit clot-bound thrombin, and is a more effective inhibitor of both venous and arterial thrombosis in animal models. Moreover, in a rabbit thrombosis model, ATH has been shown to decrease clot mass and fibrin accretion, while the contrary was observed for UFH. From these observations, it was suggested that ATH may enhance fibrin breakdown and thus led to investigations into the effects of UFH and ATH on fibrinolysis. In vitro studies have shown that UFH enhances antithrombin inhibition of plasmin. In addition, ATH displays a slightly greater inhibition of plasmin generation and activity. Such studies were conducted in purified systems, in the absence of other plasmin inhibitors naturally present in plasma. Therefore, the aim of the present study was to compare the effects of UFH, LMWH, and ATH on plasmin generation in plasma. Methods: At 37°C tissue plasminogen activator (tPA) and soluble fibrin fragments (fib) were added to normal adult pooled platelet poor plasma supplemented with 0.35, 0.7, 1.4, or 2.1 U anti-Xa/ml UFH, LMWH, or ATH, to initiate plasmin generation (8.93nM tPA and 300µg/ml fib). At various time points, subsamples were mixed with excess plasminogen activator inhibitor 1 (PAI-1) (55.12nM) to stop further plasmin generation. The plasmin concentration at each time point was determined using a plasmin-specific chromogenic substrate and a standard curve produced from purified plasmin. Results: Comparisons of mean area under the curve (AUC) for plasmin generation displayed a significant decrease in plasmin generation in the presence of all three anticoagulants at all doses tested (p<0.05). Comparing the anticoagulants at similar doses, plasmin generation was significantly decreased in the presence of ATH (15384.66±1930.23nM/min) compared to LMWH (23892.28±3090.54nM/min) at 0.7 U/ml (p<0.05). At a dose of 1.4 U/ml, there was significantly less plasmin generated, over time, in the presence of UFH (20089.49±3022.1623nM/min) and ATH (19273.86±1805.7323nM/min) when compared to LMWH (24743.18±1265.1023nM/min) (p<0.05). There was no significant difference in plasmin inhibition between UFH and ATH at any of the doses tested. Conclusion: The present study supports previous findings that UFH and ATH can facilitate antithrombin inhibition of plasmin. It is also observed that LMWH catalyzes the inhibition of plasmin by antithrombin but possibly to a lesser extent. These findings suggest that ATH has a similar inhibitory effect on plasmin generation and activity in plasma compared to UFH, despite its overall superior anticoagulant properties. Therefore, previous in vivo observations displaying decrease in clot mass with administration of ATH was due to its enhanced anticoagulant abilities and not fibrinolysis enhancement. These findings add to our understanding of ATH mechanisms of action and aid in its development for clinical use. Disclosures No relevant conflicts of interest to declare.

Characterization of Elution Chromatography Fractions from CIS-Polybutadiene by GPC

1970 ◽  
Vol 43 (6) ◽  
pp. 1439-1450 ◽  
Author(s):  
W. V. Smith ◽  
S. Thiruvengada
Keyword(s):  
Molecular Weight ◽  
Molecular Weight Distribution ◽  
Weight Distribution ◽  
Low Molecular Weight ◽  
Molecular Weight Distributions ◽  
Weight Distributions ◽  
Log Normal ◽  
Analytical Fractionation ◽  
Molecular Weight Fractions ◽  
Elution Chromatography

Abstract A preparative fractionation of about 23 g of a commercial cis-polybutadiene rubber is described. The method employed was a solvent elution chromatographic method with very little temperature gradient. The molecular weight distributions of the fractions obtained were determined by an analytical fractionation of 20 mg of polymer. The method was similar to the preparative fractionation and involved solvent elution chromatography. The fractions obtained were assayed for quantity, molecular weight, and molecular weight distribution by GPC. The low molecular weight fractions of the preparative fractionation had molecular weight distributions which could be closely approximated by two log normal distributions, the low molecular weight component having the narrower width. The ratio of weight to number average molecular weight was found to be about 1.1 for these samples. The higher molecular weight fractions could also be approximated by two log normal distributions; however, in these fractions the low molecular weight component had a very broad distribution but constituted only a small portion of the sample. The widths of the GPC curves of the fractions correlate satisfactorily with the molecular weight distributions found by the analytical refractionations. The GPC width is a sensitive criterion of the width of the molecular weight distribution even when only two columns are used. It is felt that the analytical fractionation procedure presented gives more detailed information on the molecular weight distribution than is easily obtainable from an ordinary GPC curve.

Molecular Weight Determinations Of Low Molecular Weight (LMW) Heparins By Ultracentrifugation And High Pressure Liquid Chromatography

1981 ◽  
Author(s):  
Grant Barlow ◽  
N Sugisaka ◽  
F J Petracek
Keyword(s):  
Molecular Weight ◽  
High Pressure ◽  
Liquid Chromatography ◽  
High Pressure Liquid Chromatography ◽  
Low Molecular Weight ◽  
Analytical Ultracentrifuge ◽  
Molecular Weights ◽  
Molecular Weight Distributions ◽  
Weight Distributions ◽  
Heparin Fractions

Molecular weights were independently determined on nitrous acid depolymerized LMW heparin fractions ranging from 2-15 daltons using the analytical ultracentrifuge and high pressure liquid chromatography (HPLC).Sedimentation-diffusion equilibria were obtained in the analytical ultracentrifuge using speeds ranging from 20,000 to 56,000 rpm. Near theta conditions were obtained using 0.5M NaCl as the solvent. Calculations of molecular weight distributions and, from those figures, weight average molecular weights were made using the method described by Scholte (N.Y. Acad Sci. 164, 156, 1969). The results show that weight average values as low as 2,000 daltons can be determined.Sedimentation-diffusion equilibria were obtained in the analytical ultracentrifuge using speeds ranging from 20,000 to 56,000 rpm. Near theta conditions were obtained using 0.5M NaCl as the solvent. Calculations of molecular weight distributions and, from those figures, weight average molecular weights were made using the method described by Scholte (N.Y. Acad Sci. 164, 156, 1969). The results show that weight average values as low as 2,000 daltons can be determined.The HPLC results were obtained using previously described methods (Fed Proc. 36, 89, 1977) and a new highly efficient gel column (TSK gels). Fractionated dextrans were used as reference standards.

Pharmacodynamic Differences of An Anti-Xa Enriched Low Molecular Weight Heparin, AVE 5026 in Comparison to Enoxaparin and Unfractionated Heparin.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4171-4171
Author(s):  
Debra Hoppensteadt ◽  
Angel Gray ◽  
Evangelos Litinas ◽  
Brigitte Kaiser ◽  
Jawed Fareed
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Half Life ◽  
Low Molecular Weight Heparin ◽  
Thrombin Generation ◽  
Time Course ◽  
Fold Increase ◽  
Low Molecular Weight ◽  
Thrombin Time ◽  
Primate Model

Abstract Abstract 4171 AVE5026 (Sanofi-Aventis, Paris, France) represents an anti-Factor (F) Xa enriched ultra low molecular weight heparin (ULMWH) (Mw=2.4 Kda; anti-FXa activity ∼160 U/mg). In comparison to Enoxaparin it has a lower anti-FIIa activity (∼2 U/mg). The oligosaccharide composition of AVE5026 also differs from Enoxaparin and other LMWHs. Besides the molecular and compositional differences, the biologic half-life of AVE5026 (18-20 hours) is significantly longer than Enoxaparin (4-6 hours). In order to compare the other pharmacodynamic differences between AVE5026, Enoxaparin and unfractionated heparin (UFH), a primate model (macaca mulatto) was used since its tissue factor pathway inhibitor (TFPI) profile is comparable to the human response. Individual groups of primates (n=6) were administered with 1 mg/kg SC of either AVE5026, Enoxaparin or UFH. Heptest and APTT measurements were determined on whole blood (WB) and plasma was analyzed for APTT, Heptest, thrombin time (TT), anti-FXa and anti-FIIa effects at varying periods up to 28 hours. TFPI antigen was measured using the assay from Stago (Parsipanny, NJ). Functional TFPI measurements were determined using the kit from American Diagnostica (Stamford, CT). In contrast to UFH, in the WB assays, neither the AVE5026 nor the Enoxaparin produced a strong effect on the APTT and TT, however both demonstrated a strong effect on the heptest assay. AVE5026 produced a much stronger effect with a longer half-life (T½=11 hrs) in comparison to Enoxaparin (T½=6 hrs). In the plasma based systems only UFH produced a measurable effect on the APTT and TT. However, in the heptest and anti-FXa assays, both AVE5026 and Enoxaparin produced a stronger effect, which was much longer with AVE5026 (2-3 fold increase). The plasma time course of TFPI antigen release was longer with AVE5026 in comparison to Enoxaparin and UFH. The ratios of immunologic to functional TFPI levels were also higher in the primates administered with AVE 5026. In the thrombin generation test, AVE5026 produced a sustained effect which lasted longer than Enoxaparin (T½ =16.8 hrs vs. 9.2 hrs.). These results show that AVE5026 produces stronger anti-FXa effects in primates which are associated with a higher circulating level of TFPI and more pronounced suppression of thrombin generation compared to Enoxaparin and UFH. Disclosures: Hoppensteadt: Sanofi-Aventis: Research Funding.

Comparison of Branded Enoxaparin (Lovenox) and a Biosimilar Version of Enoxaparin (Fibrinox)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4385-4385
Author(s):  
Walter Jeske ◽  
Elizabeth McGeehan ◽  
Omer Iqbal ◽  
Debra Hoppensteadt ◽  
Jeanine M. Walenga ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Thrombin Generation ◽  
Conflicts Of Interest ◽  
Average Molecular Weight ◽  
Molecular Profile ◽  
Distribution Analysis ◽  
Thrombin Time ◽  
Plasma Samples ◽  
Branded Product ◽  
Inhibition Of Thrombin

Abstract Abstract 4385 Several biosimilar versions of branded enoxaparin (Lovenox, Sanofi-Aventis, Paris, France) have recently become available throughout the world. These biosimilar enoxaparin preparations are distributed by multiple suppliers in Asia and in North and South America. Enoxaparin represents a complex mixture of oligosaccharides obtained by alkaline depolymerization of porcine mucosal heparin. It is the most widely used low molecular weight heparin which has been validated for clinical use in multiple indications. While the molecular profile and anti-Xa potencies of some of the biosimilar versions of enoxaparin are comparable, product based differences have been reported amongst some of the biosimilar versions of enoxaparin. The purpose of this study was to compare the biochemical and pharmacologic profile of one biosimilar version of enoxaparin, namely Fibrinox (Sandoz SA, Buenos Aires, Argentina) with the branded product Lovenox. The products were compared in equigravimetric amounts, assuming equivalent potency (100 AXa U/mg). Both products exhibited comparable molecular weight profiles in terms of average molecular weight and oligosachharide distribution. Analysis of the antithrombin binding hexasaccharide fractions of Fibrinox and Lovenox indicated the presence of eight distinct hexasaccharides. The relative proportions these hexasaccharides differed between Fibrinox and Lovenox. The anti-Xa and anti-IIa activities were comparable. In the whole blood clot-based assays such as TEG and ACT, both agents produced similar anticoagulant effects. In the plasma based assays such as the APTT, Heptest and thrombin time, both products showed comparable anticoagulant effects in the normal human pooled plasma samples. However, in plasma samples collected from patients with liver disease who were apparently anticoagulant free, the two products showed differences in their anticoagulant effects in the APTT assay (p<0.05). In the TF mediated thrombin generation assay, Fibrinox produced a stronger inhibition of thrombin generation compared to Lovenox (IC50; Fibrinox, 1.6 μ g/ml, Lovenox 2.2 μ g/ml). No differences were observed between the two products in the agonist induced platelet aggregation assays. However in the 14C serotonin release study, Fibrinox produced a stronger HIT serum mediated 14C release (p<0.05). Differences in the fibrinokinetic profile and the inhibition of thrombin activatable fibrinolytic inhibitor activation were observed with these LMWHs. These studies suggest while both the molecular profile and the pharmacopoeial potency of Fibrinox is similar to the branded product, these drugs can be differentiated in some of the other assays and should be evaluated in terms of additional pharmacologic mechanisims to demonstrate bioequivalence. Disclosures: No relevant conflicts of interest to declare.

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