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Biomedical subjects

J Fareed

Publications and source records attributed to J Fareed.

At least 181 records · Page 10Linked to original sources
PubMed1994

Fibrinolytic compromise by simultaneous administration of site-directed inhibitors of thrombin.

Newly developed synthetic and recombinant thrombin inhibitors possess strong anticoagulant effects. Despite these effects, interactions of these agents with enzymes in the fibrinolytic network result in the modulation of such proteases as t-PA, u-PA and streptokinase. The inhibitory spectrum of several thrombin inhibitors [D-Phe-Pro-Arg-H(GYKI 14166), D-MePhe-Pro-Arg-H(GYKI 14766), Boc-D-Phe-Pro-Arg-H (GYKI 14451), Ac-D-Phe-Pro-boroArg-OH (DuP 714), recombinant hirudin (r-Hir) and unfractionated porcine mucosal heparin complexed with antithrombin III (Heparin/AT-III)] was studied towards various serine proteases such as tissue plasminogen activator (t-PA), plasmin, plasminogen/streptokinase complex, urokinase and kallikrein. Aprotinin was also studied in the same systems as the thrombin inhibitors. All four tripeptide derivatives were found to inhibit t-PA, plasmin and plasminogen/streptokinase complex at micromolar concentrations (IC50: 0.57 mM-3.3 microM). Boc-D-Phe-Pro-Arg-H and Ac-D-Phe-Pro-boroArg-OH also inhibited urokinase, while Ac-D-Phe-Pro-boroArg-OH inhibited kallikrein as well (IC50: 0.15 mM-16 microM). In contrast, r-Hir and Heparin/AT-III did not inhibit any of these enzymes at millimolar concentrations (IC50 > or = 1 mM). Aprotinin inhibited plasmin, plasminogen/streptokinase complex and kallikrein at micromolar concentrations (IC50: 3.1-0.85 microM). In a rabbit thrombolysis model, where pre-formed clots are lysed by streptokinase, simultaneous administration of D-MePhe-Pro-Arg-H or Ac-D-Phe-Pro-boroArg-OH, at concentrations approximately 1 mumol/kg, i.v. resulted in complete inhibition of the fibrinolytic process. Aprotinin at 0.1 mumol/kg, i.v. produced similar inhibition. These results demonstrate that thrombin inhibitors may exert significant antiprotease actions against various fibrinolytic enzymes.

Amino Acid Sequence↗
PubMed1994

Antithrombotic agents stimulate the synthesis and modify the sulfation pattern of a heparan sulfate proteoglycan from endothelial cells.

Low molecular weight heparins, namely CY 216 and CY 222 (Sanofi/Choay); OP 622 and OP 386 (Opocrin); PK 10169 (Pharmuka); an oligosaccharide prepared from heparin by heparitinase II digestion; chemically sulfated glycosaminoglycans and polysaccharide namely Suleparoid (Syntex), Aprosulate (Luitpold-Werk); chemically modified glycosaminoglycans GAGPS and MPS (Luitpold-Werk) as well as unmodified heparin stimulate two to three fold the synthesis of a heparan sulfate with antithrombotic activity secreted by endothelial cells in culture. The stimulation is concentration dependent and specific for the endothelial cell. The [35S]-heparan sulfate synthesized in the presence of heparin and/or the tested antithrombotic agents has shown a high degree of sulfation of the iduronic acid residues as revealed by the analyses of the disaccharide products formed from the heparan sulfate by the action of bacterial heparitinases. The features of the above compounds in common with heparin are their polymeric nature and a high change density, as well as their pharmacological activities as potent antithrombotic agents "in vivo". These combined observations reinforce the proposition that the antithrombotic activity of heparin, low molecular weight heparins and the chemically modified polysaccharides could be related to the increased production of this peculiar heparan sulfate by endothelial cells.

Animals↗
PubMed1994

Role of tissue factor pathway inhibitor in post surgical deep venous thrombosis (DVT) prophylaxis in patients treated with low molecular weight heparin.

Low molecular weight heparins (LMWHs) are now considered to be the drugs of choice for prophylaxis against deep venous thrombosis (DVT) in post operative patients undergoing both general and orthopaedic surgical procedures. Despite extensive research, the exact mechanism of the antithrombotic activity of LMWHs remains unclear. These agents have been shown to activate the fibrinolytic system and to directly inhibit both the activity and the generation of factor Xa and thrombin. New evidence suggests that LMWHs also stimulate the release of endogenous tissue factor pathway inhibitor (TFPI) from the vascular endothelium. This study was designed to investigate the role of TFPI in mediating the antithrombotic activity of LMWHs. We measured the plasma levels of TFPI in a group of post orthopaedic surgery patients treated with daily subcutaneous injections of LMWH and a group of patients treated with placebo. In the placebo group (n = 25), the plasma TFPI levels were slightly elevated immediately after surgery but returned to their baseline value by the fifth post operative day. In contrast, in the group of patients treated with LMWH (n = 34), the plasma levels of TFPI increased significantly and remained elevated for up to 7 days following surgery. However, the TFPI levels in both groups showed wide patient to patient variability. These results indicate that LMWHs stimulate the release of TFPI into the bloodstream of post surgical patients. This suggests the importance of TFPI in mediating the antithrombotic activity of LMWHs.

Aged↗
PubMed1994

Low molecular weight dermatan sulfate as an antithrombotic agent. Structure-activity relationship studies.

A structure-activity relationship of low molecular weight dermatan sulfate was undertaken to understand better this new non-heparin, glycosaminoglycan-based antithrombotic agent. A dermatan sulfate prepared from bovine intestinal mucosa [average molecular weight (MWavg) 25,000], and currently in clinical trials as an antithrombotic agent, was used in this study. Dermatan sulfate was partially depolymerized using hydrogen peroxide and copper(II) as catalyst to MWavg 5600 to obtain a low molecular weight dermatan sulfate. This low molecular weight dermatan sulfate was then fractionated by gel permeation chromatography to obtain four subfractions having MWavg 7800, 5500, 4200 and 1950. The dermatan sulfate, low molecular weight dermatan sulfate and its subfractions showed substantially different optical rotations. The 1H-NMR spectroscopic analysis of dermatan sulfate samples showed some differences including increased content of GalpNAc4S6S residues and improved resolution in ring resonances for low molecular weight dermatan sulfate fractions, primarily the result of reduced molecular weight and lowered heterogeneity. Saccharide compositional analysis relied on chondroitin ABC lyase treatment followed by capillary electrophoresis. Polyacrylamide gel-based oligosaccharide mapping was also performed by treating dermatan sulfate samples with chondroitin B, AC and ABC lysases. These analyses showed increased amounts of sulfation as the MWavg decreased. In vitro bioassay showed maximum anti-Xa activity in the 4.2 kDa fraction and maximum heparin cofactor II-mediated anti-IIa activity in the 5.5 kDa fraction. The in vivo antithrombotic activity of these fractions was measured using a modified Wessler stasis thrombosis model. The 4.2 kDa fraction showed greater antithrombotic activity than the other low molecular weight dermatan sulfate fractions, dermatan sulfate, and low molecular weight dermatan sulfate. This enhanced activity may result from several structural features of the 4.2 kDa fraction including: a high content of 4,6- and 2,4-disulfated disaccharide sequences; the requirement of specific chain length; a change in the ratio of iduronic to glucuronic acid; and the presence of chondroitin ABC lyase resistant material.

Animals↗
PubMed1994

Comparative studies on the inhibitory spectrum of recombinant hirudin, DuP 714 and heparin on thrombin and factor Xa generation in biochemically defined systems.

The effect of antithrombotic drugs on the generation of serine proteases was studied in a biochemically defined system in which the prothrombin complex concentrate Konyne provided the necessary coagulation factors in the absence of plasma. The amount of thrombin and factor Xa generation was measured with a chromogenic substrate on a microcentrifugal analyzer. Furthermore, the assay was modified by supplementation with either purified antithrombin III or factor V. The synthetic peptide Ac-(D)Phe-Pro-boroArg-OH (DuP 714) was shown to be the most effective inhibitor of thrombin and also had strong inhibitor actions against factor Xa generation. Recombinant hirudin (rH) was nearly as active as DuP 714 on thrombin generation, however, it was less effective on factor Xa generation. With rH no concentration-dependent inhibition of factor Xa generation was found, i.e. over a wide range of concentration it only produced a steady inhibition of about 40-50% without further increase. The addition of AT-III to the system did not influence the action of DuP 714 or rH, but it strongly increased the inhibitory effects of unfractionated heparin (PMH) as well as of a low molecular weight heparin (LMWH) on both thrombin and factor Xa generation. The addition of factor V to the assay system did not cause any changes in the activity of all agents on protease generation.

Amino Acid Sequence↗
PubMed1994

Protamine sulfate neutralization of the anticoagulant activity of Aprosulate, a synthetic sulfated lactobionic acid amide.

Aprosulate or lactobionic acid is a highly sulfated analogue of heparin which is currently undergoing clinical trials in Europe as a potential antithrombotic drug. Aprosulate exerts a strong anticoagulant effect in plasma as a result of its interaction with heparin cofactor II. In this study, the ability of protamine sulfate to neutralize the anticoagulant activity of Aprosulate was investigated. In vitro, ex vivo, and in vivo coagulation studies were performed using various clotting assays such as the APTT, Heptest, and thrombin time as a measure of the anticoagulant activity of Aprosulate. In the first study, protamine sulfate when administered in vitro to plasma samples containing various concentrations of Aprosulate was found to effectively neutralize the anticoagulant activity of the Aprosulate in both normal human and normal monkey plasma systems. However, the relative index of neutralization of Aprosulate was assay dependent. Protamine sulfate was also found to antagonize the anticoagulant effects of Aprosulate in an ex vivo study. The ex vivo supplementation of protamine sulfate to plasma samples collected at various time intervals following the subcutaneous administration of Aprosulate to a group of primates completely neutralized the anticoagulant activity of the Aprosulate. In a third in vivo study, protamine sulfate when injected intravenously into the bloodstream of a group of primate was found to completely neutralize the anticoagulant effects of a previously administered dosage of Aprosulate. The results of these three studies clearly suggest that protamine sulfate can be used to effectively neutralize the anticoagulant activity of Aprosulate.

Animals↗
PubMed1994

Feasibility study of heparin mass calibrator as a GPC calibrator for heparins and low molecular weight heparins.

The proposed European Pharmacopoeial (EP) method for molecular weight determination of low molecular weight heparins (LMWHs) has been shown to have a range which is too narrow to allow for the accurate molecular weight determinations of all LMWHs. We have recently shown that a chemically degraded benzyl ester of unfractionated heparin, ITH-3, is a better calibrator using this methodology. Data is presented here which indicates that this calibrator cannot only be used to determine the molecular weights of LMWHs but also of unfractionated heparins. Therefore, it is now renamed heparin mass calibrator or HMC because of this extension of range. Weight average molecular weight, number average molecular weight, peak molecular weight, and dispersity values were calculated using the HMC calibration and a reference narrow-range 19-calibrator method for various LMWHs and unfractionated heparins. Values for the parameters calculated using the HMC calibration were found not to be significantly different from those of the reference method until the molecular weight exceeded 15.0 kDa. In contrast, the molecular weight profile obtained with the proposed EP method was significantly different from the reference method for samples > 8.0 kDa. The range exhibited by the HMC calibrator should allow it to be used for both LMWHs and unfractionated heparins.

Chromatography, High Pressure Liquid↗
PubMed1994

Current trends in the development of anticoagulant and antithrombotic drugs.

Developments in biotechnology, synthetic chemistry, and extraction methods have contributed significantly to provide many newer antithrombotic and anticoagulant drugs. Many of these drugs exhibit mechanisms of actions distinct from heparin and oral anticoagulants. The depolymerization of heparin has resulted in the development of LMWHs. These drugs have now attained the agent of choice status for the prophylaxis of postsurgical and medical thrombotic disorders. LMWHs are now being clinically evaluated for the treatment of established thrombosis and prevention of post-acute angioplasty occlusion and reocclusion. Many newer applications of these agents will be proposed in coming years. Synthetic and recombinant antithrombin agents, such as hirudin and hirulog, have been claimed to exhibit effective anticoagulant and antithrombotic actions. The clinical data, however, are rather limited, and additional validation studies are needed. These agents, however, provide an alternate anticoagulation approach in patients who are refractory to the actions of heparin or who developed heparin-induced thrombocytopenia. Both hirudin and peptide conjugates are undergoing extensive clinical trials throughout the world in various indications. Once validated, their optimized use will provide physicians and surgeons an alternate anticoagulant approach for heparin-compromised patients. Glycosaminoglycans, such as dermatan sulfate, heparan sulfate, and other mixtures, have been developed for various indications. These drugs, however, are relatively inferior to LMWHs for the prophylaxis of thromboembolism. Although these agents have been used for phlebitis and other indications, well-designed objective clinical trials are not available at this time. Because these agents exhibit other effects, such as the effect on smooth muscle cell proliferation, these may be of some value in the control of post-percutaneous transluminal coronary angioplasty restenosis. Several synthetic analogs of heparin and related glycosaminoglycans have also been developed. One of these agents is a synthetic pentasaccharide that represents the AT-III binding site in the heparin molecule. This agent produces a strong anti-Xa effect and is devoid of any antithrombin actions. This agent is currently being developed for the prophylaxis of thromboembolism. The synthetic pentasaccharide is devoid of any effects on platelets and thus does not produce any thrombocytopenic effects. Thus it may be useful in those patients who develop thrombocytopenia and white clot syndrome. A hypersulfated lactobionic acid analog has also been developed as an antithrombotic agent. This agent was initially found to produce its antithrombotic action via HC-II. More recent data, however, show that it also releases TFPI from endogenous sites.(ABSTRACT TRUNCATED AT 400 WORDS)

Anticoagulants↗
PubMed1994

Automation and quality control in the coagulation laboratory.

Hemostasis is a balance between complex interactions of directly opposing systems (coagulation and fibrinolysis) with seemingly unrelated systems at both the enzymatic and cellular levels (platelets, endothelium, leukocytes). It should not be surprising that coagulation disorders often accompany many different disease states. Because the function of each protein involved in coagulation is now better defined, newer methodologies have been developed to assay them. In this regard, the hemostasis laboratory can take a two-step approach to diagnosis: global screening and targeted analysis. Several new global test systems provide more detailed, quantitative, and more physiologically relevant evaluations than earlier assays allowed. In addition, individual enzymes, inhibitors, cellular release products, and low molecular weight products of activation reactions (molecular markers) can now be measured in sensitive, specific assays. With this new perspective, genetic predisposition to pathologic hemostatic conditions can be identified through molecular biology and can be identified during the early stages of disease (i.e., at subclinical stages before major pathologic complications are established), and more specifically targeted prophylactic, as well as therapeutic drug interventions, can be administered. The molecular markers of hemostatic activation that can be assessed by various immunochemical methods provide very early evidence of thrombotic, fibrinolytic, or platelet-involved aberrations. Technological advances in methodology and instrumentation have changed the scope of all clinical laboratories but, in particular, that of the coagulation laboratory. The dramatic growth and development have resulted from the influences of clinical chemistry, clinical immunology, pharmacology, biochemistry, and biotechnology. Analytical instruments for use in hemostatic testing go beyond plasma or whole blood clot-based readers, platelet aggregometers, and microscopes to a range of automated, discrete, chemistrylike analyzers, spectrophotometers, microliter ELISA systems, RIA systems, and multiprobe instruments designed to measure simultaneously the different assay end-points of colorimetric and clotting assays and flow cytometers. Instruments are designed for batch processing of single tests on multiple samples or multiple test panels on a single sample. Versatility ranges from instruments that measure only the final reaction solution, by end-point or kinetic analysis, to instruments that automatically pipet reagents and sample, incubate, and analyze the reaction for truly walk-away assay performance. Typically, a wider range of assays are available in automated laboratories as opposed to laboratories performing manual assays.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1993

The antithrombotic and anticoagulant effects of a synthetic tripeptide and recombinant hirudin in various animal models.

The pharmacologic activities of two thrombin inhibitors (D-MePhe-Pro-Arg-H, recombinant-hirudin) were compared in two animal models. The antithrombotic effect was investigated in vivo in rabbits using a modified Wessler stasis thrombosis model. During these experiments, blood was drawn for ex vivo testing to determine the coagulation profile and to determine plasma concentrations using pre-constructed calibration curves. A dose-dependent antithrombotic effect was observed for both agents. On an equigravimetric basis (100 micrograms/kg i.v.), r-hirudin showed a stronger antithrombotic effect than the tripeptide, which correlated well with the ex vivo anticoagulant effect. No adverse reactions were observed during this study. In a rabbit ear bleeding model, a dose and time dependent hemorrhagic effect was observed for both agents. Only slight bleeding effects were observed at 1.0 mg/kg dosages. These studies show that the tripeptide D-MePhe-Pro-Arg-H and r-hirudin are specific thrombin inhibitors with potent antithrombotic effects and a high therapeutic (antithrombotic/hemorrhagic) index. Furthermore, the results of these two animal models and ex vivo analyses can be used to determine the therapeutic index of thrombin inhibitors.

Amino Acid Sequence↗
PubMed1993

A simulated post-angioplasty low molecular weight heparin schedule in a non-human primate model.

Due to a variety of pathophysiologic processes the long-term success rate of percutaneous transluminal angioplasty (PTCA) is only 50-70%. Acute restenosis also occurs in 30-40% of patients. Currently, studies are in progress to investigate the influence of low molecular weight heparin (LMWH) prophylaxis on the patency rate after PTCA. Our aim was to determine an optimal schedule to start the LMWH prophylaxis after the routinely performed heparinization. The alterations of the hemostatic parameters during the drug regimen change-over were evaluated. Non-human primates (Macaca mulatta) were divided into 6 treatment groups (n = 3/group). Three groups received heparin i.v. at 15 U/kg to mimic the end phase of therapeutic treatment infusion given 12-24 hrs. after PTCA. Three groups received full heparinization (250 U/kg i.v.) to mimic patients without the above interim phase therapy. Following both regimens, LMWH (Mono-Embolex) (1 mg/kg s.c.) was started at various intervals. The group initially treated with 15 U/kg heparin exhibited a continued anticoagulant effect when LMWH was started 30 min. after the heparin injection. Whereas, when LMWH was started after 2 hrs. the measurable anticoagulant effect was lost during 1 and 3 hrs. after the heparin injection. When LMWH was started 2 or 4 hrs. after the 250 U/kg dose, the anticoagulant response was sustained. Aside from the anti-IIa and the anti-Xa activity, there was no significant difference in other coagulation parameters between these two regimens. The fibrinolytic system was not altered in the therapeutic heparinization group. However, after the initial bolus of 250 mg/kg heparin, the monkeys treated with LMWH exhibited higher t-PA and D-dimer levels. Although our data shows definite differences between the two drug treatment schedules, further studies are warranted before an optimal drug regimen can be suggested for clinical use.

Angioplasty, Balloon↗
PubMed1993

Molecular weight profiling of low molecular weight heparins utilizing a heparinase degraded oligosaccharide mixture as a calibrator.

Heparinase degraded heparin fragments (HDHF) are enriched with a UV chromophore and can be utilized as calibrators to determine the molecular weight profile of low molecular weight heparins (LMWH's). In a standard protocol (1), the second to the last peak is assumed to be a hexasaccharide with a molecular weight of 1.8 kDa. All other peak molecular weights in the elution profile are assigned based upon this assumption. In this study, synthetic analogues of heparin with a defined molecular weight have been used to investigate the validity of this assumption. These compounds included a sulfated bis-lactobionic acid amide (2.4 kDa), a pentasaccharide (1.7 kDa), and lactose polysulfate (1.2 kDa). With reference to these internal standards, the second to the last peak of the HDHF mixture was found to elute after the pentasaccharide and close to the lactose polysulfate suggesting that it is a tetrasaccharide. For additional validation, calibration curves were constructed using individual calibrators as the reference method as well as the HDHF method. Several low molecular weight heparins were profiled for their molecular weight using these methods. In comparison to the reference method, the molecular weights obtained with the HDHF method were 25-40% higher. When the results were recalculated assuming the molecular weight of the second to the last peak as 1.2 kDa, the HDHF results compared well with the reference method. Additionally, it is seen that the HDHF method does not identify molecular components greater than 8.0 kDa.

Calibration↗
PubMed1993

Molecular weight and biochemical profile of a chemically modified heparin derivative, Suleparoide.

Recently, a new chemically modified derivative of heparin (Suleparoide, Syntex Laboratories Buenos Aires, Argentina) was introduced for the prophylaxis of thrombosis and treatment of vascular disorders. This agent is claimed to contain a depolymerized, chemically modified, heparin derivative with similar biologic actions as heparan sulfate. To study the pharmacologic profile of this agent, we have defined its molecular weight distribution profile, utilizing a computerized gel permeation chromatographic system equipped with ultraviolet and refractive index detectors. Suleparoide exhibited a normal molecular distribution profile with no contaminants. It exhibited a weight average of 9.3 K DA and an apparent peak MW of 8.0 K DA. Approximately 50% of the molecular components were < 5.0 K DA and 40% > 5.0 K DA. The results from these studies on the mechanisms show that Suleparoide has anticoagulant activity primarily mediated through Heparin Cofactor-II (HC-II) and because of its novel mechanism of action, further investigations on the biochemical profile of Suleparoide are carried out. Global clotting tests such as Activated Partial Thromboplastin Time (APTT), Heptest and Thrombin Time (TT) revealed a concentration dependent effect in all assays. Plasma samples supplemented with Suleparoide exhibited no significant anti-Xa and anti-IIa activities. However, in the HC-II mediated inhibitory assay for IIa, Suleparoide exhibited significant activity. In contrast, the Antithrombin-III (AT-III) mediated inhibition of IIa was much weaker.

Antithrombin III↗
PubMed1993

Studies on the pharmacokinetics and pharmacodynamics of recombinant hirudin (rHV2-Lys 47) after intravenous and subcutaneous administration in dogs.

In recent years, the pharmacological and biochemical characterization of hirudins has taken a major upswing due to the availability of this natural polypeptide in recombinant form. Despite this, the current knowledge on the pharmacokinetics and pharmacodynamics of recombinant hirudin (rH) appears to be incomplete. The present study was designed to investigate the relationship between plasma concentrations of rH with corresponding antithrombin responses after intravenous (i.v.) and subcutaneous (s.c.) administration in dogs. Four male, Mongrel dogs were each injected with an i.v. (bolus) dose (1 mg/kg) of one specific variant of rH, i.e. rH with a lysine residue in position 47 (rHV2-Lys 47). The dogs were injected with a s.c. dose (1 mg/kg) of rHV2-Lys 47 after one week. After each dose, blood was collected at different time intervals, plasma separated and stored at -70 degrees C. Plasma concentrations of rHV2-Lys 47 were determined using an enzyme-linked immunosorbent assay (ELISA) method and pharmacokinetic parameters were determined using standard non-compartmental methods. The ex vivo antithrombin activity of the drug was measured using activated partial thromboplastin time (APTT), calcium-thrombin time (Ca++TT) and a chromogenic anti-IIa assay. The results from this study indicate that the pharmacokinetic behavior of rHV2-Lys 47 is strongly influenced by the route of administration. In all three functional assays used, a significant correlation was obtained after i.v. administration between plasma concentrations and corresponding responses over the time period of the study when compared to s.c. administration. The results are indicative of a probable structural and functional modification of this rH variant after s.c. administration which may be responsible for the altered pharmacokinetics and pharmacodynamics after s.c. dosing.

Animals↗
PubMed1993

Alteration of pharmacokinetics and pharmacodynamics of recombinant hirudin (rHV2-Lys 47) after repeated intravenous administration in dogs.

Native hirudin is a heterogenous polypeptide obtained from the medicinal leech, Hirudo medicinalis. Recent advances in molecular biological techniques have led to the availability of large amounts of hirudin in the recombinant form. Recombinant hirudins (rH) are currently being investigated for potential use in the prophylaxis and treatment of deep venous thrombosis (DVT), in disseminated intravascular coagulation (DIC) and during cardiovascular bypass surgery. In this study, one specific variant of rH with a lysine residue in position 47 (rHV2-Lys 47) was administered in dogs in a multiple dose regimen of 2 mg/kg (i.v. bolus) for three weeks with a dosing interval of one week. After each dose, blood samples were collected at regular time intervals, plasma separated and stored at -4 degrees C. Concentrations of rHV2-Lys 47 in each sample were determined using an enzyme-linked immunosorbent assay (ELISA). Ex vivo antithrombin responses measured included activated partial thromboplastin time (APTT), calcium-thrombin time (Ca++TT-10 NIH units/ml) and a chromogenic anti-IIa assay. It was the purpose of this study to detect any sensitization or desensitization of antithrombin responses when rHV2-Lys 47 is used in a repeated fashion such as would be expected in the prophylaxis of DVT. The results indicated that there was no attenuation in the responses; however, there was a sensitization of response as measured by the Ca++TT (10 NIH units/ml). These findings could have major implications in the clinical use of rH where this drug is expected to be used in a multiple dose regimen.

Animals↗
PubMed1993

Effects of aprotinin on anticoagulant monitoring: implications in cardiovascular surgery.

This study was designed to evaluate anticoagulant monitoring of heparin and platelet function in the presence of aprotinin. Aprotinin added to heparinized whole blood at concentrations equal to (30 micrograms/mL), twice, and four times that used in cardiopulmonary bypass operations synergistically elevated the activated clotting time (ACT) (536 +/- 73, 651 +/- 86, and 787 +/- 71 seconds, respectively) over the value with heparin alone (384 +/- 66 seconds) (p < 0.001). In addition, the ACT of heparin-aprotinin mixtures supplemented with protamine showed that the heparin was not completely neutralized (131 +/- 12 versus 98 +/- 7 seconds). Specific tests revealed that the effect on ACT caused by aprotinin is not equal to the anticoagulant effect of heparin. Thus there is a risk of under-heparinization if the ACT is used as a monitor when aprotinin is present. Furthermore, protamine doses relative to the heparin concentration, and not relative to the ACT, should be used to reverse heparin. In studying the effects of aprotinin on platelet function, there was a significant inhibition of aggregation when normal platelets were supplemented with aprotinin, but not for platelets of postoperative patients. This suggests that aprotinin may interact more favorably with nonactivated platelet surfaces, reducing or inhibiting the expression of receptors. Thus it is necessary to treat a patient with aprotinin before beginning cardiopulmonary bypass. Based on these data, the effect of aprotinin on the hemostatic system and its drug interactions must be considered to optimize safety and efficacy during cardiopulmonary bypass operations.

Aprotinin↗