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Biomedical subjects

J Fareed

Publications and source records attributed to J Fareed.

At least 307 records · Page 17Linked to original sources
PubMed1985

Neonatal and maternal fibrinolysis: activation at time of birth.

Utilizing chromogenic synthetic substrate-based methods, determination of the plasma concentration of plasminogen, alpha 2-antiplasmin, alpha 2-macroglobulin, and B beta 15-42-related peptides were made at the time of birth in both newborns and mothers. Plasminogen levels were increased in the maternal group (150 +/- 26%), and markedly decreased in the newborn group (67 +/- 14%). The major inhibitors of fibrinolysis, alpha 2-antiplasmin and alpha 2-macroglobulin, were within normal range in both groups. Determination of B beta 15-42-related peptide showed markedly increased levels in the maternal group above control values (115 +/- 102, normal 29 +/- 12); the newborn group showed values only mildly elevated above control values (39 +/- 21). The results demonstrate increased fibrinolytic activity in both groups, though the degree of activation is significantly higher in the maternal group, as reflected by the higher levels of B beta 15-42-related peptides. Fibrinopeptide A levels confirm an activation of coagulation in both maternal and newborn groups (22 +/- 4 ng/ml and 138 +/- 22 ng/ml, respectively) with a significantly increased level in newborns (2-5 ng/ml normal).

Female↗
PubMed1985

Heparin, its fractions, fragments and derivatives. Some newer perspectives.

A brief attempt has been made to provide an overview of the field of heparinology. As stated, in coming years one should witness significant developments in this area. It is, however, important to caution that the newer products derived from heparin may not behave like heparin, and one must consider their individual molecular and biochemical interactions. The available limited data on heparin may or may not be applicable to the newer heparin fractions or derivatives. Independent preclinical and clinical trials are needed to investigate the pharmacology and therapeutic actions of newer heparin derivatives.

Antithrombin III↗
PubMed1985

In vitro coagulant and amidolytic methods for evaluating the activity of heparin and a low molecular weight derivative (PK 10169).

In summary, the following points have been presented. PK 10169 produced somewhat weaker effects on the coagulant tests in comparison to heparin in various whole blood and citrated plasma assays. In the synthetic substrate assays, PK 10169 produced a pronounced inhibition of various serine proteases in the AT III supplemented system. No significant inhibition was noted in the non-AT III systems. Preliminary data show that PK 10169-AT III complex is capable of producing direct inhibition of the generation of factors Xa and XIIa. In all platelet function tests studied, this agent failed to produce any modulating effects. PK 10169 did not produce an effect on the fibrinolytic system in vitro. However, analysis of blood samples obtained from animals treated in vivo with this agent suggests activation of fibrinolysis. Thus, the mechanism of action must involve certain cellular components or endogenous modulation of the heparin fraction. The newly developed FPA generation test can be modified by various activators or blood systems to mimic closely in vivo physiology. PK 10169 produces a dose response that is more sensitive and more global by this method than the amidolytic anti-Xa or anti-IIa. In contrast to heparin, larger amounts of platelet factor 4 and protamine sulfate are needed to neutralize the anti-Xa and anti-IIa actions of this agent. Additionally, the anti-IIa component is more susceptible to neutralization than the anti-Xa component. Our studies also suggest that PK 10169 is resistant to the action of certain heparin digestive systems, such as heparinase.

Antithrombin III↗
PubMed1985

Studies on the antithrombotic effects and pharmacokinetics of heparin fractions and fragments.

The pharmacokinetics of heparin differ markedly from those of its fractions both in man and in experimental animal models. The route of administration determines the relative availability of different molecular species that exert the anti-Xa, anti-IIa, fibrinopeptide A generation inhibiting actions and the release of tissue plasminogen activator-like activity from the endothelial cell lining. The bioavailability of heparin fractions has proved to be much greater than heparin after subcutaneous or intraperitoneal administration. Most of the low molecular weight heparin fractions exhibit sustained antiprotease and antithrombotic actions. The pharmacokinetics of the specific anti-IIa and anti-Xa actions of heparin and its fractions is dependent on the molecular composition of these agents. Even if the fractions are standardized for identical potencies by the in vitro assays, the elimination rate of anti-Xa and anti-IIa actions are significantly different for each fraction. The antithrombotic actions of heparin and its fractions also vary widely in the rabbit stasis thrombosis model. Different fractions show variable antithrombotic actions against defined thrombogenic challenges. Moreover, selection and potency of a thrombogenic agent is of crucial importance in these studies. The primate (Macaca mulatta) model offers a useful preclinical model for the pharmacologic evaluation of the low molecular heparin fractions. Since the coagulation system and heparinizability index of this model approximate a human response, the data may be used to reflect therapeutic and prophylactic responses, as well as to assess toxic effects, such as bleeding.

Animals↗
PubMed1985

Validity of serine protease inhibition tests in the evaluation and monitoring of the effect of heparin and its fractions.

The advent of heparin fractions for clinical use has prompted a reevaluation of the available methods for the assaying of heparin activity in blood. Newly developed heparin fractions are routinely evaluated in terms of their anti-Xa and anti-IIa amidolytic USP, APTT, and anti-Xa coagulant actions. A wide variation between these assays exists due to the use of nonstandard reagents and varying assay conditions. Amidolytic assays, although more biochemically defined than coagulant assays, do not use a natural substrate and work in a diluted plasma system. This may account for discrepancies and differing sensitivities between results in the amidolytic and coagulant assays. The APTT, PTT, and TT may not be effected by the LMFs, and these are the tests currently used to monitor patients on heparin therapy. A poor correlation is observed between the global tests with the newly developed anti-Xa and anti-IIa assays. Furthermore, marked differences in the inhibitory responses are observed with heparin and its fractions. The anti-Xa and anti-IIa assays may provide a more sensitive assay than the APTT, but the poor correlation between assays suggests a multiple effect of heparin and its fractions. Which assay or assays are the best measure of the antithrombotic efficacy of this drug remains to be determined. However, a random selection of an assay is surely not a proper means to monitor these drugs, and a battery of current methodology should be considered.(ABSTRACT TRUNCATED AT 250 WORDS)

Amides↗
PubMed1985

Usefulness of fibrinopeptide A generation tests in experimental and clinical studies with low molecular weight heparin fractions.

FPA generation test provides a sensitive tool to study the events leading to the production of fibrin from fibrinogen. Drug modulation of pathways resulting in thrombin generation can be readily assessed utilizing the FPA generation test. In circumstances in which conventional clotting and amidolytic methods fail to detect any antiprotease effects, the FPA generation test provides the sensitivity to study these actions. The FPA generation test demonstrates the collective action of antithrombotic agents on inhibition of activation of the pathways leading to the generation of thrombin. The generation systems are easily modified by activators to provide identification of sites, components, and modulating interaction of various heparin derivatives on the hemostatic system. The FPA generation test assesses the overall inhibitory effects of heparin and thus provides insight into the pharmacokinetics of the biologically active components of these agents. Currently, the FPA generation test may be utilized to demonstrate pharmacokinetics and pharmacodynamics but has limited quantitative capacity in this regard. The FPA generation test performed on native plasma may provide insight into the great variation in individual hemostatic parameters important to dosage determinations.

Blood Coagulation Tests↗
PubMed1985

A primate model (Macaca mulatta) to study the pharmacokinetics of heparin and its fractions.

We have extensively studied the hemostatic parameters and the responses to the anticoagulant action of heparin and its fractions in the primate model (M. mulatta) and found these to be identical to those obtained in humans. The functional properties of antithrombin III, alpha 2-antiplasmin, and platelet factor 4 were also identical to humans in amidolytic and coagulant assays. Human antibodies against FPA, B beta 15-42 peptide, platelet factor 4, and thromboxane B2 reacted with the primate antigen, and assays were developed to measure these parameters in primates. Infusion of activated prothrombin complex concentrates (more than 100 U/kg/day) on a continual basis up to 3 days resulted in a hypercoagulable state manifested by an elevation of FPA, thromboxane B2, and changes in the thrombelastographic patterns. Similarly, infusion of homologous primate serum also resulted in a hypercoagulable state, as was evident by a sharp increase in the FPA levels. The antithrombotic effects of intravenous and subcutaneous administration of heparin, its low molecular fraction, and their constituents were studied after intravenous and subcutaneous injections. The low molecular weight fractions showed the most effective antithrombotic effects, whereas somewhat milder protection was observed with the starting material and highly anionic fraction. The prolongation of global tests, such as the APTT, TT, and changes in the thromboelastogram did not correlate with the reduction in the blood markers of hypercoagulable state. A modified simplate bleeding time method was used to study the effect of heparin and its fractions on the bleeding profile of heparin fractions. The components of fibrinolytic systems were also measurable in both the clot-based and amidolytic methods to predict the profibrinolytic actions of heparin fractions in its mode. These studies suggest that plasma markers, such as the platelet release proteins, products of thrombin activation, and prostaglandin metabolites, may provide better indices in the monitoring of the antithrombotic actions of newer heparins and antithrombotic drugs. Studies suggest that the pathophysiologic responses after a thrombogenic trigger in the primate model are close to humans, and drug modulation of these may provide relevant clinical information. This model provides the most similar preclinical model to study the actions of heparin fractions.

Animals↗
PubMed1985

A modified stasis thrombosis model to study the antithrombotic actions of heparin and its fractions.

The original stasis thrombosis model of Wessler has been modified. Numerous thrombogenic agents were evaluated for their pathophysiologic effects and were classified in terms of stasis clot in the jugular vein. Alterations produced in coagulation parameters, such as the PT, APTT, thrombin time, activated recalcification time (Hemachron), and thrombelastographic pattern were recorded. Since the pathophysiologic activation of the hemostatic system varies considerably in different diseases, a proper animal model along with a proper type of thrombogenic trigger should be carefully selected to produce pathogenesis and to study the therapeutic responses of heparin and its derivatives. In the modified stasis thrombosis model, besides monitoring the formation of the jugular vein stasis clot, it is proposed that the following tests may be useful to establish hypercoagulable states: Functional levels of various coagulation factors, platelet counts, fibrinogen levels, and whole blood activated clotting times. The nature of activation processes in each thrombogenic challenge should be carefully analyzed in terms of pathways involved; for example, the administration of heterologous serum (such as human, monkey) to rabbits produces anaphylactoid reactions, including hemolysis, thrombocytopenia, clinical chemistry abnormalities (enzymes), and many problems that may involve the complement and immune systems. All previous data obtained using heterologous sera as a thrombogenic trigger are of questionable value as to the efficacy of some of the antithrombotic agents tested against it. In addition to the species and the thrombogenic challenge, the following factors may contribute significantly to the pathophysiologic response and its alteration by various agents: (1) Composition of the thrombogenic agent; (2) effect of preparatory drugs, such as anesthetics, on the hemostatic parameters; (3) alterations on injection time, volume, osmolarity, and temperature; (4) variations in the circulation time of the thrombogenic agent and stasis time of the ligated jugular vein stasis segment; and (5) blood sample collection and handling. Since the kallikrein-kinin cascade is closely associated with the coagulation and the fibrinolytic network, a systemic monitoring of blood pressure may provide information on the effect of thrombogenic agents on hemodynamics.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

An objective assessment of the interaction of heparin and its fractions with human platelets.

We have shown that heparin and heparin fractions cause in vitro platelet aggregation in a large portion of a normal population. Furthermore, this aggregation occurs in a concentration-dependent manner and is not related to the anti-Xa activity of heparin or its fractions. In addition, it appears that at least part of the mechanism by which heparin induces aggregation is through the production of thromboxane. However, this is not the sole mechanism, since approximately 20% aggregation still occurs when thromboxane production is totally inhibited or the thromboxane receptor is completely blocked. Furthermore, although protamine (at the concentrations used) completely neutralizes the anticoagulant activity of heparin, it does not always completely inhibit the platelet aggregating activity of heparin. Finally, we have shown that heparin alone promotes thromboxane production and PF4 release in a whole blood system. Additional studies are needed to characterize further the mechanisms of heparin-induced platelet aggregation.

Adenosine Triphosphate↗
PubMed1985

Studies on the profibrinolytic actions of heparin and its fractions.

Utilizing modified immunochemical methods (ELISA and radioimmunoassay) tissue plasminogen activator, B beta 15-42 RPs and protein C antigen levels were measured in man and a subhuman primate model after subcutaneous and intravenous administration of various low molecular weight heparin fractions. A wide scatter in the data was observed in the t-PA and B beta 15-42 RP levels; however, statistical analysis of the data revealed that certain low molecular weight heparin fractions increased the levels of these endogenous markers of fibrinolysis. No significant alteration in the protein C levels was noted at any time; however, a wide scatter in these data was also evident. The profibrinolytic actions of low molecular weight heparin fractions may be related to the release of t-PA, which is easily measured in plasma. Since it has strong affinity for endogenous sites (thrombus, surface), wide scatter in the data may occur. Physical exercise may also increase the levels. Most of the results reported in our studies represent data on blood samples that were obtained using the simple venipuncture method. We also find that the intravenous administration of the low molecular weight heparin fractions also caused a shortening of the ELT. Since the low molecular weight heparin fractions are heterogeneous in nature, the profibrinolytic actions may be related to one or more of these constituent fragments. Thus, the molecular identity of the profibrinolytic component of low molecular weight fractions remains unknown at this time. Also unknown is if there is a relationship between this effect and anticoagulant activity.

Animals↗
PubMed1985

Efficacy of S-2441, a synthetic oligopeptide, in a rat model for gram-negative bacteremia.

In vitro effects of S-2441, H-D-Pro-Phe-Arg-NH-Heptyl, include potent anti-bradykinin activity and broad-spectrum inhibition of serine proteases involved in the coagulation cascade. In this study, rats infused with 7.8 X 10(8) viable Escherichia coli were treated either with saline (group A) or with intravenous (0.1 mg) and intraperitoneal (0.4 mg) doses of S-2441 (group B). Survival rates for groups A and B were 68% and 98%, at 12 hours (P less than 0.001), and 37% and 73% at 24 hours (P less than 0.001), respectively. Hematologic studies revealed that S-2441 significantly inhibited E. coli-induced prolongation of prothrombin time and partial thromboplastin time as well as a rapid decrease in the values of factor X, anti-thrombin III, and fibrinogen. In addition, S-2441 attenuated E. coli-induced hypoglycemia and a marked reduction of serum complement level. Ultrastructural evaluation of the liver demonstrated that S-2441 prevented the development of extensive sinusosoidal microthrombosis and hepatocellular necrosis. The results indicate that S-2441 affords protection in lethal gram-negative bacteremia owing in part to attenuation of disseminated intravascular coagulation and complement-mediated reactions. The findings are consistent with the concept that S-2441 and related oligopeptides modulate serine protease-mediated responses involving inhibition of active enzymes with competitive antagonism of pharmcologically active products formed during the activation of coagulation, fibrinolytic, kallikrein, and complement systems.

Animals↗
PubMed1984

Comparative study of protease inhibitors on coagulation abnormalities in canine pancreatitis.

Coagulation abnormalities induced by pancreatitis were studied in 36 dogs. The 12 dogs in group I underwent a duodenotomy alone. The six dogs in groups II, III, IV, and V had pancreatitis induced by bile injection (1 cc/kg) into the pancreatic duct. Twenty minutes after bile-induced pancreatitis, group III was given 1.0 mg/kg aprotinin (trasylol), group IV was given 10 mg/kg S-2441, a new synthetic protease inhibitor, and group V was given 0.5 mg/kg alpha 2-antitrypsin by intravenous infusion over 10 min. Blood was drawn for amylase, protime (PT), partial thromboplastin time (PTT), fibrinogen, and platelets, in addition to markers of hypercoagulation, fibrinopeptide A, and antithrombin III, and markers of fibrinolysis, B beta 15-42 immunoreactive peptide (IP), and alpha 2-antiplasmin at baseline, 1/2, 1, 3, 6, 24, 48, and 72 hr after duodenotomy or bile injection. There was no significant difference in PT, platelets, antithrombin III, and fibrinopeptide A among the five groups. With the induction of pancreatitis (group II), serum amylase was significantly elevated but fibrinogen only became elevated at 24 hr and PTT at 48 hr. The increase in B beta 15-42 IP seen 30 min after induction of pancreatitis and the decrease in alpha 2-antiplasmin were blunted by aprotinin, alpha 1-antitrypsin, and S-2441, but inhibition of the rise in amylase and B beta 15-42 IP only reached significance with S-2441 (P less than 0.05). Pancreatitis-induced fibrinolysis was inhibited by S-2441 suggesting that synthetic protease inhibitors may play a therapeutic role in pancreatitis.

Acute Disease↗