Biomedical subjects

Jawed Fareed

Publications and source records attributed to Jawed Fareed.

68 records · Page 4Linked to original sources

PubMed2002

The blood-brain barrier accessibility of a heparin-derived oligosaccharides C3.

Although heparin-derived oligosaccharide(s) (HDO) have been clinically used for the management of neurological disorders, such as stroke and Alzheimer's disease (AD), very little information on the mechanism of their therapeutic action is known. To test the hypothesis that HDO may pass through the blood-brain barrier (BBB) to mediate their effects, a pharmacodynamic (PD) model was developed and the presence of HDO in the cerebrospinal fluid (CSF) was used as a BBB accessibility index. Rats were treated with an ultralow molecular weight (MW) heparin fragment C3 via the intravenous or subcutaneous routes at 5-10 mg/kg. At varying periods, the plasma, CSF, and brain samples were collected, and functional anti-factor Xa activities were measured to quantitate the CSF/plasma ratios (CPR) and the brain uptake. C3 showed CPR of 1.7% and 0.8% after intravenous and subcutaneous injections, respectively. These findings were verified by intravenous administration of tritium-labeled C3 followed by detection of the radioactivity in the CSF and brain homogenates. These data suggest that ultralow MW HDO may pass through the BBB.

Animals↗

PubMed2002

Molecular and biochemical profiling of a heparin-derived oligosaccharide, C3.

This study was designed to characterize a heparin-derived oligosaccharide (HDO), C3, using chemical and biochemical methods. Although previous studies have suggested C3 as a promising compound in the treatment of Alzheimer's disease (AD), its molecular and biochemical properties are still unknown. In this study, the molecular profiles and anticoagulant effects of C3 were investigated. To characterize the molecular and biochemical properties of C3, gel permeation chromatography (GPC), polyacrylmide gel electrophoresis (PAGE), radiolabeling and anticoagulant assays, such as activated partial thromboplastin time (APTT), Heptest, and anti-factor Xa assay, were used. The GPC profile revealed that C3 was an ultra-low-molecular-weight (MW) heparin mixture. The multiple components in C3 were studied with PAGE analysis. Tritium-labeled C3 exhibited similar biological properties as nonlabeled materials. The biological assays showed that C3 and its components exhibited weak anticoagulant effect. These results demonstrated the applicability of the combination of GPC, PAGE, and coagulation assays to characterize the molecular and biochemical profile of HDO. In addition, the low anticoagulant effect of C3 suggests that this compound could be a relatively low-risk adjunct in the treatment of AD.

Animals↗

PubMed2002

Prevalence, isotype, and functionality of antiheparin-platelet factor 4 antibodies in patients treated with heparin and clinically suspected for heparin-induced thrombocytopenia. The pathogenic role of IgG.

Antibodies to heparin-platelet factor 4 (PF4) complexes have been observed in patient with heparin-induced thrombocytopenia (HIT) syndrome. These antibodies may be of various isotypes and differ with respect to their ability to activate platelets/endothelial cells. This study determined the isotypes and functionality of antiheparin-platelet factor 4 (AHPF4) antibodies in 111 patients treated with heparin and clinically suspected for HIT. In this patient population, 50% had detectable AHPF4 cumulative IgA, IgG, and IgM (determined by enzyme-linked immunosorbent assay, ELISA), but only 35% was positive when tested with the (14)C-serotonin release assay (SRA). Using antihuman Ig specific for different isotypes, we found that 50% of the 111 samples was positive for IgG, 45% for IgM, and 37% for IgA. In 50 normal human serum (NHS) samples, only two were positive for IgG, but 33 were positive for IgM, indicating a potential humoral response to the heparin-PF4 complex prior to heparin administration. Patients that were ELISA(+) for AHPF4 antibody titer were subdivided into SRA-positive (+) and SRA-negative (-) groups. The SRA(+) group had a mean ELISA optical density (OD) for AHPF4 IgA/IgG/IgM of 2.1, while the SRA(-) group had a mean OD of 0.8 (P<.001). The SRA(+) group had greater mean OD values for all three individual isotypes. Using flow cytometry, we determined the ability of different patient samples to activate platelets. Samples that contained IgG and were SRA(+) activated platelets (as measured by microparticle generation and P-selectin expression) in the presence of therapeutic concentrations of heparin. NHS and samples containing IgA and/or IgM that were SRA(-) were not able to produce microparticles nor were they able to increase expression of P-selectin. Together, these data indicate that IgG is the principal mediator of platelet activation in patients with HIT, with IgA and IgM playing a less significant role in the pathophysiology of this syndrome.

Antigen-Antibody Reactions↗

PubMed2002

Preparation and anticoagulant activity of the phosphosulfomannan PI-88.

A yeast-derived phosphomannan mixture was chemically sulfonated and the composition and structure of the product mixture was studied. This phosphosulfomannan mixture, PI-88, is currently under clinical evaluation as an anti-cancer agent. Analysis using capillary electrophoresis demonstrated that PI-88 was a multi-component mixture. Gel permeation chromatography provided four fractions of PI-88 that contained components which differed in size from disaccharide to hexasaccharide, and by degree of sulfation. These fractions were characterised by spectroscopic and chromatographic methods and the structure of PI-88 is that expected based on the structure of the phosphomannan starting material. The anticoagulant activity of these fractions was evaluated and the structural requirements for activity are described.

Anticoagulants↗

PubMed2002

Practical issues in the development of argatroban: a perspective.

Argatroban was the very first antithrombin agent that was approved for clinical use. It represents a synthetic arginomimetic drug with multiple pharmacologic properties. Unlike other antithrombin drugs, argatroban is a reversible antithrombin agent. Furthermore, it modulates endothelial cell function and downregulates various inflammatory and thrombotic cytokines. Argatroban is an effective anticoagulant agent, which at equivalent anticoagulant levels (activated clotting time; ACT) produces a stronger anticoagulant effect in comparison to heparins and hirudins. At a comparable ACT (300 s), argatroban produces much stronger inhibition of thrombin generation as measured by F(1.2) and thrombin-antithrombin complex generation. Argatroban does not generate any neutralizing or non-neutralizing antibodies and, therefore, it does not require any dosage adjustment during the course of therapy as other thrombin inhibitors require. The pharmacological profile of argatroban is unique as this antithrombin drug not only inhibits thrombogenesis but also modulates cellular functions. Because of its broad spectral actions, argatroban will have more expanded indications.

Animals↗

PubMed2002

Reference ranges of the dilute tissue thromboplastin inhibition and dilute Russell's viper venom tests revisited.

Reference ranges for two well-recognized tests for the lupus anticoagulant were determined utilizing 98 healthy subjects. The purpose of the study was to compare the reference ranges for the dilute tissue thromboplastin inhibition test on this group of healthy subjects calculated by parametric and nonparametric statistical methods, and to compare these results with results obtained on subsets of 20 and 40 randomly selected individuals from the group of 98. The same procedures were followed for the dilute Russell's viper venom test. Results were recorded in seconds of clotting times and in ratios (subject/mean of that set or subset). Statistical analysis revealed Gaussian distribution of the results in the large group as well as in each subset for both tests. The results showed more variation between sets of the dilute tissue thromboplastin inhibition test than of the dilute Russell's viper venom test. Nonparametrically calculated reference ranges were wider than those determined by a parametric method, especially if confidence intervals are provided for both reference ranges in the group of 94 controls or in a subset of 40 subjects. The nonparametric technique utilizes all data for the calculation of reference ranges of such sample sizes no matter how wide the results are spread. There was no significant difference between the reference ranges of subsets and the whole group (p > 0.05) calculated by both statistical techniques.

Adolescent↗

PubMed2002

Reference intervals of the dilute tissue thromboplastin inhibition and dilute Russell's viper venom tests revisited.

Reference intervals for two well-recognized tests for the lupus anticoagulant were determined using 98 healthy subjects. The purpose of the study was to compare the reference intervals for the dilute tissue thromboplastin inhibition test on this group of healthy subjects calculated by parametric and nonparametric statistical methods, and to compare these results with results obtained on subsets of 20 and 40 randomly selected individuals from the group of 98. The same procedures were followed for the dilute Russell's viper venom test. Results were recorded in seconds of clotting times and in ratios (subject/mean of that set or subset). Statistical analysis revealed Gaussian distribution of the results in the large group as well as in each subset for both tests. The results showed more variation between sets of the dilute tissue thromboplastin inhibition test than of the dilute Russell's viper venom test. Nonparametrically calculated reference intervals were wider than those determined by the parametric method, especially if confidence intervals are provided for both reference limits in a group of 94 controls or in a subset of 40 subjects. The nonparametric technique uses all data for the calculation of reference interval of such sample sizes no matter how widely spread the results are. There was no significant difference between the reference intervals of subsets and the whole group (p > 0.05) calculated by both statistical techniques. Very few outliers were observed among these subjects in both tests.

Blood Coagulation Tests↗

PubMed2002

Monitoring of argatroban in ARG310 study: potential recommendations for its use in interventional cardiology.

Argatroban is a peptidomimimetic synthetic direct thrombin inhibitor with reversible and specific properties resulting in predictable anticoagulant effects. Usually, argatroban therapy is monitored by the activated dotting time (ACT) or activated partial thromboplastin time (aPTT). While other global dotting tests for the monitoring of anticoagulants are useful, their applicability to antithrombin agents (particularly of argatroban at higher dosages) is rather questionable. In this study, we sought to compare the argatroban anticoagulant levels in patients undergoing percutaneous transluminal angioplasty (PTCA) and stenting procedures, utilizing both functional and absolute quantitation methods. Argatroban produced a comparable increase of ACT and HMT, 5 to 10 minutes after administration. The level of anticoagulation achieved (400-450 seconds with ACT and HMT) following a slow bolus of argatroban (350 microg/kg) was maintained throughout the procedure using 25 microg/kg/min infusion. Following discontinuation of argatroban at the end of the procedure, the ACTs and HMTs showed a comparable progressive reduction in the anticoagulant response, which reflected the elimination of argatroban 2 to 3 hours after the procedure. No significant differences between the three methods (Hemotec, Hemochron, and HMT) were noted at any given sampling time. Argatroban dosage at 350 microg/kg intravenous slow bolus followed by 25 microg/kg/min infusion was adequate to perform PTCA and stenting procedures. There was no incidence of bleeding complications. Absolute quantitation of argatroban levels in patient plasmas by a newly developed HPLC method was found to be quite comparable with the ecarin dotting time (ECT) results. The ECT system was found to be less sensitive when compared to other tests, and therefore, could be used as a point-of-care test during the PTCA/stenting procedures to monitor argatroban.

Angioplasty, Balloon, Coronary↗

PubMed2002

Effects of a synthetic factor Xa inhibitor (JTV-803) on various laboratory tests.

Synthetic direct inhibitors of factor Xa are capable of prolonging the global anticoagulant assay times in a concentration-dependent fashion. The relative degree of thrombin generation inhibition at an equivalent prolongation is not similar to the results observed with heparins and oral anticoagulant drugs. In addition, the direct factor Xa inhibitors prolong the Russell's viper venom test (RWT) and Heptest clotting times. Ecarin clotting time (ECT) and thrombin time (TT) remain unaffected. The kinetics of factor Xa inhibition are markedly different than those observed with pentasaccharide and heparins. Therefore, the methods developed for heparins and pentasaccharides may not be applicable for the monitoring of factor Xa inhibitors. To test the feasibility of using the prothrombin time (PT), International Normalized Ratio (INR), activated partial thromboplastin time (aPTT), Heptest, thrombin time, RVVT, ECT, and a modified anti-Xa amidolytic assay, to monitor a synthetic factor Xa inhibitor, normal human pool plasma samples were spiked with a synthetic factor Xa inhibitor in the concentration range of 0 to 1 microg/mL and 0 to 25 microg/mL. Different laboratory tests were performed and INR and other ratios were calculated. The anticoagulant effects on whole blood were measured using the activated clotting time (ACT). Further studies on the effect of factor Xa inhibitor on platelet aggregation; factor II, VII, and X functional levels; and fibrinopeptide A (FPA) generation were carried out at equivalent INR levels in comparison to oral anticoagulant and antithrombin agents. FPA generation at equivalent anticoagulant level in comparison to heparin (twice the baseline) was also carried out. Factor Xa inhibitor produced a concentration-dependent prolongation of the ACT. ACT was doubled at a concentration of 4 to 5 microg/mL. There was a marked difference in the prolongation of the PT by a synthetic factor Xa inhibitor dependent on the ISI of the PT reagent used. When the results were calculated to determine INR, marked variations were noted between the recombinant thromboplastin and rabbit brain thromboplastin. The rabbit brain thromboplastin reagent gave markedly high INR values. Similar results were observed when different aPTT reagents were studied. In the anti-Xa assay, modification of the incubation time was employed to extend the proper sensitivity range. These studies warrant further investigation to understand the mechanism of action of factor Xa inhibitors.

Anticoagulants↗

PubMed2002

Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent.

Fondaparinux (Arixtra, Sanofi-Synthélabo/Organon) is the first of a new class of antithrombotic agents distinct from low molecular weight heparins (LMWHs) and heparin. It is a chemically synthetic pentasaccharide mimicking the site of heparin that binds to antithrombin III (AT). It exhibits only factor (F) Xa (FXa) inhibitor activity via binding to AT, which in turn inhibits thrombin generation. In contrast to heparin and LMWH, plasma anti-Xa activity corresponds directly to levels of fondaparinux. It does not release tissue factor pathway inhibitor (TFPI). There is nearly complete bioavailability by the sc. route, rapid onset of action, a prolonged half-life in both iv. and sc. (14 - 20 h) dosing regimens and no metabolism preceding renal excretion. Phase IIb clinical studies have identified a dose of 2.5 mg once-daily for prophylaxis of venous thrombosis. Four Phase III studies (n > 7000) have demonstrated a combined 50% relative risk reduction of venous thromboembolic events in orthopaedic surgery patients in comparison to the LMWH, enoxaparin. Haemmorrhagic complications for fondaparinux were either comparable to or higher than those for LMWH. The activated partial thromboplastin time (aPTT) is not affected by fondaparinux. At present, laboratory monitoring is not recommended. Clinical trials for treatment of established thrombosis, coronary syndromes and adjunct to thrombolytic therapy are in progress.

Animals↗

PubMed2002

Antithrombotic agents in the treatment of severe sepsis.

Sepsis, a systemic inflammatory syndrome, is a response to infection and when associated with multiple organ dysfunction is termed severe sepsis. It remains a leading cause of mortality in the critically ill. The response to the invading microorganisms may be considered as a balance between a pro-inflammatory and an anti-inflammatory reaction. While an inadequate pro-inflammatory reaction and a strong anti-inflammatory response could lead to overwhelming infection and the death of the patient, a strong and uncontrolled pro-inflammatory response, manifested by the release of pro-inflammatory mediators may lead to microvascular thrombosis and multiple organ failure. Endotoxin triggers sepsis via the release of various mediators such as tumour necrosis factor-alpha and interleukin-1 (IL-1). These cytokines activate the complement and coagulation systems, release adhesion molecules, prostaglandins, leukotrienes, reactive oxygen species and nitric oxide. Other mediators involved in the sepsis syndrome include IL-1, -6 and -8; arachidonic acid metabolites; platelet activating factor; histamine; bradykinin; angiotensin; complement components and vasoactive intestinal peptide. These pro-inflammatory responses are counteracted by IL-10. Most of the trials targeting the different mediators of the pro-inflammatory response have failed due to a lack of correct definition of sepsis. Understanding the exact pathophysiology of the disease will enable more advanced treatment options. Targeting the coagulation system with various anticoagulant agents including, activated protein C, and tissue factor pathway inhibitor (TFPI) is a rational approach. Many clinical trials have been conducted to evaluate these agents in severe sepsis. While trials on antithrombin and TFPI were not so successful, the double-blind, placebo-controlled, Phase III trial of recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) was successful, creating a significant decrease in mortality when compared to the placebo group. A better understanding of the pathophysiologic mechanism of severe sepsis will provide better treatment options, and combination antithrombotic treatment may provide a multipronged approach for the treatment of severe sepsis.

Journal Article↗

PubMed2002

Antithrombotics and thrombolytics in stroke.

Although angioplasty, stenting and thrombolysis of the cerebral circulation are being attempted with increasing frequency, antithrombotic and antiplatelet regimens have not yet been standardized in the treatment of stroke. Safety and efficacy of antithrombotic therapies during cerebrovascular interventions may depend onclinical presentation and carotid lesion characteristics. Platelet glycoprotein (GP) IIb/IIIa receptor antagonists might have potential value as a monotherapy or as an adjunctive therapy with thrombolytics or interventional procedures. However, the risk of cerebral hemorrhage may be higher in patients with acute stroke than in subjects with transient ischemic attack (TIA) or partial occlusion. For high-risk cerebrovascular lesions such as basilar artery, atherothrombosis or acute carotid artery occlusion, initial experience suggests that platelet GPIIb/IIIa receptor antagonists may have implications in reducing acute re-occlusion rates during the various interventional procedures. The aim of this paper is to review the use of antithrombotics as prophylaxis treatment in stroke, in addition, to comparing the benefits/risks of using thrombolytics as acute intervention.

Atrial Fibrillation↗

PubMedDate not supplied

Air travel-associated venous thromboembolism.

Long-distance air travel is increasing and cases of venous thromboembolism (VTE) following air travel have attracted both considerable public attention and legal claims against airlines. VTE is a common disorder worldwide with a notably high incidence in older individuals. Many biochemical factors that lead to, or accentuate, thrombus formation are associated with increased risk of VTE. These factors include thrombophilia, activated protein C resistance and factor V Leiden, prothrombin gene mutation, antiphospholipid antibodies, protein S and protein C deficiencies, and methylene tetrahydrofolate reductase polymorphism and homocysteinemia. Individual physical characteristics including age, weight and height are significant for personal risk of VTE as are other factors such as use of oral contraceptives in women. In the case of air travel-related venous thrombosis, superimposed upon these individual factors are the environmental factors directly related to air travel. Travel-related factors include stasis associated with prolonged periods of immobility, physiological stresses resulting from exposure to the cabin environment (low humidity and hypoxia) in long-haul flight and other in-flight factors. It is suggested that passenger behavior (movement, avoidance of dehydration and of alcohol) and appropriate pharmacological prophylaxis for high-risk travelers can reduce the likelihood of VTE. Physical prophylaxis (use of compression stockings or in-flight exercise devices) may also be of general benefit to passengers. It is recommended that airlines become more proactive in educating passengers concerning the dangers of VTE and in promoting passenger actions that can reduce risk. Airlines should also work to avoid cramped seating conditions (seat size and pitch) that contribute to prolonged immobility. Governments and regulatory authorities should mandate the provision of adequate seating conditions and a good cabin environment and should support studies that will define risks and determine the efficacy of protocols to minimize dangers of VTE. Increased long-haul air traffic and an aging population suggest that travel-related VTE may present a growing healthcare threat and has highlighted a need for additional biomedical research into the causes and potential solutions to this problem.

Aircraft↗

PubMedDate not supplied

Hemostatic modulation with the liver dialysis device in humans with advanced liver disease.

BACKGROUND/AIMS: To determine the alterations in coagulation and fibrinolysis occurring in patients treated with the liver dialysis device. METHODOLOGY: Patients with advanced liver disease treated with the liver dialysis device were studied immediately before and after the liver dialysis device treatment. SETTING: A university hospital intensive care unit. PATIENTS: Thirteen consecutive patients with advanced liver disease being evaluated for or awaiting liver transplantation. INTERVENTION: 4-6 hours of liver dialysis treatment for management of hepatic encephalopathy. OUTCOME MEASURES: A panel of coagulation and anticoagulation factors, as well as fibrinolytic and anti-fibrinolytic factors plus measures of activation of inflammation and soluble adhesion factors. RESULTS: The liver dialysis device used was found to be associated with activation of both coagulation and fibrinolytic pathways, activation of inflammation reactants, and an increase in sL-selectin levels. CONCLUSIONS: Liver dialysis device activates both coagulant and fibrinolytic pathways, activates inflammatory response, but these responses are limited to the vascular compartment by an increase in sL-selectin levels.

Aged↗