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Biomedical subjects

J Fareed

Publications and source records attributed to J Fareed.

At least 127 records · Page 7Linked to original sources
PubMed1996

Defibrotide mediated inhibition of serotonin, endothelin-I, thromboxane, and serum induced contraction of canine femoral and pulmonary arterial rings.

Defibrotide is a polydeoxyribonucleotide derived agent with a weight average of 15 to 18 kDa. By virtue of its chemical nature, this polyelectrolyte agent exerts multiple pharmacologic actions at various plasmatic and cellular sites. In recent studies, this agent has been demonstrated to exhibit cardioprotective and vasomodulatory actions. To test the effect of defibrotide on the vascular smooth muscle contractile responses, its effects were evaluated on contractile response induced by agonists in canine femoral and pulmonary arterial smooth muscle preparation. These arterial preparations were harvested from anesthetized and anticoagulated (Heparinized 3-5 U/ml) dogs. Defibrotide was administered to dogs at 10 mg/kg, i.v. and segments of canine arteries were harvested at 30 minutes after the administration of this agent. The control and defibrotide treated canine arterial ring preparations were tested against serotonin, endothelin-I, serum and control platelet rich plasma(PRP) with arachidonic acid(AA). The contractile response of arterial rings obtained for treated groups were measured using serotonin, endothelin-I, serum and PRP/AA as agonists. The contractile action of serotonin, endothelin-I, serum and PRP/AA were inhibited by pretreatment of the animal with defibrotide. The arterial ring isolated from dogs treated with defibrotide exhibited a weaker contraction. These studies support the hypothesis that defibrotide modulates endothelial function and the response to the contractile actions of various agonists may be related to this effect.

Animals↗
PubMed1996

New class of heparin derivatives with a potent antithrombotic effect and a very limited hemorrhagic activity.

Eight heparin derivatives (HD1 to HD8) were prepared by mixing various doses of protamine with a fixed amount of heparin. After centrifugation and elimination of the formed complex, the supernatant was lyophilized and titrated. A dose of 5 mg (dry weight)/kg of these heparin derivatives was injected subcutaneously to rats in classical thrombosis model induced by stasis. Antithrombotic, hemorrhagic and anticoagulant activities are investigated and compared to those of Unfractionated Heparin (UFH) and LMWH (Enoxaparin). Seven rats in each group were studied. Significant antithrombic effect was exhibited by HD1, HD2, HD3, and HD4 which decreased progressively. Only HD1, HD2, and HD3 augmented hemorrhagic activity but to a lower degree than UFH and LMWH. No change was observed by coagulation assays; Activated Partial Thromboplastin Time (APTT) and Diluted Thrombin Time (dTT) and there was no effect on platelet aggregation except for UFH. These heparin derivatives might present advantages over UFH and LMWH in the treatment of thrombosis.

Animals↗
PubMed1996

Flow cytometric evaluation of the effect of various thrombin inhibitors on platelet activation in whole blood.

In an in vitro study the effect of various thrombin inhibitors (argatroban, efegatran, DuP 714, recombinant hirudin and PEG-hirudin) on platelet activation in whole blood was investigated. Blood was drawn from normal human volunteers using the double syringe technique without use of a tourniquet to avoid autoaggregation of platelets. Blood was anticoagulated with either argatroban, efegatran, DuP 714, hirudin or PEG-hirudin at final concentrations of 10 micrograms/ml. Blood samples were then incubated at 37 degrees C either with saline, r-tissue factor, arachidonic acid, adenosine diphosphate or collagen. At definite times (1, 2.5, 5, 10 min) aliquots were taken and after various steps of fixative procedure the percentage of platelet activation was measured using fluorescent monoclonal antibodies to platelet surface receptors GPIIIa (CD-61) and P-selectin (CD-62). Flow cytometric analysis showed a platelet activation after all agonists used. All thrombin inhibitors studied caused a nearly complete inhibition of r-tissue factor-mediated platelet activation. In contrast, after activation with the other agonists an increased percent CD-62 expression was found with a maximum after 2.5 to 5 min. The results show that in whole blood thrombin inhibitors are effective in preventing platelet activation induced by r-tissue factor. The formation of active serine proteases including thrombin may be effectively inhibited by these agents. The observations further suggest that while thrombin inhibitors may control serine proteases, these agents do not inhibit the activation of platelets mediated by other agonists.

Adenosine Diphosphate↗
PubMed1996

Modulation of platelet function and vascular smooth muscle contractile actions by a novel, selective, highly potent 5-HT2 antagonist (SR46349).

SR46349 is a novel, selective 5-HT2 receptor antagonist with the chemical structure {trans, 4-[(3Z)3-(2-dimethylaminoethyl) oxyimino-3(2-flurophenyl) propen-1-yl]phenol hemifumarate}. This agent has been found to exhibit antithrombotic actions in animal models of thrombosis. In order to investigate the effects of this agent on agonist induced vascular smooth muscle contraction, we utilized rabbit aortic ring and rat aortic strip preparations. Serotonin and platelet rich plasma (PRP) activated with arachidonic acid (AA) were used to determine the modulatory effect of SR46349. The IC50 for SR46349 was found to be: 1) rabbit aortic ring: 0.4 +/- 0.1 ng/ml for 5-HT and 0.25 +/- 0.05 ng/ml for PRP/AA. 2) rat aortic strip: 0.5 +/- 0.1 ng/ml for 5-HT and 0.3 +/- 0.1 ng/ml for PRP/AA. These results indicate that SR46349 is a highly potent inhibitor of aortic smooth muscle contraction. To further study the structure-activity relationship, we utilized the cis derivative of this agent, SR46615. This agent was found to be a relatively weaker inhibitor of the agonist induced aortic smooth muscle contraction. The studies reported here provide also comparative data on ketanserin, ritanserin and two new serotonin antagonists on the smooth muscle modulatory actions.

Animals↗
PubMed1996

Coagulation and fibrinolytic parameters in patients with pulmonary hypertension.

BACKGROUND: Vascular endothelium reacts to various pathophysiologic stimuli by releasing several autocoids and cytokines that can be used along with the coagulation and fibrinolytic markers for the diagnosis of hemostatic alterations. Several newer markers for vascular distress, such as tissue plasminogen activator (TPA), tissue plasminogen activator inhibitor-1 (PAI-1), TPA/PAI-1 complex, and the newly reported inhibitor of the coagulation process, namely, tissue factor pathway inhibitor (TFPI), have been implicated in the pathogenesis of pulmonary hypertension. METHODS: To investigate the behavior of endothelial cells at basal and time-dependent venous stasis-induced changes, various markers were measured in patients with primary and secondary pulmonary hypertension and compared with healthy human volunteers (controls) without any family history of thromboembolism or history of hypertensive disorders. The right atrial pressure (RAP) and pulmonary arterial pressure were measured and the hemostatic parameters were correlated to determine the relevance of these parameters with the alterations in the present indices. RESULTS: A fibrinolytic deficit exists in patients with pulmonary hypertension, indicated by the prolongation of the euglobulin clot lysis time at basal conditions and after the venous occlusion test. This defect was mainly due to increased production of PAI-1 by endothelium (patients 59.8 +/- 22.3 AU/ml; controls 30.3 +/- 14.5 AU/ml; p = 0.005). We also report for the first time that a decrease in tissue factor pathway inhibitor antigen was also observed in these patients when RAP was > 9 mmHg [controls 95.6 +/- 61.6 ng/ml; patients with RAP > 9 mmHg 47.2 +/- 19.2 ng/ml (p = 0.044); patients with RAP > 9 mmHg 96.6 +/- 32.4 ng/ml (p = 0.002 compared with patients with RAP > 9 mmHg)], indicating endothelial cell and hemostatic disturbances. CONCLUSIONS: We conclude that the euglobulin clot lysis time was prolonged in patients with pulmonary hypertension compared with controls. The impairment of the fibrinolytic system was due to an elevated concentration of PAI-1. In RAP > 9 mmHg, an additional prothrombotic factor is the decrease in plasma tissue factor pathway inhibitor antigen. It appears from this study that antithrombotic treatment is indicated in these patients.

Adolescent↗
PubMed1996

Preclinical studies on a low molecular weight heparin.

Some major developments in the area of antithrombotic therapy have occurred during the past decade. Of these, the concept of fractionation of heparin has resulted in the development of several products from this agent. The introduction of low molecular weight heparins (LMWHs) has added a new chapter to the prophylactic and therapeutic management of thromboembolic disorders. These agents are now globally accepted as drugs of choice for post-surgical prophylaxis of deep vein thrombosis (DVT). Currently, the LMWHs are being developed for various therapeutic and cardiovascular indications. Reviparin is an optimized LMWH prepared by controlled nitrous acid digestion of porcine mucosal heparin. This drug has been developed using validated procedures and exhibits a relatively narrow molecular weight distribution in contrast to most other commercially available LMWHs. The specific activity in anticoagulant assays is approximately 32 U/mg whereas the specific activity in terms of anti-Xa units is 120 anti-Xa U/mg. Reviparin is capable of producing a dose- and time-dependent antithrombotic effect in animal models of thrombosis. While the ex vivo effects initially occur at dosages that are antithrombotic, this agent has been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. This agent has also been found to release tissue factor pathway inhibitor (TFPI) after both intravenous and subcutaneous administration. Repeated administration of reviparin produces progressively stronger antithrombotic effects. The current studies are designed to provide additional data on its molecular profile using new calibration methods and additional results on the pharmacological studies in a dose-dependent manner. In particular, the release of TFPI following i.v. and s.c. administration in a primate model is described. The effect of repeated administration mimicking the post-surgical prophylaxis of DVT is also reported in terms of any increase in the antithrombotic or haemorrhagic effects of this agent. Comparative antithrombotic and pharmacological studies are also reported to compare the pharmacological profiles of reviparin, nadroparin and enoxaparin.

Animals↗
PubMed1996

Laboratory assays and duplex scanning outcomes after symptomatic deep vein thrombosis: preliminary results.

PURPOSE: The purpose of this article was to assess a number of hematologic and fibrinolytic assays at the time of diagnosis of deep vein thrombosis (DVT) and at several intervals over a period of 6 months afterward and to correlate these results with the results of serial duplex scanning. METHODS: Thirty-five patients (average age 61, range 18 to 82) with acute symptomatic DVT confirmed by duplex scanning were included. On diagnosis, blood was drawn, and plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor (PAI), D-dimer (DD), and tissue factor pathway inhibitor (TFPI) were determined. Duplex scanning and all laboratory assays were repeated 1 week, 1 month, 3 months, and 6 months thereafter. RESULTS: The rate of DVT complete resolution 6 months after diagnosis was 57%. Whereas plasma levels of PAI were similar throughout the 6-month follow-up period, t-PA increased significantly 1 week after diagnosis and decreased thereafter. Both DD and TFPI levels decreased significantly after diagnosis compared with presentation values. Comparing these assay levels between patients with complete resolution versus partial or no resolution, PAI levels were significantly higher during the first week in patients with poor outcome. Plasma levels of t-PA were higher in cases with good outcome, and DD levels were higher in patients with poor outcome. TFPI levels were similar in both outcome groups. CONCLUSIONS: Patients with complete DVT resolution on duplex scanning at 6 months had significantly lower levels of PAI on presentation and after 1 week than did those with incomplete lysis. Although differences were not significant, t-PA levels were higher and DD lower in patients with good outcome. Our results suggest that certain plasma fibrinolytic assays might correlate with the outcome of DVT, as assessed by duplex ultrasonography.

Adolescent↗
PubMed1996

Pharmacological profiling of recombinant tissue factor pathway inhibitor.

Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine protease inhibitor found within the vascular system that is known to be released upon heparin administration. Tissue factor pathway inhibitor regulates the extrinsic pathway by inhibiting both factors VIIa and Xa. The role of TFPI in the prevention of thrombosis is currently being elucidated. These studies describe the pharmacological profile of recombinant variants of this inhibitor that have recently been made available for study. Recombinant TFPI (rTFPI) exhibits potent anticoagulant (PT) and antiprotease actions (anti-Xa). While carboxy truncated forms of the inhibitor were not observed to prolong the PT, potent anti-Xa effects were still noted. In a rabbit model of stasis-thrombosis, full-length rTFPI dose-dependently inhibited thrombus formation, producing a complete inhibition of thrombosis at a dose of 500 micrograms/kg. At doses that were antithrombotically effective, minor increases in blood loss were observed in a rabbit ear bleeding model. The effect of TFPI on the inhibition of platelet activation was assessed using a flow cytometric assay. Three hundred nmol/L of rTFPI were observed to block the activation of platelets by 4.5 pmol/L recombinant tissue factor. In addition to participating in the maintenance of hemostasis, rTFPI may prove to be an effective therapeutic modality for preventing thrombus formation.

Amino Acid Sequence↗
PubMed1996

Hemodynamic and fibrinolytic consequences of intermittent pneumatic compression: preliminary results.

OBJECTIVE: To elucidate the time course and magnitude of hemodynamic and fibrinolytic changes associated with sequential gradient intermittent pneumatic compression (SGIPC). DESIGN: Two-phase, intervention and response investigation in normal volunteers. MATERIALS AND METHODS: Subjects were assigned to control (phase I) or compression (phase II) groups. Serial blood samples were obtained via femoral venous catheters for tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1), tPA-PAI-1 complex (tPA-PAI), and euglobulin lysis time (ELT) from all subjects and for fibrin degradation products (FbDP) and fibrinogen degradation products (FgDP) from phase II subjects. Duplex venous scanning was carried out on phase II subjects before and during SGIPC. RESULTS: Catheter placement caused elevations in PAI-1 and tPA-PAI, which stabilized within 4 hours of catheter insertion. In phase II, SGIPC induced significant increases in FbDP, FgDP, and tPA-PAI and decreases in ELT and PAI-1, all of which quickly reverted to baseline on termination of compression. Femoral venous blood flow increased by more than 100% with SGIPC. CONCLUSIONS: Sequential gradient intermittent pneumatic compression induces prompt, but short-lived, alterations in both fibrinolytic and hemodynamic function. Noncontinuous SGIPC may result in suboptimal thromboembolic prophylaxis.

Adult↗
PubMed1996

Successful Coronary Interventions Performed with Argatroban Anticoagulation in Patients with Heparin-Induced Thrombocytopenia and Thrombosis Syndrome.

Patients with heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) frequently have coincident vascular disease. Patients with HITTS who require vascular procedures have often been excluded from vascular intervention because intravascular procedures require heparin. Re-exposure to heparin places these patients at great risk for reactivation of thrombosis related to HIT antibody. We present our initial experience with an alternative anticoagulant to heparin, argatroban in patients with HIT antibody who underwent 14 coronary interventions. All 14 coronary lesions were treated successfully and no patient suffered an HITTS-related or an argatroban-related complication.

Journal Article↗
PubMed1996

Physical and pharmacologic manipulation of the vascular system as measured by the release of TFPI and other mediators of antithrombotic actions.

Utilizing highly sensitive monoclonal based assays, we have measured various mediators of antithrombotic action including t-PA, prostacyclin and tissue factor pathway inhibitor (TFPI). To evaluate the pharmacologic stimulation of these mediators, blood from patients treated with heparin and low molecular weight heparin in (LMWH) at various dosages, group of patients treated with oral polydeoxyribonucleotide (defibrotide), a synthetic analogue of heparin, namely aprosulate (Luitpold Pharma, Munich, Germany) were analyzed for various vascular mediators. Similarly, to evaluate patients treated with physical modalities such as the sequential compression devices alone and sequential compression devices in combination with LMWHs were tested for these same parameters. Heparin produced a marked release of TFPI and t-PA after i.v. administration. After subcutaneous administration, a relatively smaller elevation of these parameters were seen. Several of the LMWHs produced varying effects on the release of TFPI and t-PA and the area under the curve after the s.c. injection was found to be much higher than i.v. administration. Defibrotide administration after i.v. and oral administration also resulted in a significant increase in the TFPI and t-PA antigen levels. However, the prostacyclin metabolite 6-keto-PGF1 alpha was much higher than the values obtained the heparins. Repeated administration of a hypersulfated heparin analogue produced marked increase in TFPI in both i.v. and s.c. studies. These results indicate that besides directly acting on plasmatic mediators, antithrombotic drugs are capable of releasing endogenous mediators of antithrombotic actions. Physical manipulation of the vascular system can also produce these effects. Thus, both physical and pharmacologic means can be used to produce an antithrombotic state to mediate their prophylactic and therapeutic effects.

Anticoagulants↗
PubMed1996

Deep venous thrombosis prophylaxis with low molecular weight heparin and elastic compression in patients having total hip replacement. A randomised controlled trial.

Seventy-eight patients having elective total hip replacement were randomised into 3 groups A) control; B) low molecular weight heparin: (enoxaparin 40 mg once daily) and C) enoxaparin (40 mg once daily) plus graduated elastic compression (TEDR stockings) for 8-12 days. All patients had a preoperative perfusion lung scan and chest X-Ray and a postoperative perfusion/ventilation scan together with bilateral ascending venography on days 8-12. A blood sample was taken preoperatively, on the 1st, 3rd and 5th postoperative day and at the end of the study. The control group received placebo injections. The venograms and V/Q scans were reported blindly by an independent panel of three and one radiologists respectively. An independent panel of assessors stopped entry in the control group when a total of 45 patients were admitted according to Ethics Committee directives. The study continued with groups B and C. The incidence of DVT (including isolated asymptomatic calf thrombi) was as follows: Group A (n = 14) 93%; Group B (n = 32) 38%; Group C (n = 32) 25% (chi 2; p < 0.001 for group A versus B or C). The incidence of proximal DVT was: Group A 57%; group B 28%; group C 13% (chi 2; p = 0.057 for group A versus B and p < 0.005 for group A versus C). The incidence of silent pulmonary embolism (PE) (new defect on V/Q scan) was 28% (8 out of 29) in patients with and 5% (2 out of 43) in patients without DVT (chi 2; p < 0.02). The combination of high TAT and low anti-Xa activity on the 1st postoperative day identified a high risk group of patients who had a 56% incidence of proximal DVT on the 8th to 12th postoperative day. Further studies are needed to confirm the suggested increased efficacy in prophylaxis by the combination of LMWH and GEC as compared with LMWH alone.

Aged↗
PubMed1996

Current trends in antithrombotic drug and device development.

During the past decade, many significant developments in the clinical management of thrombotic and vascular disorders have occurred. In particular, several newer approaches for the prophylactic and therapeutic management of such disorders as venous thrombosis, acute myocardial infarction, and stroke have been introduced. This has been possible because of the understanding of the molecular mechanisms involved in the thrombogenic process, which plays a key role in the pathophysiology of thrombotic and vascular disorders. With the increased knowledge of the pathophysiology of thrombosis have come advances in drug treatment possibilities. Advances in biotechnology and separation techniques have contributed to the development of many newer antithrombotic, anticoagulant, and thrombolytic drugs. Many new drugs and devices based on newer concepts are currently being tested in various clinical trials. Hirudin, hirulog, GPIIb/IIIa targeting antibodies, and tissue factor pathway inhibitor are some examples. From these current developments, it can be appreciated that antithrombotic drugs represent a wide spectrum of natural, synthetic, semisynthetic, and biotechnology-produced agents with marked differences in chemical composition, physicochemical properties, biochemical actions, and pharmacologic effects. The use of physical means to treat thrombotic disorders and advanced means of drug delivery add to the expanding nature of treatment. The endogenous actions of the antithrombotic drugs are quite complex. It is no longer valid to assume that an antithrombotic drug must produce an anticoagulant action in blood, as do the classical heparin and oral anticoagulants. Many of these new drugs do not produce any alteration of currently measurable blood-clotting parameters, yet they are effective therapeutic agents because of their interactions with the elements of the blood and the vasculature. Another perspective is that several of these agents require endogenous transformation to become active products. Therefore, it becomes important to rely on the pharmacodynamic actions of these agents rather than on other in vitro characteristics to assess potency or efficacy. Hematologic and vascular modulation play a key role in the mediation of the antithrombotic actions of these drugs, involving red cells, white cells, platelets, endothelial cells, and blood proteins. Thus, an optimal antithrombotic drug approach will include the targeting of all possible sites involved in thrombogenesis. Antithrombotic and anticoagulant drugs will also be useful in the development of such biomedical devices as stents and other vascular support material. Polytherapeutic approaches utilizing combinations of drugs may turn out to be the most effective in the management of thrombotic disorders.

Combined Modality Therapy↗
PubMed1996

Plasma levels of the molecular markers of coagulation and fibrinolysis in patients with peripheral arterial disease.

In 103 patients with peripheral arterial disease (PAD) of the lower limbs, coagulation and fibrinolytic parameters were evaluated to identify hemostatic abnormalities characteristic of this patient population. PAD was defined as clinically stable Leriche stage 2 (based on clinical history, peripheral pulses, ankle-arm index, and treadmill test) for at least 3 months, walking distance > 100 m, and no other major illnesses, rest pain, or trophic lesions. Defibrotide, a polydeoxyribonucleotide derivative with vascular effects, was administered to the patients as part of a multicenter trial. The PAD patients exhibited a prothrombotic state as evidenced by high D-dimer in all but 24% of the patients (average 797 +/- 802 vs. 163 +/- 54 ng/mL normal population; p < 0.001) and high thrombin-antithrombin III complex (TAT) levels (10.2 +/- 8.9 vs. 2.5 + 1.5 ng/mL; p < 0.001) with low to normal levels of protein C (86 +/- 25 vs. 102 +/- 18%; p < 0.01) and plasminogen activator inhibitor-1 (PAI-1) antigen (5.9 +/- 4.5 vs. 1.3 + 0.7 ng/mL; p < 0.001) were elevated in 79% of the patients. These results suggest that there is ongoing thrombosis in the majority of PAD patients. Differences from normal controls were observed for t-PA, PAI-1, protein C, and protein S; however, it is not certain that the thrombosis in patients with PAD is due to these factors.

Adult↗