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Biomedical subjects

J Fareed

Publications and source records attributed to J Fareed.

At least 109 records · Page 6Linked to original sources
PubMed1998

A supersulfated low-molecular-weight heparin (IK-SSH) increases plasma levels of free and total tissue factor pathway inhibitor after intravenous and subcutaneous administration in humans.

Unfractionated as well as low-molecular-weight heparins (LMWH) are known to cause an increase in blood levels of tissue factor pathway inhibitor (TFPI). To study the effect of a newly developed supersulfated LMWH (IK-SSH, Iketon Farmaceutici) on TFPI concentrations in human plasma, the compound was injected into volunteers at doses of 0.14, 0.33 and 0.66 mg/kg intravenously or 0.33, 0.66 and 1.0 mg/kg subcutaneously. At certain known times blood was drawn and plasma levels of both total and free TFPI were measured using enzyme-linked immunosorbent assay methodology. Baseline plasma concentrations of TFPI were 72.2+/-3.1 ng/ml for total and 10.8+/-0.8 ng/ml for free TFPI. Intravenous or subcutaneous injection of IK-SSH led to a strong and long-lasting rise in TFPI levels which were increased more than 5-fold for total TFPI and more than 30-fold for free TFPI. Maximum TFPI levels were reached 5-10 min after intravenous and 60 min after subcutaneous administration. IK-SSH caused prolongation of ex-vivo clotting times in the APTT and Heptest assay, whereas thrombin time was not affected. Anticoagulant actions of IK-SSH showed a significant correlation to plasma concentrations of TFPI and they are thought to be based at least partially on the release of TFPI from vascular sites.

Adult↗
PubMed1998

Transplantation of lymph node fragments in a rabbit ear lymphedema model: a new method for restoring the lymphatic pathway.

The treatment of lymphedema by medical or surgical means remains a difficult task, and no technique is presently satisfactory. We established a rabbit ear chronic lymphedema model in which sequential lymph node fragments were transplanted to restore lymphatic pathways. Twenty New Zealand White rabbits were divided into two groups of 10 animals. One group served as the control, and the other was the transplantation group. A 3-cm-wide strip of skin and subcutaneous tissue including all the lymphatics was excised circumferentially from the root part of the right ear in each rabbit. The vascular pedicle in the control group was wrapped with a "bridge" strip of skin from the ventral ear to protect it from drying. In the transplantation group, the auricular lymph node was harvested from the contralateral ear, cut into 1- to 2-mm slices, and implanted next to the vascular pedicle where the lymph vessels had been resected. Water displacement measurements in both groups revealed significant edema (p < 0.001) compared with the contralateral ear at 3 days. Peak swelling was observed at 10 days in both groups. Volumes decreased in both groups postoperatively. The volume measured as percentage change in the lymph node transplantation group was significantly lower than in the control group at 2 months and continuing to the end of the experiment (p < 0.001). Indirect lymphographic examination revealed that the distal lymphatic vessels of the control group were increased in number, dilated, and did not allow proximal passage of dye. Light microscopy revealed the vascular pedicle to be surrounded by dense scar tissue in the "bridge." The transplantation group showed free passage of dye through the bridge. Microscopic examination showed regenerated lymphoid tissue with sinuses along the artery and vein of the "bridge." Many channels with a layer of endothelial cells were also noted. Electron microscopy confirmed these sites to be regenerated lymph vessels. Lymphatic tissue can regenerate after fragment transplantation. This lymph tissue seems to regenerate lymphatic vessels that may function for drainage. The results suggest that this simple technique may be applicable in a clinical situation to prevent or treat obstructive lymphedema.

Animals↗
PubMed1998

Low molecular weight heparin prevents the pulmonary hemodynamic and pathomorphologic effects of endotoxin in a porcine acute lung injury model.

Tumor necrosis factor alpha (TNF-alpha) activity, platelet and neutrophil degranulation and margination, and increased vascular permeability are central to the pathophysiology of endotoxin-mediated acute lung injury. Nonanticoagulant activities of low molecular weight heparin (LMWH) include solubilization of the TNF-alpha receptor protein, inhibition of neutrophil adhesion, and regulation of thromboxane B2 (TXB2) biosynthesis. In this study, we evaluated the ability of LMWH to modulate TNF-alpha and TXB2 activity during endotoxemia and the subsequent effects on pulmonary hemodynamics. Domestic pigs 8-10 weeks old were anesthetized and catheterized for standard cardiopulmonary measurements and the lungs harvested for cuff:vessel ratio, myeloperoxidase activity, and permeability index. Pigs were randomly assigned to one of four groups: lipopolysaccharide (LPS) (n = 6), given .5 microg/kg/h Escherichia coli LPS intravenously for 6 h; saline control (n = 5); LMWH (n = 5), given .5 mg/kg LMWH for 30 min, followed by .5 mg/kg/h; and LMWH + LPS (same dosages, n = 6). Administration of LPS resulted in increased plasma TNF-alpha and TXB2 activity; increased pulmonary arterial pressure, pulmonary vascular resistance, and alveolar-arterial oxygen tension; decreased systemic arterial oxygen tension; and pulmonary edema. The cardiopulmonary parameters for the LMWH-treated pigs did not differ from those of the saline-treated control pigs. Pretreatment with LMWH attenuated the LPS-mediated TNF-alpha and TXB2 activity and attenuated LPS-mediated pulmonary hypertension, hypoxemia and neutrophil emigration, and edema formation. In conclusion, the data show that the protective effects of LMWH in this model of acute lung injury are associated with altered neutrophil adhesion and TNF-alpha and thromboxane activity.

Animals↗
PubMed1998

The first report of successful carotid stent implant using argatroban anticoagulation in a patient with heparin-induced thrombocytopenia and thrombosis syndrome: a case report.

We report the first successful carotid stent implant in a patient with heparin-induced thrombocytopenia and thrombosis syndrome who presented with recurrent neurologic deficits secondary to severe carotid stenosis. Argatroban anticoagulation was used for the carotid stent deployment. We also present laboratory data that document effective procedural anticoagulation.

Aged↗
PubMed1998

Synthetic and recombinant antithrombin drugs.

As the final enzyme in the activation of the coagulation system, the serine protease, thrombin, is believed to be an important target for the development of new anticoagulant/antithrombotic drugs. Direct thrombin inhibitors are either derived from natural sources, such as hirudin or are chemically synthesised, such as argatroban. The coupling of hirudin or parts of it with other entities leads to novel agents with different pharmacokinetic and pharmacodynamic characteristics, such as polyethylene glycol (PEG)-hirudin or the hirulogs. Due to the reversible or irreversible inactivation of the enzyme, thrombin inhibitors exert strong anticoagulant effects that can be measured in global clotting assays. Furthermore, these compounds inhibit thrombin-induced platelet reactions and influence other cellular, receptor-mediated actions of thrombin, e.g., on vascular cells. Directly acting thrombin inhibitors prevent blood clotting and are also capable of inhibiting clot-associated thrombin; however, they do not effectively block the further generation of the enzyme. Comprehensive experimental studies suggest that thrombin inhibitors may be effective drugs in a wide range of intravascular thrombus formation, also including the inhibition of vascular restenosis. Recent clinical trials revealed the effectiveness of direct thrombin inhibitors in various thrombotic and cardiovascular indications, but also a tendency to an increased risk of bleeding complications. At present, thrombin inhibitors are the most promising class of drugs for the initial therapy of patients with heparin-induced thrombocytopaenia (HIT) or the heparin-induced thrombocytopaenia and thrombosis syndrome (HITTS). They are also useful for the management of venous thrombosis and for acute ischaemic syndromes as well as for invasive procedures. However, with regard to the long-term outcome, a superiority of thrombin inhibitors over heparin has not yet been demonstrated. Several important issues, such as monitoring, pharmacological antagonism and drug interactions will also play an important role in the development of these new drugs. Further clinical trials are required to confirm the effectiveness of direct thrombin inhibitors in the prophylaxis and treatment of various thromboembolic and cardiovascular disorders.

Journal Article↗
PubMed1998

Recombinant TFPI and variants: potential implications in the treatment of cardiovascular disorders.

The Kunitz-type proteinase inhibitor, tissue factor pathway inhibitor (TFPI), is the only endogenous inhibitor of the tissue factor (TF)-mediated coagulation pathway that plays a dominant role in normal haemostasis. TFPI exerts its action by binding to factor Xa (FXa) forming a TFPI-FXa complex that then, in a second step, binds and effectively inhibits the TF-factor VIIa (FVIIa) complex. Both full-length TFPI and chemically modified forms (e.g., truncated, glycosylated or phosphorylated TFPI variants) exert various pharmacological effects. The anticoagulant and antiplatelet actions of TFPI, its potency in inhibiting thrombin and FXa generation, as well as its favourable antithrombotic effectiveness seen in different animal models of venous and arterial thrombosis make this inhibitor a promising agent that could be potentially useful in several clinical indications. The inhibitory action of TFPI is accelerated by heparin. Heparin, as well as low molecular weight heparin (LMWH) derivatives, release TFPI from the vascular endothelium, an effect which seems to contribute mainly to the antithrombotic effectiveness of these drugs. The clinical relevance of TFPI is still undefined. Based on the beneficial actions in animal studies, as well as on the results obtained in first clinical investigations, TFPI is expected to be effective in the treatment of various diseases, such as disseminated intravascular coagulation, sepsis, coronary syndromes, stroke and acute respiratory distress syndrome (ARD). Further clinical trials should clarify the role of TFPI and more importantly define its potential usefulness as a prophylactic and/or therapeutic agent.

Journal Article↗
PubMed1998

Useful laboratory tests for studying thrombogenesis in acute cardiac syndromes.

We review laboratory tests that evaluate thrombogenesis during acute coronary syndromes. These tests have been found to be valuable research tools in more clearly understanding the pathophysiology of acute coronary syndromes. In particular, we describe tissue factor, tissue factor pathway inhibitor, prothrombin fragment 1.2, thrombin-antithrombin complex, fibrinopeptide A, tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), t-PA-PAI complex, Bbeta 15-42-related peptides, fibrinogen degradation products, fibrin degradation products, D-dimer, platelet factor 4, beta-thromboglobulin, 5-hydroxytryptamine, thromboxane B2, prostacyclin, endothelin, angiotensin-converting enzyme, soluble thrombomodulin, C1-esterase inhibitor, anaphylotoxins C3a, C4a, and C5a, bradykinin, tumor necrosis factor, leukotriene C4, platelet activating factor, anti-phospholipid antibody, and von Willebrand factor. Some of these tests may prove to be useful in clinical diagnosis and management of acute coronary syndromes. Clinical outcome studies are needed to determine which tests may be cost effective and medically useful.

Acute Disease↗
PubMed1998

Low molecular weight heparins: are they different?

In addition to their use in postsurgical and medical prophylaxis of deep vein thrombosis (DVT), low molecular weight heparins (LMWHs) are being developed for cardiovascular and cerebrovascular indications. Because of manufacturing differences, each LMWH exhibits distinct pharmacological and biochemical profiles that may influence clinical performance. The specific activity of these agents in anticoagulant assays ranges from 35 to 45 anti-IIa U/mg or 80 to 120 anti-Xa U/mg. LMWHs are capable of producing product-specific dose- and time-dependent antithrombotic effects in animal models of thrombosis. While the ex vivo effects are initially present at antithrombotic doses, these agents have been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. In experimental animal models and in various clinical trials, these agents have also been found to release tissue factor pathway inhibitor (TFPI) after both intravenous and subcutaneous administration. Repeated administration of LMWHs produces progressively stronger antithrombotic effects. However, the hemorrhagic responses vary and are largely product dependent. The product-dependent release of TFPI following intravenous and subcutaneous administration in a primate model also demonstrates the relevance of this inhibitor to the actions of LMWHs. The effect of repeated administration of LMWH mimicking the postsurgical prophylaxis of DVT exhibited product-based augmentation of the antithrombotic or hemorrhagic effects.

Animals↗
PubMed1998

Role of neuropeptides in pathogenesis of reflex sympathetic dystrophy.

In 1993, a study was undertaken at the Hand Clinics of Loyola University Medical Center in Chicago to investigate the role of the neuropeptides in the pathogenesis of Reflex Sympathetic Dystrophy. All of the patients had recurrent or continuous pain, swelling, and stiffness of one or both extremities following either acute trauma or surgical intervention. All of the patients showed a markedly increased level of bradykinin as well as calcitonin gene-related peptide. The levels of bradykinin were four times as high as the controls. A few showed increased levels of the other neuropeptides. With these results, we agree with Veldman, Goris and others who consider Reflex Sympathetic Dystrophy to be an exaggerated regional inflammatory disorder.

Adult↗
PubMed1997

Efficacy of pentasaccharide in a dog model of hemodialysis.

A synthetic heparin pentasaccharide with sole anti-Xa actions has been evaluated for its antithrombotic efficacy in a dog model of hemodialysis. Various dosages of pentasaccharide, 400-800 nmol/kg, were compared with a single bolus dose of unfractionated heparin (250 U/kg). The primary endpoint in these studies was the duration of dialysis time. In addition, dialyzer filter content, venous trap protein, celite and saline ACT and hematocrit measurement. Pentasaccharide at dosages of 600 and 800 nmol/kg produced an extension of dialysis time (> 180 minutes) in contrast to unfractionated heparin at 250 U/kg which only produced antithrombotic effects for periods of up to 150 +/- 42 minutes (n = 5). At a lower dosage of 400 nmol/kg pentasaccharide produced weaker effects and the dialysis circuit was patent for periods of 122 +/- 14.8 (n = 5) minutes. The saline and celite ACT times were not extended at any dosage of pentasaccharide; however, at 250 U/kg, a strong effect was noted with unfractionated heparin (> 800 secs, 647 +/- 211 secs.), respectively. A dose dependent antithrombotic effect was also evident in the studies on the filter clots and venous trap protein content. No difference in the hematocrit was noted in any group. These results clearly suggest that despite the fact that pentasaccharide does not produce any prolongation of the coagulation times, it produces a dose dependent antithrombotic effect in this model of dog hemodialysis. Furthermore, these results also suggest that pentasaccharide at an appropriate dosage can be used as an alternate antithrombotic agent during hemodialysis.

Animals↗
PubMed1997

In vitro studies on the effect of activated protein C on platelet activation and thrombin generation.

The effect of activated protein C (APC) on agonist-induced platelet activation and on thrombin generation after intrinsic (IA) and extrinsic (EA) activation of the coagulation system was studied by flow cytometry and by measuring levels of prothrombin fragment F1+2. In platelet activation studies blood drawn from healthy volunteers was anticoagulated with 10 micrograms/ml APC and incubated at 37 degrees C either with saline, recombinant tissue factor (r-TF), arachidonic acid (AA), ADP or collagen. At definite times aliquots were taken and processed for flow studies. Platelet activation was measured using fluorescent monoclonal antibodies to platelet surface receptors GPIIIa (CD-61) and P-selectin (CD-62). Flow cytometric analysis showed platelet activation after all agonists used. APC did not influence AA-, ADP- and collagen-induced platelet activation but completely inhibited activation of platelets induced by r-TF. The effect of APC on r-TF-mediated platelet activation was concentration-dependent in the range of 0.5 to 20 micrograms/ml showing an increase in CD-62 expression at lower concentrations. In citrated and APC-anticoagulated blood the generation of thrombin was studied after IA and EA. At 10 and 20 micrograms/ml APC effectively prevented blood clotting which rapidly occurred especially after EA. The amount of thrombin generated via the extrinsic pathway was reduced by APC whereas after IA F1+2 levels measured in the presence of APC were still strongly increased. These results indicate that small amounts of thrombin generated by r-TF are sufficient to activate platelets as well as blood coagulation. APC exerts strong concentration-dependent anticoagulant actions and effectively prevents activation of platelets.

Cells, Cultured↗
PubMed1997

Vasomodulatory action of clopidogrel and ticlopidine.

Clopidogrel is a thienopyridine derived antiplatelet drug that has currently undergone extensive clinical trials in the management of various arterial disorders related to platelet activation. While the proposed mechanism of its pharmacologic action is believed to be the inhibition of ADP mediated direct and indirect actions on platelet adhesion/aggregation and other activation processes, several other observed pharmacologic actions suggest that this drug may also have additional sites of action. Ticlopidine also belongs to the same class of ADP receptor inhibitor and is extensively used for prevention of ischemic disorders. In order to investigate the vasomodulatory action of clopidogrel and ticlopidine, rabbit and rat isolated tissue preparation systems were used. Clopidogrel and ticlopidine were found to produce dose dependent vasomodulatory actions in rabbit or rat treated with 30 minutes intravenous administration. The aortas harvested from both the rabbits and rats treated with clopidogrel or ticlopidine exhibited marked desensitization to the serotonin, endothelin-1, serum and platelet rich plasma/arachidonic acid mixtures. Both control rabbit aortic rings and rat aortic strips did not produce any inhibition of the serotonin induced contraction. These data suggest that clopidogrel and ticlopidine plays an important role in producing these vasomodulatory actions. Furthermore these observations indicate that both the clopidogrel and ticlopidine also modulate the vascular sites which may be contributory to the observed clinical effects.

Animals↗
PubMed1997

Topical application of low molecular weight heparin in a rabbit traumatic anastomosis model.

Low molecular weight heparins (LMWHs) are antithrombotic drugs composed of lower molecular weight components of heparin with an apparent molecular weight in the range of 4.0-8.0 KDA. These agents have been used clinically for several years. They have different mechanisms of action compared to heparin, a longer half-life and much higher bioavailability. Anticoagulant drugs such as heparin have been used topically in our previous studies to avoid bleeding complications observed with systemic administration. In this study, low molecular weight heparin (Certoparin, Sandoz) was topically administered in a rabbit ear arterial crush-avulsion thrombosis model and compared with heparin. The animals were divided into three groups: LMWH, heparin and saline control groups. In the LMWH group, the patency rate was 71% (10 of 14) at both 1 and 7 days. The patency rate in the heparin group was 95% (19 of 20) at 24 hrs and 80% (16 of 20) at 7 days. In the saline control group, the vessel patency rate was 17% at 24 hrs and 13% at 7 days. Clotting times such as ACT, PT and APTT performed on samples drawn one hour after drug administration were within the normal ranges for both the control and the treatment groups. The results suggest that topical administration of LMWH prevents the occurrence of thrombosis at the traumatic anastomosis site to a similar degree as heparin.

Administration, Topical↗
PubMed1997

Biochemical and pharmacologic characteristics of Reviparin, a low-molecular-mass heparin.

The introduction of low-molecular-mass heparins (LMMHs) has added a new dimension to the prophylactic and therapeutic management of thromboembolic disorders. These agents are now globally accepted as drugs of choice for postsurgical prophylaxis of deep vein thrombosis (DVT). Currently, the LMMHs are being developed for various therapeutic and cardiovascular indications. Reviparin is an optimized LMMH prepared by controlled nitrous acid digestion of porcine mucosal heparin. This drug has been developed utilizing validated procedures and exhibits a relatively narrow molecular mass distribution in contrast to most other commercially available LMMHs. The specific activity in the anticoagulant assays is approximately 40 U/mg whereas the specific activity in amidolytic anti-Xa assays is approximately 100 anti-Xa U/mg. Reviparin is capable of producing dose- and time-dependent antithrombotic effects in animal models of thrombosis. Although ex vivo anticoagulant effects are initially observed at dosages that are antithrombotic, this agent has been found to produce sustained antithrombotic effects when ex vivo anticoagulant actions are not measurable. Repeated administration of this LMMH induces progressively stronger antithrombotic effects. This drug has also been found to release tissue factor pathway inhibitor (TFPI) following both intravenous (IV) and subcutaneous (SC) administration. The studies included in this article are designed to provide additional data on the molecular profile using new calibration methods and additional results on pharmacologic studies. In particular, the release of TFPI following IV and SC administration to nonhuman primates is described. The effect of repeated administration of Reviparin mimicking the postsurgical prophylaxis of DVT is also reported in terms of any augmentation of the antithrombotic or hemorrhagic effects of this agent.

Animals↗
PubMed1997

Current status on new anticoagulant and antithrombotic drugs and devices.

Several new drugs for the management of thromboembolic disorders have recently become available. Low-molecular-weight heparins are being evaluated for the prophylaxis of medical and surgical deep venous thrombosis and pulmonary embolism; for the treatment of pre-existing thrombosis; and for cases of coronary syndrome (unstable angina, myocardial infarction), thrombotic and ischemic stroke, interventional cardiology, pregnancy, cancer, and transplantation-associated thrombosis. A chemically synthesized heparin pentasaccharide, which has purely anti-factor Xa activity and does not induce thrombocytopenia, is also in clinical trial. Thrombin inhibitors, such as hirudin and argatroban, are a practical anticoagulant substitute where heparin cannot be used. They are also useful for the management of coronary syndrome and as adjunct therapy. The antiplatelet agent ticlopidine and its analogue, clopidogrel, which does not produce blood dyscrasia, are effective for the secondary prevention of thrombotic stroke and the management of combined arterial thrombotic syndromes. Glycoprotein-targeting antibodies, synthetic derivatives, and peptides (some of which are orally bioavailable) have added a new dimension to the management of arterial thrombosis and high-risk patients having angioplasty. Plasma-derived agents, such as antithrombin III, are available for the management of thrombophilia and disseminated intravascular coagulation. Compression devices and the foot pump, alone and in combination with pharmacologic agents, have been used successfully. Combination therapy using various agents in different proportions have also been found useful. Although there is much enthusiasm in this quickly developing area and clinical trials are demonstrating the antithrombotic efficacy of the new drugs, safety considerations require additional clinical validation. Long-term outcomes and costs also need to be addressed objectively.

Adult↗
PubMed1997

Low molecular weight heparins: a developmental perspective.

Low molecular weight heparins (LMWHs) are now universally accepted as drugs of choice for post-surgical prophylaxis of deep vein thrombosis (DVT). Currently these agents are also being developed for the treatment of thrombosis and various cardiovascular indications. Due to manufacturing differences, each of the LMWHs exhibits a distinct pharmacological and biochemical profile. The specific activity of these agents in the anticoagulant assays ranges from 35 - 45 anti-IIa U/mg, whereas the specific activity in terms of anti-Xa units is designated as 80 - 145 anti-Xa U/mg. These LMWHs are capable of producing product-specific dose- and time-dependent antithrombotic effects in animal models of thrombosis. While the ex vivo effects are initially present at doses that are antithrombotic, these agents have been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. In experimental animal models and in various clinical trials, these agents have also been found to release tissue factor pathway inhibitor (TFPI) after both iv. and sc. administration. Repeated administration of LMWHs produces progressively stronger antithrombotic effects; however, the haemorrhagic responses vary and are largely dependent on the product used. The release of TFPI following iv. and sc. administration in a primate model also demonstrates product individuality and the relevance of this inhibitor to the actions of LMWHs. Furthermore, repeated administration, mimicking the post-surgical prophylaxis of DVT, leads to product-based augmentation of the antithrombotic or haemorrhagic effects. Antithrombotic and haemorrhagic studies are discussed, comparing the pharmacological profile of some of the available LMWHs. Product individuality, in terms of relative potency in different assays and the failure of standardisation protocols to provide any guidelines for product substitution and prediction of the clinical effects, is also addressed.

Journal Article↗