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J Fareed

Publications and source records attributed to J Fareed.

At least 253 records · Page 14Linked to original sources
PubMed1991

A double-blind, multicenter, placebo-controlled, dose comparison study of orally administered defibrotide: preliminary results in patients with peripheral arterial disease.

Defibrotide is a polydeoxyribonucleotide drug known to modulate the endothelial cell release of t-PA, PAI, and PGI-2 and to improve blood flow and perfusion. A double-blind, multicenter, placebo-controlled, dose comparison study was carried out to test the long-term efficacy and safety of defibrotide in patients with PAD (Leriche stage 2). Informed patients suffering from PAD were enrolled, and after a 15-day washout period were randomly allocated in a double-blind fashion to one of the three following treatments: defibrotide 400 mg (1 cps) b.i.d. for 6 months, defibrotide 400 mg o.d., or placebo. Absolute walking distance (AWD, treadmill) and ankle-arm pressure ratio (Winsor Index, WI) were evaluated at the beginning and after 30, 90, and 180 days after therapy. Two hundred twenty seven patients were recruited and 193 patients were included in the final analysis (800 mg: 67; 400 mg: 60; placebo: 66). All treatments brought about an increase in AWD placebo = +17%; 400 mg = +47%, 800 mg = +52%); however, patients treated with defibrotide exhibited a significantly better AWD at the end of treatment in comparison with placebo (p less than 0.01). AWD was not significantly different in the 400-mg and 800-mg groups. There was a trend indicating a possible improvement of WI after defibrotide, with higher WI in 800-mg patients in comparison with placebo (p less than 0.05). However, this difference was partly due to a decrease in arterial blood pressure elicited by the drug. The tolerability in all groups was optimal. These results indicate that orally administered defibrotide exerts symtomatic benefit in PAD patients and daily doses of 400 or 800 mg seem to be equivalent.

Administration, Oral↗
PubMed1991

Molecular profile and mapping of dermatan sulfates from different origins.

A method for characterization and molecular profiling of acidic polysaccharides (such as dermatan sulfates) has been developed. A variety of dermatan sulfates, fractionated dermatan sulfates and low molecular weight dermatan sulfates, were examined. First, bacterial lyase-type enzymes (chondroitinase ABC) were used to depolymerize the polysaccharides. Then, mapping of these oligosaccharides (comparable to peptide mapping of proteins) was performed using gradient PAGE and SAX-HPLC. Bands and peaks observed in these maps were identified using oligosaccharide standards of defined chemical structures and physical properties. The resulting map can be used to point to structural differences among these dermatan sulfates regarding their size, charge, degree of sulfation, and contamination. Fine details of fragmentation patterns and absence or presence of contaminants were detected by silver staining of gels. These differences, particularly the content of----4)alpha-IdoA(1----3)- beta-D-GalNAc4S6S(1----sequences (detected using SAX-HPLC as delta UA(1----3)-beta-D-GalNAc4S6S) may play an important role influencing the activity of dermatan sulfates to potentiate HC II inhibition of Factor IIa.

Animals↗
PubMed1991

Effect of dermatan sulfate and heparan sulfate on platelet activity compared to heparin.

Three different assay systems were studied to determine the effect of dermatan sulfate and heparan sulfate on the activation of platelets. These studies were conducted on an equigravimetric basis for the three glycosaminoglycans. Concentrations were chosen at which differential effects of the three agents could be discerned (10 to 25 micrograms/ml for the HIPA and HIT systems). In the AIPA system where only minimal effects were observed, a higher concentration of 100 micrograms/ml was used. This higher level corresponded to the circulating levels of dermatan sulfate and heparan sulfate required for antithrombotic activity in an animal model (Fareed et al, data not shown). Heparin and saline systems were used as positive and negative controls. Human platelets were studied in a CPDA-1 anticoagulated PRP system. A PRP system was used because it is more physiologic than a washed platelet system. PRP contains all the plasma components and platelet-associated proteins that are present in vivo. One disadvantage, however, is the removal of calcium by the anticoagulant CPDA-1, which may induce a nonphysiologic aberration in the aggregation effect. Overall, these three platelet system studies revealed little to no platelet aggregation response in the presence of dermatan or heparan. Heparin, on the other hand, produced variable but measurable increases, particularly in the heparin-induced thrombocytopenia platelet aggregation system. In the HIPA system (no agonist), only a slight increase was found with heparin, whereas no increase in platelet response was noted with either dermatan or heparan.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Comparative antithrombotic and hemorrhagic effects of dermatan sulfate, heparan sulfate and heparin.

Dermatan sulfate and heparan sulfate are currently under development as potential antithrombotic drugs. In our studies we have evaluated the relative antithrombotic and bleeding effects of these two agents in comparison to heparin, the commonly used anticoagulant. In a rabbit model of stasis thrombosis, a 500 micrograms/kg IV dose of dermatan or heparan produced 50-60% inhibition of induced in vivo thrombosis. At 750 micrograms/kg, both agents produced greater than 75% inhibition of thrombosis. Ex vivo measurement of plasma samples obtained from these animals demonstrated variable clotting effects at the lower dose and a proportional increase in the clotting activity at the higher dose. No anti-Xa or anti-IIa activity was observed in any sample. In contrast, animals treated with only 100 micrograms/kg heparin showed complete inhibition of induced thrombosis with significant anti-Xa and anti-IIa activities as well as prolongation of the clotting assays (APTT, TT and HeptestR). In the hemorrhagic studies utilizing a rabbit ear blood loss model, a 5.0 mg/kg IV dose of dermatan or heparan produced much less blood loss than heparin. On a gravimetric basis, dermatan and heparan were 10 fold less hemorrhagic than heparin. These results indicate that the relative contribution of plasmatic and cellular sites to the mediation of the antithrombotic action of heparin, dermatan and heparan differ. Although the antithrombotic dosages of dermatan and heparan are higher than heparin, due to the different mechanisms of action of each agent, a better safety index may be provided by dermatan and heparan than heparin.

Animals↗
PubMed1990

Heparin-induced platelet aggregation. II. Dose/response relationships for two low molecular weight heparin fractions (CY 216 and CY 222).

We have previously shown that unmodified heparin (bovine lung or porcine mucosal) and a low molecular weight heparin fraction, PK 10169, cause platelet aggregation in a dose and molecular weight-dependent manner. In this report, we show that two other low molecular weight heparin fractions, CY 216 and CY 222, also cause platelet aggregation in a dose and molecular weight-dependent manner. Utilizing heparin and defined fractions of CY 216 and CY 222 separated on the basis of molecular weight, we determined dose/response (D/R) relationships for each of these agents and their individual fractions. In comparison to an unmodified porcine mucosal heparin, CY 216 yielded a D/R curve that was shifted down and to the right, indicating that this agent is less potent in causing platelet aggregation. The D/R curve for CY 222, which has a lower molecular weight that CY 216, was shifted further down and to the right, indicating that it was less potent than CY 216. The D/R curves obtained with the fractions of CY 216 and CY 222 demonstrate that as the molecular weight of the fractions decrease, they become progressively less potent in causing platelet aggregation. Fractions with molecular weights of less than approximately 3,000 daltons are essentially without activity in causing platelet aggregation. Platelet aggregation studies with CY 216 and CY 222 fractions separated on the basis of affinity for antithrombin III (AT III) indicate that the platelet aggregating activity of these agents may not be related to their affinity for AT III. However, these latter results are not conclusive and need to be expanded.

Factor Xa Inhibitors↗
PubMed1990

Oligosaccharide mapping of low molecular weight heparins: structure and activity differences.

Low molecular weight heparins from a variety of commercial sources were examined. These had been prepared by several methods including peroxidative cleavage, nitrous acid cleavage, chemical beta-elimination, enzymatic beta-elimination, and chromatographic fractionation. The molecular weight and polydispersity of these low molecular weight heparins showed greater differences than were observed for typical commercial heparin preparations. Considerable differences were also observed in the antithrombin III mediated anti factor Xa activity, the heparin cofactor II mediated antifactor IIa activity, and the USP activity of these low molecular weight heparins. An oligosaccharide-mapping technique (comparable to the peptide mapping of proteins) was applied to these low molecular weight heparins in an effort to understand the structural features responsible for their activity differences. Heparin lyase from Flavobacterium heparinum was first used to depolymerize the low molecular weight heparin into its constituent oligosaccharides. The oligosaccharides present in the resultant mixture were identified and quantitated by using standard oligosaccharides of defined structure on gradient polyacrylamide gel electrophoresis and strong anion exchange high pressure liquid chromatography. Six of the oligosaccharide products have been identified and represent nearly 90 wt % of heparin's mass. Even though all the low molecular weight heparins showed these six oligosaccharide components, their content in each varied greatly, accounting for 20 to over 90% of their mass. The antithrombin III mediated anti factor Xa activities of the low molecular weight heparins correlated only poorly to the concentration of a hexasaccharide containing a portion of heparin's antithrombin III binding site. The heparin cofactor II mediated antifactor IIa activity, however, could not be correlated to these six oligosaccharides of known structure nor to the molecular weight or charge density of these low molecular weight heparins. The low molecular weight heparins prepared by different methods each showed a new distinctive oligosaccharide in their maps. Their isolation and structural characterization, which included two-dimensional NMR and fast atom bombardment mass spectrometry, indicated that these unusual oligosaccharides result from end-sugar modification during chemical depolymerization. Both gel electrophoresis and high-pressure liquid chromatography mapping techniques showed a greater structural diversity between low molecular weight heparins than had previously been observed between similarly analyzed commercial heparins.

Factor Xa Inhibitors↗
PubMed1990

Global and molecular hemostatic markers in acute myeloid leukemia.

Patients with acute myeloid leukemia have multiple hemostatic and thrombotic complications, which may or may not result from disseminated intravascular coagulation. Previous studies incorporating routine coagulation analyses failed to detect any clinically useful information in most of these patients. In this study, the first comprehensive evaluation of the various aspects of the hemostatic system in a population of patients with acute myeloid leukemia was performed. Eighteen patients (23-71 years of age) were studied at either diagnosis or relapse. Hemostatic studies were performed at onset and on days 3, 7, and 30 after initiation of therapy. The bone marrow blast counts ranged from 8% to 98%; prothrombin time and activated partial thromboplastin time showed only minor prolongations in a few of these patients. However, in all patients measurement of platelet-associated markers revealed elevated platelet factor 4 and thromboxane B2 and normal 6-keto-prostaglandin F1 alpha levels. Fibrinolytic markers showed an increase in D-dimer and tissue plasminogen activator and a decrease in alpha 2-antiplasmin levels. Plasminogen, plasminogen activator inhibitor, and fibrinogen levels were normal. Coagulation markers demonstrated a decrease in protein C and antithrombin III levels and an elevation of the thrombin-antithrombin complex. The pretreatment values for all hemostatic markers studied were similar to the values obtained on days 3, 7, and 30 during treatment. This investigation demonstrated a subclinical activation of the components of the hemostatic system possibly leading to a hypercoagulable state. Although only six patients (33%) experienced hemorrhagic complications, the risk of bleeding and/or thrombosis was strongly evident in all patients. The significance of finding abnormal levels of specific molecular markers of hemostasis will be established in the future application of such markers in clinical evaluations of leukemic patients known to be at risk for coagulation disorders.

Acute Disease↗
PubMed1990

Pharmacologic profile of a low molecular weight heparin (enoxaparin): experimental and clinical validation of the prophylactic antithrombotic effects.

Some 10 low molecular weight heparin products are currently available for commercial use. Enoxaparin and fraxiparin appear to be the most developed low molecular weight heparins. Many well-designed clinical trials have been carried out for different clinical indications with both of these products. As shown in both experimental and clinical settings, the prophylactic antithrombotic efficacy of enoxaparin is distinct from other low molecular weight heparins. Enoxaparin has provided consistently impressive clinical results. Moreover, at comparable dosages, other products have exhibited safety/efficacy profiles different from that of enoxaparin. The clinical performance of each low molecular weight heparin is characteristic of only that particular agent. Besides the commercially available low molecular weight heparin preparations, some 14 other agents are under development at this time. Although each product has similar basic characteristics, their biological actions should be studied carefully. Apart from differences in the physicochemical properties, the pharmacologic actions of these agents may differ significantly. Only results from valid clinical trials will show similarities or differences between the low molecular weight heparins. Other manufacturers should follow the lead of enoxaparin and conduct their own clinical trials on each of their products.

Animals↗
PubMed1989

Comparative pharmacology of low molecular weight heparins: implications of manufacturing processes on biological effects.

With the recent development of numerous low molecular weight heparins (LMWHs), a certain amount of concern has become evident as to the equivalency of each agent. In a comprehensive study, we have taken the seven available LMWHs to directly compare their in vitro and in vivo (subcutaneous) antithrombotic properties in one laboratory setting. Where possible, various batches of one LMWH were evaluated. Our findings were that variations of in vivo activity were observed between the LMWHs studied. Some activities were significantly different from placebo, whereas others were not. Depending on the assay chosen significant differences could also be observed for the in vitro activity.

Animals↗
PubMed1989

Antithrombotic activity of recombinant hirudin in the rat: a comparative study with heparin.

Hirudin, a potent inhibitor of blood coagulation, differs in its antithrombotic activity according to the source of isolation. It was therefore of interest to study recombinant hirudin. Hirudin was obtained by a genetic process from E. coli. Its antithrombotic action was investigated in an experimental (rat) model of venous thrombosis and was compared to heparin whose results are known. Heparin (400 micrograms/kg) and hirudin (12.5, 25 and 50 micrograms/kg) present an antithrombotic effect and limit the extension of an existing thrombus (p less than 0.05). Higher heparin dosages increase the bleeding time mean value (p less than 0.05) whereas hirudin does not. So, recombinant hirudin presents the same antithrombotic action as heparin but with very inferior dosage. This activity seems not dose-dependent and is associated to weak hemorrhagic effects.

Animals↗
PubMed1989

Antithrombotic drugs in pelvic surgery.

From the discussion, it is clear that several agents are available for the prophylactic antithrombotic management of pelvic surgery. Unlike other surgical procedures, the interventions are performed in women with many physiologic and pathologic predisposing factors. There is an increased risk of bleeding in these patients and the selection of an antithrombotic drug with a high safety to efficacy ratio is imperative. Although the introduction of newer drugs, such as defibrotide and low molecular weight heparins, provides certain advantages over the conventional drugs, large-scale prospective clinical trials are required to justify their use. Combination therapy will also be a useful and more effective approach in the management of pelvic surgical patients. However, optimization of dosage and an empiric determination of the safety and efficacy of different drugs used in combination will have to be made. Newer therapeutic agents will have a direct impact in this area in coming years. The practicing clinician should keep an open mind to provide better patient care.

Female↗