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J Fareed

Publications and source records attributed to J Fareed.

At least 271 records · Page 15Linked to original sources
PubMed1989

In vitro studies of the interaction of heparin, low molecular weight heparin and heparinoids with platelets.

Heparin, low molecular weight heparins, and heparinoids were studied for their ability to inhibit the aggregation of platelets by various agonists and for their ability to adhere to collagen. Heparin was a very effective inhibitor of aggregation with collagen and with ristocetin as it was with adhesion to collagen. The heparinoids showed little effect on aggregation or adhesion. Heparan sulfate and pentosan polysulfate did show slight inhibitory activity against collagen aggregation and adhesion and both interacted with the antibody induced by heparin therapy. It is of interest that dermatan sulfate and the pentasaccharide were almost inert in these experiments, and are unlikely to induce bleeding by inhibition of platelet function. It is highly probable that interference with the interaction of von Willebrand factor with platelets and collagen is a major mechanism for bleeding in the heparinized patient.

Adenosine Diphosphate↗
PubMed1989

Biochemical and pharmacologic inequivalence of low molecular weight heparins.

LMW heparin fractions obtained from various sources must not be considered as bioequivalent in both the in vitro and in vivo responses. Because of compositional variations, these agents exhibit individual behavior and should be considered as distinct drugs whose safety and efficacy profile must be determined separately. Currently, there is no valid LMW heparin standard available, however, different LMW heparins can be profiled in identical test systems. It is erroneous to assume that most LMW heparins will behave in a similar fashion in terms of safety and efficacy. The need for defined tests to characterized these agents is evident and efforts to profile their actions should be made at both the basic and applied levels. Needless to say, the true efficacy of LMW heparins can only be validated in well-designed randomized clinical trials. Optimization of LMW heparins in preclinical pharmacologic studies, as reported here, is a crucial factor in the development of these agents. The superior clinical efficacy/safety performance of some of the LMW heparins in contrast to other LMW heparins is a result of extensive preclinical pharmacologic investigations undertaken to optimize the therapeutic index of these agents. Such optimization studies have not been conducted during the development of many LMW heparins, resulting in decreased efficacy and undue complications.

Animals↗
PubMed1989

Hostile personality characteristics and prostaglandins in essential hypertension.

The hostile personality characteristic of dominance was shown to be significantly lower in a group of 34 male patients with essential hypertension than in a general illness control group (n = 17) in the USA. This replicates a previous finding from research in Greece into this and other conditions of presumably psychogenic origin. Nonspecific neurotic syndromes (as identified by the Present State Examination, a semistructured interview) were more prevalent in hypertensives than in controls, but no clear neurotic cases were found. Levels of the prostaglandins 6-keto prostaglandin F1A and thromboxane B2 did not differ significantly between groups, but the former was positively correlated with dominance in the control group. An interpretation of these results in terms of the repressed hostility theory is offered.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Recent development in antithrombotic therapy.

The present work reviews many newer concepts in antithrombotic therapy which have been introduced due to the understanding of the molecular thrombotic processes and to the advances in biotechnology and separation techniques.

Arteriosclerosis↗
PubMed1988

Importance of a 3-O-sulfate group in a heparin pentasaccharide for antithrombotic activity.

Previous theoretical and experimental evidence led to the formulation of a specific pentasaccharide structure which represents the site in heparin for binding to antithrombin III. This pentasaccharide was subsequently synthesized. A pentasaccharide of the same structure but lacking only the sulfate group on the hydroxyl group of the middle glucosamine (position C-3) was also synthesized to test the structure - activity relationships. Previous biochemical studies showed the 3-O-desulfated pentasaccharide to have a low affinity binding to AT III and to be devoid of the high anti-factor Xa activity characteristic of the pentasaccharide. Our in vivo studies, in a venous stasis thrombosis model proved the 3-O-desulfated pentasaccharide, at equigravimetric dosages, to be devoid of the antithrombotic activity previously reported for the pentasaccharide. These studies confirm the fact that inhibition of factor Xa at a high level of activity produces an antithrombotic effect.

Animals↗
PubMed1988

The inhibition of the generation of thrombin and the antithrombotic effect of a pentasaccharide with sole anti-factor Xa activity.

A chemically synthesized heparin pentasaccharide (Institut Choay, Paris, France) has been shown to exhibit an antithrombotic action in a rabbit stasis induced thrombosis model, in an IV dose range of 25 to 200 micrograms/kg (0.5 to 3.5 micrograms/ml plasma circulating concentrations). Ex vivo plasma analysis from treated animals revealed expected anti-factor Xa activity but no direct inhibitory effect against thrombin. Global anticoagulant activities were not found by PT and APTT methods. Platelet activation remained unaffected at the antithrombotic dosages of pentasaccharide. To more specifically elucidate the anti-factor Xa mediated antithrombotic mechanism of action of this pentasaccharide, it was studied in several thrombin generation assays. Pentasaccharide added to human and rabbit plasmas in vitro from 0 to 5.0 micrograms/ml produced a concentration dependent effect up to a 35 to 50% inhibition of generated thrombin. In ex vivo studies similar concentration dependent inhibition of thrombin generation was observed. Analysis of plasma obtained from animals in which a complete antithrombotic effect was observed in vivo demonstrated an approximate 45 to 55% inhibition of thrombin generation. These results indicate that a relationship exists between the pentasaccharide induced inhibition of experimental venous stasis thrombosis and the inhibition of thrombin generation.

Animals↗
PubMed1988

Thrombin inhibition with dipeptidyl argininals.

Human alpha- and gamma-thrombins (with high and essentially no fibrinogen clotting activities, respectively) were inhibited in chromogenic substrate assays by the dipeptidyl argininals: antipain less than leupeptin less than H-D-Phe-Pro-argininal approximately Boc-D-Phe-Pro-argininal. In clotting assays with alpha-thrombin, I50 values were slightly higher than Ki values from chromogenic substrate assays, except for a somewhat lower I50 for antipain. Our data cautions the use of argininal proteinase inhibitors in the assessment of thrombin functions, and the high potency of H-D-Phe-Pro-argininal and its derivative suggest pharmaceutical applications.

Antipain↗
PubMed1988

Neonatal and maternal platelets: activation at time of birth.

Determination of the plasma concentrations of beta-thromboglobulin (BTG), thromboxane B2 (TxB2) and platelet factor 4 (PF4) were made at the time of birth in 18 newborns and their respective mothers. Both groups show significant elevation of all these molecular markers, suggesting marked platelet activation. The elevated TxB2 levels in the newborn group, 25 +/- 8 pg/ml, are compatible with a normally functioning and activated platelet prostaglandin pathway. Mode of delivery, vaginal or caesarean section, does not significantly influence the degree of activation in either group. Ultrastructural platelet examination did not reveal any morphologic differences between maternal and newborn platelets. There appears to be marked activation of the newborn and maternal platelet systems at the time of birth, and we postulate that this may explain in part the transient platelet dysfunction observed in newborns.

Blood Platelets↗
PubMed1988

Mechanical and histologic changes in canine vein grafts.

Mechanical and histological studies were performed on dog femoral veins after their implantation as grafts to bypass the ligated femoral arteries. The vein grafts dilated rapidly after implantation with 90% of maximum dilation occurring at 4 weeks. Both the native veins and the vein grafts were highly compliant up to 35-50 mm Hg, but were virtually nondistensible at higher pressures. When implanted with end-to-side anastomoses (end of vein to side of artery), the compliance of the anastomotic region resembled that of the artery rather than that of the vein. This was due to the distensibility of the artery at arterial pressure, as compared with the almost rigid vein. Histologic examination showed that intimal hyperplasia was greater after end-to-side anastomosis than after end-to-end anastomosis (P less than 0.05) and that this increased hyperplasia was reduced by treatment with aspirin and dipyridamole (P less than 0.05). By contrast, medial thickening was increased in all grafts compared with native veins (P less than 0.05), but was not different in end-to-end, end-to-side, and aspirin/dipyridamole-treated end-to-side grafts. These data suggest that intimal hyperplasia and medial thickening are separate responses to different stimuli.

Anastomosis, Surgical↗
PubMed1988

Diagnosis of acute megakaryoblastic leukemia by flow cytometry and immunoalkaline phosphatase techniques. Utilization of new monoclonal antibodies.

This report demonstrates a case of acute megakaryoblastic leukemia evolving in a patient with idiopathic myelofibrosis with myeloid metaplasia. A presumptive diagnosis was made by cytochemical stains, alpha-naphthyl acetate esterase, and alpha-naphthyl butyrate esterase. The diagnosis was established by electron microscopic platelet peroxidase studies of the peripheral blood blast cells and supported by flow cytometry and immunoalkaline phosphatase studies. Specific monoclonal antibodies directed against platelet glycoproteins Ib (6D1) and IIb/IIIa (10E5), which have not been described frequently in analyzing leukemia, were used for flow cytometry and direct immunoalkaline phosphatase technique. Cytogenetic studies demonstrated a deletion of the long arm of chromosome 6 with breakpoints at bands q15 and q23, and ring chromosome 6 (p25, q27). The diagnosis of megakaryoblastic leukemia requires accurate cytochemical stains, platelet peroxidase by electron microscopic examination, and studies employing specific monoclonal antibodies directed against platelets and megakaryoblasts. The exact origin of the circulating megakaryoblasts in these cases is not known and needs additional investigation.

Acute Disease↗
PubMed1988

Pharmacokinetics of heparins differing in mean molecular weight using a Xa amidolytic and Heptest clotting method.

The pharmacokinetics of heparins ranging in mean MW from 23,000 to 4,500 were determined using a new clotting test (Heptest) and an anti-Xa, amidolytic method. No significant difference between the two methods was observed in the calculated values for distribution volume (Vd), halflife (t1/2), plasma clearance (Clp) or area under the concentration-time curve (AUC) for heparins of any MW. However, when pharmacokinetic parameters calculated from both methods were compared as a function of MW, significant differences were observed. Values for t1/2 averaged from the two methods increased with decreasing MW. The t1/2 values were 30, 35, and 50 min for the 23,000, 13,300, and 5,100 MW fractions, respectively. Similarly, AUC increased with decreasing MW while Clp decreased. All heparins were observed to have VdS approximating the plasma compartment. A slightly larger Vd was observed with the lowest MW heparin.

Animals↗
PubMed1988

Comparative study on the in vitro and in vivo activities of seven low-molecular-weight heparins.

Different low-molecular-weight (LMW) heparins are produced by fractionation, enzymatic and chemical methods. Although the manufacturer's assigned molecular weights of these agents are similar (around 5,000 daltons), they exhibit considerable molecular structural heterogeneity due to the variations in the manufacturing process. In vitro standardization of these LMW heparins produces highly variable results due to the variability of assay specificity. In a comparative study with seven LMW heparins, differences were found in molecular weight distribution, antifactor Xa activity, antifactor IIa activity, Heptest activity, USP potency, platelet interactions, protamine and platelet factor 4 neutralization and charge density ratios. Relative antithrombotic actions varied between the seven agents and the ratio of the intravenous:subcutaneous effects were inconsistent with expected results based on in vitro properties or observed ex vivo effects. These products were not bioequivalent in equigravimetric or equipharmacopeial dosages (antifactor Xa, USP). Although the intravenous bioavailability was proportional to the potency for an individual agent, the subcutaneous bioavailability of the same agent showed differences from that of the intravenous regimen. In addition, significant differences between the bleeding profiles of these agents were noted in both intravenous and subcutaneous routes. The bleeding profiles did not correlate well with the relative proportion of the antifactor Xa component. However, some relationship to the bleeding effect was observed with the antifactor IIa and activated-partial-thromboplastin-time activities. These LMW heparins produced different effects on platelets as studied in the heparin-induced thrombocytopenia and platelet activation systems. These observations suggest that the individual composition of each LMW heparin determines its in vivo behavior which may account for the different safety/efficacy ratios observed in clinical trials.

Animals↗
PubMed1988

Validity of the newly established low-molecular-weight heparin standard in cross-referencing low-molecular-weight heparins.

Four low-molecular-weight-heparin (LMWH) preparations have recently become available for clinical usage. Some ten preparations are currently under preclinical development. The safety/efficacy profile of each of these LMWHs is now known to be quite distinct from one and other. In order to minimize the variations in the pharmacologic responses and to cross-reference different products on a common scale, the WHO has recently introduced a LMWH standard. This standard is a nitrous-acid-depolymerized product provided by KabiVitrum (Stockholm, Sweden) with a specific physiochemical and biological profile. Although the in vitro characteristics of this standard are comparable to other LMWH, the in vivo behavior of this reference and the parent product, Fragmin, are quite different in comparison to other products. In a well-defined uniform biochemical and pharmacologic screening, seven LMWH were compared at WHO reference-adjusted potency using pharmacologically valid dose-response curves. Cross-referencing of various LMWHs against the WHO standard in terms of anti-Xa activity resulted in a marked elevation of the anti-IIa component of some of the LMWHs. Establishment of this WHO standard stipulated that the clinical performance of cross-referenced LMWHs would be equivalent to one another and variation in potency could be minimized. Our data suggest that utilizing the WHO, standard individual potency (anti-Xa)-adjusted LMWHs exhibit distinct safety/efficacy profiles which were not related in their observed in vitro potency. Each LMWH has distinct multiparametric molecular and biochemical characteristics which determine the pharmacologic activities of individual agents. Thus cross-referencing of LMWHs by one in vitro assay is of questionable value as it may result in serious dosimetric errors, resulting in serious thrombotic and bleeding complications.

Animals↗