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Jawed Fareed

Publications and source records attributed to Jawed Fareed.

At least 19 recordsLinked to original sources
PubMed2007

Relative neutralization of the biological actions of sulfaminoheparosans (K5 derivatives) and heparins by protamine sulfate.

Biosynthetic, semisynthetic, and synthetic analogues of heparins are currently developed as substitute antithrombotic agents for heparin. Sulfaminoheparosan (SAH) represents a bacterial polysaccharide (K5)-derived antithrombotic polymer from which pharmacologically active products with varying molecular weights (5-25 kDa) can be derived. These agents have been shown to exhibit pharmacologic effects comparable to heparins. The objective of this investigation is to determine the relative neutralization profile of various SAH derivatives, also called as bioheparins, by protamine sulfate. Four SAH fractions with varying molecular weights (20, 9, 7, and 6 kDa), a low molecular weight heparin (LMWH), tinzaparin, and unfractionated heparin (UFH) were supplemented to normal human pool plasma over a concentration range of 6.2 to 100 microg/mL. A fixed amount of protamine sulfate at 25 microg/mL (final concentration) was supplemented to determine the neutralization profile by performing tests such as prothrombin time (PT), activated partial thromboplastin time (APTT), Heptest, prothrombin-induced clotting time (PiCT), and amidolytic anti-Xa and anti-IIa assays. Protamine sulfate produced varying degrees of neutralization of all bioheparin fractions in the clotting assays. In the amidolytic anti-IIa assay relatively stronger inhibition was noted for all agents than inhibition of FXa. On a cumulative basis the neutralization profile of SAHs was comparable with heparins. These results suggest that the anticoagulant activities of SAH derivatives can be antagonized by protamine sulfate. These studies warrant further in vivo investigation to validate the relative neutralization profile of sulfaminoheparosans.

Bacterial Capsules↗
PubMed2006

Molecular weight dependent tissue factor pathway inhibitor release by heparin and heparin oligosaccharides.

Heparin and low molecular weight heparins exert their vascular effects by mobilizing tissue factor pathway inhibitor (TFPI) from the vascular endothelium into the blood circulation. We compared the influence of molecular weight on the TFPI release by heparin and its fractions in a non-human primate model. Primates were treated with unfractionated heparin, a low molecular weight heparin (gammaparin), or a heparin-derived oligosaccharide mixture (C3). Endothelial TFPI release was determined using both immunologic and functional assays. After intravenous administration, all agents significantly increased TFPI levels (p<0.05) in a dose dependent manner. The increase produced by unfractionated heparin and gammaparin was greater than that by C3 at an equal dosage (p<0.05). With subcutaneous injection, all agents produced less TFPI release. Repeated administration of heparin-derived oligosaccharides gradually increased TFPI release. A 1.89 fold increase in TFPI levels was observed 4 days after C3 treatment (2.5 mg/kg). Our findings indicated that TFPI release is dependent on the molecular weight of heparin and its derivatives. Heparin oligosaccharides exert their vascular effects through increased TFPI release after long-term repeated administration.

Animals↗
PubMed2006

The use of a HEMOCHRON JR. HEMONOX point of care test in monitoring the anticoagulant effects of enoxaparin during interventional coronary procedures.

BACKGROUND: Enoxaparin is increasingly used for the anticoagulation of patients undergoing percutaneous coronary intervention (PCI). Several reports have suggested the utility of using point of care tests in monitoring the anticoagulation levels of enoxaparin in patients undergoing PCI. The objective of this study was to evaluate a new point-of-care test (POCT) HEMONOX in monitoring the anticoagulant effect of enoxaparin in non citrated fresh whole blood samples from patients undergoing elective PCI procedure. METHODS: Following IRB approval, blood samples were obtained from fifty-four patients who received two sequential intravenous doses of enoxaparin; 0.1 mg/kg followed 5 min later by 0.4 mg/kg for a total of 0.5 mg/kg. Blood was drawn at baseline and at 5, 10, 30 and 60 min post first bolus for evaluation in the clot-based POCT HEMONOX, ACT and aPTT and the chromogenic anti-Xa activity assay. RESULTS: HEMONOX clotting time (CT) at baseline was 62.6 +/- 6.2 secs, (n = 32) in healthy donors and statistically higher in PCI patients (71.6 +/- 9.1 secs, p = 0.0001). The peak HEMONOX response that was always achieved at 10 min post bolus was >100 secs in all 54 patients, of these 83% yielded CT >150 secs (range: 150-466). There was no detectable anti-Xa activity level at baseline while peak HEMONOX CT corresponded to therapeutic levels (0.85 +/- 0.14 U/ml; range: 0.61-1.34). Both HEMONOX CT and anti-Xa level significantly decreased at the time of sheath removal. HEMONOX CT at peak response suggested 3 patient subgroups with different levels of sensitivity to enoxaparin: low, intermediate and high responders. The correlation between anti-Xa activity level and HEMONOX CT was >or=0.85 in each patient subgroup when data from the 3 critical time points; baseline (absence of drug), peak response (10 min post bolus) and sheath removal (60 min post bolus) were analyzed. The correlation diminished to >or=0.83 when the analyses included data from all 5 time points [baseline, 5, 10, 30, and 60 min post bolus]. The HEMONOX test was the most sensitive POCT to measure the anticoagulant effects of enoxaparin. All patients completed PCI successfully. CONCLUSION: The HEMONOX test may be able to guide anticoagulation with enoxaparin during PCI. The HEMONOX assay is a one step whole blood coagulation test performed on the HEMOCHRON Jr. Signature + POC system. The method was evaluated to monitor the anticoagulant level of enoxaparin in blood samples from patients undergoing PCI after receiving an intravenous dose of 0.5 mg/kg. The results suggest a clear distinction of HEMONOX CT between the baseline value of untreated patients and patients achieving therapeutic enoxaparin levels.

Adult↗
PubMed2006

In vivo heparan sulfate treatment alters the immune response of normal and LLC-bearing mice.

Despite the large amount of research dedicated to the understanding and treatment of tumor growth, the majority of cancers continue to lack effective therapeutic options. As in the case of most solid tumors, growth requires evasion of the host immune system. Our previous work using the Lewis Lung Carcinoma (LLC) model of tumor bearing (TB)-mice has shown several tumor-induced immune suppressing effects to be present. These effects include a decreased T-cell proliferative response to Con A and altered cytokine secretion patterns that favor neither a Th1 nor a Th2 response. To address these immune alterations, immune modulating approaches have been a central area of study. Of the many potential immune modulating compounds, we believe promising therapeutic potential lies in the heparin family. Heparan sulfate (HS), in particular, has been shown to increase T-cell proliferative response in non TB-mouse splenocytes as well as promotion of a beneficial Th1 response. In this paper, we studied the potential of HS to decrease tumor burden via in vivo treatment of TB-mice. Results showed both normal and TB-mice splenocytes had a dose response change in proliferation as a result of HS treatment. Furthermore, splenocytes from HS treated TB-mice showed a potentially beneficial decrease in basal level proliferation. On gross examination, HS treatment produced a decrease in tumor surface necrosis with a visible (2 +/- 1.8%) surface necrotic area in treated mice as opposed to a (43 +/- 16%) surface necrotic area in untreated mice. HS treatment decreased TB-mice splenomegaly when comparing mice spleen weights in treated (0.3 +/- 0.05 g) vs. untreated (0.14 +/- 0.02 g) groups. These results show a potential role of HS as an immune modulating agent with antitumor properties.

Adjuvants, Immunologic↗
PubMed2006

The effects of rosiglitazone treatment on the fibrinolytic system in patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus (DM) are at risk for the development of cardiovascular diseases, which can in part be explained by disturbances in the hemostatic and fibrinolytic systems. The effects of rosiglitazone treatment on the fibrinolytic system and insulin sensitivity in patients with type 2 DM were assessed. Twenty-four patients with type 2 DM and 28 healthy subjects were enrolled in the study. Plasma global fibrinolytic capacity (GFC), tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) levels were measured. Insulin resistance was calculated by hoemostasis model assessment. Patients with type 2 DM then were placed on rosiglitazone (4 mg/day, for 12 weeks) in addition coexistent medication, and baseline tests were repeated. There was no difference between mean t-PA levels of the two groups. PAI-1 levels were higher in diabetic patients than control subjects (p < 0.01). Diabetic patients had lower GFC and t-PA/PAI-1 levels than control subjects (p < 0.05, p < 0.05). PAI-1 levels were positively correlated with waist circumference in diabetic group (r = 0.4, p < 0.05). After rosiglitazone treatment, there was no difference in mean plasma levels of GFC, t-PA, PAI-1 and t-PA/PAI-1 in diabetics. Insulin sensitivity significantly improved after the addition of rosiglitazone treatment in diabetic patients (p < 0.01). The short-term and low-dose treatment with rosiglitazone in type 2 diabetic patients has no effects on the fibrinolytic system, although it improves insulin sensitivity.

Adult↗
PubMed2006

Warfarin-induced skin necrosis: a case report.

Warfarin-induced skin necrosis is an unusual complication of anticoagulation therapy associated with high morbidity. A patient is presented who had protein C deficiency and in whom this complication developed twice within a short time as a result of delayed diagnosis. Early recognition of this syndrome has important implications in the treatment of such patients and may reduce the severity of complications.

Adult↗
PubMed2006

Modulatory effects of Escherichia coli capsular-derived sulfaminoheparosans and heparins on tissue factor-mediated activation of platelets: flow cytometric analysis.

Sulfaminoheparosans (alternatively known as bioheparins) represent sulfated derivatives obtained from the K5 capsular polysaccharide of Escherichia coli. Previous studies have shown that these agents are structurally comparable to heparins and capable of exerting anticoagulant and antiprotease effects like heparins. Furthermore they are also able to release tissue factor pathway inhibitor (TFPI). Tissue factor (TF) plays a vital role in the pathogenesis of thrombotic and cardiovascular disorders. Anticoagulants such as heparins and bioheparins inhibit this thrombogenic mediator and thereby downregulate the activation of prothrombin and factor X. This study was carried out to determine the effects of several bioheparin fractions and heparins on TF-mediated platelet activation and their direct effect on platelets using human whole blood flow cytometry. Four different sulfaminoheparosan fractions with mean molecular weights of 20, 9, 7, and 6 kDa were tested for their inhibitory effects on platelet activation at two different concentrations (100 and 10 microg/mL). Unfractionated heparin and a low-molecular-weight heparin, tinzaparin, were also tested under the same experimental conditions for comparative modulatory responses. Fresh whole blood from healthy female and male volunteers (n = 5) was mixed with each of these agents and incubated with TF (diluted thromboplastin C) to activate platelets. Platelets were labeled with the antibodies CD61 FITC (GP IIIa) and CD62 PE (P-selectin). The data were analyzed in terms of percent platelet aggregation and platelet P-selectin expression. At 100 microg/mL, all of these agents strongly and significantly inhibited (approximately 40%) the platelet activation induced by TF in comparison to saline control. The inhibitory effects of each of these agents were slightly weaker (approximately 24% inhibition) at 10 microg/mL. The inhibitory effects of these agents on P-selectin expression correspond to their effects on platelet aggregation. At 100 microg/mL all the agents produced greater than 80% inhibition of P-selectin expression whereas at 10 microg/mL, the inhibition is greater than 70% except for bio-20 kDa, which produced less than 50% of inhibition. No molecular weight dependence was observed with bioheparin fractions in terms of inhibitory effects on platelet aggregation or P-selectin expression. None of the bioheparins and heparins exhibited any direct effects on platelets. These observations suggest that both the bioheparins and heparins are capable of inhibiting TF-mediated activation of platelets. Thus the therapeutic effects of bioheparins in the TF-mediated pathogenesis of platelet activation may be similar to those of heparins.

Anticoagulants↗
PubMed2006

Product individuality of commercially available low-molecular-weight heparins and their generic versions: therapeutic implications.

The currently available brand-name low-molecular-weight heparins (LMWHs) in the United States include dalteparin (Pfizer), enoxaparin (Aventis), and tinzaparin (Pharmion). Other products available, in Europe, include certoparin (Novartis), reviparin (Abbott), nadroparin (GlaxoSmithkline), and parnaparin (Alpha-Wasserman). Each of these LMWHs has a characteristic molecular weight profile and biological activity in terms of an anti-FXa and anti-FIIa potency. The mean molecular weight of these drugs ranges from 4.0 kDa to 7.0 kDa and the anti-FXa:anti-FIIa ratio ranges from 1.5 to 3.5. These agents may also be characterized by the presence of specific chemical end groups such as 2-O-sulfo-4-enepyranosuronic acid at the nonreducing terminus (enoxaparin) or 2,5-anhydro-D-mannose at the reducing terminus (dalteparin). Further, the component oligosaccharide chains exhibit product-specific distribution profiles. It is now widely accepted that individual LMWHs are chemically unique agents and cannot be interchanged therapeutically. Each commercial LMWH has been individually developed for specific clinical indications, which are dose and product dependent. Recently, several generic LMWHs have become available in India (Cutenox and Markaparin) and South America (dilutol, clenox, dripanina), and three companies have filed for regulatory approval of a generic version of enoxaparin in the United States. As the primary aim of a generic drug is to reduce cost without compromising patient care, a generic drug is required to be chemically and biologically equivalent to the pioneer drug. Because LMWHs represent complex natural mucopolysaccharide drugs that have undergone chemical and enzymatic modifications, physicochemical and biological information in addition to molecular weight and anti-FXa:anti-FIIa ratio should be used to determine generic equivalency to the branded drug. We have utilized a previously reported approach to systematically compare three generic versions of enoxaparin obtained from India and Brazil with the branded enoxaparin (Lovenox) available in the United States. Testing included molecular and structural profiling, evaluation in clot-based and amidolytic anti-FXa and anti-FIIa assays, and heparinase-I digestion profiles. While the molecular profiles (4.8 +/- 1.8 kD) and anticoagulant potencies as determined by activated partial thromboplastin time (APTT) were comparable for all four agents, the generic products showed variations in the thrombin time (TT) and Heptest assays. Two generic and the branded enoxaparin were readily digested by heparinase-I, losing most of their anticoagulant activity, but one generic product resisted digestion. This may have been due to a unique structural feature in this product. These studies show that, while generic LMWHs may exhibit acceptable molecular weight and anti-FXa profiles, they can exhibit assay-based differences and digestion profiles. Testing in animal models to determine safety, efficacy, and pharmacodynamic parameters may be important to verify equivalence. In order to assure that the generic LMWHs are equivalent to branded LMWHs such that equivalent clinical results are obtained, there is a need to develop clear stepwise guidelines that will establish equivalency in terms of physical, chemical, biochemical, pharmacokinetic, and pharmacodynamic properties for these anticoagulant drugs.

Blood Coagulation Tests↗
PubMed2006

Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period.

This study evaluated enoxaparin alone versus initial enoxaparin followed by warfarin in secondary prevention of venous thromboembolic events in adults with active malignancy. Cancer patients (n = 122) with acute symptomatic venous thromboembolic events were randomly allocated to receive subcutaneous enoxaparin 1.0 mg/kg every 12 hours for 5 days, followed by 1.0 mg/kg daily (group 1a) or 1.5 mg/kg daily (group 1b) for 175 days, or subcutaneous enoxaparin 1.0 mg/kg every 12 hours for at least 5 days and until a stable international normalized ratio of 2 to 3 was achieved on oral warfarin begun on day 2 and continued to day 180 (group 2). There were no significant differences in major and minor bleeding rates between treatment groups. No bleeding events were intracranial or fatal. Enoxaparin treatment was feasible, generally well tolerated, and effective for a 180-day period in the secondary prevention of venous thromboembolic events in patients with active malignancy.

Adult↗
PubMed2006

Clinical applications of bioinformatics, genomics, and pharmacogenomics.

Elucidation of the entire human genomic sequence is one of the greatest achievements of science. Understanding the functional role of 30,000 human genes and more than 2 million polymorphisms was possible through a multidisciplinary approach using micro-arrays and bioinformatics. Polymorphisms, variations in DNA sequences, occur in 1% of the population, and a vast majority of them are single nucleotide polymorphisms. Genotype analysis has identified genes important in thrombosis, cardiac defects, and risk of cardiac disease. Many of the genes show a significant correlation with polymorphisms and the incidence of coronary artery disease and heart failure. In this chapter, the application of current state-of-the-art genomic analysis to a variety of these disorders is reviewed.

Computational Biology↗
PubMed2005

Unfractionated heparin, low molecular weight heparins, and pentasaccharide: basic mechanism of actions, pharmacology, and clinical use.

During the past decade, a large number of new anticoagulant and antithrombotic drugs have been developed. These agents represent a wide variety of substances that are derived using natural sources, biotechnology-based methods, and synthetic approaches. Because of the structural and molecular characteristics, these agents exhibit physicochemical and functional diversities. Thus, each of these classes of drugs controls thrombogenesis by way of distinct mechanisms. The main classes of these new drugs include peptides, peptidomimetics, heparinomimetics, and recombinant proteins. Despite these significant developments, heparin and heparin-derived drugs have continued to play a major role in the management of thrombotic and cardiovascular disorders.

Fondaparinux↗
PubMed2005

Development of generic low molecular weight heparins: a perspective.

It is clear that the introduction of generic versions of low molecular weight heparins (LMWHs) is inevitable; however, it is important that the generic products are manufactured in strict compliance with the manufacturing specification of the branded product. Furthermore, regulatory agencies should require additional data on the chemical biologic, pharmacologic/toxicologic, and dose-response relationship in specific settings. Although there is strong opposition to stop the introduction of these drugs, their development will reduce cost and permit availability to all patients who need them. Some objective guidelines for the proper development of these drugs are needed. Only expert groups and advisory panels to the regulatory bodies can develop these guidelines.

Drug Approval↗
PubMed2005

Functional characterization of antibodies against heparin-platelet factor 4 complex in heparin-induced thrombocytopenia patients in Asian-Indians: relevance to inflammatory markers.

Occurrence of heparin-induced thrombocytopenia (HIT) was investigated for 33 Indian patients undergoing cardiovascular surgery who received unfractionated heparin (UFH). Platelet counts were performed prior to the initiation of UFH therapy and 5-16 days post therapy. Heparin-induced platelet aggregation, C-serotonin release assay, and enzyme-linked immmunosorbent assay (ELISA) tests were performed in all the patients to detect the antibodies formed against the complex of heparin and platelet factor 4 (HPF4). Levels of inflammatory markers/mediators such as CD40 ligand (CD40L) and C-reactive protein (CRP) were also measured in the patient plasmas utilizing ELISA tests. Based on clinical observations and laboratory diagnoses, five patients (15%) were considered to have confirmed HIT. Despite wide variations in the titers of inflammatory markers, patients who tested ELISA-positive for HPF4 antibodies showed markedly elevated levels of both soluble CD40L and C-reactive protein. Most strikingly, the C-serotonin release assay-positive patients showed up to a 10-fold increase in the level of CD40L. It is concluded that approximately 15% Asian-Indian patients receiving UFH during cardiovascular surgery develop functional HPF4 antibodies, which are associated with the increased levels of inflammatory markers/mediators in this catastrophic HIT syndrome.

Adolescent↗
PubMed2005

Prevention of fatal pulmonary embolism and mortality in surgical patients: a randomized double-blind comparison of LMWH with unfractionated heparin.

The incidences of fatal pulmonary embolism and death in surgical patients receiving low-molecular-weight heparin thromboprophylaxis have not been previously determined in large, adequately designed clinical trials and information on the relative efficacy and safety of unfractionated and low-molecular-weight heparin in preventing these clinical endpoints is not available. In a double-blind study, 23078 surgical patients randomly received the low-molecular-weight heparin, certoparin (3000 anti Xa IU) subcutaneously once-daily, or unfractionated heparin (5000 IU) subcutaneously three-times daily, for a minimum of 5 days. The primary outcome measure, autopsy-proven fatal pulmonary embolism recorded up to 14 days after the end of prophylaxis, occurred in 0.152% (95% confidence interval (CI) 0.10, 0.20%; 35 of 23078 patients) of cases, with no significant difference between the certoparin-treated patients (0.147% (95% CI 0.077, 0.217%; 17 of 11542 patients) and patients treated with unfractionated heparin (0.156% (95% CI 0.084, 0.228%; 18 of 11,536 patients, P=0.868). The autopsy rate was 70.2%. Comparing mortality, there was no significant difference between the groups (1 .44% [166 of 11542 certoparin patients] versus 1.27% [146 of 11536 unfractionated heparin patients]; P=0.279). The safety profiles of both treatment groups were similar. Once-daily certoparin and three-times daily unfractionated heparin are equally effective and safe in reducing fatal pulmonary embolism and death to low levels in surgical patients and mirror the findings of comparative efficacy studies using surrogate endpoints.

Adult↗
PubMed2005

Argatroban treatment for patients with intolerance to heparin and hirudin.

Argatroban is a synthetic thrombin inhibitor that acts independently of any cofactor. It inhibits free as well as fibrin- and clot-bound thrombin. The clinical history of two patients is presented, both with previous allergic reactions toward heparin and hirudin. In both patients, antibodies against hirudin were documented. Argatroban was successfully used in both patients without any side effects. We conclude argatroban to be the drug of choice in patients with intolerance to heparin and hirudin. Moreover, genetic variations affecting the hepatic catabolism of argatroban might exist, because very different dosages of argatroban were needed in the two patients.

Adolescent↗