Pharmacodynamic Properties of the Low Molecular Weight Heparin, Tinzaparin: Effect of Molecular Weight Distribution on Plasma Tissue Factor Pathway Inhibitor in Healthy Human Subjects

Mousa, Shaker A.; Bozarth, Jeffrey M.; Barrett, Jeffrey S.

doi:10.1177/0091270003254793

Cited by 28 publications

(24 citation statements)

References 51 publications

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“…28,29 The peak TFPI concentration we observed was at 1 hour after dosing. This is similar to the response reported by Mousa et al 24 in healthy male and female human volunteers. Peak values for anti-factor IIa and Xa values were also observed 1 hour after dosing.…”

Section: Discussionsupporting

confidence: 92%

“…23 Total TFPI enzyme-linked immunosorbent assay (ELISA)-The AssayMax Human TFPI ELISA kit (AssayPro; Brooklyn, New York) was used for the quantitative analysis of total antigenic TFPI in citrated plasma (assay range: 0-10 ng/mL; intra-assay CV: 9%; interassay CV: 17%). The protocol was carried out as described by Mousa et al 24 SNAC bioanalytical assay-Following protein precipitation, samples were directly injected into an HPLC equipped with an Applied Biosystems MDS Sciex API 4000A liquid chromatography/tandem mass spectrometry (LC/MS/MS) system. For details on the analytical methodology, the method of validation, and the analytical within-study quality control procedures, see Brayden et al 19…”

Section: Pharmacokinetics/pharmacodynamicsmentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Oral Heparin Solid Dosage Form in Healthy Human Subjects.

Mousa

Zhang

Aljada

et al. 2007

Blood

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Heparin is not orally absorbed, presumably because of its size and polyanionic charge and hence is administered parenterally, either by continuous or intermittent infusion or by subcutaneous (SC) injection. However, a formulation that would result in absorption of heparin after oral administration would provide an attractive alternative to parenteral heparin. In that regard several attempts to develop effective non-parenteral heparin formulations have been reported, but they have met with limited success. The present investigation determined the molecular structure, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of oral unfractionated heparin (UFH) containing oral absorption enhancer Sodium N-[8-(2-hydroxybenzoyl) amino] caprylate, salcaprozate sodium (SNAC) and assessed the safety and tolerability of orally dosed heparin solid dosage form versus other routes. Sixteen healthy men were included in this single-dose, three-way crossover, randomized, open-label study. The different arms of the study were as follow: Treatment A- Subjects randomized to Treatment A received two capsules of UFH/SNAC soft gelatin capsules for a total dose of 75,000 U heparin sodium with 150 mL of water; Treatment B: Subjects randomized to Treatment B received 1 mL of heparin sodium USP parenteral 10,000 U/mL via SC injection; Treatment C: Subjects randomized to receive 75,000 U heparin sodium milled powder for oral solution with 150 mL of water; and Treatment D: Subjects randomized to receive 0.5 mL of heparin sodium USP parenteral 5,000 U/mL via IV bolus. Each subject was randomly assigned to receive three of the four treatments so that a total of 12 subjects received each treatment. To characterize the PK of SNAC after oral heparin/SNAC administration and the PD of heparin following the administration of heparin IV, SC, PO alone and PO as heparin/SNAC, 21 blood samples were drawn from all of the subjects receiving treatment A, B, C, and D at the following time points: within 30 minutes pre-dose, at 2, 5, 10, 15, 20, 25, 30, 35, 40, 45 minutes, and at 1,1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours post-dose. Blood was drawn into sodium citrate tubes for assessment of anti-factor Xa, anti-factor IIa, aPTT, and SNAC. Disaccharide compositional analysis was performed using capillary high-performance liquid chromatography with electrospray ionization mass spectrometry detection. The PD of heparin was obtained from analysis of plasma anti-factor Xa, anti-factor IIa, aPTT, and total tissue factor pathway inhibitor (TFPI) data. The molecular weight properties and the disaccharide composition of orally administered UFH/SNAC and parenterally administered UFH are identical and consistent with the starting standard UFH administered and achieved anti-factor Xa: anti-factor IIa of 1:1. This is the first true pharmacokinetic study to measure the chemical compositions of heparin administered by different routes.

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Section: Discussionsupporting

confidence: 92%

Section: Pharmacokinetics/pharmacodynamicsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Oral Heparin Solid Dosage Form in Healthy Human Subjects.

Mousa

Zhang

Aljada

et al. 2007

Blood

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“…LMWHs were shown to inhibit P-and L-selectin as well as integrin-mediated formation of tumor thrombi, and to alter tumor neo-angiogenesis. This effect is primarily based on their ability to induce the prolonged release of TFPI from binding sites on endothelial cells [81,82]. TFPI acts by inhibiting TF-FVIIa complex, leading to activation of Factor X, inhibition of thrombin generation and PAR-2 activation, and disruption of pro-angiogenic signaling [83,84].…”

Section: Vte In Pancreatic Cancer: a Model Of Hypercoagulability And mentioning

confidence: 99%

Primary Thromboprophylaxis in Pancreatic Cancer Patients: Why Clinical Practice Guidelines Should Be Implemented

Farge

Bournet

Conroy

et al. 2020

Cancers

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Exocrine pancreatic ductal adenocarcinoma, simply referred to as pancreatic cancer (PC) has the worst prognosis of any malignancy. Despite recent advances in the use of adjuvant chemotherapy in PC, the prognosis remains poor, with fewer than 8% of patients being alive at 5 years after diagnosis. The prevalence of PC has steadily increased over the past decades, and it is projected to become the second-leading cause of cancer-related death by 2030. In this context, optimizing and integrating supportive care is important to improve quality of life and survival. Venous thromboembolism (VTE) is a common but preventable complication in PC patients. VTE occurs in one out of five PC patients and is associated with significantly reduced progression-free survival and overall survival. The appropriate use of primary thromboprophylaxis can drastically and safely reduce the rates of VTE in PC patients as shown from subgroup analysis of non-PC targeted placebo-controlled randomized trials of cancer patients and from two dedicated controlled randomized trials in locally advanced PC patients receiving chemotherapy. Therefore, primary thromboprophylaxis with a Grade 1B evidence level is recommended in locally advanced PC patients receiving chemotherapy by the International Initiative on Cancer and Thrombosis clinical practice guidelines since 2013. However, its use and potential significant clinical benefit continues to be underrecognized worldwide. This narrative review aims to summarize the main recent advances in the field including on the use of individualized risk assessment models to stratify the risk of VTE in each patient with individual available treatment options.

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“…While primarily used in the treatment and prevention of venous thrombosis, LMWHs have been found to impair tumor neoangiogenesis, as shown in Figure 4. This effect is primarily based on their ability to prompt the prolonged release of tissue factor pathway inhibitor (TFPI) from binding sites on endothelial cells [69,70]. TFPI acts by inhibiting the TF-FVIIa complex and the subsequent activation of FX; it, therefore, disrupts the formation of thrombin and the activation of PAR-2, resulting in the abrogation of proangiogenic signaling [71,72].…”

Section: Effects On Angiogenesis/tumor Vasculaturementioning

confidence: 99%

Mechanisms of the Antitumor Activity of Low Molecular Weight Heparins in Pancreatic Adenocarcinomas

Bokas

Papakotoulas

Sarantis

et al. 2020

Cancers

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Immune checkpoint inhibitors have revolutionized cancer treatment in the last decade. Despite the progress in immunotherapy, most pancreatic cancer patients still do not derive benefit when receiving immune-based therapies. Recently, resistance mechanisms to immune therapies have been mainly focused on tumor microenvironment properties. Pancreatic cancer is considered one of the most lethal and difficult to treat tumors due to its highly immunosuppressive and desmoplastic microenvironment. Low molecular weight heparins (LMWHs) have been used for the treatment and prevention of thromboembolic disease in these patients. However, many nonanticoagulant properties attributed to LMWHs have been described. Exploiting LMWH properties in a combined treatment modality with immune checkpoint inhibition and chemotherapy could provide a new approach in the management of pancreatic adenocarcinoma patients. The ability of LMWH to interfere with various aspects of the tumor microenvironment could result in both the alleviation of immunosuppression and improvement in drug delivery within the tumor, leading to higher cancer cell destruction rates and more potent immune system activity that would, ultimately, lead to better patient outcomes.

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Pharmacodynamic Properties of the Low Molecular Weight Heparin, Tinzaparin: Effect of Molecular Weight Distribution on Plasma Tissue Factor Pathway Inhibitor in Healthy Human Subjects

Cited by 28 publications

References 51 publications

Pharmacokinetics and Pharmacodynamics of Oral Heparin Solid Dosage Form in Healthy Human Subjects.

Pharmacokinetics and Pharmacodynamics of Oral Heparin Solid Dosage Form in Healthy Human Subjects.

Primary Thromboprophylaxis in Pancreatic Cancer Patients: Why Clinical Practice Guidelines Should Be Implemented

Mechanisms of the Antitumor Activity of Low Molecular Weight Heparins in Pancreatic Adenocarcinomas

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