Biomedical subjects

Jeanine Walenga

Publications and source records attributed to Jeanine Walenga.

6 recordsLinked to original sources

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↗

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↗

PubMed2004

Generic low-molecular-weight heparins: some practical considerations.

It is now widely accepted that various low-molecular-weight heparins (LMWHs) exhibit specific molecular and structural attributes that are determined by the type of manufacturing process used. For example, enoxaparin, which is prepared by benzylation followed by alkaline hydrolysis of unfractionated heparin (UFH), exhibits a double bond at the nonreducing end and the presence of a unique bicyclic structure namely 1,6 anhydromanno glucose or mannose, or both, at the reducing end. Similarly, the other LMWHs, such as dalteparin, nadroparin, tinzaparin, and parnaparin, exhibit specific structural characteristics that may contribute to their own unique biochemical and pharmacological profiles. These unique features may not exhibit any major influence on the routinely determined anti-Xa and anti-IIa activities. However, these may have an impact on the pharmacokinetics and other biological actions such as the interactions with growth factors, blood components, and vascular cells. This is the reason for the initial caution for the noninterchangeability of the anti-Xa adjusted dosing of the different LMWHs. Although the nonanticoagulant biological effects of these drugs are poorly understood at this time, they are now recognized as contributing significantly to the overall therapeutic effects of these drugs. Because some of these drugs have proved to be effective in the management of cancer-associated thrombosis and exhibit improvements in mortality outcome, these LMWHs may also produce several other effects by modulating inflammatory processes, apoptosis, and other regulatory functions related to cellular functions at different levels. Thus, the interactions of these LMWHs with antithrombin and heparin cofactor II are not the only determinants of their biological actions. Release of tissue factor pathway inhibitor (TFPI), regulation of cytokines, nitric oxide, and eicosanoids contribute to their individuality. Such properties are not only dependent on the oligosaccharide sequence and consensus sites but also depend mainly on microchemical and structural attributes in these drugs. European Pharmacopoeia (EP) and the World Health Organization (WHO) have developed guidelines to characterize these agents in terms of their molecular and biological profile. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA) consider each of these drugs as distinct pharmacological agents. This has prompted the requirement for product-specific clinical data for the approval of their use in various clinical indications. There is a clear concern regarding the development of potential generic versions of branded products and the submissions by generic manufacturers for the regulatory approval of generic interchangeability that refers to the substitution of an apparent chemically identical and bioequivalent versions of the branded LMWHs. Currently, there are no regulatory guidelines or consensus opinions on the acceptance of generic versions of the branded products. Because the LMWHs represent not only a biological entity but also product-specific molecular and structural attributes, the acceptance of a generic version must be based on clearly defined guidelines stipulating minimal molecular and structural, biological, and clinical validation requirements. It is therefore to be stressed that each of the LMWHs is a distinct drug entity that characteristically exhibits a product-based therapeutic spectrum in different thrombotic and nonthrombotic disorders. Thus, until the establishment of valid regulatory guidelines for the generic interchangeability of the commercially available LMWHs is completed, generic substitutes are not recommended.

Anticoagulants↗

PubMed2003

Benefit-risk assessment of treatments for heparin-induced thrombocytopenia.

Patients with heparin-induced thrombocytopenia (HIT) are at high risk of thrombosis and should be treated with alternative anticoagulant therapy to reduce complications. The current treatment of choice is one of the approved direct thrombin inhibitors, argatroban or lepirudin. These drugs have been proven to be safe and effective in multicentre clinical trials where dosage regimens have been established for prophylaxis and treatment of thrombosis. Argatroban has also been tested and approved for use in invasive cardiology procedures in the HIT patient. Dosage regimens for other clinical uses, such as cardiac surgery, have not yet been established for either drug. The safety and effectiveness of the thrombin inhibitors is dependent on their use according to established guidelines. Other treatment options that may be effective for the patient with HIT include dextran, plasmapheresis, intravenous gammaglobulin and aspirin (acetylsalicylic acid). Although used historically, these options have not been tested in rigorous clinical trials. For life- and limb-threatening thrombosis, thrombolytic agents and/or surgery may provide benefit. Because the risk of bleeding is high from these procedures, they should be performed only by an experienced practitioner. Several studies have shown that patients with HIT requiring continued anticoagulation are best managed with a warfarin derivative initiated while under full anticoagulation with a thrombin inhibitor. There is a risk of skin necrosis and bleeding if guidelines for dose administration and monitoring of warfarin are not followed. Subsequent use of heparin or a low molecular weight heparin after resolution of the clinical episode of HIT can be hazardous, particularly within the first 3 months. If laboratory testing is negative, heparin may be cautiously reinstituted for short-term use (1-2 hours) with monitoring for platelet count decrease and thromboembolism. The pregnant patient with HIT requiring anticoagulation represents a particular challenge, where there is no drug of choice at present. Although today there are realistic treatment options for the patient with HIT, the morbidity and mortality associated with this disease have not been eliminated. Awareness and early treatment of HIT remain important components of the clinical care for patients exposed to heparins. Future therapeutic developments based on a better understanding of the pathophysiology of HIT may further improve clinical outcomes. Despite some limitations, the current treatment options for patients with HIT provide unparalleled benefit compared with the treatment options available only a few years ago.

Animals↗

PubMed2003

Pharmacodynamic and pharmacokinetic properties of enoxaparin : implications for clinical practice.

Enoxaparin is a low-molecular-weight heparin (LMWH) that differs substantially from unfractionated heparin (UFH) in its pharmacodynamic and pharmacokinetic properties. Some of the pharmacodynamic features of enoxaparin that distinguish it from UFH are a higher ratio of anti-Xa to anti-IIa activity, more consistent release of tissue factor pathway inhibitor, weaker interactions with platelets and less inhibition of bone formation. Enoxaparin has a higher and more consistent bioavailability after subcutaneous administration than UFH, a longer plasma half-life and is less strongly bound to plasma proteins. These properties mean that enoxaparin provides a more reliable anticoagulant effect without the need for laboratory monitoring, and also offers the convenience of once-daily administration. Clinical studies have confirmed that these pharmacological advantages translate into improved outcomes. There are important pharmacokinetic and pharmacodynamic differences between enoxaparin, other LMWHs and UFH, and therefore these molecules cannot be regarded as interchangeable.

Age Factors↗