Biochemical and Pharmacologic Characteristics of Reviparin, a Low-Molecular-Mass Heparin

Jeske, Walter; Fareed, Jawed; Eschenfelder, Volker; Iqbal, Omer; Hoppensteadt, Debra; Ahsan, Ahmad

doi:10.1055/s-2007-996079

Cited by 10 publications

(6 citation statements)

References 12 publications

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“…A further comparison was made between these data and those from subjects taking the GPIIb/IIIa‐antagonists with aspirin alone. Reviparin has a mean molecular weight of 3.900 Da and shows a ratio of anti‐Xa/anti‐IIa activity > 3.6 [20]. The pharmacological profile of reviparin resembles that of enoxaparin [21].…”

Section: Introductionsupporting

confidence: 92%

Pharmacodynamic characterization of the interaction between abciximab or tirofiban with unfractionated or a low molecular weight heparin in healthy subjects

Klinkhardt

Graff

Westrup

et al. 2001

Brit J Clinical Pharma

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Aims The objective of our study was to de®ne the interaction between either unfractionated heparin (UFH) or a low molecular weight heparin, reviparin (REV), and the pharmacodynamic pro®le of the GPIIb/IIIa-antagonists abciximab (ABC) or tiro®ban (T). Methods Two studies each containing 18 healthy subjects were performed, and all were pretreated with aspirin (ASA) for 3 days. Volunteers then received UFH (5000 IU bolus/infusion 7 IU kg x1 h x1 for 7 h, n=6), REV (4200-anti-Xa-IU s.c., n=6) or placebo (n=6). One hour later, ABC (study I) or T (study II) were given by i.v. infusion for 6 h. The pharmacodynamic effects measured were bleeding time (BT), ®brinogen-binding at the GPIIb/IIIa-receptor (FIB), expression of the platelet secretion marker CD62, and ADP (20 mM)-and collagen (5 mg ml x1 )-induced platelet aggregation. Results After treatment with both GPIIb/IIIa-antagonists, prolongation of BT occurred to a similar magnitude (approximately 25±30 min) and was not affected by UFH or REV-comedication. ABC or T with ASA alone resulted in nearly the same magnitude of reduction in FIB and platelet aggregation. After coadministration with UFH, FIB was signi®cantly higher (thus less inhibited) than after after T+ASA alone (19t16% vs 55t36%) or ABC+ASA alone (8t9% vs 32t11%). This attenuation of FIB was not seen with REV. Inhibition of ADP-and collagen-induced aggregation tended to be attenuated by treatment with UFH (e.g. ADP-induced aggregation at 0.25 h after ABC+ASA alone =13t4%; after coadministration with UFH=40t26%). No such changes were noted with REV. Minor reductions in CD62-expression were seen in subjects given ABC or T alone, but expression was not affected by UFH or REV. Conclusions Co-medication with UFH attenuated platelet inhibition during treatment with GPIIb/IIIa-antagonists, but these effects were not seen with the low molecular weight heparin reviparin. The results show that administration of reviparin together with abciximab or tiro®ban did not adversely affect the pharmacodynamic pro®le of these GPIIb/IIIa-antagonists.

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Section: Introductionsupporting

confidence: 92%

Pharmacodynamic characterization of the interaction between abciximab or tirofiban with unfractionated or a low molecular weight heparin in healthy subjects

Klinkhardt

Graff

Westrup

et al. 2001

Brit J Clinical Pharma

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“…Independent of triggering coagulation, the TF/VIIa protease complex can promote developmental and tumor angiogenesis through protease‐activated receptor‐2 (PAR‐2) signaling (91). Importantly, heparins suppress TF gene expression and enhance the release of TFPI (92–95). TFPI is synthesized and constitutively secreted by ECs.…”

Section: Tissue Factor and Heparanase In Tumor Growth And Evidence Ofmentioning

confidence: 99%

Low‐molecular‐weight heparins and angiogenesis

Norrby¹

2006

APMIS

122

107

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The involvement of the vascular system in malignancy encompasses not only angiogenesis, but also systemic hypercoagulability and a pro-thrombotic state, and there is increasing evidence that pathways of blood coagulation and angiogenesis are reciprocally linked. In fact, cancer atients often display hypercoagulability resulting in markedly increased thromboembolism, which requires anti-coagulant treatment using heparins, for example. Clinical trials reveal that treatment with various low-molecular-weight heparins (LMWHs) improves the survival time in cancer patients receiving chemotherapy compared with those receiving unfractionated standard heparin (UFH) or no heparin treatment, as well as in cancer patients receiving LMWH as thrombosis prophylaxis during primary surgery. This anti-tumor effect of the heparins appears to be unrelated to their anti-coagulant activity, but the mechanisms involved are not fully understood. Tumor growth and spread are dependent on angiogenesis and it is noteworthy that the most potent endogenous pro- and anti-angiogenic factors are heparin-binding proteins that may be affected by systemic treatment with heparins. Heparin and other glycosaminoglycans play a role in vascular endothelial cell function, as they are able to modulate the activities of angiogenic growth factors by facilitating the interaction with their receptor and promoting receptor activation. To date, preclinical studies have demonstrated that only LMWH fragments produced by the heparinase digestion of UFH, i.e. tinzaparin, exert anti-angiogenic effects in any type of tissue in vivo. These effects are fragment-mass-specific and angiogenesis-type-specific. Data on the effect of various LMWHs and UFH on endothelial cell capillary tube formation and proliferation in vitro are also presented. We hope that this paper will stimulate and facilitate future research designed to elucidate whether the anti-angiogenic or anti-tumor effects of commercial LMWHs in their own right are agent specific and whether anti-angiogenic properties increase the anti-tumor properties of the LMWHs in the clinic.

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“…Heparin inhibits AP-1 binding to DNA [66] Fibrin is a scaffold for tumour growth, protects tumours from NK cells and participates in angiogenesis [43,67] Heparin inhibits fibrin formation [44] Angiogenesis Angiogenesis supports tumour growth [68,69] Heparin inhibits angiogenesis [70][71][72] TF stimulates angiogenesis [73] Heparin inhibits TF expression and enhances tissue factor pathway inhibitor [74,75] VEGF, IL-8 and hepatocyte growth factor/scatter factor stimulate angiogenesis [76][77][78] Heparin is anionic and may bind to the clusters of basic amino acids in these proteins and inhibit their activity [reviewed in 39] VEGF binding to the KDR/flk-1 receptor complex requires a positively charged amino acid surface [79] Heparin is highly negatively charged and may interfere with binding and, therefore, angiogenesis Tumour adhesion to vascular endothelial cell surfaces is a critical step in metastasis [81] Heparin binds to and may inactivate molecules involved in adhesion (e.g. selectins and heparan sulphate proteoglycans) and alter the adhesive properties of tumour and endothelial cells [82,83] Complement promotes metastasis in experimental models [84] Heparin inhibits the classical and alternative pathways of complement activation [85] MMPs facilitate metastasis [86] Heparin could bind to the highly positively charged active sites of MMPs and inhibit their activity [reviewed in 39] Thrombin and plasminogen activators can activate MMP [86] Heparin inhibits thrombin and plasminogen activators, and could thus inhibit MMP activity indirectly [44] Thrombospondin facilitates migration, attachment and spreading of tumour cells [87] Heparin can inhibit thrombospondin binding to receptors [88] Serine proteases (e.g.…”

Section: Carcinogenesis and Tumour Growthmentioning

confidence: 99%

The Use of Heparin for Treating Human Malignancies

Ornstein

Zacharski

1999

Pathophysiol Haemos Thromb

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There is a substantial amount of data implicating coagulation mechanisms in the pathogenesis of malignancy. Studies in some experimental animal models have shown that the anticoagulant heparin limits tumour growth and metastasis and prolongs survival. Experience with the effects of heparin on human malignancy is limited primarily to settings in which it was given either to prevent or to treat thrombosis in patients who also had cancer. However, these studies have shown noteworthy apparent improvement in cancer outcome with heparin, especially with low-molecular-weight heparin. There are several possible mechanisms by which heparin could potentially alter the natural history of cancer progression because of its ability to modify the cellular and molecular environment of tumour cells. This experience provides the rationale for definitive clinical trials of heparin in patients with cancer and also for further experimentation to define the mechanisms of antineoplastic activity by this familiar class of drugs.

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Biochemical and Pharmacologic Characteristics of Reviparin, a Low-Molecular-Mass Heparin

Cited by 10 publications

References 12 publications

Pharmacodynamic characterization of the interaction between abciximab or tirofiban with unfractionated or a low molecular weight heparin in healthy subjects

Pharmacodynamic characterization of the interaction between abciximab or tirofiban with unfractionated or a low molecular weight heparin in healthy subjects

Low‐molecular‐weight heparins and angiogenesis

The Use of Heparin for Treating Human Malignancies

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