Factor VIII and DDAVP reverse the effect of recombinant desulphatohirudin (CGP 39393) on bleeding in the rat

Butler, K.D.; Dolan, Sara L.; Talbot, Mark; Wallis, Robert B.

doi:10.1097/00001721-199306000-00011

Cited by 32 publications

(21 citation statements)

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“…Since hirudin is a specific tight-binding thrombin inhibitor, substances supporting in trinsic thrombin generation like factor Vila (concentrates) or factor VIII:C concentrates have been tested [4,7,22], Even at high dose levels, in prestudies (data not shown) we ob served only partial r-hirudin activity neutral izing effects in the established models. Spe cific high-affinity antibodies directed against r-hirudin failed to reduce hirudin action suffi ciently.…”

Section: Discussionmentioning

confidence: 94%

“…How ever, in case of emergency or nonavailability of appropriate dialyzers, several compounds have been investigated during the last years in order to provide an antidote. Substances which neutralize heparin, as for example prot amine sulfate, platelet factor 4 or polylysine, did not show any effect on the anticoagulant action of r-hirudin [4], Recently, factor VIII has been reported to be successfully tested as a potential antidote [7], Furthermore, the use of recombinant factor Vila as well as thrombin derivatives, active site blocked thrombin mol ecules or meizothrombin were investigated for their potential clinical value as neutraliz ing agents of the r-hirudin action [4,8,9]. Moreover, activated prothrombin complex concentrates are discussed as potential anti dotes [4,5], Since the latter are registered and clinically introduced compounds, we investi gated their usefulness as antidote to r-hirudin in rabbit and rat models.…”

Section: Introductionmentioning

confidence: 98%

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Investigation of Activated Prothrombin Complex Concentrate as Potential Hirudin Antidote in Animal Models

Diehl

Römisch²,

Hein³

et al. 1995

Pathophysiol Haemos Thromb

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The specific thrombin inhibitor r-hirudin (HBW 023) has been demonstrated to be effective in preventing thrombosis in preclinical models. Up to now, no bleeding complications have been observed using therapeutically effective doses in animal studies. However, in case of inadvertent overdosing the occurrence of undesired impairment of coagulation cannot be excluded. As a potential antidote an activated prothrombin complex concentrate (APC) was tested on its ability to normalize blood coagulation. APC given as bolus injections 5 min after termination of 1-hour r-hirudin infusions of 0.1, 0.3, 1.0 and 3.0 mg/kg neutralized the r-hirudin-induced prolongation of whole blood coagulation time in rabbits completely within 5 min without any clot formation in the blood vessels or capillaries of the heart, kidneys, or lungs. Furthermore, bleeding time prolongation induced by bolus application of 3.0 and 30.0 mg/kg r-hirudin was significantly inhibited by APC within 5 min. These results suggest that administration of APC may be an effective way to reverse the effects of r-hirudin in the coagulation system in case of inadvertent overdosing of r-hirudin.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 98%

Investigation of Activated Prothrombin Complex Concentrate as Potential Hirudin Antidote in Animal Models

Diehl

Römisch²,

Hein³

et al. 1995

Pathophysiol Haemos Thromb

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“…A dose of 1 ug/kg DDAVP reduced bleeding time in rats that were made coagulopathic by an overdose of an antithrombotic drug [24], presumably through a mechanism involving elevation of vWF. In our study, an elevation in plasma vWF was not detectable even after adjusting statistically for the potential dilutional effect of the volume of drug infused.…”

Section: Discussionmentioning

confidence: 96%

Efficacy of FDA-approved hemostatic drugs to improve survival and reduce bleeding in rat models of uncontrolled hemorrhage

et al. 2006

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“…Tryp sin hydrolysis of bovine factor VIII gives rise to the forma tion of peptides with MW of 1,000-25,000 D. These pep tides have been shown to be able to reduce the bleeding time significantly in animals and men [9][10][11], There is a reduc tion of about 25% and it can reach 49% in rabbits treated with heparin [9], Studies carried out in man have shown that giving VF does not lead to any statistically significant change in the plasma clotting parameters or in platelet aggregation [12,13]. VF exerts its effects in vessel walls and promotes vessel integrity [2][3][4][5] without influencing the mechanisms of hae mostasis.…”

Section: Discussionmentioning

confidence: 99%

Bovine Factor VIII Derivative in the Treatment of Non-Proliferative Diabetic Retinopathy

et al. 1995

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The complexity of the pathogenesis of diabetic retinopathy (DR) makes it difficult to produce effective drugs for its treatment. Among the active principles recently suggested, the peptide fraction of bovine factor VIII of the clotting cascade deserves particular attention. Bovine factor VIII derivatives (vascular factor, VF) have been shown to have significant effects on the capillary basement membrane and on vascular endothelium and they are able to stabilise vessel walls. The aim of this study was to assess the effectiveness of VF in diabetic patients with non-proliferative DR. Nineteen consecutive patients (37 eyes) affected by non-proliferative DR were included in the study and randomly assigned to VF or placebo. An ophthalmological examination, colour photographies and a retinal fluorescein angiography were carried out before as well as 3 and 6 months after inclusion. Every eye in the study was classified in accordance with the ETDRS criteria. While the progress of macular oedema and visual acuity was very similar in the two groups (VF and placebo), there was no deterioration, i.e., no change to a worse classification than that at the start, in any of the eyes in the group treated with VF, but deterioration was seen in 19% of the eyes treated with the placebo. On the basis of these results, VF may ensure some protection of the blood-retinal barrier against the harmful influence of diabetic microangiopathy.

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Factor VIII and DDAVP reverse the effect of recombinant desulphatohirudin (CGP 39393) on bleeding in the rat

Cited by 32 publications

References 0 publications

Investigation of Activated Prothrombin Complex Concentrate as Potential Hirudin Antidote in Animal Models

Investigation of Activated Prothrombin Complex Concentrate as Potential Hirudin Antidote in Animal Models

Efficacy of FDA-approved hemostatic drugs to improve survival and reduce bleeding in rat models of uncontrolled hemorrhage

Bovine Factor VIII Derivative in the Treatment of Non-Proliferative Diabetic Retinopathy

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