Dataset Information

In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα.

ABSTRACT: The interaction of platelet GPIbα with von Willebrand factor (VWF) is essential to initiate platelet adhesion and thrombosis, particularly under high shear stress conditions. However, no drug targeting GPIbα has been developed for clinical practice. Here we characterized anfibatide, a GPIbα antagonist purified from snake (Deinagkistrodon acutus) venom, and evaluated its interaction with GPIbα by surface plasmon resonance and in silico modeling. We demonstrated that anfibatide interferds with both VWF and thrombin binding, inhibited ristocetin/botrocetin- and low-dose thrombin-induced human platelet aggregation, and decreased thrombus volume and stability in blood flowing over collagen. In a single-center, randomized, and open-label phase I clinical trial, anfibatide was administered intravenously to 94 healthy volunteers either as a single dose bolus, or a bolus followed by a constant rate infusion of anfibatide for 24 h. Anfibatide inhibited VWF-mediated platelet aggregation without significantly altering bleeding time or coagulation. The inhibitory effects disappeared within 8 h after drug withdrawal. No thrombocytopenia or anti-anfibatide antibodies were detected, and no serious adverse events or allergic reactions were observed during the studies. Therefore, anfibatide was well-tolerated among healthy subjects. Interestingly, anfibatide exhibited pharmacologic effects in vivo at concentrations thousand-fold lower than in vitro, a phenomenon which deserves further investigation.Trial registration: Clinicaltrials.gov NCT01588132.

SUBMITTER: Li BX

PROVIDER: S-EPMC8175443 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα.

Li Benjamin Xiaoyi BX Dai Xiangrong X Xu Xiaohong Ruby XR Adili Reheman R Neves Miguel Antonio Dias MAD Lei Xi X Shen Chuanbin C Zhu Guangheng G Wang Yiming Y Zhou Hui H Hou Yan Y Ni Tiffany T Pasman Yfke Y Yang Zhongqiang Z Qian Fang F Zhao Yanan Y Gao Yongxiang Y Liu Jing J Teng Maikun M Marshall Alexandra H AH Cerenzia Eric G EG Li Mandy Lokyee ML Ni Heyu H

Scientific reports 20210603 1

The interaction of platelet GPIbα with von Willebrand factor (VWF) is essential to initiate platelet adhesion and thrombosis, particularly under high shear stress conditions. However, no drug targeting GPIbα has been developed for clinical practice. Here we characterized anfibatide, a GPIbα antagonist purified from snake (Deinagkistrodon acutus) venom, and evaluated its interaction with GPIbα by surface plasmon resonance and in silico modeling. We demonstrated that anfibatide interferds with bot ...[more]

PMID: 34083615

Similar Datasets

Project description:AimsClopidogrel is the most commonly prescribed thienopyridine as part of dual anti-platelet therapy for the treatment of cardiovascular diseases. However, clopidogrel responsiveness shows variability based on CYP2C19 polymorphism. Therefore, we planned a study with an objective of evaluating safety, tolerability, pharmacodynamics and pharmacokinetics of a novel thienopyridine antiplatelet agent AT-10 in healthy Indian subjects compared with standard dosage regimen of clopidogrel based on their CYP2C19 genotyping.MethodsTwo CYP2C19 genotype-based groups were identified, that is, poor metabolisers and extensive metabolisers, with 20 subjects in each group (n=40) for participating in a randomised, two-period, crossover study. Each study period lasted 6 days including administration of loading and maintenance doses of AT-10 (40 mg/10 mg) or clopidogrel (300 mg/75 mg). The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 6 at several time intervals.ResultsOverall result of pharmacodynamic parameters showed that mean %inhibition of platelet aggregation between AT-10 and clopidogrel in all subjects at 6 hours postdose (loading dose) (AT-10: clopidogrel; 73.30% vs 18.53%) and 6 hours postdose on day 6 (maintenance dose) (AT-10: clopidogrel; 83.41% vs 51.19 %) obtained from the AT-10 group was significantly higher than the clopidogrel group. Further, %inhibition of platelet aggregation from AT-10 treatment in poor metaboliser group was significantly higher than the clopidogrel treatments in extensive metaboliser group.Overall pharmacokinetic comparison in all subjects indicates that AT-10 gives greater exposure to active Metabolite H4 than clopidogrel.ConclusionAT-10 showed better inhibition of platelet aggregation in poor metabolizers as compared to Clopidogrel. AT-10 may emerge as a potential alternative to Clopidogrel as an anti-platelet drug. It can be further developed in clinical studies for the unmet medical needs in management of CVDs and overcome the pharmacogenomic limitations of Clopidogrel.Trial registration numberClinical Trial Registry-India URL: http://ctri.nic.in.Registration numberCTRI/2021/03/032206.

Project description:BackgroundThe venom of Bothrops lanceolatus, a viperid species endemic to the Lesser Antillean Island of Martinique, induces thrombosis in a number of patients. Previous clinical observations indicate that thrombotic events are more common in patients bitten by juvenile specimens. There is a need to develop an experimental model of this effect in order to study the mechanisms involved.Methodology/principal findingsThe venoms of juvenile and adult specimens of B. lanceolatus were compared by (a) describing their proteome, (b) assessing their ability to induce thrombosis in a mouse model, and (c) evaluating their in vitro procoagulant activity and in vivo hemostasis alterations. Venom proteomes of juvenile and adult specimens were highly similar, albeit showing some differences. When injected by the intraperitoneal (i.p.) route, the venom of juvenile specimens induced the formation of abundant thrombi in the pulmonary vasculature, whereas this effect was less frequent in the case of adult venom. Thrombosis was not abrogated by the metalloproteinase inhibitor Batimastat. Both venoms showed a weak in vitro procoagulant effect on citrated mouse plasma and bovine fibrinogen. When administered intravenously (i.v.) venoms did not affect classical clotting tests (prothrombin time and activated partial thromboplastin time) but caused a partial drop in fibrinogen concentration. The venom of juvenile specimens induced partial alterations in some rotational thromboelastometry parameters after i.v. injection. When venoms were administered i.p., only minor alterations in classical clotting tests were observed with juvenile venom, and no changes occurred for either venom in rotational thromboelastometry parameters. Both juvenile and adult venoms induced a marked thrombocytopenia after i.p. injection.Conclusions/significanceAn experimental model of the thrombotic effect induced by B. lanceolatus venom was developed. This effect is more pronounced in the case of venom of juvenile specimens, despite the observation that juvenile and adult venom proteomes are similar. Adult and juvenile venoms do not induce a consumption coagulopathy characteristic of other Bothrops sp venoms. Both venoms induce a conspicuous thrombocytopenia. This experimental model reproduces the main clinical findings described in these envenomings and should be useful to understand the mechanisms of the thrombotic effect.

Dataset Information

In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα.

Publications

In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets