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Qiang Zhang - One of the best experts on this subject based on the ideXlab platform.
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increase of the pharmacological and pharmacokinetic efficacy of negatively charged polypeptide Recombinant Hirudin in rats via parenteral route by association with cationic liposomes
Journal of Controlled Release, 2008Co-Authors: Meng Meng, Xuan Zhang, Yu Liu, Xueqing Wang, Hua Zhang, Jiancheng Wang, Yibo Wang, Qiang ZhangAbstract:Two biodegradable cationic lipids, stearylamine and DC-Chol, were chosen to investigate the effect of cationic lipids on the in vitro and in vivo characteristics of hydrophilic proteins or peptides of low isoelectric point. Thrombin inhibitor Recombinant Hirudin variant-2 (rHV2) was selected as the model drug. The cationic lipids were found to achieve higher entrapment efficiency of rHV2 in liposomes than zwitterionic lipids. The positively charged liposomes became less positive and relatively stable in serum after loading rHV2. The cationic liposomes induced sustained release of rHV2 in the presence of plasma, significantly prolonged the antithrombotic efficacy and plasma level of rHV2 after intravenous injection in rats in comparison with neutral lipid liposomes, especially for stearylamine group. Both clotting times correlated well with plasma rHV2 levels. No serious adverse events were observed and physical state of rats was satisfactory for all the formulations. Electrostatic interaction between negative charge of rHV2 and cationic liposomes was confirmed and it might affect all the characteristics of rHV2 loaded cationic vehicles. The findings suggest that cationic liposomes may be a potential sustained-release delivery system for parenteral administration of hydrophilic proteins or peptides with low isoelectric point to prolong efficacy and improve bioavailability.
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controlled delivery of Recombinant Hirudin based on thermo sensitive pluronic f127 hydrogel for subcutaneous administration in vitro and in vivo characterization
Journal of Controlled Release, 2007Co-Authors: Wanliang Lu, Xuan Zhang, Xueqing Wang, Hua Zhang, Jiancheng Wang, Tianyan Zhou, Qiang ZhangAbstract:Here we investigated thermo-sensitive Pluronic® F127 (PF127) hydrogel for the controlled release of peptide and protein drugs after subcutaneous injection, using an antithrombotic polypeptide, Recombinant Hirudin variant-2 (rHV2), as the model drug. The in vitro release experiment performed with a membrane-less model at 37 °C showed that the release of antithrombotic activity of rHV2 from PF127 gel followed zero-order kinetics and correlated well with the weight percentage of PF127 dissolved, indicating a dissolution-controlled release mechanism. The in vivo result obtained after subcutaneous injection of rHV2-loaded PF127 gel in normal rats demonstrated that PF127 gel improved the bioavailability, prolonged the antithrombotic effect of rHV2, and induced detectable plasma rHV2 concentration for a longer time in comparison with rHV2 aqueous solution. Differential scanning calorimetry, dynamic light scattering and Fourier transform infrared spectroscopy provided evidence of the interaction between PF127 and rHV2, but such interaction was unlikely to interfere the feasibility of this drug delivery system. Our current in vitro and in vivo study suggested that PF127 gel may be useful as an injectable delivery vehicle for peptides and proteins with short half-lives to prolong their therapeutic effect, increase their bioavailability and improve the clinic outcome.
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controlled delivery of Recombinant Hirudin based on thermo sensitive pluronic f127 hydrogel for subcutaneous administration in vitro and in vivo characterization
Journal of Controlled Release, 2007Co-Authors: Yu Liu, Xuan Zhang, Xueqing Wang, Hua Zhang, Jiancheng Wang, Tianyan Zhou, Qiang ZhangAbstract:Here we investigated thermo-sensitive Pluronic(R) F127 (PF127) hydrogel for the controlled release of peptide and protein drugs after subcutaneous injection, using an antithrombotic polypeptide, Recombinant Hirudin variant-2 (rHV2), as the model drug. The in vitro release experiment performed with a membrane-less model at 37 degrees C showed that the release of antithrombotic activity of rHV2 from PF127 gel followed zero-order kinetics and correlated well with the weight percentage of PF127 dissolved, indicating a dissolution-controlled release mechanism. The in vivo result obtained after subcutaneous injection of rHV2-loaded PF127 gel in normal rats demonstrated that PF127 gel improved the bioavailability, prolonged the antithrombotic effect of rHV2, and induced detectable plasma rHV2 concentration for a longer time in comparison with rHV2 aqueous solution. Differential scanning calorimetry, dynamic light scattering and Fourier transform infrared spectroscopy provided evidence of the interaction between PF127 and rHV2, but such interaction was unlikely to interfere the feasibility of this drug delivery system. Our current in vitro and in vivo study suggested that PF127 gel may be useful as an injectable delivery vehicle for peptides and proteins with short half-lives to prolong their therapeutic effect, increase their bioavailability and improve the clinic outcome.
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nasal Recombinant Hirudin 2 delivery absorption and its mechanism in vivo and in vitro studies
Biological & Pharmaceutical Bulletin, 2005Co-Authors: Yujie Zhang, Qiang Zhang, Xiaoliang Wang, Jianning Sun, Yikun Sun, Mingxia ChenAbstract:The objective of this study was to investigate the feasibility of systemic absorption of Recombinant Hirudin-2 (rHV2) by nasal delivery, and its possible absorption mechanism. The degradation of rHV2 in the nasal tissue homogenate and extracts of mucosae of rabbit, as well as the degradation inhibition of enzyme inhibitor (bacitracin) was evaluated. The bioavailability of rHV2 and the improvement with enhancers, after nasal administration in rats was investigated. For further understanding of the transport and uptake characteristics of rHV2, in vitro transport experiment under various conditions using diffusion chamber technique in excised rabbit nasal epithelium was performed. It was found that rHV2 underwent rapid degradation in rabbit nasal homogenate, but it was more stable in the extracts of nasal mucosae surface. Bacitracin was able to inhibit the degradation of rHV2 to certain extent. rHV2 was detected in the rat plasma by chromogenic substrate assay after nasal administration and some enhancers also significantly increased the nasal absorption of rHV2. The transport and uptake of rHV2 across nasal epithelium was concentration-dependent and unsaturated, and was significantly inhibited by low temperature, NaN3, DNP and colchicines, while was less affected by alteration of transport direction. These results demonstrate that the possible absorption mechanism of rHV2 by nasal mucosa appears to be associated with the endocytosis as well as passive diffusion process.
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permeation enhancing effects of chitosan formulations on Recombinant Hirudin 2 by nasal delivery in vitro and in vivo
Acta Pharmacologica Sinica, 2005Co-Authors: Yujie Zhang, Xuan Zhang, Xiaoliang Wang, Jianning Sun, Qiang ZhangAbstract:Permeation-enhancing effects of chitosan formulations on Recombinant Hirudin-2 by nasal delivery in vitro and in vivo
Fritz Mertzlufft - One of the best experts on this subject based on the ideXlab platform.
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elimination of Recombinant Hirudin by modified ultrafiltration during simulated cardiopulmonary bypass assessment of different filter systems
Anesthesia & Analgesia, 2000Co-Authors: Andreas Koster, Roland Hansen, Matthias Loebe, Frank Merkle, Herrmann Kuppe, Roland Hetzer, George J Crystal, Fritz MertzlufftAbstract:UNLABELLED Recombinant Hirudin (r-Hirudin) is being used increasingly in patients with heparin-induced thrombocytopenia type II. Renal failure has been demonstrated to prolong the half-life of r-Hirudin and to cause bleeding in patients who have undergone cardiopulmonary bypass (CPB). We assessed the ability of different filter systems for modified ultrafiltration to eliminate r-Hirudin in vitro using simulated CPB. r-Hirudin concentration was measured (chromogenic laboratory standard plus ecarin clotting time) before and after filtration, and its elimination was calculated using both controlled system flow and arterial inflow (separate pump). Four hemofilters (Renoflow II, Baxter; Arylane H4, Cobe; Ultraflux AV 600, Fresenius; and BCS 110 Plus, Iostra) and two plasmapheresis filter systems (ASAHI Plasmaflow OP, Diamed; and PF 2000 N, Gambro) were assessed (5 filters of each brand = 30 filters) in a closed in vitro CPB system applying conditions usually occurring during CPB. Ten plasmapheresis filters showed a greater ability than 20 hemofilters to eliminate r-Hirudin (60%-70% vs 15%-42%) within the shortest time (80 vs 180 s). Among the four hemofilter systems, the Arylane H4 filter provided the most effective (42%) r-Hirudin elimination. Elimination of r-Hirudin was markedly improved using plasmapheresis systems, compared with hemofilter systems. Our findings may be relevant to patients with impaired renal function, who have been administered r-Hirudin during CPB. IMPLICATIONS Modified ultrafiltration may enhance the elimination of Recombinant-Hirudin, although plasmapheresis systems provide the most rapid and complete elimination of Recombinant-Hirudin during simulated cardiopulmonary bypass. The decision to use a specific system will ultimately depend on the prevailing clinical situation and overall health of the patient.
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a quick assay for monitoring Recombinant Hirudin during cardiopulmonary bypass in patients with heparin induced thrombocytopenia type iiadaptation of the ecarin clotting time to the act ii device
The Journal of Thoracic and Cardiovascular Surgery, 2000Co-Authors: Reas Koster, Roland Hansen, Mathias Bauer, Fritz Mertzlufft, Matthias LoebeAbstract:Abstract Background: Recombinant Hirudin is increasingly advocated as a promising alternative anticoagulation for patients with heparin-induced thrombocytopenia type II during cardiopulmonary bypass. This requires monitoring of the ecarin clotting time. No commercial ecarin clotting time assay is available for clinical use. We adapted the ecarin clotting time to the easy-to-handle ACT II device. Methods: Three different concentrations of the ecarin reagent (20, 10, 5 U/mL) were investigated as preliminary studies. Standard calibration curves were constructed for concentrations of Recombinant Hirudin ranging from 0 to 5 μg/mL. In vivo samples were collected from patients with heparin-induced thrombocytopenia type II who underwent cardiopulmonary bypass, and the values were compared with the values obtained by the chromogenic method. The final concentration for the assay of 5 IU/mL ecarin was further assessed in vitro for reproducibility and the influence of variations in hematocrit, platelet count, and procoagulants. Results: All three concentrations of ecarin revealed linearity to 5 μg/mL concentrations of Recombinant Hirudin. The ecarin concentration of 5 U/mL revealed the best correlation (0.87) to the laboratory method, was reproducible over the whole Recombinant Hirudin range, and was not influenced by the variations in the in vitro setup. Conclusions: The ACT II/ecarin clotting time with an ecarin concentration of 5 U/mL is a simple and reliable assay for monitoring Recombinant Hirudin during cardiopulmonary bypass. Use of this assay allows a wider use of Recombinant Hirudin in patients with heparin-induced thrombocytopenia type II during bypass and thereby may contribute to the safer management of these patients. (J Thorac Cardiovasc Surg 2000;119:1278-83)
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Recombinant Hirudin as an alternative for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II: a 1-year experience in 57 patients.
Journal of cardiothoracic and vascular anesthesia, 2000Co-Authors: Andreas Koster, Roland Hansen, Herrmann Kuppe, Roland Hetzer, George J Crystal, Fritz MertzlufftAbstract:Objective: To explore the possible use of Recombinant Hirudin (r-Hirudin) as an alternative to heparin for anticoagulation during cardiovascular surgery. Design: Retrospective analysis. Setting: Two university hospitals. Participants: Fifty-seven patients with heparin-induced thrombocytopenia type II (HIT II) in whom r-Hirudin was used during cardiovascular surgery with cardiopulmonary bypass (CPB). Interventions: None. Measurements and Main Results: The r-Hirudin concentration was monitored on-line, at the point of the patient's care using the ecarin clotting time and maintained in the range of 3 to 4 μg/mL. The r-Hirudin elimination at the conclusion of CPB was augmented through modified zero-balanced ultrafiltration and forced diuresis. The duration of CPB was 63 to 246 minutes. The r-Hirudin requirement per minute of CPB was 0.016 to 0.035 μg/kg/min, and the 24-hour blood drainage was 50 to 2,200 mL. Of the 57 patients, 54 fully recovered, including 9 patients who did not require any allogenic products. Four patients, all with impaired renal function, showed prolonged r-Hirudin elimination and excessive bleeding and required surgical reexploration. Three patients died as a result of complications unrelated to the perioperative management. Conclusion: This study provides evidence that r-Hirudin can be used safely and effectively for routine anticoagulation during CPB in patients diagnosed with HIT II. Almost 95% of the patients in whom it was used were discharged uneventfully. Patients with perioperative renal failure, however, showed increased bleeding. Copyright © 2000 by W.B. Saunders Company
J P Bassand - One of the best experts on this subject based on the ideXlab platform.
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subcutaneous Recombinant Hirudin hbw 023 versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs a multicentre prospective dose ranging randomized trial international multicentre Hirudin study group
Thrombosis and Haemostasis, 1997Co-Authors: Francois Schiele, Gilles Grollier, J P Bassand, F Lindgaerde, Henry Eriksson, A Wallmark, P O Hansson, M Sjo, Marco Moia, A CamezAbstract:The aim of this multicentre, prospective, randomised, dose-ranging study was to compare the safety and efficacy of subcutaneous Recombinant Hirudin (HBW 023) against intravenous sodium heparin in acute lower limb deep venous thrombosis (DVT). Patients were randomized to treatment with either HBW 023 or heparin for 5 +/- 1 days. HBW 023 was given according to body-weight in three dose groups. Thromboembolic disease was assessed by phlebography and ventilation/perfusion (V/Q) scanning on Day 1 and Day 5 +/- 1. One hundred and fifty-five patients were enrolled, of these 121 were evaluable for efficacy analysis. Significantly fewer patients on HBW 023 developed new V/Q abnormalities during the treatment period, (p = 0.006). There was no difference between the groups in thrombus extension or regression, major bleeding complications or serious adverse events. There were significantly fewer findings of new V/Q mismatch after treatment with HBW 023, and anticoagulant control was superior in these patients.
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use of Recombinant Hirudin as antithrombotic treatment in patients with heparin induced thrombocytopenia
American Journal of Hematology, 1995Co-Authors: Francois Schiele, Alain Vuillemenot, Y Kieffer, P Kramarz, T Anguenot, Yvette Bernard, J P BassandAbstract:Heparin-induced thrombocytopenia is a rare but severe complication of heparin therapy that can result in severe venous or arterial thromboembolic events and whose treatment remains partially unanswered. Recombinant Hirudin is potentially effective as an antithrombotic treatment in the management of heparin-induced thrombocytopenia, given its potent antithrombin effects without known interaction with platelets. We report the results obtained with intravenous Recombinant Hirudin (HBW 023) administered on a compassionate basis to patients suffering from heparin-induced thrombocytopenia. Six patients suffering from heparin-induced thrombocytopenia were submitted to intravenous Recombinant Hirudin (HBW 023) administered at a dose of 0.05 mg/kg/hr after an initial bolus injection of 0.07 mg/kg in the case of a venous thromboembolic event, and at a dose of 0.15 mg/kg/hr with the same initial bolus injection in the case of an arterial thromboembolic event. Whenever possible, oral anticoagulation with acenocoumarol was introduced at the same time as Recombinant Hirudin, which was interrupted as soon as the international normalized ratio reached 3. Clinical events, particularly thromboembolism and bleeding, were noted; activated partial thromboplastin time (aPTT), and platelet count were assessed throughout the administration of Recombinant Hirudin. Heparins responsible for heparin-induced thrombocytopenia were porcine sodium or calcium heparinate in four cases, nadroparin in one case, and enoxaparin in one case. Thrombocytopenia was discovered on routine systematic platelet count in two patients and after the occurrence of arterial and venous thromboembolism in two patients, respectively. After discontinuation of heparin and the onset of Recombinant Hirudin, clinical evolution was uneventful in all patients, with no recurrence of thromboembolism, limb amputation, or hemorrhagic complication. The aPTT ratio varied from 1.8 to 3.5 (median 2.4) throughout administration of Recombinant Hirudin. Platelet count rose from nadir (median value 60 x 10(9), 15 to 90) to above 100 x 10(9)/L in every patient within 3-6 days (median 5), after discontinuation of heparin. Intravenous administration of Recombinant Hirudin ensured safe anticoagulation in patients with heparin-induced thrombocytopenia and made it possible to wait for oral anticoagulation to become efficient and platelet count to return to normal values without occurrence or recurrence of thromboembolism.
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a pilot study of subcutaneous Recombinant Hirudin hbw 023 in the treatment of deep vein thrombosis
Thrombosis and Haemostasis, 1994Co-Authors: Francois Schiele, A Camez, Alain Vuillemenot, Ph Kramarz, Y Kieffer, J Soria, Claudine Soria, M Mirshahi, J P BassandAbstract:BACKGROUND Recombinant Hirudin, a pure, specific antithrombin could be more effective than heparin in the treatment of deep vein thrombosis, but its short half-life requires constant intravenous infusion, whereas subcutaneous administration of Recombinant Hirudin can ensure stable and prolonged plasma levels. The aim of our study was to assess the pharmacokinetics, the results on the coagulation variables, and the safety of a Recombinant Hirudin (HBW 023) administered subcutaneously in patients suffering from deep vein thrombosis. METHODS Recombinant Hirudin (HBW 023) was administered subcutaneously to 10 patients with recent deep vein thrombosis, at a dose of 0.75 mg/kg of body weight twice daily for 5 days, after which standard heparin and acenocoumarol were introduced. Bilateral lower limb venography, and pulmonary angiography, and/or ventilation-perfusion lung scan were carried out on day 1 prior to Recombinant Hirudin injection and repeated on day 5. aPTT and Recombinant Hirudin plasma levels were serially assessed after the 1st and the 10th injections. Prothrombin fragments 1 + 2, thrombin-antithrombin III complexes, fibrin degradation products were collected on days 1 and 5. RESULTS Clinical evolution was uneventful in all but one patient who had a probable recurrence of pulmonary embolism on day 4. No hemorrhagic complication, no untoward biological event was observed. On days 5, Marder score was unchanged or had decreased. Plasma levels of Recombinant Hirudin peaked in between 3 and 4 h following the injection. aPTT values paralleled, and were significantly correlated with plasma levels of Recombinant Hirudin on day 1 as well on day 5 (r = 0.903, r = 0.948 respectively). Fragment 1 + 2, and thrombin antithrombin complexes non-significantly decreased from day 1 to day 5. CONCLUSIONS Subcutaneous administration of Recombinant Hirudin ensures prolonged stable plasma levels of Recombinant Hirudin which results in efficient anticoagulation. A dose-ranging study conducted with subcutaneous Recombinant Hirudin in comparison to conventional heparin therapy may answer the question as to efficacy.
Yu Liu - One of the best experts on this subject based on the ideXlab platform.
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increase of the pharmacological and pharmacokinetic efficacy of negatively charged polypeptide Recombinant Hirudin in rats via parenteral route by association with cationic liposomes
Journal of Controlled Release, 2008Co-Authors: Meng Meng, Xuan Zhang, Yu Liu, Xueqing Wang, Hua Zhang, Jiancheng Wang, Yibo Wang, Qiang ZhangAbstract:Two biodegradable cationic lipids, stearylamine and DC-Chol, were chosen to investigate the effect of cationic lipids on the in vitro and in vivo characteristics of hydrophilic proteins or peptides of low isoelectric point. Thrombin inhibitor Recombinant Hirudin variant-2 (rHV2) was selected as the model drug. The cationic lipids were found to achieve higher entrapment efficiency of rHV2 in liposomes than zwitterionic lipids. The positively charged liposomes became less positive and relatively stable in serum after loading rHV2. The cationic liposomes induced sustained release of rHV2 in the presence of plasma, significantly prolonged the antithrombotic efficacy and plasma level of rHV2 after intravenous injection in rats in comparison with neutral lipid liposomes, especially for stearylamine group. Both clotting times correlated well with plasma rHV2 levels. No serious adverse events were observed and physical state of rats was satisfactory for all the formulations. Electrostatic interaction between negative charge of rHV2 and cationic liposomes was confirmed and it might affect all the characteristics of rHV2 loaded cationic vehicles. The findings suggest that cationic liposomes may be a potential sustained-release delivery system for parenteral administration of hydrophilic proteins or peptides with low isoelectric point to prolong efficacy and improve bioavailability.
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Increase of the pharmacological and pharmacokinetic efficacy of negatively charged polypeptide Recombinant Hirudin in rats via parenteral route by association with cationic liposomes
journal of controlled release, 2008Co-Authors: Meng Meng, Yu Liu, Yibo Wang, Wang Jian-cheng, Zhang Hua, Wang Xue-qing, Zhang Xuan, Lu Wan-liang, Zhang QiangAbstract:Two biodegradable cationic lipids, stearylamine and DC-Chol, were chosen to investigate the effect of cationic lipids on the in vitro and in vivo characteristics of hydrophilic proteins or peptides of low isoelectric point. Thrombin inhibitor Recombinant Hirudin variant-2 (rHV2) was selected as the model drug. The cationic lipids were found to achieve higher entrapment efficiency of rHV2 in liposomes than zwitterionic lipids. The positively charged liposomes became less positive and relatively stable in serum after loading rHV2. The cationic liposomes induced sustained release of rHV2 in the presence of plasma, significantly prolonged the antithrombotic efficacy and plasma level of rHV2 after intravenous injection in rats in comparison with neutral lipid liposomes, especially for stearylamine group. Both clotting times correlated well with plasma rHV2 levels. No serious adverse events were observed and physical state of rats was satisfactory for all the formulations. Electrostatic interaction between negative charge of rHV2 and cationic liposomes was confirmed and it might affect all the characteristics of rHV2 loaded cationic vehicles. The findings suggest that cationic liposomes may be a potential sustained-release delivery system for parenteral administration of hydrophilic proteins or peptides with low isoelectric point to prolong efficacy and improve bioavailability. (C) 2008 Elsevier B.V. All rights reserved.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000256955200002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Chemistry, MultidisciplinaryPharmacology & PharmacySCI(E)EIPubMed13ARTICLE2113-11912
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controlled delivery of Recombinant Hirudin based on thermo sensitive pluronic f127 hydrogel for subcutaneous administration in vitro and in vivo characterization
Journal of Controlled Release, 2007Co-Authors: Yu Liu, Xuan Zhang, Xueqing Wang, Hua Zhang, Jiancheng Wang, Tianyan Zhou, Qiang ZhangAbstract:Here we investigated thermo-sensitive Pluronic(R) F127 (PF127) hydrogel for the controlled release of peptide and protein drugs after subcutaneous injection, using an antithrombotic polypeptide, Recombinant Hirudin variant-2 (rHV2), as the model drug. The in vitro release experiment performed with a membrane-less model at 37 degrees C showed that the release of antithrombotic activity of rHV2 from PF127 gel followed zero-order kinetics and correlated well with the weight percentage of PF127 dissolved, indicating a dissolution-controlled release mechanism. The in vivo result obtained after subcutaneous injection of rHV2-loaded PF127 gel in normal rats demonstrated that PF127 gel improved the bioavailability, prolonged the antithrombotic effect of rHV2, and induced detectable plasma rHV2 concentration for a longer time in comparison with rHV2 aqueous solution. Differential scanning calorimetry, dynamic light scattering and Fourier transform infrared spectroscopy provided evidence of the interaction between PF127 and rHV2, but such interaction was unlikely to interfere the feasibility of this drug delivery system. Our current in vitro and in vivo study suggested that PF127 gel may be useful as an injectable delivery vehicle for peptides and proteins with short half-lives to prolong their therapeutic effect, increase their bioavailability and improve the clinic outcome.
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Controlled delivery of Recombinant Hirudin based on thermo-sensitive Pluronic (R) F127 hydrogel for subcutaneous administration: In vitro and in vivo characterization
journal of controlled release, 2007Co-Authors: Yu Liu, Zhang Hua, Wang Xue-qing, Zhang Xuan, Lu Wan-liang, Wang Han-cheng, Zhou Tian-yan, Zhang QiangAbstract:Here we investigated thermo-sensitive Pluronic((R)) F127 (PF127) hydrogel for the controlled release of peptide and protein drugs after subcutaneous injection, using an antithrombotic polypeptide, Recombinant Hirudin variant-2 (rHV2), as the model drug. The in vitro release experiment performed with a membrane-less model at 37 degrees C showed that the release of antithrombotic activity of rHV2 from PF127 gel followed zero-order kinetics and correlated well with the weight percentage of PF127 dissolved, indicating a dissolution-controlled release mechanism. The in vivo result obtained after subcutaneous injection of rHV2-loaded PF127 gel in normal rats demonstrated that PF127 gel improved the bioavailability, prolonged the antithrombotic effect of rHV2, and induced detectable plasma rHV2 concentration for a longer time in comparison with rHV2 aqueous solution. Differential scanning calorimetry, dynamic light scattering and Fourier transform infrared spectroscopy provided evidence of the interaction between PF127 and rHV2, but such interaction was unlikely to interfere the feasibility of this drug delivery system. Our current in vitro and in vivo study suggested that PF127 gel may be useful as an injectable delivery vehicle for peptides and proteins with short half-lives to prolong their therapeutic effect, increase their bioavailability and improve the clinic outcome. (c) 2006 Elsevier B.V All rights reserved.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000244928100011&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Chemistry, MultidisciplinaryPharmacology & PharmacySCI(E)EIPubMed86ARTICLE3387-39511
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pharmacodynamics and pharmacokinetics of Recombinant Hirudin via four non parenteral routes
Peptides, 2005Co-Authors: Yu Liu, Xuan Zhang, Xueqing Wang, Hua Zhang, Qiang ZhangAbstract:Abstract One of Recombinant Hirudin variants, rHV2, a polypeptide used as an anticoagulant agent in clinic, was administered to anesthetized rats via intratracheal, buccal, nasal and rectal routes. Prolongation in clotting time and thrombin time was measured to calculate pharmacological bioavailability. Plasma concentration of rHV2 was determined using a chromogenic thrombin substrate assay and pharmacokinetic parameters were obtained on the basis of a non-compartmental model. Intravenous administration was also performed as the gold standard by which the other routes were compared. Difference in pharmacological bioavailability (P.A.), bioavailability ( F ) and absorption rate of rHV2 was found for the four non-parenteral routes. The rank order for both P.A. and F was intratracheal > nasal > buccal > rectal. Absorption was more rapid after both intratracheal and rectal administration ( t max ∼ 20–40 min), compared with that after nasal and rectal administration. It is evident that the pulmonary route is preferable to other three routes for successful systemic delivery of rHV2.
Francois Schiele - One of the best experts on this subject based on the ideXlab platform.
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subcutaneous Recombinant Hirudin hbw 023 versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs a multicentre prospective dose ranging randomized trial international multicentre Hirudin study group
Thrombosis and Haemostasis, 1997Co-Authors: Francois Schiele, Gilles Grollier, J P Bassand, F Lindgaerde, Henry Eriksson, A Wallmark, P O Hansson, M Sjo, Marco Moia, A CamezAbstract:The aim of this multicentre, prospective, randomised, dose-ranging study was to compare the safety and efficacy of subcutaneous Recombinant Hirudin (HBW 023) against intravenous sodium heparin in acute lower limb deep venous thrombosis (DVT). Patients were randomized to treatment with either HBW 023 or heparin for 5 +/- 1 days. HBW 023 was given according to body-weight in three dose groups. Thromboembolic disease was assessed by phlebography and ventilation/perfusion (V/Q) scanning on Day 1 and Day 5 +/- 1. One hundred and fifty-five patients were enrolled, of these 121 were evaluable for efficacy analysis. Significantly fewer patients on HBW 023 developed new V/Q abnormalities during the treatment period, (p = 0.006). There was no difference between the groups in thrombus extension or regression, major bleeding complications or serious adverse events. There were significantly fewer findings of new V/Q mismatch after treatment with HBW 023, and anticoagulant control was superior in these patients.
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use of Recombinant Hirudin as antithrombotic treatment in patients with heparin induced thrombocytopenia
American Journal of Hematology, 1995Co-Authors: Francois Schiele, Alain Vuillemenot, Y Kieffer, P Kramarz, T Anguenot, Yvette Bernard, J P BassandAbstract:Heparin-induced thrombocytopenia is a rare but severe complication of heparin therapy that can result in severe venous or arterial thromboembolic events and whose treatment remains partially unanswered. Recombinant Hirudin is potentially effective as an antithrombotic treatment in the management of heparin-induced thrombocytopenia, given its potent antithrombin effects without known interaction with platelets. We report the results obtained with intravenous Recombinant Hirudin (HBW 023) administered on a compassionate basis to patients suffering from heparin-induced thrombocytopenia. Six patients suffering from heparin-induced thrombocytopenia were submitted to intravenous Recombinant Hirudin (HBW 023) administered at a dose of 0.05 mg/kg/hr after an initial bolus injection of 0.07 mg/kg in the case of a venous thromboembolic event, and at a dose of 0.15 mg/kg/hr with the same initial bolus injection in the case of an arterial thromboembolic event. Whenever possible, oral anticoagulation with acenocoumarol was introduced at the same time as Recombinant Hirudin, which was interrupted as soon as the international normalized ratio reached 3. Clinical events, particularly thromboembolism and bleeding, were noted; activated partial thromboplastin time (aPTT), and platelet count were assessed throughout the administration of Recombinant Hirudin. Heparins responsible for heparin-induced thrombocytopenia were porcine sodium or calcium heparinate in four cases, nadroparin in one case, and enoxaparin in one case. Thrombocytopenia was discovered on routine systematic platelet count in two patients and after the occurrence of arterial and venous thromboembolism in two patients, respectively. After discontinuation of heparin and the onset of Recombinant Hirudin, clinical evolution was uneventful in all patients, with no recurrence of thromboembolism, limb amputation, or hemorrhagic complication. The aPTT ratio varied from 1.8 to 3.5 (median 2.4) throughout administration of Recombinant Hirudin. Platelet count rose from nadir (median value 60 x 10(9), 15 to 90) to above 100 x 10(9)/L in every patient within 3-6 days (median 5), after discontinuation of heparin. Intravenous administration of Recombinant Hirudin ensured safe anticoagulation in patients with heparin-induced thrombocytopenia and made it possible to wait for oral anticoagulation to become efficient and platelet count to return to normal values without occurrence or recurrence of thromboembolism.
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a pilot study of subcutaneous Recombinant Hirudin hbw 023 in the treatment of deep vein thrombosis
Thrombosis and Haemostasis, 1994Co-Authors: Francois Schiele, A Camez, Alain Vuillemenot, Ph Kramarz, Y Kieffer, J Soria, Claudine Soria, M Mirshahi, J P BassandAbstract:BACKGROUND Recombinant Hirudin, a pure, specific antithrombin could be more effective than heparin in the treatment of deep vein thrombosis, but its short half-life requires constant intravenous infusion, whereas subcutaneous administration of Recombinant Hirudin can ensure stable and prolonged plasma levels. The aim of our study was to assess the pharmacokinetics, the results on the coagulation variables, and the safety of a Recombinant Hirudin (HBW 023) administered subcutaneously in patients suffering from deep vein thrombosis. METHODS Recombinant Hirudin (HBW 023) was administered subcutaneously to 10 patients with recent deep vein thrombosis, at a dose of 0.75 mg/kg of body weight twice daily for 5 days, after which standard heparin and acenocoumarol were introduced. Bilateral lower limb venography, and pulmonary angiography, and/or ventilation-perfusion lung scan were carried out on day 1 prior to Recombinant Hirudin injection and repeated on day 5. aPTT and Recombinant Hirudin plasma levels were serially assessed after the 1st and the 10th injections. Prothrombin fragments 1 + 2, thrombin-antithrombin III complexes, fibrin degradation products were collected on days 1 and 5. RESULTS Clinical evolution was uneventful in all but one patient who had a probable recurrence of pulmonary embolism on day 4. No hemorrhagic complication, no untoward biological event was observed. On days 5, Marder score was unchanged or had decreased. Plasma levels of Recombinant Hirudin peaked in between 3 and 4 h following the injection. aPTT values paralleled, and were significantly correlated with plasma levels of Recombinant Hirudin on day 1 as well on day 5 (r = 0.903, r = 0.948 respectively). Fragment 1 + 2, and thrombin antithrombin complexes non-significantly decreased from day 1 to day 5. CONCLUSIONS Subcutaneous administration of Recombinant Hirudin ensures prolonged stable plasma levels of Recombinant Hirudin which results in efficient anticoagulation. A dose-ranging study conducted with subcutaneous Recombinant Hirudin in comparison to conventional heparin therapy may answer the question as to efficacy.