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Thromb Haemost 1997; 77(01): 127-132
DOI: 10.1055/s-0038-1655919
Coagulation
Schattauer GmbH Stuttgart

Effect of a 15-Minute Infusion of DDAVP on the Pharmacokinetics and Pharmacodynamics of ™REVASC during a Four-Hour Intravenous Infusion in Healthy Male Volunteers

Dipti M Amin
1   The Guy's Drug Research Unit (GDRU Ltd), London
,
Timothy G K Mant
1   The Guy's Drug Research Unit (GDRU Ltd), London
,
Stephen M Walker
2   The Ciba Pharmaceuticals, Horsham, UK
,
Roger Kerry
3   The Ciba Phamaceuticais, Basel, Switzerland
,
Peter Lloyd
2   The Ciba Pharmaceuticals, Horsham, UK
,
Gilbert Lefèvre
4   The Laboratories Ciba-Geigy, Rueil-Malmaison, France
,
Philippe Close
3   The Ciba Phamaceuticais, Basel, Switzerland
› Author Affiliations
Further Information

Publication History

Received 18 April 1996

Accepted after revision 03 October 1996

Publication Date:
11 July 2018 (online)

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Summary

Plasma pharmacokinetics, effect on coagulation parameters, and safety and tolerability of an intravenous infusion of ™REVASC before, during and after a DDAVP infusion were investigated.

Twelve healthy volunteers were given an intravenous bolus dose followed by a constant rate four-hour infusion of ™REVASC. Fifteen-minute infusions of 0.9% saline and DDAVP were started two and three hours respectively after the start of the ™REVASC infusion.

Plasma ™REVASC concentrations were not affected by either the saline or DDAVP infusion. ™REVASC infusion produced an increase in APTT which plateaued between 0.5 and 3 hours. After the DDAVP infusion there was a tendency towards a new lower plateau whilst the ™REVASC infusion continued. There were no serious adverse events or bleeding episodes throughout the study.

In conclusion, the co-administration of intravenous DDAVP has no effect on the plasma pharmacokinetics of ™REVASC and partially reverses the ™REVASC-induced increase in APTT. This may represent a role for DDAVP in the partial reversal of anticoagulation induced by ™REVASC.

 

  • References

  • 1 Johnson PH. Hirudin: Clinical potential of a thrombin inhibitor. Annu Rev Med 1994; 45: 165-177
    CrossrefPubMedSearch in Google Scholar
  • 2 Monreal M, Costa J, Salva P. Pharmacological properties of hirudin and its derivatives: potential clinical advantages over heparin. Drugs and Ageing 1996; Vol 08 No 3 171-82
    CrossrefPubMedSearch in Google Scholar
  • 3 Mezhack B, Heim J, Rink H, Zimmermann W, Maerki W. Desulfato- hirudin, a specific thrombin inhibitor; expression and secretion in yeast. Thromb Res. (supplement 07) 1987: 33
    Search in Google Scholar
  • 4 Grossenbacher H, Auden JAL, Bill K, Maerki WMaschler. Isolation and characterisation of recombinant desulphato-hirudin from yeast, a highly selective thrombin inhibitor. Thromb Res. (supplement 07) 1987: 34
    Search in Google Scholar
  • 5 Markwardt F, Hauptmann J, Brüggener E. Pharmacological studies on the antithrombotic action of hirudin in experimental animals. Thromb Haemost 1982; 47 (03) 226-229
    Thieme ConnectPubMedSearch in Google Scholar
  • 6 Ishikawa A, Hafter R, Seemuller V, Gokel JM, Graeff H. The effects of hirudin on endotoxin induced disseminated intra-vascular coagulation (DIC). Thromb Res 1980; 19: 351-358
    CrossrefPubMedSearch in Google Scholar
  • 7 Markwardt F. Prevention of coronary thrombosis by hirudin. In: Cardiovascular Pharmacology. Papp JGy. (ed) 1987. pp 495-546
    Search in Google Scholar
  • 8 Hauptmann J, Bruggener E, Markwardt F. Effect of heparin, hirudin and a synthetic thrombin inhibitor on antithrombin II in thrombin-induced disseminated intra-vascular coagulation in rats. Haemostasis 1987; 17: 321-328
    PubMedSearch in Google Scholar
  • 9 Talbot MD. Biology of recombinant hirudin (CGP 39 393): A new prospect in the treatment of thrombosis. Semin Thromb Haemostas 1989; Vol 15 No 3 293-301
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 Markwardt F. Development of hirudin as an antithrombotic drug. Thrombosis Research 1994; Vol 74 No.1 1-23
    CrossrefPubMedSearch in Google Scholar
  • 11 Markwardt F, Nowak G, Sturzebecher J, GrieBbach U, Walsmann P, Vogel G. Pharmacokinetics and anticoagulation effect of hirudin in man. Thromb Haemost 1984; 52: 160-163
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Bichler J, Fichtl B, Siebeck M, Fichtl B. Pharmacokinetics and pharmacodynamics of hirudin in man after single subcutaneous and intravenous bolus administrations. Drug Res 1988; 38 I 704-710
    PubMedSearch in Google Scholar
  • 13 Verstraete M, Nurmohamed M, Kienast J, Siebeck M, Silling-Engelhardt G, Büller H, Hoet B, Bichler J, Close P. Biologic effect of recombinant hirudin (CGP 39 393) in human volunteers. Journal of the American College of Cardiology 1993; Vol 22 No. 4 1080-1088
    CrossrefPubMedSearch in Google Scholar
  • 14 Bichler J, Siebeck M, Fichtl B, Fritz H. Pharmacokinetics, effect on clotting tests and assessment of the immunogenic potential of hirudin after a single subcutaneous or intravenous bolus administration in man. Haemostasis 1991; 21 (suppl) 137-141
    PubMedSearch in Google Scholar
  • 15 Marbet GA, Verstraete M, Kienast J, Graf P, Hoet B, Tsakiris DA, Silling-Engelhardt G, Close P. Clinical pharmacology of intravenously administered recombinant desulfatohirudin (CGP 39 393) in healthy volunteers. Journal of Cardiovascular Pharm 1993; 22: 364-372
    PubMedSearch in Google Scholar
  • 16 Schenk JF, Glusa E, Radizwon P, Butti A, Markwardt F, Breddin HK. A recombinant hirudin (IK-HIR02) in healthy volunteers. I. Effects on coagulation parameters and bleeding time. Haemostasis 1996; 26 (03) 140-149
    PubMedSearch in Google Scholar
  • 17 Cannon CP, Braunwald E. Hirudin: Initial results in acute myocardial in farction, unstable angina and angioplasty. Journal of the American College of Cardiology 1995; Vol 25 No. 7 Suppl 30S-37S
    CrossrefPubMedSearch in Google Scholar
  • 18 Weitz JI, Hirsh J. New anticoagulants hirudin and hirulog in the treatment of acute conorary syndromes. Cardiology in Review 1995; Vol 03 No. 4 196-204
    CrossrefPubMedSearch in Google Scholar
  • 19 Fox KAA. Hirudin in unstable angina pectors. Rationale and preliminary data from the APT pilot study. European Heart Journal 1995; Vol 16 SupplD 28-32
    PubMedSearch in Google Scholar
  • 20 Serruys PW, Herrman JPR, Simon R, Rutsch W, Bode C, Laarman GJ, Van-Dijk R, Van-den-Bos AA, Umans VAWN, Fox KAA, Close P, Deckers JW. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. New England Journal of Medicine 1995; 333 No. 12 757-763
    CrossrefPubMedSearch in Google Scholar
  • 21 Herrmann JPR, Simon R, Umans VAWN, Peerboom PF, Keane D, Runierse JJMM, Bach D, Kobi P, Kerry R, Close P, Deckers JW, Serruys PW. Evaluation of recombinant hirudin (CGP 39393/™REVASC) in the prevention of restenosis after percutaneous transluminal coronary angioplasty. Rationale and design of the HELVETICA trial, a multicentre randomised double blind heparin controlled study. European Heart Journal 1995; Vol 16 Suppl. L 56-62
    PubMedSearch in Google Scholar
  • 22 Eriksson BI, Exman S, Kalebo P, Zachrisson B, Bach D, Close P. Prevention of deep vein thrombosis after total hip replacement: Direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996; Vol 347 No. 9002 635-639
    CrossrefPubMedSearch in Google Scholar
  • 23 Cofrancesco E, Cortellaro M, Leonardi P, Corradi A, Ravasi F, Bertocchi F. Markers of haemostatic system activation during thromboprophylaxis with recombinant hirudin in total hip replacement. Thromb Haemost 1996; 75 (03) 407-411
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Williams DJ, Mahomed A, Eriksson BI. Hirudin CGP 39393 as thromboprophylaxis (19). Lancet 1996; 347 (9014) 1561-1562
    PubMedSearch in Google Scholar
  • 25 Mannucci PM. Desmopressin (DDAVP) for treatment of disorders of haemostasis. Prog in Haemostasis and Thrombosis 1986; 19-45
    PubMedSearch in Google Scholar
  • 26 Berntrup E. The treatment of haemophilia, including prophylaxis, constant infusion and DDAVP. Bailliere’s Clinical Haematology 1996; 09 (02) 259-271
    PubMedSearch in Google Scholar
  • 27 Mannucci PM, Cattaneo M. Desmopressin: A non-transfusional treatment of haemophilia and von Willebrand Disease. Haemostasis 1992; 22: 276-280
    PubMedSearch in Google Scholar
  • 28 David J. Desmopressin and haemostasis. Regulatory Peptides 1993; 45: 311-317
    CrossrefPubMedSearch in Google Scholar
  • 29 Lusher JM. Response to DDAVP in von Willebrand Disease. Haemostasis 1994; 24: 276-284
    PubMedSearch in Google Scholar
  • 30 Derkay CS, Werner E, Plotnick E. Management of children with von Willebrand disease undergoing adenotonsillectomy. American Journal of Otolaryngology-Head and Neck Medicine and Surgery 1996; 17 (03) 172-177
    PubMedSearch in Google Scholar
  • 31 MacGregor IR, Roberts EM, Prowse CV, Broomhead AF, Ozolins M, Litka P. Fibrinolytic and haemostatic responses to desamino-d-arginine vasopressin (DDAVP) adminstered by intravenous and subcutaneous routes in healthy subjects. Thromb Haemost 1988; 59 (01) 34-39
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Mannucci PM. Desmopressin: A nontransfusional form of treatment for congenital and acquired bleeding disorders. Blood 1988; 72: 1449-1455
    PubMedSearch in Google Scholar
  • 33 Kim HC, Salva K, Fallot PL, Karp GI, Eisele J, Matts L, Heller I, Saidi P. Patients with prolonged bleeding time of undefined etiology and their responses to desmopressin. Thromb Haemost 1988; 59 (02) 221-224
    Thieme ConnectPubMedSearch in Google Scholar
  • 34 Casonato A, Pontara E, Bertomoro A, Zucchetto A, Zerbinati A, Girolami A. On the discrepant post-DDAVP increase of FVIII: C and von Willebrand factor in some patients with severe von Willebrand’s disease (2). British Journal of Haematology 1995; 91 (02) 512-513
    CrossrefPubMedSearch in Google Scholar
  • 35 Beck KH, Bleckmann U, Mohr P, Kretschmer V. DDAVP’s shortening of the bleeding time seems due to plasma von Willebrand factor. Seminars in Thrombosis and Haemostasis 1995; 21 (Suppl. 02) 40-43
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 DiMichele DM, Hathaway WME. Use of DDAVP in inherited and acquired platelet dysfunction Am J Haematol. 1990; 33: 39-45
    PubMedSearch in Google Scholar
  • 37 Mckeown LP, Connaghan G, Wilson O, Hansmann K, Merryman P, Gralnick HR. l-Desamino-8-arginine-vasopressin corrects the haemostatic defects in type 2B von Willebrands disease. American Journal of Hematology 1996; 51 (02) 158-163
    CrossrefPubMedSearch in Google Scholar
  • 38 Rao AK, Ghosh S, Sun L, Disa J, Pickens P, Polansky M. Mechanisms of platelet dysfunction and response to DDAVP in patients with congenital platelet function defects – a double blind placebo controlled trial. Thromb Haemost 1995; 74 (04) 1071-1078
    Thieme ConnectPubMedSearch in Google Scholar
  • 39 Janssen MJFMM, Van-der-Meulen J. The bleeding risk in chronic haemodialysis: preventive strategies in high risk patients. Netherlands Journal of Medicine 1996; Vol 48 No. 5 198-207
    CrossrefPubMedSearch in Google Scholar
  • 40 Agnelli G, Parise P, Levi M, Cosmi B, Nenci GG. Effects of desmopressin on hemostasis in patients with liver cirrhosis. Haemostasis 1995; 25 (05) 241-247
    PubMedSearch in Google Scholar
  • 41 Schulam S, Johnsson H. Heparin, DDAVP and the bleeding time. Thromb Haemost 1991; 65 (03) 242-244
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Schiele F, Vuillemenot A, Kramarz P, Kieffer Y, Anguenot T, Bernard Y, Bassand JP. Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia. American Journal of Haematology 1995; 50 (01) 20-25
    CrossrefPubMedSearch in Google Scholar
  • 43 Schiele F, Vuillemenot A, Mouhat T, Kieffer Y, Anguenot T, Bernard Y, Bassand JP. Recombinant hirudin anticoagulation in patients with heparin- induced thrombocytopenia. Presse Medicale 1996; 25 (16) 757-760
    PubMedSearch in Google Scholar
  • 44 Lethagen S, Rugam P. The effect of DDAVP and placebo on platelet function and prolonged bleeding time induced by oral acetylsalicylic acid intake in healthy volunteers. Thromb Haemost 1992; 67 (01) 185-186
    Thieme ConnectPubMedSearch in Google Scholar
  • 45 Mannuci PM, Lusher JM. Desmopressin and thrombosis. Lancet 1989; 02: 675
    PubMedSearch in Google Scholar
  • 47 Cattaneo M, Harris AS, Stromberg U, Mannucci PM. The effects of desmopressin on reducing blood loss in cardiac surgery – a meta-analysis of double-blind, placebo controlled trials. Thromb Haemost 1995; 74 (04) 1064-1070
    Thieme ConnectPubMedSearch in Google Scholar
  • 48 Clagett GP, Valentine RJ, Myers SI, Chervu A, Heller JA. Does desmopressin improve hemostasis and reduce blood loss from aortic surgery – a randomised, double blind study. Journal of Vascular Surgery 1995; 22 (03) 223-230
    CrossrefPubMedSearch in Google Scholar
  • 49 Butler KD, Dolan SL, Talbot MD, Wallis RB. Factor VIII and DDAVP reverse the effect of recombinant desulphatohirudin (CGP 39 393) on bleeding in the rat. Blood Coagulation & Fibrinolysis 1994; 04: 459-464
    PubMedSearch in Google Scholar
  • 50 Bove CM, Casey B, Marder VJ. DDAVP reduces bleeding during continued hirudin administration in the rabbit. Thromb Haemost 1996; 03: 471-475
    Thieme ConnectPubMedSearch in Google Scholar
  • 51 Ibbotson SH, Grant PJ, Kerry R, Findlay VS, Prentice CRM. The influence of infusions of DDAVP in vivo on the anticoagulant effect of recombinant hirudin in vitro. Throm Haemost 1991; 65 (01) 64-66
    PubMedSearch in Google Scholar
  • 52 Schlaeppi JM, Vekemans S, Rink H, Chang JY. Preparation of monoclonal antibodies to hirudin and hirudin peptides. Eur J Biochem 1990; 188: 463-470
    CrossrefPubMedSearch in Google Scholar
  • 53 Spinner S, Stoffle G, Fink E. Quantitative enzyme-linked immunosorbent assay (ELISA) for hirudin. J Immunol Methods 1986; 87: 79-83
    CrossrefPubMedSearch in Google Scholar
  • 54 Biggs R, Rizza C. Human Blood Coagulation. Haemostasis and Thrombosis. 03. rd ed Blackwell Scientific Publications; Oxford, England: 1984
    Search in Google Scholar
  • 55 Richardson JH, Barkley WE. (eds) Biosafety in microbiological and biomedical laboratories. US Department of Health and Human Services, Public Health Service HHS Publication No. (CDC)84-8395 Washington, DC: 1984
    Search in Google Scholar
  • 56 Zucker S. et al Preparation of quality control specimen for coagulation. Am J Clin Pathol 1970; 53: 924-927
    CrossrefPubMedSearch in Google Scholar
  • 57 National Committee for Clinical Laboratory Standards H28P and H29P Proposed guidelines for the one stage prothrombin time and activated partial thromboplastin time tests (APTT). Villanova, PA: 1982
  • 58 Triplet DA. Laboratory evaluation of coagulation. American Society of Clinical Pathology Press, Chicago, IL: 1982
    Search in Google Scholar
  • 59 British National Formulary. 1995: 311-312
    PubMed
  • 60 Von-Gontard A, Lehmkuhl G. Desmopressin side effects. Journal of the American Academy of Child and Adolescent Psycharity 1996; Vol 35 No 2 129-30
    PubMedSearch in Google Scholar
  • 61 Close P, Bichler J, Kerry R, Ekman S, Bueller HR, Kienast J, Marbet GA, Schramm W, Verstraete M. Weak allergenicity of recombinant hirudin CGP 39 393 (™REVASC) in immunocompetent volunteers. Coronary Artery Disease 1994; 05: 943-949
    PubMedSearch in Google Scholar