Local Heparin, 6-Mercaptopurine, Prednisolone, and Mizoribine Delivery in a Canine Renal Allograft Model

  • Scott A. Gruber
  • Shengguang Xiao
  • Stephen E. Hughes
Part of the Medical Intelligence Unit book series (MIU.LANDES)


Although the rat models described in the previous section elegantly emonstrate the efficacy of local immunosuppression, they have several limitations when one considers the potential for eventual clinical application. The osmotic pumps utilized for drug delivery are inaccessible within the abdomen, cannot be emptied of and refilled with drug, and can only infuse drug for a 2 week interval. As a result, long-term considerations such as pump compatibility, drug stability and catheterinduced thrombosis and infection cannot be evaluated. Furthermore, repeated blood sampling to assess regional and systemic pharmacokinetics is not practical. Despite the generalized species simililarity which exists in the pharmacokinetic advantage of regional drug delivery,1 the results obtained from these models may not be entirely relevant to higher animals and man in view of significant species differences in drug disposition and pharmacologic activity, a point well illustrated by the corticosteroids.2–6 Finally, heterotopic placement of the transplanted organ to increase the pharmacokinetic advantage achievable from local infusion of a particular drug is not clinically feasible.


Renal Allograft Heparin Dose Lateral Chest Wall Pharmacokinetic Advantage Local Immunosuppression 
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  1. 1.
    Dedrick RL. Interspecies scaling of regional drug delivery. J Pharm Sci 1986; 75: 1047.PubMedCrossRefGoogle Scholar
  2. 2.
    Clayman HN. Corticosteroids and lymphoid cells. New Eng J Med 1972; 287: 388.CrossRefGoogle Scholar
  3. 3.
    Shewell J, Long DA. A species difference with regard to the effect of cortisone acetate on body weight, gamma-globulin and circulating antitoxin levels. J Hyg 1956; 54: 452.PubMedCrossRefGoogle Scholar
  4. 4.
    Clayman HN, Moorhead JW, Benner WH. Corticosteroids and lymphoid cells in vitro I. Hydrocortisone lysis of human guinea pig, and mouse thymus cells. J Lab Clin Med 1971; 78: 499.Google Scholar
  5. 5.
    Fauci AS, Dale DC, Balow JE. Glucocorticosteroid therapy: mechanisms of action and clinical considerations. Ann Int Med 1976; 84: 304.PubMedCrossRefGoogle Scholar
  6. 6.
    Gruber SA, Hrushesky WJM, Canafax DM et al. Local prednisolone infusion of canine renal allografts. Transplantation 1989; 48: 1072.PubMedCrossRefGoogle Scholar
  7. 7.
    Gruber SA, Cipolle RJ, Canafax DM et al. An implantable pump for intrarenal infusion of immunosuppressants in a canine autotransplant model. Pharm Res 1988; 12: 781.CrossRefGoogle Scholar
  8. 8.
    Gruber SA, Canafax DM, Erdmann GR et al. The pharmacokinetic advantage of local 6-mercaptopurine infusion in a canine renal transplant model. Transplantation 1989; 48: 928.PubMedCrossRefGoogle Scholar
  9. 9.
    Martz E, Benacerraf B.: Inhibition of immune cell-mediated killing by heparin. Clin Immunol Immunopath 1973; 1: 533.CrossRefGoogle Scholar
  10. 10.
    Cohen S, Benacerraf B, McCluskey RT et al. Effect of anticoagulants on delayed hypersensitivity reactions. J Immunol 1967; 98: 351.PubMedGoogle Scholar
  11. 11.
    MacDonald A, Busch GJ, Alexander JL et al. Heparin and aspirin in the treatment of hyperacute rejection of renal allografts in presensitized dogs. Transplantation 1970; 9: 1.PubMedCrossRefGoogle Scholar
  12. 12.
    Piper J. The fate of heparin in rabbits after intravenous injection. Filtration and tubular secretion in the kidneys. Acta Pharmacol (Copenh) 1947; 3: 373.CrossRefGoogle Scholar
  13. 13.
    McAllister BM, Demis DJ. Heparin metabolism: isolation and characterization of uroheparin. Nature 1966; 212: 293.PubMedCrossRefGoogle Scholar
  14. 14.
    Boneu B, Caranobe C, Cadroy Y et al. Pharmacokinetic studies of standard unfractionated heparin, and low molecular weight heparins in the rabbit. Semin Thromb Hemost 1988; 14: 18.PubMedCrossRefGoogle Scholar
  15. 15.
    Gruber SA, Cipolle RJ, Canafax DM et al. Pharmacodynamics of local heparin delivery in a canine renal allograft model. J Pharmacol Exp Ther 1990; 252: 733.PubMedGoogle Scholar
  16. 16.
    Gruber SA, Hrushesky WJM, Cipolle RJ et al. Local immunosuppression with reduced systemic toxicity in a canine renal allograft model. Transplantation 1989; 48: 936.PubMedCrossRefGoogle Scholar
  17. 17.
    Retik AB, Dubernard J-M, Hester WJ et al. A study of the effects of intraarterial immunosuppressive drug therapy on canine renal allografts. Surgery 1966; 60: 1242.PubMedGoogle Scholar
  18. 18.
    Terz JJ, Crampton R, Miller D et al. Regional infusion chemotherapy for prolongation of kidney allografts. J Surg Res 1969; 9: 13.PubMedCrossRefGoogle Scholar
  19. 19.
    Ruers TJM, Buurman WA, Smits JFM et al. Local treatment of renal allografts, a promising way to reduce the dosage of immunosuppressive drugs. Transplantation 1986; 41: 156–61.PubMedCrossRefGoogle Scholar
  20. 20.
    Ruers TJM, Daeman MJAP, Thijssen HHW et al. Sensitivity of graft rejection in rats to local immunosuppressive therapy. Transplantation 1988; 46: 820.PubMedCrossRefGoogle Scholar
  21. 21.
    Ackerman RW, Barnard CN. The effect of direct infusions of cortisone into the renal artery of a transplanted kidney. S A Med J 1966; 40: 83.Google Scholar
  22. 22.
    Dougherty JC, Nehlsen SL, Minick R et al. Failure of regional immunosuppressive therapy to modify renal allograft rejection. Transplantation 1968; 6: 554.PubMedCrossRefGoogle Scholar
  23. 23.
    Homan WP, French ME, Fabre JW et al. The interaction of cyclosporin A with other immunosuppressive agents in dog recipients of renal allografts. Transplant Proc 1980; 12: 287.PubMedGoogle Scholar
  24. 24.
    Kountz SL, Cohn RB. Initial treatment of renal allografts with large intrarenal doses of immunosuppressive drugs. Lancet 1969; 1: 338.PubMedCrossRefGoogle Scholar
  25. 25.
    Laupacis A, Keown PA, Rankin RN et al. Intraarterial methylprednisolone and heparin (IAT) for the treatment of refractory renal transplant rejection episodes. Transplant Proc 1982; 14: 693.PubMedGoogle Scholar
  26. 26.
    Mizuno K, Tsujino M, Takada M et al. Studies on bredinin I. isolation, characterization and biological properties. J Antibiot (Tokyo) 1974; 27: 775.CrossRefGoogle Scholar
  27. 27.
    Koyama H, Tsuji M. Genetic and biochemical studies on the activation and cytotoxic mechanism of bredinin a potent inhibitor of purine biosynthesis in mammalian cells. Biochem Pharmacol 1983; 32: 3547.PubMedCrossRefGoogle Scholar
  28. 28.
    Kokado Y, Ishibahi M, Jiang H et al. Low-dose ciclosporin, mizoribine and prednisolone in renal transplantation: a new triple-drug therapy. Clin Transplantation 1990; 4: 191.Google Scholar
  29. 29.
    Mita K, Akiyama N, Nagao T et al. Advantages of mizoribine over azathioprine in combination therapy with cyclosporine for renal transplantation. Transplant Proc 1990; 22: 1679.PubMedGoogle Scholar
  30. 30.
    Erdmann GR, Gruber SA, McGuiggan MM et al. Determination of mizoribine in plasma using ion pair high performance liquid chromatography. J Chromatogr 1989; 494: 354.PubMedGoogle Scholar
  31. 31.
    Murase J, Mizuno K, Kawai K et al. Absorption, distribution, metabolism, and excretion of bredinin in rats. Pharmacometrics 1978; 15: 829.Google Scholar
  32. 32.
    Lee HA, Slapak M, Venkatraman G et al. Mizoribine as an alternative to azathioprine in triple therapy. Immunosuppressive regimens in cadaveric renal transplantation: two successive studies. Tranplant Proc 1995; 27: 1050.Google Scholar
  33. 33.
    Uchida H, Yokota K, Akiyama N et al. Effectiveness of a new drug, bredinin, on canine kidney allotransplant survival. Transplant Proc 1979; 11: 865.PubMedGoogle Scholar
  34. 34.
    Gregory C, Gourley I, Haskins S et al. Effects of mizoribine on canine renal allograft recipients. Amer J Vet Res 1988; 49: 305.PubMedGoogle Scholar
  35. 35.
    Gruber SA, Erdmann GR, Burke BA et al. Mizoribine pharmacokinetics and pharmacodynamics in a canine renal allograft model of local immunosuppression. Transplantation 1992; 53: 12.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • Scott A. Gruber
  • Shengguang Xiao
  • Stephen E. Hughes

There are no affiliations available

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