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Use of sphingosine-1-phosphate 1 receptor agonist, KRP-203, in combination with a subtherapeutic dose of cyclosporine A for rat renal transplantation.

AbstractBACKGROUND:
We demonstrate the long-term effectiveness of KRP-203 treatment in combination with a subtherapeutic dose of cyclosporine A (CsA) on rat renal allografts.
METHODS:
We tested the effect of KRP-203 in combination with CsA using a rat skin allograft model. The Pharmacokinetic interaction between CsA and KRP-203 was evaluated. The selectivity of KRP-203 for sphingosine-1-phosphate (S1P)1 and S1P3 receptors were investigated in vitro. Heart rate alteration following bolus injection of phosphorylated KRP-203 (KRP-203-P) or FTY720 (FTY720-P) was also monitored in rats. Finally, the long-term effectiveness of KRP-203 in conjunction with a low dose of CsA was investigated in a rat renal transplantation model.
RESULTS:
Administration of KRP-203 with CsA prolonged skin allograft survival. KRP-203 and CsA had no effect on the pharmacokinetics of the other. While FTY720-P activated both S1P1 and S1P3 receptors, KRP-203-P selectively activated S1P1, but not the S1P3 receptor (EC50:>1000 nM). Compared to FTY720-P, a tenfold higher dose of KRP-203-P was necessary to induce transient bradycardia. With a low dose of CsA (1 mg/kg/day), KRP-203 (0.3 mg/kg/day) significantly prolonged renal allograft survival (P<0.05, survival time: 9.8 days (CsA) vs. >27.4 days (CsA+KRP)). Although a higher dose of CsA (3 mg/kg/day) alone kept recipients alive, this caused severe renal graft dysfunction. Use of KRP-203 (3 mg/kg/day) in conjunction with CsA markedly improved graft function (P<0.05, creatinine clearance: 0.41+/-0.25 ml/min [CsA] vs. 1.15+/-0.16 ml/min [CsA+KRP]).
CONCLUSIONS:
The selectivity of KRP-203 for S1P1 reduces the risk of bradycardia, and the combination therapy of KRP-203 with CsA represents a safe and effective strategy for use in renal transplantation.
AuthorsJun Fujishiro, Shinji Kudou, Satomi Iwai, Masafumi Takahashi, Yoji Hakamata, Miki Kinoshita, Satoru Iwanami, Shigeru Izawa, Tokutaro Yasue, Kohei Hashizume, Takashi Murakami, Eiji Kobayashi
JournalTransplantation (Transplantation) Vol. 82 Issue 6 Pg. 804-12 (Sep 27 2006) ISSN: 0041-1337 [Print] United States
PMID17006328 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • KRP-203
  • Receptors, Lysosphingolipid
  • Sulfhydryl Compounds
  • Cyclosporine
Topics
  • Animals
  • Calcium Signaling (physiology)
  • Cyclosporine (therapeutic use)
  • Drug Therapy, Combination
  • Graft Survival
  • Heart Rate (drug effects)
  • Kidney Transplantation (immunology)
  • Major Histocompatibility Complex
  • Male
  • Rats
  • Rats, Inbred F344
  • Receptors, Lysosphingolipid (agonists)
  • Sulfhydryl Compounds (therapeutic use)
  • Transplantation, Homologous

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