Synergistic suppression of rat neointimal hyperplasia by rapamycin and imatinib mesylate: implications for the prevention of accelerated arteriosclerosis.
BACKGROUND
Accelerated arteriosclerosis remains a major limitation to therapeutic interventions such as angioplasty, stent deployment, and solid organ transplantation. Rapamycin, a powerful new immunosuppressant set to replace calcineurin inhibitors in the transplant setting, and imatinib mesylate, a receptor tyrosine kinase inhibitor, are both angioprotective. Here, we explored the pharmacological and therapeutic interactions of these two agents in a rat model of neointimal hyperplasia.


METHODS
Wistar rats, subjected to balloon catheter-induced aortic injury, received daily drug treatment until postoperative day 14 and were subsequently sacrificed or followed up to day 40 without further treatment. Development of neointimal lesions was assessed histologically and immunohistochemically. Steady-state rapamycin levels in whole blood were determined by HPLC-UV.


RESULTS
Rapamycin and imatinib, administered individually or in combination, produced no signs of overt toxicity. Continuous postoperative therapy with either rapamycin (0.5-1.5 mg/kg/day) or imatinib (2- 50 mg/kg/day) dose-dependently suppressed neointimal hyperplasia on day 14. Combined treatment (0.5 or 1 + 10 mg/kg/day, respectively) showed a trend towards synergistic action on day 14. Withdrawal of medication on day 14 nullified the early therapeutic effect of either agent by day 40. In contrast, early combination therapy (1 + 10 mg/kg/day) achieved long-term suppression of neointimal hyperplasia by approximately 81%. Notably, coadministration of imatinib appeared to reduce exposure to rapamycin, although this finding did not reach statistical significance.


CONCLUSIONS
Short-term combination therapy with rapamycin and imatinib is well tolerated and produces synergistic, sustained suppression of neointimal hyperplasia in rats. Subject to clinical evaluation, this new drug regimen may afford definitive prophylaxis against accelerated arteriosclerosis.
Vamvakopoulos
Joannis E
JE
The Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Petrov
Lyubomir
L
Aavik
Silja
S
Lehti
Satu
S
Aavik
Einari
E
Hayry
Pekka
P
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001012:Aorta, Abdominal / Q000293:injuries / Q000473:pathology*; D001161:Arteriosclerosis / Q000517:prevention & control*; D001549:Benzamides; D004357:Drug Synergism; D006965:Hyperplasia / Q000517:prevention & control*; D000068877:Imatinib Mesylate; D008297:Male; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000493:pharmacokinetics / Q000627:therapeutic use*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D020123:Sirolimus