2005 Dr. Gary J. Becker Young Investigator Award: periprocedural oral administration of the leflunomide analogue FK778 inhibits neointima formation in a double-injury rat model of restenosis.
OBJECTIVE
To test the efficacy of limited oral administration of the new leflunomide analogue FK778 for suppression of neointima proliferation in a double-injury restenosis model in the rat.


METHODS
For induction of aortic lesions, silicon cuffs were placed operatively around the infrarenal aortas of Lewis rats. After 21 days, the aortic cuffs were removed and the lesions were dilated with 2-F Fogarty catheters inserted via the left common carotid artery. The novel immunosuppressant FK778 was administered at a dose of 5 mg/kg body weight (group 1) or 15 mg/kg body weight (group 2) in a total of 38 animals. For both doses, three different periinterventional time periods, each with a 5-day course of oral FK778, were defined as follows: (i) days -2 to 2, (ii) days 1-5, and (iii) days 7-11, with six or seven rats in each group. After 3 weeks, intima/media ratios were assessed morphometrically and immunohistochemistry for quantification of intimal alpha-actin expression was performed.


RESULTS
In both dose groups, there was a trend toward inhibition of neointima formation when the 5-day course of FK778 was started before or 1 day after the intervention. However, in the lower-dose group, inhibition of neointima was not statistically significant regardless of the time frame of treatment (groups 1a-c). With the higher dose, suppression of intimal hyperplasia was significant when FK778 was administered between days 1 and 5 after angioplasty (group 2b; P<.01). Expression of alpha-actin in the intima of FK778-treated rats was significantly reduced when the drug was started 2 days before angioplasty in group 1a (P<.05) or 1 day after angioplasty in both dosage groups (group 1b, P<.01; group 2b, P<.05).


CONCLUSIONS
In the double-injury rat model presented, balloon-mediated proliferation of smooth muscle cells in the intima with consecutive intimal thickening was influenced by FK778 in a dose-dependent manner. However, long-term studies are needed to exclude a delay of vascular healing in this particular model.
Jahnke
Thomas
T
Department of Diagnostic Radiology, Municipal Hospital, Rendsburg, Germany. jahnke@medscape.com
Schäfer
Fritz K W
FK
Bolte
Hendrik
H
Rector
Lars
L
Schäfer
Phillip J
PJ
Brossmann
Joachim
J
Fändrich
Fred
F
Hedderich
Jürgen
J
Heller
Martin
M
Müller-Hülsbeck
Stefan
S
D000199:Actins / Q000032:analysis; D000284:Administration, Oral; D000480:Alkynes; D000800:Angioplasty, Balloon; D000818:Animals; D004195:Disease Models, Animal; D006965:Hyperplasia; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007555:Isoxazoles / Q000008:administration & dosage*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D009570:Nitriles; D051381:Rats; D011917:Rats, Inbred Lew; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D000199:Actins; D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide