Terbinafine inhibits the mitogenic response to platelet-derived growth factor in vitro and neointimal proliferation in vivo.
Terbinafine [(E)-N(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthale nemethanamine], an antimycotic agent that inhibits fungal squalene epoxidase activity, was examined for its effects on platelet-derived growth factor (PDGF)-stimulated aortic smooth muscle cell DNA synthesis in vitro and neointimal proliferation in vivo. Exposure of bovine aortic smooth muscle cells to 0.25 to 25 microM terbinafine resulted in a concentration-dependent inhibition of PDGF-induced mitogenesis as determined by [3H]thymidine incorporation into DNA or cell number. The IC50 for inhibition of PDGF-stimulated smooth muscle cell DNA synthesis was approximately 5 microM. Micromolar concentrations of terbinafine also suppressed the mitogenic response to PDGF in fibroblasts. Neither the binding of [125I]PDGF to its plasma membrane receptors nor the uptake of [3H]thymidine or [3H]uridine was affected significantly by terbinafine. Oral administration of terbinafine (200 mg/kg/day) to rats for 2 days before and 14 days after balloon catheter injury to the carotid artery was associated with a 40% decrease in the area of the neointimal lesion. These observations indicate that terbinafine is both a potent in vitro antagonist of the smooth muscle cell mitogenic response to PDGF and an effective, well-tolerated p.o. active inhibitor of neointimal proliferation in vivo.
Nemecek
G M
GM
Sandoz Research Institute, East Hanover, New Jersey.
St Denny
I H
IH
Van Valen
R G
RG
McCarthy
L A
LA
Handley
D A
DA
Stütz
A
A
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D009281:Naphthalenes / Q000494:pharmacology*; D010105:Oxygenases / Q000037:antagonists & inhibitors*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000032:analysis; D017479:Receptors, Platelet-Derived Growth Factor; D050603:Squalene Monooxygenase; D000077291:Terbinafine
D000935:Antifungal Agents; D009281:Naphthalenes; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D005346:Fibroblast Growth Factors; D004247:DNA; D010105:Oxygenases; D050603:Squalene Monooxygenase; D017479:Receptors, Platelet-Derived Growth Factor; D000077291:Terbinafine