title: Simultaneous intra/extravascular administration of antiproliferative agents as a new strategy to inhibit restenosis: the peak of reactive cell proliferation as a hallmark for the duration of the treatment.
abstract: BACKGROUND
  Strictly intravascular approaches for the treatment of postangioplasty restenosis are effective in the intima and the inner parts of the media but may be insufficient to control redundant pathways in the more outer parts of the media and the adventitia. An inverse situation may occur subsequently to a strictly extravascular approach, like the recently suggested pericardial approach in pigs. We hypothesized that simultaneous intra/extravascular administration of anti-restenotic agents inhibits restenosis by blocking all stimulatory pathways in the entire arterial wall.
  
  
  METHODS
  Fresh hearts of 25 domestic pigs were obtained from a local slaughterhouse. Left anterior descending coronary arteries (LAD) were harvested, cut into cylindric 5 mm segments, and cultured as ex vivo porcine organ cultures (POCs). After 9 bar ballooning simultaneous intra/extravascular administration of high dose diltiazem (50 microg/mL) was carried out for a period of 1, 2, 3, 4, 5, 6, and 7 days. At day 7 and 28 proliferative activity (BrdU), neointimal thickening, and staining against smooth muscle alpha-actin and vWF was analysed.
  
  
  RESULTS
  7 days after ballooning administration of diltiazem for 4, 5, 6, and 7 days inhibited reactive cell proliferation by more than 50% (n.s.) as compared to control, 28 days after ballooning administration for 6 and 7 days inhibited neointimal thickening by more than 75% (p < 0.05). Simultaneous intra/extravascular administration of high dose diltiazem did not affect the expression of vWF in endothelial cells or smooth muscle alpha-actin in smooth muscle cells.
  
  
  CONCLUSIONS
  Simultaneous intra/extravascular administration of high dose diltiazem (50 microg/mL) has to be maintained for at least 6 days to achieve a significant inhibition of neointimal thickening. The data demonstrate the importance of the maximal reactive cell proliferation (= day 7 in the POC-model) for the calculation of the duration of the treatment period.
authors.affiliation: Department of Internal Medicine II-Cardiology, University of Ulm, Germany. rainer.voisard@medizin.uni-ulm.de
authors.forename: Rainer
authors.initials: R
authors.lastname: Voisard
authors.forename: Eva
authors.initials: E
authors.lastname: Kucharczyk
authors.forename: Ute
authors.initials: U
authors.lastname: Deininger
authors.forename: Regine
authors.initials: R
authors.lastname: Baur
authors.forename: Vinzenz
authors.initials: V
authors.lastname: Hombach
mesh_terms: D000800:Angioplasty, Balloon; D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D002455:Cell Division / Q000187:drug effects; D023903:Coronary Restenosis / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D004110:Diltiazem / Q000008:administration & dosage*; D004730:Endothelium, Vascular / Q000473:pathology; D006965:Hyperplasia / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009924:Organ Culture Techniques; D013552:Swine; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
chemical_list: D002317:Cardiovascular Agents; D004110:Diltiazem