Combination of paclitaxel and nitric oxide as a novel treatment for the reduction of restenosis.
The combination of a nitric oxide (NO) donor and a paclitaxel-NO donor conjugate coated on a vascular stent was tested in a rabbit iliac artery model of stenosis as a potential therapy for restenosis. Paclitaxel was conjugated with a NO donor at the 7-position to give compound 7. An adamantane-based NO donor 14 was synthesized and combined with 7 to provide a burst of NO in the first few critical hours following injury to the vessel wall. Both 7 and 14 demonstrated antiproliferative activity (IC(50) = 20 nM and 15 microM, respectively) and antiplatelet activity (IC(50) = 10 and 1 microM, respectively). Stents were coated with a layer of a polymer containing test compounds. The total amount of NO eluted from the stents after a 6 h implantation in the rabbit iliac artery was 35%, 95%, and 69% of the original content for the stents coated with 7, 14, and the combination of 7 and 14, respectively. The antistenotic activity of 7 and 14 was determined in a 28-day rabbit model with two control groups (uncoated stents and polymer-coated stents) and two study groups (paclitaxel-coated stents and stents coated with the combination of 7 and 14). Polymer-coated stents caused inflammation and increased stenosis by 39% when compared to the uncoated stents. The stents coated with 7 plus 14 were as good as the uncoated stents, 41% better than the polymer-coated stents and 34% better than the paclitaxel-coated stents. These data indicate a beneficial effect of adding NO to an antiproliferative agent (paclitaxel) and suggest a potential therapeutic combination for the treatment of stenotic vessel disease.
Lin
Chia-En
CE
NitroMed, Inc., 12 Oak Park Drive, Bedford, Massachusetts 01730, USA. glin@nitromed.com
Garvey
David S
DS
Janero
David R
DR
Letts
L Gordon
LG
Marek
Przemyslaw
P
Richardson
Stewart K
SK
Serebryanik
Diana
D
Shumway
Matthew J
MJ
Tam
S William
SW
Trocha
A Mark
AM
Young
Delano V
DV
D000218:Adamantane / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003251:Constriction, Pathologic / Q000188:drug therapy; D007083:Iliac Artery / Q000187:drug effects / Q000473:pathology; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009603:Nitroso Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D012008:Recurrence; D015607:Stents; D014652:Vascular Diseases / Q000188:drug therapy*
C485231:7-(3-methyl-3-nitrosothiobutyryl)paclitaxel; D000970:Antineoplastic Agents; C485232:N,N-dimethyl-2-(2-(nitrosothio)adamantan-2-yl)acetamide; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D010975:Platelet Aggregation Inhibitors; D009569:Nitric Oxide; D017239:Paclitaxel; D000218:Adamantane