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J Med Chem ; 47(9): 2276-82, 2004 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-15084126

RESUMO

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.


Assuntos
Adamantano/síntese química , Antineoplásicos/síntese química , Doadores de Óxido Nítrico/síntese química , Óxido Nítrico/metabolismo , Compostos Nitrosos/síntese química , Paclitaxel/síntese química , Inibidores da Agregação Plaquetária/síntese química , Stents , Doenças Vasculares/tratamento farmacológico , Adamantano/análogos & derivados , Adamantano/química , Adamantano/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Constrição Patológica/tratamento farmacológico , Artéria Ilíaca/efeitos dos fármacos , Artéria Ilíaca/patologia , Técnicas In Vitro , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/farmacologia , Compostos Nitrosos/química , Compostos Nitrosos/farmacologia , Paclitaxel/análogos & derivados , Paclitaxel/química , Paclitaxel/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Coelhos , Recidiva
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