Combination of Paclitaxel and Nitric Oxide as a Novel Treatment for the Reduction of Restenosis

• Published in: Journal of medicinal chemistry Vol. 47; no. 9; pp. 2276 - 2282
• Main Authors: Lin, Chia-En, Garvey, David S, Janero, David R, Letts, L. Gordon, Marek, Przemyslaw, Richardson, Stewart K, Serebryanik, Diana, Shumway, Matthew J, Tam, S. William, Trocha, A. Mark, Young, Delano V
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.04.2004; Amer Chemical Soc
• Subjects: Adamantane - analogs & derivatives; Adamantane - chemical synthesis; Adamantane - chemistry; Adamantane - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Chemistry, Medicinal; Constriction, Pathologic - drug therapy; Diseases of the cardiovascular system; Iliac Artery - drug effects; Iliac Artery - pathology; In Vitro Techniques; Life Sciences & Biomedicine; Medical sciences; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Nitric Oxide - metabolism; Nitric Oxide Donors - chemical synthesis; Nitric Oxide Donors - chemistry; Nitric Oxide Donors - pharmacology; Nitroso Compounds - chemical synthesis; Nitroso Compounds - chemistry; Nitroso Compounds - pharmacology; Paclitaxel - analogs & derivatives; Paclitaxel - chemical synthesis; Paclitaxel - chemistry; Paclitaxel - pharmacology; Pharmacology & Pharmacy; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - chemistry; Platelet Aggregation Inhibitors - pharmacology; Rabbits; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Recurrence; Science & Technology; Stents; Vascular Diseases - drug therapy; CHEMISTRY; BALLOON ANGIOPLASTY; CYSTEINE; STENT; CORONARY ANGIOPLASTY; Cell proliferation; Terpenoid; Drug combination; Rabbit; Instrumental dilatation; Lagomorpha; Stent; Iliac artery; Antiplatelet agent; Restenosis; Thionitroso compound; Vertebrata; Experimental disease; Nitric oxide donor; Mammalia; Treatment; Animal; Taxane derivatives; Paclitaxel; Diterpene; Complication; Inhibitor; Modified material
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0304111

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 (IC50 = 20 nM and 15 μM, respectively) and antiplatelet activity (IC50 = 10 and 1 μM, 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.