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(Circulation. 2004;109:1558-1563.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Novel Oral Formulation of Paclitaxel Inhibits Neointimal Hyperplasia in a Rat Carotid Artery Injury Model

Dong-Woon Kim, MD; Jin-Sook Kwon, DVM; Young-Gyu Kim, MD; Maeng Sup Kim, PhD; Gwan-Sun Lee, PhD; Tae-Jin Youn, MD; Myeong-Chan Cho, MD

From the Departments of Internal Medicine (D.-W.K., J.-S.K., T.-J.Y., M.-C.C.) and Neurosurgery (Y.-G.K.), College of Medicine, Chungbuk National University, Cheongju, and Hanmi Pharmaceutical Co Ltd, Central Research Institute (M.S.K., G.-S.L.), Sungam, Korea.

Correspondence to Dong-Woon Kim, MD, Department of Internal Medicine, Chungbuk National University Hospital, 62 Gaeshin-Dong, Heungduk-Gu, Cheongju, 361-711, Korea. E-mail kdwoon{at}chungbuk.ac.kr

Received March 27, 2003; de novo received October 15, 2003; revision received November 24, 2003; accepted December 5, 2003.

Background— Paclitaxel has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal formation. This study tested whether novel oral formulations of paclitaxel can prevent neointimal formation in a rat carotid artery injury model.

Methods and Results— Oral formulations of paclitaxel (0, 5, 7.5, or 10 mg/kg) were administered to 40 rats by gavage for 5 days after injury. The peak plasma levels of paclitaxel administered at 5, 7.5, and 10 mg/kg were 61±16, 89±22, and 108±28 nmol/L, respectively. Treatment effects were assessed 11 days after injury. The angiographic minimum luminal diameters of the oral paclitaxel groups treated at 5, 7.5, and 10 mg/kg were 6.28±2.09, 6.97±1.79, and 7.97±1.57 AU, and these were significantly larger than that of the control group (4.67±1.45 AU). The oral paclitaxel groups (5, 7.5, 10 mg/kg; 0.05±0.05, 0.04±0.03, 0.05±0.03 mm²) showed significant neointimal formation reductions versus the control group (0.13±0.05 mm²). All rats survived to study completion. Only 2 animals in the 10 mg/kg group experienced weight loss (10%) and loose stools between 4 and 6 days after injury. All other animals appeared healthy during the study. For comparison purposes, intraperitoneal formulations of paclitaxel (0 or 2 mg/kg) were administered by injection to 15 rats. We confirmed that the intraperitoneal administration of paclitaxel also effectively inhibited neointimal formation.

Conclusions— Oral formulations of paclitaxel provide an effective means of inhibiting proliferative response to vascular injury in the rat. Thus, oral formulations of paclitaxel may prevent human restenosis without significant toxicity.

Key Words: paclitaxel • angioplasty • restenosis

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