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Background— Drug-coated balloons are rapidly emerging as a therapeutic alternative for the interventional treatment of peripheral vascular disease. The purpose of this study was to test the hypothesis that an angioplasty balloon coated with the mTOR inhibitor zotarolimus (ZCB) would inhibit neointimal hyperplasia in a novel injury-based superficial femoral artery model in the familial hypercholesterolemic swine. Methods and Results— A total of 44 familial hypercholesterolemic swine were included (12 designated to study tissue pharmacokinetics and 32 to study safety and efficacy). Fogarty balloon denudation was performed in all superficial femoral artery segments, followed by balloon angioplasty. In the pharmacokinetic study, a total of 24 ZCBs (300 μg/cm 2 ) were used. Zotarolimus was detected in arterial tissue at 5 minutes (162 ng/mg of tissue), 24 hours (5.9 ng/mg of tissue), and 28 days (0.007 ng/mg of tissue) after ZCB inflation. In the safety and efficacy study, superficial femoral artery segments were randomized to either high-dose (600 μg/cm 2 , n=16), low-dose (300 μg/cm 2 , n=16), or paired uncoated balloons (high-dose ZCB control, n=16; low-dose ZCB control, n=16). At 28 days, the percentage of angiographic stenosis was similar among all tested groups. Histological analysis demonstrated a reduction in neointimal formation in both ZCB groups compared with controls (high-dose ZCB 44% reduction, P =0.007; low-dose ZCB 22% reduction, P =0.08). There was no evidence of delayed arterial healing or vascular toxicity in any of the ZCB groups. Conclusions— The single delivery of zotarolimus via coated balloon is feasible, and therapeutic levels are maintained up to 28 days. The ZCB technology appears to be effective in the reduction of neointimal proliferation in the superficial femoral artery of the familial hypercholesterolemic swine.

For peripheral endovascular intervention, self-expanding (SE) stents are commonly oversized in relation to target arteries to assure optimal wall apposition and prevent migration. However, the consequences of oversizing have not been well studied. The purpose of this study was to examine the effects of SE stent oversizing (OS) with respect to the kinetics of late stent expansion and the long-term histological effects of OS. Pairs of overlapped 8 × 28-mm Nitinol SE stents were implanted into the iliofemoral arteries of 14 Yucatan swine. Due to variations in target artery size, the stent-to-artery ratio ranged from 1.2:1 to 1.9:1. Lumen and stent diameters were assessed by quantitative angiography at the time of implantation. Following angiographic assessment at 6 months, stented arteries were perfusion-fixed, sectioned, and stained for histological analysis. Immediately following implantation, the stents were found to be expanded to a range of 4.7–7.1 mm, largely conforming to the diameter of the recipient target artery. The stents continued to expand over time, however, and all stents had enlarged to nearly their 8-mm nominal diameter by 6 months. The histological effects of OS were profound, with marked increases in injury and luminal area stenosis, including a statistically significant linear correlation between stent-to-artery ratio and area stenosis. In this experimental model of peripheral endovascular intervention, oversized Nitinol SE stents are constrained by their target artery diameter upon implantation but expand to their nominal diameter within 6 months. Severe OS (stent-to-artery ratio >1.4:1) results in a profound long-term histological response including exuberant neointimal proliferation and luminal stenosis.

Objective. To evaluate the effect of SK&F 106615 on joint integrity in rats with adjuvant-induced arthritis (AIA). Methods. AIA was induced in Lewis rats on day 0, and the animals were treated either prophylactically (days 0–16 or days 0–23) or therapeutically (days 10–23) with SK&F 106615. Efficacy was determined by measurements of paw inflammation, bone mineral density (BMD) using dual x-ray absorptiometry, and magnetic resonance imaging (MRI). Joint integrity was also determined histologically, and serum interleukin-6 (IL-6) levels were measured as a marker of the antiinflammatory effects of the compound. Results. Prophylactic treatment (days 0–16) of AIA rats with SK&F 106615 significantly inhibited paw volume at doses of 5–45 mg/kg/day given orally on 5 days each week. Extensive evaluation of joint integrity in rats treated with SK&F 106615 20 mg/kg/day orally for 23 days showed inhibition of paw volume, normalization of BMD, and significant improvement in disease by MRI and histologic assessment compared with the AIA controls. Elevated levels of serum IL-6 in AIA rats were reduced dramatically by SK&F 106615. Therapeutic treatment (days 10–23) resulted in similar protective effects measured by paw inflammation, BMD, and MRI. In the therapeutic protocol, serum IL-6 appeared to be a more sensitive marker of antiinflammatory activity than paw edema. Conclusion. Symptoms of AIA in rats are significantly reduced by prophylactic and therapeutic treatment with SK&F 106615. Of particular note, this compound appears to exert a protective effect on joint integrity and to have disease-modifying properties.

Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60% to 70% of melanomas, 29% to 83% of papillary thyroid carcinomas, 4% to 16% colorectal cancers, and a lesser extent in serous ovarian and non–small cell lung cancers. The V600E mutation is found in the vast majority of cases and is an activating mutation, conferring transforming and immortalization potential to cells. CEP-32496 is a potent BRAF inhibitor in an in vitro binding assay for mutated BRAFV600E (Kd BRAFV600E = 14 nmol/L) and in a mitogen-activated protein (MAP)/extracellular signal–regulated (ER) kinase (MEK) phosphorylation (pMEK) inhibition assay in human melanoma (A375) and colorectal cancer (Colo-205) cell lines (IC50 = 78 and 60 nmol/L). In vitro, CEP-32496 has multikinase binding activity at other cancer targets of interest; however, it exhibits selective cellular cytotoxicity for BRAFV600E versus wild-type cells. CEP-32496 is orally bioavailable in multiple preclinical species (>95% in rats, dogs, and monkeys) and has single oral dose pharmacodynamic inhibition (10–55 mg/kg) of both pMEK and pERK in BRAFV600E colon carcinoma xenografts in nude mice. Sustained tumor stasis and regressions are observed with oral administration (30–100 mg/kg twice daily) against BRAFV600E melanoma and colon carcinoma xenografts, with no adverse effects. Little or no epithelial hyperplasia was observed in rodents and primates with prolonged oral administration and sustained exposure. CEP-32496 benchmarks favorably with respect to other kinase inhibitors, including RAF-265 (phase I), sorafenib, (approved), and vemurafenib (PLX4032/RG7204, approved). CEP-32496 represents a novel and pharmacologically active BRAF inhibitor with a favorable side effect profile currently in clinical development. Mol Cancer Ther; 11(4); 930–41. ©2012 AACR.

CEP-7055, a fully synthetic, orally active N,N-dimethylglycine ester of CEP-5214, a C3-(isopropylmethoxy)–fused pyrrolocarbazole with potent pan–vascular endothelial growth factor receptor (VEGFR) kinase inhibitory activity, has recently completed phase I clinical trials in cancer patients. These studies evaluated the antitumor efficacy of CEP-7055 using orthotopic models of glioblastoma and colon carcinoma in combination with temozolomide, and irinotecan and oxaliplatin, respectively, for their effects on primary and metastatic tumor burden and median survival. Chronic administration of CEP-7055 (23.8 mg/kg/dose) and temozolomide resulted in improvement of median survival of nude mice bearing orthotopic human glioblastoma xenografts compared with temozolomide alone (261 versus 192 days, respectively; P ≤ 0.02). Reductions in neurologic dysfunction, brain edema, hemorrhage, and intratumoral microvessel density (CD34 staining) were observed in glioma-bearing mice receiving CEP-7055 alone, temozolomide alone, and the combination of CEP-7055 and temozolomide relative to vehicle and to temozolomide monotherapy. The administration of CEP-7055 in combination with irinotecan (20 mg/kg/dose i.p. × 5 days), and to a lesser degree with oxaliplatin (10 mg/kg/dose i.v.), showed reductions on primary colon carcinoma and hepatic metastatic burden in the CT-26 tumor model relative to that achieved by irinotecan and oxaliplatin monotherapy. These data show the significant efficacy and tolerability of optimal efficacious doses of CEP-7055 when given in combination with temozolomide and irinotecan relative to monotherapy with these cytotoxic agents in preclinical orthotopic glioma and colon carcinoma models and lend support for the use of these treatment regimens in a clinical setting in patients with glioblastoma and colon carcinoma. [Mol Cancer Ther 2006;5(7):1744–53]

The use of intravascular stents in the femoropopliteal artery (FPA) continues to be controversial due to the potential fractures in the dynamic environment. The purpose of this study was to (1) develop a representative in-vitro model that simulates physiological motion of the FPA during knee and hip flexion and (2) use the model to characterize the types and ranges of stent distortion produced by extremity movement. This model eliminates inconsistencies often observed in cadaveric models and clinical subjects due to individual anatomical differences, and allows testing with large sample sizes in a controlled environment for variable (tubing length, material, diameter, and thickness) modification. A comparative evaluation of axial mechanical property and elasticity was conducted between the tubing intended to simulate arteries and the ex-vivo porcine carotid arteries, favoring the selection of silicone tubing. The model was assessed for its unstented and stented arterial bending and axial compression under three physiological motions: straight leg, walking (knee/hip flexion 70°/20°), and sitting/stair climbing (knee/hip flexion 90°/90°). Self-expanding nitinol stents implanted in the simulated mid-superficial femoral artery and popliteal artery (PA) of the model exhibit axial compression of 4.5±0.3 % and 7±0.3 % (knee/hip flexion 70°/20°), and 8.4±0.7 % and 8±0.2 % (knee/hip flexion 90°/90°). Stents implanted in the simulated PA exhibit bending of 40° and 74° from knee/hip angle changes to 70°/20° and to 90°/90°, respectively. The model demonstrated stent bending and compression as previously observed in cadaver studies. Additional analysis of stent motion (torsion, localized bending, radial compression) may be evaluated with more advanced imaging techniques and additional model development. The data generated in these analyses could support appropriate modes and parameters for stent fatigue testing, and better understanding of vascular device performance in the dynamic FPA.