ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast ffi ovary > prostate > colon. The LD 50 and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophorbased paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophorbased paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater efficacy and intratumor delivery of ABI-007.Paclitaxel is a naturally occurring complex diterpenoid product extracted from the bark of the western yew, Taxus brevifolia (1). The unique mechanism of paclitaxel of stabilizing tubulin polymer and promoting microtubule assembly effectively inhibits mitosis, motility, and intracellular transport within cancerous cells and results in antineoplastic activity against a wide variety of malignancies (2 -4). Paclitaxel is widely used for the treatment of breast, lung, and advanced ovarian cancers (5).Because paclitaxel has very little aqueous solubility, Cremophor-based paclitaxel uses a Cremophor EL/ethanol vehicle. The amount of Cremophor EL necessary to deliver the requisite doses of paclitaxel is significantly higher than that given with any other marketed drug containing Cremophor EL, reaching plasma concentrations up to 0.4% and remaining >0.1% for 24 hours following a dose of 175 mg/m 2 (6). The Cremophor EL -containing paclitaxel formulation causes severe allergic, hypersensitivity, and anaph...

No abstract

The intraperitoneal injection of insulinproducing islets immunoprotected by an alginate-poly(amino acid) membrane is a potential method of reversing diabetes without the need for lifelong immunosuppression

No abstract

Objective:To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD).Methods:The consistency of changes in the six-minute walk distance (Δ6MWD) was compared across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented four sets of inclusion/exclusion criteria (n=383 patients, in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n=430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the trial's inclusion/exclusion criteria for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data.Results:Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 meters (i.e., better outcomes in RWD/NHD) to 19.5 meters (i.e., worse outcomes in RWD/NHD), and were not statistically significant before or after covariate adjustment.Conclusions:Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the collaborative Trajectory Analysis Project rendered this study feasible.

Aim: In a previous study, a 130-nm nanoparticle albumin-bound paclitaxel (nab-paclitaxel) demonstrated improved efficacy and safety profile compared with solvent-based paclitaxel (sb-paclitaxel) in Caucasian patients with metastatic breast cancer (MBC). The aim of the present randomized study was to compare the response rates and safety profile of nab-paclitaxel with sb-paclitaxel in Chinese patients with MBC. Methods:In the present open-label, multicenter study, 210 patients with MBC were randomly assigned to receive nab-paclitaxel 260 mg/m 2 intravenously (i.v.) over 30 min every 3 weeks (q3w) with no premedication or sb-paclitaxel 175 mg/m 2 i.v. over 3 h q3w with standard premedication. Results:The overall response rate was 54 and 29% in patients treated with nab-paclitaxel and sb-paclitaxel, respectively (P < 0.001). nab-paclitaxel induced a higher response rate in patients who were <65 years old, patients who were receiving first-line therapy, patients who had no prior anthracycline therapy, patients who had Յ or >3 metastatic lesions, and patients who had visceral disease. The progression-free survival (PFS) period was 7.6 months for nab-paclitaxel and 6.2 months for sb-paclitaxel (P = 0.118). Despite the 49% higher paclitaxel dose in patients receiving nab-paclitaxel compared with patients receiving sb-paclitaxel, the safety profile was similar in both treatment groups. The most common grades 3 and 4 adverse event (AE) in both arms was neutropenia. The most common grade 3 nonhematologic AE was peripheral neuropathy, and no grade 4 peripheral neuropathy was observed. Conclusion: Compared with sb-paclitaxel, nab-paclitaxel demonstrated superior efficacy, an acceptable safety profile, and a trend toward increased PFS in patients with MBC.

Introduction: In this study we characterized disease progression over 48 weeks among boys receiving deflazacort vs prednisone/prednisolone placebo arm treatment in two recent Duchenne muscular dystrophy (DMD) clinical trials.Methods: Ambulatory boys with DMD receiving placebo in the phase 3 ataluren (N = 115) and tadalafil (N = 116) trials were included. The trials required at least 6 months of prior corticosteroid use and stable baseline dosing. Associations between corticosteroid use and 48-week changes in ambulatory function were estimated using mixed models.Adjusted differences between corticosteroid groups were pooled in a meta-analysis.Results: In the meta-analysis, deflazacort-treated patients vs prednisone/prednisolonetreated patients experienced, on average, lower declines of 28.3 meters on 6-minute walk distance (95% confidence interval [CI], 5.7, 50.9; 2.9 seconds on rise from supine [95% CI, 0.9, 4.9 seconds]; 2.3 seconds on 4-stair climb [95% CI, 0.5, 4.1 seconds]; and 2.9 [95% CI, 0.1, 5.8] points on the North Star Ambulatory Assessment linearized score).Discussion: Deflazacort-treated patients experienced significantly lower functional decline over 48 weeks.

No abstract