Safe Cytotoxic Drug Preparation Using Closed-system Transfer Device: Technical and Practical Evaluation of a New Device (Vialshield/Texium) Comparatively to a Reference One (Phaseal).

Closed-system transfer devices enhance the drug handlers' protection against hazardous drugs exposure by prohibiting the escape of liquid or vapor from the system. PhaSeal (Becton Dickinson), a reference closed-system transfer device, includes a vial protector with an expansion chamber, and an injector with an enclosed needle. VialShield (CareFusion) is another more recent closed-system transfer device including an expansion-chamber and a non-return valve, designed to be used in association with Texium (CareFusion), a closed, needle-free male luer with its preassembled syringe. Evaluation of VialShield/Texium was done comparatively to a classic spike device (Spike Swan, Codan) and PhaSeal. Evaluation methods consisted in practical evaluation by pharmacy technicians (evaluation of ease to use by nine operators in practical conditions during a complete week of production), microbiological safety performance (by Media Fill Test), and leakage assessment (fluorescein, titanium tetrachloride smoke, and radioactive tracer). Results showed that 100% of those operators evaluated would be ready to use VialShield/Texium for daily use, whereas only 75% of them would be ready to use PhaSeal. The use of PhaSeal and VialShield/Texium increased the duration of preparations compared to Spike Swan. No microbiological growth was observed with any of the three devices. A leakage of smoke was observed only with Spike Swan. Fluorescein leakage assessment confirmed that PhaSeal is a performing closed system with a dry connection. Spike Swan showed fluorescein leaks. Fluorescein drops were visible on the connection sites of the VialShield/Texium. Nevertheless, no fluorescein was found on compress after connections swapping. Transfer performance, assessed using technetium-99m, was 98.1 ± 1.4%, 97.9 ± 1.1% and 97.0 ± 1.3% and dead volume of the devices, were 1.0 ± 0.8%, 1.7 ± 0.6%, and 3.0 ± 1.1% for Spike Swan, PhaSeal, and VialShield/Texium, respectively. VialShield/Texium appeared as a very interesting device with performances close to PhaSeal (except dry connection), with a higher satisfaction assessment from the operators.

Stability of a highly concentrated solution of epirubicin for conventional transcatheter arterial chemoembolization.

INTRODUCTION: Epirubicin is widely used for conventional transcatheter arterial chemoembolization (cTACE) in patients with hepatocellular-carcinoma. However, there is no data about its stability in solution at concentration higher than 2 mg/L, yet needed when mixing it with a standard volume of Lipiodol(®) to produce an efficient water-in-oil emulsion. The aim of this study was therefore to evaluate the stability of a highly concentrated solution of epirubicin for cTACE and verify whether epirubicin solution could be prepared in advance. MATERIALS AND METHODS: Fifty milligrams of epirubicin were dissolved in 6 mL of 0.9% sodium chloride and conditioned in brown polypropylene syringe. Physical and chemical stability assays including particles and HPLC-DAD analysis were performed in triplicate, using series of 5 syringes stored over 72 h at 4±2 °C followed by 4h at 22±4°C. RESULTS: Neither weight loss nor pH or spectrum change occurred. No haze or turbidity was observed and the number of subvisible particles was below the recommended limits. Epirubicin concentration remained above 95% of the initial value over the 72 h of storage at +4 °C followed by 4h at 22±4 °C and no degradation was observed. CONCLUSION: Epirubicin at 50mg/6 mL in 0.9% NaCl conditioned in brown propylene syringe is stable for at least 72 h at 4±2 °C with additional 4h at 22±4 °C allowing its preparation in advance for programmed cTACE and the standardization of its use in clinical practice.

Visual compatibility of defibrotide with selected drugs during simulated Y-site administration.

PURPOSE: The visual compatibility of a solution of defibrotide (the only drug recommended for treatment and prophylaxis of hepatic venoocclusive disease) with solutions of various drugs commonly administered in bone marrow transplant procedures was studied. METHODS: Solutions of 43 drug products in concentrations typically used in clinical practice were evaluated in 1:1 mixtures with defibrotide solution in glass tubes kept at room temperature. The evaluated products included antiinfectious, corticoid, sedative, analgesic, and cardiovascular agents widely used for hematopoietic stem cell transplantation and other marrow transplant procedures; in most cases, test solutions were prepared via dilution in or reconstitution with sterile water, 0.9% sodium chloride injection, or 5% dextrose injection. The mixtures were visually observed immediately after manual mixing and at specified time points (60, 150, and 240 minutes). Visual compatibility was defined as the absence of color change, haze, fibers, particles, gas generation, and precipitate formation. The effect of mixing order on visual compatibility was ascertained. RESULTS: Of the 43 tested drug solutions, 36 were found to be visually compatible with the defibrotide solution over the entire four-hour study period. Solutions of 7 drugs (amikacin, furosemide, midazolam, mycophenolate mofetil, nicardipine, tobramycin, and vancomycin) were visually incompatible with defibrotide solution. In some cases, evidence of incompatibility was observed intermittently or was dependent on mixing order. CONCLUSION: Defibrotide solution was found to be visually compatible with solutions of 36 i.v. products that are likely to be coadministered with the drug in a bone marrow transplant unit. Seven drug solutions were visually incompatible with defibrotide solution.

Aseptic simulation test for cytotoxic drug production in isolators.

PURPOSE: The results of a media-fill test (MFT) study to validate processes for cytotoxic drug preparation inside and outside aseptic compounding isolators are presented. METHODS: Using an MFT protocol adapted to institution-specific production conditions, the pharmacy team at a hospital in France performed a series of tests to verify the efficacy of decontamination and sterile compounding procedures, as required by French compendial standards, while assessing the performance of its team of 12 isolator operators; all operators were tested on three occasions, producing 10 MFT samples per test for a total of 30 samples per operator. The team also tested alternative compounding systems (i.e., two closed-system transfer devices and a classic spike system) for use during power outages or other emergencies precluding drug preparation within isolators. MFTs were performed using a standard tryptone soy broth-based test kit under worst-case conditions. RESULTS: The hospital's facilities for cytotoxic drug preparation were found to be in conformance with applicable sterility standards. Bacterial growth was not detected in any of the MFT samples produced by isolator operators during the study (total n = 360). In one instance, an MFT sample prepared using a closed-system transfer device was found to be contaminated due to improper cleaning of the medication vial, highlighting the importance of strict adherence to proper decontamination procedures. CONCLUSION: A hospital's practices for preparation of sterile products according to applicable good manufacturing guidelines, as well as emergency procedures for cytotoxic drug preparation outside isolators, were validated by the results of an MFT study.

Cisplatin dose adjustment in patients with renal impairment, which recommendations should we follow?

BACKGROUND: Nephrotoxicity is the dose-limiting side effect of cisplatin justifying the assessment of renal function for dose adjustment. OBJECTIVE: To determine whether appropriate dose adjustment is made in patients with renal impairment using the Cockcroft-Gault (CG) or the abbreviated Modification of Diet in Renal Disease (aMDRD) formulas to estimate the glomerular filtration rate (GFR). SETTING: The study was conducted in a 1,000-bed university hospital. METHOD: Two years of cisplatin prescriptions were retrospectively compared to the 4 and 3 ranges estimated glomerular filtration rate (eGFR)-stratified dosing recommendations (4RR and 3RR respectively). MAIN OUTCOME MEASURE: Cisplatin dose in mg/m(2) based on kidney function and according to the dosing recommendations. RESULTS: Among 1,364 cycles of cisplatin, 156 (11.4 %) were prescribed for 70 patients with eGFR < 60 mL/min and a median age of 67.4 years. For 57 (36 %) of these cycles, doses were not reduced. When reduced, prescribed doses were not different than recommended doses according to 4RR using CG (% of protocol, 63 ± 12 vs. 64 ± 17) while it was significantly lower using aMDRD (% of protocol, 66 ± 12 vs. 81 ± 22, p < 0.01) and significantly higher according to 3RR using both CG and aMDRD (% of protocol, 63 ± 12 vs. 50 ± 3 and 66 ± 12 vs. 50.7 ± 4.0 respectively, p < 0.01). Prescription of at least one appropriate dose according to 4RR and using aMDRD was associated with a statistically significant higher median total cumulative dose (% of protocol, 89.9 vs. 75.1 % respectively, p < 0.01) without higher decrease of eGFR over time. CONCLUSION: Cisplatin dose adjustment in patients with renal impairment must be improved. Estimating GFR with the aMDRD formula and adding an intermediary level of dose reduction for patients with eGFR from 50 to 59.9 mL/min may result in a higher cumulative dose of cisplatin without higher renal toxicity, which may significantly impact on the effectiveness of the chemotherapy. A prospective evaluation remains needed to assess the benefit/risk ratio of this dose adaptation schedule, taking into account the variability of the GFR estimates.

Bcl-2-enhanced efficacy of microtubule-targeting chemotherapy through Bim overexpression: implications for cancer treatment.

Bcl-2 is commonly overexpressed in tumors, where it is often associated with unfavorable outcome. However, it has also been linked to a favorable sensitivity to microtubule-targeting agents (MTAs). We show that Bcl-2-overexpressing lung and breast cancer cells were more sensitive to both paclitaxel and vinorelbine. Bcl-2 over-expression also significantly potentiated in vivo efficacy of paclitaxel, in terms of tumor volume decrease and survival benefits, in models of nude mice bearing lung cancer xenografts. To further investigate this favorable effect of Bcl-2, a genomic approach was taken. It revealed that Bcl-2 overexpression induced up-regulation of the proapoptotic protein Bim in lung cancer cells and that, conversely, Bcl-2 silencing decreased Bim expression level. A gene regulation study implicated the transcription factor Forkhead box-containing protein, class O3a in Bim up-regulation. Lastly, we show that Bim was responsible for MTA-triggered lung cancer cell death through a dynamin-related protein 1-mediated mitochondrial fragmentation. The Bcl-2-governed Bim induction evidence offers for the first time an explanation for the favorable higher sensitivity to treatment shown by Bcl-2-overexpressing cells. We suggest that Bim could be a powerful predictive factor for tumor response to MTA chemotherapy. Our data also give new insight into some failures in the efficacy of therapies targeted against Bcl-2.

Transcriptional down-regulation of Bcl-2 by vinorelbine: identification of a novel binding site of p53 on Bcl-2 promoter.

The Bcl-2 family contains a panel of proteins which are conserved regulators of apoptosis in mammalian cells, like the anti-apoptotic protein Bcl-2. According to its significant role in altering susceptibility to apoptosis, the deciphering of the mechanism of Bcl-2 expression modulation may be crucial for identifying therapeutics strategies for cancer. Treatment with microtubule-targeting agents, including taxanes and Vinca alkaloids, generally leads to a decrease in Bcl-2 intracellular amounts. Whereas the interest for these chemotherapeutics is accompanied by advances in the fundamental understanding of their anticancer properties, the molecular mechanism underlying changes in Bcl2 expression remains poorly understood. We report here that p53 contributes to vinorelbine-induced Bcl-2 down-regulation. Indeed, the decrease in Bcl-2 protein levels observed during vinorelbine-induced apoptosis was correlated to the decrease in mRNA levels, as a result of the inhibition of Bcl-2 transcription and promoter activity. In this context, we evaluated p53 contribution in the Bcl-2 transcriptional down-regulation. We identified, by chromatin immunoprecipitation, a novel p53 binding site in the Bcl-2 promoter, within a region upstream P(1) promoter. We showed that vinorelbine treatment increased this interaction in A549 cells. This work strengthens the links between p53 and Bcl-2 at a transcriptional level, upon microtubule-targeting agent treatment. Our study also provides answers that will be useful to assess microtubule-targeting agents' mechanism of action and that may help to better understand and increase their effectiveness.