Gj Sewell

Studies on the decontamination of surfaces exposed to cytotoxic drugs in chemotherapy workstations

Objective. The aim of this study was to examine the removal and deactivation of cytotoxic contamination from surfaces of a pharmaceutical isolator workstation. Methods. Three marker cytotoxic drugs were evaluated in three phases using decontamination technologies currently available in the pharmaceutical and healthcare environments. Phase I investigated the physical removal of contamination by detergents. Phase II and III investigated the effectiveness of detergents and Vaporised Hydrogen Peroxide (VHP®) in degrading cytotoxic drugs, respectively. Results. 5-Flurouracil, doxorubicin and cyclophosphamide were removed from a surface by wiping with detergents. VHP® and alkaline detergents caused degradation of doxorubicin. The observed effect with detergent cleaning was pH dependent, but neither of the technologies applied had any effect on the chemical stability of 5-flurouracil and cyclophosphamide under the conditions tested.

The degradation of carboplatin in aqueous solutions containing chloride or other selected nucleophiles

Abstract The degradation kinetics of carboplatin in aqueous solution in the presence and absence of chloride ions were studied at elevated temperatures (43–70 °C) at pH 7.0 and at various pH values at 70 °C. Reaction rates were then extrapolated to temperatures of interest (infusion storage temperature, ‘in-use’ infusion temperature and body temperature) from Arrhenius plots. Additionally, the effects of pH and added chloride, thiosulphate, thiocyanate, azide and iodide on the rate of degradation of carboplatin were determined in an attempt to obtain a greater insight into the mechanism of nucleophilic substitution of carboplatin.

The stability of carboplatin, diamorphine, 5-fluorouracil and mitozantrone infusions in an ambulatory pump under storage and prolonged 'in-use' conditions.

Drug infusions can be exposed for prolonged periods to ‘in‐use’ conditions where the temperature of an infusion in a holster‐worn infusion pump may reach 37°C. In this study, the stability of three cytotoxic drug infusions (carboplatin, 5‐fluorouracil and mitozantrone) and one analgesic infusion (diamorphine HCl) was determined in Parker Micropump medication reservoirs under refrigerated storage and prolonged in‐use conditions. The stability of the three cytotoxic drug infusions was unaffected by 14 days storage at either 4 or 37°C. The diamorphine HCl infusion was stable over 14 days storage at 4°C but under in‐use conditions at 37°C, drug degradation became significant (> 5%) if storage exceeded 7 days.

Platinum-based anticancer drugs in waste waters of a major UK hospital and predicted concentrations in recipient surface waters.

Concentrations of the cytotoxic platinum-based anticancer drugs, as total Pt, have been measured over a three week period in one of the main drains and in the effluent of the oncology ward of a major UK hospital (Derriford, Plymouth). Concentrations of Pt were highly variable in both discharges, and ranged from about 0.02 to 140 μg L(-1) in the oncology effluent and from about 0.03 to 100 μg L(-1) in the main drain. A comparison of drug administration figures over the study period with an estimate of the quantity of Pt discharged through the drains suggests that about 22% of total Pt is emitted to the environment from the hospital with the remainder being discharged by treated patients in the wider community. Administration figures for the three Pt-based drugs used in the hospital (cisplatin, carboplatin and oxaliplatin) coupled with published measurements on the removal of the drugs by conventional sewage treatment allowed the concentrations of Pt arising from each drug to be predicted in recipient surface waters as a function of water flow rate. For conditions representative of the region under study, concentrations of total Pt between a few tens and in excess of 100 pg L(-1) are predicted, with the principal form of the metal occurring as carboplatin and its metabolites. Although predicted concentrations are below EMEA guidelines warranting further risk assessment, the presence of substances in surface waters that are potentially carcinogenic, mutagenic and teratogenic and yet whose environmental effects are not understood is cause for concern.

Occupational exposure to anti-cancer drugs: A review of effects of new technology

Because anti-cancer drugs are non-selective, they affect both cancerous and non-cancerous cells. Being carcinogenic and mutagenic, many anticancer drugs therefore present a major health risk to healthcare staff working with them. This paper reviews the means by which exposure to anti-cancer drugs in the workplace may be monitored, assessed and reduced. Both biological monitoring, using non-selective methods or compound-selective methods, and environmental monitoring have provided information on the nature and degree of exposure in the workplace. Pharmaceutical isolators, used for the compounding of cytotoxic IV infusions and the preparation of injectable drugs, provide a physical barrier between pharmacists and cytotoxic drugs and reduce direct exposure. However, the interior of isolators and the contents thereof (e.g. infusion bags and syringes) are readily contaminated by aerosols and spillages and afford a secondary source of exposure to pharmacists, nurses and cleaning staff. Closed system transfer devices (CSTDs), designed to prohibit the transfer of contaminants into the working environment during drug transfer between the vial and syringe, have been successful in further reducing, but not eliminating surface contamination. Given that the number of patients requiring treatment with chemotherapeutic agents is predicted to increase, further efforts to reduce occupational exposure to anti-cancer drugs, including the refinement and wider use of CTSDs, are recommended.

Risks and concerns about supplementary prescribing: survey of primary and secondary care pharmacists

Objective (of the study)To provide data on the views of chief pharmacists (CPs) and primary care trust pharmacists (PCTPs) on the risks and concerns surrounding supplementary prescribing.SettingSecondary and primary care within England.MethodPostal questionnaire surveys of chief pharmacists and primary care trust pharmacists.Main Outcome MeasureSignificance of the association between the extracted factors.ResultsThe response rate was 68% for both the primary care (183/271) and secondary care surveys (97/143). The survey tool was subjected to factor analysis and reliability testing. For both sectors, the three factors that were extracted described concerns over the training model for supplementary prescribing, concerns about the professional competency/responsibility of the supplementary prescribers once trained, and positivity about the implementation of supplementary prescribing. For both sectors, as trusts have more experience of supplementary prescribing by nurses, the respondents had less concerns about the supplementary prescribing training model. For secondary care, as the total number of pharmacists employed within the trust increases, the respondents had less concerns over the limitations of the supplementary prescribing training model.ConclusionAlthough both sectors have concerns over the training model for supplementary prescribing and also professional competence and responsibility once trainees qualify, there is overall a positive attitude towards supplementary prescribing and there is a belief that pharmacists wish to take this role on.

Studies on the mechanism of microbial N-demethylation of codeine by cell-free extracts of Cunninghamella bainieri

Abstract Cell-free extracts have been prepared from the fungus Cunninghamella bainieri which retain high levels of N -demethylase activity against codeine and other drug molecules. Extraction required both disruption and solubilization, indicating that the N -demethylase enzyme is probably membrane bound. The carbon monoxide-reduced u.v. difference spectrum of the extract suggests the presence of a cytochrome P -450. The effect of specific inhibitors and the generation of formaldehyde during the transformation suggest a mono-oxygenase mediated mechanism. Kinetic studies have shown that N -demethylation is unlikely to occur via the N -oxide intermediate. Instead it is proposed that N -demethylation proceeds via the transient N -hydroxymethyl intermediate.

Physical and chemical stability of paclitaxel infusions in different container types

Objectives. To determine the physicochemical stability of generic (Teva Pharmaceuticals) paclitaxel infusions (0.3 and 1.2 mg/mL) in 0.9% sodium chloride or 5% glucose in polyolefin (Viaflo®), low-density polyethylene (Ecoflac®), and glass containers at 2-8 and 25°C. Methods. Paclitaxel infusions of various concentration/diluent/container combinations were prepared. Containers were light-protected and incubated at test temperatures with further analysis at predetermined intervals of 1-3 days for up to 30 days. Infusions were monitored for pH, weight loss, precipitation, colour change, and subvisual particulates as indicators of physical stability, and assayed for drug concentration to determine chemical stability. Results. Precipitation was the limiting factor. Infusions of paclitaxel (0.3 mg/mL) in 0.9% sodium chloride remained stable for 13, 16 and 13 days at 2-8°C in polyolefin, low-density polyethylene and glass containers, respectively; in 5% glucose for 13, 18, and 20 days, respectively. At 25°C, paclitaxel infusions (0.3 mg/mL) remained stable for 3 days in all diluent/container combinations with the exception of 5% glucose in glass, where stability reached 7 days. Paclitaxel infusions (1.2 mg/mL) in 0.9% sodium chloride remained stable for 9, 12, and 8 days at 2-8°C in polyolefin, low-density polyethylene and glass containers, respectively; in 5% glucose for 10, 12, and 10 days, respectively. At 25°C, paclitaxel 1.2 mg/mL remained stable for 3 days in all diluent/container combinations with the exception of glass, where stability reached 5 days in 0.9% sodium chloride diluent, and 7 days in 5% glucose. Conclusion. Paclitaxel stability was influenced by storage temperature, with longer shelf-life at 2-8°C, and also by drug concentration, where 0.3 mg/mL infusions were more stable than 1.2 mg/mL for all diluent/container combinations. Physical stability (precipitation) was the limiting parameter in each case.

Improved LC assay for the determination of mitozantrone in plasma: Analytical considerations

Preliminary method development studies on mitozantrone (MTZ) revealed a number of characteristics which were found to be important in the analysis of patient samples for pharmacokinetic studies. MTZ rapidly bound to glass, particularly at low concentrations (< 10 ng ml-1), necessitating the use of silanized glassware or polypropylene tubes for the handling of all solutions containing MTZ. MTZ was also found to react with two commonly-used antioxidants; sodium metabisulphite and EDTA. However, solutions containing MTZ were found to be stabilized by the addition of ascorbic acid (0.5% w/v). In the absence of ascorbic acid, MTZ underwent rapid, biphasic degradation in plasma at 24 and 37 degrees C, with terminal half-lives of approximately 70 h. Ascorbic acid (0.5% 2/v) was found to stabilize plasma samples containing MTZ throughout work-up procedures and during frozen storage. The addition of ascorbic acid to the sample collection vial was also necessary to prevent MTZ degradation in the eluting solvent of the solid-phase extraction system. Another important consideration was the requirement for an equilibration period of > 5 min after the addition of ametantrone (AM) internal standard to plasma samples. This was essential, since the slope of the calibration plot obtained using non-equilibrated plasma was approximately 30% of that obtained for calibration plots using equilibrated plasma, and would result in erroneous determination of MTZ plasma concentrations. The fully developed assay was rapid, precise and sensitive (relative errors at 1 ng ml-1 = 2.3%). MTZ concentrations determined using the LC method described in this report correlated well with an independently developed ELISA technique (r = 0.995, n = 20).

The chemical and physical stability of three intravenous infusions subjected to frozen storage and microwave thawing

Abstract This study is concerned with the physical and chemical stability of erythromycin, fusidic acid and methylprednisolone infusions when subjected to frozen storage and microwave thawing. Stability-indicating HPLC assays were developed for the active principle of each infusion. In each case, storage of infusions for 12 months at −20°C, followed by microwave thawing, resulted in no drug loss. The chemical stability of erythromycin and fusidic acid infusions thawed after 6 months storage at −20°C and subjected to three further freeze/thaw cycles was also demonstrated. Physical stability of the infusions was unaffected by frozen storage and microwave thawing, there being only minor changes in pH, infusion weight and sub-visual particulate levels. Prolonged frozen storage and rapid microwave thawing under the conditions described may be used to facilitate the batch-scale preparation of the three infusions detailed in this report.