Evaluation of the stability profile of anticancer drugs: A review of Ifosfamide and Mesna regimen for the treatment of metastatic soft tissue sarcoma.

PURPOSE: This paper aims to summarise and critically review the existing published literature with regard to clinical considerations as well as stability testing studies of Ifosfamide and Mesna. It also aims to highlight the factors that should be considered when designing and conducting stability testing experiments. SUMMARY: Ifosfamide and Mesna are currently given to patients for 14 days continuous home-based infusion for the treatment of soft tissue sarcoma. No previous work has evaluated their stability for more than 7 days under real-life conditions so the current regimen involves patients visiting hospital twice during the 14-day treatment. This may create extra disruption to patients' life style as well as increasing the workload for cancer services. CONCLUSION: There is a need to conduct stability testing experiments for Ifosfamide and Mesna taking into consideration all of the highlighted factors to mimic standard clinical practice.

In situ formation of low molecular weight organogelators for slick solidification.

We have investigated the in situ formation of Low Molecular Weight Organogelator (LMWO) molecules in oil-on-water slicks through dual reactive precursor injection. This method alleviates the need for any carrier solvent or prior heating, therefore reducing the environmental impact of LMWOs, giving instantaneous gelation, even at low temperatures (-5 °C). We show minimal leaching from our gels into the water layer.

A semi-automatic approach to the characterisation of dark chocolate by Nuclear Magnetic Resonance and multivariate analysis.

Tracing the geographical origin of chocolate is of increasing importance owing to the market growth of cocoa products of high quality and especially where value is derived from those products being of single origin. The NMR analysis of methanolic/aqueous extracts of dark chocolate samples from Peru, Venezuela and Madagascar is reported and 42 different chemical constituents are identified, quantified and analysed using multivariate techniques. This paper describes a simple non-destructive protocol, which look at the chemical profile for chocolate samples from these three geographical locations and demonstrates potential for assessing the provenance of chocolate products, which has implications in food quality, safety and authenticity.

1H NMR quantification of spray dried and spray freeze-dried saccharide carriers in dry powder inhaler formulations.

Quantitative analysis using proton NMR (1H qNMR) has been employed in various areas such as pharmaceutical analysis (e.g., dissolution study), vaccines, natural products analysis, metabolites, and macrolide antibiotics in agriculture industry. However, it is not routinely used in the quantification of saccharides in dry powder inhaler (DPI) formulations. The aim of this study was to develop a 1H NMR method for the quantification of saccharides employed in DPI formulations. Dry powders as DPI carriers were prepared by spray drying (SD) and spray freeze drying (SFD) using three saccharides: namely D-mannitol, D-sorbitol and D-(+)-sucrose. The calibration curves constructed for all three saccharides demonstrated linearity with R2 value of 1. The 1H qNMR method produced accurate (relative error %: 0.184-3.697) and precise data with high repeatability (RSD %: 0.517-3.126) within the calibration curve concentration range. The 1H qNMR method also demonstrated significant sensitivity with low values of limit of detection (0.058 mM for D-mannitol, 0.045 mM for D-(+)-sucrose, and 0.056 mM for D-sorbitol) and limit of quantitation (0.175 mM for D-mannitol, 0.135 mM for D-(+)-sucrose, and 0.168 mM for D-sorbitol). Pulmonary deposition via impaction experiments of the three saccharides was quantified using the developed method. It was found that SFD D-mannitol (68.99%) and SFD D-(+)-sucrose (66.62%) exhibited better delivered dose (total saccharide deposition in throat and all impactor stages) than SD D-mannitol (49.03%) and SD D-(+)-sucrose (57.70%) (p < 0.05). The developed 1H qNMR methodology can be routinely used as an analytical method to assess pulmonary deposition in impaction experiments of saccharides employed as carriers in DPI formulations.

A rapid LC-MS method for determination of plasma anion profiles of acidotic patients.

In metabolic acidosis, the concentrations of anions associated with intermediary metabolism are increased and can make a significant contribution to the observed acidosis. Here we describe a method for the rapid determination of the plasma ultrafiltrate profile of these anions using liquid chromatography coupled to electrospray ionisation mass spectrometry (LC/ESI-MS). The ultrafiltrate from patients with acidosis resulting from various causes were examined and the results compared to control values. Using the LC/ESI-MS method described, a unique plasma ultrafiltrate anion profile was obtained for each of the groups studied that provides rapid diagnosis of the type of underlying acidosis.

New investigations into the stability of Mesna using LC-MS/MS and NMR.

INTRODUCTION: It is important for sarcoma patients to receive the correct dose of Mesna as an adjuvant with ifosfamide to reduce the risk of hemorrhagic cystitis. This paper describes a study conducted to evaluate the physicochemical stability of Mesna for injection formulation over 14 days. METHODS: Mesna samples (n = 4, 20 mg/ml) were incubated in glass vials at 37 + 0.5ºC. Mesna concentrations were determined by liquid chromatography-mass spectrometry (LC-MS/MS), and nuclear magnetic resonance spectroscopy (NMR) was used to detect degradation products. Evaporative losses and pH were also monitored. RESULTS: Our results differed from those published in existing literature. Both LC-MS/MS and NMR indicated that Mesna was unstable. The mean percentage decrease in Mesna concentration was 40% by day 14 of the analysis. The presence of Mesna's dimer Dimesna was detected on day 0 and its concentration increased over time. Dimesna was the only by-product identified. CONCLUSION: Both LC-MS/MS and NMR analyses confirmed the instability of Mesna and its conversion into Dimesna.

Circulating anions usually associated with the Krebs cycle in patients with metabolic acidosis.

INTRODUCTION: Acute metabolic acidosis of non-renal origin is usually a result of either lactic or ketoacidosis, both of which are associated with a high anion gap. There is increasing recognition, however, of a group of acidotic patients who have a large anion gap that is not explained by either keto- or lactic acidosis nor, in most cases, is inappropriate fluid resuscitation or ingestion of exogenous agents the cause. METHODS: Plasma ultrafiltrate from patients with diabetic ketoacidosis, lactic acidosis, acidosis of unknown cause, normal anion gap metabolic acidosis, or acidosis as a result of base loss were examined enzymatically for the presence of low molecular weight anions including citrate, isocitrate, alpha-ketoglutarate, succinate, malate and d-lactate. The results obtained from the study groups were compared with those obtained from control plasma from normal volunteers. RESULTS: In five patients with lactic acidosis, a significant increase in isocitrate (0.71 +/- 0.35 mEq l-1), alpha-ketoglutarate (0.55 +/- 0.35 mEq l-1), malate (0.59 +/- 0.27 mEq l-1), and d-lactate (0.40 +/- 0.51 mEq l-1) was observed. In 13 patients with diabetic ketoacidosis, significant increases in isocitrate (0.42 +/- 0.35 mEq l-1), alpha-ketoglutarate (0.41 +/- 0.16 mEq l-1), malate (0.23 +/- 0.18 mEq l-1) and d-lactate (0.16 +/- 0.07 mEq l-1) were seen. Neither citrate nor succinate levels were increased. Similar findings were also observed in a further five patients with high anion gap acidosis of unknown origin with increases in isocitrate (0.95 +/- 0.88 mEq l-1), alpha-ketoglutarate (0.65 +/- 0.20 mEq l-1), succinate (0.34 +/- 0.13 mEq l-1), malate (0.49 +/- 0.19 mEq l-1) and d-lactate (0.18 +/- 0.14 mEq l-1) being observed but not in citrate concentration. In five patients with a normal anion gap acidosis, no increases were observed except a modest rise in d-lactate (0.17 +/- 0.14 mEq l-1). CONCLUSION: The levels of certain low molecular weight anions usually associated with intermediary metabolism were found to be significantly elevated in the plasma ultrafiltrate obtained from patients with metabolic acidosis. Our results suggest that these hitherto unmeasured anions may significantly contribute to the generation of the anion gap in patients with lactic acidosis and acidosis of unknown aetiology and may be underestimated in diabetic ketoacidosis. These anions are not significantly elevated in patients with normal anion gap acidosis.

Selective inhibition of the cellular sodium pump by emicymarin and 14ß anhydroxy bufadienolides.

Partial inhibition of the sodium pump (Na/K-ATP-ase) by a circulating inhibitor is known to occur in humans. The objectives of this study were to determine the effects of novel bufadienolides lacking an oxygen at C14 on sodium pumps in human erythrocytes and leucocytes, dog kidney and pig brain and to document the importance of the stereochemistry at C17 on the ability to inhibit these sodium pumps. 14α bufadienolides were weak inhibitors of all preparations studied. 3ß-OH,5ß,14ß bufadienolide produced near-total inhibition of dog kidney and pig brain Na/K-ATP-ase. Over the same concentration range, it maximally inhibited the sodium pump of erythrocytes by 70% and leucocytes by 47%. The inhibition profile induced in the leucocyte sodium pump deviated significantly from the simple sigmoidal relationship present in the other preparations over the 3×10(-5) to 1×10(-7) mol/l concentration range. Allo-emicymarin (17α) was confirmed to be a weak inhibitor of the sodium pump/ATP-ase compared with emicymarin (17ß) but both were weaker inhibitors of the leucocyte sodium pump than that of the other preparations. Molecules with the C14 in the ß configuration are more efficacious than in the α configuration. In the case of emicymarin, the attachment of the furone at C17 in the α configuration results in substantially weaker inhibitory activity than in the beta configuration, seen in most cardenolides and bufadienolides. Unlike ouabain and bufalin that show no specificity of action in these preparations, 3ß- OH,5ß,14ß bufadienolide selectively inhibits the activity of at least one low-prevalence subset of the leucocyte Na/K-ATP-ase.