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Dimethyl sulfate (DMS) and monomethyl sulfate (MMS) are potential genotoxic impurities created during synthesis of some active pharmaceutical ingredients. While there are a few methods to determine the genotoxic compound DMS, the determination of MMS has not been reported. Novel and sensitive methods to rapidly, simply and efficiently quantify both MMS and DMS impurities in API-salts to determine if patients could potentially meet the threshold of toxicological concern (TTC 1.5 μg per day) were developed and validated according to ICH guidelines. The extremely polar and charged analyte MMS was determined using LC-MS/MS based on reversed-phase ion-pair chromatography with no sample extraction required, and a 5 minute method run time. DMS was determined using liquid–liquid extraction using MTBE and analysed by GC-MS with a 6 minute method run time. These methods provide good recovery, accuracy, and precision over a wide concentration range (2 to 64 μg mL−1 for MMS and 0.1 to 20 μg mL−1 for DMS), which adequately cover the current threshold of toxicological concern.

Reliable analytical methods are needed for the determination of pyrethroid pesticides residues in biological tissues such as whole blood and plasma, meat, eggs, milk, brain, liver, and adipose tissue for monitoring of levels in livestock and for human risk assessment. A review of the current literature is given, with consideration to extraction techniques, sample preparation, and chromatographic approaches including both conventional and new technologies.

The polyunsaturated fatty acids (PUFA) arachidonic acid (AA, n-6) and eicosapentaenoic acid (EPA, n-3) are precursors of eicosanoids and other lipid mediators which have critical roles in inflammation. The mediators formed from the different PUFA have different potencies. We hypothesised that metabolic changes associated with colonic mucosal inflammation would modify the bioavailability of the eicosanoid precursors AA and EPA.Colonic mucosa biopsies were obtained from patients with ulcerative colitis and from matched controls. Inflammation was graded endoscopically and histologically. Esterified and non-esterified fatty acids were determined within the biopsies using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry, respectively.Biopsy samples were collected from 69 UC patients (54 providing both inflamed and non-inflamed mucosa) and 69 controls. Inflamed mucosa had higher AA (p0.001) and lower EPA (p0.010) contents and a higher AA:EPA ratio (p0.001). Inflamed mucosa also had higher docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) and lower linoleic acid (LA) and α-linolenic acid (α-LNA) contents (all p0.001), compared to non-inflamed and controls. There were significant correlations between severity of inflammation and contents of AA, DPA and DHA (positive correlations) and of LA, α-LNA and EPA (negative correlations).Higher AA, AA:EPA ratio, DPA and DHA and lower LA, α-LNA and EPA are seen in inflamed mucosa in UC and correlate with severity of inflammation. This suggests an alteration in fatty acid metabolism in the inflamed gut mucosa, which may offer novel targets for intervention and should be considered if nutritional strategies are used.

Objectives To determine the metabolism of captopril n-carboxyl derivatives and how this may impact on their use as transdermal prodrugs. The pharmacological activity of the ester derivatives was also characterised in order to compare the angiotensin converting enzyme inhibitory potency of the derivatives compared with the parent drug, captopril. Methods The metabolism rates of the ester derivatives were determined in vitro (using porcine liver esterase and porcine ear skin) and in silico (using molecular modelling to investigate the potential to predict metabolism). Key findings Relatively slow pseudo first-order metabolism of the prodrugs was observed, with the ethyl ester displaying the highest rate of metabolism. A strong relationship was established between in-vitro methods, while in-silico methods support the use of in-vitro methods and highlight the potential of in-silico techniques to predict metabolism. All the prodrugs behaved as angiotensin converting enzyme inhibitors, with the methyl ester displaying optimum inhibition. Conclusions In-vitro porcine liver esterase metabolism rates inform in-vitro skin rates well, and in-silico interaction energies relate well to both. Thus, in-silico methods may be developed that include interaction energies to predict metabolism rates.

Reliable analytical methods are needed for the determination of pyrethroid pesticides residues in biological tissues such as whole blood and plasma, meat, eggs, milk, brain, liver, and adipose tissue for monitoring of levels in livestock and for human risk assessment. A review of the current literature is given, with consideration to extraction techniques, sample preparation, and chromatographic approaches including both conventional and new technologies.

Most drugs are designed primarily for oral administration, but the activity and stability profiles desirable for this route often make them unsuitable for transdermal delivery. We were therefore interested in designing analogues of captopril, a model drug with poor percutaneous penetration, for which the sustained steady-state blood plasma level associated with transdermal delivery (and which is unattainable orally) would be particularly beneficial. Quantitative structure—permeability relationships (QSPRs) predicted that ester and thiol prodrug derivatives of captopril would have lower maximal transdermal flux (Jm) than the parent drug, since the increases in permeability coefficient (kp) of prodrugs would be outweighed by the reductions in aqueous solubility. Therefore, the aim of this study was to synthesize a series of prodrugs of captopril and to determine if a QSPR model could be used to design therapeutically viable prodrugs. Molecules with the highest predicted kp values were synthesized and characterized, and Jm measured in Franz diffusion cells from saturated aqueous donor across porcine skin (fresh and frozen). In-vitro metabolism was also measured. Captopril and the prodrugs crossed the skin relatively freely, with Jm being highest for ethyl to butyl esters. Substantial first-order metabolism of the prodrugs was observed, suggesting that their enhanced percutaneous absorption was complemented by their metabolic performance. The results suggested that QSPR models provided excellent enhancements in drug delivery. This was not seen at higher lipophilicities, suggesting that issues of solubility need to be considered in conjunction with any such use of a QSPR model.

In the development of bioadhesive patch devices for percutaneous local anesthesia, the tensile properties of the films produced after the casting of the gel intermediates is of key importance to the clinical compliance of the product, and its effective delivery of the local anesthetic agent. A range of bioadhesive patches were formulated and their mechanical and in vitro permeation properties determined. Altering formulation significantly altered the mechanical properties of films. The tensile properties of the films could be modified to allow concomitant benefits in the mechanical and drug permeation properties of the films, ensuring that patches not only exerted clinically beneficial effects, but are also mechanically robust. Tetracaine was found to plasticize films and while this effect was weak, it was significant both statistically and potentially also in the effect it has on the clinical use of these devices. Drug release from tetracaine patches demonstrate the same trends as found previously across polydimethylsiloxane films. By altering the formulation of the patch device, the drug release from the device to the skin is readily and accurately controlled, and was not solely a function of the stratum corneum barrier properties but additionally of the formulation.

Introduction The polyunsaturated fatty acids (PUFA) arachidonic acid (AA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) are generated from dietary essential fatty acids linoleic acid (LA) and α-linolenic acid (αLNA) and direct dietary intake. AA and EPA are substrates for eicosanoid inflammatory mediators that may have critical roles in immunomodulation in Ulcerative Colitis (UC). Dietary supplementation studies alter the availability of specific PUFA (eg, EPA), but clinical studies have been disappointing leading to the hypothesis that the PUFA biosynthetic pathway in inflamed tissue may be altered. This study evaluated PUFA bioavailability in inflamed and uninflamed mucosa from UC patients and compared to matched controls. Methods Ethical approval was obtained. Patients were prospectively recruited from outpatients9 clinics. Mucosal biopsies at flexible sigmoidoscopy (FS) were taken from active UC patients within inflamed (active) and endoscopically normal proximal mucosa (internal control). Age-sex matched patients undergoing FS for IBS or similar presentations were compared (external controls). Mucosal samples were saponified, deuterated internal standards added, lipids hydrolysed and fatty acids derivatised prior to liquid-liquid extraction into heptane. PUFA were quantified by gas chromatography mass spectrometry. Data was expressed as percentage mass abundance and compared using Wilcoxon signed rank pair analysis for non-parametric data. Results 69 active UC patients (54 paired normal/inflamed mucosa) and 69 controls were compared. No biologically significant differences were noted between endoscopically normal mucosa from UC patients and external controls other than DPA (p Conclusion PUFA bioavailability within normal mucosa in UC patients is not significantly different from matched controls; however, inflamed mucosa demonstrates significant differences in the bioavailability of PUFA with a reduction in LA and αLNA and a divergent change in AA and EPA leading to a significant increase in the AA/EPA ratio. These findings suggest alteration of the fatty acid biosynthetic pathway in inflamed tissue and may suggest that alternative therapeutic strategies are required to modify the eicosanoid profile in UC.