Development of sampling methods for Raman analysis of solid dosage forms of therapeutic and illicit drugs

The results of a study aimed at determining the most important experimental parameters for automated, quantitative analysis of solid dosage form pharmaceuticals (seized and model 'ecstasy' tablets) are reported. Data obtained with a macro-Raman spectrometer were complemented by micro-Raman measurements, which gave information on particle size and provided excellent data for developing statistical models of the sampling errors associated with collecting data as a series of grid points on the tablets' surface. Spectra recorded at single points on the surface of seized MDMA-caffeine-lactose tablets with a Raman microscope (lambda(ex) = 785 nm, 3 mum diameter spot) were typically dominated by one or other of the three components, consistent with Raman mapping data which showed the drug and caffeine microcrystals were ca 40 mum in diameter. Spectra collected with a microscope from eight points on a 200 mum grid were combined and in the resultant spectra the average value of the Raman band intensity ratio used to quantify the MDMA: caffeine ratio, mu(r), was 1.19 with an unacceptably high standard deviation, sigma(r), of 1.20. In contrast, with a conventional macro-Raman system (150 mum spot diameter), combined eight grid point data gave mu(r) = 1.47 with sigma(r) = 0.16. A simple statistical model which could be used to predict sigma(r) under the various conditions used was developed. The model showed that the decrease in sigma(r) on moving to a 150 mum spot was too large to be due entirely to the increased spot diameter but was consistent with the increased sampling volume that arose from a combination of the larger spot size and depth of focus in the macroscopic system. With the macro-Raman system, combining 64 grid points (0.5 mm spacing and 1-2 s accumulation per point) to give a single averaged spectrum for a tablet was found to be a practical balance between minimizing sampling errors and keeping overhead times at an acceptable level. The effectiveness of this sampling strategy was also tested by quantitative analysis of a set of model ecstasy tablets prepared from MDEA-sorbitol (0-30% by mass MDEA). A simple univariate calibration model of averaged 64 point data had R-2 = 0.998 and an r.m.s. standard error of prediction of 1.1% whereas data obtained by sampling just four points on the same tablet showed deviations from the calibration of up to 5%.

Study of electron-beam propagation through preionized dense foam plasmas

The transport of an intense electron-beam produced by the Vulcan petawatt laser through dense plasmas has been studied by imaging with high resolution the optical emission due to electron transit through the rear side of coated foam targets. It is observed that the MeV-electron beam undergoes strong filamentation and the filaments organize themselves in a ringlike structure. This behavior has been modeled using particle-in-cell simulations of the laser-plasma interaction as well as of the transport of the electron beam through the preionized plasma. In the simulations the filamentary structures are reproduced and attributed to the Weibel instability.

Fully nonlinear ion-sound waves in a dense Fermi magnetoplasma

The nonlinear propagation of ion-sound waves in a collisionless dense electron-ion magnetoplasma is investigated. The inertialess electrons are assumed to follow a non-Boltzmann distribution due to the pressure for the Fermi plasma and the ions are described by the hydrodynamic (HD) equations. An energy balance-like equation involving a new Sagdeev-type pseudo-potential is derived in the presence of the quantum statistical effects. Numerical calculations reveal that the profiles of the Sagdeev-like potential and the ion-sound density excitations are significantly affected by the wave direction cosine and the Mach number. The present studies might be helpful to understand the excitation of nonlinear ion-sound waves in dense plasmas such as those in superdense white dwarfs and neutron stars as well as in intense laser-solid density plasma experiments.

Neutral gas depletion mechanisms in dense low-temperature argon plasmas

Neutral gas depletion mechanisms are investigated in a dense low-temperature argon plasma-an inductively coupled magnetic neutral loop (NL) discharge. Gas temperatures are deduced from the Doppler profile of the 772.38 nm line absorbed by argon metastable atoms. Electron density and temperature measurements reveal that at pressures below 0.1 Pa, relatively high degrees of ionization (exceeding 1%) result in electron pressures, p(e) = kT(e)n(e), exceeding the neutral gas pressure. In this regime, neutral dynamics has to be taken into account and depletion through comparatively high ionization rates becomes important. This additional depletion mechanism can be spatially separated due to non-uniform electron temperature and density profiles (non-uniform ionization rate), while the gas temperature is rather uniform within the discharge region. Spatial profiles of the depletion of metastable argon atoms in the NL region are observed by laser induced fluorescence spectroscopy. In this region, the depletion of ground state argon atoms is expected to be even more pronounced since in the investigated high electron density regime the ratio of metastable and ground state argon atom densities is governed by the electron temperature, which peaks in the NL region. This neutral gas depletion is attributed to a high ionization rate in the NL zone and fast ion loss through ambipolar diffusion along the magnetic field lines. This is totally different from what is observed at pressures above 10 Pa where the degree of ionization is relatively low (

Proteasome inhibitors: a therapeutic strategy for haematological malignancy

The proteasome is a multicatalytic enzyme complex responsible for the regulated degradation of intracellular proteins. In recent years, inhibition of proteasome function has emerged as a novel anti-cancer therapy. Proteasome inhibition is now established as an effective treatment for relapsed and refractory multiple myeloma and offers great promise for the treatment of other haematological malignancies, when used in combination with conventional therapeutic agents. Bortezomib is the first proteasome inhibitor to be used clinically and a second generation of proteasome inhibitors with differential pharmacological properties are currently in early clinical trials. This review summarises the development of proteasome inhibitors as therapeutic agents and describes how novel assays for measuring proteasome activity and inhibition may help to further delineate the mechanisms of action of different proteasome inhibitors. This will allow for the optimized use of proteasome inhibitors in combination therapies and provide the opportunity to design more potent and therapeutically efficacious proteasome inhibitors.