Proefschrift Universiteit van Amsterdam. / Met samenvatting in het Nederlands.

Proefschrift Universiteit van Amsterdam. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit van Amsterdam. / Auteursnaam op omslag: Edwin P.C. Mes. Met bibliogr., lit. opg. - Met samenvatting in het Engels.

Proefschrift Universiteit van Amsterdam. / Met lit.opg. en samenvatting in het Nederlands.

Proefschrift Universiteit van Amsterdam. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Thesis (doctoral)--Technische Universiteit Delft, 1998. / Summary also in Dutch. Includes bibliographical references.

Thesis (doctoral)--Technische Universiteit Delft, 1998. / Summary also in Dutch. Includes bibliographical references.

Long-term cosmic-ray modulation studies using ab initio numerical modulation models require an understanding of the solar-cycle dependence of the heliospheric diffusion tensor. Such an understanding requires information as to possible solar-cycle dependences of various basic turbulence quantities. In this study, 1-minute resolution data for the N-component of the heliospheric magnetic field spanning from 1974 to 2012 is analysed using second-order structure functions constructed assuming a simple three-stage power-law frequency spectrum. This spectrum is motivated observationally and theoretically, and has an inertial, an energycontaining and a cutoff-range at small frequencies to ensure a finite energy density. Of the turbulence quantities calculated from 27-day averaged second-order structure functions, only the magnetic variance and the spectral level show a significant solar-cycle dependence, much less so the spectral index in the energy range. The spectral indices in the inertial range, as well as the turnover and cutoff scales do not appear to depend on the level of solar activity. The ratio of the variance to the square of the magnetic field also appears to be solar-cycle independent. These results suggest that the dominant change in the spectrum over several solar-cycles is its level. Comparisons of the results found in this study with relevant published observations of turbulence quantities are very favourable. Furthermore, when the magnetic variances and heliospheric magnetic magnitudes calculated in this study are used as inputs for theoretically motivated expressions for the mean free paths and turbulence-reduced drift lengthscale, clear solar-cycle dependencies in these quantities are seen. Values for the diffusion and drift lengthscales during the recent unusual solar minimum are found to be significantly higher than during previous solar minima. / MSc (Space Physics), North-West University, Potchefstroom Campus, 2015

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammation and pain (Escribano et al., 2003:203). Diclofenac, a classical NSAID, is considerably more effective as an analgesic, antipyretic and anti-inflammatory drug than other traditional NSAIDs, like indomethacin and naproxen (Grosser et al., 2011:986). However, the use of diclofenac is known for its many side effects, such as gastric disorders, while fluid and sodium retention are also commonly observed (Rossiter, 2012:391). Since topical diclofenac offers a more favourable safety profile, it is a valuable substitute for oral NSAID therapy in the treatment of osteoarthritis (Roth & Fuller, 2011:166). The benefits of topically applied NSAIDs, compared to oral administration and systemic delivery, include the easy cessation of treatment, should effects become troublesome (Brown et al., 2006:177), the avoidance of extensive, first-pass metabolism (Cleary, 1993:19; Kornick, 2003:953; Prausnitz & Langer, 2008:1261; Lionberger & Brennan, 2010:225), reduced systemic side effects (Colin Long, 2002:41), convenience of application and improved patient compliance (Cleary, 1993:19; Prausnitz & Langer, 2008:1261). An approach that is often applied in optimising the solubility and dissolution rate of poorly water soluble, weak electrolytes is to prepare a salt of the active pharmaceutical ingredient (API) (Minghetti et al., 2007:815; O’Connor & Corrigan, 2001:281-282). Diclofenac is frequently administered as a salt, due to the high partition coefficient and very low water solubility of this molecule (Fini et al., 1999:164). Formulating for efficacy (FFETM) is a software programme designed by JW Solutions to facilitate the formulation of cosmetic ingredients or solvents into a product that would optimally deliver active ingredients into the skin. The notion is built upon solubility, i.e. solubility of the active ingredient in the formulation and solubility of the formulation in the skin. This programme could also be employed to optimise amounts of predetermined ingredients, to propose formulations that would ensure optimal drug delivery, to calculate the skin delivery gap (SDG) and to demonstrate transdermal permeation of active ingredients and excipients (JW Solutions Software, 2013a). When the SDG is known, it mathematically indicates the optimal active ingredient and topical delivery vehicle to use (JW Solutions, 2013b). In this study, diclofenac sodium (DNa), diclofenac diethylamine (DDEA) and diclofenac N-(2- hydroxyethyl) pyrrolidine (DHEP) were each formulated in the following emulgels: * An emulgel optimised towards the stratum corneum (SC) (enhancing drug delivery into this layer and deeper tissues) (oily phase ~30%), * A more hydrophilic emulgel (oily phase ~15%), and * A more lipophilic emulgel (oily phase ~45%). Components of the oily phase and its respective amounts, as well as the SDG of formulations were determined by utilising the FFETM software of JW Solutions (2013a). The aqueous solubilities of DNa, DDEA and DHEP were determined and their respective values were 11.4 mg/ml, 8.0 mg/ml and 11.9 mg/ml, all indicative of effortless percutaneous delivery (Naik et al., 2000:319). Log D (octanol-buffer distribution coefficient) (pH 7.4) determinations for DNa, DDEA and DHEP were performed and their values established at 1.270 (DNa), 1.291 (DDEA) and 1.285 (DHEP). According to these values, diclofenac, when topically applied as a salt in a suitable vehicle, should permeate transdermally without the aid of radical intervention (Naik et al., 2000:319; Walters, 2007:1312). Membrane release studies were also carried out in order to determine the rate of API release from these new formulations. Results confirmed that diclofenac was indeed released from all nine of the formulated emulgels. The more hydrophilic DNa formulation released the highest average percentage of diclofenac (8.38%) after 6 hours. Subsequent transdermal diffusion studies were performed to determine the diclofenac concentration that permeated the skin. The more hydrophilic DNa emulgel showed the highest average percentage skin diffusion (0.09%) after 12 hours, as well as the highest average flux (1.42 ± 0.20 μg/cm2.h). The concentrations of diclofenac in the SC-epidermis (SCE) and epidermis-dermis (ED) were determined through tape stripping experiments. The more lipophilic DNa emulgel demonstrated the highest average concentration (0.27 μg/ml) in the ED, while the DNa emulgel that had been optimised towards the SC, had the highest concentration in the SCE (0.77 μg/ml). / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Long-term cosmic-ray modulation studies using ab initio numerical modulation models require an understanding of the solar-cycle dependence of the heliospheric diffusion tensor. Such an understanding requires information as to possible solar-cycle dependences of various basic turbulence quantities. In this study, 1-minute resolution data for the N-component of the heliospheric magnetic field spanning from 1974 to 2012 is analysed using second-order structure functions constructed assuming a simple three-stage power-law frequency spectrum. This spectrum is motivated observationally and theoretically, and has an inertial, an energycontaining and a cutoff-range at small frequencies to ensure a finite energy density. Of the turbulence quantities calculated from 27-day averaged second-order structure functions, only the magnetic variance and the spectral level show a significant solar-cycle dependence, much less so the spectral index in the energy range. The spectral indices in the inertial range, as well as the turnover and cutoff scales do not appear to depend on the level of solar activity. The ratio of the variance to the square of the magnetic field also appears to be solar-cycle independent. These results suggest that the dominant change in the spectrum over several solar-cycles is its level. Comparisons of the results found in this study with relevant published observations of turbulence quantities are very favourable. Furthermore, when the magnetic variances and heliospheric magnetic magnitudes calculated in this study are used as inputs for theoretically motivated expressions for the mean free paths and turbulence-reduced drift lengthscale, clear solar-cycle dependencies in these quantities are seen. Values for the diffusion and drift lengthscales during the recent unusual solar minimum are found to be significantly higher than during previous solar minima. / MSc (Space Physics), North-West University, Potchefstroom Campus, 2015