Applying quantitative methods in the assessment of outcomes of pharmacotherapy of psoriasis

Healthcare providers and policy makers are faced with an ever-increasing number of medical publications. Searching for relevant information and keeping up to date with new research findings remains a constant challenge. It has been widely acknowledged that narrative reviews of the literature are susceptible to several types of bias and a systematic approach may protect against these biases. The aim of this thesis was to apply quantitative methods in the assessment of outcomes of topical therapies for psoriasis. In particular, to systematically examine the comparative efficacy, tolerability and cost-effectiveness of topical calcipotriol in the treatment of mild-to-moderate psoriasis. Over the years, a wide range of techniques have been used to evaluate the severity of psoriasis and the outcomes from treatment. This lack of standardisation complicates the direct comparison of results and ultimately the pooling of outcomes from different clinical trials. There is a clear requirement for more comprehensive tools for measuring drug efficacy and disease severity in psoriasis. Ideally, the outcome measures need to be simple, relevant, practical, and widely applicable, and the instruments should be reliable, valid and responsive. The results of the meta-analysis reported herein show that calcipotriol is an effective antipsoriatic agent. In the short-tenn, the pooled data found calcipotriol to be more effective than calcitriol, tacalcitol, coal tar and short-contact dithranol. Only potent corticosteroids appeared to have comparable efficacy, with less short-term side-effects. Potent corticosteroids also added to the antipsoriatic effect of calcipotriol, and appeared to suppress the occurrence of calcipotriol-induced irritation. There was insufficient evidence to support any large effects in favour of improvements in efficacy when calcipotriol is used in combination with systemic therapies in patients with severe psoriasis. However, there was a total absence of long-term morbidity data on the effectiveness of any of the interventions studied. Decision analysis showed that, from the perspective of the NHS as payer, the relatively small differences in efficacy between calcipotriol and short-contact dithranol lead to large differences in the direct cost of treating patients with mildto-moderate plaque psoriasis. Further research is needed to examine the clinical and economic issues affecting patients under treatment for psoriasis in the UK. In particular, the maintenance value and cost/benefit ratio for the various treatment strategies, and the assessment of patient's preferences has not yet been adequately addressed for this chronic recurring disease.

Soft [beta]-adrenoceptor agonists for topical use in psoriasis

Psoriasis is characterised by epidermal proliferation and inflammation resulting in the appearance of elevated erythematous plaques. The ratio of c~AMP/c~GMP is decreased in psoriatic skin and when the epidermal cell surface receptors are stimulated by β-adrenergic agonists, intracellular ATP is transformed into c-AMP, thus restoring the c~AMP/c~GMP levels. This thesis describes a series of β-adrenoceptor agonists for topical delivery based upon the soft-drug approach. Soft drugs are defined as biologically active, therapeutically useful chemical compounds (drugs) characterised by a predictable and controllable In vivo destruction (metabolism) to non-toxic moieties. after they achieve their therapeutic role, The N-substituent can accommodate a broad range of structures and here the alkoxycarbonylethyl group has been used to provide metabolic susceptability. The increased polarity of the dihydroxy acid, expected after metabolic conversion of the soft~drug, ethyl N-[2'-(3',4'-dihydroxyphenyl)-2'-hydroxyethyl]-3- aminopropionate, should eliminate agonist activity. Further. to prevent oxidation and enhance topical delivery, the catechol hydroxyl groups have been esterified to produce a pro-soft-drug which generates the soft-drug in enzymic systems. The chemical hydrolysis of the pro-soft-drug proceeded via the formation of the dlpivaloyloxy acid and it failed to generate the active dihydroxy ester soft-drug. In contrast, in the presence of porcine liver carboxyesterase, the hydrolysis of the pro-soft drug proceeded via the formation of the required active soft-drug. This compound, thus, has the appropnate kinetic features to enable it to be evaluated further as a drug for the treatment of psoriasis. The pH rate-profile for the hydrolysis of soft-drug indicated a maximum stability at pH ∼ 4.0. The individual rate constants for the degradation and the pKa were analysed by nonlinear regression. The pKa of 7.40 is in excellent agreement with that determined by direct titration (7.43) and indicates that satisfactory convergence was achieved. The soft-drug was poorly transported across a silicone membrane; it was also air-sensitive due to oxidation of the catechol group. The transport of the pro-soft-drug was more efficient and, over the donor pH range 3-8, increased with pH. At lower values, the largely protonated species was not transported. However, above pH 7. chemical degradation was rapid so that a donor pH of 5-6 was optimum. The β-adrenergic agonist activity of these compounds was tested in vitro by measuring chronotropic and inotropic responses in the guinea pig atria and relaxation of guinea pig trachea precontracted with acetylcholine (10-3 M). The soft~drug was a full agonist on the tracheal preparation but was less potent than isoprenaline. Responses of the soft~drug were competitively antagonised by propranolol (10-6 M). The soft~drug produced an increase in force and rate of the isolated atrial preparatIon. The propyl analogue was equally potent with ED50 of 6.52 x 10-7 M. In contrast, at equivalent doses, the dihydroxy acid showed no activity; only a marginal effect was observed on the tracheal preparation. For the pro~soft-drug, responses were of slow onset, in both preparations, with a slowly developing relaxatlon of the tracheal preparatlon at high concentrations (10-5 M). This is consistent with in vitro results where the dipivaloyl groups are hydrolysed more readily than the ethyl ester to gIve the active soft-drug. These results confirm the validity tif the pro-soft-drug approach to the deUvery of β-adrenoceptor agonists.

Azidoprofen as a soft anti-flammatory agent for the topical treatment of Psoriasis

Azidoprofen {2-(4-azidophenyl)propionic acid; AZP}, an azido-substituted arylalkanoic acid, was investigated as a model soft drug candidate for a potential topical non-steroidal anti-inflammatory agent (NSAIA). Reversed-phase high performance liquid chromatography (HPLC) methods were developed for the assay of AZP, a series of ester analogues and their· degradation products. 1H-NMR spectroscopy was also employed as an analytical method in selected cases. Reduction of the azido-group to the corresponding amine has been proposed as a potential detoxification mechanism for compounds bearing this substituent. An in vitro assay to measure the susceptibility of azides towards reduction was developed using dithiothreitol as a model reducing agent. The rate of reduction of AZP was found to be base-dependent, hence supporting the postulated mechanism of thiol-mediated reduction via nucleophilic attack by the thiolate anion. Prodrugs may enhance topical bioavailability through the manipulation of physico-chemical properties of the parent drug. A series of ester derivatives of AZP were investigated for their susceptibility to chemical and enzymatic hydrolysis, which regenerates the parent acid. Use of alcoholic cosolvents with differing alkyl functions to that of the ester resulted in transesterification reactions, which were found to be enzyme-mediated. The skin penetration of AZP was assessed using an in vitro hairless mouse skin model, and silastic membrane in some cases. The rate of permeation of AZP was found to be a similar magnitude to that of the well established NSAIA ibuprofen. Penetration rates were dependent on the vehicle pH and drug concentration when solutions were employed. In contrast, flux was independent of pH when suspension formulations were used. Pretreatment of the skin with various enhancer regimes, including oleic acid and azone in propylene glycol, promoted the penetration of AZP. An intense IR absorption due to the azide group serves as a highly diagnostic marker, enabling azido compounds to be detected in the outer layers of the· stratum corneum following their application to skin, using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). This novel application enabled a non-invasive examination of the percutaneous penetration enhancement of a model azido compound in vivo in man, in the presence of the enhancer oleic acid.

Characterisation of staphylococci associated with atopic eczema and chronic plaque psoriasis

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The vibrational spectra of rectangular plates

The wire drive pulse-echo system has been extensively used to excite and measure modes of vibration of thin rectangular plates. The frequency spectra of different modes have been investigated as a function of the material elastic moduli and the plate geometry. Most of the work was carried out on isotropic materials. For square plates a wide selection of materials were used. These were made isotropic in their in-plane dimensions where the displacements are taking place. The range of rnaterials enabled the dependence on Poisson's ratio to be investigated. A method of determining the value of Poisson's ratio resulted from this investigation. Certain modes are controlled principally by the shear modulus. Of these the fundamental has two nodal lines across the plate surface. One of them, which has nodes at the corners, (the Lame mode) is uniquely a pure shear mode where the diagonal is a full wave length. One controlled by the Young's modulus has been found. The precise harmonic relationship of the Lame mode series in square and rectangular plates was established. Use of the Rayleigh-Lamb equation has extended the theoretical support. The low order modes were followed over a wide range of sides ratios. Two fundamental types of modes have been recognised; These are the longitudinal modes where the frequency is controlled by the length of the plate only and the 2~f product has an asymptotic value approaching the rod velocity. The other type is the in-plane flexural modes (in effect a flexurally vibrating bar where the -2/w is the geometrical parameter). Where possible the experimental work was related to theory. Other modes controlled by the width dimension of the plate were followed. Anisotropic materials having rolled sheet elastic symmetry were investigated in terms of the appropriate theory. The work has been extended to examine materials from welds in steel plates.

The chemical structure and mechanical properties of phenolic resins and related polymers

Paper-based phenolic laminates are used extensively in the electrical industry. Many small components are fabricated from these materials by the process known as punching. Recently an investigation was carried out to study the effect of processing variables on the punching properties. It was concluded that further work would be justified and that this should include a critical examination of the resin properties in a more controlled and systematic manner. In this investigation an attempt has been made to assess certain features of the resin structure in terms of thermomechanical properties. The number of crosslinks in the system was controlled using resins based on phenol and para-cresol formulations. Intramolecular hydrogen bonding effects were examined using substituted resins and a synthetically derived phenol based on 1,3-di-(o-hydroxyphenyl) propane.. A resin system was developed using the Friedel Crafts reaction to examine inter-molecular hydrogen bonding at the resin-paper interface. The punching properties of certain selected resins were assessed on a qualitative basis. In addition flexural and dynamic mechanical properties were determined in a general study of the structure-property relationships of these materials. It has been shown that certain features of the resin structure significantly influenced mechanical properties. :F'urther, it was noted that there is a close relationship between punching properties, mechanical damping and flexural strain. This work includes a critical examination of the curing mechanism and views are postulated in an attempt to extend knowledge in this area of the work. Finally, it is argued that future work should be based on a synthetic approach and that dynamic mechanical testing would provide a powerful tool In developing a deeper understanding of the resin fine structure.

The isolation and identification of dermatologically active constituents of coal tar

The production and uses of coal tar are reviewed as are the uses of steroids and cytotoxic agents in the treatment of psoriasis with a review of the condition also. An attempt was made to improve the efficaciousness and cosmetic acceptability of a low temperature tar, by screening fractions of this tar, derived from a variety of separation procedures. The most efficacious fraction was the highest boiling acid fraction, which is believed to consist mainly of mono- and di-hydric phenols. A time and concentration study showed that the optimum regime was the application of a 10% concentration in 5% wool fat in soft, yellow paraffin daily for 21 days. The mouse tail skin was selected as an experimental model, to ascertain the efficaciousness of fractions, because of the similarities between this skin and the psoriatic lesion. The activity of a fraction was monitored by the inducement of a granular layer in the mouse tail epidermis. Because coal tar is not an easy medium to work with, and the active fractions showed no increase in cosmetic acceptability over the parent coal tar, likely coal tar constituents were selected for screening on the basis of phenolic character, and the molecular weight range elucidated by mass spectroscopy. 32 potential anti-psoriatic agents were screened on mouse tail. Two catechols, 3,5-di-t-butyl and 4-t-butyl catechols were active. Other structures showed little or no activity. 24 catechols were screened and two extremely active catechols were discovered, 3-methyl-5-t-octyl and 5-methyl-3-t-octyl catechols. The screening of catechol-rich coal tar fractions and a coal tar fraction which had had the catechols removed by oxidation, showed that some anti-psoriatic activity was contained in the catechol fraction of coal tar. Attempts to elucidate the mode of action of these two compounds met with little success, but two modes of action are suggested.

Lipophilic antifolates as potential antipsoriatic agents

The lipophilic dihydrofolate reductase (DHFR) inhibitor m-azidopyrimethamine (MZP) was investigated for suitability for development as a topical antipsoriatic agent. The clinical features and treatments for psoriasis were reviewed. High performance liquid chromatography (HPLC) was employed as the main analytical method, with UV spectroscopy being used in some cases. Reduction of the azido-group was proposed as a potential detoxification mechanism for MZP. The rates of reduction of a series of substituted phenyl azide compounds by dithiothreitol were investigated and found to depend on the substitution pattern of the aryl azide molecular, with electron deficient azides exhibiting faster rates of reduction in the system studied. The rates of reduction of MZP and analogous compounds were also studied using this model. The skin penetration of MZP was assessed using an in vitro hairless mouse skin model. The rate of permeation (flux) of MZP across hairless mouse skin was found to be dependent on the quantity of propylene glycol used as cosolvent in the vehicle and the pH. The use of a pretreatment regime of oleic acid in propylene glycol was shown to greatly increase the penetration of MZP through the hairless mouse skin as compared to application without pretreatment, or pretreatment with other penetration enhancers. The metabolism of MZP was studied in in vitro models comprising skin homogenates, SV-K14 human keratinocyte cell cultures and skin commensal bacterial cultures. No conversion of MZP to the corresponding amine was detected in any of the models. The growth inhibitory properties of MZP were investigated in an in vitro SV-K14 human keratinocyte cell culture model and compared with those of other DHFR inhibitors. [14C]-pyrimethamine was shown to be taken up by the SV-K14 keratinocytes.

Structural behaviour of glass reinforced plastics

The aim of this research is to promote the use of G.R.P. as a structural material. In the past, the use of G.R.P. has been confined to non-load carrying applications. Such uses are still rapidly increasing but in addition significant changes have been made during the last decade in the development of semi-structural and now even fully structural applications. Glass-reinforced plastic is characterized by a high strength but a relatively low modulus of elasticity. For this reasona G.R.P. structure can expect to show large deformations as a result of which the individual structural members will fail under load due to a loss of stability rather than approaching the ultimate strength of the material. For this reason the selection of the geometrical shapes of G.R.P. structural elements is considered to be an important factor in designing G.R.P. structures. The first chapter of this thesis deals with a general review of the theoretical and experimental methods used to describe the structural properties of G.R.P. The research programme includes five stages dealing with the structural behaviour of G.R.P. The first stage (Chapter 2) begins with selecting and designing an optimum box beam cross-section which gives the maximum flexural and torsional rigidity. The second stage of investigation (Chapter 3) deals with beam to beam connections. A joint was designed and manufactured with different types of fasteners used to connect two beam units. A suitable fastener was selected and the research extended to cover the behaviour of long span beams using multiple joints. The third part of the investigation includes a study of the behaviour of box beams subjected to combined bending, shear and torsion. A special torque rig was developed to perform the tests. Creep deformation of 6 m span G.R.P. was investigated as the fourth stage under a range of loading conditions. As a result of the phenomenon of post buckling behaviour exhibited in the compression flange during testing of box beams during earlier stages of the investigation it was decided to consider this phenomenon in more detail in the final stage of the investigation. G.R.P. plates with different fibre orientation were subjected to uniaxial compression and tested up to failure. In all stages of the investigation theoretical predictions and experimental results were compared and generally good correlation between theory and experimental data was observed.

Web strength of rolled steel joists

This work is concerned with the behaviour of thin webbed rolled steel joists or universal beams when they are subjected to concentrated loads applied to the flanges. The prime concern is the effect of high direct stresses causing web failure in a small region of the beam. The review shows that although many tests have been carried out on rolled steel beams and built up girders, no series of tests has restricted the number of variables involved to enable firm conclusions to be drawn. The results of 100 tests on several different rolled steel universal beam sections having various types of loading conditions are presented. The majority of the beams are tested by loading with two opposite loads, thus eliminating the effects of bending and shear, except for a small number of beams which are tested simply supported on varying spans. The test results are first compared with the present design standard (BS 449) and it is shown that the British Standard is very conservative for most of the loading conditions included in the tests but is unsafe for others. Three possible failure modes are then considered, overall elastic buckling of the web, flexural yielding of the web due to large out of plane deflexions and local crushing of the material at the junction of the web and the root fillets. Each mode is considered theoretically and developed to establish the main variables, thus enabling a comparison to be made with the test results. It is shown that all three failure modes have a particular relevance for individual loading conditions, but that determining the failure load given the beam size and the loading conditions is very difficult in certain instances. Finally it is shown that there are some empirical relationships between the failure loads and the type of loading for various beam serial sizes.

Theoretical modelling of the sulcated spring

Replacement of the traditional coil spring with one of more fibre-reinforced plastic sulcated springs is a future possibility. Spring designers of metallic coil springs have design formulae readily available, and software packages specific to coil spring design exist. However, the sulcated spring is at the prototype stage of development, so literature on these springs is very sparse. The thesis contains information on the market for sulcated springs, and their advantages and disadvantages. Literature on other types of fibre reinforced plastic springs has also been reviewed. Design software has been developed for the sulcated spring along similar lines to coil spring design software. In order to develop the software, a theoretical model had to be developed which formed the mathematical basis for the software. The theoretical model is based on a choice of four methods for calculating the flexural rigidity; beam theory, plate theory, and lamination theory assuming isotropic and orthoropic material properties. Experimental results for strain and spring stiffness have been compared with the theoretical model, and were in good agreement. Included in the design software are the results of experimental work on fatigue, and design limiting factors to prevent or warn against impractical designs. Finite element analysis has been used to verify the theoretical model developed, and to find the better approximation to the experimental results. Applications and types of assemblies for the sulcated spring were discussed. Sulcated spring designs for the automotive applications of a suspension, clutch and engine valve spring were found using the design computer software. These sulcated spring designs were within or close to the space of the existing coil spring and yield the same performance. Finally the commercial feasibility of manufacturing the sulcated spring was assessed and compared with the coil spring, to evaluate the plausibility of the sulcated spring replacing the coil spring eventually.

Acousto-optic modulation in a microstructured plastic optical fibre Bragg grating

The present work addresses the control of the mPOF Bragg grating spectrum properties through acousto-optic modulation. For the first time, the interaction of a flexural acoustic wave, generated by longitudinal excitation of different frequencies, with the Bragg grating will be presented. Also it will be demonstrated the quasi linear relationship between PZT load and maximum reflected power/ 3dB bandwidth of the reflected spectrum.

Effects of fibre reinforcement on the mechanical properties of brushite cement

In this study the effect of structure and amount of polyglactin fibre incorporation into a brushite forming calcium phosphate cement system and the effect of mechanical compaction on the fibre modified system were investigated. In comparison the effect of resorbable polycaprolactone surface coating of cement specimens was investigated. The results showed that, apart from the mechanical properties of the reinforcing material, the structure of the incorporated fibres, regular or random, is crucial for the resulting flexural strength and modulus of elasticity. Fibre reinforcement could also be combined with mechanical compaction of the cement/fibre composite paste leading to a possible 7-fold increase in flexural strength or an almost 5-fold increase in modulus of elasticity. Reinforcement of the tensile surface of cement grafts may ultimately improve strength where required, especially in conjunction with bone fixation devices. © 2005 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

The effect of bioglass addition on mechanical and physical properties of photoactive UDMA-TEGDMA resin composites

Light curable dimethacrylate resin composites undergo free radical photopolymerisation in response to blue light (wavelength 450-500 nm) and may offer superior handling and setting characteristics for novel hard tissue repair materials. The current investigation aims to determine the optimum formulation of bisphenol-A glycidyl methacrylate and triethyleneglycoldimethacrylate (bisGMA/TEGDMA) or urethane dimethacrylate (UDMA)/TEGDMA resin mixtures and the effect of Bioglass incorporation on the rate of polymerisation (RP), degree of conversion (DC) and flexural strength (FS) of light-curable filled resin composites (FRCs). Experimental photoactive resins containing a range of bisGMA, UDMA and TEGDMA ratios and/or filled with non-silanised irregular or spherical 45S5-Bioglass (50 μm; 5-40 wt%) and/or silanised silicate glass filler particulates (0.7 μm; 50-70 wt%) were tested. RP and DC were analysed in real-time using nearinfrared spectroscopy. FS of resins and FRCs were determined using three-point flexural strength tests. UDMA/TEGDMA resins exhibited increased DC compared with bisGMA/TEGDMA resins (p<0.05). The addition of spherical particles of Bioglass had a detrimental effect on the FS (p>0.05), whereas they increased DC of UDMA/TEGDMA resins (p<0.05). Addition of irregular shaped Bioglass particles increased the FS of UDMA/TEGDMA resins up to 20 wt% Bioglass (p<0.05). The flexibility and strength conferred by the urethane group in UDMA may result in enhanced physical and mechanical properties compared with conventional resins containing bulky (bisGMA) molecules. Addition of 45S5-Bioglass with specific filler content, size and morphology resulted in enhanced mechanical and physical properties of UDMA/TEGDMA composites. © (2014) Trans Tech Publications, Switzerland.