The stability and formulation of topical analgesics

High-performance liquid chromatographic methods are developed for the simultaneous determination of various salicylates, their p-hydroxy isomers and nicotinic acid esters. The method is sensitive enough to detect trace amounts (~µM/L)of the product generated from cross reactivity between the drugs and the vehicle. The developed method also allows analysis of various topical products containing salicylate and nicotinate esters in their formulations. Applying this method, the degradation profiles of salicylates, nicotinates, p-hydroxy benzoate, o-methoxy benzoate and aspirin prodrugs in alkaline media are determined. The profile for alkyl salicylate degradation is found to be first order (A---? B) When the alcoholic radical is similar to that of the ester. In alcohol having a radical different from that of the ester function, the degradation is found to proceed through competitive transesterification and hydrolysis. The intermediates are identified following synthesis and isolation. The rate and extent of transesterification depends on the proportion of alcohol present in the system. Equations are presented to model the time profiles of reactant and product concentration. The reactions are base catalysed and the predominant pathway involves a concerted solvent attack upon the salicylate anion. Competitive hydrolysis of both ester components also follows this mechanism at moderate pH values but rates increase under strongly alkaline conditions as direct hydroxide attack becomes significant. In contrast, transesterification is independent of base concentration once full ionization is accomplished. The competitive hydrolysis is modelled using equations involving the dielectric constant of the medium. A range of other esters are also shown to undergo base-catalysed transesterification. In non-alcoholic solution phenyl salicylate undergoes a concentration-dependent oligomerisation which yields salsalate among the products. Competitive transesterification and hydrolysis also occur in products for topical use which have vehicles based upon alcohol, glycol or glycol polymers. Such reactions may compromise stability assessments, pharmaceutical integrity and delivery profiles.

The effects of the environment on the stability and expression of genetically engineered plasmids

The lac promoter is widely used in plasmid expression systems, even though it is prone to catabolite repression. As a consequence glycerol is often used as an alternative carbon source. Three plasmids containing various sizes of the staphylococcal protein A (SPA) gene, which are under the control of the lac promoter were investigated in continuous culture, to evaluate the effects of nutrient limitations on their stability and expression. The fears of catabolite repression were dispelled as a low expression plasmid (pPA16) produced a greater amount of truncated SPA under glucose limiting conditions (11 ug mg-1 cell protein) when compared to that using glycerol (8 ug mg-1 cell protein). Segregational instability was also observed under glycerol limiting conditions at all the dilution rates investigated. Whereas pPA16 was relatively stable under glucose limiting conditions, with SPA production being continuous. Experiments using excess glycerol with limited ammonium increased the stability of pPA16, (when compared to limited glycerol) with expression of SPA being continuous but reduced (6 ug mg-1 cell protein). With excess glucose and limited ammonium the copy numbers remained high but expression of SPA paralled that produced under glucose limiting conditions. This might indicate that the higher levels of glucose are reducing expression (catabolite repression) or that the low level of ammonium is affecting protein production. A high expression plasmid (pPA31) produced nearly 100 ug full length SPA mg-1 cell protein, while another high expression plasmid (pPA34) producing truncated SPA proved to be very unstable. An ELISA was developed to detect the SPA produced by these experiments, which could be adapted for western blotting or immunogold probing using electron microscopy. SPA was localised in electron lucent areas present in the periplasmic space of the E. coli host harbouring pPA16. While in the same host containing pPA31, SPA was localised not only in electron lucent areas but also around the whole of the outer-membrane.

Studies of the stability and metabolism of tumour inhibitory tetrazinones

Temozolomide is an imidazotetrazinone with antineoplastic properties. It is structurally related to dacarbazine. Temozolomide was not metabolized in vitro by liver fractions. Chemical decomposition appears to play an important r^ole in its in vitro and in vivo disposition. In contrast, 3-methylbenzotriazinone, a structural analogue, was metabolized by hepatic microsomes to afford benzotriazinone and a hydrophilic metabolite. The cytotoxicity of temozolomide, dacarbazine, 5-[3-(hydroxy-methyl-3-methyl-triazen-1-yl]imidazole-5-carboxamide (HMMTIC) and 3-monomethyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) were investigated in TLX5 murine lymphoma cells. Unlike dacarbazine, which was not toxic, MTIC, HMMTIC and temozolomide were cytotoxic in the absence of microsomes. Decarbazine was only cytotoxic in the presence of microsomes. The formation of MTIC from dacarbazine, HMMTIC and temozolomide was determined by reversed phase high performance liquid chromatography in mixtures incubated under conditions identical to those described before. MTIC was generated chemically from temozolomide and HMMTIC metabolically from dacarbazine. Using [14C]temozolomide, it was found that, in mice, the major route of excretion of the drug is via the kidneys. An acidic metabolite (metabolite I) was found in the urine of mice which had received temozolomide but its identity has not been established. 1H NMR, UV and chemical analyses revealed that Metabolite I possesses an intact NNN linkage and the site of metabolism is at the N3 methyl group. A further acidic metabolite (metabolite II) was found in the urine of patients. Metabolite II was unambiguously identified as the 8-carboxylic acid derivative of temozolomide. In vitro cytotoxicity assay showed that ony metabolite II is cytotoxic but not metabolite I. Pharmacokinetic studies of temozolomide and MTIC in vivo were performed on mice bearing TLX5 tumour. Temozolomide was eliminated from the plasma monophasically with a t1/2 of 0.7hr. MTIC was identified as a product of decomposition. MTIC was eliminated rapidly with a t1/2 of 2min. Though temozolomide shares many biochemical and biological similarities with clinically used dacarbazine, the results obtained in this study show that it differs markedly in its pharmacokinetic properties from dacarbazine, as temozolomide produced relatively sustained plasma levels which were reflected by drug concentrations in the tumour.

Stability and in vivo activity of topical corticosteroid dilutions

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Constructing institutional change: emergence, contestation and convergence of business models in the field of Java application servers

How are innovative new business models established if organizations constantly compare themselves against existing criteria and expectations? The objective is to address this question from the perspective of innovators and their ability to redefine established expectations and evaluation criteria. The research questions ask whether there are discernible patterns of discursive action through which innovators theorize institutional change and what role such theorizations play for mobilizing support and realizing change projects. These questions are investigated through a case study on a critical area of enterprise computing software, Java application servers. In the present case, business practices and models were already well established among incumbents with critical market areas allocated to few dominant firms. Fringe players started experimenting with a new business approach of selling services around freely available opensource application servers. While most new players struggled, one new entrant succeeded in leading incumbents to adopt and compete on the new model. The case demonstrates that innovative and substantially new models and practices are established in organizational fields when innovators are able to refine expectations and evaluation criteria within an organisational field. The study addresses the theoretical paradox of embedded agency. Actors who are embedded in prevailing institutional logics and structures find it hard to perceive potentially disruptive opportunities that fall outside existing ways of doing things. Changing prevailing institutional logics and structures requires strategic and institutional work aimed at overcoming barriers to innovation. The study addresses this problem through the lens of (new) institutional theory. This discourse methodology traces the process through which innovators were able to establish a new social and business model in the field.

Stability and continuity of parentally reported child eating behaviours and feeding practices from 2 to 5 years of age

Previous research suggests that many eating behaviours are stable in children but that obesigenic eating behaviours tend to increase with age. This research explores the stability (consistency in individual levels over time) and continuity (consistency in group levels over time) of child eating behaviours and parental feeding practices in children between 2 and 5 years of age. Thirty one participants completed measures of child eating behaviours, parental feeding practices and child weight at 2 and 5 years of age. Child eating behaviours and parental feeding practices remained stable between 2 and 5 years of age. There was also good continuity in measures of parental restriction and monitoring of food intake, as well as in mean levels of children's eating behaviours and BMI over time. Mean levels of maternal pressure to eat significantly increased, whilst mean levels of desire to drink significantly decreased, between 2 and 5 years of age. These findings suggest that children's eating behaviours are stable and continuous in the period prior to 5 years of age. Further research is necessary to replicate these findings and to explore why later developmental increases are seen in children's obesigenic eating behaviours. © 2011 Elsevier Ltd.

Target spatial frequency determines the response to conflicting defocus- and convergence-driven accommodative stimuli

Asthenopia, or visual fatigue, is a frequent complaint from observers of stereoscopic three-dimensional displays. It has been proposed that asthenopia is a consequence of anomalous oculomotor responses generated by conflict between accommodative and convergence stimuli. The hypothesis was examined by measuring accommodation and convergence continuously with a Shin-Nippon SRW5000 infrared autorefractor and a limbus tracking device. Subjects viewed a high contrast Maltese Cross target at three levels of Gaussian filter target blur under conditions of relatively low- and high-conflict between accommodation and convergence stimuli, the latter inducing the sensation of stereopsis. Under the low-conflict conditions accommodation was stable, but convergence-driven accommodation was dominant when the target was extremely blurred. Under the high-conflict conditions the role of convergence-driven accommodation increased systematically with the degree of target blur. It is proposed that defocus-driven accommodation becomes weak when the target comprises low spatial frequency components. Large accommodative overshoots to step stimuli that are not blurred or only mildly blurred were consistently observed and are attributed to the initial accommodative response being convergence-driven. Whereas the possibility that high-conflict conditions are a cause of asthenopia has been previously reported, this is the first evidence that they specifically affect accommodative responses while viewing stereoscopic displays. © 2005 Elsevier Ltd. All rights reserved.

Stability and continuity of women's core beliefs and psychopathological symptoms from pregnancy to one year postpartum

Unhealthy core beliefs are theorized to be stable constructs throughout the life-span, but no research to date, outside of the context of clinical intervention, has addressed this claim over a period of greater than 6 weeks. This study explores the stability and continuity of core beliefs and psychopathological symptoms in a group of women over a major life event and for 1 year subsequently. Eighty-seven women completed measures assessing their core beliefs and psychopathological symptoms during pregnancy and at 6 and 12 months after giving birth. General maternal psychopathological symptoms significantly decreased across the group between pregnancy and 6 months postpartum, and between pregnancy and 1 year, but showed evidence of stability in the ranks of individuals across time. The majority of core beliefs remained both stable and continuous throughout this period of major transition. These findings generally support the theoretical contention that core beliefs are relatively stable and continuous self-constructs. Science+Business Media, LLC.

Practical Stability and Vector-Lyapunov Functions for Impulsive Differential Equations with "Supremum"

Stability of nonlinear impulsive differential equations with "supremum" is studied. A special type of stability, combining two different measures and a dot product on a cone, is defined. Perturbing cone-valued piecewise continuous Lyapunov functions have been applied. Method of Razumikhin as well as comparison method for scalar impulsive ordinary differential equations have been employed.

Stability and Instability of Solitary Wave Solutions of a Nonlinear Dispersive System of Benjamin-Bona-Mahony Type

2000 Mathematics Subject Classification: 35B35, 35B40, 35Q35, 76B25, 76E30.

Fullerene-capped copolymers for bulk heterojunctions: device stability and efficiency improvements

A fullerene end-capped polymer-compatibilizer based on poly(3-hexylthiophene) (P3HT) was synthesized and demonstrated to have a remarkable effect on both the stability and efficiency of devices made from exemplar P3HT and [6,6]-phenyl C61-butyric acid methyl ester (PCBM). P3HT with ethynyl chain-ends and α-azido-ω-bromo-PS were prepared via Grignard metathesis (GRIM) and atom transfer radical polymerisation, respectively. “Click” chemistry resulted in the preparation of poly(3-hexylthiophene)-block-ω-bromo-polystyrene (P3HT-b-PS-Br), and subsequent atom transfer radical addition chemistry with fullerene (C60) yielded the donor–acceptor block copolymer P3HT-b-PS-C60. Both P3HT-b-PS-Br and P3HT-b-PS-C60 were considered as compatibilizers with P3HT/PCBM blends, with the study detailing effects on active-layer morphology, device efficiency and stability. When used at low concentrations, both P3HT-b-PS-Br (1%) and P3HT-b-PS-C60 (0.5%) resulted in considerable 28% and 35% increases in efficiencies with respect to devices made from P3HT/PCBM alone. Furthermore, P3HT-b-PS-C60 (0.5%) resulted in an important improvement in device stability.

The financial stability and access to financing of SMEs in Hungary

The present study was prepared within the framework of cooperation between the Competitiveness Research Centre, operating within the Institute of Business Economics of Corvinus University of Budapest, and the National Association of Entrepreneurs, based on a commission from the latter. Th e goal of the study was to survey the self-financing capabilities and borrowing opportunities of majority Hungarian-owned small and medium-sized enterprises (SMEs), and to identify potential problems. The results of the research revealed that the high proportion of owner’s equity in the financing structure is not due to difficulties with borrowing, but because enterprises that cover their fi nancing primarily from their own resources have other financing opportunities at their disposal. Although general satisfaction with banks shows a diminishing tendency, it can still be interpreted favourably. The majority of companies have not encountered serious borrowing difficulties. With regard to the system of competitive tenders, company managers have sensed some improvement, but general satisfaction is still lacking. Although the research results suggest that the primary obstacle to growth in 2013 was not the lack of credit or external funding, it is important to emphasize that start-ups, young enterprises and micro-enterprises, which struggle the most with financing worries, were not represented in the analysed database.

"Rentier States" or the Relationship between Regime Stability and Exercising Power in Post-Soviet Central Asia

The paper intends to give an insight into the relations of the economic and political systems of the Central Asian republics using the theoretical framework of the "rentier economy" and "rentier state" approach. The main findings of the paper are that two (Kazakhstan and Turkmenistan) of the five states examined are commodity export dependent “full-scale” rentier states. The two political systems are of a stable neo-patrimonial regime character, while the Kyrgyz Republic and Tajikistan, poor in natural resources but dependent on external rents, may be described as "semi-rentier" states or "rentier economies". They are politically more instable, but have an altogether authoritarian, oligarchical “clan-based” character. Uzbekistan with its closed economy, showing tendencies of economic autarchy, is also a potentially politically unstable clan-based regime. Thus, in the Central Asian context, the rentier state or rentier economy character affects the political stability of the actual regimes rather than having a direct impact on whether power is exercised in an autocratic or democratic way.