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We study [Roll, R., A mean/variance analysis of tracking error. J. Portfolio Manage., 1992, 18, 13–22.] conjecture that there exists an implicit value in index-tracking (IVIT) relative to forming m...

RationaleAsthma is a chronic airway disease driven by multiple immunologic pathways that determine the clinical response to therapy. Current diagnostic methods are incapable of discriminating subtypes of asthma and guiding targeted treatment. We hypothesized that sputum cytokine profiles could help to identify immunologically-defined disease subtypes and individualize therapy in patients with severe asthma.ObjectivesDefine asthma subtypes associated with sputum alarmin and cytokine levels.MethodsCross-sectional analysis of clinical features and sputum from 200 asthmatic patients was performed. 10 cytokines belonging to alarmin, T2, and non-T2 pathways were measured. Pearson correlation was used to identify cytokine modules. Latent class analysis was used to cluster patients by cytokine expression.Measurements and Main ResultsThree modules of highly correlated cytokines were identified including a non-T2 module, the IL-1βmod (IL-1β, IL-6, GCSF), and two distinct T2 modules: TSLPmod (TSLP, IL-4, IL-5, IL-9) and IL-33mod (IL-33, IL-13, IL-21). The TSLPmod was associated with asthma severity, airway obstruction, eosinophilia, and elevated FeNO. Patient clustering revealed three subgroups; two different subgroups showed expression of T2 modules.ConclusionsAnalysis of sputum cytokines revealed three discrete signaling modules in patients with asthma. Unexpectedly, the inclusion of alarmins led to separation of canonical T2 cytokines into two unique modules; IL-5 grouped with TSLP, while IL-13 grouped with IL-33. In addition, patient clustering revealed two distinct endotypes associated with T2 immune signaling. These findings indicate a new layer of immunologic heterogeneity within the T2 paradigm, and suggest that sputum cytokine profiling may hold diagnostic utility for patients with asthma.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. Acurrent challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

We propose a simple approach to bridge between portfolio theory and machine learning. The outcome is an out-of-sample machine learning efficient frontier based on two assets, high risk and low risk. By rotating between the two assets, we show that the proposed frontier dominates the mean–variance efficient frontier out-of-sample. Our results, therefore, shed important light on the appeal of machine learning into portfolio selection under estimation risk.

Background Chronic infections with Pseudomonas aeruginosa are a leading cause of morbidity in patients with cystic fibrosis (CF). Tobramycin nebulizer solution (TNS) is indicated for maintenance therapy in CF patients. TOBI® is a tobramycin nebulizer solution (TNS) approved by FDA for maintenance therapy for patient with CF. Adherence to recommended therapy in CF has always been a challenge and new generation nebulizers are increasingly used “off label” to reduce the time required for inhalation, potentially improving patient compliance. Objectives To assess the performance of selected recent nebulizer delivery systems for determination the optimum combinations to deliver TOBI®. Using the relative lung bioavailability of TOBI® to the lungs in healthy volunteers, following inhalation from selected nebulizer delivery systems, using a urinary pharmacokinetics method. In vitro aerodynamic characteristics of the nebulized dose were also determined. Methods Serial urine samples were collected from 12 healthy volunteers up to 24 h post-inhalation of TOBI® inhaled solution following delivery by Pari LC Plus®, Sidestream®, NE-U22-E Omron® and Aeroneb® Go nebulizers. In vitro aerodynamic characteristics of the nebulized dose were also determined according to the CEN (Committee European de Normalization) method. Results The mean (SD) relative lung bioavailability from Pari LC Plus®, Sidestream®, Omron®, and Aeroneb® Go nebulizers was 4.9 (0.5), 3.9 (0.5), 7.1 (1.3), and 7.7 (0.7) %, respectively. The mean (SD) mass median aerodynamic diameter (MMAD) of the drug particles from the same systems was 2 (0.2), 2 (0.2), 1.2 (0.03) and 2.0 (0.1) μm, and the corresponding fine particle doses (FPD) were 2.2 (0.23), 1.5 (0.2), 3.44 (0.3) and 2.8 (0.3) mg. Conclusion The data obtained from in-vitro and in-vivo studies reflect poor relative lung bioavailability of tobramycin following jet nebulization.

Using account-level credit card data from six major commercial banks from January 2009 to December 2013, we apply machine-learning techniques to combined consumer tradeline, credit bureau, and macroeconomic variables to predict delinquency. In addition to providing accurate measures of loss probabilities and credit risk, our models can also be used to analyze and compare risk management practices and the drivers of delinquency across banks. We find substantial heterogeneity in risk factors, sensitivities, and predictability of delinquency across banks, implying that no single model applies to all six institutions. We measure the efficacy of a bank's risk management process by the percentage of delinquent accounts that a bank manages effectively, and find that efficacy also varies widely across institutions. These results suggest the need for a more customized approached to the supervision and regulation of financial institutions, in which capital ratios, loss reserves, and other parameters are specified individually for each institution according to its credit risk model exposures and forecasts.

Lung function declines with age. Decreased elastic recoil of the lungs, impaired mucociliary clearance, and skeletal muscle weakness all contribute to decreased lung function and compromised airway function and clearance. As a result of these changes, cough and dyspnea become increasingly common in older adults. Between these changes to the airway and scarring processes in the lung from conditions like pneumonia, chronic lung diseases increase with age. Importantly, multimorbidity from cardiac, gastrointestinal, and nasopharyngeal causes is more prevalent with age and complicates elucidating the exact cause of respiratory symptoms. While many of the changes are inevitable with time, healthy pulmonary aging depends on physical activity, proper diet and weight management, avoidance of smoking and environmental exposures, and guideline-based lung cancer screening. This chapter will discuss the pathophysiology of lung diseases in older adults while also considering strategies for optimizing lung health with age.

The equity of too-big-to-fail banks could be deemed less risky due to implicit government guarantees. However, such guarantees could also amplify a moral hazard problem that induces large banks to take excessive risk. If such risk is mispriced by the market due to the increased complexity of large banks, then cross-sectional differences in realized stock returns should reflect corrections in market expectations rather than differences in the cost of capital. Proposing a novel diversification index to account for complexity, we find robust evidence consistent with mispricing among the most diversified large banks and attribute it to greater channels of uncertainty and interconnectedness.

We study Roll’s (1992) conjecture that there may exist an implicit value in index-tracking (IVIT) relative to forming mean-variance (MV) optimal portfolios under estimation error. While index-tracking portfolios are deemed MV inefficient ex-ante, it is unclear whether this is the case when taking into account estimation error in the parameters of the portfolio selection problem. To investigate this, we derive an analytical definition for the opportunity cost facing the MV investor who does not index-track, building on the expected out-of-sample utility framework of Kan & Zhou (2007). Our findings, both analytical and empirical, indicate that such opportunity cost is positive and statistically significant. The existence of an IVIT (positive opportunity cost) is strongly associated with a reduction in the portfolio’s induced estimation risk under index tracking relative to an MV-efficient portfolio of equal target mean return. Under cases of high estimation error, we show that increased IVIT translates to improved metrics of portfolio performance, such as higher risk-adjusted returns, lower volatility, higher Sharpe-ratio, lower turnover, and larger certainty equivalent returns. Moreover, our paper reconciles the theoretical propositions with the out-of-sample performance empirically. The cross-sectional regression results indicate that a one standard deviation increase in the proposed IVIT translates to an annual increase of 4%-5% in the out-of-sample Sharpe-ratio and a 6%-15% decrease in the monthly portfolio turnover.

Using Roberts (2015) loan-level data from 2000 to 2011, we find that the inception of CDS trading on reference firms’ debt is associated with a decreased number and lower probability of amendments, restatements, and rollovers to existing lenders of bank loans. Reference firms are also less likely to terminate loans prematurely or refinance with different lenders after the inception of CDS trading and tend to exhibit longer loan maturities. Our evidence is consistent with the empty creditor problem arising from CDS trading and the resulting decrease in the negotiation power of borrowers. Our research contributes to understanding how financial innovations alter bank-lending relationships.

Whether or not to give research results back to individuals whose specimens are used for biomedical research is a subject of considerable controversy. Much of the debate has been focused around the ethical and legal concerns with some consideration of broader social issues such as whether or not people will be affected by such information for employment or health care. Much less attention has been paid to biobanks that collect the specimens used to generate the research findings and the issues and operational requirements for implementing return of individual research results. In this article, we give the biobanks’ perspective and highlight that given the diversity among the types of biobanks, it may be difficult to design and implement a blanket policy in this complex area. We discuss the variability in the types of biobanks and some important issues that should be considered in determining whether or not research results should be provided to individuals whose specimens are used in biomedical research. We also discuss challenges that should be considered in implementing any approaches to the return of research results.

The main goal of this work was to quantify the detection of colistin at low levels in urine samples through the practical application of mixed surfactant micellar electrokinetic chromatography–laser-induced fluorescence (MEKC-LIF) analysis method using its advantage of sensitivity and to examine direct injection of biological samples. Colistin (po- lymyxin E) has neither strong UV chromophore nor fluorophore. So, its assay for metabolism, pharmacokinetics studies for bioavailability and bioequivalence are difficult because of poor detectability. Therefore an enhanced UV or fluores-cence detection by chemical derivatization is required. MEKC-LIF method was proposed for colistin with a 488/520 nm argon-ion laser using a pre-CE derivatization with fluorescein isothiocyanate (FITC). Borate buffer was used as background buffer (BGB). The different parameters affecting the proposed derivatization reaction including concentration of the derivatizing reagent, reaction time and temperature were studied and optimized. The derivative was stable for up to 3 days. Different micelles (TX-100 and SDS) were examined as BGB additives separately but negative-charged mixed micelles (SDS/TX-100) were shown to be the best additive to BGB for the analysis of colistin particularly in human urine as they enhance both selectivity and sensitivity of the proposed method. BGB was used with pH 9.5, 10 kV, 8 s inj time, capillary length 75 cm × 75 μm ID (66 cm effective length), detection was LIF Ex 488 nm; Em 520 nm. The method was applied to colistin analysis in human urine and the recovery was > 98% (n = 5). LOD and LOQ in urine after pre-column derivatization using FITC were 100 and 250 ng/ml, respectively. Urine samples were analysed by direct injection without sample pre-treatment. The mechanism of enhancement of fluorescence of the derivative by surfactant was proposed.

Chronic infections with Pseudomonas aeruginosa are a leading cause of morbidity in patients with cystic fibrosis (CF). The aim of tobramycin inhalation therapy in CF patients with chronic pulmonary infection is to deliver high amounts of drug directly to the site of infection. TOBI(®) is a tobramycin nebulizer solution (300 mg/5 ml) approved by FDA for maintenance therapy for patient with CF. The 20% tobramycin sulfate solution was reported as the optimal and maximal concentration.Nebulization of high strength tobramycin solution (20% tobramycin sulfate) (HSTS) has been assessed in this study by using different selected high performance nebulizer delivery systems: two different designs of jet nebulizers, and three new nebulizers based on vibrating mesh technology. The aerosol particle size distribution and output characteristics were measured for in vitro performance assessment of the nebulizer systems. The methodology was adapted from the current European standard, EN 13544-1:2001E.The particle size distribution characteristic measurements showed that all tested nebulizers may be suitable for inhalation of HSTS. The mean (SD) of highest percentage of fine particles (5 μm) was 77.64 (2.3) % for Sidestream(®), at flow rate 16 L/min. The highest respirable inhaled mass was for Pari LC Plus(®) combined with PariBoyN(®) compressor, with mean (SD) 90.85 (8.6) mg. The mean (SD) of highest drug wastage percentage was 63.9 (3.9) % for Sidestream(®) jet nebulizer combined with compressed air cylinder at flow rate 16 L/min, while the lowest was 2.3 (0.26) % for NE-U22 Omron(®) (high frequency).The HSTS can be nebulized by all tested nebulisers but the high frequency NE-U22 Omron(®) and Aeroneb Go(®) are more efficient. When the HSTS compared to TOBI(®), the respirable inhaled dose was increased to more than 73%.

One of the major challenges for modern biorepositories is gaining visibility and recognition as professional infrastructures and service providers, in front of national regulatory bodies, institutional review boards (IRB), data protection authorities, research funding organizations, and the diagnostic and pharmaceutical industries. This recognition is necessary to ensure biorepository-specific law texts and IRB and data protection guidelines are drawn up, and to attract public and private funding. All the above elements and especially the last are necessary for long term biorepository sustainability. There are two ways to ensure this

Fixed-dose combinations of artesunate and amodiaquine hydrochloride provide challenges in product development due to the incompatibility of the two agents. This is particularly critical for paediatric preparations which can often be presented in liquid form. The studies reported in this article aimed to develop an understanding of the factors responsible for this incompatibility, whilst assessing the feasibility of developing a stable paediatric formulation. The stability characteristics of fast-disintegrating granular formulations containing intimate mixtures of both agents and single agent granules blended prior to production of unit doses were therefore studied under a range of storage conditions. The granular products remained stable over the 3-month period under stressed accelerated conditions, in contrast to control samples containing both drugs in combined granular form, which demonstrated reductions in artesunate content at elevated humidity. It was hypothesized that loss of active agent content for artesunate was accelerated by access to the water of crystallization of amodiaquine as demonstrated by the more facile dehydration of amodiaquine when a mixture of the two agents was analysed by differential scanning calorimetry (DSC). It was therefore concluded that a stable, versatile paediatric preparation of the two drugs could be prepared by blending pre-formulated granules containing the individual constituents rather than producing a combined granule comprising intimate mixtures of the two agents.

Objectives Currently, suspensions prepared from micronised drug substances are the only delivery system marketed for nebulisation of steroids, and reported inconsistent or low bioavailability arising from their use provides a rationale for researching alternative formulations. Supercritical fluid processing of drug substances to obtain respirable-sized particles has been used over the last decade to formulate dry powder inhalers. We aimed thus to process budesonide powder to improve its deposition characteristics. Methods In an attempt to overcome the limitations of nebuliser suspensions when prepared from micronised drug particles, budesonide powder was processed using a supercritical fluid based process and suspended using Tween 80 as a surfactant to provide an aqueous nebuliser formulation. The in-vitro characteristics of the emitted dose on nebulisation for the prepared suspension were then compared to a commercially available suspension formulation of budesonide using a jet and a vibrating mesh nebuliser. Key findings The results showed a significant improvement of the in-vitro deposition properties of the suspension containing supercritical fluid engineered budesonide particles. Conclusions The results indicated the benefit of such materials compared with traditionally micronised drug powders.

The purpose of this study was to use Artificial Neural Networks (ANNs) in identifying factors, in addition to surfactant and internal phase content, that influence the particle size of nanoemulsions. The phase diagram and rheometric characteristics of a nanoemulsion system containing polysorbate 80, ethanol, medium chain triglycerides and normal saline loaded with budesonide were investigated. The particle size of samples of various compositions prepared using different rates and amounts of applied energy was measured. Data, divided into training, test and validation sets, were modelled by ANNs. The developed model was assessed and found to be of high quality. The model was then used to explore the effect of composition and processing factors on particle size of the nanoemulsion preparation. The study demonstrates the potential of ANNs in identifying critical parameters controlling preparation for this system, with the total amount of applied energy during preparation found to be the dominant factor in controlling the final particle size.

A reversed-phase liquid chromatography method involving pre-column derivatisation with fluorescein isothiocyanate (FITC, isomer I) for determination of tobramycin in urine samples after inhalation has been developed. FITC reacts with the primary amino groups of tobramycin and other aminoglycosides under mild conditions to form a highly fluorescent and stable derivative. The chromatographic separation was carried out on a Phenomenex Luna C(18) column at ambient temperature using a constant flow rate of 1 ml/min and mobile phase of acetonitrile-methanol-glacial acetic acid-water (420:60:5:515, v/v/v/v). The tobramycin-FITC derivative was monitored by fluorescent detection at an excitation wavelength 490 nm and emission wavelength 518 nm. The linearity of response for tobramycin was demonstrated at 11 different concentrations of tobramycin extracted from spiked urine, ranging from 0.25 to 20 microg/ml. Tobramycin and neomycin were extracted from spiked urine by a solid phase extraction clean-up procedure on a carboxypropyl-bonded phase (CBA) weak cation-exchange cartridge, and the relative recovery was >99% (n=5). The limit of detection (LOD) and limit of quantitation (LOQ) in urine were 70 and 250 ng/ml, respectively. The method had an accuracy of

The difficulties with ‘retained organs’ in the UK have resulted in a new legislation relating to human organs, tissues, and bodies – the Human Tissue Act 2004 and the Human Tissue Act Scotland 2006 are now in place. The new laws apply to a wide range of activities including transplantation, education, clinical audit, the practice of autopsies, anatomical examination and others, including the use of human tissues in research. Pathobiology research that uses human tissues is now undertaken in a regulated environment in the UK. The details of these regulations are described and the consequences discussed. In the second part of the paper the patient’s views and expectations in this new setting are forwarded.

A rapid, simple and specific fluorometric procedure is described for the analysis of the anticholinergic drug, tiotropium bromide (TIO) in bulk and in capsule formulation. The method is sensitive and is based on the reaction of this drug as a quaternary ammonium compound with the fluorogenic reagent 9, 10-dimethoxyanthracene-2-sulphonate (DMOAS) as counter ion in acidic medium and the proposal of the reaction pathway was postulated. The hydrophobic ion-pair formed was extracted in dichloroethane and measured spectrofluorometrically at 450 nm after excitation at 385 nm. The fluorescence intensity-concentration plot was rectilinear over the ranges of 7-30 ng ml-1 y=mx+b, r2=0, 9991 (m =12.054; b =156.27) . The detection limit was 0.0326 ng ml-1 based upon United States Pharmacopeia (USP 2002) . The different parameters affecting the reaction pathway were studied and optimized. The proposed method was successfully applied to the analysis of tiotropium capsules. No interference was observed from pharmaceutical excepients such as lactose.

We examine the empirical relationship between leverage and the weighted-average cost of capital (WACC) for U.S. banks from 1996 to 2012. Our paper differs significantly from prior studies that examine this issue in that we explore this relationship for different asset-size classes of banks. Not taking this approach results in misestimating the effects of changes in leverage on the WACCs of banks. We estimate that doubling equity capital (halving leverage) would likely have a minor effect on the WACCs of the six largest banks, while having a greater effect on smaller banks’ WACCs.

Novel and efficient separations of pharmaceutical substances were achieved using oil-in-water microemulsion eluent and a conventional C18 packing with a flow rate of 1 mL/min−1. Attempts to decrease analysis time was limited due to the high viscosity of the microemulsion which generated relatively high back-pressures. Monolithic columns gave 3-fold lower back-pressures and allowed flow rates of 4 mL/min−1. with the same microemulsion mobile phase which permitted rapid separations to be achieved. Separation of a test-mix of paraben preservatives was achieved in both isocratic and gradient mode in less than 1 min. The monolith-microemulsion combination was applied to rapidly quantitatively analyse two formulated products with excellent linearity, accuracy and repeatability. Quantitative analysis times were under 90 seconds. Successful quantitation of both nicotine lozenges and naprosyn tablets was performed using this approach.

An optimization methodology is introduced for investigating the separation and the retention behavior of analytes on a new fluorinated reversed-phase packing. Ten basic compounds were selected as test probes to study the predictive models developed by using SPSS and MATLAB software. A two-level orthogonal array design (OAD) was used to extract significant parameters. The significant factors were optimised using a central composite design to obtain the quadratic relationship between the dependent and the independent variables. Using this strategy, response surfaces were derived as the 3D and contour plots, and mathematical models were defined for the separation. The models had a satisfactory coefficient (R2 > 0.97, n = 16). For the test compounds, the best separation condition was: MeCN/30 mM phosphate buffer pH 7.1(55.5:44.5, v/v) and 10 basic solutes were resolved in 22 min. The significant influence of the concentration of buffer shows that different mechanisms of separation for basic compounds on the fluorinated packing exist compared with a common ODS stationary phase.

Microemulsions are dispersions of nanometre-sized droplets of an immiscible liquid within another liquid. Droplet formation is facilitated by the addition of surfactants and often also cosurfactants. Microemulsions are classified as either oil-in-water (O/W) (oil droplets such as octane dispersed throughout aqueous buffer) or water-in-oil (W/O) (aqueous droplets in oil such as hexane). Both microemulsion types have been used as mobile phases for separation in microemulsion HPLC (MELC). There has been a recent increase of interest in this area with new applications and developments such as gradient elution and optimisation of methods using experimental design. O/W microemulsions have been employed as eluents for RP-HPLC while W/O microemulsions have been used for normal phase chromatography. Separations can have superior speed and efficiency to conventional HPLC modes while offering a unique selectivity with excellent resolution. The capability for quantitative and stability-indicating analysis has also been demonstrated. Specific advantages include the ability to operate at low UV wavelengths and elimination of the need for an equilibration rinse between gradients. Operational issues associated with the use of MELC have been identified including the need to add salt to the gradient eluent, relatively high back-pressures and increased need for equipment cleaning compared to conventional RP eluent. This report details the different microemulsion types and compositions used and their reported applications. The use of gradient and isocratic elution is described. The effects on separations of varying operating parameters such as temperature, oil type and concentration, surfactant type and concentration, sample solvent, column type, and organic solvent addition will be discussed and illustrated.

Phototransduction in Drosophila is a phosphoinositide-mediated signalling pathway. Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a central role in this process, and its levels are tightly regulated. A photoreceptor-specific form of the enzyme CDP-diacylglycerol synthase (CDS), which catalyzes the formation of CDP-diacylglycerol from phosphatidic acid, is a key regulator of the amount of PIP2 available for signalling. cds mutants develop light-induced retinal degeneration. We report here the isolation and characterization of two murine genes encoding this enzyme, Cds1 and Cds2. The genes encode proteins that are 73% identical and 92% similar but exhibit very different expression patterns. Cds1 shows a very restricted expression pattern but is expressed in the inner segments of the photoreceptors whilst Cds2 shows a ubiquitous pattern of expression. Using fluorescent in situ hybridization we have mapped Cds1 and Cds2 to chromosomes 5E3 and 2G1 respectively. These are regions of synteny with the corresponding human gene localization (4q21 and 20p13). Transient transfection experiments with epitope tagged proteins have also demonstrated that both are associated with the endoplasmic reticulum.

This report records the Fourth meeting of the European Network of Research Tissue Bank (Brussels, 18th March 2004) which was attended by Mel Read MEP. The existing membership of this informal group represents European Human Research Tissue Bankers, biomedical researchers seeking access to human tissue and allied groups including animal welfare representatives. This Fourth meeting provided a forum to update members on individual activity in this area. A particular focus of this meeting was to consider the status of this group and future affiliations to increase the profile and activity of this Network. This meeting addressed differences in legislative and ethical requirements governing the use of human tissue in biomedical research in the different countries represented. Future activity of the ENRTB, planned at this meeting, will target harmonisation of current differences which are currently barriers to increased access to human tissue for biomedical research. Through the harmonisation of procurement, processing and distribution of human tissue specimens the ENRTB will provide a mechanism to benefit human health through increased use of human tissue in pharmacotoxicological studies and the associated replacement of animal tests.

Efficient and novel oil-in-water microemulsion HPLC (MELC) separations of a range of solutes have been performed on conventional reversed-phase HPLC columns using gradient elution. This work follows previous successful separations using isocratic oil-in-water MELC [1]. It was found that by changing certain variables, peak-peak resolution, separation selectivity, efficiency and solute retention could be manipulated. The method was compatible with very low UV detection wavelengths. A robust separation method was developed for the quantitative analysis of 2 steroids in a combination-inhaled product for asthma. The method offered similar chromatography and run time when compared with conventional HPLC modes, thus demonstrating its potential for routine use. Stability-indicating methods were developed to separate synthetic and degradative impurities from the main component peaks in 4 pharmaceutical products. The methods offered quicker analysis times and equivalent selectivity to conventional HPLC modes. In developing the separations the effect on the chromatography of varying the operating parameters was studied.

Electrophoretic mobility of salmeterol and phenylpropanolamine in capillary electrophoresis has been determined using acetate buffer containing different concentrations of water, methanol and acetonitrile. Maximum electrophoretic mobilities for salmeterol and phenylpropanolamine have been observed at water-methanol-acetonitrile (5:50:45, v/v) and (3:60:37, v/v), respectively, while minimum mobilities of both compounds occurred at methanol-acetonitrile (30:70, v/v). The generated experimental data have been used to evaluate a mathematical model to compute the electrophoretic mobility of the analytes. The proposed model reproduced the mobility data with mean percentage deviations within 1-4%.

The clinicopathologic correlation of two patients with primary intraocular lymphoma is described, both of whom had a rare and unusual presentation of hypopyon uveitis. Sampling of aqueous fluid proved the cytopathologic diagnosis of B-cell lymphoma in the first patient. In the second patient an iris biopsy confirmed a T-cell lymphoma. The samples were examined using haematoxylin and eosin, and immunohistochemical stains. These patients were diagnosed with primary intraocular lymphoma on initial presentation with hypopyon uveitis. Secondary glaucoma was noted in the patient with T-cell lymphoma. Both cases appeared confined to the eye and initially responded favourably to aggressive chemotherapy and radiotherapy, but later went on to develop systemic involvement. Clinicians should be aware of this dramatic mode of presentation, which is unusual for ocular lymphoma.

The electrophoretic mobilities of two beta-blocker drugs, i.e., labetalol and atenolol, have been determined in a mixed solvent background electrolyte system containing sodium acetate+acetic acid as buffering agent and different volume fractions of water, methanol and ethanol using capillary electrophoresis. The produced data and three other sets collected from a recent work are employed to study the accuracy and prediction capability of a mathematical model to calculate the electrophoretic mobility with respect to the volume fractions of the solvents in the mixture. The results show that the proposed model is able to correlate/predict the mobility within an acceptable error range and it is possible to use the model in industry to achieve the optimum solvent composition for the buffer where using a ternary solvent system is required. The average percentage deviations (APDs) obtained for correlated and predicted data points are 0.71-2.48 and 1.72-4.39%, respectively. The accuracy of the proposed model is compared with that of a mixture response surface method and the results show that the proposed model is superior from both correlation and prediction points of view. The possibility of calculation of the mobility of chemically related drugs in water-methanol-ethanol mixtures using the proposed model is also shown and the produced prediction APD is approximately 8%.

Applicability of a mathematical model to predict the electrophoretic mobility of structurally related analyses is shown using generated mobility data for beta-blockers in a mixed aqueousmethanolic buffer. The mobilities of atenolol, alprenolol, labetalol and metoprolol in binary mixed solvent buffers containing different concentrations of methanol have been employed to train the model. Then the mobilities of propranolol, timolol and acebutalol have been predicted using the trained model. The produced mean prediction errors employing two and one experimental data points for three beta-blockers are 1.6 and 2.8%, respectively, which is easily within experimental uncertainty.

The electrophoretic mobilities of three beta-blocker drugs, practolol, timolol and propranolol, have been measured in electrolyte systems with mixed binary and ternary water-methanol-ethanol solvents with acetic acid/sodium acetate as buffer using capillary electrophoresis. The highest mobilities for the analytes studied have been observed in pure aqueous, the lowest values in ethanolic buffers. The measured electrophoretic mobilities have been used to evaluate the accuracy of a mathematical model based on a mixture response surface method that expresses the mobility as a function of the solvent composition. Mean percentage error (MPE) has been computed considering experimental and calculated mobilities as an accuracy criterion. The obtained MPE for practolol, timolol and propranolol in the binary mixtures are between 0.9 and 2.6%, in the ternary water-methanol-ethanol solvent system the MPE was about 2.7%. The MPE values resulting from the proposed equation lie within the experimental relative standard deviation values and can be considered as an acceptable error.

Gentamicin and netilmicin (internal standard) were extracted from urine using C18 solid-phase extraction cartridges (94.3% recovery) and then derivatised with o-phthalaldehyde and 3-mercaptopropionic acid. The derivative was stable for >6 h. The mobile phase methanol-glacial acetic acid-water (800:20:180, v/v), contained 0.02 M sodium heptanesulfonic acid, pH 3.4, and was passed at 1.0 ml min(-1) through a C18 column with fluorescence detection (excitation 340 nm, emission 418 nm). The four main components of gentamicin (C1, C1a, C2, C2a) and netilmicin, the internal standard, were separated. Using the C1a gentamicin peak, linearity was demonstrated from 0.5 to 10 microg ml(-1) and the limit of detection was 75 microg l(-1). Following 80-mg oral, 40-mg intravenous and 80-mg nebulised administration, the mean (SD) gentamicin urinary excretion was zero, 38.27 (0.96) and 1.93 (0.28) mg, respectively. Despite the relatively low lung deposition following inhalation of gentamicin the assay developed can be used to quantify the low urinary concentrations. Using this assay it should be possible to carry out urinary pharmacokinetic studies to identify the relative lung deposition of gentamicin following different methods of inhalation.

The bioavailability of a novel anticancer drug has been estimated in a cannulated mouse model, in which full pharmacokinetic profiles were obtained from a single animal. After with-drawing serial blood samples from the animal, small volumes of the plasma were prepared and analysed by the direct on-line injection of plasma into a turbulent flow chromatography extraction system linked to mass spectrometric detection. The use of these techniques significantly reduced both the number of animals needed to perform the experiment and the amount of active drug synthesised for administration whilst still maintaining adequate sensitivity to provide suitable pharmacokinetic profiles.

A cosolvency model to predict the solubility of drugs at several temperatures was derived from the excess free energy model of Williams and Amidon. The solubility of oxolinic acid, an antibacterial drug, was measured in aqueous (water+ethanol) and non-aqueous (ethanol+ethyl acetate) mixtures at several temperatures (20, 30, 35, 40 degrees C). Oxolinic acid displays a solubility maximum in each solvent mixture at solubility parameter values of 32 and 22 MPa(1/2). The temperature and heat of fusion were determined from differential scanning calorimetry. The solvent mixtures do not produce any solid phase change during the solubility experiments. The experimental results and those from the literature were employed to examine the accuracy and prediction capability of the proposed model. An equation was obtained to represent the drug solubility changes with cosolvent concentration and temperature. The model was also tested using a small number of experimental solubilities at 20 and 40 degrees C showing reasonably accurate predictions. This is important in pharmaceutics because it save experiments that are often expensive and time consuming.

An equation for calculating the electrophoretic mobility of an analyte with respect to the concentration of organic modifier in mixed aqueous–organic modifier running buffer was derived from mixture response surface methodology. In order to assess the accuracy and predictability of the proposed model, the electrophoretic mobilities of four aliphatic amines and imidazole (background absorber) were measured in mixed water–methanol running buffer containing 0–100% v/v methanol by capillary zone electrophoresis with indirect UV detection. The accuracy of the proposed model was examined by fitting all the experimental data points. The predictability of the model was then evaluated by employing six training data points to compute the model constants, and the mobility at the other data points was predicted by the trained model. The proposed model gave accurate results for the correlation and prediction, with mean percentage errors for the amines studied of 0.6% to 0.5% and 1.5% to 1.1%, respectively.

In previous reports of microemulsion electrokinetic chromatography (MEEKC), analysis times were typically in the order of 10 min as high-ionic strength buffers were used. These buffers produced high currents which limit the voltages which can be applied, therefore, analysis times could not be reduced. The primary cause of the high-ionic strength is the relatively high concentrations of surfactants required to form the microemulsion. The surfactant concentration can be lower when using an oil with a smaller surface tension. This preliminary study showed that migration times in MEEKC can be reduced to below 1 min by using a combination of an optimum microemulsion composition, high voltage, high temperature, short capillaries by injecting via the "short end", or by simultaneously applying pressure and voltage. Long injection sequences and quantitation were found to be possible with minimum buffer depletion effects.

A microemulsion electrokinetic chromatography (MEEKC) method has been developed and validated for the determination of both naproxen and rizatriptan benzoate and their degradation products. This method is based on a previously reported generic procedure using widely applicable separation conditions with no additional method development. The methods were shown to be stability indicating and quantitative. Accuracy, linearity, and repeatability were good. Internal standards were employed to improve injection precision and detector linearity. An LOD of 0.2 μg mL -1 for naproxen and 1 μg mL -1 for rizatriptan benzoate was obtained. This work is the first reported validated MEEKC method for these drugs and shows that a generic methodology can be successfully implemented in routine quality control testing.

The mole fraction solubility of salmeterol xinafoate was determined in various concentrations of dioxane in aqueous binary mixture. Maximum solubility was observed in 90% v/v dioxane and solubility parameter of the solute was estimated from solubility peak equal to 24.99 MPa(0.5). The predicting capability of four different cosolvency models was also evaluated employing a five data point training set. The solubility data at other cosolvent concentrations were predicted using the trained models, with percentage average errors for 28 drug solubility data sets in water-cosolvent mixtures lying between 12.5 and 15.0%. Further predictive model is proposed for accurate solubility predictions based on a minimum number of experiments. The percentage average error where tested was 10.6%.

In a drug development program improved speed of the development phase is constantly being explored. But much effort and time is usually expended in finding suitable methods for pharmaceutical and biomedical analyses. In contrast, a mathematical model has been presented here to correlate/predict electrophoretic mobility of acidic and basic analytes in capillary electrophoresis at different concentrations of organic modifier. This model could help analysts to find the optimum concentration of organic modifier for a successful analysis. The accuracy and predictability of the proposed model have been shown using generated mobility data (five basic drugs in water-methanol mixed running buffer) and previously published data sets collected from a recent publication. Using this model the average percentage errors for correlative and predictive equations were 0.64 and 1.35%, respectively. The accuracy of the model was also examined against those of previously published models where the results are comparable. © 2001 John Wiley & Sons, Inc. J Micro Sep 13: 346–350, 2001

Microemulsion electrokinetic capillary chromatography (MEEKC) is similar to micellar electrokinetic chromatography (MEKC) in that it separates neutral solutes based on their chromatographic retention factors. In MEEKC solutes partition between the aqueous phase and oil droplets, which are moving through the solution. The background to MEEKC is described including novel approaches to method development and optimisation. In this case water-immiscible octane forms minute oil droplets that are coated with SDS and butan-1-ol. The effects were evaluated using a test-mixture containing nine components of insoluble and soluble acids, bases and neutrals. Selectivity has been adjusted by use of a large number of factors including organic solvent, co-surfactant, urea, temperature, cyclodextrins, ion-pair reagent. Previous reports on the selectivity in MEEKC have concentrated only on neutral solutes. Separation selectivity was drastically changed with addition of alcohol such as butan-1-ol, propan-2-ol, cyclodextrin or using a low pH buffer. Microemulsion preparation process or filtration of the buffer did not affect the separation. The separation was largely unaffected by the use of methanol or acetonitrile, surfactant concentration, buffer type, oil type, sample diluent or type of the counter-ion. Migration times were dramatically altered with the use of ion-pair reagent and buffer concentration. It was also demonstrated that temperature variations alter the migration time but not the selectivity.

The development of a stability-indicating capillary zone electrophoresis (CZE) method for the determination of the drug azathioprine (AZA) and its related substances in bulk and dosage forms is described. Theophylline was used as an internal standard to improve quantitative results. The method was fully validated in terms of repeatability (n = 10, RSD for migration time and peak area ratio were 0.15% and 0.60%, respectively), reproducibility (n = 5, RSD of peak area ratio was 0.84%), linearity at two ranges of the azathioprine concentration, limits of detection (LOD) and quantitation (LOQ), and robustness. The method was applied for determination of the drug in bulk and a commercial tablet dosage form (recovery 98.3-101.3%) and in powder for injection (recovery 98.7-100.6%). The method was fast and reliable for the analysis of AZA and its related substances in bulk and dosage forms.

Previously published cosolvency models are critically evaluated in terms of their ability to mathematically correlate solute solubility in binary solvent mixtures as a function of solvent composition. Computational results show that the accuracy of the models is improved by increasing the number of curve-fit parameters. However, the curve-fit parameters of several models are limited. The combined nearly ideal binary solvent/Redlich-Kister, CNIBS/R-K, was found to be the best solution model in terms of its ability to describe the experimental solubility in mixed solvents. Also resented is an extension of the mixture response surface model. The extension was found to improve the correlational ability of the original model.