The use of Bayesian methodology in the development and validation of a tiered assessment approach towards prediction of rat acute oral toxicity.

There exists consensus that the traditional means by which safety of chemicals is assessed-namely through reliance upon apical outcomes obtained following in vivo testing-is increasingly unfit for purpose. Whilst efforts in development of suitable alternatives continue, few have achieved levels of robustness required for regulatory acceptance. An array of "new approach methodologies" (NAM) for determining toxic effect, spanning in vitro and in silico spheres, have by now emerged. It has been suggested, intuitively, that combining data obtained from across these sources might serve to enhance overall confidence in derived judgment. This concept may be formalised in the "tiered assessment" approach, whereby evidence gathered through a sequential NAM testing strategy is exploited so to infer the properties of a compound of interest. Our intention has been to provide an illustration of how such a scheme might be developed and applied within a practical setting-adopting for this purpose the endpoint of rat acute oral lethality. Bayesian statistical inference is drawn upon to enable quantification of degree of confidence that a substance might ultimately belong to one of five LD50-associated toxicity categories. Informing this is evidence acquired both from existing in silico and in vitro resources, alongside a purposely-constructed random forest model and structural alert set. Results indicate that the combination of in silico methodologies provides moderately conservative estimations of hazard, conducive for application in safety assessment, and for which levels of certainty are defined. Accordingly, scope for potential extension of approach to further toxicological endpoints is demonstrated.

Emergency re-admissions to hospital due to adverse drug reactions within 1 year of the index admission.

AIM: The proportion of re-admissions to hospital caused by ADRs is poorly documented in the UK. The aim of this study was to evaluate the impact of ADRs on re-admission to hospital after a period as an inpatient. METHODS: One thousand patients consecutively admitted to 12 wards were included. All subsequent admissions for this cohort within 1 year of discharge from the index admission were retrospectively reviewed. RESULTS: Of the 1000 patients included, 403 (40.3%, 95% CI 39.1, 45.4%) were re-admitted within 1 year. Complete data were available for 290 (70.2%) re-admitted patients, with an ADR contributing to admission in 60 (20.8%, 95% CI 16.4, 25.6%) patients. Presence of an ADR in the index admission did not predict for an ADR-related re-admission (10.5% vs. 7.2%, P=0.25), or re-admission overall (47.2% vs. 41.2%, P=0.15). The implicated drug was commenced in the index admission in 33/148 (22.3%) instances, with 37/148 (25%) commenced elsewhere since the index admission. Increasing age and an index admission in a medical ward were associated with a higher incidence of re-admission ADR. The most frequent causative drugs were anti-platelets and loop diuretics, with bleeding and renal impairment the most frequent ADRs. Over half (52/91, 57.1%) of the ADRs were judged to be definitely or possibly avoidable. CONCLUSIONS: One fifth of patients re-admitted to hospital within 1 year of discharge from their index admission are re-admitted due to an ADR. Our data highlight drug and patient groups where interventions are needed to reduce the incidence of ADRs leading to re-admission.

Attitudes and opinions of nursing and medical staff regarding the supply and storage of medicinal products before and after the installation of a drawer-based automated stock-control system.

OBJECTIVES: This study assessed the attitudes of Emergency Department (ED) staff regarding the introduction of an automated stock-control system. The objectives were to determine attitudes to stock control and replenishment, speed of access to the system, ease of use and the potential for future uses of the system. The study was carried out in the Countess of Chester Hospital NHS Foundation Trust (COCH) ED, which is attended by over 65,000 patients each year. METHODS: All 68 ED staff were sent pre-piloted, semi-structured questionnaires and reminders, before and after automation of medicines stock control. KEY FINDINGS: Pre-implementation, 35 staff (66.1% of respondents) reported that problems occurred with access to medicine storage keys 'very frequently' or 'frequently'. Twenty-eight (52.8%) respondents 'agreed' or 'strongly agreed' that medicines were quickly accessed, which rose to 41 (77%) post-automation (P < 0.001). Improvement was reported in stock replenishment and storage of stock injections and oral medicines, but there were mixed opinions regarding storage of bulk fluids and refrigerated items. Twenty-seven (51.9%) staff reported access to the system within 1 min and 17 (32.7%) staff reported access within 1-2 min. The majority of staff found the system 'easy' or 'very easy' to use and there was a non-significant relationship between previous use of information technology and acceptance of the system. CONCLUSIONS: From a staff satisfaction perspective, automation improved medicines storage, security and stock control, and addressed the problem of searching for keys to storage areas. Concerns over familiarity with computers, queuing, speed of access and an improved audit trail do not appear to have been issues, when compared with the previous manual storage of medicines.

Trichloroethylene-induced formic aciduria in the male C57 Bl/6 mouse.

1, 1, 2-Trichloroethylene (TCE) is of environmental concern, due to evaporation while handling, chemical processing and leakage from chemical waste sites, leading to its contamination of ground water and air. For several decades there has been issues about possible long term health effects of TCE but recently the International Agency for Research on Cancer (IARC) and the US Environmental Protection Agency classified TCE as a human carcinogen. Links having been established between occupational exposures and kidney cancer and possible links to non-Hodgkin lymphoma and liver cancer, but there is more still more to learn. In male rats, TCE produces a small increase in the incidence of renal tubule tumours but not in female rats or mice of either sex. However, chronic renal injury was seen in these bioassays in both sexes of rats and mice. The mechanism of kidney injury from TCE is thought to be due to reductive metabolism forming a cysteine conjugate that is converted to a reactive metabolite via the enzyme cysteine conjugate ß-lyase. However, TCE also produces a marked and sustained formic aciduria in male rats and it has been suggested that long term exposure to formic acid could lead to renal tubule injury and regeneration. In this study we have determined if TCE produces formic aciduria in male mice following a single and repeat dosing. Male C57 Bl/6OlaHsd mice were dosed with 1000mg/kg by ip injection and urine collected overnight 24, 48, 72 and 96h after dosing. Formic acid was present in urine 24h after dosing, peaked around 48h at 8mg formic acid excreted/mouse, and remained constant over the next 24h and was not back to normal 96h after dosing. This was associated with a marked acidification of the urine. Plasma creatinine and renal pathology was normal. Plasma kinetics of formic acid showed it was readily cleared with an initial half-life of 2.42h followed by a slower rate with a half-life of 239h. Male mice were then dosed twice/week at 1000mg/kg TCE for 56days, as anticipated there was a marked and sustained formic aciduria over the duration of the study. This was associated with acidification of the urine, mild diuresis and a marked fall in urinary ammonia. Six biomarkers of renal injury KIM-1, NGAL, NAG, Cystatin-c, Albumin and IL-18 were measured in urine over time and they all showed a small increase at the later time points indicative of early markers of renal injury. However, there was no histological evidence of renal damage or renal tubule cell proliferation after 8 weeks' exposure to TCE. The concentration of formic acid in plasma at the end of the study was 1.05±0.61mM compared to control, 0.39±0.17mM. In the liver, formic acid was present at a concentration of 1mM in both control and treated mice while in the kidney it was higher at 2mM in both treated and controls. We also report that trichloroacetic acid (TCA) a metabolite of TCE also causes formic aciduria, at doses likely to arise in vivo after 1000mg/kg TCE namely 16 and 32mg/kg. Urinary formic acid peaked 24h after dosing at 4mg formic acid excreted/mouse. Thus, as in male and female rats (Yaqoob et al., 2013) male mice show a marked formic aciduria following TCE which after 8 weeks' exposure did not produce renal injury, but the small rise in renal biomarkers suggest renal damage may occur following longer exposure. Thus, TCE-induced formic aciduria may be a contributor factor in the chronic renal injury seen in male and female rats and mice.

Use of artificial neural networks in the QSAR prediction of physicochemical properties and toxicities for REACH legislation.

With the introduction of the REACH legislation in the European Union, there is a requirement for property and toxicity data on chemicals produced in or imported into the EU at levels of 1 tonne/year or more. This has meant an increase in the in silico prediction of such data. One of the chief predictive approaches is QSAR (quantitative structure-activity relationships), which is widely used in many fields. A QSAR approach that is increasingly being used is that of artificial neural networks (ANNs), and this chapter discusses its application to the range of physicochemical properties and toxicities required by REACH. ANNs generally outperform the main QSAR approach of multiple linear regression (MLR), although other approaches such as support vector machines sometimes outperform ANNs. Most ANN QSARs reported to date comply with only two of the five OECD Guidelines for the Validation of (Q)SARs.

A waste walk through clinical pharmacy: how do the 'seven wastes' of Lean techniques apply to the practice of clinical pharmacists.

AIMS AND OBJECTIVES: This study used a 'Lean' technique, the 'waste walk' to evaluate the activities of clinical pharmacists with reference to the seven wastes described in 'Lean' including 'defects', 'unnecessary motion', 'overproduction', 'transport of products or material', 'unnecessary waiting', 'unnecessary inventory' and 'inappropriate processing'. The objectives of the study were to categorise the activities of ward-based clinical pharmacists into waste and non-waste, provide detail around what constitutes waste activity and quantify the proportion of time attributed to each category. SETTING: This study was carried out in a district general hospital in the North West of England. METHOD: Staff were observed using work-sampling techniques, to categorise activity into waste and non-waste, with waste activities being allocated to each of the seven wastes described earlier and subdivided into recurrent themes. KEY FINDINGS: Twenty different pharmacists were observed for 1 h on two separate occasions. Of 1440 observations, 342 (23.8%) were categorised as waste with 'defects' and 'unnecessary motion' accounting for the largest proportions of waste activity. CONCLUSION: Observation of clinical pharmacists' activities has identified that a significant proportion of their time could be categorised as 'waste'. There are practical steps that could be implemented in order to ensure their time is used as productively as possible. Given the challenges facing the UK National Health Service, the adoption of 'Lean' techniques provides an opportunity to improve quality and productivity while reducing costs.

Effect of lubricant type and concentration on the punch tip adherence of model ibuprofen formulations.

A model formulation, comprising ibuprofen and direct compression lactose (Tablettose 80) was used to assess the influence of two lubricants, magnesium stearate and stearic acid, on punch tip adherence. Lubricant concentrations were varied from 0.25% to 2% w/w. Formulations in the presence and absence of 0.5% w/w colloidal silica (Aerosil 200) were examined, to assess the influence of the glidant on the anti-adherent effects of the lubricants. Differential scanning calorimetry (DSC) was used to examine the effect of the lubricants on the melting temperature of ibuprofen. Tablets were compacted using a single punch tablet press at 10 kN using hard chrome-plated punches or at 40 kN using uncoated steel punches, tooling was 12.5-mm diameter in each case. The upper punch faces were characterized by obtaining Taylor Hobson Talysurf surface profiles. Following compaction, ibuprofen attached to the face was quantified by spectroscopy. At low concentrations of each lubricant, the levels of sticking observed were similar. Whilst sticking increased at magnesium stearate concentrations above 1%, sticking with stearic acid remained relatively constant at all concentrations. DSC revealed that the melting temperature of ibuprofen was lowered by the formation of eutectic mixtures with both lubricants. However, the onset temperature of melting and melting point were lowered to a greater extent with magnesium stearate compared with stearic acid. When using uncoated tooling at 40 kN, the deleterious effects of magnesium stearate on the tensile strength of the tablets also contributed to sticking. When using chrome-plated punches at 10 kN, the tensile strength reduction by the presence of magnesium stearate was less pronounced, as was the level of sticking.

Effect of punch tip geometry and embossment on the punch tip adherence of a model ibuprofen formulation.

The sticking of a model ibuprofen-lactose formulation with respect to compaction force, punch tip geometry and punch tip embossment was assessed. Compaction was performed at 10, 25 or 40 kN using an instrumented single-punch tablet press. Three sets of 'normal' concave punches were used to evaluate the influence of punch curvature and diameter. The punches were 10, 11 and 12 mm in diameter, respectively. The 10-mm punch was embossed with a letter 'A' logo to assess the influence of an embossment on sticking. Flat-faced punches (12.5 mm) were used for comparison with the concave tooling. Surface profiles (Taylor Hobson Talysurf 120) of the upper punch faces were obtained to evaluate the surface quality of the tooling used. Following compaction, ibuprofen attached to the upper punch face was quantified by spectroscopy. Increasing punch curvature from flat-faced punches to concave decreased sticking. Altering punch diameter of the concave punches had no effect on sticking when expressed as microg mm(-2). The embossed letter 'A' logo increased sticking considerably owing to the probable concentration of shear stresses at the lateral faces of the embossed logo.

Effects of surface roughness and chrome plating of punch tips on the sticking tendencies of model ibuprofen formulations.

The sticking of three model ibuprofen-lactose formulations with respect to compaction force and the surface quality of the upper punch were assessed. Compaction was performed at 10, 25 or 40 kN using an instrumented single-punch tablet press. Two sets of 12.5-mm flat-faced punches were used to evaluate the influence of surface quality. A third set of chrome-plated tooling was also used. Surface profiles (Taylor Hobson Talysurf 120) of the normal tooling upper punches indicated a large difference in quality. The punches were subsequently classified as old (Ra = 0.33 microm) or new (Ra = 0.04 microm) where Ra is the mean of all positive deviations from zero. Surface profiles of sample tablets were also obtained. Following compaction, ibuprofen attached to the face was quantified by spectroscopy. Punch surface roughness, compaction force and the blend composition were all significant factors contributing to sticking. Chrome plating of punch faces increased sticking at a low compaction force but decreased sticking at higher forces. Surface roughness of the tablets did not correlate with the corresponding data for sticking, indicating that this is not a suitable method of quantifying sticking.

Comparative assessment of methods to develop QSARs for the prediction of the toxicity of phenols to Tetrahymena pyriformis.

Quantitative structure-activity relationships (QSARs) for the toxicity of 200 phenols to the ciliated protozoan Tetrahymena pyriformis, and the validation of the QSARs using a test set of a further 50 compounds, are reported. The phenols are structurally heterogeneous and represent a variety of mechanisms of toxic action including polar narcosis, weak acid respiratory uncoupling, electrophilicity, and those compounds capable of being metabolised or oxidised to quinones. For each compound, a total of 108 physico-chemical descriptors have been calculated. A variety of methods were utilised to develop QSARs and are compared. The response-surface, or two parameter, approach was found to be successful, but only following the removal of compounds known to form quinones. Stepwise regression produced a seven parameter QSAR with good statistical fit, but was less interpretable and transparent than the response-surface. Partial least squares produced a good model for phenolic toxicity following supervised selection of parameters, this, however, was the least transparent of all approaches attempted. In all approaches, a large number of outliers were observed, typically these were compounds capable of being metabolised to quinones. The strengths and weaknesses of each of the approaches to predict the toxicity of the validation (test) set of phenols to T. pyriformis are discussed.

Measuring the impact of long-term medicines use from the patient perspective.

Polypharmacy is increasing, seemingly inexorably, and inevitably the associated difficulties for individual patients of coping with multiple medicines rise with it. Using medicines is one aspect of the burden associated with living with a chronic condition. It is becoming increasingly important to measure this burden particularly that relating to multiple long-term medicines. Pharmacists and other health professionals provide a myriad of services designed to optimise medicines use, ostensibly aiming to help and support patients, but in reality many such services focus on the medicines, and seek to improve adherence rather than reducing the burden for the patient. We believe that the patient perspective and experience of medicines use is fundamental to medicines optimisation and have developed an instrument which begins to quantify these experiences. The instrument, the Living with Medicines Questionnaire, was generated using qualitative findings with patients, to reflect their perspective. Further development is ongoing, involving researchers in multiple countries.

Issues potentially affecting quality of life arising from long-term medicines use: a qualitative study.

BACKGROUND: Polypharmacy is increasing and managing large number of medicines may create a burden for patients. Many patients have negative views of medicines and their use can adversely affect quality of life. No studies have specifically explored the impact of general long-term medicines use on quality of life. OBJECTIVE: To determine the issues which patients taking long-term medicines consider affect their day-to-day lives, including quality of life. SETTING: Four primary care general practices in North West England. METHODS: Face-to-face interviews with adults living at home, prescribed four or more regular medicines for at least 1 year. Interviewees were identified from primary care medical records and purposively selected to ensure different types of medicines use. Interviews were recorded, transcribed and analysed thematically. RESULTS: Twenty-one interviews were conducted and analysed. Patients used an average of 7.8 medicines, 51 % were preventive, 40 % for symptom relief and 9 % treatment. Eight themes emerged: relationships with health professionals, practicalities, information, efficacy, side effects, attitudes, impact and control. Ability to discuss medicines with health professionals varied and many views were coloured by negative experiences, mainly with doctors. All interviewees had developed routines for using multiple medicines, some requiring considerable effort. Few felt able to exert control over medicines routines specified by health professionals. Over half sought additional information about medicines whereas others avoided this, trusting in doctors to guide their medicines use. Patients recognised their inability to assess efficacy for many medicines, notably those used for prophylaxis. All were concerned about possible side effects and some had poor experiences of discussing concerns with doctors. Medicines led to restrictions on social activities and personal life to the extent that, for some, life can revolve around medicines. CONCLUSION: There is a multiplicity and complexity of issues surrounding medicines use, which impact on day-to-day lives for patients with long-term conditions. While most patients adapt to long-term medicines use, others did so at some cost to their quality of life.

Consensus QSAR models: do the benefits outweigh the complexity?

This study has assessed the use of consensus regression, as compared to single multiple linear regression, models for the development of quantitative structure-activity relationships (QSARs). To provide a comparison, four data sets of varying size and complexity were analyzed: silastic membrane flux, toxicity of phenols to Tetrahymena pyriformis, acute toxicity to the fathead minnow and flash point. For each data set, a genetic algorithm was used to develop a model population and the performance of consensus models was compared to that of the best single model. Two consensus models were developed, one using the top 10 models, and the other using a subset of models chosen to provide maximal coverage of model space. The results highlight the ability of the genetic algorithm to develop predictive models from a large descriptor pool. However, the consensus models were shown to offer no significant improvements over single regression models, which are as statistically robust as the equivalent consensus models. Consensus models developed from a selection of the best QSARs were shown not to be superior to a selection of diverse in "model space" QSARs. For the data sets analyzed in this study, and in light of the Organization for Economic Cooperation and Development principles for the validation of QSARs, the increase in model complexity when using consensus models does not seem warranted given the minimal improvement in model statistics.

Structure-based classification of antibacterial activity.

The aim of this study was to develop a simple quantitative structure-activity relationship (QSAR) for the classification and prediction of antibacterial activity, so as to enable in silico screening. To this end a database of 661 compounds, classified according to whether they had antibacterial activity, and for which a total of 167 physicochemical and structural descriptors were calculated, was analyzed. To identify descriptors that allowed separation of the two classes (i.e. those compounds with and without antibacterial activity), analysis of variance was utilized and models were developed using linear discriminant and binary logistic regression analyses. Model predictivity was assessed and validated by the random removal of 30% of the compounds to form a test set, for which predictions were made from the model. The results of the analyses indicated that six descriptors, accounting for hydrophobicity and inter- and intramolecular hydrogen bonding, provided excellent separation of the data. Logistic regression analysis was shown to model the data slightly more accurately than discriminant analysis.