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Falls can lead to hospitalisation and death in older people. Polypharmacy is a major risk factor, and deprescribing fall-risk increasing drugs (FRIDs) is one of several possible important preventive measures. The objective of this study was to explore the factors that influence doctors when deprescribing FRIDs in a hospital setting.Semi-structured interviews were conducted with consultant geriatricians and hospital doctors experienced in dealing with patients aged 65 years or older, at a large academic teaching hospital (~ 1000 beds), Dublin, Ireland. The interviews were directed by an interview guide and audio recorded and transcribed verbatim, with subsequent thematic analysis in NVivo 12 software.A total of 18 participants were interviewed. Barriers to deprescribing included: insufficient time, incomplete patient records, changing medications initiated by other specialists and difficulties following up patients after discharge. Facilitators included: enhanced documentation through electronic patient records, the support of other healthcare professionals such as clinical pharmacists, and patients' engagement, which is considered essential for the success of the deprescribing process's outcome.Deprescribing FRIDs in older adults in the hospital setting is challenging. Implementation of the process in practice requires combined effort from stakeholders to tackle everyday work environment challenges. Future studies are required examining the clinical effect of the suggested interventions and exploring patients' involvement in deprescribing decisions.

Objectives: This report describes the design and ongoing implementation of online patient-facing experiences within an undergraduate pharmacy programme, redesigned from classroom activities due to the SARS CoV-2 (COVID-19) pandemic. Methods: Two patient-facing experiences were pre-recorded for sharing with students online in the academic year 2020-21. Live webinars with the patients will accommodate questions and answers. Aligned case-based workshops have been redesigned from in-class activities to online workshops. Stufflebeam’s CIPP model of evaluation has been employed as an overall framework of evaluation. Roddy’s ‘four pillars’ for student success in online teaching were used to evaluate the online component. The perspectives of two participating patients regarding the online experience were obtained through semi-structured telephone interviews using suggested discussion themes. Results: Classroom-based patient-facing experiences in both cardiology and diabetes have been redesigned for an online format. Potential problems and resolutions were identified against the ‘four pillars’ to support students. Evaluation of patients' perspectives highlighted their motivations for participation and the importance patients place on pharmacists’ communication skills. Student perceptions of all components will be evaluated through anonymous online surveys upon roll-out. Conclusion: The COVID-19 pandemic has necessitated pedagogical modifications. The educational benefits of patient-facing experiences can continue through online activities, while protecting vulnerable groups.

Background Discharge and transfer between healthcare facilities put older adults at risk of medication-related problems and early readmission. This review examined the evidence for pharmacist interventions at discharge and patients’ care quality. Methods Eight databases were searched systematically from inception to date, using the appropriate search strategy for each. A search for grey literature was conducted on eight further websites. No filters (e.g. language/dates) were applied. Only prospective randomized/quasi-randomized controlled studies involving patients > 65 years of both genders, discharged alive from hospital, were included. The criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions formed the basis of the assessment, conducted using RevMan 5.3. Results 9738 articles were obtained: 8120 unique articles after duplicate removal. Following screening, 12 studies were identified for inclusion. Interventions comprised follow up, medication review and patient counselling at discharge. Of these, 10 were delivered by pharmacists alone, while the remainder were delivered by pharmacists within a multidisciplinary team. Outcome measures included readmission rates, length of stay, medication adherence and care quality. Nine studies showed significant improvements over standard care, e.g. a decrease in hospital admissions (0.68 OR, p=0.002), improved compliance (P However, three studies did not report positive results: Two reported non-significant improvement but the third reported poorer readmission rates. Risk of bias was low but the high baseline standard of care reduced the scope for improvement in two of these studies. Conclusion The review summarizes pharmacist interventions’ efficacy and their effect on care quality indicators where possible. The majority of interventions at discharge significantly enhanced patients’ care quality. The findings should prove valuable to decision-makers when planning or improving discharge and post-discharge services.

The design, implementation and evaluation of a year 1 pharmacy-integrated learning component, using the World Health Organisation’s (WHO) analgesic ladder as a scaffold for case-based learning, is described. A novel aspect of the integrated component is the mapping of the cases to the national Core Competency Framework (CCF) for Pharmacists in Ireland and to the school’s own cross-cutting curricular integration themes. The integrated cases were student led and delivered through peer-to-peer teaching for 68 first-year pharmacy students. The integrated cases mapped strongly to three of the CCF’s domains, namely, personal skills, organisation and management skills and supply of medicines. With regard to the school’s curricular integrative themes, the cases mapped strongly to the curricular integration themes of professionalism and communications; medicines sourcing, production and use; and safe and rational use of medicines. Highlights from an anonymous online student survey were the recognition by students of the importance of core science knowledge for practice, the enabling of integrated learning and the suitability of the integrated component for entry-level. While a majority of students were found to favour individual work over group work, future iterations will need to consider a greater degree of group work with a view to reducing the volume of content and time required to complete the cases.

Background Guidelines recommend that patients treated with inhalers receive adherence counseling and device training. Digital technologies that assess both inhaler adherence and technique have been developed. Using these technologies community pharmacists, who have regular contact with patients, are well placed to deliver personalized inhaler education. Objective To determine the impact of a pharmacist intervention, informed by digital technology, on inhaler technique and adherence of patients with asthma in the community. Methods A cluster randomized, parallel-group, multisite pharmacy study was conducted over 6 months. All study groups had an electronic device (inhaler compliance assessment device) attached to their maintenance inhaler. A biofeedback group received personalized inhaler training informed by data recorded by the device. The demonstration group received inhaler training, by physical demonstration with a placebo inhaler. The control group received usual care. The primary outcome was inhaler adherence, which was classified as “actual adherence” and expressed as the proportion of expected drug accumulation if adherence and technique had been perfect. Secondary outcomes were quality-of-life scores as measured by the St George's Respiratory Questionnaire, symptoms, and exacerbations. Results A total of 152 participants (n = 74 biofeedback, n = 56 demonstration, and n = 22 control) were recruited. Asthma was the predominant condition among participants (n = 83), with chronic obstructive pulmonary disease (n = 55) and asthma/chronic obstructive pulmonary disease overlap also reported (n = 8). In intention-to-treat analysis, adherence in the biofeedback group during month 2 was 62%, 18% higher (95% CI, 6 to 30) than that in the demonstration group (P = .004) and 24% higher (95% CI, 9 to 40) than that in the control group (P = .003). During month 6, adherence was 14% higher (95% CI, −1 to 30; P = .07) in the biofeedback group than in the demonstration group and 31% higher (95% CI, 13 to 48; P = .001) than in the control group. At the end of the study, the biofeedback group had a sustained fall in St George's Respiratory Questionnaire from baseline, −6.1 (95% CI, −9 to −0.4; P = .04) and had significantly improved daily respiratory symptoms. Conclusions Community pharmacist–delivered inhaler training informed by a digital technology improved adherence and health status.

To develop a pharmacokinetic model describing total and unbound teicoplanin concentrations in patients with haematological malignancy and to perform Monte Carlo simulations to evaluate target attainment of unbound trough concentrations with various dose regimens. This was a hospital-based clinical trial (EudraCT 2013-004535-72). The dosing regimen was 600/800 mg q12h for three doses then 600/800 mg daily. Serial total and unbound teicoplanin concentrations were collected. Maximum protein binding was estimated from serum albumin concentration. Population pharmacokinetic analyses and Monte Carlo simulations were conducted using Pmetrics®. Target total and unbound trough concentrations were ≥20 and ≥1.5 mg/L, respectively. Thirty adult patients were recruited with a mean (SD) bodyweight of 69.1 (15.8) kg, a mean (SD) CLCR of 72 (41) mL/min and a median (IQR) serum albumin concentration of 29 (4) g/L. A three-compartment complex binding pharmacokinetic model best described the concentration-time data. Total and unbound teicoplanin concentrations were related by serum albumin concentration and a dissociation constant. CLCR and bodyweight were supported as covariates for CL and volume of the central compartment, respectively. Dosing simulations showed that high CLCR was associated with reduced probability of achieving target total and unbound trough concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound trough concentrations. A method to estimate the unbound teicoplanin concentration from the measured total concentration at different serum albumin concentration was demonstrated. Standard teicoplanin dosing regimens should be used with caution in patients with haematological malignancy. Bodyweight, CLCR and serum albumin concentration are important considerations for appropriate dosing.

Objective To investigate current practices with teicoplanin in patients with haematological malignancy in centres throughout the UK and Ireland with respect to indication for usage and timing of introduction in febrile neutropenia, dosage regimens and therapeutic drug monitoring practices. Methods An online survey was distributed to 598 haematology and oncology pharmacists representing 168 institutions throughout the UK and Ireland. Survey questions were aimed at identifying typical hospital practices for teicoplanin use specifically in patients with haematological malignancy in terms of empiric use strategies, dosage regimens and therapeutic drug monitoring. Participants were asked to base their answers on actual practice or policy in their hospitals and not on personal opinions. Results A total of 51 pharmacists participated in the survey. Responses indicated that teicoplanin is widely used in adult patients with haematological malignancy in the UK and Ireland, but evidence–practice gaps for empiric use strategies in febrile neutropenia were noted. For dose selection, the manufacturer9s Summary of Product Characteristics was heavily relied upon in UK and Irish institutions, rather than therapeutic drug monitoring, as an indicator of therapeutic dosing. Conclusions Despite emerging evidence to support targeted prescribing, aggressive dosing and routine therapeutic drug monitoring, findings suggest that many centres do not use teicoplanin in this way. The findings suggest inappropriate use of teicoplanin in these patients. Improving the translation of available evidence into regular practice may improve patient outcomes and reduce unnecessary teicoplanin usage. Pharmacists could aid this process through education and increased involvement in drug therapy decisions.

This paper describes the design and implementation of elements of an integrated competency-focused pharmacy programme in the School of Pharmacy and Pharmaceutical Sciences (SoPPS), Trinity College Dublin (TCD), Ireland. Following a national review of pharmacy education and training in Ireland in 2010, and subsequent publication of legislation in 2014, the School has implemented a five-year integrated programme of pharmacy education and training, leading to the award of a Master’s degree in Pharmacy (M. Pharm.). Curricular integration has been achieved by underpinning the new programme with a national competency framework for pharmacists and through the utilisation of curricular integration themes. Programme integration also encompasses embedded experiential learning placements in Years 2, 4 and 5 of the five-year programme. The new five-year integrated pharmacy programme, which commenced in 2015, replaced the 4 + 1 model of education and training where a four-year Bachelor’s degree was followed by a one-year internship, which was a distinct and separate element of the students’ training.

Objectives To describe the population pharmacokinetics of teicoplanin in adult patients with haematological malignancies receiving higher than standard doses, and to perform Monte Carlo simulations to determine dosing regimens associated with optimal teicoplanin concentrations. Methods This was a hospital-based clinical trial (EudraCT 2013–004535–72). Nine blood samples were collected on Day 3, plus single trough samples on Days 7 and 10, and 24 and 48 hours after the last dose. Teicoplanin minimum inhibitory concentrations were determined for Gram-positive isolates from study patients. Population pharmacokinetic analyses and Monte Carlo dosing simulations were undertaken using Pmetrics. Results Thirty adult haematological malignancy patients were recruited with a mean (SD) loading dose, age, total body weight, and creatinine clearance of 9.5 (1.9) mg/kg, 63 (12) years, 69.1 (15.8) kg, and 72 (41) mL/min, respectively. A three-compartment linear pharmacokinetic model best described the teicoplanin concentration data. Covariates supported for inclusion in the final model were creatinine clearance for clearance and total body weight for volume of the central compartment. The median (IQR) area under the concentration-time curve from 48 to 72 hours (AUC 48–72h ) was 679 (319) mg.h/L. There was a strong correlation between the AUC 48–72h and trough concentration at 72 hours (Pearson correlation coefficient 0.957, p Conclusions To increase the number of patients achieving optimal teicoplanin concentrations an individualized dosing approach, based on body weight and creatinine clearance, is recommended.

The objective of this study was to explore the following aspects of teicoplanin use in patients with hematological malignancy: early attainment of target trough concentrations with current high-dose teicoplanin regimens, variability in unbound teicoplanin fractions, factors associated with observed total and unbound trough concentrations, efficacy and toxicity, and renal function estimation. This was a single-center, prospective study. Samples for determination of trough concentrations were taken on days 3, 4, 7, and 10. Total and unbound teicoplanin concentrations were determined using validated high-performance liquid chromatography methods. Regression analyses were used to identify the factors associated with the trough concentration. Thirty teicoplanin-treated adults with hematological malignancy were recruited. Despite the use of dosages higher than the conventional dosages, the proportions of patients with a trough concentration of ≥20 mg/liter at 48 h and at 72 h were 16.7% and 37.9%, respectively. Renal function was significantly negatively associated with total trough concentrations at 48 h and 72 h ( P < 0.05). For an average hematological malignancy patient (creatinine clearance = 70 ml/min), sequential loading doses of at least 12 mg/kg of body weight may be needed to achieve early adequate exposure. In the absence of measured creatinine clearance, estimates obtained using the Cockcroft-Gault (total body weight) equation could prove to be an acceptable surrogate. The unbound fractions of teicoplanin were highly variable (3.4 to 18.8%). Higher unbound fractions were observed in patients with low serum albumin concentrations. Teicoplanin was well tolerated. Teicoplanin loading doses higher than those in current use appear to be necessary. Increased dosing is needed in patients with increased renal function. The high variability in protein binding supports the contention for therapeutic drug monitoring of unbound teicoplanin concentrations. (This study has been registered with EudraCT under registration no. 2013-004535-72.)

Background Poor adherence to inhaled medication may lead to inadequate symptom control in patients with respiratory disease. In practice it can be difficult to identify poor adherence. We designed an acoustic recording device, the INCA® (INhaler Compliance Assessment) device, which, when attached to an inhaler, identifies and records the time and technique of inhaler use, thereby providing objective longitudinal data on an individual’s adherence to inhaled medication. This study will test the hypothesis that providing objective, personalised, visual feedback on adherence to patients in combination with a tailored educational intervention in a community pharmacy setting, improves adherence more effectively than education alone. Methods/design The study is a prospective, cluster randomised, parallel-group, multi-site study conducted over 6 months. The study is designed to compare current best practice in care (i.e. routine inhaler technique training) with the use of the INCA® device for respiratory patients in a community pharmacy setting. Pharmacies are the unit of randomisation and on enrolment to the study they will be allocated by the lead researcher to one of the three study groups (intervention, comparator or control groups) using a computer-generated list of random numbers. Given the nature of the intervention neither pharmacists nor participants can be blinded. The intervention group will receive feedback from the acoustic recording device on inhaler technique and adherence three times over a 6-month period along with inhaler technique training at each of these times. The comparator group will also receive training in inhaler use three times over the 6-month study period but no feedback on their habitual performance. The control group will receive usual care (i.e. the safe supply of medicines and advice on their use). The primary outcome is the rate of participant adherence to their inhaled medication, defined as the proportion of correctly taken doses of medication at the correct time relative to the prescribed interval. Secondary outcomes include exacerbation rates and quality of life measures. Differences in the timing and technique of inhaler use as altered by the interventions will also be assessed. Data will be analysed on an intention-to-treat and a per-protocol basis. Sample size has been calculated with reference to comparisons to be made between the intervention and comparator clusters and indicates 75 participants per cluster. With an estimated 10 % loss to follow-up we will be able to show a 20 % difference between the population means of the intervention and comparator groups with a power of 0.8. The Type I error probability associated with the test of the null hypothesis is 0.05. Discussion This clinical trial will establish whether providing personalised feedback to individuals on their inhaler use improves adherence. It may also be possible to enhance the role of pharmacists in clinical care by identifying patients in whom alteration of either therapy or inhaler device is appropriate. Registration ClinicalTrials.gov NCT02203266. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1362-9) contains supplementary material, which is available to authorized users.

Currently, studies on adherence to inhaled medications report average adherence over time. This measure does not account for variations in the interval between doses, nor for errors in inhaler use.To investigate whether adherence calculated as a single area under the (concentration-time) curve (AUC) measure, incorporating the interval between doses and inhaler technique, was more reflective of patient outcomes than were current methods of assessing adherence.We attached a digital audio device (INhaler Compliance Assessment) to a dry powder inhaler. This recorded when the inhaler was used, and analysis of the audio data indicated if the inhaler had been used correctly. These aspects of inhaler use were combined to calculate adherence over time, as an AUC measure. Over a 3-month period, a cohort of patients with asthma was studied. Adherence to a twice-daily inhaler preventer therapy using this device and clinical measures were assessed.Recordings from 239 patients with severe asthma were analyzed. Average adherence that was based on the dose counter was 84.4%, whereas the ratio of expected to observed accumulated AUC, actual adherence, was 61.8% (P 0.01). Of all the adherence measures, only adherence calculated as AUC reflected changes in asthma quality of life, β-agonist reliever use, and peak expiratory flow over the 3 months (P 0.05 compared with other measures of adherence).Adherence that incorporates the interval between doses and inhaler technique, and calculated as AUC, is more reflective of changes in quality of life and lung function than are the currently used measures of adherence. Clinical trial registered with www.clinicaltrials.gov (NCT 01529697).

Background Very limited data have been published about the design of medication safety programmes in hospitals. Objective To describe a template for the structure and operation of a medication safety programme in an acute tertiary setting. Methods/results A model of an ideal medication safety programme was developed by combining the lessons learnt by the lead author in the role of medication safety officer in an acute teaching hospital for 7 years with the published accounts of best practice from the literature. Conclusions Given the limited guidance currently available regarding the structure and operation of such programmes, this template goes some way towards addressing a gap in the current patient safety literature. It should be of practical value to healthcare organisations considering either introducing a medication safety programme for the first time or expanding an existing system.

Medication error reporting systems in hospitals are faced with the challenge of processing vast numbers of reports which identify a myriad of safety issues. With such large volumes of data and limited resources it makes sense to adopt a prioritisation approach. Several published studies have focused solely on the subset of errors which cause patient harm. The majority of such research has concerned the individual analysis of criteria associated with medication errors. However, the research described here used an alternative approach which involved linking the three criteria of medication class, patient outcome, and type of error, in order to describe the medication-related scenarios presenting greatest risk to the organisation. To identify the highest-priority medication-related risks in an acute teaching hospital. To profile harmful medication errors submitted to a voluntary reporting system in a tertiary healthcare setting in Ireland. A database of medication errors, reported via an internal voluntary reporting system over a 5-year period, was analysed. The criteria of medication class, patient outcome and type of error were analysed separately and then cross-tabulated. The medication classes, error types and adverse patient outcomes most frequently associated with harm were identified. The cross-tabulation highlighted ten priority risk areas which accounted for the majority of patient harm. A cross-tabulation strategy for prioritising medication-associated risks was successfully applied to a hospital database comprising medication errors. The profile developed for harmful medication errors in this acute tertiary healthcare setting was broadly in line with that published for error reporting systems internationally.

To assess the safety culture in an acute medical admissions unit (AMAU) of a teaching hospital in order to benchmark results against international data and guide a unit-based, integrated, risk management strategy.The safety attitudes questionnaire (SAQ), a validated instrument for the measurement of safety culture was applied to an AMAU. All AMAU healthcare staff (n = 92) were surveyed: doctors, nurses, healthcare assistants (HCAs) and allied healthcare professionals (AHPs). Safety attitude scores for the overall unit and individual caregiver types were assessed across six domains of safety culture.When compared against an international benchmark, the AMAU scored significantly higher for four of the six safety domains: p0.01 for 'teamwork climate', 'safety climate' and 'stress recognition' and p0.05 for 'job satisfaction'. The difference between nurse manager scores and the overall mean for the study group was statistically significant for the domains of 'teamwork climate' (p0.05) and 'safety climate' (p0.01). HCAs scored significantly lower relative to staff overall with regard to 'working conditions' (p0.05) and 'perceptions of management' (p0.01).The SAQ was successfully applied to an AMAU setting giving a valuable insight into staff issues of concern across the safety spectrum: employee and environmental safety, clinical risk management and medication safety.

In this study, we report the SAR and characterization of two groups of isosorbide-based cholinesterase inhibitors. The first was based directly on the clinically used nitrate isosorbide mononitrate (ISMN) retention of the 5-nitrate group and introduction of a series of 2-carbamate functionalities. The compounds proved to be potent and selective inhibitors of human plasma butyrylcholinesterase ( huBuChE). In the second group, the nitrate ester was removed and replaced with a variety of alkyl and aryl esters. These generally exhibited nanomolar potency with high selectivity for BuChE over acetylcholinesterase (AChE). The most potent and selective compound was isosorbide-2-benzyl carbamate-5-benzoate with an IC 50 of 4.3 nM for BuChE and50000 fold selectivity over human erythrocyte AChE. Inhibition with these compounds is time-dependent, competitive, and slowly reversible, indicating active site carbamylation.

Isosorbide-2-benzylcarbamate-5-benzoate, a novel butyrylcholinesterase inhibitor, shows interspecies variation in its inhibitory activity (IC(50) of 4.3 nM for human plasma butyrylcholinesterase, but 1.09 microM for mouse plasma butyrylcholinesterase). Stability studies revealed that this drug is resistant to hydrolysis by human plasma (no degradation in 1 h). However, it was found to undergo rapid degradation when incubated with mouse plasma or mouse liver homogenate, yielding benzyl carbamate and benzoic acid. The addition of the carboxylesterase inhibitor bis-(4-nitrophenyl) phosphate (BNPP) inhibited the degradation of the novel drug, indicating that it may be a substrate for both butyrylcholinesterase and carboxylesterase. The absence of carboxylesterase from human plasma explains the drug's stability in this medium. In vivo, pharmacodynamic studies on single doses of 1 mg/kg to naive male C57BL/6 mice revealed maximal plasma butyrylcholinesterase inhibition 20 min after intraperitoneal administration (approximately 60% inhibition) and 1 h after administration by gavage (approximately 45% inhibition). While this plasma butyrylcholinesterase inhibition was short-lived, the drug also penetrated the blood-brain barrier resulting in a slight (10-15%) but persistent (> or =72 h) reduction in brain butyrylcholinesterase activity.

In 2010, our hospital introduced a higher target teicoplanin trough concentration of ≥20 mg/L by Day 3 for haematological malignancy patients. This study aimed to explore whether target trough concentrations were achieved, to identify factors associated with trough concentrations attained, and to assess clinical efficacy with teicoplanin treatments and nephrotoxicity. This was a retrospective, single-centre, cohort study of 172 teicoplanin treatments in 104 adults with haematological malignancy. Mixed-effects regression was used to evaluate factors affecting trough concentrations, and logistic regression was used to assess the relationship between trough concentrations and treatment outcomes. Nephrotoxicity was assessed using the RIFLE criteria. Considerable variability in trough concentrations was observed, with trough concentrations ≥20 mg/L rarely achieved early in therapy. A mixed-effects regression model explaining 52% of the variation in trough concentrations was developed. Dose and day of therapy were positively associated with trough concentration, whilst estimated renal function and, interestingly, acute myeloid leukaemia diagnosis were negatively associated (P

Objectives: To determine the extent of pharmacists' participation in methadone services, type of services provided, views on current service provision and suggestions for future service developments.Methods and setting: An anonymous postal questionnaire was distributed to all community pharmacies in the greater Dublin area (n=291) and in Glasgow (n=200), excluding 12 pharmacies in each city that had participated in the pilot study.Key findings: The response rates were 50% (146/291) and 56% (112/200) for Dublin and Glasgow respectively. Participation in methadone services was considerably higher in Glasgow (80%, 90/112, of respondents) than in Dublin (38%, 55/146) and the number of patients per pharmacy was higher. A majority of pharmacists participating in methadone services (76% in Dublin, 92% in Glasgow) felt they had a professional responsibility to provide such services. In both cities the most common grounds for lack of service provision were business reasons, including risk to staff or property and ...

The objective of this study was to compare two aspirin prodrugs, isosorbide diaspirinate (ISDA) and a nitroaspirin (ISMNA), with aspirin in terms of effects on dog platelet function after administration of a single oral dose. Groups of six dogs were administered ISDA (2 mg kg−1), ISMNA (4 mg kg−1) or aspirin (2 mg kg−1). Blood was sampled at 1, 2, 4, 8, 12 and 24 h post-dosing and evaluated for capacity to generate post-clotting thromboxane (TX)B2. The aggregation response to arachidonic acid (AA) (100 μM), ADP (30 μM) or collagen (10 μg mL−1) was estimated at each time-point using the whole blood impedance method. Plasma ISMN following oral administration of ISMNA was also measured and compared with plasma ISMN following administration of a physical mixture of ISMN and aspirin. ISDA administration (2 mg kg−1) was associated with a significant reduction (P< 0.05) in serum TXB2 at 12 and 24 h (>90%) post-dosing and persistent inhibition of AA-induced platelet aggregation. ISDA administration caused a more marked depression of post-clotting TXB2 levels than aspirin in this study, although its ability to inhibit platelet aggregation was less consistent than that of aspirin. The nitroaspirin ISMNA was least effective at inhibiting platelet aggregation response or TXB2 production. The ISMN AUC0–24h for the ISMNA-treated dogs was 77% of that for the physical mix-treated dogs and the tmax was delayed. This study indicates that the two aspirin esters cause aspirin-like effects on platelet function, probably through aspirin release, when administered orally to dogs.

Objective To investigate the views and experiences of community pharmacists in Ireland regarding their role in benzodiazepine supply and the potential for role expansion. Methods A postal questionnaire was issued to a random, geographically stratified sample of community pharmacies in Ireland. Key findings The response rate was 37.6%. Pharmacists’ awareness of the national source of benzodiazepine guidelines was low (26.6% previously aware). Benzodiazepine prescriptions were frequently encountered in practice and commonly for extended durations of 28 days. Pharmacists’ involvement in roles extending beyond dispensing was limited. In the 6 months prior to the questionnaire, fewer than half of pharmacists reported having suggested discontinuation to a patient (43.7%) or having contacted a prescriber about a patient’s benzodiazepine use (47.1%). Pharmacists acknowledged their potential to undertake a more extensive role in benzodiazepine supply and expressed willingness to do so in practice. Conclusions This study adds to the limited body of existing literature regarding community pharmacists’ role in benzodiazepine supply. The findings indicate the need to revisit existing benzodiazepine guidelines to improve pharmacists’ awareness of them and to address long-term prescribing. The apparent lack of active pharmacist involvement in roles and activities extending beyond dispensing needs to be addressed. Given that most pharmacists encountered benzodiazepine prescriptions at least once daily in practice, they are well positioned to promote safe and appropriate benzodiazepine use. Sizeable proportions of pharmacists expressed willingness to expand upon their existing role and facilitate long-term patients in attempting discontinuation. Further research is needed to explore barriers and facilitators to pharmacists undertaking extended roles in benzodiazepine supply in greater detail.

Tumour vasculature targeting has been a very active area of cancer drug discovery over the last decade. Growth of solid tumours beyond a certain point requires a sufficient blood supply in order for them to develop and metastasise. While novel anti-angiogenic and vascular disrupting agents represent an important contribution to the armoury of anti-cancer agents they nevertheless usually require combination with standard cytotoxic therapy in order to demonstrate positive clinical outcomes. In line with this consensus, a new concept has arisen, namely the design of functional hybrids where at least one component of the design targets a tumour angiogenic/vasculature pathway. This review will outline examples of such hybrid/conjugate-based approaches. Emphasis will be placed on their preclinical evaluation with particular focus on the RGD/NGR-conjugates, heparin-related hybrids and antibody-drug conjugates. In conclusion, the benefits and shortcomings of hybrids under development will be discussed in the context of future directions and applications.

Background Cross-sectional observational studies suggest that between 50% and 60% of patients misuse a dry powder inhaler, whereas studies with electronic monitors indicate that patients sometimes overuse/underuse their inhalers. It is not known what impact errors and erratic use have on inhaler adherence. Objectives The purpose of this study was to longitudinally quantify when and how patients adhered to a twice-daily preventer treatment by using a novel acoustic recording device attached to an inhaler (INhaler Compliance Assessment). Methods Patients with a history of asthma or chronic obstructive pulmonary disease (n = 123) from primary care and community pharmacies were given an INhaler Compliance Assessment-adapted inhaler for 1 month. Analysis of the audio files provided quantitative information on time and technique of inhaler use. Results Data were available for 103 patients. Twenty-one patients (20%) used their inhaler in the correct manner at the correct interval. There were 5045 audio files with attempted inhalations, of which 1204 had technique errors (24%). Errors included inadequate flow (27%), drug priming without inhalation (19%), exhalation into the inhaler (18%), and multiple inhalations (25%). On average, participants made errors 20% of the time. Of 60 doses expected to be taken in a month per person, on average 49 doses (82%) were attempted and when errors were accounted for, the average number of actual doses taken was 34 doses (57%; P Discussion These data highlight that ineffective and irregular inhaler use is common and when combined in a single calculation indicate that only 20% of participants used their inhaler correctly and on time.

Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design, we have produced isosorbide-2-benzyl carbamate-5-salicylate, an inhibitor of high potency (150 pM) and selectivity for human BuChE over AChE (666000) and CES2 (23000). Modeling and mutant studies indicate that it achieves its exceptional potency because of an interaction with the polar D70/Y332 cluster in the PAS of BuChE in addition to pseudosubstrate interactions with the active site.

Isosorbide-2-carbamate-5-esters are highly potent and selective butyrylcholinesterase inhibitors with potential utility in the treatment of Alzheimer’s Disease (AD). They are stable in human plasma but in mouse plasma they undergo hydrolysis at the 5-ester group potentially attenuating in vivo potency. In this paper we explore the role of the 5-position in modulating potency. The focus of the study was to increase metabolic stability while preserving potency and selectivity. Dicarbamates and 5-keto derivatives were markedly less potent than the ester class. The 2-benzylcarbamate-5-benzyl ether was found to be potent (IC50 52 nM) and stable in the presence of mouse plasma and liver homogenate. The compound produces sustained moderate inhibition of mouse butyrylcholinesterase at 1 mg/kg, IP.

We report herein that a variety of isosorbide di-esters, previously reported to be novel substrates for butyrylcholinesterase (BuChE, EC 3.1.1.8), are in fact inhibitors of the homologous enzyme acetylcholinesterase (AChE), with IC 50 values in the micromolar range. In vitro studies show that they are mixed inhibitors of the enzyme, and thus the ternary enzyme-inhibitor–substrate complex can form in acetylcholinesterase. This is rationalised by molecular modelling which shows that the compounds bind in the mid-gorge area. In this position, simultaneous substrate binding might be possible, but the hydrolysis of this substrate is prevented. The di-esters dock within the butyrylcholinesterase gorge in a very different manner, with the ester sidechain at the 5-position occupying the acyl pocket at residues Leu286 and Val288, and the 2-ester binding to Trp82. The carbonyl group of the 2-ester is susceptible to nucleophilic attack by Ser198 of the catalytic triad. The larger residues of the acyl pocket in acetylcholinesterase prevent binding in this manner. The results complement each other and explain the differing behaviours of the esters in the cholinesterase enzymes. These findings may prove very significant for future work.

The potential polyamine antagonist action of N1-dansyl-spermine (a potent NMDA antagonist) was assessed in two in vivo mouse models of polyamine action. Co-administration of N1-dansyl-spermine (2-10 microg, i.c.v.) with spermine (100 microg, i.c.v.) resulted in a dose-dependent antagonism of the spermine-induced CNS excitation (body tremor and fatal tonic convulsions). In addition, the same dose of N1-dansyl-spermine antagonised spermine's enhancement of NMDA-induced convulsions. These results suggest that N1-dansyl-spermine is in vivo a potent antagonist of the CNS effects of spermine and of its action at the positive polyamine modulatory site on the NMDA receptor.