Sheila A. Ryder

Abstract: 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.

Abstract: Introduction: It is estimated by the Global Initiative for Asthma (GINA) that Ireland has the fourth highest prevalence of asthma worldwide. The objectives of this study were to compare the current state of asthma management among patients as estimated by their general practitioners (GPs) and practice nurses, to explore the frequency of patient counselling on a variety of asthma management issues, and to compare the communication frequency between these practitioners and community pharmacists. Materials & Methods: Two anonymous postal questionnaires for self-completion (one for GPs and one for practice nurses) were distributed to every general practice surgery listed in the Irish classified telephone directory in January 2011. To increase the response rate a reminder letter was posted five weeks later. Responses were coded and analysed using SPSS v.16. Results: 29% of GPs and 19% of nurses responded to the survey. Overall, a greater proportion of GPs than nurses believed that their patients had good asthma management and a good understanding of asthma and their medications (p<0.01, chi-squared test, in each case). Of 15 asthma management interventions specified, 14 differed significantly in the frequency with which they were conducted by the two groups of health professionals and 12 were carried out significantly more frequently by GPs than nurses (p<0.01, chi-squared test). However, a number of interventions considered important in the appropriate management of asthma were conducted infrequently by both groups; only 15% of respondents in each group ‘always’ advised patients on the importance of using a peak flow meter to monitor asthma control. Communication of both GPs and practice nurses with community pharmacists was infrequent and did not differ between the two groups. Discussions, Conclusion: GPs generally carried out the specified asthma management interventions significantly more frequently than nurses and this may explain the differences in opinions on asthma management between the two groups. However, as a number of important interventions are being conducted infrequently by both groups, this may potentially lead to sub-optimal asthma control.

Abstract: BACKGROUND: 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. AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Abstract: Introduction: The overwhelming majority of inpatient prescribing is undertaken by the most junior member of the team, i.e. the intern, a fact that has previously raised concerns about the quality of prescribing. Currently, no legal requirements exist in Ireland regarding a pre-determined level of seniority or expertise to be attained before doctors are allowed to prescribe high-risk medications. Consequently, high-risk medications may legally be prescribed by the most inexperienced prescribers—newly qualified doctors. Aim: To develop and implement a set of prescribing constraints in order to reduce the risk of harmful errors arising from the prescription of high-alert medications by junior doctors. Materials & Methods: A set of restrictions applicable to certain classes of medication was compiled based on published evidence of high-alert medications and those medications which were known to have caused serious harm in our hospital. Results: Four categories of constraints were proposed for high-alert medications according to the level of risk perceived to be associated with certain classes of medication or specific individual agents. The constraints for the first three categories related to the seniority of doctor required to be involved in the prescribing process. The constraints in relation to Category 4 (treatment doses of low molecular weight heparins) related to details which needed to be present on the prescription before a nurse was authorised to administer against it, i.e. dose per kg, patient weight, and total dose required. Discussions, Conclusion: The challenge in developing these constraints was in balancing the drive for optimal patient safety with the practical demands of a major teaching hospital, i.e. the flexibility needed to manage a patient load of high complexity and turnover, and the promotion of an environment which facilitates junior doctors in learning to prescribe independently. The factors identified as critical to the successful development and implementation of the initiatives were the high level of corporate and consultant support and the multidisciplinary approach adopted throughout the process.

Abstract: 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.

Abstract: Introduction: There is ample international evidence that poor quality prescription writing increases the risk of serious medication errors. Research has confirmed that didactic sessions and passive dissemination of guidelines are not effective means of modifying prescriber behaviour. Conversely, a combination of serial audit and feedback is known to be a successful technique for improving the quality of prescribing. The aim of this study was to design, implement, and evaluate a process of serial audits combined with feedback to prescribers, at both a general and individual level, to address the quality of prescription writing in an acute teaching hospital. Materials & Methods: A baseline audit of prescription writing quality was undertaken in September 2009. An awareness campaign was launched between November 2009 and January 2010 which promoted safe prescribing techniques by outlining acceptable prescribing standards and the risks of non-compliance with these. Standards for prescription writing were compiled and uploaded onto the medication safety intranet site to which staff were referred. Re-audits of the quality of prescription writing were undertaken in February and May 2010 and January 2011. Results: The process of audit and feedback resulted in an overall statistically significant improvement in allergy box completion between the baseline and the first and second re-audits, respectively. However, a rebound effect was observed between the second and third re-audits, where the trend towards improved compliance began to reverse. A statistically significant decline was observed in the percentage of prescribers non-compliant with forensic identity requirements between baseline and each subsequent re-audit. The percentage of prescriptions with omission of key medication-related data and the percentage of prescriptions deemed unclear decreased significantly between the baseline and each successive audit. A significant decrease was also observed in relation to the use of unapproved abbreviations between baseline and the first and third reaudits, respectively. Discussions, Conclusion: Audit and feedback proved to be a successful strategy in significantly improving the quality of prescription writing in our hospital in relation to a number of criteria. However, it is clear to the researchers that any improvements in the quality of prescription writing observed to date will only be sustained by an ongoing process of audit and feedback. The process of audit and feedback, although effective, was labour-intensive and requires highlevel corporate and consultant support to be successful.

Abstract: The Benzodiazepine Committee was established in 2000 to investigate benzodiazepine prescribing and use in Ireland, and to develop good practice guidelines. It has been widely documented that benzodiazepines are often inappropriately prescribed and/or misused. However, little research has been published on community pharmacists’ role in benzodiazepine supply. The main aims of this study were to assess the attitudes, experiences and knowledge of community pharmacists regarding current benzodiazepine policy and practices, and to explore their views on dosage reduction/discontinuation. Ethical approval was granted by the Faculty of Health Sciences Research Ethics Committee, Trinity College Dublin. The study comprised an anonymous, self-administered, cross-sectional, postal questionnaire, which was distributed to half the community pharmacies registered in Ireland (sample size 857). Pharmacies were selected from the Pharmaceutical Society of Ireland’s community pharmacy register using geographically stratified random sampling. A reminder was issued five weeks after distribution. All viable data were coded and entered into PASW Statistics 18.0 for analysis. The response rate was 38% (322). It was found that awareness among community pharmacists of official sources of benzodiazepine guidelines is low (33%, 103), but that the vast majority (93%, 287) agree that such guidelines are relevant to them. A large minority of pharmacists (47%, 148) agree they have a professional responsibility to facilitate compliance with relevant prescribing guidelines. Long-term benzodiazepine use, in contravention of prescribing guidelines, was reported to be widespread. In most respondents’ pharmacies benzodiazepine prescriptions were presented at least once daily (23%, 71) or several times daily (65%, 206) and only 38% (118) of respondents estimated that the most common benzodiazepine prescription duration was shorter than 28 days. When asked to estimate the proportion of their patients using benzodiazepines long-term the mean reported figure was 50.4% (std. dev. ± 31.1). Half of the respondents (n = 156) reported that none of their long-term patients had undergone dosage reduction/discontinuation in the last six months. A majority (53%, 166) stated they had not contacted a prescriber about a patient’s benzodiazepine use in the six months before the questionnaire; however a positive association was found between the proportion of patients reported to have undergone gradual dosage reduction and contact by community pharmacists with prescribers concerning patients’ benzodiazepine use (p = 0.005, χ2-test). Community pharmacists agreed (83%, 258) that they would be willing to play an active role in facilitating patient initiation in benzodiazepine discontinuation/dosage reduction programmes. The findings indicate that anticipated outcomes of the Benzodiazepine Committee’s report have not been achieved, as long-term benzodiazepine prescribing and use is still perceived as common. The Committee recommended that all dependent patients should be encouraged to withdraw, and should regularly (at least annually) be offered detoxification. Community pharmacists believe in prescribers’ professional autonomy (fewer than half feel obliged to facilitate prescribing guideline compliance as an abstract concept, perhaps believing justifiable exceptions to the guidelines may be common) but this does not detract from their willingness to facilitate dosage reduction/discontinuation where inappropriate benzodiazepine use has clearly developed. Furthermore, guideline awareness was low; greater education on the Committee’s recommendations might lead to greater appreciation of their worth and motivation to enforce them proactively. This study’s findings have led to a multifaceted intervention (currently underway) entailing the collaboration of community pharmacists and general practitioners in identifying suitable patients who are willing to attempt benzodiazepine dose reduction/discontinuation and implementing a structured reduction/withdrawal programme.

Abstract: Introduction: The primary-secondary care interface provides significant opportunities for medication errors to arise. There has been limited research into mechanisms to facilitate seamless transfer across this interface. The aim of this study was to focus on the potential contribution of community pharmacy services at the interface. Materials & Methods: The opinions of community and hospital pharmacists were sought in relation to the current situation by means of questionnaires. A log book of communications between a community pharmacy and hospitals was maintained. A comparison of new discharge and post-discharge prescriptions was also performed. The data was coded and analysed in SPSS v.16. Results: There is currently little communication across the interface at the time of discharge, with 11% of community pharmacists reporting no contact by a hospital at this time and a further 80% stating that they were only contacted occasionally. Hospital pharmacists reported ongoing difficulties in attempting to obtain a medication history on admission. Both parties agreed that the introduction of standard protocols and a designated seamless care pharmacist would improve medication safety at the interface. Most communication occurred between the community pharmacy and hospital on a Friday and also after 3 pm in the evening. When communication did occur the issue was resolved in 81% of all cases. Medication that required a follow up prescription from a patient’s family doctor following a hospital visit was incorrectly transcribed by the family doctor in 27% of cases. Discussions, Conclusion: The involvement of community pharmacists occurs irregularly at present. There is dissatisfaction with the current situation. Pharmacists at either side of the interface are aware of the importance of the role that the other plays in seamless care, with both parties favouring the introduction of processes to facilitate seamless care at the interface. The involvement of the community pharmacist in the discharge process, through the dispensing of hospital discharge prescriptions, helped to reduce the number of medication errors that could occur at the primary-secondary care interface.

Abstract: Introduction: Drug-related problems and medication errors, many preventable, are known to make a significant contribution to morbidity and mortality. The point of transfer between primary and secondary care provides significant opportunities for medication errors to arise, especially in the absence of structured transfer protocols. There has been limited national and international research into mechanisms to facilitate seamless transfer across the primary-secondary care interface. This study attempts to identify the current arrangements that are in place and the opinions of healthcare professionals of those arrangements. Materials & Methods: The opinions of community pharmacists, hospital pharmacists and general practitioners in relation to the current procedures in place for the admission and discharge of patients, with particular reference to drug therapy, were sought. This was done by means of self-administered, anonymous, postal questionnaires which were distributed nationwide. The data were coded and analysed in SPSS v. 16. Standard statistical parameters were calculated and statistically significant relationships were determined using ANOVA and the chi-squared test where appropriate, taking p<0.05 to be significant. Results: There is currently very little communication across the interface at the time of discharge, with 10.7% of community pharmacists reporting that they have never been contacted by a hospital to inform them of the imminent discharge of a patient, with a further 79.8% stating that they were only contacted occasionally. On the other side of the interface, hospital pharmacists reported ongoing difficulties in attempting to obtain a patient medication history on admission, with 75.5% of respondents stating that they regularly, often or always encountered these difficulties. Discussions, Conclusion: The majority of community and hospital pharmacists and general practitioners were dissatisfied with the management of drug therapy during the hospital discharge process. All three groups of healthcare professionals felt that the introduction of a structured seamless care programme linking hospitals, general practitioners and community pharmacists to be important or very important. It is intended that the results of this analysis will feed into a protocol for a pilot seamless care programme based in the community pharmacy.

Abstract: Introduction: The Benzodiazepine Committee was established in 2000 to investigate benzodiazepine prescribing and use in Ireland, and to develop good practice guidelines. It has been widely documented that benzodiazepines are often inappropriately prescribed and/ or misused. However, little research has been published on community pharmacists’ role in benzodiazepine supply. The main aim of this study was to assess the attitudes, experiences and knowledge of community pharmacists regarding current benzodiazepine policy and practices. Materials & Methods: The study consisted of an anonymous, self-administered, postal questionnaire of community pharmacists. The questionnaire was distributed to a random, geographically stratified sample of 857 community pharmacies in Ireland. All viable data was coded and entered into PASW Statistics 18.0 for analysis. Results: The response rate was 38%. It was found that there is a low level of awareness (33%) among community pharmacists of official sources of benzodiazepine guidelines but that the vast majority (93%) agree that such guidelines are relevant to them. A large proportion of pharmacists (47%) agree that they have a professional responsibility to ensure prescriber adherence to relevant guidelines. Long-term benzodiazepine use, in contravention of prescribing guidelines, was reported to be widespread. Community pharmacists agree (77%) that they possess the necessary knowledge and skills to engage with patients on the subject of benzodiazepine use and the vast majority (83%) of them would be willing to play an active role in initiating patients in benzodiazepine discontinuation/dosage reduction programmes. Discussions, Conclusion: The findings indicate that anticipated outcomes of the Benzodiazepine Committee’s report have not been achieved, as long-term prescribing and use is still perceived to be common. Community pharmacists have acknowledged their potential and willingness to play a role in ensuring benzodiazepine guideline compliance and facilitating dosage reduction/discontinuation. This could lead to improved benzodiazepine prescribing and use in primary care. However a number of issues must be addressed, such as the low level of guideline awareness. Given the large proportion of pharmacists who agree that they have a professional responsibility to ensure prescribers adhere to relevant guidelines, increasing community pharmacists’ awareness of benzodiazepine guidelines could lead to enhanced enforcement.

Abstract: Introduction: According to the Global Burden of Asthma report, 14.6% of the Irish population suffer from asthma. The objectives of this study were to investigate the current state of asthma management among patients in primary care, as estimated by their community pharmacists; to identify any aspects of asthma management that are infrequently addressed on counselling; to ascertain factors influencing pharmacists’ ability to counsel; and to investigate communication between pharmacists and other health-care professionals Materials & Methods: An anonymous postal questionnaire for self-administration was distributed to every community pharmacy registered with the Pharmaceutical Society of Ireland in 2010, with a reminder letter five weeks later. Responses were coded and analysed using SPSS v. 16. Results: The response rate was 43%. Respondents estimated that the mean percentage of their asthma patients who used their inhalers properly was 56% and typically, only 11% of their patients used a peak flow meter regularly. 71% of respondents believed that their asthma patients had low expectations of asthma management. On average, respondents ‘often’ conducted interventions with their asthma patients. However, the frequency with which interventions were carried out varied greatly depending on the intervention. 65% of respondents ‘always’ demonstrated the use of a newly prescribed inhalation device. However, 67% ‘never’ advised patients to ask their GP for an asthma management plan. There were significant age/ experience-related differences in the frequency with which several interventions were made (p<0.05, chi-squared test). 85% of respondents believe time is a major limitation that influences their ability to counsel. 57% of respondents typically communicate with a GP about an asthma patient once a week, but 17% stated that, on average they have no such communication. 30% of respondents indicated that a more structured method of communication is needed. Discussions, Conclusion: Community pharmacists believe that their patients’ level of asthma management is sub-optimal. The majority of respondents have a narrow perception of their role in asthma management, evidenced by the frequency with which non-medication related interventions are conducted. A significant improvement in communication between pharmacists and both GPs and practice nurses is vital to improve asthma management in primary care.

Abstract: 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.

Abstract: 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 (IC(50) 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.

Abstract: 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: p < 0.01 for ’teamwork climate’, ’safety climate’ and ’stress recognition’ and p < 0.05 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’ (p < 0.05) and ’safety climate’ (p < 0.01). HCAs scored significantly lower relative to staff overall with regard to ’working conditions’ (p < 0.05) and ’perceptions of management’ (p < 0.01). 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.

Abstract: 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 IC50 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.

Abstract: 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 and >50000 fold selectivity over human erythrocyte AChE. Inhibition with these compounds is time-dependent, competitive, and slowly reversible, indicating active site carbamylation.

Abstract: Isosorbide-2-benzylcarbamate-5-benzoate, a novel butyrylcholinesterase inhibitor, shows interspecies variation in its inhibitory activity (IC50 of 4.3 nM for human plasma butyrylcholinesterase, but 1.09 mu M 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 after male C57BL/6 mice revealed maximal plasma butyrylcholinesterase inhibition 20 min after intraperitoneal administration (similar to 60% inhibition) and 1 h after administration by gavage (similar to 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 (>= 72 h) reduction in brain butyrylcholinesterase activity.

Abstract: The potential polyamine antagonist action of N-1-dansyl-spermine (a potent NMDA antagonist) was assessed in two in vivo mouse models of polyamine action. Co-administration of N-1-dansyl-spermine (2-10 mug, i.c.v.) with spermine (100 mug, 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 N-1-dansylspermine antagonised spermine’s enhancement of NMDA-induced convulsions. These results suggest that N-1-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.

Abstract: 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)B-2. The aggregation response to arachidonic acid (AA) (100 muM), ADP (30 muM) or collagen (10 mug 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 AUC(0-24h) for the ISMNA-treated dogs was 77% of that for the physical mix-treated dogs and the t(max) 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.