Dosage Form Modification, a Simulation Activity between Nursing and Pharmacy Students.

Background: The aim of this exploratory pilot study was to evaluate student perceptions of a simulation activity involving undergraduate nursing and pharmacy students. The key question was "how do nursing and pharmacy students respond in an immersive collaborative simulation activity which involves medication dosage form modification?" Methods: One hundred nursing students participated in a simulated exercise where patients required medications for which there were barriers to administration. Fourteen pharmacy students were also present in the simulated health environment, observing the work of the nursing students and being available to provide advice regarding medication administration to the nursing students. A mixed methods approach was employed for this exploratory pilot study, where both nursing and pharmacy students were invited to complete a survey regarding the experience at the end of the simulation exercise and pharmacy students completed a reflection. Both surveys and reflections were analyzed. Results: Survey results indicated very high satisfaction regarding the exercise for both pharmacy and nursing students. Analysis of pharmacy student reflections also indicated apprehension regarding their preparedness to contribute to the exercise, enjoyment in participation, their understanding of the value of collaboration between the two groups of students, and also recognition of their need to be more prepared for such situations. Conclusion: This study assessed student perceptions and did not formally evaluate learning outcomes. The interprofessional immersive simulated learning opportunity was viewed as valuable by both nursing and pharmacy students. The immersive simulation provided teaching staff with the opportunity to develop a new approach for the teaching of dosage form modification to both nursing and pharmacy students in an interprofessional setting.

Does high on-treatment platelet aggregability reflect poor individual response to clopidogrel?

INTRODUCTION: On-treatment platelet aggregability represents the major form of functional assessment for patients treated with P2Y12 receptor antagonists, with "high" on-treatment platelet aggregability (HTPA) predicting thrombotic risk. However HTPA reflects a variable combination of pre-treatment hyperaggregability and poor response to P2Y12 antagonists. We have previously shown that integrity of platelet adenylate cyclase/cAMP signaling, assessed with PGE1, is a strong predictor of individual responses to clopidogrel. We therefore sought to determine the extent to which HTPA reflects impaired platelet responsiveness to clopidogrel. METHODS: Using data from our previous investigations of acute and sub-acute effects of clopidogrel, we analyzed the relationship between on-treatment aggregability and acute/steady state responsiveness to clopidogrel, utilizing ADP, the thromboxane A2 mimetic U46619, and thrombin receptor-activating peptide (TRAP) as pro-aggregants. The relationship between anti-aggregatory response to PGE1 and both on-treatment and pre-treatment aggregability was also examined. RESULTS AND CONCLUSIONS: With all 3 pro-aggregants, (1) response to clopidogrel after 4 h, as measured by ΔADP response, exhibits a strong inverse relationship with on-treatment aggregation, with a similarly inverse relationship between pre-treatment PGE1 response and on-treatment aggregability; (2) there is a weaker inverse relationship between clopidogrel response and pre-treatment platelet aggregability, and a significant inverse relationship between pre-treatment PGE1 response and pre-treatment platelet aggregability. Furthermore, pre-treatment PGE1 response also predicts on-treatment platelet aggregability in response to ADP at steady state. Thus, HTPA largely represents clopidogrel resistance.

New Developments in Platelet Cyclic Nucleotide Signalling: Therapeutic Implications.

Altered platelet physiology may contribute to the emergence of thrombosis in patients with many forms of cardiovascular disease. Excess platelet activation may reflect increased stimulation of pro-aggregatory pathways. There is, however, increasing evidence that excessive platelet response, due to impaired efficacy of anti-aggregatory autacoids such as nitric oxide (NO) and prostacyclin (PGI2), may be just as important. For example, diminished platelet response to NO has been documented in acute and chronic myocardial ischaemia, heart failure, aortic valve disease and in the presence of hyperglycaemia. This "NO resistance" has been shown to reflect both the scavenging of NO by reactive oxygen species and dysfunction of its intracellular "receptor", soluble guanylate cyclase. Importantly, these abnormalities of NO signalling are potentially reversible through judicious application of pharmacotherapy. The analogous condition of impaired PGI2/adenylate cyclase (AC) signalling has received comparatively less attention to date. We have shown that platelet response to prostaglandin E1 (PGE1) is frequently impaired in patients with symptomatic myocardial ischaemia. Because the effects of ADP receptor antagonists such as clopidogrel and ticagrelor at the level of the P2Y12 receptor are coupled with changes in activity of AC, impaired response to PGE1 might imply both increased thrombotic risk and a reduced efficacy of anti-aggregatory drugs. Accordingly, patient response to treatment with clopidogrel is determined not only by variability of clopidogrel bio-activation, but also extensively by the integrity of platelet AC signalling. We here review these recent developments and their emerging therapeutic implications for thrombotic disorders.

Subtle renal dysfunction and bleeding risk in atrial fibrillation: symmetric dimethylarginine predicts HAS-BLED score.

BACKGROUND: Risk of substantial haemorrhage represents a critically important limitation to effective anti-thrombotic treatment in patients with atrial fibrillation (AF). While it is known that this risk is increased in anticoagulated patients either in the presence of anti-aggregatory drugs or concomitant renal insufficiency, there are currently few data on the potential interactions between endogenous platelet aggregability and bleeding risk. OBJECTIVE: We therefore evaluated in a cohort of AF patients: (1), the putative relationship between platelet aggregability and HAS-BLED score; (2), the potential biochemical bases for such a relationship. METHODS: Patients were included as part of SAFETY, a randomised controlled trial evaluating outpatient management of AF patients. Platelet response to ADP was evaluated via whole blood impedance aggregometry; clinical and biochemical correlates of platelet aggregation were sought via univariate and multivariate analysis. RESULTS: Platelet aggregation correlated inversely (r=-0.220, p<0.05) with HAS-BLED score. Univariate biochemical correlates of decreased platelet aggregation were plasma concentrations of symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). On multivariate analyses, plasma SDMA concentration (ß=-0.318, p<0.01), platelet content of thioredoxin-interacting protein (Txnip, ß=0.261, p<0.05) and plasma thrombospondin-1 (TSP-1, ß=0.249, p<0.05) concentration were predictive of platelet ADP response. Consistent with previous reports, plasma SDMA concentrations were strongly and inversely correlated with estimated glomerular filtration rate (eGFR, r=-0.780, p<0.001). CONCLUSIONS: These data therefore suggest that (1), physiologically impaired, like pharmacologically impaired, platelet aggregability may increase bleeding risk in anticoagulated AF patients; (2), the biochemical basis for this may include impaired effects of nitric oxide (via Txnip, TSP-1) but also concomitant renal dysfunction.

Determinants of subacute response to clopidogrel: relative impact of CYP2C19 genotype and PGE1/adenylate cyclase signalling.

BACKGROUND: and HYPOTHESES: The signal transduction pathway modulated by activation or blockade of platelet P2Y12 receptors is linked to PGE1-stimulated adenylate cyclase effects, but this link's impact on P2Y12 receptor antagonist response is uncertain. We therefore tested the hypothesis that pre-treatment platelet responsiveness to PGE1 predicts subsequent responsiveness to clopidogrel. METHODS: In order to maximise heterogeneity of platelet responsiveness to PGE1 we investigated both healthy subjects (n=30) and patients with CHD undergoing elective coronary stenting (n=22), all genotyped for common CYP2C19 variants associated with clopidogrel sensitivity (CS). We determined baseline pre-clopidogrel platelet sensitivity to the inhibitory effects of PGE1 by ADP-induced whole blood aggregation. Clopidogrel was administered for 7days utilising a weight-based regimen. CS was expressed as change (Δ) in ADP-induced aggregation and in VASP-phosphorylation (VASP-P). We used univariate and multivariate analysis to correlate such parameters with PGE1 sensitivity, BMI and presence/absence of CHD. RESULTS: In the study cohort, pre-treatment responsiveness to PGE1 varied widely (70±28 [standard deviation (SD)]% inhibition of aggregation: range 10 to 100%). In the entire study cohort, pre-treatment PGE1 sensitivity correlated with CS irrespective of genotype. On univariate analysis, CS was not significantly greater for patients without than those with loss-of-function mutations. Moreover, at multivariate analysis, PGE1 sensitivity, but not genotype, was a strong correlate of ΔADP and ΔVASP-P (P<0.0001 for both). CONCLUSIONS: The integrity of the cAMP pathway is a major determinant of subacute CS.

Impaired platelet nitric oxide response in patients with new onset atrial fibrillation.

BACKGROUND: Clinical factors associated with thromboembolic risk in AF patients are well characterized and include new onset AF. Biochemically, AF is associated with inflammatory activation and impairment of nitric oxide (NO) signalling, which may also predispose to thromboembolism: the bases for variability in these anomalies have not been identified. We therefore sought to identify correlates of impaired platelet NO signalling in patients hospitalized with atrial fibrillation (AF), and to evaluate the impact of acuity of AF. METHODS: 87 patients hospitalized with AF were evaluated. Platelet aggregation, and its inhibition by the NO donor sodium nitroprusside, was evaluated using whole blood impedance aggregometry. Correlates of impaired NO response were examined and repeated in a "validation" cohort of acute cardiac illnesses. RESULTS: Whilst clinical risk scores were not significantly correlated with integrity of NO signalling, new onset AF was associated with impaired NO response (6 ± 5% inhibition versus 25 ± 4% inhibition for chronic AF, p<0.01). New onset AF was a multivariate correlate (p<0.01) of impaired NO signalling, along with platelet ADP response (p<0.001), whereas the associated tachycardia was not. Platelet ADP response was predicted by elevation of plasma thrombospondin-1 concentrations (p<0.01). Validation cohort evaluations confirmed that acute AF was associated with significant (p<0.05) impairment of platelet NO response, and that neither acute heart failure nor acute coronary syndromes were associated with similar impairment. CONCLUSION: Recent onset of AF is associated with marked impairment of platelet NO response. These findings may contribute to thromboembolic risk in such patients.