Oral platelet aggregation inhibitors are widely used for the treatment and prevention of cardiovascular diseases, including coronary stent thrombosis. Premature discontinuation following percutaneous coronary intervention would pose a grave risk of in-stent thrombosis, acute myocardial infarction and eventual death. Although they share the same mechanism of adenosine diphosphate P2Y12 platelet receptor inhibition, they belong to either the chemical class of thienopyridines (clopidogrel, prasugrel, and ticlopidine) or cyclopentyl-triazolo-pyrimidines (ticagrelor and cangrelor). This case describes the first documented crossreactive hypersensitivity of clopidogrel towards both its fellow thienopyridine, prasugrel, as well as the structurally dissimilar ticagrelor, and its subsequent successful desensitisation.
BACKGROUND: Cardiac sodium-calcium exchange (NCX1) is the dominant calcium (Ca) efflux mechanism in cardiomyocytes and is strongly regulated by pH. However, the role of NCX1 pH sensitivity in normal cardiac function is unknown. METHODS: We used CRISPR/Cas9 to produce a pH-resistant NCX1 mouse by replacing the histidine at position 165 of NCX1 with an alanine (H165A). Hearts were studied using echocardiography and ECG. RNA and protein expression levels were assessed using qPCR and Western blotting. Isolated ventricular cardiomyocytes were loaded with Ca indicators and patch clamped to record intracellular Ca transients and membrane current and voltage. RESULTS: H165A mice live into adulthood with slightly reduced LV systolic function, normal heart rate and shortened QT interval. Both male and female animals exhibit reduced growth, but females eventually reach normal body weight. In patch clamped myocytes, NCX current (INCX) evoked by voltage ramps was reduced by 35% (at +80 mV). Lowering pHi to 6.5 using Na-Acetate had no effect on INCX in H165A myocytes, whereas the same intervention in wildtype (WT) inhibited INCX by 69% (at +80 mV, p<0.01). There was no change in H165A ventricular cardiomyocyte Ca transients measured with fura-2 AM. However, action potential duration was reduced 68%, consistent with the shorter QT interval. This coincided with a 37% reduction in L-type Ca current and increased expression of repolarizing K+ channels. H165A mice are also resistant to ischemia/reperfusion injury. CONCLUSIONS: The H165A mutation attenuates pH regulation of NCX1 in mice, is associated with reduced growth and accelerates cardiac repolarization without compromising excitation-contraction coupling. The mutation also confers cardioprotection. The H165A mouse is the first evidence that pH regulation of NCX1 affects cardiac physiology and is a potential model for studying the role of NCX1 pH-sensitivity on both physiological and pathophysiological cardiac function.
Background Prescribing errors not only impose safety risks, but also delay hospital discharges and adversely affect patient satisfaction. The effect of reducing environmental interruptions on prescribing errors has not been published previously. Aim The aim of this study was to determine the combined effect of two ‘do not disturb’ (DND) strategies in decreasing the average number of prescribing errors by reducing distractions during discharge prescription writing. A secondary aim was to assess the effect of the interventions on prescription correction time. Methods In all, 392 discharge prescriptions from two general medical wards of a teaching hospital were audited over a 10‐week period in a prospective interventional before‐and‐after audit. Clinical pharmacists collected data on the number and type of errors, and time taken to correct errors. DND vests and workstations were made available during the intervention phase. Junior medical officers (JMO) provided daily feedback to the nurse unit managers (NUM) on the number and source of distractions, as well as the use of DND vests and workstations after the intervention. Results The percentage of error‐free discharge prescriptions increased from 29.7% before to 51.5% after the intervention (p < 0.0001). The mean number of errors per prescription decreased from 1.7 to 1.1 (p < 0.01) in both wards combined. The median time taken to correct erroneous prescriptions did not change significantly. Feedback provided by JMOs showed a marked reduction in interruptions, with 73% stating they were not interrupted at all or just once during prescribing after the intervention, compared with 17% before the intervention. Conclusion DND strategies decreased the rate of erroneous prescriptions.
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