Search

Adverse drug events (ADEs) represent an expensive societal burden that disproportionally affects older adults. Therefore, value-based organizations that provide care to older adults—such as the Program of All-Inclusive Care for the Elderly (PACE)—should be highly motivated to identify actual or potential ADEs to mitigate risks and avoid downstream costs. We sought to determine whether PACE participants receiving medication risk mitigation (MRM) services exhibit improvements in total healthcare costs and other outcomes compared to participants not receiving structured MRM. Data from 2545 PACE participants from 19 centers were obtained for the years 2018 and 2019. We compared the year-over-year changes in outcomes between patients not receiving (control) or receiving structured MRM services. Data were adjusted based on participant multimorbidity and geographic location. Our analyses demonstrate that costs in the MRM cohort exhibited a significantly smaller year-to-year increase compared to the control (MRM: USD 4386/participant/year [95% CI, USD 3040−5732] vs. no MRM: USD 9410/participant/year [95% CI, USD 7737−11,084]). Therefore, receipt of structured MRM services reduced total healthcare costs (p < 0.001) by USD 5024 per participant from 2018 to 2019. The large majority (75.8%) of the reduction involved facility-related expenditures (e.g., hospital admission, emergency department visits, skilled nursing). In sum, our findings suggest that structured MRM services can curb growing year-over-year healthcare costs for PACE participants.

Intersubject variability in drug response, whether related to efficacy or toxicity, is well recognized clinically. Over the years, drug selection from our pharmacologic armamentarium has moved from providers' preferred choices to more personalized treatments as clinicians' decisions are guided by data from clinical trials. Since the advent of more accessible and affordable pharmacogenomic (PGx) testing, the promise of precise pharmacotherapy has been made. Results have accumulated in the literature with numerous examples demonstrating the value of PGx to improve drug response or prevent drug toxicity. Unfortunately, limited availability of reimbursement policies has dampened the enthusiasm of providers and organizations. The clinical application of PGx knowledge remains difficult for most clinicians under real-world conditions in patients with numerous chronic conditions and polypharmacy. This may be due to phenoconversion, a condition where there is a discrepancy between the genotype-predicted phenotype and the observed phenotype. This condition complicates the interpretation of PGx results and may lead to inappropriate recommendations and clinical decision making. For this reason, regulatory agencies have limited the transfer of information from PGx laboratories directly to consumers, especially recommendations about the use of certain drugs. This mini-review presents cases (mexiletine, propafenone, clopidogrel, warfarin, codeine, procainamide) from historical observations where drug response was modified by phenoconversion. The cases illustrate, from decades ago, that we are still in great need of advanced clinical decision systems that cope with conditions associated with phenoconversion, especially in patients with polypharmacy., Competing Interests: None., (AJTR Copyright © 2021.)

Low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for the development of atherosclerotic cardiovascular disease. Statins have been the gold standard for managing cholesterol levels and reducing the risks associated with atherosclerotic cardiovascular disease; however, many patients do not achieve their cholesterol goals or are unable to tolerate this drug class due to adverse drug events. Recent studies of non-statin cholesterol lowering drugs (i.e., ezetimibe, PCSK9 inhibitors) have demonstrated cardiovascular benefits; and new drugs [i.e., bempedoic acid (BDA), inclisiran] have produced promising results in pre-clinical and clinical outcome trials. This narrative review aims to discuss the place in therapy of ezetimibe, PCSK9 inhibitors, BDA, and inclisiran and describe their relative pharmacokinetic (PK) profiles, efficacy and safety as monotherapy and combination therapy, and cardiovascular benefit(s) when used for hypercholesterolemia., Competing Interests: CB, NA, and JT are employed by the company Tabula Rasa HealthCare. The handling Editor declared a shared affiliation, though no other collaboration, with one of the authors JT., (Copyright © 2021 Bardolia, Amin and Turgeon.)

Oxycodone is a widely used opioid for the management of chronic pain. Analgesic effects observed following the administration of oxycodone are mediated mostly by agonistic effects on the μ-opioid receptor. Wide inter-subject variability observed in oxycodone efficacy could be explained by polymorphisms in the gene coding for the μ-opioid receptor ( OPRM1 ). In humans, oxycodone is converted into several metabolites, particularly into oxymorphone, an active metabolite with potent μ-opioid receptor agonist activity. The CYP2D6 enzyme is principally responsible for the conversion of oxycodone to oxymorphone. The CYP2D6 gene is highly polymorphic with encoded protein activities, ranging from non-functioning to high-functioning enzymes. Several pharmacogenetic studies have shown the importance of CYP2D6-mediated conversion of oxycodone to oxymorphone for analgesic efficacy. Pharmacogenetic testing could optimize oxycodone therapy and help achieve adequate pain control, avoiding harmful side effects. However, the most recent Clinical Pharmacogenetics Implementation Consortium guidelines fell short of recommending pharmacogenomic testing for oxycodone treatment. In this review, we (1) analyze pharmacogenomic and drug-interaction studies to delineate the association between CYP2D6 activity and oxycodone efficacy, (2) review evidence from CYP3A4 drug-interaction studies to untangle the nature of oxycodone metabolism and its efficacy, (3) report on the current knowledge linking the efficacy of oxycodone to OPRM1 variants, and (4) discuss the potential role of CYP2D6 brain expression on the local formation of oxymorphone. In conclusion, we opine that pharmacogenetic testing, especially for CYP2D6 with considerations of phenoconversion due to concomitant drug administration, should be appraised to improve oxycodone efficacy.

The use of electronic health records allows for the application of a novel medication risk score for the rapid identification of ambulatory patients at risk of adverse drug events. We sought to examine the longitudinal association of medication risk score with mortality. This retrospective cohort study included patients whose data were available through electronic health records from multiple health care organizations in the United States that provided data as part of a Patient Safety Organization. Patients were included if they had ≥1 visit and ≥1 medication in their record between January 1, 2011, to June 30, 2017. Cox proportional hazards regression was used to examine the association between continuous and categorized medication risk score with all-cause mortality. Among 427,103 patients, the median age was 50 years (interquartile range, 29-64 years); 61% were female; 50% were White, 11% were Black, and 38% were Hispanic; and 6873 had a death date recorded. Patients 30 to 49 years old had the highest hazard ratios (HRs), followed by the 50- to 64-year-olds and lastly those 65 years or older. Controlling for all covariates, 30- to 49-year-olds with a score of 20 to 30 (versus <10) had a 604% increase in the hazard of death (HR, 7.04; 95% confidence interval [CI], 3.86-12.85), 50- to 64-year-olds had a 254% increase (HR, 3.54; 95% CI, 2.71-4.63), and ≥65-year-olds had an 87% increase (HR, 1.87; 95% CI, 1.67-2.09). The medication risk score was independently associated with death, adjusting for multimorbidities and other conditions. Risk was found to vary by age group and score. Results suggest that pharmaceutical interventions among those with elevated scores could improve medication safety for patients taking multiple medications., Competing Interests: Tabula Rasa HealthCare has funded the research included in this article, of which V.M., J.T., and R.B. are all employees and shareholders. The rest of the authors disclose no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

(1) Background: There is limited evidence related to the efficacy of advanced clinical decision support systems (CDSS) on the quantity of high-quality clinical recommendations in a pharmacy-related medication therapy management (MTM) setting. The study aimed to assess the effect of an advanced CDSS on the quantity of relevant clinical pharmacist recommendations in a call center MTM setting. (2) Methods: This pre-test/post-test with comparator group study compared clinical skills assessment scores between certified MTM pharmacists in March 2020. A Wilcoxon Signed Rank test assessed the difference between pre- and post-test scores in both groups. (3) Results: Of 20 participants, the majority were less than 40 years old (85%) with a Doctor of Pharmacy degree (90%). Nine were female. Intervention group participants had less than three years of experience as a pharmacist. The control group had less than three years (40%) or seven to ten years (40%) of experience. There was a significant increase in intervention group scores between pre- (median = 3.0, IQR = 3.0) and post-test segments (median = 6.5, IQR = 4.0, p = 0.02). There was no significant change between control group pre- and post-test segments ( p = 0.48). (4) Conclusion: Pharmacist exposure to an advanced CDSS was associated with significantly increased quantity of relevant clinical recommendations in an MTM pharmacy setting.

The relevance of endogenous 4β-hydroxycholesterol (4β-OHC) plasma concentrations or of the 4β-OHC/total cholesterol concentration ratio (4β-OHC ratio) as surrogate markers of cytochrome P450 3A (CYP3A) activity was evaluated in individuals with (n = 38) or without (n = 35) type 2 diabetes (T2D). Midazolam was used as a comparator to validate exploratory measures of phenotypic CYP3A activity. Metabolic ratios of orally administered midazolam in nondiabetic and diabetic populations correlated significantly with 4β-OHC (r s  = 0.64 and 0.48; P ≤ 0.003) and 4β-OHC ratio (r s  = 0.69 and 0.46; P ≤ 0.003), respectively. Activity of CYP3A was lower in the T2D population compared with nondiabetic subjects; this decrease was reflected in 4β-OHC concentrations (24.33 vs. 12.58 ng/mL; P < 0.0001) and 4β-OHC ratio (0.13 vs. 0.09 (× 10 4 ); P < 0.0002). These results suggest that 4β-OHC should be considered as a valid, convenient, and easy to use endogenous biomarker of CYP3A activity in patients., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Aim: To evaluate the impact of AGTR1 A1166C (rs5186) on the response to candesartan in patients with heart failure., Materials & Methods: Prospective, multicentre, open-label study. We studied 299 symptomatic patients with heart failure presenting a left ventricular ejection fraction ≤40%., Results: Reductions in the primary end points of natriuretic peptides were not significantly associated with AGTR1 A1166C. Nevertheless, carrying the 1166C allele was associated with a greater compensatory increase in renin activity (p = 0.037) after 16 weeks of treatment with candesartan and a more modest effect on aldosterone concentrations (p = 0.022)., Conclusion: AGTR1 1166C carriers may experience a greater long-term compensatory renin-angiotensin-aldosterone system activation following treatment with candesartan. Whether these associations ultimately influence clinical outcomes requires investigation. Clinicaltrials.gov : NCT00400582.

The high prevalence of inappropriate polypharmacy in geriatric populations is unacceptable. Traditional medication risk mitigation (MRM) strategies have proven to be effective at improving polypharmacy, but these strategies have not consistently translated into positive health outcomes. Enhanced MRM strategies, such as using pharmacogenomics information, are needed, and these strategies need to be tested. A formidable challenge is successfully integrating pharmacogenomic information into clinical practice. As the medication experts on health care teams, pharmacists have a clear role to play in developing, integrating, and assessing enhanced MRM strategies to improve therapeutic outcomes for geriatric patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Given their expertise in pharmacotherapy, pharmacists are well positioned to play a leading role in the implementation of pharmacogenomics in clinical practice. However, little is known about the opinions of pharmacists towards pharmacogenomics or their willingness to integrate this new field in their practice., Methods: We conducted a survey of 284 pharmacists practicing in the province of Québec (Canada) to describe the opinions, expectations and concerns of pharmacists toward pharmacogenomics., Results: Pharmacists were very hopeful regarding the potential role of pharmacogenomics. Moreover, more than 95% of responders would be willing to recommend pharmacogenomic testing. Nevertheless, only 7.7% of pharmacists currently felt comfortable advising patients based on pharmacogenomic test results. Accordingly, the majority of responders (96.6%) indicated that they would like to undertake continuing education related to pharmacogenomics., Conclusion: Pharmacists are extremely hopeful towards pharmacogenomic testing. Furthermore, a vast majority is willing to integrate these tests as part of their clinical practice. Proper education will be required if the integration of pharmacogenomics in patient care is to be optimal.

This guideline is intended to provide a basis for informed decision-making regarding genetic testing to identify those individuals who will not benefit from codeine therapy, as well as those who are at an increased risk for codeine-induced toxicity. This guideline addresses the following key questions: 1) Should genetic testing for CYP2D6 be performed in patients prior to the initiation of codeine therapy? 2) How should patients with an indication for codeine therapy be managed based on their genotyping results for CYP2D6?

Aim: The goal of this study was to evaluate the performance of four warfarin pharmacogenetic algorithms in a real clinical setting, namely the algorithms of Gage et al., Michaud et al., Wadelius et al. and the International Warfarin Pharmacogenetics Consortium algorithm., Patients & Methods: Data was obtained retrospectively for 605 patients who had initiated warfarin therapy at the Montreal Heart Institute. Warfarin dosing and International Normalized Ratio history were obtained from hospital charts and CYP2C9 and VKORC1 polymorphisms were genotyped., Results: The four algorithms produced similar accuracy with mean absolute error ranging from 1.36-1.52 mg/day and adjusted R(2) from 40-44%. Gage's algorithm and Wadelius' algorithm predicted the largest proportion of patients within ± 20% of their observed stable warfarin dose. For patients requiring low doses, Gage's algorithm provided the highest proportion of patients within ideal dose range (36.3%), while Wadelius' algorithm performed the best for patients requiring high doses (37.3% of patients within ideal dose range)., Conclusion: Our study demonstrates the value of published pharmacogenetic dosing algorithms for the prediction of warfarin doses, in particular for patients with low or high therapeutic dose requirements.

Background: Polypharmacy increases the risk of cytochrome P450-based drug-drug interactions (CYP450-DDIs), leading to decreased therapeutic efficacy or increased drug toxicity., Objective: The aims of this study were to investigate the utility of a new CYP450-DDI software, InterMED-Rx, in aiding pharmacists in detecting CYP450-DDIs in hospitalized elderly patients and to ascertain pharmacists' agreement on how to intervene for each CYP450-DDI., Methods: A consensus panel of geriatric pharmacists first established guidelines for managing clinically relevant pharmacokinetic CYP450-DDIs. A prospective study was then conducted of patients newly admitted to a geriatric hospital whose pharmaceutical profile underwent analysis with InterMED-Rx. Rates and types of interventions were recorded., Results: Pharmacists' interrater agreement on how to manage CYP450-DDIs was initially only moderate (Cohen's κ, 0.51; 95% CI, 0.39-0.62), but improved subsequent to deliberation (Cohen's κ, 0.79; 95% CI, 0.70-0.88). Persistent disagreement involved interactions between 2 drugs with similar affinities for the same cytochrome. One hundred patients with polypharmacy (≥5 medications) aged 82.3 years (range, 65-96), with a mean (SD) of 12.2 (4.1) drugs (range, 5-27) were recruited for the prospective study. Eighty percent of patients had at least 1 CYP450 DDI detected with InterMED-Rx. A total of 238 CYP450-DDIs were identified involving CYP3A4 (70.2%), CYP2D6 (22.7%), and CYP2C9 (3.4%) substrates or inhibitors. Nineteen percent of patients received immediate medication adjustment, and 39% required follow-up of clinical signs, symptoms, and laboratory tests to determine whether future modification was needed. More than one half (56%) of all patients who required clinical follow-up had further medication adjustment prior to discharge., Conclusions: Use of the InterMED-Rx software identified elderly patients at risk for pharmacokinetic interactions and facilitated interventions aimed at reducing adverse drug events. Although consensus can be reached among pharmacists on how to intervene for many CYP450-DDI scenarios, certain situations allow for multiple intervention strategies., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)

Wide intra- and inter-subject variability in antiretroviral drug response is observed. Pharmacotherapy of HIV-infected patients is challenging considering the great numbers of co-morbidities increasing the risk of drug-drug interactions. Drug-metabolism enzymes and drug-transporters regulate drug access to the systemic circulation, target cells and sanctuary sites; these factors determine pharmacokinetics and could explain variability in efficacy and adverse drug reactions associated with antiretroviral drugs. Notions related to the major enzymes (CYP450s and UGTs) involved in antiretroviral metabolism and drugtransporters are reviewed with an attention paid on genetic polymorphisms. Genetic polymorphisms affecting the activity or the expression of membrane proteins in the transport of drugs would be highlighted with examples such as neurotoxicity with efavirenz, nephrotoxicity with tenofovir, hepatotoxicity with nevirapine and hyperlibirubinemia associated with indinavir and atazanavir. The objective is to provide a better understanding on mechanisms involved in drugdisposition of antiretroviral helping out health care providers in the management of pharmacotherapy of HIV-infected patients.

Drug-induced QT interval prolongation is a condition likely to be aggravated by diabetes. The objective of this study was to evaluate how glucose concentration may modulate drug effects on ventricular repolarization and on cardiac repolarizing potassium currents. Guinea pig hearts were Langendorff-retroperfused and monophasic action potential duration (MAPD) was measured. Glucose (1, 5 or 20 mmol/L) was tested with either dofetilide (a specific I(Kr) blocker), chromanol 293B (a specific I(Ks) blocker) or both. Effects of glucose (1, 5 or 20 mmol/L) on I(Kr) blockade mediated by dofetilide were also measured in HERG-transfected HEK293 cells in the absence vs presence of the P-glycoprotein drug transporter, using the whole cell patch-clamp technique. Our results suggest that both hypo- and hyperglycemia potentiate the MAPD-prolonging and I(Kr)-blocking properties of dofetilide. P-glycoprotein drug extrusion efficacy appears as a key determinant of dofetilide's I(Kr)-blocking effect. This efficacy appears to be affected by glucose concentration, particularly hyperglycemia.

Background: Adequate platelet inhibition before percutaneous coronary intervention (PCI) reduces periprocedural and long-term ischemic complications. Reduced response to clopidogrel has been associated with subsequent major adverse cardiovascular events. Strategies to optimize platelet inhibition pre-PCI are under investigation. This study evaluated the effect on platelet aggregation of four different dosing regimens of clopidogrel given before elective PCI in a randomized, prospective, double-blind, and placebo-controlled design., Methods: One hundred twenty participants were randomized to one of four groups of clopidogrel: (a) 300 mg on the day prior to angiography; (b) 600 mg on the day prior to angiography; (c) 300 mg followed by 75 mg daily started 1 week prior to angiography; and (d) 300 mg followed by 150 mg daily started 1 week prior to angiography. Platelet aggregation was assessed by light transmission aggregometry (LTA) after stimulation with adenosine diphosphate 20 microM at baseline and at the time of diagnostic coronary angiography. The absolute change in platelet aggregation between these two time points was considered the main outcome measure., Results: At the time of diagnostic coronary angiography, the 300-mg/150-mg daily regimen achieved the greatest decrease in platelet aggregation (37 +/- 19%), while the 300 mg regimen provided the smallest (20 +/- 22%), an absolute difference between the two groups of 17.2 +/- 5.1% (P = 0.005)., Conclusions: A 300-mg loading dose of clopidogrel followed by 150 mg daily for 1 week prior to coronary angiography provides more effective platelet inhibition, as defined by LTA, compared to the standard 300-mg loading dose regimen at the time of coronary intervention.

Underlying mechanisms of drug-induced long QT syndrome are not fully understood. Our objective was to evaluate gender-related differences for block of the rapid (I(Kr) ) or/and the slow (I(Ks)) components of the delayed rectifier potassium current in prepubertal male and female guinea pigs (n = 120) treated with or without verapamil. Indapamide (I(Ks) blocker) prolonged the monophasic action potential duration at 90% repolarisation (MAPD( 90)) in females more than in males (15.1 + 0.5 vs 9.7 + 1.3 msec; P < .05) in verapamil treated animals. In contrast, MAPD(90) prolongation induced by domperidone or dofetilide (I(Kr) blockers) was not different between genders. Verapamil treatment augmented prolongation of MAPD( 90) caused by dofetilide or domperidone (P < .01). In conclusion, 1) females exhibited greater prolongation of MAPD(90) when exposed to indapamide, 2) no gender-related differences were observed for I( Kr) blockers, and 3) verapamil treatment did not uncover gender-related differences in I(Kr) or I(Ks) block, although it augmented prolongation of cardiac repolarization by I(Kr) blockers.

Background: The benefits of angiotensin II receptor blockers (ARBs) in patients with heart failure who are treated with standard pharmacotherapy, including an angiotensin-converting enzyme (ACE) inhibitor, were demonstrated in 2 large randomized trials. It is currently impossible to determine which patient will benefit from the addition of an ARB., Objective: To explore the impact of selected candidate genes on the hemodynamic, neurohormonal, and antiinflammatory effects of candesartan in patients with heart failure who are already being treated with an ACE inhibitor., Methods: We investigated the impact of 10 candidate genetic polymorphisms on the effects of candesartan in patients with heart failure who are treated with an ACE inhibitor. We evaluated their impact on acute (2 wk) and long-term (24 wk) changes in blood pressure and N-terminal proB-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) during treatment with candesartan., Results: Thirty-one patients were included. Homozygotes of the AGTR1 A1166 allele (n = 13) had a greater decrease in systolic (-9.1 +/- 4.7 vs 1.1 +/- 3.3 mm Hg; p = 0.04 by analysis of variance [ANOVA], adjusting for dose) and diastolic blood pressure (-5.1 +/- 1.5 vs 1.9 +/- 1.9 mm Hg; p = 0.005 by ANOVA, adjusting for dose) compared with C1166 allele carriers (n = 18) following 2 weeks of treatment. After 6 months of treatment, C1166 carriers experienced a greater decrease in NT-proBNP (-151.4 [-207; -19.8] ng/L vs 147.3 [-61.3; 882.9] ng/L; p = 0.03) and hsCRP (-0.8 [-2.2; -0.03] mg/L) vs 0.2 [-1.8; 5.3] mg/L; p = 0.09) compared with patients carrying the AA1166 genotype. No other significant association was found., Conclusions: The results of this proof-of concept study provide the first evidence that the AGTR1 A1166C polymorphism could influence the response to candesartan in patients with heart failure who are receiving ACE inhibitors. Validation of these exploratory findings in larger populations is required before use of the AGTR1 A1166C genotype can be incorporated into clinical practice.

Background: Women are at an increased risk of drug-induced long QT syndrome (LQTS). This major cardiac adverse effect may lead to malignant polymorphic ventricular tachycardias, termed torsades de pointes, which may degenerate into ventricular fibrillation and cause sudden death., Objective: This article reviews current evidence and remaining gaps in knowledge about drug-induced LQTS in women., Methods: Using the search terms gender, sex, and sex differences in combination with cardiac electrophysiology, long QT syndrome, HERG, membrane transporters, and cytochromes, we conducted a systematic review of the available literature in the PubMed database. Relevant English- and French-language publications (to October 2007) on sex differences in LQTS were identified., Results: Clinical and experimental studies have reported that gonadal hormones play a role in sex-related differences of QT interval prolongation. Androgens may diminish drug effects on heart repolarization, and estrogens may facilitate arrhythmias. Furthermore, sex-related differences in the density of ion channels may partially explain this phenomenon. However, the magnitude of hormone-dependent differences observed in these studies remains very small compared with the large differences observed in clinical settings. Therefore, many scientists agree that the mechanisms responsible for sex-related differences in the risk of proarrhythmia from drugs remain largely undefined., Conclusions: Other factors, such as sex-related modulation of drug disposition in situ, may fill the gaps in our understanding of the sex differences observed in drug-induced LQTS. We suggest that mechanisms such as the modulation of the pharmacokinetics of IKr (rapid component of the delayed rectifier potassium current) blockers, via modulation of intra- and extracellular concentrations, may be of major importance. Sex-specific changes in drug transport and metabolism will result in different plasma and intracellular levels acting along a dose-response effect on IKr block. Consequently, important hormone-dependent factors such as metabolic enzymes and membrane transporters need to be investigated in new basic research studies.

Prolongation of the QT interval has been observed during treatment with olanzapine, a thienobenzodiazepine antipsychotic agent. Our objectives were 1) to characterize the effects of olanzapine on cardiac repolarization and 2) to evaluate effects of olanzapine on the major time-dependent outward potassium current involved in cardiac repolarization, namely I(Kr) (I(Kr): rapid component of the delayed rectifier potassium current).Isolated, buffer-perfused guinea pig hearts (n = 40) were stimulated at different pacing cycle lengths (150-250 msec) and exposed to olanzapine at concentrations ranging from 1 to 100 microM. Olanzapine increased monophasic action potential duration measured at 90% repolarization (MAPD90) in a concentration-dependent manner by 6.7 +/- 0.7 msec at 3 microM but by 26.0 +/- 4.3 msec at 100 microM (250 msec cycle length). Increase in MAPD(90) was also reverse frequency dependent; 30 microM olanzapine increased MAPD90 by 28.0 +/- 6.2 msec at a pacing cycle length of 250 msec but by only 18.9 +/- 2.2 msec at a pacing cycle length of 150 msec. Experiments in HERG-transfected (HERG: human ether-a-gogo-related gene) HEK293 cells (n = 36) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: tail current was decreased 50% at olanzapine 3.8 microM. Olanzapine possesses direct cardiac electrophysiological effects similar to those of class III anti-arrhythmic drugs. These effects were observed at concentrations that can be measured in patients under conditions of impaired drug elimination such as renal or hepatic insufficiency, during co-administration of other CYP1A2 substrates/inhibitors or after drug overdose. These results offer a new potential explanation for QT prolonging effects observed during olanzapine treatment in patients.

Aims: We sought to compare the results obtained from six major platelet function tests in the assessment of the prevalence of aspirin resistance in patients with stable coronary artery disease., Methods and Results: 201 patients with stable coronary artery disease receiving daily aspirin therapy (> or =80 mg) were recruited. Platelet aggregation was measured by: (i) light transmission aggregometry (LTA) after stimulation with 1.6 mM of arachidonic acid (AA), (ii) LTA after adenosine diphosphate (ADP) (5, 10, and 20 microM) stimulation, (iii) whole blood aggregometry, (iv) PFA-100, (v) VerifyNow Aspirin; urinary 11-dehydro-thromboxane B(2) concentrations were also measured. Eight patients (4%, 95% CI 0.01-0.07) were deemed resistant to aspirin by LTA and AA. The prevalence of aspirin resistance varied according to the assay used: 10.3-51.7% for LTA using ADP as the agonist, 18.0% for whole blood aggregometry, 59.5% for PFA-100, 6.7% for VerifyNow Aspirin, and finally, 22.9% by measuring urinary 11-dehydro-thromboxane B(2) concentrations. Results from these tests showed poor correlation and agreement between themselves., Conclusion: Platelet function tests are not equally effective in measuring aspirin's antiplatelet effect and correlate poorly amongst themselves. The clinical usefulness of the different assays to classify correctly patients as aspirin resistant remains undetermined.

Several medications, including drugs prescribed for noncardiac indications, have been associated with a prolongation of the QT interval on the surface electrocardiogram. Under certain circumstances, this clinical manifestation may reflect an increased risk for patients presenting with a polymorphic ventricular tachycardia known as torsade de pointes. Drugs that prolong the QT interval belong to several pharmacological classes, but most of them share one pharmacological effect: they lengthen cardiac repolarization mostly by blocking specific cardiac K+ channels. The potent blocking of cardiac K+ channels and excessive lengthening of cardiac repolarization favour the development of membrane oscillations (early afterdepolarizations) due to Ca2+/Na+ re-entry. Early afterdepolarizations, when propagated, may trigger torsade de pointes. In addition to excessive lengthening of the QT interval, other predisposing factors to drug-induced torsade de pointes include bradycardia, electrolyte imbalance, female sex and genetic polymorphisms in various ion channel constituents. In brief, drug-induced torsade de pointes is a relatively rare event in the entire population, which nonetheless carries the risk of lethal consequences. Consequently, drug surveillance programs are very active in identifying drugs that induce the prolongation of the QT interval. Recent data have allowed us to better understand the underlying electrophysiological mechanisms of the syndrome and better identify predisposing factors.

Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors. The drug and its active glucuronide metabolite impair the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol through inhibition of a membrane transporter yet to be identified. Absorption of ezetimibe is rapid and not altered by food content following oral administration. The drug is not metabolized by the cytochrome P450 system but extensive glucuronidation takes place in the intestine. Consequently, plasma concentrations of ezetimibe represent approximately 10% of total ezetimibe in plasma. Enterohepatic recirculation observed for ezetimibe and its glucuronimide significantly increases the residence time of these compounds in the intestine, at their site of action. Elimination of ezetimibe glucuronimide appears impaired in elderly patients and patients with renal insufficiency with plasma concentrations increased 1.5- to 2-fold. So far, no drug interaction study has been associated with major changes in either the pharmokinetics of ezetimibe or coadministered drugs.