[THE MINI-CLINICAL EVALUATION EXERCISE (MINI CEX): PROMOTING OBSERVATION, EVALUATION AND FEEDBACK IN MEDICAL EDUCATION: TOWARDS THE IMPLEMENTATION OF COMPETENCE-BASED MEDICAL EDUCATION IN ISRAEL].

INTRODUCTION: Competence-based medical education (CBME) re-shaped medical education in North America and in Europe and is making its first steps in Israel in recent years. This article reviews the literature regarding the Mini-Clinical Evaluation Exercise (mini-CEX), a tool for the evaluation of clinical competencies in CBME. The mini-CEX has been adopted by the American Board of Internal Medicine (ABIM) and the European Federation of Internal Medicine (EFIM) and is cited in leading documents of these organizations on medical education. The mini-CEX allows direct observation on a clinical encounter of a learner (medical student or resident) and a patient by a skilled clinician (observer). The mini-CEX provides the basis for the provision of feedback to the learner by the observer following the observation.

Gastrointestinal manifestations of synthetic cannabinoids: a retrospective cohort study.

BACKGROUND: Synthetic cannabinoids (SC) are chemical substances which activate cannabinoid receptors similarly to tetrahydrocannabinol, but with a higher efficacy. These substances are used as illicit recreational drugs, often smoked as herbal mixtures. The continuing availability and rapid evolution of SC is an ongoing health risk. The adverse effects of SC are wide ranging, and span from mild behavioral changes to death. Knowledge regarding gastrointestinal (GI) manifestations of SC use is sparse. METHODS: Single tertiary-care referral medical center retrospective study. RESULTS: The medical records of patients presented to hospital emergency care due to SC use between January 2014 and February 2018 were retrieved from Hadassah Mount Scopus Hospital's computerized database. The records were reviewed for clinical outcomes and laboratory tests. Fifty-five (55) patients were identified with a hospital presentation due to SC use. Twenty-one (21) out of 55 patients (38%) reported gastrointestinal complaints. The most common complaints were abdominal pain and vomiting. Of those, 28% had recurrent emergency department presentations due to abdominal pain and 66% presented with leukocytosis. Serum lactate was elevated in 66% of patients with GI manifestations. One patient had an abnormal computerized tomography (CT) abdominal angiography scan, which was compatible with intestinal ischemia. CONCLUSIONS: The clinical spectrum of gastrointestinal manifestations in SC intoxication ranges from mild symptoms, such as abdominal pain and vomiting, to even more severe symptoms suggestive of intestinal ischemia. Clinicians should be aware that abdominal pain and other gastrointestinal complaints can be associated with SC use.

Gender differences in the effect of medical humanities program on medical students' empathy: a prospective longitudinal study.

BACKGROUND: Previous studies have suggested that Medical students' empathy declines during medical school, especially during the clinical studies. The aim of this study was to examine. Changes in medical students' empathy during their first clinical experience, and to determine the impact of gender and humanities curriculum on empathy changes. METHODS: In this prospective longitudinal study, 262 4th year students from three consecutive classes were assessed. Empathy was assessed before and at 4th-year-end, using the Jefferson Scale of Physician Empathy-Student Version (JSPE-S). The three classes differed in humanities curriculum [limited Medical Humanities (MH(lim)) vs. extended Medical Humanities (MH(ext))], and in admission system [Personal Interview (PI) vs. multiple mini interviews (MMI)]. RESULTS: Overall, there was a small but significant decrease in JSPE-S during the fourth year (114.40 ± 11.32 vs. 112.75 ± 14.19, p = 0.034). Among men there was a statistically significant decline in JSPE-S during the fourth year, and the MH(ext) (but not the MH(lim)) was associated with the decline (t(35) = 2.38, p = 0.023). Women students showed no decline in empathy during the fourth-year of studies, regardless of type of humanities program. In addition, women who participated in MH(ext) had a higher JSPE-S scores during the 4th -year as compared to women who participated in MH(lim). CONCLUSION: Pre-clinical humanities program was associated with a decline in empathy among men medical students during the fourth-year of medical studies. Gender differences in response to medical humanities programs require further study.

Calcium Channel Blockers and the Risk for Lung Cancer: A Population-Based Nested Case-Control Study.

BACKGROUND: It has been suggested that calcium channel blockers (CCBs) may increase the risk of lung cancer; however, current evidence is conflicting and limited. OBJECTIVE: Investigate the associations between CCB use and lung cancer. METHODS: We conducted a population-based nested case-control study. A cohort was formed of patients prescribed their first antihypertensive agent from 2000 to 2014. CCB exposure information was obtained by identification of all prescriptions dispensed during study follow-up. Cases were patients newly diagnosed with lung cancer during follow-up. Each case was matched with 10 controls by age, sex, calendar year of cohort entry, and duration of follow-up. Multivariate conditional logistic regression was used to estimate odds ratios (ORs) with 95% CIs of lung cancer associated with ever use of CCBs. RESULTS: During a median follow-up of 6.2 years, we identified 4174 cases of lung cancer. Ever use of CCBs was associated with an increased risk of lung cancer (adjusted OR = 1.13; 95% CI = 1.06-1.21), when compared with the use of other antihypertensive drugs. A duration-response relation was observed, with the ORs gradually increasing with longer cumulative duration of CCB use (<5 years: OR = 1.12, 95% CI = 1.04-1.20; 5-10 years: OR = 1.22, 95% CI = 1.07-1.40; >10 years: OR = 1.33, 95% CI = 0.90-1.96; P trend < 0.001). Conclusion and Relevance: The results of this large population-based study indicate that the use of CCBs is associated with a modest but significant increase in the risk of lung cancer. This association appeared to increase with longer duration of use.

Management strategies of the interaction between direct oral anticoagulant and drug-metabolizing enzyme inducers.

Little is known regarding the management of direct oral anticoagulants (DOACs) in patients with enzyme-inducing drugs (EID). The use of EID may lead to sub-therapeutic concentrations of DOACs and to treatment failure. Thus, many patients on EIDs cannot benefit from the advantages of DOACs. This was a retrospective study, evaluating the management of hospitalized patients with DOACs. Characteristics of hospitalized patients with a prescription for DOACs, with and without EIDs, were summarized and evaluated, and management strategies addressing the potential interaction were documented, including the use of DOAC concentration monitoring. During the period evaluated, 1596 hospitalized patients with prescriptions for DOACs were identified. Most patients received apixaban (n = 1227, 77%), followed by rivaroxaban (240, 15%), and dabigatran (129, 8%). Twenty-two patients (1.4%) had concomitant EIDs. Demographic and clinical characteristics of hospitalized patients with DOACs were similar in those receiving EID and those not. Management strategies included stopping DOAC or EID (41%), and DOAC dose increase (14%). During management of these interactions, DOAC concentrations were measured for 11 of 22 patients and were below the 5th percentile of expected concentration for six of these patients. The management of patients with DOAC concentration measurement differed significantly from those without (p = 0.005), as they were much less likely to have one of the medications stopped and more often had the DOACs' dose increased. Among hospitalized patients with DOACs, EIDs are not rare. DOAC concentrations are often low in the presence of EIDs. DOAC concentration monitoring may be useful in settings requiring both DOAC and EIDs.

The hemodynamic response to constant dobutamine infusion: the effect of ADRB1 389 polymorphism and sex.

OBJECTIVES: Prolonged activation of the ß-1 adrenergic receptor (ADRB1) is associated with receptor desensitization. This process has been suggested to have important pathophysiological and clinical implications in conditions such as congestive heart failure. The contribution of genetic factors to this process is a subject of ongoing research. We have previously shown that the ADRB1 389 polymorphism affects the response to incremental dose infusion of the ADRB agonist dobutamine. The aim of the current study was to determine whether the ADRB1 389 polymorphism affects the hemodynamic response to constant dose infusion of dobutamine in healthy patients. PATIENTS AND METHODS: Healthy patients were recruited according to their ADRB1 49 and 389 genotypes [15 Arg389Arg, 10 Gly389Arg, and 10 Gly389Gly patients (all Ser49Ser), 21 men and 14 women]. Following a standardized protocol of dose increase, 6 mcg/kg/min dobutamine was infused over 2 h. Heart rate (HR), blood pressure (BP), and active plasma renin (PR) were measured. Standardized exercise (1 min) was performed at three time points during infusion. RESULTS: In all patients, resting systolic BP was significantly decreased during infusion [144.4±11.5 vs. 140.3±12.2 mmHg (mean±SD), P=0.007]. There was no change in HR, and PR following 120 min of dobutamine infusion. ADRB1 389 genotypes were not associated with HR, systolic BP, and PR changes during dobutamine infusion (all P>0.05, repeated measures analysis of variance). Sex was associated with response to dobutamine. Among women, but not in men, resting HR significantly increased, and diastolic blood pressure (DBP) significantly decreased during dobutamine infusion [HR: 76.0±7.3 to 86.3±17.5 beats per minute (P=0.023), and DBP 78.5±8.49 mmHg to 72.36±6.16 (P=0.041) (repeated measures analysis of variance)]. CONCLUSION: In healthy patients, the ADRB1 389 genotype was not associated with hemodynamic changes during constant dobutamine infusion. In women, but not in men, HR significantly increased and DBP decreased during 2 h of infusion.

Systematic Review, Meta-analysis, and Network Meta-analysis of the Cardiovascular Safety of Macrolides.

Studies reporting an increased risk for cardiac toxicities with macrolide antibiotics have raised concern regarding their cardiovascular safety. We sought to assess the cardiac safety of macrolide antibiotics as a class and of the individual agents by conducting a systematic review and network meta-analysis. Medline, Embase, and the Cochrane Library were searched up to February 2018 for studies reporting on cardiovascular outcomes with macrolides. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random-effects models and odds ratios (OR), and 95% confidence intervals (CI) were calculated for arrhythmia, cardiovascular death, and myocardial infarction (MI). A total of 33 studies and data on 22,601,032 subjects were retrieved and included in the current meta-analyses. Macrolide use was not associated with the risk of arrhythmia or cardiovascular mortality. In the primary analysis, macrolide use was associated with a small but statistically significant 15% increase in risk for MI (OR = 1.15 [95% CI, 1.01 to 1.30]). In indirect network meta-analysis, erythromycin and clarithromycin were ranked considerably more likely to be associated with a higher risk for MI and significantly associated with increased risk of MI compared to azithromycin (OR = 1.58 [95% CI, 1.18 to 2.11] and OR = 1.41 [95% CI, 1.11 to 1.81], respectively). Our findings indicate that macrolide antibiotics as a group are associated with a significant risk for MI but not for arrhythmia and cardiovascular mortality. Among the macrolides, erythromycin and clarithromycin were associated with a greater risk of MI. However, it is possible that the association between macrolide use and risk of MI is the result of residual confounding.

WITHDRAWN: Cognition and Dementia Related Adverse Effects with Sacubitril-Valsartan: Analysis of the FDA Adverse Event Report System Database.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.cardfail.2018.04.009. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Cognition- and Dementia-Related Adverse Effects With Sacubitril-Valsartan: Analysis of the FDA Adverse Event Report System Database.

BACKGROUND: Because neprilysin is involved in the degradation of amyloid-beta, there is concern that the angiotensin-neprilysin inhibitor sacubitril-valsartan could increase the risk for dementia. METHODS: We analyzed adverse event cases submitted to the Food and Drug Administration Adverse Event Report System from July 2015 to March 2017. Cognition- and dementia-related adverse event cases were defined with the use of broad and narrow structured medical queries. RESULTS: During the period evaluated, 9,004 adverse event reports (out of a total of 2,249,479) involved the use of sacubitril-valsartan. Based on the broad definition, sacubitril-valsartan was associated with cognition- and dementia-related adverse events in 459 reports (5.1%), but this was lower than the proportion of these reports among other medications (6.6%, reporting odds ratio [ROR] 0.72, 95% confidence interval [CI] 0.65-0.79). Restricting the comparison to cases with age >60 years and with the use of a comparator group with heart failure resulted in no association between sacubitril-valsartan and dementia-related adverse events, with the use of both the broad and the narrow definitions (ROR 0.87, 95% CI 0.76-1.02, and ROR 1.06, 95% CI 0.4-3.16, respectively). CONCLUSION: Sacubitril-valsartan is not associated with a disproportionately high rate of short-term dementia-related adverse effect reports. Long-term studies assessing cognitive outcomes are required to better establish the medication's cognition effects.

Gender Differences in Efficacy and Safety of Direct Oral Anticoagulants in Atrial Fibrillation: Systematic Review and Network Meta-analysis.

BACKGROUND: Studies indicate that women with atrial fibrillation (AF) are less likely to receive anticoagulants despite their higher risk of stroke compared with men. OBJECTIVE: To evaluate whether the efficacy and safety of direct oral anticoagulants (DOACs) differ in women with AF as compared with men. Our secondary aim was to examine gender differences regarding the safety and efficacy of specific DOACs. DATA SOURCES: MEDLINE, EMBASE, Cochrane, and ClinicalTrials.gov were searched through March 2017. STUDY SELECTION AND DATA EXTRACTION: Randomized clinical trials that reported on major bleeding and stroke with DOACs in women and men with AF were included. Meta-analysis and network meta-analysis was performed. DATA SYNTHESIS: Five trials met the inclusion criteria. Among 66 389 patients, 37.8% were women. Women treated with DOACs were at higher risk of stroke and systemic embolism compared with men (RR = 1.19; 95% CI = 1.04-1.35; I2 = 10%) but there was a significantly lower risk of major bleeding in women compared with men (RR = 0.86; 95% CI = 0.78-0.94; I2 = 0%). Network meta-analyses suggested differences between various DOACs in men and women. LIMITATIONS: Patient-level data enabling control for differences in baseline risk and head-to-head comparisons between DOACs were not available. Relevance to Patient Care and Clinical Practice: Undertreatment with DOACs among women cannot be justified. CONCLUSION: Women treated with DOACs had a lower rate of major bleeding and higher rate of stroke and systemic emboli compared with men. Further investigation of DOACs, including differences between the DOACs in specific populations is warranted.

Drug interaction as a predictor of direct oral anticoagulant drug levels in atrial fibrillation patients.

Data are limited on the effects of drug interactions on direct-acting oral anticoagulant (DOAC) levels. We evaluated the effects of the use of interacting drugs on DOAC levels in patients with atrial fibrillation (AF). We reviewed data of AF patients tested for DOAC levels in 2013-2017. The primary outcomes were drug levels exceeding the expected steady-state range, and in the highest quartile. A multivariate analysis was performed to evaluate the correlation of treatment by the use of interacting drugs, CYP3A4 and P-glycoprotein (P-gp) inhibitors, with the primary outcomes. Overall, 147 patients underwent DOAC level measurement [dabigatran (n = 31), rivaroxaban (n = 29), apixaban (n = 87)]. Thirty-three (22.4%) had drug levels exceeding the expected range. Seventy-nine (53.7%) patients were treated with at least one interacting drug. In multivariate analysis, the concomitant use of interacting drugs was an independent predictor for drug levels exceeding the expected range (OR 3.3, 95% CI 1.20-9.05). The defined daily dose of the interacting drug correlated positively with DOAC levels (r = 0.29, P = 0.001). Co-treatment with interacting drugs was associated with extremely high levels of dabigatran, (OR 16.6, 95% CI 1.29-215.18) but not of the other DOAC examined. Concomitant use of interacting drugs is associated with high DOAC levels in patients with AF. Further investigation is warranted to establish the differences between specific DOAC, evaluate the effect on patient outcomes, and characterize the role of DOAC monitoring in this setting.

Clinical Spectrum and Mechanism of Acute Kidney Injury in Patients with Diabetes Mellitus on SGLT-2 Inhibitors.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) (such as canagliflozin, empagliflozin, and dapagliflozin) are widely used to treat patients with type 2 diabetes mellitus (T2DM) to improve glycemic, cardiovascular and renal outcomes. However, based on post-marketing data, a warning label was added regarding possible occurrence of acute kidney injury (AKI). OBJECTIVES: To describe the clinical presentation of T2DM patients treated with SGLT2i who were evaluated for AKI at our institution and to discuss the potential pathophysiologic mechanisms. METHODS: A retrospective study of a computerized database was conducted of patients with T2DM who were hospitalized or evaluated for AKI while receiving SGLT2i, including descriptions of clinical and laboratory characteristics, at our institution. RESULTS: We identified seven patients in whom AKI occurred 7-365 days after initiation of SGLT2i. In all cases, renin-angiotensin-aldosterone system blockers had also been prescribed. In five patients, another concomitant nephrotoxic agent (injection of contrast-product, use of nonsteroidal anti-inflammatory drugs or cox-2 inhibitors) or occurrence of an acute medical event potentially associated with AKI (diarrhea, sepsis) was identified. In two patients, only the initiation of SGLT2i was evident. The mechanisms by which AKI occurs under SGLT2i are discussed with regard to the associated potential triggers: altered trans-glomerular filtration or, alternatively, kidney medullary hypoxia. CONCLUSIONS: SGLT2i are usually safe and provide multiple benefits for patients with T2DM. However, during particular medical circumstances, and in association with usual co-medications, particularly if baseline glomerular filtration rate is decreased, patients treated with SGLT2i may be at risk of AKI, thus warranting caution when prescribed.

Genetic variation in alpha2-adrenoreceptors and heart rate recovery after exercise.

Heart rate recovery (HRR) after exercise is an independent predictor of adverse cardiovascular outcomes. HRR is mediated by both parasympathetic reactivation and sympathetic withdrawal and is highly heritable. We examined whether common genetic variants in adrenergic and cholinergic receptors and transporters affect HRR. In our study 126 healthy subjects (66 Caucasians, 56 African Americans) performed an 8 min step-wise bicycle exercise test with continuous computerized ECG recordings. We fitted an exponential curve to the postexercise R-R intervals for each subject to calculate the recovery constant (kr) as primary outcome. Secondary outcome was the root mean square residuals averaged over 1 min (RMS1min), a marker of parasympathetic tone. We used multiple linear regressions to determine the effect of functional candidate genetic variants in autonomic pathways (6 ADRA2A, 1 ADRA2B, 4 ADRA2C, 2 ADRB1, 3 ADRB2, 2 NET, 2 CHT, and 1 GRK5) on the outcomes before and after adjustment for potential confounders. Recovery constant was lower (indicating slower HRR) in ADRA2B 301-303 deletion carriers (n = 54, P = 0.01), explaining 3.6% of the interindividual variability in HRR. ADRA2A Asn251Lys, ADRA2C rs13118771, and ADRB1 Ser49Gly genotypes were associated with RMS1min. Genetic variability in adrenergic receptors may be associated with HRR after exercise. However, most of the interindividual variability in HRR remained unexplained by the variants examined. Noncandidate gene-driven approaches to study genetic contributions to HRR in larger cohorts will be of interest.

Effects of sex and the common ADRB1 389 genetic polymorphism on the hemodynamic response to dobutamine.

INTRODUCTION: The ADRB1 389 polymorphism affects responses to the ß-1 adrenergic receptor (ß1AR) agonist in vitro. Previous studies on its effect on the response to dobutamine stress echocardiography were conflicting. In addition, sex differences in the response to dobutamine have been suggested. The aim of this study was to determine whether the ADRB1 389 polymorphism affects the hemodynamic response to dobutamine in healthy individuals including men and women. PARTICIPANTS AND METHODS: Healthy individuals were recruited according to their ADRB1 49 and 389 genotypes [15 Arg389Arg, 10 Gly389Arg, and 10 Gly389Gly individuals, (all Ser49Ser), 21 men and 14 women]. Dobutamine was infused at 2, 4, and 6 mcg/kg/min. Standardized exercise was performed during the last minute of each infusion. RESULTS: Resting heart rate (HR) response to 6 mcg/kg/min dobutamine (ΔHR) was 4.7-fold larger in Arg389Arg than in Gly389Gly [(mean ± SD) 12.95 ± 6.99, 2.75 ± 1.65 bpm, respectively, PANOVA=0.012]. Renin response to dobutamine (ΔRenin) was 3.9-fold greater in Arg389Arg than in Gly389Gly (PANOVA=0.032). Among Arg389Gly heterozygotes, ΔHR and ΔRenin were not significantly different from either homozygote group. In multivariate analysis for ΔHR variance, significant contributions were observed for genotype (P=0.011), baseline HR (P=0.011), and borderline effect for sex (P=0.049). CONCLUSION: In healthy individuals, HR and renin responses to dobutamine were more than three-fold greater among ADRB1 Arg389 compared with Gly389 homozygotes. Future studies on the effect of the ADRB1 389 polymorphism on dobutamine stress echocardiography should compare Arg389 and Gly389 homozygotes.

The effect of medical students' gender, ethnicity and attitude towards poetry-reading on the evaluation of a required, clinically-integrated poetry-based educational intervention.

BACKGROUND: Art-based interventions are widely used in medical education. However, data on the potential effects of art-based interventions on medical students have been limited to small qualitative studies on students' evaluation of elective programs, and thus their findings may be difficult to generalize. The goal of this study is to examine, in an unselected students' population, the effect of students' gender, ethnicity and attitude towards poetry on their evaluation of a clinically-integrated poetry-based educational intervention. METHODS: A required Clinically- Oriented Poetry-reading Experience (COPE) is integrated into the 4th year internal medicine clerkship. We constructed a questionnaire regarding the program's effects on students. Students completed the questionnaire at the end of the clerkship. We performed a Confirmatory Factor Analysis, and examined the relationship between students' evaluation of the program and students' ethnicity, gender, attitude towards poetry-reading, and the timing of the program (early/late) during the fourth year. RESULTS: 144 students participated in the program, of which 112 completed the questionnaires. We identified two effect factors: "student-patient" and "self and colleagues". The average score for "student-patient" factor was significantly higher as compared to the "self and colleagues" factor.Evaluation the "student- patient" effect factor was higher among Arab and Druze as compared to Jewish students. Students' attitude towards poetry-reading did not correlate with the "student-patient" effect, but correlated with the "self and colleagues" effect. The evaluation of the "self and colleagues" effect was higher among students who participated in the program during their second as compared with the first clerkship. Students' gender was not associated with any of the effects identified. Students favored obligatory participation in COPE as compared with elective course format. CONCLUSIONS: According to students' evaluation, a format of integrated, obligatory poetry-based intervention may be suitable for enhancing "student-patient" aims in heterogeneous student populations. The higher evaluation of the "patient-student" effect among Arab and Druze as compared to Jewish students may be related to cultural differences in the perception of this component of medical professionalism. Further research can provide insight into the effect of cultural and ethnic differences on actual empathy of medical students in patient encounters.

The Effect of Levetiracetam Compared with Enzyme-Inducing Antiseizure Medications on Apixaban and Rivaroxaban Peak Plasma Concentrations.

BACKGROUND AND OBJECTIVE: Post-stroke epilepsy represents an important clinical challenge as it often requires both treatment with direct oral anticoagulants (DOACs) and antiseizure medications (ASMs). Levetiracetam (LEV), an ASM not known to induce metabolizing enzymes, has been suggested as a safer alternative to enzyme-inducing (EI)-ASMs in patients treated with DOACs; however, current clinical guidelines suggest caution when LEV is used with DOACs because of possible P-glycoprotein induction and competition (based on preclinical studies). We investigated whether LEV affects apixaban and rivaroxaban concentrations compared with two control groups: (a) patients treated with EI-ASMs and (b) patients not treated with any ASM. METHODS: In this retrospective observational study, we monitored apixaban and rivaroxaban peak plasma concentrations (Cmax) in 203 patients treated with LEV (n = 28) and with EI-ASM (n = 33), and in patients not treated with any ASM (n = 142). Enzyme-inducing ASMs included carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine. We collected clinical and laboratory data for analysis, and DOAC Cmax of patients taking LEV were compared with the other two groups. RESULTS: In 203 patients, 55% were female and the mean age was 78 ± 0.8 years. One hundred and eighty-six patients received apixaban and 17 patients received rivaroxaban. The proportion of patients with DOAC Cmax below their therapeutic range was 7.1% in the LEV group, 10.6% in the non-ASM group, and 36.4% in the EI-ASM group (p < 0.001). The odds of having DOAC Cmax below the therapeutic range (compared with control groups) was not significantly different in patients taking LEV (adjusted odds ratio 0.70, 95% confidence interval 0.19-2.67, p = 0.61), but it was 12.7-fold higher in patients taking EI-ASM (p < 0.001). In an analysis in patients treated with apixaban, there was no difference in apixaban Cmax between patients treated with LEV and non-ASM controls, and LEV clinical use was not associated with variability in apixaban Cmax in a multivariate linear regression. CONCLUSIONS: In this study, we show that unlike EI-ASMs, LEV clinical use was not significantly associated with lower apixaban Cmax and was similar to that in patients not treated with any ASM. Our findings suggest that the combination of LEV with apixaban and rivaroxaban may not be associated with decreased apixaban and rivaroxaban Cmax. Therefore, prospective controlled studies are required to examine the possible non-pharmacokinetic mechanism of the effect of the LEV-apixaban or LEV-rivaroxaban combination on patients' outcomes.

Variation in the α(2A) adrenoceptor gene and the effect of dexmedetomidine on plasma insulin and glucose.

OBJECTIVES: Sympathetic activation inhibits insulin secretion through activation of pancreatic α(2)A adrenoreceptors (α(2A)ARs). A common genetic α(2A)AR variant (rs553668) is associated with impaired insulin secretion. α(2A)R agonists would be expected to decrease insulin secretion, but their effects on glucose homeostasis in humans are poorly characterized. We examined the hypotheses that the selective α(2A)R agonist, dexmedetomidine, decreases plasma insulin levels and increases plasma glucose levels in humans and that these effects are modified by genetic α(2A)AR variants. METHODS: Healthy, fasting, White (n=31) and Black (n=33) participants aged between 18 and 45 years received three sequential infusions of placebo (normal saline) at 30-min intervals, followed by three infusions of dexmedetomidine (0.1, 0.15, and 0.15 mcg/kg). Plasma insulin and glucose concentrations were measured at baseline and after the administration of placebo and dexmedetomidine. We genotyped ADRA2A rs553668 and rs2484516, which characterize haplotypes 4 and 4b, respectively. RESULTS: Dexmedetomidine decreased fasting insulin concentrations by 37%, from a median value after placebo administration of 7.9 µU/ml (interquartile range: 6.0-12.6) to 4.9 µU/ml (interquartile range: 3.5-7.9; P<0.001). Plasma glucose concentrations increased from 76±6 to 79±7 mg/dl (P<0.001). The rs2484516 variant allele was associated with higher baseline insulin concentrations before (P=0.001) and after adjustment for potential confounders (P=0.014) and a greater decrease in insulin concentration after dexmedetomidine administration (P=0.016), which was no longer significant after adjustment for baseline concentrations and other confounders (P=0.58). CONCLUSION: Low-dose dexmedetomidine decreased plasma insulin concentration and mildly increased plasma glucose concentration in healthy fasting individuals. The ADRA2A genetic variation may affect baseline insulin concentrations and thus the insulin decrease after dexmedetomidine administration.

The common Arg389gly ADRB1 polymorphism affects heart rate response to the ultra-short-acting ß(1) adrenergic receptor antagonist esmolol in healthy individuals.

The ß1-adrenergic receptor (ß1AR) Arg389Gly polymorphism affects responses to orally administered ß1AR antagonists (ß-blockers) in vivo. However, the effect of this polymorphism on the early heart rate response to ß-blockers has not been evaluated. The aim of this study was to determine the effect of the Arg389Gly polymorphism on the inhibition of exercise-induced tachycardia by esmolol, an ultra-short-acting intravenously administered ß1AR antagonist. Healthy nonsmoking White individuals were enrolled on the basis of their ADRB1 genotype, including carriers of 0, 1 or 2 Arg389 alleles (n=9 in each group, total 27, 18 men). Placebo and esmolol were infused consecutively for 10 min each, separated by 30 min. At the end of each infusion, participants performed dynamic handgrip exercise. Heart rate and blood pressure were compared among three ADRB1 genotypes. Carriers of 0, 1, or 2 Arg389 alleles varied significantly in both exercise-induced tachycardia during esmolol (P(ANOVA)=0.030) and esmolol inhibition of exercise-induced tachycardia [0.78±7.70, 5.11±4.05, 10.22±9.78 bpm, respectively (P=0.014)]. The early effect of esmolol on exercise-induced tachycardia was significantly greater among Arg389 than in Gly389 homozygote healthy individuals (NCT01388036).