Judith E. Soberman

Effects of grapefruit juice on intestinal P-glycoprotein: evaluation using digoxin in humans.

Study Objectives. To determine the effects of grapefruit juice on the pharmacokinetics of oral digoxin, a P‐glycoprotein substrate not metabolized by cytochrome P450 3A4, in healthy volunteers, and to assess whether polymorphic multidrug‐resistance‐1 (MDR1) expression contributes to interindividual variability in digoxin disposition.

Exercise Capacity and Cardiovascular/Metabolic Characteristics of Overweight and Obese Individuals With Type 2 Diabetes: The Look AHEAD clinical trial

OBJECTIVE— We examined associations of cardiovascular, metabolic, and body composition measures with exercise capacity using baseline data from 5,145 overweight and/or obese (BMI ≥25.0 kg/m2) men and women with type 2 diabetes who were randomized participants for the Look AHEAD (Action for Health in Diabetes) clinical trial. RESEARCH DESIGN AND METHODS— Peak exercise capacity expressed as METs and estimated from treadmill speed and grade was measured during a graded exercise test designed to elicit a maximal effort. Other measures included waist circumference, BMI, type 2 diabetes duration, types of medication used, A1C, history of cardiovascular disease, metabolic syndrome, β-blocker use, and race/ethnicity. RESULTS— Peak exercise capacity was higher for men (8.0 ± 2.1 METs) than for women (6.7 ± 1.7 METs) (P < 0.001). Exercise capacity also decreased across each decade of age (P < 0.001) and with increasing BMI and waist circumference levels in both sexes. Older age, increased waist circumference and BMI, a longer duration of diabetes, increased A1C, a history of cardiovascular disease, having metabolic syndrome, β-blocker use, and being African American compared with being Caucasian were associated with a lower peak exercise capacity for both sexes. Hypertension and use of diabetes medications were associated with lower peak exercise capacity in women. CONCLUSIONS— Individuals with diabetes who are overweight or obese have impaired exercise capacity, which is primarily related to age, female sex, and race, as well as poor metabolic control, BMI, and central obesity.

Beta-Blockers after Myocardial Infarction: Do Benefits Ever Outweigh Risks in Asthma?

β-Blockers are well documented to prolong life in patients after myocardial infarction (MI), yet patients who also have asthma are frequently and understandably denied this therapy. We reviewed the literature (via MEDLINE) for the past 35 years for β-blocker-induced asthma, and reexamined potential β-blocker use in the context of NIH guidelines for asthma classification and management. Because β-blockers can cause fatal or life-threatening asthma, their use should be avoided in moderate to severe persistent asthmatics. Benefits of low-dose β1-blockers (e.g. atenolol 50 mg daily) may outweigh risks in some patients with mild intermittent or well-controlled mild persistent asthma. Further study is needed to verify that low doses of β1-blockers are effective in prolonging life after MI, and that use specifically in mild intermittent or mild persistent asthma per NIH classification is safe.

A Dyshomeostasis of Electrolytes and Trace Elements in Acute Stressor States: Impact on the Heart

Acute stressor states are associated with a homeostatic activation of the hypothalamic-pituitary-adrenal axis. A hyperadrenergic state follows and leads to a dyshomeostasis of several intra- and extracellular cations, including K+, Mg2+, and Ca2+. Prolongation of myocardial repolarization and corrected QT interval (QTc) of the ECG are useful biomarkers of hypokalemia and/or hypomagnesemia and should be monitored to address the adequacy of cation replacement. A dyshomeostasis of several trace elements, including Zn2+ and Se2+, are also found in critically-ill patients to compromise metalloenzyme-based antioxidant defenses. Collectively, dyshomeostasis of these electrolytes and trace elements have deleterious consequences on the myocardium: atrial and ventricular arrhythmias; induction of oxidative stress with reduced antioxidant defenses; and adverse myocardial remodeling, including cardiomyocytes lost to necrosis and replaced by fibrous tissue. To minimize such consequences during hyperadrenergic states, systematic surveillance of electrolytes and trace elements, together with QTc, are warranted. Plasma K+ and Mg2+ should be maintained at ≥4.0 mEq/L and ≥2.0 mg/dL, respectively (the 4 and 2 rule).

Effects of paroxetine on the pharmacokinetics and pharmacodynamics of immediate-release and extended-release metoprolol.

Study Objective. To compare the effects of paroxetine on the pharmacokinetics and pharmacodynamics of the immediate‐release (IR) and extended‐release (ER) formulations of metoprolol.

Prevalence and Predictors of Abnormal Cardiovascular Responses to Exercise Testing Among Individuals With Type 2 Diabetes: The Look AHEAD (Action for Health in Diabetes) study

OBJECTIVE We examined maximal graded exercise test (GXT) results in 5,783 overweight/obese men and women, aged 45–76 years, with type 2 diabetes, who were entering the Look AHEAD (Action for Health in Diabetes) study, to determine the prevalence and correlates of exercise-induced cardiac abnormalities. RESEARCH DESIGN AND METHODS Participants underwent symptom-limited maximal GXTs. Questionnaires and physical examinations were used to determine demographic, anthropometric, metabolic, and health status predictors of abnormal GXT results, which were defined as an ST segment depression ≥1.0 mm, ventricular arrhythmia, angina pectoris, poor postexercise heart rate recovery (<22 bpm reduction 2 min after exercise), or maximal exercise capacity less than 5.0 METs. Systolic blood pressure response to exercise was examined as a continuous variable, without a threshold to define abnormality. RESULTS Exercise-induced abnormalities were present in 1,303 (22.5%) participants, of which 693 (12.0%) consisted of impaired exercise capacity. ST segment depression occurred in 440 (7.6%), abnormal heart rate recovery in 206 (5.0%), angina in 63 (1.1%), and arrhythmia in 41 (0.7%). Of potential predictors, only greater age was associated with increased prevalence of all abnormalities. Other predictors were associated with some, but not all, abnormalities. Systolic blood pressure response decreased with greater age, duration of diabetes, and history of cardiovascular disease. CONCLUSIONS We found a high rate of abnormal GXT results despite careful screening for cardiovascular disease symptoms. In this cohort of overweight and obese individuals with type 2 diabetes, greater age most consistently predicted abnormal GXT. Long-term follow-up of these participants will show whether these abnormalities are clinically significant.

Prevalence and predictors of abnormal cardiovascular responses to exercise testing among persons with type 2 diabetes. The Look AHEAD Study

OBJECTIVE We examined maximal graded exercise test (GXT) results in 5,783 overweight/obese men and women, aged 45–76 years, with type 2 diabetes, who were entering the Look AHEAD (Action for Health in Diabetes) study, to determine the prevalence and correlates of exercise-induced cardiac abnormalities. RESEARCH DESIGN AND METHODS Participants underwent symptom-limited maximal GXTs. Questionnaires and physical examinations were used to determine demographic, anthropometric, metabolic, and health status predictors of abnormal GXT results, which were defined as an ST segment depression ≥1.0 mm, ventricular arrhythmia, angina pectoris, poor postexercise heart rate recovery (<22 bpm reduction 2 min after exercise), or maximal exercise capacity less than 5.0 METs. Systolic blood pressure response to exercise was examined as a continuous variable, without a threshold to define abnormality. RESULTS Exercise-induced abnormalities were present in 1,303 (22.5%) participants, of which 693 (12.0%) consisted of impaired exercise capacity. ST segment depression occurred in 440 (7.6%), abnormal heart rate recovery in 206 (5.0%), angina in 63 (1.1%), and arrhythmia in 41 (0.7%). Of potential predictors, only greater age was associated with increased prevalence of all abnormalities. Other predictors were associated with some, but not all, abnormalities. Systolic blood pressure response decreased with greater age, duration of diabetes, and history of cardiovascular disease. CONCLUSIONS We found a high rate of abnormal GXT results despite careful screening for cardiovascular disease symptoms. In this cohort of overweight and obese individuals with type 2 diabetes, greater age most consistently predicted abnormal GXT. Long-term follow-up of these participants will show whether these abnormalities are clinically significant.

Cardioselective beta-blockers in patients with asthma and concomitant heart failure or history of myocardial infarction: when do benefits outweigh risks?

Beta-adrenergic blocker therapy has clearly established benefits in the management of heart failure, including reduced mortality, improved left ventricular function, and decreased symptoms (1–5). Beta-blockers are one component of standard care for long-term management of heart failure (6). These agents are also well documented to prolong life after acute myocardial infarction (AMI) (7–9). Beta-blocker therapy post AMI, both on admission to the emergency department and long term, is the standard of care (10). Several reports suggest underuse of beta-blockers in post myocardial infarction (MI) patients and patients with heart failure (11–17). Noncardioselective beta-blockers are contraindicated in asthma due to numerous reports of severe bronchospasm and death or near death experiences since initial reports in the mid-1960s (18–24). However, use of cardioselective beta-blockers clearly reduces the incidence of bronchospasm, and these agents will save lives and improve the quality of life in appropriately selected asthma patients with cardiovascular disease. Because the risk of bronchospasm with cardioselective agents is not completely eliminated, particularly at higher doses, care must be exercised in choosing which patients with asthma should receive these agents (25–27). A recent meta-analysis and an accompanying editorial concluded that cardioselective beta-blockers do not produce clinically significant bronchospasm and should not be withheld in patients with ‘‘mild to moderate reactive airway disease (28,29).’’ Although this suggestion is generally true, this review closely examines some important aspects of cardioselective beta-blocker use in patients with asthma. Because at least 5% of the American population has asthma, the question of safety of cardioselective beta-blockers in patients with concomitant heart failure or history of MI has obvious importance. The significance of this question is further heightened with the exponential growth of the aging population. Although a lesser but similar concern exists for chronic obstructive pulmonary disease patients, the focus in this review is asthma.

Effect of disease states on theophylline serum concentrations: are we still vigilant?

The use of theophylline has decreased over the past decade because of concerns over the risks of serious adverse effects as well as availability of more effective, safer drugs. Because of this decline in use, some clinicians may not be alert to the marked effect of some disease states on theophylline serum concentrations. The purpose of this review is to heighten awareness of the effect of decompensated heart failure, cor pulmonale, hepatic dysfunction, thyroid disease, and febrile illness on theophylline serum concentrations. Because many patients receive some benefit from this drug, safe use by clinicians requires closer monitoring of serum concentrations in patients with factors that alter theophylline clearance, including several disease states.

Carvedilol therapy after cocaine-induced myocardial infarction in patients with asthma.

Introduction:Cocaine-induced myocardial infarction (MI) is well documented. Current literature recommends avoiding beta-blockers in the acute care setting, but after discharge from the hospital, benefits of beta-blocker use may outweigh risks in patients with recent MI resulting from cocaine use. Cardioselective beta-blocker therapy has been demonstrated to be beneficial in post-MI patients with nonsevere asthma. This review article is to compare the risks and benefits of using carvedilol in patients with asthma who have had cocaine-induced MI. Methods:The authors searched the English literature from 1984 to July 2010 via PubMed, EMBASE and SCOPUS using the following search terms: “cocaine-induced myocardial infarction AND treatment,” “cocaine AND carvedilol,” “beta blockers AND asthma,” and “carvedilol AND asthma.” All studies and case reports related to carvedilol use associated with bronchospasm in patients with asthma and carvedilol use after cocaine-induced MI were included. Results:Carvedilol has theoretical advantages in patients who use cocaine, but there are no controlled studies confirming the superior efficacy of this agent. Reports of carvedilol use in patients with asthma are rare, but findings include increased asthma symptoms and hospitalization in some patients. Fatal asthma has also been reported because of this noncardioselective beta-blocker. Conclusions:Based on a lack of evidence supporting the theoretical advantages but documented risks associated with its use in patients with asthma, carvedilol should be avoided in asthma patients who have a history of cocaine-induced MI. Cardioselective beta-blockers should be used in post-MI patients with nonsevere asthma.