Kathleen A. Packard

Effects of histamine on Th1/Th2 cytokine balance

Atopic asthma is a chronic inflammatory disorder of the airways where upon exposure to allergens, the body mounts an immune response. This disease is associated with an increase in the number of Th2 (T helper type 2) cells and Th2 cytokines and a decrease in the number of Th1 (T helper type 1) cells and Th1 cytokines. Histamine plays an important role in the pathogenesis of atopic asthma through differential regulation of T helper lymphocytes. Histamine enhances the secretion of Th2 cytokines such as IL-4 (interleukin-4), IL-5, IL-10 and IL-13 and inhibits the production of Th1 cytokines IL-2 and IFNgamma (interferon-gamma) and monokine IL-12. It has been shown that histamine can modulate the cytokine network through upregulation of PGE(2) (prostaglandin E(2)) and NO (nitric oxide). Histamine also affects cytokine production via H2 receptors and through the activation of PKA (protein kinase A). We have also demonstrated that the Jak-STAT (Janus kinase-signal transducers and activators of transcription) pathway is involved in histamine-mediated regulation of Th2 cytokines IL-5, IL-10, IL-13 and Th1 cytokine IFNgamma. While standard treatment of asthma consists of beta-receptor agonists and inhaled corticosteroids, the elucidation of histamines control over the cytokine network and the Th1/Th2 balance provides a basis for the potential use of antihistamines in the prevention and treatment of atopic asthma. Several other anti-allergic agents to modulate the Th1/Th2 balance are under current investigation based on this paradigm. These include cytokines, cytokine antagonists, anti-IgE, and vaccinations. As more advances are made in our understanding of histamine and its control over the Th1/Th2 balance, the use of new therapeutic targets such as these will play a prominent role in disease management.

Pharmacologic Prophylaxis of Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery: Beyond β‐Blockers

Postoperative atrial fibrillation (POAF) is a frequent complication of cardiac surgery that increases patient morbidity, length of stay, and hospital costs. A substantial body of evidence exists evaluating various pharmacologic and nonpharmacologic methods to decrease the occurrence of POAF in an effort to decrease its burden on the health care system. Evidence‐based guidelines support the use of β‐blockers as standard prophylaxis of POAF in patients undergoing cardiac surgery. Traditional prophylactic therapy for POAF targets the sympathetic nervous system, refractory period, and atrial conduction. However, associations between the development of POAF and the inflammatory process, oxidative stress, and atrial remodeling have prompted the investigation of novel therapies targeting these processes. To evaluate the role of pharmacologic strategies beyond β‐blockers in the prevention of POAF we conducted a search of the PubMed database to identify studies published from 1950–February 2009. Emphasis was placed on how these therapies could be used in patients intolerant to β‐blockers or as additive therapy in high‐risk patients. We found that sufficient evidence exists to recommend the use of amiodarone, sotalol, and possibly magnesium as monotherapy in patients unable to take β‐blockers or as add‐on therapy for the prevention of POAF Currently, available evidence does not support the use of propafenone, procainamide, digoxin, thiazolidinediones, triiodothyronine, or calcium channel blockers in the prevention of POAF Preliminary evidence suggests that dofetilide, angiotensin‐converting enzyme inhibitors, angiotensin II receptor blockers, 3–hydroxy‐3–methylglutaryl coenzyme A reductase inhibitors (statins), nonsteroidal antiinflammatory drugs, corticosteroids, omega‐3 fatty acids, ascorbic acid, N‐acetylcysteine, and sodium nitroprusside may be effective in preventing POAF. Additional large‐scale, adequately powered clinical studies are needed to determine the benefit of these agents before they can be considered for routine use.

New and emerging anticoagulant therapy for atrial fibrillation and acute coronary syndrome.

Thrombosis is an underlying cause of many cardiovascular disorders, and generation of thrombi in the arterial circulation can lead to unstable angina, myocardial infarction, or ischemic stroke. Antithrombotic therapy is widely used, with proven benefit to prevent ischemic stroke and thromboembolic events in patients with atrial fibrillation (AF) or to prevent further ischemic complications in patients with acute coronary syndrome (ACS). Traditional anticoagulants (including unfractionated heparin, low‐molecular‐weight heparin, and warfarin) and antiplatelet agents (including aspirin, clopidogrel, and prasugrel) are typically used for these indications. Limitations to their use include variable pharmacokinetic and pharmacodynamic profiles, inability to inhibit fibrin‐bound thrombin, risk of heparin‐induced thrombocytopenia, delayed onset of action, numerous drug interactions, need for substantial laboratory monitoring and dosage titrations, hyporesponsiveness or resistance, hypersensitivity, adverse events, and bleeding. To overcome some of the limitations of traditional agents, new antithrombotic agents under development are highly selective for specific coagulation factors blocking the synthesis of thrombin. Clinicians must have an understanding of the new anticoagulants to aid in the selection of appropriate therapies for patients. We describe the most relevant phases II and III clinical trials that evaluated several recent emerging anticoagulant drugs for use in patients with AF or ACS. The advantages of many new agents include predictable pharmacodynamic response and pharmacokinetic parameters, allowing for fixed oral dosing with no need for laboratory monitoring. For patients with AF, dabigatran is already approved for the prevention of stroke and systemic embolism, rivaroxaban appears to be an effective alternative to warfarin in high‐risk patients, and apixaban may also be an effective alternative to aspirin in patients unable to take warfarin. Otamixaban shows promise as an intravenous alternative for patients with ACS in the acute care setting. Likewise, rivaroxaban, dabigatran, and darexaban with or without dual antiplatelet therapy may be beneficial for secondary prevention of ischemic events in patients with ACS.

ACE Inhibitor—Induced Bronchial Reactivity in Patients with Respiratory Dysfunction

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are often associated with an increased incidence of cough and bronchial responsiveness that may cause further deterioration of patients with impaired pulmonary function. OBJECTIVE: To review the available literature on the incidence of cough and bronchial responsiveness associated with ACE-inhibitor therapy in patients with asthma, chronic obstructive pulmonary disease (COPD), and congestive heart failure (CHF). DATA SOURCES: Literature was accessed through MEDLINE (1985–September 2001). Key search terms included cough, bronchospasm, asthma, congestive heart failure, chronic obstructive pulmonary disease, ACE inhibitors, and angiotensin II receptor blockers. DATA SYNTHESIS: The literature reports several cases of increased bronchial responsiveness associated with ACE inhibitors. Larger, controlled studies evaluating the increased risk in patients with pulmonary dysfunction are limited. Data from these trials are summarized in this article. CONCLUSIONS: The literature shows that patients with primary airway disease such as asthma and COPD are not at an increased risk of developing cough or bronchoconstriction as a result of ACE-inhibitor therapy. Despite the ability of ACE inhibitors to improve exercise tolerance, perfusion, and gas transfer, patients with CHF may be at higher risk of developing cough than the general population. Whether this cough is attributed to ACE inhibition or increased left-ventricular dysfunction remains uncertain. If increased bronchial responsiveness does occur, angiotensin II receptor antagonists are another reasonable option.

Comparison of gemfibrozil and Fenofibrate in patients with dyslipidemic coronary heart disease

Study Objective. To compare the lipid‐lowering effects of gemfibrozil and fenofibrate in patients with dyslipidemic coronary heart disease.

Antipsychotic use and the risk of rhabdomyolysis

Rhabdomyolysis is not a well-understood adverse effect of antipsychotic use. Proposed mechanisms suggest involvement of serotoninergic and/or dopaminergic blockade. The purpose of this study was to describe the relationship between antipsychotic use and rhabdomyolysis. Patients admitted with rhabdomyolysis and taking an antipsychotic from January 2009 to October 2011 were included. Background demographics, laboratory data, medical and physical history, concomitant medications, and hospital course data were collected. Of the 673 cases admitted with rhabdomyolysis, 71 (10.5%) were on an antipsychotic. This is significantly greater when compared to the general US population, where only 1.3% of individuals take an antipsychotic drug (P < .0001). Cause of rhabdomyolysis was not documented in 38% of cases, and antipsychotic use was suspected in 10% of cases. No significant correlations were found between antipsychotic type and other patient-specific parameters. Seventeen (25%) of these patients were taking 2 or more antipsychotics. The largest percentage was on quetiapine (Seroquel®; AstraZeneca, Wilmington, Delaware), the most commonly prescribed antipsychotic in the United States. Antipsychotic use is a risk factor for rhabdomyolysis and seems to be more common in those taking multiple agents. More research needs to be done to determine which antipsychotics have a higher risk and which receptors are involved. Providers should be aware of rhabdomyolysis associated with antipsychotic use.

Reflections from an interprofessional education experience: evidence for the core competencies for interprofessional collaborative practice.

The Core Competencies for Collaborative Practice identify the skills needed by every health care provider to be successful in implementing interprofessional practice. Health professions students need to build skills for interprofessional practice as emerging professionals. Reflection is a core skill needed for successful interprofessional practices. This study identifies themes from an interprofessional education research project and discusses their congruency with the Competencies.

Esmolol versus diltiazem in atrial fibrillation following coronary artery bypass graft surgery.

SUMMARY Purpose: Atrial fibrillation (AF) is the most common arrhythmic complication following coronary artery bypass graft surgery (CABG). The efficacy and safety of esmolol and diltiazem were compared in patients with post-CABG AF. Methods: This study was a retrospective medical record review of consecutive patients with post-CABG AF >15 min in duration with a ventricular rate >110 b.p.m. who received either i.v. esmolol (n = 59) or i.v. diltiazem (n = 48) with or without concomitant digoxin therapy at a single university-affiliated teaching hospital. Treatment success was defined as either cardioversion to sinus rhythm or a reduction in the ventricular rate to <90 b.p.m. at 24 h after the start of therapy. Time to treatment success and the occurrence of adverse effects were considered secondary outcomes. Results: A total of 107 patients with post-CABG AF were treated with i.v. esmolol (n = 59) or i.v. diltiazem (n = 48). The mean maximum dose of esmolol and diltiazem were 115 ± 38 μg/kg/min and 11.2 ± 3.5 mg/h, respectively. The average duration of the esmolol and diltiazem infusions were 19.3 ± 8.5 h and 20.1 ± 11.3 h, respectively. Based on the combined efficacy endpoint of cardioversion or ventricular rate control, esmolol was significantly more effective than diltiazem (90% vs 77%; p = 0.038). Time to treatment success was significantly better for esmolol than diltiazem at all time points (1, 2,4,6,12, and 24 h post-treatment). The overall incidence of adverse effects was 44% with esmolol and 60% with diltiazem (p = 0.04). Rates of drug discontinuance for adverse effects were significantly less for esmolol (20%) compared with diltiazem (38%) (p = 0.04). Conclusions: Esmolol is significantly more effective than diltiazem in the management of post-CABG AF. More patients converted to sinus rhythm with esmolol as compared to diltiazem. Esmolol was associated with fewer adverse effects than diltiazem, including adverse effects leading to drug discontinuance. Due to study design limitations (retrospective data collection), an adequately powered randomised, controlled trial is needed to confirm these preliminary findings.

Comment: Fatal Intracranial Bleed Potentially Due to a Warfarin and Influenza Vaccine Interaction

Objective:To report a case of fatal intracranial bleeding possibly due to an interaction between warfarin and inactivated influenza vaccination.Case Summary:A 64-year-old white male was admitted to the hospital after becoming unresponsive. The family reported a 2-day history of bleeding from the patients rectum prior to admission. He had no recent changes in medical conditions or medication regimen, which included warfarin for stroke prophylaxis secondary to atrial fibrillation. The patient had received an inactivated influenza vaccine 4½ weeks prior to presentation, at which time his international normalized ratio (INR) was 2.0. Upon admission, the patients INR was greater than 15: INR values over the previous 6 months had been relatively stable {range 1.4–4.7). A noncontrast computed tomography scan of the head showed a large parenchymal hemorrhagic infarction involving the left temporal, parietal, and occipital lobes. In the emergency department, the patient received a nitroglycerin infusion to maint...

Emerging Antiplatelet Therapy for Coronary Artery Disease and Acute Coronary Syndrome

Antiplatelet therapy is used widely with proven benefit for the prevention of further ischemic cardiac complications in patients with known coronary artery disease (CAD) and a history of acute coronary syndrome (ACS). The limitations of conventional antiplatelet therapy with aspirin, clopidogrel, or prasugrel, as well as the fact that rates of recurrent ischemic events still remain high with use of these agents, underscore the need to investigate alternate agents that may further reduce event rates while limiting bleeding risk. The selection of antiplatelet therapy is further influenced by the following: ticagrelor was approved in July 2011 by the United States Food and Drug Administration (FDA),and clopidogrel is slated to become available as a generic productin 2012. We provide an overview of emerging agents for the treatment of CAD and ACS, including the reversible P2Y12 antagonists ticagrelor, cangrelor, and elinogrel, and a new class of oral protease‐activated receptor‐1 (PAR‐1) inhibitors, vorapaxar and atopaxar.The recentlyapproved P2Y12 antagonists prasugrel and ticagrelor demonstrate enhanced ability to prevent adverse cardiac outcomes. However, this comes at a cost of a potential increased risk of bleeding. New adverse effects have also emerged, including dyspnea for all of the reversible P2Y12 antagonists (ticagrelor, cangrelor, and elinogrel) and ventricular pauses for ticagrelor. In addition, the newer P2Y12 antagonists have a faster onset and offset. Two of these agents, cangrelor and elinogrel, are available as intravenous formulations, which may provide additional benefits in patients whoundergo coronary artery bypass graft (CABG) surgery. Trials with the PAR‐1 inhibitors have also shown trends toward reductions in cardiac events, but not without the possibility of increased bleeding. More than ever, as the arsenal of antiplatelet therapy expands, health care providers need to understand the pharmacologic and pharmacodynamic differences between conventional and emerging antiplatelet therapies forpatients with ACS and CAD. Health care providers must also carefully assess patient‐specific factors such as risk of thrombosis, concomitant disease states, age, drug adherence, and aspirin dose, and plan for those patients who will be undergoing CABG when selecting antiplatelet therapy in order to optimally balance bleeding and thrombosis risk.