Baseline values from the electrocardiograms of children and adolescents with ADHD

<p>Abstract</p> <p>Background</p> <p>An important issue in pediatric pharmacology is the determination of whether medications affect cardiac rhythm parameters, in particular the QT interval, which is a surrogate marker for the risk of adverse cardiac events and sudden death. To evaluate changes while on medication, it is useful to have a comparison of age appropriate values while off medication. The present meta-analysis provides baseline ECG values (i.e., off medication) from approximately 6000 children and adolescents with attention-deficit/hyperactivity disorder (ADHD).</p> <p>Methods</p> <p>Subjects were aged 6–18 years and participated in global trials within the atomoxetine registration program. Patients were administered a 12-lead ECG at study screening and cardiac rhythm parameters were recorded. Baseline QT intervals were corrected for heart rate using 3 different methods: Bazett's, Fridericia's, and a population data-derived formula.</p> <p>Results</p> <p>ECG data were obtained from 5289 North American and 641 non-North American children and adolescents. Means and percentiles are presented for each ECG measure and QTc interval based on pubertal status as defined by age and sex. Prior treatment history with stimulants and racial origin (Caucasian) were each associated with significantly longer mean QTc values.</p> <p>Conclusion</p> <p>Baseline ECG and QTc data from almost 6000 children and adolescents presenting with ADHD are provided to contribute to the knowledge base regarding mean values for pediatric cardiac parameters. Consistent with other studies of QT interval in children and adolescents, Bazett correction formula appears to overestimate the prevalence of prolonged QTc in the pediatric population.</p

Do Stress Responses Promote Leukemia Progression? An Animal Study Suggesting a Role for Epinephrine and Prostaglandin-E2 through Reduced NK Activity

In leukemia patients, stress and anxiety were suggested to predict poorer prognosis. Oncological patients experience ample physiological and psychological stress, potentially leading to increased secretion of stress factors, including epinephrine, corticosteroids, and prostaglandins. Here we tested whether environmental stress and these stress factors impact survival of leukemia-challenged rats, and studied mediating mechanisms. F344 rats were administered with a miniscule dose of 60 CRNK-16 leukemia cells, and were subjected to intermittent forced swim stress or to administration of physiologically relevant doses of epinephrine, prostaglandin-E2 or corticosterone. Stress and each stress factor, and/or their combinations, doubled mortality rates when acutely applied simultaneously with, or two or six days after tumor challenge. Acute administration of the β-adrenergic blocker nadolol diminished the effects of environmental stress, without affecting baseline survival rates. Prolonged β-adrenergic blockade or COX inhibition (using etodolac) also increased baseline survival rates, possibly by blocking tumor-related or normal levels of catecholamines and prostaglandins. Searching for mediating mechanisms, we found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis. In contrast, the direct effects of stress factors on CRNK-16 proliferation, vitality, and VEGF secretion could not explain or even contradicted the in vivo survival findings. Overall, it seems that environmental stress, epinephrine, and prostaglandins promote leukemia progression in rats, potentially through suppressing cell mediated immunity. Thus, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended β-blockade and COX inhibition

PPARγ agonists as therapeutics for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by the deposition of β-amyloid within the brain parenchyma and is accompanied by the impairment of neuronal metabolism and function, leading to extensive neuronal loss. The disease involves the perturbation of synaptic function, energy, and lipid metabolism. The development of amyloid plaques results in the induction of a microglial-mediated inflammatory response. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor whose biological actions are to regulate glucose and lipid metabolism and suppress inflammatory gene expression. Thus, agonists of this receptor represent an attractive therapeutic target for AD. There is now an extensive body of evidence that has demonstrated the efficacy of PPARγ agonists in ameliorating disease-related pathology and improved learning and memory in animal models of AD. Recent clinical trials of the PPARy agonist rosiglitazone have shown significant improvement in memory and cognition in AD patients. Thus, PPARγ represents an important new therapeutic target in treating AD