Iatrogenic QT Abnormalities and Fatal Arrhythmias: Mechanisms and Clinical Significance

Severe and occasionally fatal arrhythmias, commonly presenting as Torsade de Pointes [TdP] have been reported with Class III-antiarrhythmics, but also with non-antiarrhythmic drugs. Most cases result from an action on K+ channels encoded by the HERG gene responsible for the IKr repolarizing current, leading to a long QT and repolarization abnormalities. The hydrophobic central cavity of the HERG-K+ channels, allows a large number of structurally unrelated drugs to bind and cause direct channel inhibition. Some examples are dofetilide, quinidine, sotalol, erythromycin, grepafloxacin, cisapride, dolasetron, thioridazine, haloperidol, droperidol and pimozide. Other drugs achieve channel inhibition indirectly by impairing channel traffic from the endoplasmic reticulum to the cell membrane, decreasing channel membrane density (pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol). Whereas, ketoconazole, fluoxetine and norfluoxetine induce both direct channel inhibition and impaired channel trafficking. Congenital long QT syndrome, subclinical ion-channel mutations, subjects and relatives of subjects with previous history of drug-induced long QT or TdP, dual drug effects on cardiac repolarization [long QT plus increased QT dispersion], increased transmural dispersion of repolarization and T wave abnormalities, use of high doses, metabolism inhibitors and/or combinations of QT prolonging drugs, hypokalemia, structural cardiac disease, sympathomimetics, bradycardia, women and older age, have been shown to increase the risk for developing drug-induced TdP. Because most of these reactions are preventable, careful evaluation of risk factors and increased knowledge of drugs use associated with repolarization abnormalities is strongly recommended. Future genetic testing and development of practical and simple provocation tests are in route to prevent iatrogenic TdP

Monoamine Release by Compound 48/80 from Nonmast Cell Compartments in Mouse Brain Slices1

ABSTRACT In the present study we investigated the specificity of the releasing effects of compoun

Glucose Abnormalities in Hispanics: How Long Before Type 2 Diabetes Mellitus?

Objectives. To determine the screening value of fasting plasma glucose and insulin in detecting glucose intolerance and diabetes mellitus (DM) in “healthy” Hispanics. Background. Glucose abnormalities precede development of diabetes mellitus. However, only fasting glucose levels are used in clinical practice, and its diagnostic value varies among ethnicities. Methods. Oral glucose tolerance testing was conducted in 592 Hispanics. A cross-sectional design was employed. Results. GA were found in 34% of subjects, defined as impaired fasting glucose (IFG) (13.3%), IGT (6.9%), combined IFG+IGT (7.8%) and type2-DM (6.5%). FPG of 5.6-6.9mmol/l diagnostic of IFG missed 47.1% of subjects with IGT, and FPG \u3e 7.0mmol/l missed 53.9% of DM. IFG showed a sensitivity of 52.9 % and a specificity of 83% in predicting IGT. The diagnostic yield, expressed by the positive predictive value was poor (36.8%). GA were associated with abdominal obesity, hypertriglyceridemia, hyperinsulinemia, hypertension and metabolic syndrome (MS). Prevalence of MS was greater in DM=IFG+IGT \u3e IGT=IFG \u3e controls. Post-load hyperinsulinemia and hyperglycemia was higher in IGT than in IFG; whereas HOMA-IR was higher in IFG. Insulin secretion was reduced in DM, IFG-IGT and IGT. Conclusion. Diagnosis of GA must include both, fasting and 2-hour post-load glucose levels. Presence of fasting and post-load hyperglycemia-hyperinsulinemia in one individual may explain the increased risk in combined IFG-IGT and in DM. Because of its 19 high prevalence, silent course, and associated increased risk, full-scale screening programs and aggressive management of GA must be implemented

Mechanisms of Hypertension Associated with Obesity

Background. Obesity is extremely common in people with high BP. However, the mechanisms by which BP increases in obese subjects are unknown. Objectives. We are interested in understanding the role of dietary salt and the BP reactivity to dietary salt (salt sensitivity) in the genesis of hypertension associated with obesity. We have recently shown that individuals with the metabolic syndrome are more salt sensitive that those without the syndrome. In addition, we have reported that high salt intake is associated with indices of obesity (BMI, weight and waist circumference). However, not all obese individuals have high BP, nor weight loss lowers BP in all subjects. Methods and Results. Therefore, a prospective study was designed to investigate the role of the salt sensitive (SS) and the salt resistant (SR) phenotypes in determining the degree of BP lowering induced by weight loss. Overweight/obese classified as SS or SR (n=45; BMI:27-35 kg/m2) entered a 1-year program of dietary restriction, aerobic exercise and metformin. Comparable reductions in obesity (8-10%), triglyceride (25%), and fasting insulin concentrations (40%) were observed in SR and SS individuals. In SS subjects the intervention lowered SBP/DBP by 8.8/6.1 mmHg, albuminuria by 63%, and decreased the subject’s SS. Neither BP nor albuminuria was modified in SR by the intervention. However, in obese SS individuals, restricting dietary salt lowered BP to a similar extent to the BP reduction achieved with the one-year intervention (weight loss). Conclusions. Our findings indicate that BP lowering induced by the lifestyle-metformin intervention appears to be determined by the SR/SS phenotype. Correcting adiposity in SS lowers BP because it makes the BP insensitive to dietary salt (corrects the SS phenotype). Therefore, weight loss and correction of metabolic abnormalities lowers BP in obese SS but not in obese SR, suggesting that the SR phenotype protects from obesity-induced increases in BP. These findings suggest that most of the hypertension associated with obesity is determined by dietary salt intake due to the development of a SS phenotype. The mechanisms (genetic or acquired) that determine the SS phenotype are under investigation

Lipid Nanoparticles in Lung Cancer Therapy

This manuscript explores the use of lipid nanoparticles (LNPs) in addressing the pivotal challenges of lung cancer treatment, including drug delivery inefficacy and multi-drug resistance. LNPs have significantly advanced targeted therapy by improving the precision and reducing the systemic toxicity of chemotherapeutics such as doxorubicin and paclitaxel. This manuscript details the design and benefits of various LNP systems, including solid lipid–polymer hybrids, which offer controlled release and enhanced drug encapsulation. Despite achievements in reducing tumor size and enhancing survival, challenges such as manufacturing complexity, biocompatibility, and variable clinical outcomes persist. Future directions are aimed at refining targeting capabilities, expanding combinatorial therapies, and integrating advanced manufacturing techniques to tailor treatments to individual patient profiles, thus promising to transform lung cancer therapy through interdisciplinary collaboration and regulatory innovation

Farmakologi: ulasan bergambar

x, 666 hlm. : ilus. ; 28,5 cm

Conductive polymers for cardiac tissue engineering and regeneration.

Cardiovascular diseases, such as myocardial infarction, are considered a significant global burden and the leading cause of death. Given the inability of damaged cardiac tissue to self-repair, cell-based tissue engineering and regeneration may be the only viable option for restoring normal heart function. To maintain the normal excitation-contraction coupling function of cardiac tissue, uniform electronic and ionic conductance properties are required. To transport cells to damaged cardiac tissues, several techniques, including the incorporation of cells into conductive polymers (CPs) and biomaterials, have been utilized. Due to the complexity of cardiac tissues, the success of tissue engineering for the damaged heart is highly dependent on several variables, such as the cell source, growth factors, and scaffolds. In this review, we sought to provide a comprehensive overview of the electro CPs and biomaterials used in the engineering and regeneration of heart tissue

Simvastatin Induces Nucleoporins Rae1/ mrnp41 and Nup98 via a STAT-1 Pathway, and Modulates Vesicular Stomatitis Virus Replication

Introduction. Statins, the cholesterol-lowering drugs, are known to exert pleiotropic effects that include inhibition of viruses such as HIV, HCV, polio and influenza-A. VSV is the prototype virus for take-over of nuclear pore complex (NPC) function via blockage of mRNA export; an effect antagonized by upregulation of Rae-1 and Nup98. Both nucleoporins are required for mRNA export and for the infection/replication of VSV, influenza A and polio viruses. Case Presentation. To determine a possible effect of statins on the NPC and on VSV replication, we investigated the effects of statins on VSV replication and on the expression of Rae1 and Nup98. Here we show for the first time that Simvastatin inhibits VSV replication and up-regulates both Nup98 and Rae1, in a concentration and STAT1- dependent manner. Simvastatin reversed VSV mRNA export block, a typical cytopathic effect of VSV on infected cells, and inhibited VSV replication. Deviation From the Expected. A low concentration of Simvastatin (0.125μM) and Pravastatin (0.1-4 μM) induced increases in VSV proteins and titers. Discussion. Here we reported that Simvastatin altered the replication of VSV and reduced the inhibition of gene expression induced by VSV. Conclusion. When drugs are directed towards cellular components, they could exert broad-range antiviral therapy. Simvastatin may be one example of drugs that modulate host factors needed for viral replication. Furthermore, modulation of antiviral nucleoporins might be an essential strategy of defense for both innate and adaptive immunity. Grant. The present studies were funded by NSU Chancellor\u27s Faculty Research & Development Grant No. 335508

Rebound Upregulation of Inflammatory Cytokines After Statin Withdrawal

Objective. The development of atherosclerosis relies heavily on production of inflammatory cytokines, therefore we investigated whether statin treatment withdrawal leads to upregulation of cytokines. Background. Cardiovascular disease is the leading cause of death in the US. The HMG-CoA reductase inhibitors (statins) are indicated in the prevention of cardiovascular morbidity and mortality due to atherosclerosis. However, discontinuation of statin treatment induces a rebound dysfunction associated with cardiovascular events. The mechanism underlying these events is unknown and there are no treatment strategies available. Methods. Vascular Smooth Muscle Cells (VSMCs) from Sprague-Dawley rats were cultured in vitro. The VSMCs were treated with simvastatin (1uM or 3uM) for 24h with or without TNF-alpha (5 ng/ml), followed by statin withdrawal (WD). Supernatants of cultures were analyzed for cytokines. Results. VSMC withdrawal of simvastatin without TNF-alpha, increased the CXCL1 by 30% (+/- 2%) and 43% (+/- 2.5%) after 6h and 10h WD respectively. The levels of other pro-atherogenic cytokines examined did not differ significantly from control. WD of VSMCs treated with simvastatin (3uM) and TNF-alpha induced significant increased the protein levels of: (a) CXCL1 by 960% (+/- 300%); (b) CCL2/MCP1 by 300% (+/- 20%); and (c) RANTES by ~400% (+/- 80). Conclusion. Our data suggest that VSMC response to simvastatin treatment and withdrawal may be influenced by a patient’s previous exposure to inflammatory factors. The data support observations that patients with existing cardiovascular dysfunction are at greater risk of adverse rebound effects due to statin withdrawal. Grants. NSU President’s Faculty Research and Development Grant 2008-09