The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

Ambient particulate matter (PM) can increase the incidence of arrhythmia. However, the arrhythmogenic mechanism of PM is poorly understood. This study investigated the arrhythmogenic mechanism of PM. In Sprague-Dawley rats, QT interval was increased from 115.0 ± 14.0 to 142.1 ± 18.4 ms (p = 0.02) after endotracheal exposure of DEP (200 μg/ml for 30 min, n = 5). Ventricular premature contractions were more frequently observed after DEP exposure (100%) than baseline (20%, p = 0.04). These effects were prevented by pretreatment of N-acetylcysteine (NAC, 5 mmol/L, n = 3). In 12 Langendorff-perfused rat hearts, DEP infusion of 12.5 μg/ml for 20 min prolonged action potential duration (APD) at only left ventricular base increasing apicobasal repolarization gradients. Spontaneous early afterdepolarization (EAD) and ventricular tachycardia (VT) were observed in 8 (67%) and 6 (50%) hearts, respectively, versus no spontaneous triggered activity or VT in any hearts before DEP infusion. DEP-induced APD prolongation, EAD and VT were successfully prevented with NAC (5 mmol/L, n = 5), nifedipine (10 μmol/L, n = 5), and active Ca^2 +/calmodulin-dependent protein kinase II (CaMKII) blockade, KN 93 (1 μmol/L, n = 5), but not by thapsigargin (200 nmol/L) plus ryanodine (10 μmol/L, n = 5) and inactive CaMKII blockade, KN 92 (1 μmol/L, n = 5). In neonatal rat cardiomyocytes, DEP provoked ROS generation in dose dependant manner. DEP (12.5 μg/ml) induced apoptosis, and this effect was prevented by NAC and KN 93. Thus, this study shows that in vivo and vitro exposure of PM induced APD prolongation, EAD and ventricular arrhythmia. These effects might be caused by oxidative stress and CaMKII activation.     

Does terfenadine-induced ventricular tachycardia/fibrillation directly relate to its QT prolongation and Torsades de Pointes?

BACKGROUND AND PURPOSE

Terfenadine has been reported to cause cardiac death. Hence, we investigated its pro-arrhythmic potential in various in vitro models.

EXPERIMENTAL APPROACH

Pro-arrhythmic effects of terfenadine were investigated in rabbit isolated hearts and left ventricular wedge preparations. Also, using whole-cell patch-clamp recording, we examined its effect on the human ether-à-go-go-related gene (hERG) current in HEK293 cells transfected with hERG and on the I_Na current in rabbit ventricular cells and human atrial myocytes.

KEY RESULTS

Terfenadine concentration- and use-dependently inhibited I_Na in rabbit myocytes and in human atrial myocytes and also inhibited the hERG. In both the rabbit left ventricular wedge and heart preparations, terfenadine at 1 µM only slightly prolonged the QT- and JT-intervals but at 10 µM, it caused a marked widening of the QRS complex, cardiac wavelength shortening, incidences of in-excitability and non-TdP-like ventricular tachycardia/fibrillation (VT/VF) without prolongation of the QT/JT-interval. At 10 µM terfenadine elicited a lower incidence of early afterdepolarizations versus non- Torsades de Pointes (TdP)-like VT/VF (100% incidence), and did not induce TdPs. Although the concentration of terfenadine in the tissue-bath was low, it accumulated within the heart tissue.

CONCLUSION AND IMPLICATIONS

Our data suggest that: (i) the induction of non-TdP-like VT/VF, which is caused by slowing of conduction via blockade of I_Na (like Class Ic flecainide), may constitute a more important risk for terfenadine-induced cardiac death; (ii) although terfenadine is a potent hERG blocker, the risk for non-TdP-like VT/VF exceeds the risk for TdPs; and (iii) cardiac wavelength (λ) could serve as a biomarker to predict terfenadine-induced VT/VF.     

Predictor of rehabilitation outcome for dysphagia

Objective

Predicting whether dysphagia will resolve is very difficult, but is obviously important for patients and their families as well as for physicians. This study retrospectively evaluated potential prognostic indicators for dysphagia in order to examine the feasibility of predicting the outcome.

Methods

Data on 123 patients who received initial treatment for dysphagia between April 2008 and March 2010 were reviewed. The patient population included 63 men and 60 women, with a mean age of 81.4 years. All the patients underwent physical examination and video-endoscopy (VE) at the initial assessment, and video-fluorography (VF) was also done if necessary. We used the “Food Intake Level Scale” (FILS) to classify the severity of dysphagia as follows: “no oral intake” (FILS score: 1–3), “oral intake and alternative nutrition” (FILS score: 4–6), and “oral intake alone” (FILS score: 7–10). The patient's age, primary disease, cognitive ability, and general condition were evaluated as potential factors associated with the severity of dysphagia. Each patient underwent assessment at every 2 weeks to evaluate the progress of their dysphagia.

Results

Forty-six patients were classified as “no oral intake” (FILS score: 1–3) at the initial examination and subsequently showed improvement to “oral intake and alternative nutrition” (FILS score: 4–6) or “oral intake alone” (FILS score: 7–10). They were compared with 43 patients who were also “no oral intake” at the second examination after training in swallowing. The combination of stroke and cognitive dysfunction showed a sensitivity of 75.9% (22/29) and specificity of 78.3% (18/23) for predicting no improvement of dysphagia, and was a statistically significant parameter. The presence of disuse syndrome showed a sensitivity of 66.0% (31/47) and specificity of 71.4% (30/42) for predicting no improvement of dysphagia, and this was also a significant parameter.

Conclusion

The results of this study suggest that a combination of factors other than stroke, including cognitive dysfunction and a decrease in activity of daily living (ADL) influence the outcome of dysphagia. It is not rare for patients who resume oral intake to be readmitted within a year for symptoms such as fever. Therefore, effective rehabilitation programs should be developed for the impairments of elderly patients and common disabilities such as dysphagia.     

Levosimendan improves postresuscitation myocardial dysfunction after beta-adrenergic blockade

In earlier studies, we found that a nonselective beta-adrenergic blocking agent, propranolol, facilitated cardiac resuscitation, reduced postresuscitation myocardial ectopy, and improved postresuscitation survival. However, the potential adverse effects and specifically the negative inotropic actions of propranolol prompted our further investigation of the potential value of a non-beta-adrenergic inotropic drug, levosimendan, in conjunction with propranolol, for minimizing postresuscitation myocardial dysfunction after successful resuscitation from cardiac arrest. Ventricular fibrillation was induced and untreated for 7 minutes in 15 domestic pigs, which were divided into propranolol, propranolol plus levosimendan, and control groups. Propranolol was administered as a bolus dose of 0.1 mg/kg during cardiac arrest. Electrical defibrillation was attempted after 12 minutes of cardiac arrest including 5 minutes of precordial compression. Levosimendan was administered at 10 minutes after successful resuscitation in a dose of 20 microg/kg and followed by infusion of 0.4 microg/kg/min over the ensuing 220 minutes. Propranolol reduced energies or numbers of defibrillatory shocks and postresuscitation myocardial ectopy, and it improved postresuscitation myocardial dysfunction. When levosimendan was added, postresuscitation myocardial contractile function was improved even more.     

Cost-Based Price Calculation of Mexiletine for Nondystrophic Myotonia

ObjectivesMexiletine is a long-known drug used for the treatment of arrhythmias and repurposed in the 1980s for patients with nondystrophic myotonia (NDM). Recently, the price of mexiletine in Europe increased significantly after registration as an orphan drug for NDM. This led to international discussions on affordability and willingness to reimburse mexiletine in the absence of background information that would justify such a price. Our objective was to calculate a cost-based price for mexiletine for adult patients with NDM based on detailed information on development costs.MethodsWe calculated a fair price based on a cost-based pricing model for commercial mexiletine to treat adults with NDM using a recent European drug-pricing model as a framework to include actual costs incurred. Three scenarios were applied: 1 with minimum estimated costs, 1 with maximum estimated costs, and 1 with costs as if mexiletine was innovative.ResultsThe calculated fair price of mexiletine per patient per year (PPPY) is €452 for the minimum scenario and €1996 for the maximum scenario. By using hypothetical R&D costs used for innovative drugs, the price would be €6685 PPPY. In Europe, the list price of mexiletine ranges from €30 707-60 730 PPPY, based on 600 mg daily.ConclusionsThe current list price for mexiletine in Europe is manifold higher than any scenario of the cost-based models. Accounting for the reduced costs for clinical development in a repurposing scenario, the cost-based pricing model provides a fair commercial price range, which can be used as benchmark for pricing negotiations and/or reimbursement decisions.