Screening for drugs potentially interfering with MCT8-mediated T3 transport in vitro identifies dexamethasone and some commonly used drugs as inhibitors of MCT8 activity.

BACKGROUND: Monocarboxylate transporter 8 (MCT8) is the first thyroid hormone transporter that has been linked to a human disease. Besides genetic alterations other factors might impair MCT8 activity. AIM: This study aimed at investigating whether some common drugs having a structural similarity with TH and/or whose treatment is associated with thyroid function test abnormalities, or which behave as antagonists of TH action can inhibit MCT8-mediated T3 transport. METHODS: [125I]T3 uptake and efflux were measured in COS-7 cells transiently transfected with hMCT8 before and after exposure to increasing concentrations of hydrocortisone, dexamethasone, prednisone, prednisolone, amiodarone, desethylamiodarone, dronedarone, buspirone, carbamazepine, valproic acid, and L-carnitine. The mode of inhibition was also determined. RESULTS: Dexamethasone significantly inhibited T3 uptake at 10 µM; hydrocortisone reduced T3 uptake only at high concentrations, i.e. at 500 and 1000 µM; prednisone and prednisolone were devoid of inhibitory potential. Amiodarone caused a reduction of T3 uptake by MCT8 only at the highest concentrations used (44% at 50 µM and 68% at 100 µM), and this effect was weaker than that produced by desethylamiodarone and dronedarone; buspirone resulted a potent inhibitor, reducing T3 uptake at 0.1-10 µM. L-Carnitine inhibited T3 uptake only at 500 mM and 1 M. Kinetic experiments revealed a noncompetitive mode of inhibition for all compounds. All drugs inhibiting T3 uptake did not affect T3 release. CONCLUSION: This study shows a novel effect of some common drugs, which is inhibition of T3 transport mediated by MCT8. Specifically, dexamethasone, buspirone, desethylamiodarone, and dronedarone behave as potent inhibitors of MCT8.

Studies on Core-Shell Nanocapsules of Felodipine: In Vitro-In Vivo Evaluations.

The present study aimed for in vitro-in vivo-in silico simulation studies of experimentally designed (32-factorial) Capmul PG-8-cored, Eudragit RSPO-Lutrol F 127 nanocapsules to ferry felodipine using GastroPlus™. The in silico parameter sensitivity analysis for pharmacokinetic parameters was initially assessed to justify the preparation of felodipine-loaded nanocapsules (FLNs) with enhanced solubility to overcome the bioavailability issues of felodipine. The overall integrated desirability ranged between 0.8187 and 0.9488 for three optimized FLNs when analyzed for mean particle size, zeta potential, encapsulation efficiency, and in vitro dissolution parameters. The morphological evaluation (SEM, TEM, and AFM) demonstrated spherical nanoparticles (200-300 nm). Validated LC-MS/MS analysis demonstrated enhanced relative bioavailability (13.37-fold) of optimized FLN as compared to suspension. The simulated regional absorption of the FLN presented significant absorption from the cecum (26.3%) and ascending colon (20.1%) with overall absorption of 67.4% from the GIT tract. Furthermore, in vitro-in vivo correlation demonstrated the Wagner-Nelson method as the preferred model as compared to mechanistic and numerical deconvolution on the basis of least mean absolute prediction error, least standard error of prediction, least mean absolute error, and maximum correlation coefficient (r 2 = 0.920). The study demonstrated enhanced oral absorption of felodipine-loaded nanocapsules, and GastroPlus™ was found to be an efficient simulation tool for in vitro-in vivo-in silico simulations.

Reduced Food-Effect on Intestinal Absorption of Dronedarone by Self-microemulsifying Drug Delivery System (SMEDDS).

The oral absorption of dronedarone (DRN), a benzofuran derivative with anti-arrhythmic activity, is significantly affected by food intake. The absolute bioavailability of the marketed product (Multaq, Sanofi, U.S.) was about 4% without food, but increased to 15% when administered with a high fat meal. Therefore, to reduce the food-effect on the intestinal absorption of DRN, a novel self-microemulsifying drug delivery system (SMEDDS) was formulated and the comparative in vivo absorption studies with the marketed product were carried out using male beagle dogs either in the fasted or fed state. The SMEDDS consisted of the drug, Labrafil M 1944CS, and Kolliphor EL in a weight ratio of 1 : 1 : 2, rapidly formed a fine oil-in-water emulsion with a droplet size less than 50 nm. An in vivo absorption study revealed that the area-under-curve (AUC0-24 h) and maximal plasma concentration (Cmax) were 10.4-fold (p<0.05) and 8.6-fold (p<0.05) higher, respectively, after the marketed product was orally administered to beagles in the fed state when compared to those in the fasted state. This food-effect were remarkably alleviated by SMEDDS formulation, with AUC0-24 h and Cmax 2.9-fold (p<0.05) and 2.6-fold (p<0.05) higher in the fed state when compared to the fasted state, by facilitating intestinal absorption of DRN in the fasted state. The results of this study suggest that SMEDDS may decrease the differences in oral absorption of DRN between the prandial states, improving therapeutic efficacy as well as patient compliance.

Electrophysiological and haemodynamic effects of vernakalant and flecainide in dyssynchronous canine hearts.

AIMS: About one-third of patients with mild dyssynchronous heart failure suffer from atrial fibrillation (AF). Drugs that convert AF to sinus rhythm may further slowdown ventricular conduction. We aimed to investigate the electrophysiological and haemodynamic effects of vernakalant and flecainide in a canine model of chronic left bundle branch block (LBBB). METHODS AND RESULTS: Left bundle branch block was induced in 12 canines. Four months later, vernakalant or flecainide was administered using a regime, designed to achieve clinically used plasma concentrations of the drugs, n = 6 for each drug. Epicardial electrical contact mapping showed that both drugs uniformly prolonged myocardial conduction time. Vernakalant increased QRS width significantly less than flecainide (17 ± 13 vs. 34 ± 15%, respectively). Nevertheless, both drugs equally decreased LVdP/dtmax by ∼15%, LVdP/dtmin by ∼10%, and left ventricular systolic blood pressure by ∼5% (P = n.s. between drugs). CONCLUSIONS: Vernakalant prolongs ventricular conduction less than flecainide, but both drugs had a similar, moderate negative effect on ventricular contractility and relaxation. Part of these reductions seems to be related to the increase in dyssynchrony.

Cardiac responses to the intrapericardial delivery of metoprolol: targeted delivery compared to intravenous administration.

Anti-arrhythmic drugs have narrow therapeutic ranges and typically can engender harmful side effects. The intrapericardial (IP) delivery of anti-arrhythmic agents proposes to achieve higher myocardial levels while minimizing plasma concentrations, thus diminishing systemic side effects. Furthermore, IP delivery enables concentrations at the target site to be more precisely controlled. Our study objective was to compare the relative cardiac effects of intrapericardial administration of metoprolol to standard intravenous (IV) delivery in a swine surgical model. In order to answer the question of how IP metoprolol affects sinus tachycardia, atrial electrophysiology, and pharmacokinetics compared with IV delivery, a medial sternotomy was performed on 21 swine that were divided into three groups: (1) After inducing sinus tachycardia, metoprolol boluses were delivered IP (n = 4) or IV (n = 4); (2) metoprolol was administered either IP (n = 3) or IV (n = 3) with saline controls (n = 3), and electrophysiologic data were collected; (3) metoprolol levels were tracked both in the blood (IV, n = 2) and pericardial (IP, n = 2) fluid. After either IP or IV delivery of metoprolol, heart rates were lowered significantly to 70% and 73% of control rate, respectively. The therapeutic effect of IV-administered metoprolol was considerably reduced after 1 h but was sustained longer in the IP group. Additionally, ventricular contractility and mean arterial pressure parameters were significantly lower in IV-treated animals but were nearly unaffected in IP-treated animals. With IP administration, the elimination half-life of metoprolol in pericardial fluid was 14.4 min with negligible accumulations in the plasma, whereas with IV delivery, the elimination half-life in plasma was 11.1 min with negligible amounts found in the pericardial fluid. The targeted intrapericardial delivery of metoprolol effectively lowers heart rates for sustained periods of time, with minimal effect on either ventricular contractility or mean arterial pressure. We did not observe dramatic changes in induced atrial fibrillation times or refractory periods using this model.

Oral vanoxerine prevents reinduction of atrial tachyarrhythmias: preliminary results.

BACKGROUND: Vanoxerine is a promising, new, investigational antiarrhythmic drug. The purpose of this study was to test the hypothesis that oral dosing of vanoxerine would first terminate induced atrial flutter (AFL) and atrial fibrillation (AF), and then prevent their reinduction. METHODS: In 5 dogs with sterile pericarditis, on the fourth day after creating the pericarditis, we performed electrophysiologic (EP) studies at baseline, measuring atrial excitability, refractoriness (AERP), and conduction time (CT) when pacing from the right atrial appendage, Bachmann's bundle (BB), and the posteroinferior left atrium at cycle lengths (CLs) of 400, 300, and 200 ms. Then, after induction of AFL or AF, all dogs received hourly oral doses of vanoxerine: 90 mg, followed by 180 mg and 270 mg. Blood was obtained to determine plasma vanoxerine concentrations at baseline, every 30 minutes, when neither AFL nor AF were inducible, and, finally, 1 hour after the 270 mg dose. Then we repeated the baseline EP studies. RESULTS: Four dogs had inducible, sustained AFL, and 1 dog only had induced, nonsustained AF. In 4 AFL episodes, oral vanoxerine terminated the AFL and then rendered it noninducible after an average of 111 minutes (range 75-180 minutes) after the first dose was administered. The mean vanoxerine plasma level at the point of noninducibility was 84 ng/mL, with a narrow range of 76-99 ng/mL. In the dog with induced, nonsustained AF, it was no longer inducible at a drug level of 75 ng/mL. Vanoxerine did not significantly (1) prolong the AERP except at BB, and then only at the faster pacing CLs; (2) change atrial excitability thresholds; (3) prolong atrial conduction time, the PR interval, the QRS complex or the QT interval. CONCLUSIONS: Orally administered vanoxerine effectively terminated AFL and rendered it noninducible. It also suppressed inducibility of nonsustained AF. These effects occurred at consistent plasma drug levels. Vanoxerine's insignificant or minimal effects on measured electrophysiologic parameters are consistent with little proarrhythmic risk.

Vernakalant selectively prolongs atrial refractoriness with no effect on ventricular refractoriness or defibrillation threshold in pigs.

Vernakalant is a novel antiarrhythmic agent that has demonstrated clinical efficacy for the treatment of atrial fibrillation. Vernakalant blocks, to various degrees, cardiac sodium and potassium channels with a pattern that suggests atrial selectivity. We hypothesized, therefore, that vernakalant would affect atrial more than ventricular effective refractory period (ERP) and have little or no effect on ventricular defibrillation threshold (DFT). Atrial and ventricular ERP and ventricular DFT were determined before and after treatment with vernakalant or vehicle in 23 anesthetized male mixed-breed pigs. Vernakalant was infused at a rate designed to achieve stable plasma levels similar to those in human clinical trials. Atrial and ventricular ERP were determined by endocardial extrastimuli delivered to the right atria or right ventricle. Defibrillation was achieved using external biphasic shocks delivered through adhesive defibrillation patches placed on the thorax after 10 seconds of electrically induced ventricular fibrillation. The DFT was estimated using the Dixon "up-and-down" method. Vernakalant significantly increased atrial ERP compared with vehicle controls (34 ± 8 versus 9 ± 7 msec, respectively) without significantly affecting ventricular ERP or DFT. This is consistent with atrial selective actions and supports the conclusion that vernakalant does not alter the efficacy of electrical defibrillation.

Abbott ARCHITECT clinical chemistry and immunoassay systems: digoxin assays are free of interferences from spironolactone, potassium canrenoate, and their common metabolite canrenone.

Spironolactone, which is metabolized to canrenone, is often used in combination with digoxin. Potassium canrenoate is a similar drug that is also metabolized to canrenone. As a result of reported interference of spironolactone, potassium canrenoate, and their common metabolite canrenone with digoxin immunoassays, we investigated potential interference of these compounds with two relatively new digoxin assays for application on ARCHITECT clinical chemistry platforms (cDig, particle-enhanced turbidimetric inhibition immunoassay) and ARCHITECT immunoassay platforms (iDig, chemiluminescent microparticle immunoassay), both from Abbott Diagnostics. When aliquots of drug-free serum pool were supplemented with various amounts of spironolactone, potassium canrenoate, and canrenone, no apparent digoxin concentration was observed using cDig assay on ARCHITECT c4000, c8000, and c16000 or iDig assay on i1000SR and i2000SR analyzers. In addition, we observed no false increase in serum digoxin value when aliquots of a digoxin pool were further supplemented with various amounts of spironolactone, potassium canrenoate, or canrenone. We conclude that both the cDig and iDig assays on the ARCHITECT analyzers are free from interferences by spironolactone, potassium canrenoate, and canrenone.

Determination of a new active steroid by high performance liquid chromatography with laser-induced fluorescence detection following the pre-column derivatization.

A sensitive analytical method for the determination of a new active steroid, butane acid-(5-androsten-17-one-3beta-ol)-diester (A1998), was developed by high performance liquid chromatography with laser-induced fluorescence detection following the pre-column derivatization with dansylhydrazine. The calibration curve for A1998 derivatization was found linear in the dynamic range from 0.025 to 5.0 microg/ml, with the precision less than 6% (CV) and the mean extraction efficiency greater than 92%. In 200 microl of plasma samples the limit of quantitation was as low as 0.025 microg/ml with a signal-to-noise ratio of 10. This assaying was further applied to the determination of the pharmacokinetic parameters of A1998 in rats with an intravenous injection of A1998. Values for clearance for elimination, volume of distribution at steady state and terminal half life in the above case were determined as 50.3+/-1.1 ml/min kg, 1329.0+/-111.0 ml/kg and 44.0+/-2.7 min, respectively.

Lovastatin specifically prevents focal ischemic ventricular tachycardia due to triggered activity.

BACKGROUND: Use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor has been associated with reduced implantable defibrillator shocks in several multicenter trials, suggesting an antiarrhythmic effect. OBJECTIVE: The purpose of this study was to determine if lovastatin had an antiarrhythmic effect in a canine model of ischemic and inducible ventricular tachycardia (VT). METHODS: Forty-seven alpha-chloralose anesthetized dogs underwent left anterior descending coronary occlusion. Three-dimensional activation mapping identified the mechanism of reinducible VT and the response to lovastatin (0.5 mg/kg IV). The endocardium was excised from foci and studied using standard microelectrode techniques with Tyrode's solution. RESULTS: Lovastatin blocked focal VT in 8 of 13 dogs (P <.01) compared with only 1 of 12 saline-treated dogs with focal VT. Lovastatin had no effect on reentrant VT. Lovastatin did not alter the effective refractory period, arterial pressure, or percentage of ischemic electrograms. Effective plasma concentration of lovastatin hydroxy acid ranged from 21-157 ng/mL (0.8-3.7 x 10(-7) M). In vitro rapid pacing, mostly with isoproterenol (5 x 10(-7) M) superfusion, produced delayed afterdepolarizations and triggered activity (9 +/- 2 action potentials). Lovastatin (10(-7) M) produced no change in action potentials or delayed afterdepolarizations. However, triggered activity was attenuated to 2 +/- 1 action potentials with lovastatin (P <.05, n = 13) but not with vehicle alone. Triggered activity returned to control after lovastatin washout (20 minutes) as well as with co-superfusion with mevalonic acid (10(-6) M, n = 5). 2,2,6,6-Tetramethylpiperidine-N-oxyl, an antioxidant that enters tissues (10(-3) M, n = 8), prevented triggered activity in a fashion similar to lovastatin. CONCLUSION: Lovastatin, in concentrations achievable in human plasma, specifically suppresses triggered activity and focal VT due to ischemia. A prenylated protein downstream from mevalonic acid may act as an antioxidant, producing the antiarrhythmic effect.

In vivo cardiac electrophysiologic and antiarrhythmic effects of an isoquinoline IKur blocker, ISQ-1, in rat, dog, and nonhuman primate.

The cardiac electrophysiologic effects of ISQ-1, an isoquinolinone I(Kur) blocker, were characterized in vivo. In rat, ISQ-1 elicited maximal 33% to 36% increases in atrial and ventricular refractoriness at a plasma concentration of 11.5 microM. In African green monkey, ISQ-1 increased atrial refractory period (maximal 17% at plasma concentration up to 20 microM) with no effect on ventricular refractory period or ECG QTc. Likewise in dog, ISQ-1 increased atrial refractory period (maximal 16% at plasma concentration up to 2 microM) with no effect on ventricular refractory period or QTc. In contrast, studies with ibutilide in nonhuman primate and dog demonstrated concomitant increases in atrial and ventricular refractoriness and QTc. Additionally, in a dog model of atrial flutter, ISQ-1 terminated ongoing flutter at doses (2.5 +/- 0.5 mg/kg IV) that selectively prolonged atrial refractoriness (13% increase), whereas flutter termination with ibutilide occurred at doses that increased both atrial and ventricular refractoriness as well as QTc. Of note, the cardiac electrophysiologic profiles displayed by ISQ-1 in these species were similar to those reported previously by our lab with a structurally distinct I(Kur) blocker. Taken together, these results further support the inhibition of I(Kur) as an approach to terminate atrial arrhythmia.

A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation derived from the effects of terfenadine, cisapride and E-4031 in the conscious chronic av node--ablated, His bundle-paced dog.

INTRODUCTION: Terfenadine, cisapride, and E-4031, three drugs that prolong ventricular repolarization, were selected to evaluate the sensitivity of the conscious chronic atrioventricular node--ablated, His bundle-paced Dog for defining drug induced cardiac repolarization prolongation. A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation was generated from these data. METHODS: Three male beagle dogs underwent radiofrequency AV nodal ablation, and placement of a His bundle-pacing lead and programmable pacemaker under anesthesia. Each dog was restrained in a sling for a series of increasing dose infusions of each drug while maintained at a constant heart rate of 80 beats/min. RT interval, a surrogate for QT interval in His bundle-paced dogs, was recorded throughout the experiment. RESULTS: E-4031 induced a statistically significant RT prolongation at the highest three doses. Cisapride resulted in a dose-dependent increase in RT interval, which was statistically significant at the two highest doses. Terfenadine induced a dose-dependent RT interval prolongation with a statistically significant change occurring only at the highest dose. The relationship between drug concentration and RT interval change was described by a sigmoid E(max) model with an effect site. Maximum RT change (E(max)), free drug concentration at half of the maximum effect (EC(50)), and free drug concentration associated with a 10 ms RT prolongation (EC(10 ms)) were estimated. A linear correlation between EC(10 ms) and HERG IC(50) values was identified. DISCUSSION: The conscious dog with His bundle-pacing detects delayed cardiac repolarization related to I(Kr) inhibition, and detects repolarization change induced by drugs with activity at multiple ion channels. A clinically relevant sensitivity and a linear correlation with in vitro HERG data make the conscious His bundle-paced dog a valuable tool for detecting repolarization effect of new chemical entities.

Pharmacokinetic-pharmacodynamic modeling of drug-induced effect on the QT interval in conscious telemetered dogs.

INTRODUCTION: To assure drug safety, the investigation of the relationship between plasma concentration and drug-induced prolongation of the QT interval of the ECG is a challenge in drug discovery. For this purpose, dofetilide was utilized to demonstrate the benefits of characterizing the complete time course of concentrations and effect in conscious beagle dogs in the assessment of drug safety. METHOD: On two separate occasions, four male and two female beagle dogs were given vehicle or the test substance, dofetilide (0.25 mumol/kg), over a 3-h intravenous infusion. Cardiovascular parameters, including QT intervals, were recorded for 24-h using radiotelemetry. The QT interval was corrected individually for heart rate, vehicle treatment, and serial correlation (QT(c)). Exposure (plasma concentration) to dofetilide was measured and described by a two-compartment model. The individual concentration-time course of dofetilide was linked to the QT(c) interval via an effect compartment and a pharmacodynamic E(max) model, to account for the observed hysteresis. RESULTS: Dofetilide induced a concentration-dependent increase in the QT(c) interval, with an EC(50) of 9 nM (3-30 nM, 95% C.I.) and an E(max) of 59+/-9 ms. A hysteresis loop was observed by plotting plasma concentrations vs. QT interval in time order, indicating a delay in onset of effect. It was found to have an equilibrium half-life of 11+/-8 min. Based on the parameters potency and E(max), a representation was made of the drug-induced changes to the QT interval. DISCUSSION: An effect compartment model was found to accurately mimic the QT interval prolongation following administration of the test substance, dofetilide. The assessment of the individual concentration-effect relationship and confounding factors such as hysteresis might provide a better prediction of the safety profiles of new drug candidates.

Bioavailability of nerodilol-based transdermal therapeutic system of nicorandil in human volunteers.

The objective of the present investigation was to design and evaluate a nerodilol-based transdermal therapeutic system (TTS) for finding its ability in providing the desired steady-state plasma concentration of nicorandil in human volunteers. The influence of EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825-rat skin composite on the in vitro permeation of nicorandil from a nerodilol-based HPMC gel drug reservoir was studied against a control (excised rat skin alone). The flux of nicorandil from the nerodilol-based HMPC drug reservoir across excised rat skin (control) was 384.0+/-4.6 microg/cm2 h and this decreased to 222.7+/-7.1 microg/cm2 h when studied across EVA2825 membrane indicating that EVA2825 membrane was effective as rate controlling membrane. The flux of the drug decreased to 183.8+/-5.7 microg/cm2 h on application of a water-based acrylic adhesive (TACKWHITE A 4MED) coat to EVA2825 membrane. However, the flux of nicorandil across adhesive-coated EVA2825-membrane-rat-skin composite was 164.8+/-1.8 microg/cm2 h, which was 1.74-times of the required flux that prompted for preparation of TTS. The nerodilol-based drug reservoir system was sandwiched between a composite of adhesive-coated EVA2825 membrane-release liner and a backing membrane. The resultant sandwich was heat-sealed to produce circle-shaped TTS (20 cm2) that were subjected to bioavailability study in human volunteers against immediate release nicorandil tablet. The nerodilol-based TTS provided a steady-state plasma concentration of 25.5 ng/ml for 24 h in human volunteers. It was concluded that the nerodilol-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations.

Pilot study: Noninvasive monitoring of oral flecainide's effects on atrial electrophysiology during persistent human atrial fibrillation using the surface electrocardiogram.

BACKGROUND: The relation between flecainide's plasma level and its influence on human atrial electrophysiology during acute and maintenance therapy of atrial fibrillation (AF) is unknown. Therefore, this study determined flecainide plasma levels and atrial fibrillatory rate obtained from the surface ECG during initiation and early maintenance of oral flecainide in patients with persistent lone AF and assessed their relationship. METHODS AND RESULTS: In 10 patients (5 males, mean age 63 +/- 14 years, left atrial diameter 46 +/- 3 mm) with persistent lone AF, flecainide was administered as a single oral bolus (day 1) followed by 200-400 mg/day (days 2-5). The initial 300 mg flecainide bolus resulted in therapeutic plasma levels in all patients (range 288-629 ng/ml) with no side effects. Flecainide plasma levels increased on day 3 and remained stable thereafter. Day 5 plasma levels were lower (508 +/- 135 vs 974 +/- 276 ng/ml, P = 0.009) in patients with daily mean flecainide doses of 200 mg compared to patients with higher maintenance doses. Fibrillatory rate obtained from the surface electrocardiogram measuring 378 +/- 17 fpm at baseline was reduced to 270 +/- 18 fpm (P < 0.001) after the flecainide bolus but remained stable thereafter. Fibrillatory rate reduction was independent of flecainide plasma levels or clinical variables. CONCLUSION: A 300 mg oral flecainide bolus is associated with electrophysiologic effects that are not increased during early maintenance therapy in persistent human lone AF. In contrast to drug plasma levels, serial analysis of fibrillatory rate allows monitoring of individual drug effects on atrial electrophysiology.

Differentiation of the electrophysiological effects on the atrial myocardium between the pure Na channel blocker, pilsicainide, and flecainide.

UNLABELLED: The purpose of this study was to identify the difference between the pure Na channel blocker, pilsicainide and Ic-antiarrhythmic drug, flecainide, on the atrial electrophysiological characteristics. METHODS: The subjects consisted of 24 patients (48 +/- 12 years-old: P-group) in whom pilsicainide was administrated intravenously (1 mg/kg/10 min) and 31 patients (47 +/- 15 years-old: F-group) in whom flecainide was administrated intravenously (2 mg/kg/10 min). The atrial effective refractory period (ERP-A), intra-atrial conduction time (CT), max intra-atrial conduction delay (Max CD), repetitive atrial firing zone (RAFZ), fragmented atrial activity zone (FAZ) and intra-atrial conduction delay zone (CDZ) were measured before and after the drugs. RESULTS: Pilsicainide and flecainide significantly prolonged the ERP-A (211 +/- 27 msec to 246 +/- 39 msec; p < 0.001, 217 +/- 25 msec to 244 +/- 33 msec; p < 0.001, respectively) and CT (121 +/- 33 msec to 149 +/- 43 msec; p < 0.001, 122 +/- 22 msec to 153 +/- 27 msec; p < 0.001, respectively) to the same degree. However, the Max CD was shortened by pilsicainide, but not by flecainide. The RAFZ, FAZ and CDZ decreased in the P-group (21 +/- 25 msec to 4 +/- 10 msec; p < 0.01, 24 +/- 24 msec to 14 +/- 18 msec; p < 0.05, 56 +/- 29 msec to 43 +/- 32 msec, p < 0.05, respectively), but not in the F-group. CONCLUSIONS: The effects of atrial conduction delays may differ between pilsicainide and flecainide. Further examination will be needed to explain this mechanism.

Interference of Uzara glycosides in assays of digitalis glycosides.

OBJECTIVE: Presentation of a case report and pharmacokinetic investigation in healthy volunteers on the potential interference between cardiac glycosides and glycosides of Uzara, a herbal antidiarrheal preparation. METHODS: Pharmacokinetic pilot investigation of apparent digitoxin and digoxin serum concentrations in 4 healthy volunteers after single-dose administration of 30 drops Uzara (approximately 1.5 ml approximately = 22 mg glycosides). RESULTS: Maximal apparent serum concentrations of digitoxin between 198.0 microg/l and 919.8 microg/l (therapeutic range: 10-25 microg/l) occurred at 4-8 hours after administration. The terminal half-life of the glycosides was 8.87 +/- 2.20 hours. For digoxin, maximal apparent serum concentrations ranged between 1.4 microg/l and 6.34 microg/l (therapeutic range: 0.9-2.0 microg/l) at 6 hours post dosing. CONCLUSIONS: Administration of a single dose of an Uzara preparation, an over-the-counter product, results in false high serum concentrations of digitoxin and digoxin. As described in the manufacturers Summary of Product Characteristics, this preparation should not be given to patients with cardiac failure or arrhythmia who require treatment with cardiac glycosides because of the demonstrated pharmacological actions of uzara glycosides.

A trial of automated safety alerts for inpatient digoxin use with computerized physician order entry.

OBJECTIVE: Automated clinical decision support (CDS) has shown promise in improving safe medication use. The authors performed a trial of CDS, given both during computerized physician order entry (CPOE) and in response to new laboratory results, comparing the time courses of clinician behaviors related to digoxin use before and after implementation of the alerts. DESIGN: Alerts were implemented to notify of the potential risk from low electrolyte concentrations or unknown digoxin or electrolyte concentrations during CPOE. Alerts were also generated in response to newly reported hypokalemia and hypomagnesemia in patients given digoxin. MEASUREMENTS: Clinician responses to the alerts for six months were compared with responses to similar situations for six months prior to implementation. RESULTS: During CPOE, checking for unknown serum values increased after implementation compared with control at one hour: 19% vs. 6% for digoxin, 57% vs. 9% for potassium, and 40% vs. 12% for magnesium as well as at 24 hours (p < 0.01 for all comparisons). Electrolyte supplementation increased with newly reported hypokalemia and hypomagnesemia after implementation at one hour: 35% vs. 6% and 49% vs. 5% for potassium and magnesium, respectively, as well as at 24 hours (p < 0.01 for all comparisons). During CPOE, supplementation for hypokalemia was not improved, whereas supplementation for hypomagnesemia improved at one hour (p < 0.05). CONCLUSION: Overall, the alerts improved the safe use of digoxin. During CPOE, alerts associated with missing levels were effective. For hypokalemia and hypomagnesemia, the alerts given during CPOE were not as effective as those given at the time of newly reported low electrolytes.

Do therapeutic doses of acarbose alter the pharmacokinetics of digoxin?

BACKGROUND: Acarbose has become an important adjuvant therapy for diabetic patients. Many of these patients are also treated with digoxin for congestive heart failure or chronic atrial fibrillation. OBJECTIVE: To evaluate a possible drug interaction between acarbose and digoxin. METHODS: An open-label, analyst-blind, randomized, crossover, two-period study was conducted in 11 healthy subjects. In period I, each subject received one single oral dose of 0.75 mg digoxin. In period II, they were given acarbose tablets, 50 mg 3 times a day for 12 days. On day 8, one hour after acarbose administration, a single oral dose of 0.75 mg digoxin was administered. The study periods were separated by a 3 week washout interval. Serum digoxin levels, over time, in the two periods were compared by standard techniques. RESULTS: There were no differences in the pharmacokinetic parameters of digoxin in the two periods, apart from a significant increase in the mean maximum serum concentration (Cmax) when digoxin was given with acarbose (5.97 compared to 4.67 g/L, P = 0.02). Simulated steady-state peak levels of digoxin (Cmax,ss) achieved with a daily dose of 0.25 mg digoxin, in the presence and absence of acarbose, were 2.89 and 2.40 g/L respectively (P = 0.05). Simulated steady-state trough (Cmin,ss) and average (Cave,ss) concentrations were similar and within the therapeutic window. CONCLUSION: There was no significant pharmacokinetic interaction between digoxin and acarbose at current therapeutic doses in the healthy volunteers. This interaction should be further studied with higher doses of acarbose and at steady-state conditions.

Analysis of toxicokinetic data using NONMEM: impact of quantification limit and replacement strategies for censored data.

The purpose of this study was to examine how best to incorporate plasma samples which fall below an assay's lower limit of quantification into the process of toxicokinetic data modeling. Secondly to establish what proportion of data can be below the quantification limit without compromising NONMEM's parameter estimates. Using pharmacokinetic parameters determined in a rat toxicokinetic study we simulated datasets that might emerge from similar experiments in which only one sample was obtained per individual. A number of quantification limits were used which resulted in increasing proportions of data values being treated as if they were below the limit of quantification (BQL). For each quantification level we incorporated BQL data into our analyses in number of ways. We compared these analysis methods with respect to how well the underlying parameter values were retrieved. Omitting BQL data values or entering them as zero led to inaccurate and biased study results. We found that incorporating BQL values using more complex substitution methods via a mixed effects model produced more reliable and less biased parameter estimates. The four substitution methods that we investigated performed similarly. Parameter estimates became less reliable and more biased as the quantification level was increased depending on the method of BQL value incorporation. Naive methods of BQL data handling can produce unreliable and biased parameter estimates. An alternative is to incorporate BQL values into a population-type model, our results showed this method to be preferable. We found it advisable that the proportion of BQL data should not exceed one third and, if possible should be less than one quarter.