In Vivo Skin Penetration of Acitretin in Volunteers Using Three Sampling Techniques

Etretinate and acitretin are given orally to treat psoriasis and various keratinization disorders. Acitretin, the main active metabolite of etretinate, has the pharmacokinetic advantage of being rapidly eliminated, but it shares etretinate's toxicologic profile. Thus a topical delivery of acitretin with no or reduced systemic adverse effects is desirable. To characterize the therapeutic potential of topically delivered acitretin, we quantitatively assessed its percutaneous penetration in healthy human volunteers. Additionally, three skin sampling techniques, the punch biopsy, the shave biopsy, and the suction blister technique, were validated to quantitate acitretin in the skin. The results suggest that topical delivery of acitretin renders skin concentrations which exceed those reported after oral administration of etretinate or acitretin. However, because of possible interlaminate drug contamination, drug localization within a particular skin compartment cannot be determined.     

Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: A positive drug-drug interaction.

ABT-378 is a potent in vitro inhibitor of the HIV protease and is currently being developed for coadministration with another HIV protease inhibitor, ritonavir, as an oral therapeutic treatment for HIV infection. In the present study, the effect of ritonavir, a potent inhibitor of cytochrome P-450 (CYP) 3A, on the in vitro metabolism of ABT-378 was examined. Furthermore, the effect of ABT-378-ritonavir combinations on several CYP-dependent monooxygenase activities in human liver microsomes was also examined. ABT-378 was found to undergo NADPH- and CYP3A4/5-dependent metabolism to three major metabolites, M-1 (4-oxo) and M-3/M-4 (4-hydroxy epimers), as well as several minor oxidative metabolites in human liver microsomes. The mean apparent K(m) and V(max) values for the metabolism of ABT-378 by human liver microsomes were 6.8 +/- 3.6 microM and 9.4 +/- 5.5 nmol of ABT-378 metabolized/mg protein/min, respectively. Ritonavir inhibited human liver microsomal metabolism of ABT-378 potently (K(i) = 0.013 microM). The combination of ABT-378 and ritonavir was much weaker in inhibiting CYP-mediated biotransformations than ritonavir alone, and the inhibitory effect appears to be primarily due to the ritonavir component of the combination. The ABT-378-ritonavir combinations (at 3:1 and 29:1 ratios) inhibited CYP3A (IC(50) = 1.1 and 4.6 microM), albeit less potently than ritonavir (IC(50) = 0.14 microM). Metabolic reactions mediated by CYP1A2, CYP2A6, and CYP2E1 were not affected by the ABT-378-ritonavir combinations. The inhibitory effects of ABT-378-ritonavir combinations on CYP2B6 (IC(50) = >30 microM), CYP2C9 (IC(50) = 13.7 and 23.0 microM), CYP2C19 (IC(50) = 28.7 and 38.0 microM), and CYP2D6 (IC(50) = 13.5 and 29.0 microM) were marginal and are not likely to produce clinically significant drug-drug interactions.     

Combination of cardiac conduction disease and long QT syndrome caused by mutation T1620K in the cardiac sodium channel

AIMS: The aim of the present study was to elucidate the molecular mechanism underlying the concomitant occurrence of cardiac conduction disease and long QT syndrome (LQT3), two SCN5A channelopathies that are explained by loss-of-function and gain-of-function, respectively, in the cardiac Na+ channel. METHODS AND RESULTS: A Caucasian family with prolonged QT interval, intermittent bundle-branch block, sudden cardiac death, and syncope was investigated. Lidocaine (1 mg/kg i.v.) normalized the prolonged QT interval and rescued bundle-branch block. An SCN5A mutation analysis was performed that revealed a C-to-A mutation at position 4859 (exon 28), predicted to change a highly conserved threonine for a lysine at position 1620. Mutant channels were characterized both in Xenopus oocytes and HEK293 cells. The T1620K mutation remarkably altered the properties of Nav1.5 channels. In particular, the voltage-dependence of the current decay time constants was largely lost. As a consequence, mutant channels inactivated faster than wild-type channels at potentials negative to -30 mV, resulting in less Na+ inward current (loss-of-function), but significantly slower at potentials positive to -30 mV, resulting in an increased Na+ inward current (gain-of-function). Moreover, we found a hyperpolarized shift of steady-state activation and an accelerated recovery from inactivation (gain-of-function). At the same time, channel availability was significantly reduced at the resting membrane potential (loss-of-function). CONCLUSION: We conclude that lysine at position 1620 leads to both loss-of-function and gain-of-function properties in hNav1.5 channels, which may consequently cause in the same individuals impaired impulse propagation in the conduction system and prolonged QTc intervals, respectively.     

Pulmonary vein isolation using second-generation single-shot devices: not all the same?

Introduction

Single-shot devices have been developed to simplify pulmonary vein isolation (PVI). Randomized studies of the second-generation cryoballoon (CB 2nd) demonstrated excellent results. There are limited data comparing results of circular pulmonary vein ablation catheter (PVAC) with conventional RF ablation or CB for PVI.

Objective

Using a sequential registry cohort and a prospective randomized study, we aimed to compare the acute and long-term results of CB 2nd and PVAC Gold.

Methods

In the registry, consecutive patients with paroxysmal atrial fibrillation (AF) undergoing their first PVI were included. The preferred method used was PVAC Gold in 2014 and CB 2nd in 2015. Subsequently, a randomized study (PVAC vs. CB 2nd) was performed. Ablation success was measured as freedom of AF or atrial tachycardias (AT) off antiarrhythmic drugs.

Results

In the registry cohort, PVAC Gold was used in 60 patients and CB 2nd in 56 patients (age 66?±?11 years, 52% male, LAD 43?±?6). In the randomized study, 20 patients were treated with PVAC Gold and 22 with CB 2nd (age 67?±?9; 43% men, LAD 40?±?7 mm). During a mean follow up of 13.2?±?3.6 months, success was 54% in PVAC Gold patients and 81% in CB 2nd cases (p?=?0.001). In the randomized study 12 months success was 50% versus 86%, p?<?0.05. Complications occurred rare in both groups.

Conclusions

Our registry data and the randomized study both suggest superiority of PVI using CB 2nd as compared with PVI using PVAC Gold.

     

Case Report: Clinical AV Nodal Reentrant Tachycardia in a Patient with Left Sided Accessory Pathway and Immediate Occurrence of Antidromic AV Reentrant Tachycardia after Slow Pathway Ablation

The only inducible arrhythmia in a patient with exclusive antegrade conducting left anterolateral accessory pathway, consists of slow/fast atrioventricular nodal reentrant tachycardia. After radiofrequency catheter ablation of the slow pathway, true antidromic AV reentrant tachycardia was easily induced by atrial pacing. Following ablation of the accessory pathway no arrhythmia could be induced.     

The functional reserve of collaterals supplying long-term chronic total coronary occlusions in patients without prior myocardial infarction.

AIMS: Chronic total coronary occlusions (CTOs) with angiographically well-developed collaterals may be considered to provide sufficient blood supply to the occluded segment, and the indication for revascularization may be questioned. Therefore, the collateral function and functional reserve in patients with a CTO without a prior Q-wave myocardial infarction (MI) were assessed. METHODS AND RESULTS: Invasive assessment of collateral function was done during successful percutaneous coronary intervention in 107 patients with a CTO and no prior Q-wave MI. Intracoronary Doppler flow velocity and pressure recordings were obtained distal to the occlusion before the first balloon inflation and collateral function indexes calculated. In 62 patients, additional pharmacological stress testing was done by intravenous adenosine (140 microg/kg/min) to assess the collateral flow reserve. Patients with normal and impaired regional dysfunction were compared. Collateral function was similar in patients with and without regional left ventricular (LV) dysfunction. In both groups, 78% collaterals provided a collateral pressure index at baseline > 0.3, sufficient to prevent ischaemia during a balloon occlusion, with a minimum of 0.2 in those with preserved LV function. A Doppler-derived function index showed a wider variation due to the high prevalence of microvascular dysfunction in CTOs. Only 7% of patients had an increase in collateral flow reserve > 2.0 during pharmacological stress, whereas coronary steal occurred in one-third independent of regional LV function. CONCLUSION: A limited increase in collateral flow and the high prevalence of coronary steal during stress underscore the functional limitation of collaterals in CTOs without prior Q-wave MI. Even presumably 'well-collateralized' CTOs may benefit from a revascularization.