Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24

Dominant mutations in the KLHL24 gene, encoding for kelch-like protein 24, have been implicated in the pathogenesis of epidermolysis bullosa simplex (EBS). So far, 26 patients from different ethnicities have been reported and all of them harboured a heterozygous KLHL24 start-codon mutation, with c.1A>G;p.Met1? being the most prevalent.1-3 Through this report, we aimed to expand the phenotypic spectrum by incorporating additional findings, in particular, dilated cardiomyopathy, seen in a Dutch family. This article is protected by copyright. All rights reserved

No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy

Aims Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure. Methods We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant. Results Forty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants. Conclusions Although PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development

Therapeutic consequences of drug interactions with theophylline pharmacokinetics

Elimination of theophylline from the body occurs mainly (approximately 90%) by biotransformation, followed by excretion of the metabolites. Consequently, drugs affecting microsomal enzyme systems in the liver may alter the elimination of theophylline. Since theophylline has a rather narrow therapeutic window, dose adjustment might be necessary. Of the sympathomimetics, isoproterenol reduces theophylline clearance by 25%, but metaproterenol and terbutaline do not. Of the antibiotics, erythromycin and troleandomycin decrease theophylline clearance by 25% and 50%, respectively. No effect was observed with tetracycline, doxycycline, amoxicillin, cefaclor, and co-trimoxazole. On the other hand, rifampin (antituberculotic agent) increases theophylline clearance by 30%. Corticosteroids (hydrocortisone, methylprednisolone, and prednisone) do not affect theophylline kinetics. Influenza vaccination also has no influence. The antiulcerative agent (H2 antagonist) cimetidine decreases theophylline clearance by 30%, but the agent ranitidine does not have any effect. Oral contraceptives may decrease theophylline elimination by 30%. Barbiturates and phenytoin may enhance theophylline clearance substantially (up to 75%). If an interaction is expected, careful monitoring of theophylline plasma concentrations is required to optimize the dos

Percutaneous absorption, metabolism, and elimination of the penetration enhancer Azone in humans after prolonged application under occlusion

Azone was applied undiluted to an extended area of the forearm and left in place for 12 h under occlusion in 3 volunteers. Azone was found to be absorbed in very low amounts (0.419 ± 0.259% of the applied dose) and accumulation in the body did not occur. As compared to a previous study, the new application conditions gave an increase in amount and percentage absorbed, but a decrease in flux. Absorbed material was excreted rapidly and almost exclusively through the urine after extensive metabolism to at least 3 rather polar compounds. These findings and the absence of treatment-related side-effects in the 3 volunteers suggest azone to be safe for human use when topically applied under occlusion

Percutaneous absorption, metabolic profiling, and excretion of the penetration enhancer azone after multiple dosing of an azone‐containing triamcinolone acetonide cream in humans

Radioactive Azone (1.6%; 1‐dodecylazacycloheptan‐2‐one) was incorporated in a therapeutic formulation containing triamcinolone acetonide at a concentration of 0.05%. This cream (TAZ) was applied for four consecutive days to human volunteers on the same 24‐cm2 application area on the forearm for 12 h under occlusion. The percutaneous absorption of Azone as measured in the excreta appeared to be only 3.47 ± 0.33% during the whole study period. Azone‐derived radioactivity was predominantly excreted by the kidneys (97.8 ± 0.4%). From the urinary excretion plot, it could be deduced that the flux of Azone through human skin increased during the study period, reaching a plateau within 2–3 d. Accumulation of Azone in the stratum corneum did not occur. Only unchanged Azone could be detected in the stratum corneum. Excretion was mainly in the form of very polar metabolites. Compared with pure Azone, the therapeutic formulation did not influence the metabolism, excretion route, or urinary elimination rate of the penetration enhancer

Percutaneous absorption of triamcinolone acetonide from creams with and without Azone® in humans in vivo

A clinical study was performed in which 0.05% triamicinolone acetonide cream (TA), containing tracer amounts of H-3-labelled steroid, was applied once on the volar aspect of the right forearm for 12 h under occlusion. No Azone was incorporated in this cream. After a wash-out period, repeated dosing of TAZ, a similar cream containing 0.05% triamcinolone acetonide and 1.6% Azone, was performed on days 4-7 on the left forearm for 12 h per day under occlusion. The TAZ-cream contained tracer amounts of the H-3 labelled steroid on days 4 and 7. Absorption, distribution, and elimination of triamcinolone acetonide were followed by measuring the amounts of H-3-steroid-derived radioactivity in plasma, tape strippings, urine, and feces. Residual analysis was performed as well. During the whole study-period 6.7 +/- 0.3% (mean +/- S.D.) of the total applied radioactivity penetrated through the skin. The first application of TAZ resulted in a 3.2-times higher percutaneous absorption of steroid than the single application of TA, indicating an increased rate of absorption of triamcinolone acetonide in the presence of Azone. After multiple dosing of TAZ, absorption further increased to 6.8 times that of a single TA dose. Nevertheless, systemic levels of triamcinolone acetonide remained very low. Tape stripping revealed that reservoir formation of steroid was less of TA, and higher levels of steroid were found in the deeper layers of the stratum corneum, immediately after removal of the last TAZ-dose. This paper reports the first evidence that Azone acts as a penetration enhancer in vivo in human skin when dosed in a therapeutic formulation

An Experimentally Based Description of the Ground-state Wavefunction for Two Weakly Coupled Electrons by Photoelectron Spectroscopy and Magnetic Susceptibility Measurements

It is possible to extract values for the transfer energy, t, and the Coulomb interaction, U, in hydrogen-like systems from a combination of photoelectron and magnetic data, as both the form of the photoelectron spectrum and the exchange splitting are determined by these quantities. This procedure is used to evaluate the ground-state wavefunction for the two weakly coupled Ti 3d electrons in (C10H8)(C5H5)2Ti2Cl2.

Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects

INTRODUCTION: Bosentan (Ro 47-0203) is a potent and mixed ETA-and ETB-receptor antagonist. Its activity has been studied in a variety of preclinical disease models. METHODS: Two double-blind placebo-controlled studies were performed to investigate the pharmacokinetics and pharmacodynamics of bosentan after single oral and intravenous doses in healthy volunteers; doses of 3, 10, 30, 100, 300, 600, 1200, and 2400 mg were given in a single ascending oral dose study, and doses of 10, 50, 250, 500, and 750 mg were given in a single ascending intravenous dose study (six subjects received active drug and two received placebo at each dose level). In an open-label crossover added to the second study, six subjects received a single oral dose of 600 mg and a single intravenous dose of 250 mg in randomized order. At regular intervals, blood pressure, pulse rate, and skin responses to intradermally injected endothelin-1 (ET-1) were recorded, and plasma levels of ET-1, proendothelin-1 (big ET-1), and ET-3, and drug and urinary levels of ET-1 and drug were determined. RESULTS: Systemic plasma clearance and volume of distribution decreased with increasing dose to limiting values of around 6 L/hr and 0.2 L/kg, respectively. The absolute bioavailability was 50% and appeared to decrease with doses above 600 mg. Plasma ET-1 increased maximally twofold (oral) and threefold (intravenous), and this increase was directly related to bosentan plasma concentrations according to an Emax model. Bosentan reversed the vasoconstrictor effect of ET-1 measured in the skin microcirculation. There was a tendency toward decreased blood pressure (approximately 5 mm Hg) and increased pulse rate (approximately 5 beats/min), neither was clearly dose dependent. Oral bosentan was well tolerated. Vomiting and local intolerability was observed at the higher intravenous doses. CONCLUSION: Bosentan is an orally bioavailable, well-tolerated, and active ET-1 antagonist with a low clearance and a moderate volume of distribution. Its intravenous use is limited because of local intolerability