Subcutaneous versus transvenous implantable cardioverter-defibrillator among drug-induced type-1 ECG pattern Brugada syndrome: a propensity score matching analysis from IBRYD study.

No real-world data are available about the complications rate in drug-induced type 1 Brugada Syndrome (BrS) patients with an implantable cardioverter-defibrillator (ICD). Aim of our study is to compare the device-related complications, infections, and inappropriate therapies among drug-induced type 1 BrS patients with transvenous- ICD (TV-ICD) versus subcutaneous-ICD (S-ICD). Data for this study were sourced from the IBRYD (Italian BRugada sYnDrome) registry which includes 619 drug-induced type-1 BrS patients followed at 20 Italian tertiary referral hospitals. For the present analysis, we selected 258 consecutive BrS patients implanted with ICD. 198 patients (76.7%) received a TV-ICD, while 60 a S-ICD (23.4%). And were followed-up for a median time of 84.3 [46.5-147] months. ICD inappropriate therapies were experienced by 16 patients (6.2%). 14 patients (7.1%) in the TVICD group and 2 patients (3.3%) in S-ICD group (log-rank P = 0.64). ICD-related complications occurred in 31 patients (12%); 29 (14.6%) in TV-ICD group and 2 (3.3%) in S-ICD group (log-rank P = 0.41). ICD-related infections occurred in 10 patients (3.88%); 9 (4.5%) in TV-ICD group and 1 (1.8%) in S-ICD group (log-rank P = 0.80). After balancing for potential confounders using the propensity score matching technique, no differences were found in terms of clinical outcomes between the two groups. In a real-world setting of drug-induced type-1 BrS patients with ICD, no significant differences in inappropriate ICD therapies, device-related complications, and infections were shown among S-ICD vs TV-ICD. However, a reduction in lead-related complications was observed in the S-ICD group. In conclusion, our evidence suggests that S-ICD is at least non-inferior to TV-ICD in this population and may also reduce the risk of lead-related complications which can expose the patients to the necessity of lead extractions.

Different roles for the acyl chain and the amine leaving group in the substrate selectivity of N-Acylethanolamine acid amidase.

N-acylethanolamine acid amidase (NAAA) is an N-terminal nucleophile (Ntn) hydrolase that catalyses the intracellular deactivation of the endogenous analgesic and anti-inflammatory agent palmitoylethanolamide (PEA). NAAA inhibitors counteract this process and exert marked therapeutic effects in animal models of pain, inflammation and neurodegeneration. While it is known that NAAA preferentially hydrolyses saturated fatty acid ethanolamides (FAEs), a detailed profile of the relationship between catalytic efficiency and fatty acid-chain length is still lacking. In this report, we combined enzymatic and molecular modelling approaches to determine the effects of acyl chain and polar head modifications on substrate recognition and hydrolysis by NAAA. The results show that, in both saturated and monounsaturated FAEs, the catalytic efficiency is strictly dependent upon fatty acyl chain length, whereas there is a wider tolerance for modifications of the polar heads. This relationship reflects the relative stability of enzyme-substrate complexes in molecular dynamics simulations.

Comparative Pharmacokinetics of Δ9-Tetrahydrocannabinol in Adolescent and Adult Male Mice.

We investigated the pharmacokinetic properties of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive constituent of cannabis, in adolescent and adult male mice. The drug was administered at logarithmically ascending doses (0.5, 1.6, and 5 mg/kg, i.p.) to pubertal adolescent (37-day-old) and adult (70-day-old) mice. Δ9-THC and its first-pass metabolites-11-hydroxy-Δ9-THC and 11-nor-9-carboxy-Δ9-THC (11-COOH-THC)-were quantified in plasma, brain, and white adipose tissue (WAT) using a validated isotope-dilution liquid chromatography/tandem mass spectrometry assay. Δ9-THC (5 mg/kg) reached 50% higher circulating concentration in adolescent mice than in adult mice. A similar age-dependent difference was observed in WAT. Conversely, 40%-60% lower brain concentrations and brain-to-plasma ratios for Δ9-THC and 50%-70% higher brain concentrations for Δ9-THC metabolites were measured in adolescent animals relative to adult animals. Liver microsomes from adolescent mice converted Δ9-THC into 11-COOH-THC twice as fast as adult microsomes. Moreover, the brains of adolescent mice contained higher mRNA levels of the multidrug transporter breast cancer resistance protein, which may extrude Δ9-THC from the brain, and higher mRNA levels of claudin-5, a protein that contributes to blood-brain barrier integrity. Finally, administration of Δ9-THC (5 mg/kg) reduced spontaneous locomotor activity in adult, but not adolescent, animals. The results reveal the existence of multiple differences in the distribution and metabolism of Δ9-THC between adolescent and adult male mice, which might influence the pharmacological response to the drug. SIGNIFICANCE STATEMENT: Animal studies suggest that adolescent exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the intoxicating constituent of cannabis, causes persistent changes in brain function. These studies generally overlook the impact that age-dependent changes in the distribution and metabolism of the drug might exert on its pharmacological effects. This report provides a comparative analysis of the pharmacokinetic properties of Δ9-THC in adolescent and adult male mice and outlines multiple functionally significant dissimilarities in the distribution and metabolism of Δ9-THC between these two age groups.

Long-term clinical outcomes of patients with drug-induced type 1 Brugada electrocardiographic pattern: A nationwide cohort registry study.

BACKGROUND: There are limited real-world data on the extended prognosis of patients with drug-induced type 1 Brugada electrocardiogram (ECG). OBJECTIVE: We assessed the clinical outcomes and predictors of life-threatening arrhythmias in patients with drug-induced type 1 Brugada ECG. METHODS: This multicenter retrospective study, conducted at 21 Italian and Swiss hospitals from July 1997 to May 2021, included consecutive patients with drug-induced type 1 ECG. The primary outcome, a composite of appropriate ICD therapies and sudden cardiac death, was assessed along with the clinical predictors of these events. RESULTS: A total of 606 patients (mean age 49.7 ± 14.7 years; 423 [69.8%] men) were followed for a median of 60.3 months (interquartile range 23.0-122.4 months). Nineteen patients (3.1%) experienced life-threatening arrhythmias, with a median annual event rate of 0.5% over 5 years and 0.25% over 10 years. The SCN5A mutation was the only predictor of the primary outcome (hazard ratio 4.54; P = .002), whereas a trend was observed for unexplained syncope (hazard ratio 3.85; P = .05). In patients who were asymptomatic at presentation, the median annual rate of life-threatening arrhythmias is 0.24% over 5 years and increases to 1.2% if they have inducible ventricular fibrillation during programmed ventricular stimulation. CONCLUSION: In patients with drug-induced type 1 Brugada ECG, the annual risk of life-threatening arrhythmias is low, with the SCN5A mutation as the only independent predictor. Unexplained syncope correlated with worse clinical outcomes. Ventricular fibrillation inducibility at programmed ventricular stimulation significantly increases the median annual rate of life-threatening arrhythmias from 0.24% to 1.2% over 5 years.

Electrophysiological Study Prognostic Value and Long-Term Outcome in Drug-Induced Type 1 Brugada Syndrome: The IBRYD Study.

OBJECTIVES: This study aimed to retrospectively assess long-term outcome and the prognostic role of electrophysiological study (EPS) for risk stratification of drug-induced type 1 Brugada syndrome (BrS) patients. BACKGROUND: BrS is a hereditary cardiac disease, predisposing to sudden cardiac death. Few real-world data are available on long-term outcomes of drug-induced type 1 BrS patients, and questions about risk stratification still remain unanswered. METHODS: The IBRYD (Italian Brugada Syndrome) study is a multicenter observational retrospective study. A total of 226 drug-induced type 1 BrS patients were enrolled from 9 Italian tertiary referral institutions. Primary endpoint was a composite of appropriate implantable cardioverter-defibrillator (ICD) therapy and sudden cardiac death. The authors further assessed clinical predictors to ICD implantation, as well as for arrhythmia induction at EPS, along with EPS as potential risk factor for the outcomes of interest. RESULTS: 142 patients (62.8%) received an ICD due to syncope and/or inducible ventricular tachyarrhythmias at EPS. During a median follow-up of 106 months, 11 patients (4.9%) experienced primary outcome events. The ICD therapy median annual incidence over 8 years was 0.38% (interquartile range: 0% to 1.47%). Ventricular tachyarrhythmia inducibility during EPS was not predictive of arrhythmic events in ICD recipients versus non-ICD patients and in symptomatic versus asymptomatic subgroups, showing a low positive predictive value (9.6% and 8.9%, respectively) versus a high negative predictive value (96.6% and 95%, respectively). The authors reported 29 ICD-related complications and 4.9% inappropriate shocks. CONCLUSIONS: Drug-induced type 1 BrS patients have a very low arrhythmic risk. Clinical decision for implantation is supported by syncope and/or EPS positivity, though they fail to stratify high-risk patients. A better risk-to-benefit ratio should be pursued, considering both arrhythmic risk and ICD-related complications.

Identification of Bivalent Ligands with Melatonin Receptor Agonist and Fatty Acid Amide Hydrolase (FAAH) Inhibitory Activity That Exhibit Ocular Hypotensive Effect in the Rabbit.

Activation of melatonin receptors and inhibition of fatty acid amide hydrolase (FAAH) have both shown potential benefits for the treatment of glaucoma. To exploit the combination of these biological activities in single therapeutic agents, we designed dual-acting compounds sharing the pharmacophore elements required for the two targets, in search for balanced potencies as MT1/MT2 agonists and FAAH inhibitors. In particular, the N-anilinoethylamide scaffold, previously developed for melatonergic ligands, was decorated at meta position with a polymethylene linker bound to an O-arylcarbamate group, substituted according to known structure-activity relationships for FAAH inhibition. For the most active series, the N-anilinoethylamide portion was also replaced with the indole scaffold of melatonin. O-Biphenyl-3-ylcarbamate derivatives were characterized by remarkable and balanced activity at both targets, in the nanomolar range for compound 29. Topical administration reduced elevated intraocular pressure in rabbits, with a longer action and improved efficacy compared to the reference compounds melatonin and URB597.