Structure-activity optimization of ryanodine receptor modulators for the treatment of catecholaminergic polymorphic ventricular tachycardia.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia disorder associated with lethal arrhythmias. Most CPVT cases are caused by inherited variants in the gene encoding ryanodine receptor type 2 (RYR2).

Objective: The goal of this study was to investigate the structure-activity relationship of tetracaine derivatives and to test a lead compound in a mouse model of CPVT.

Toxicity of waterpipe tobacco smoking: the role of flavors, sweeteners, humectants, and charcoal.

Waterpipe tobacco (WPT) smoking is a public health concern, particularly among youth and young adults. The global spread of WPT use has surged because the introduction of pre-packaged flavored and sweetened WPT, which is widely marketed as a safer tobacco alternative. Besides flavorants and sugars, WPT additives include humectants, which enhance the moisture and sweetness of WPT, act as solvents for flavors, and impart smoothness to the smoke, thus increasing appeal to users.

Mechanistic Rationale for Ketene Formation during Dabbing and Vaping.

Ketene is one of the most toxic vaping emissions identified to date. However, its high reactivity renders it relatively challenging to identify. In addition, certain theoretical studies have shown that realistic vaping temperature settings may betoo low to produce ketene.

In vitro toxicity and chemical analysis of e-cigarette aerosol produced amid dry hitting.

Dry hitting, a phenomenon produced by e-cigarettes with refillable cartridges when the liquid in the coil is low, is a common occurrence among regular vapers despite being an unintended consequence of the device. This phenomenon's hazard to public health is still unknown and needs further investigation. Lung cells cultured at the air-liquid interface were exposed to vaped aerosol consisting of 3 % w/v ethyl maltol in propylene glycol for three-second puffs every 30 seconds for 80 total puffs with either dry hit or saturated conditions.

A Review of the Toxicity of Ingredients in e-Cigarettes, Including Those Ingredients Having the FDA's "Generally Recognized as Safe (GRAS)" Regulatory Status for Use in Food.

Some firms and marketers of electronic cigarettes (e-cigarettes; a type of electronic nicotine delivery system (ENDS)) and refill liquids (e-liquids) have made claims about the safety of ingredients used in their products based on the term "GRAS or Generally Recognized As Safe" (GRAS). However, GRAS is a provision within the definition of a food additive under section 201(s) (21 U.S.

Chemical and physiological interactions between e-liquid constituents: cause for concern?

Studies of Electronic Nicotine Delivery Systems (ENDS) toxicity have largely focused on individual components such as flavour additives, base e-liquid ingredients (propylene glycol, glycerol), device characteristics (eg, model, components, wattage), use behaviour, etc. However, vaping involves inhalation of chemical mixtures and interactions between compounds can occur that can lead to different toxicities than toxicity of the individual components. Methods based on the additive toxicity of individual chemical components to estimate the health risks of complex mixtures can result in the overestimation or underestimation of exposure risks, since interactions between components are under-investigated.

Reviewing the Risk of Ketene Formation in Dabbing and Vaping Tetrahydrocannabinol-O-Acetate.

In the wake of continued consumer demand despite increasing regulatory scrutiny, there is a need to develop systematic methods for identifying the harm profile of new psychoactive substances derived from hemp. Tetrahydrocannabinol-O (THC-O)-acetate, colloquially known as THCO, is the acetate ester of the principal psychoactive compound in cannabis. The heating of THCO can create ketene gas, which is harmful to the lungs.

A First-Tier Framework for Assessing Toxicological Risk from Vaporized Cannabis Concentrates.

Vaporization is an increasingly prevalent means to consume cannabis, but there is little guidance for manufacturers or regulators to evaluate additive safety. This paper presents a first-tier framework for regulators and cannabis manufacturers without significant toxicological expertise to conduct risk assessments and prioritize additives in cannabis concentrates for acceptance, elimination, or further evaluation. Cannabinoids and contaminants (e.

Enlarging the Stokes Shift by Weakening the π-Conjugation of Cyanines for High Signal-to-Noise Ratiometric Imaging.

The signal-to-noise ratio (SNR) is one of the key features of a fluorescent probe and one that often defines its potential utility for in vivo labeling and analyte detection applications. Here, it is reported that introducing a pyridine group into traditional cyanine-7 dyes in an asymmetric manner provides a series of tunable NIR fluorescent dyes (Cy-Mu-7) characterized by enhanced Stokes shifts (≈230 nm) compared to the parent cyanine 7 dye (<25 nm). The observed Stokes shift increase is ascribed to symmetry breaking of the Cy-Mu-7 core and a reduction in the extent of conjugation.

Chemical Interactions and Cytotoxicity of Terpene and Diluent Vaping Ingredients.

Vaping devices have risen in popularity since their inception in 2007. The practice involves using a variety of commercially available devices. Internal heating systems in devices aerosolize e-liquid formulations of complex mixtures including an active ingredient (e.

Vaping Cannabinoid Acetates Leads to Ketene Formation.

Δ-THC acetate is a relatively new psychoactive cannabis product that is available online and in vape shops across the United States since it is currently largely unregulated. Because it contains a similar substructure to vitamin E acetate, which has been shown to form the poison gas ketene during vaping, we investigated potential ketene formation from Δ-THC acetate, as well as two other cannabinoids acetates, CBN acetate and CBD acetate, under vaping conditions. Ketene was consistently observed in vaped condensates from all three cannabinoid acetates as well as from a commercial Δ-THC acetate product purchased online.

Effects of Common e-Liquid Flavorants and Added Nicotine on Toxicant Formation during Vaping Analyzed by H NMR Spectroscopy.

A broad variety of e-liquids are used by e-cigarette consumers. Additives to the e-liquid carrier solvents, propylene glycol and glycerol, often include flavorants and nicotine at various concentrations. Flavorants in general have been reported to increase toxicant formation in e-cigarette aerosols, yet there is still much that remains unknown about the effects of flavorants, nicotine, and flavorants + nicotine on harmful and potentially harmful constituents (HPHCs) when aerosolizing e-liquids.

Emerging ENDS products and challenges in tobacco control toxicity research.

Electronic nicotine delivery systems (ENDS) continue to rapidly evolve. Current products pose unique challenges and opportunities for researchers and regulators. This commentary aims to highlight research gaps, particularly in toxicity research, and provide guidance on priority research questions for the tobacco regulatory community.

Chemical profiling of Cannabis varieties cultivated for medical purposes in southeastern Brazil.

Cannabis cultivation for medical purposes in Brazil has been increased in the last years. While cannabis crops are prohibited, hundreds patients have been granted with judicial authorizations and there is little information about the cultivation conditions, yields and chemical profiles of the plants. Cannabis plants contain hundreds of compounds, with cannabinoids and terpenes the main drivers of their toxicological and pharmacological properties.

The influence of terpenes on the release of volatile organic compounds and active ingredients to cannabis vaping aerosols.

Dabbing and vaping cannabis extracts have gained large popularity in the United States as alternatives to cannabis smoking, but diversity in both available products and consumption habits make it difficult to assess consumer exposure to psychoactive ingredients and potentially harmful components. This work studies the how relative ratios of the two primary components of cannabis extracts, Δ-tetrahydrocannabinol (THC) and terpenes, affect dosage of these and exposure to harmful or potentially harmful components (HPHCs). THC contains a monoterpene moiety and has been previously shown to emit similar volatile degradation products to terpenes when vaporized.

Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome that often leads to sudden cardiac death. The most common form of CPVT is caused by autosomal-dominant variants in the cardiac ryanodine receptor type-2 (RYR2) gene. Mutations in RYR2 promote calcium (Ca ) leak from the sarcoplasmic reticulum (SR), triggering lethal arrhythmias.

Identifying a role for the interaction of homocysteine and copper in promoting cardiovascular-related damage.

Observations that copper and homocysteine levels are simultaneously elevated in patients with cardiovascular disease has generated interest in investigating the interactions between copper and homocysteine. Several prior studies have shown that complexes of copper and homocysteine are toxic, leading to cardiovascular damage in vitro. It is not clear, however, why related effects do not occur with other structurally similar, more abundant cellular thiols such as glutathione and cysteine.

A simple predictive model for estimating relative e-cigarette toxic carbonyl levels.

E-cigarette devices are wide ranging, leading to significant differences in levels of toxic carbonyls in their respective aerosols. Power can be a useful method in predicting relative toxin concentrations within the same device, but does not correlate well to inter-device levels. Herein, we have developed a simple mathematical model utilizing parameters of an e-cigarette's coil and wick in order to predict relative levels of e-liquid solvent degradation.

Pine rosin identified as a toxic cannabis extract adulterant.

Pine rosin (colophony) has been identified as a potentially new adulterant in cannabis oil. Its inhalation toxicity poses a significant health concern to users. For example, pine rosin fumes are released during soldering, and have been cited as a causative agent of occupational asthma.

A Diselenide Turn-On Fluorescent Probe for the Detection of Thioredoxin Reductase.

We report the first diselenide-based probe for the selective detection of thioredoxin reductase (TrxR), an enzyme commonly overexpressed in melanomas. The probe design involves conjugation of a seminaphthorhodafluor dye with a diselenide moiety. TrxR reduces the diselenide bond, triggering a fluorescence turn-on response of the probe.

E-Cigarette or Vaping Product Use-associated Lung Injury: Developing a Research Agenda. An NIH Workshop Report.

The NHLBI convened a working group on October 23, 2019, to identify the most relevant and urgent research priorities and prevailing challenges in e-cigarette or vaping product use-associated lung injury (EVALI). Experts across multiple disciplines discussed the complexities of the EVALI outbreak, identified research priorities, and recommended strategies to address most effectively its causal factors and improve diagnosis, treatment, and prevention of this disease. Many research priorities were identified, including the need to create national and international registries of patients with EVALI, to track accurately those affected and assess outcomes.

Aerosol Gas-Phase Components from Cannabis E-Cigarettes and Dabbing: Mechanistic Insight and Quantitative Risk Analysis.

Consumption of cannabis by nontraditional methods has surged since the advent of legalization in North America and worldwide. Inhaling cannabis extracts using vaporizers and via dabbing has risen in popularity, while concerns over product safety have not hindered their proliferation. The work herein is the first step toward assessing the safety of vaporizing and dabbing concentrated cannabis extracts as a function of gas-phase reaction products.