Explore the vast range of titles available.

The US FDA recommends assessment of abuse liability (AL) for premarket tobacco product applications (PMTAs) to determine whether a new tobacco product is appropriate for the protection of public health (APPH). To assess the AL and nicotine uptake of Vuse Alto electronic nicotine tobacco products (ENDS) which offer e-liquid pods that vary in nicotine concentration, we conducted two clinical laboratory studies. The primary objective of Study 1 was to assess measures of product abuse liability (AL) in real time during and following product use. This was achieved through timed subjective effect questionnaires, physiological measures (blood pressure and heart rate), and pharmacokinetic assessments for Golden Tobacco flavor 2.4% and 5% nicotine concentration Vuse Alto products. Study 2 evaluated PK and Overall Product Liking (OPL) of four Alto flavor variants with 1.8% and 2.4% nicotine concentrations. The studies were designed as open-label, randomized, crossover studies with 9 and 7 days of confinement for Study 1 and Study 2 respectively, were employed to assess nicotine PK, subjective effects, and physiological measures (Study 1 only) for 4 h after a 10-minute ad libitum ENDS product use. Study 1 included high (usual brand [UB] cigarettes) and low abuse liability (nicotine gum) comparators. Nicotine PK of Vuse Alto products were generally similar across the three nicotine concentrations and four flavors tested in these studies. In Study 1, nicotine PK and several subjective effects (product liking, OPL, product positive/negative effects and urge to smoke) for Vuse Alto 2.4% and 5% products were determined to be in between UB cigarettes and nicotine gum. Increases in heart rate, systolic and diastolic blood pressure were observed for both products. In Study 2, nicotine PK and the OPL for Vuse Alto four flavors at 1.8% and Golden Tobacco at 2.4% were similar and comparable to the Alto products tested in Study 1. These results indicate the AL of Vuse Alto, as assessed by nicotine PK and subjective effects measures of Vuse Alto products at three nicotine concentrations and of four flavors, is significantly lower than cigarettes, and higher than nicotine gum. ENDS products deliver nicotine in a manner that satisfies smokers’ preferences while exhibiting lower AL than cigarettes. Compared to pharmaceutical smoking cessation aids, such as nicotine gum, the Vuse Alto products demonstrate nicotine PK profiles characterized by a more rapid onset and higher peak concentrations, with subjective measures such as product liking, fall between those of nicotine replacement therapy gum and combustible cigarettes. Collectively, the AL assessments indicate that Vuse Alto products may support tobacco harm reduction by providing an alternative that may help smokers migrate away from cigarette smoking.

Oral nicotine pouches (ONPs) are a newer category of smokeless tobacco products containing pharmaceutical-grade nicotine but no tobacco leaf. These products have the potential to help smokers transition away from cigarettes. To assess their potential role as alternatives to cigarettes, we evaluated the abuse liability (AL) of Velo ONPs with varying nicotine content (4-12 mg per pouch), pouch size (600 mg or 400 mg) and flavor (six varieties) in comparison to high (cigarettes) and low (nicotine replacement therapy [NRT] gum) AL comparators. Independent randomized crossover clinical studies were conducted to assess AL, including subjective effects (product liking [PL], urge to smoke, product effects, overall PL, and overall intent to use again) and nicotine pharmacokinetic (PK) parameters of Velo ONPs. Participants used test products under controlled conditions, and subjective effect measures were collected using validated questionnaires. Nicotine PK parameters, including peak nicotine concentration (C ), time to maximum concentration (T ), were assessed. Mean PL scores for all Velo ONPs (p < 0.0042) and Velo Mini Pouches (p < 0.0031) were significantly lower than cigarettes, regardless of nicotine level, pouch size, or flavor, but similar to NRT gum. Other subjective measures for Velo ONPs were less favorable than cigarettes and comparable to or lower than NRT gum. Nicotine uptake with Velo ONPs was slower (reflected by a longer T ) and had lower C than cigarettes but was comparable or slightly lower than NRT gum. Overall nicotine uptake increased with increasing nicotine content and was comparable to that of cigarettes for Velo ONPs with higher nicotine levels. Flavor had no effect on nicotine uptake of Velo ONPs. Velo ONPs demonstrated an AL profile lower than cigarettes and similar to NRT gum, suggesting a reduced potential for abuse compared to cigarettes. The slower nicotine uptake and lower peak nicotine levels further support their potential as a lower-risk alternative. These findings highlight the potential role of ONPs in tobacco harm reduction strategies by providing an alternative nicotine source with a lower AL than combustible cigarettes. The clinical studies were registered at ClinicalTrials.gov; NCT05129657, NCT05294497, and NCT05081154.

Assessment of in vitro cytotoxicity is an important component of tobacco product toxicological evaluations. However, current methods of regulatory testing involve exposing monolayer cell cultures to various preparations of aerosols from cigarettes or other emerging products such as electronic nicotine delivery systems (ENDS), which are not representative of human exposure. In the present study, a whole aerosol (WA) system was used to expose lung epithelial cultures (2D and 3D) to determine the potential of six Vuse Alto ENDS products that varied in nicotine content (1.8%, 2.4%, and 5%) and flavors (Golden Tobacco, Rich Tobacco, Menthol, and Mixed Berry), along with a marketed ENDS and a marked cigarette comparator to induce cytotoxicity and oxidative stress. The WA from the Vuse Alto ENDS products was not cytotoxic in the NRU and MTT assays, nor did it activate the Nrf2 reporter gene, a marker of oxidative stress. In summary, Vuse Alto ENDS products did not induce cytotoxic or oxidative stress responses in the in vitro models. The WA exposures used in the 3D in vitro models described herein may be better suited than 2D models for the determination of cytotoxicity and other in vitro functional endpoints and represent alternative models for regulatory evaluation of tobacco products.

In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition.

Groundwater, Earth’s largest nonfrozen freshwater reservoir, is vital for water supply security. Groundwater models help to manage complex domestic, agricultural, and industrial water demands while preserving ecosystem health under climate change. The community-driven groundwater model portal (GroMoPo) hosts groundwater model metadata to analyse biases and distribution of groundwater models. Over 450 models are currently featured on GroMoPo, with most models from high-GDP countries at local-to-regional scales. The GroMoPo initiative addresses current knowledge gaps and facilitates future collaboration and data sharing.

The current study was designed to extend our knowledge of the N-methyl- D-aspartate (NMDA) glutamate receptor system in mediating the discriminative stimulus effects of ethanol in non-human primates. To characterize the discriminative stimulus effects of the NMDA uncompetitive antagonists dizocilpine, phencyclidine (PCP) and ketamine in male and female monkeys under different ethanol training conditions. Adult male ( n=8) and female ( n=9) cynomolgus monkeys ( Macaca fascicularis) were divided into four groups and trained to discriminate 1.0 g/kg ethanol ( n=8) versus water or 2.0 g/kg ethanol ( n=9) versus water in a 2 x 2 design with training dose and sex as main group factors. Ethanol (20% w/v) solutions were administered intragastrically (IG) and responding was maintained under a fixed ratio schedule of food reinforcement. Dose-response determinations for dizocilpine [IG and intramuscular (IM)], PCP (IM) and ketamine (IM) were made under two training intervals (30 and 60 min). Dizocilpine, PCP and ketamine dose-dependently substituted for ethanol in three of four training conditions, the notable exception being in males trained with 2.0 g/kg ethanol. Ethanol-like discriminative stimulus effects were greater with IM dizocilpine than with IG dizocilpine. At the lower ethanol training dose (1.0 g/kg), there were no sex differences in the ethanol-like discriminative stimulus effects of dizocilpine, PCP or ketamine, nor were there sex differences in the potencies to produce ethanol-like discriminative stimulus effects. Sex differences were readily apparent with the higher ethanol training dose (2.0 g/kg), with the NMDA ligands failing to substitute for ethanol in male monkeys, probably due to the rate-suppressive effects of these compounds. These data suggest that NMDA receptor-mediated activity is a component to the discriminative stimulus effects of ethanol in male and female nonhuman primates. However, NMDA uncompetitive antagonists were less likely to produce discriminative stimulus effects similar to a high ethanol training dose in male monkeys. In comparison to consistent substitution by GABA(A) positive modulators for ethanol, substitution patterns produced by NMDA uncompetitive antagonists suggest a less robust mediation of the ethanol discriminative stimulus through NMDA receptor systems in nonhuman primates.

The potential therapeutic benefit of nicotinic ligands in a variety of neurodegenerative pathologies involving the CNS has energized research efforts to develop nicotinic acetylcholine receptor (nAChR) subtype-selective ligands (Bencherif and Schmitt, 2005). In particular, there has been a concerted effort to develop nicotinic compounds with selectivity for CNS nAChRs as potential pharmaceutical tools in the management of these disorders. Clinical and experimental data demonstrate a central role for alpha7 and alpha4beta2 nAChRs in cognitive function, sensory processing, mood, and neuroprotection (Bencherif and Schmitt, 2005; Buccafusco et al., 2005). The development of safe alpha7-selective ligands has been hampered by their lack of discrimination with hERG channels and 5-HT3 receptors. We have developed a number of compounds that display nanomolar affinity to the alpha7 and/or the alpha4beta2 receptor. Investigation of alpha7 functional activity showed a full range of activities from antagonists to full agonists without any significant activity at the human 5-HT3 receptor, P450 isozymes, hERG channels, or in the AMES test. Our findings demonstrate that potent and highly selective nAChR ligands can be designed.

Groundwater, Earth’s largest nonfrozen freshwater reservoir, is vital for water supply security. Groundwater models help to manage complex domestic, agricultural, and industrial water demands while preserving ecosystem health under climate change. The community-driven groundwater model portal (GroMoPo) hosts groundwater model metadata to analyse biases and distribution of groundwater models. Over 450 models are currently featured on GroMoPo, with most models from high-GDP countries at local-to-regional scales. The GroMoPo initiative addresses current knowledge gaps and facilitates future collaboration and data sharing. Les eaux souterraines, le plus grand réservoir d’eau douce non gelée de la planète, sont essentielles à la sécurité de l’approvisionnement en eau. Les modèles d’eaux souterraines aident à gérer les demandes complexes en eau domestique, agricole et industrielle tout en préservant la santé des écosystèmes face au changement climatique. Le portail communautaire de modèles d’eaux souterraines (GroMoPo) héberge des métadonnées de modèles d’eaux souterraines pour analyser les biais et la distribution des modèles d’eaux souterraines. Plus de 450 modèles sont actuellement présentés sur GroMoPo, la plupart provenant de pays à PIB élevé, à l’échelle locale ou régionale. L’initiative GroMoPo comble les lacunes actuelles en matière de connaissances et facilite la collaboration et le partage de données futurs. La mayor reserva de agua dulce no congelada de la Tierra, el agua subterránea, es vital para la seguridad del abastecimiento de agua. Los modelos de aguas subterráneas ayudan a gestionar la compleja demanda de agua para uso doméstico, agrícola e industrial, preservando al mismo tiempo la salud de los ecosistemas en un contexto de cambio climático. El portal de modelos de aguas subterráneas orientado a la comunidad (GroMoPo) contiene metadatos de modelos de aguas subterráneas para analizar los sesgos y la distribución de los modelos. En la actualidad, GroMoPo incluye más de 450 modelos, la mayoría de los cuales proceden de países con un PIB elevado y se elaboran a escala local y regional. La iniciativa GroMoPo aborda las actuales lagunas de conocimiento y facilita la colaboración y el intercambio de datos en el futuro. 地下水是地球上最大的非冰冻淡水储备，对于水供应安全至关重要。地下水模型有助于管理复杂的家庭、农业和工业用水需求，同时在气候变化的背景下保护生态系统健康。社区驱动的地下水模型门户（GroMoPo）汇集了地下水模型的元数据，以分析地下水模型的偏差和分布。目前，GroMoPo上展示了超过450个模型，绝大多数模型来自高GDP国家，涵盖从地方到区域的规模。GroMoPo倡议旨在填补当前的知识空白，促进未来的合作与数据共享。 As águas subterrâneas são os maiores reservatórios de água doce não congelada da Terra, e são essenciais para a garantia de segurança hídrica. Os modelos de águas subterrâneas auxiliam não só no gerenciamento de complexas demandas hídricas domésticas, agrícolas e industriais, como também na preservação dos ecossistemas frente às mudanças climáticas. O portal colaborativo de modelagem de águas subterrâneas (GroMoPo) armazena metadados diversos modelos hidrogeológicos para analisar os vieses e as distribuições desses modelos. Atualmente, mais de 450 modelos estão reunidos no GroMoPo, sendo a maioria proveniente de países de alto PIB e em escala local a regional. A iniciativa GroMoPo busca preencher lacunas de conhecimento e promover a colaboração e o compartilhamento de dados no futuro.