In Vivo Profiling of a Natural Alkaloid, Anatabine, in Rodents: Pharmacokinetics and Anti-Inflammatory Efficacy.

Natural alkaloids, a large class of plant-derived substances, have attracted considerable interest because of their pharmacological activities. In this study, the in vivo pharmacokinetics and anti-inflammatory profile of anatabine, a naturally occurring alkaloid, were characterized in rodents. Anatabine was found to be bioavailable and brain-penetrant following systemic administration. Following intraperitoneal (i.p.) administration (1, 2, and 5 mg/kg), anatabine caused a dose-dependent reduction in carrageenan-induced paw edema in rats; in mice, it inhibited the production of pro-inflammatory cytokines and simultaneously elevated the levels of an anti-inflammatory cytokine in a dose-dependent manner 2 h after lipopolysaccharide challenge. Furthermore, anatabine (∼10 and ∼20 mg/kg/day for 4 weeks; inhalation exposure) had effects in a murine model of multiple sclerosis, reducing neurological deficits and bodyweight loss. Comparative studies of the pharmacokinetics and anti-inflammatory activity of anatabine demonstrated its bioequivalence in rats following i.p. administration and inhalation exposure. This study not only provides the first detailed profile of anatabine pharmacokinetics in rodents but also comprehensively characterizes the anti-inflammatory activities of anatabine in acute and chronic inflammatory models. These findings provide a basis for further characterizing and optimizing the anti-inflammatory properties of anatabine.

Impact of 6-Month Exposure to Aerosols From Potential Modified Risk Tobacco Products Relative to Cigarette Smoke on the Rodent Gastrointestinal Tract.

Cigarette smoking causes adverse health effects that might occur shortly after smoking initiation and lead to the development of inflammation and cardiorespiratory disease. Emerging studies have demonstrated the role of the intestinal microbiome in disease pathogenesis. The intestinal microbiome is susceptible to the influence of environmental factors such as smoking, and recent studies have indicated microbiome changes in smokers. Candidate modified risk tobacco products (CMRTP) are being developed to provide substitute products to lower smoking-related health risks in smokers who are unable or unwilling to quit. In this study, the ApoE-/- mouse model was used to investigate the impact of cigarette smoke (CS) from the reference cigarette 3R4F and aerosols from two CMRTPs based on the heat-not-burn principle [carbon-heated tobacco product 1.2 (CHTP 1.2) and tobacco heating system 2.2 (THS 2.2)] on the intestinal microbiome over a 6-month period. The effect of cessation or switching to CHTP 1.2 after 3 months of CS exposure was also assessed. Next-generation sequencing was used to evaluate the impact of CMRTP aerosols in comparison to CS on microbiome composition and gene expression in the digestive tract of mice. Our analyses highlighted significant gene dysregulation in response to 3R4F exposure at 4 and 6 months. The findings showed an increase in the abundance of Akkermansiaceae upon CS exposure, which was reversed upon cessation. Cessation resulted in a significant decrease in Akkemansiaceae abundance, whereas switching to CHTP 1.2 resulted in an increase in Lactobacillaceae abundance. These microbial changes could be important for understanding the effect of CS on gut function and its relevance to disease pathogenesis via the microbiome.

A six-month systems toxicology inhalation/cessation study in ApoE-/- mice to investigate cardiovascular and respiratory exposure effects of modified risk tobacco products, CHTP 1.2 and THS 2.2, compared with conventional cigarettes.

Smoking is one of the major modifiable risk factors in the development and progression of chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). Modified-risk tobacco products (MRTP) are being developed to provide substitute products for smokers who are unable or unwilling to quit, to lessen the smoking-related health risks. In this study, the ApoE-/- mouse model was used to investigate the impact of cigarette smoke (CS) from the reference cigarette 3R4F, or aerosol from two potential MRTPs based on the heat-not-burn principle, carbon heated tobacco product 1.2 (CHTP1.2) and tobacco heating system 2.2 (THS 2.2), on the cardiorespiratory system over a 6-month period. In addition, cessation or switching to CHTP1.2 after 3 months of CS exposure was assessed. A systems toxicology approach combining physiology, histology and molecular measurements was used to evaluate the impact of MRTP aerosols in comparison to CS. CHTP1.2 and THS2.2 aerosols, compared with CS, demonstrated lower impact on the cardiorespiratory system, including low to absent lung inflammation and emphysematous changes, and reduced atherosclerotic plaque formation. Molecular analyses confirmed the lower engagement of pathological mechanisms by MRTP aerosols than CS. Both cessation and switching to CHTP1.2 reduced the observed CS effects to almost sham exposure levels.