Alteration of Autophagy and Glial Activity in Nilotinib-Treated Huntington's Disease Patients.

Nilotinib is a tyrosine kinase inhibitor that is safe and tolerated in neurodegeneration, it achieves CSF concentration that is adequate to inhibit discoidin domain receptor (DDR)-1. Nilotinib significantly affects dopamine metabolites, including Homovanillic acid (HVA), resulting in an increase in brain dopamine. HD is a hereditary disease caused by mutations in the Huntingtin's (HTT) gene and characterized by neurodegeneration and motor and behavioral symptoms that are associated with activation of dopamine receptors. We explored the effects of a low dose of nilotinib (150 mg) on behavioral changes and motor symptoms in manifest HD patients and examined the effects of nilotinib on several brain mechanisms, including dopamine transmission and gene expression via cerebrospinal fluid (CSF) miRNA sequencing. Nilotinib, 150 mg, did not result in any behavioral changes, although it significantly attenuated HVA levels, suggesting reduction of dopamine catabolism. There was no significant change in HTT, phosphorylated neuro-filament and inflammatory markers in the CSF and plasma via immunoassays. Whole miRNA genome sequencing of the CSF revealed significant longitudinal changes in miRNAs that control specific genes associated with autophagy, inflammation, microglial activity and basal ganglia neurotransmitters, including dopamine and serotonin.

Switching to Progressively Reduced Nicotine Content Cigarettes in Smokers With Low Socioeconomic Status: A Double-Blind Randomized Clinical Trial.

INTRODUCTION: The Food and Drug Administration issued an advanced notice of proposed rulemaking for setting a product standard for nicotine levels in cigarettes, with an emphasis on minimally or non-addicting very low nicotine content (VLNC). METHODS: A 33 week, two-arm, double-blind randomized trial conducted in Hershey, Pennsylvania, USA and Washington, DC, USA included adult daily cigarette smokers (≥5 cigarettes per day) with less than a college degree, and who had no plans to quit within the next six months. Participants were randomized to either reduced nicotine content (RNC) study cigarettes tapered every three weeks to a final VLNC (0.2 mg/cigarette) for six weeks or to usual nicotine content (UNC) study cigarettes (11.6 mg/cigarette). Outcomes included acceptability of study cigarettes measured by attrition (primary outcome), compliance, reduction in cigarette dependence and tobacco biomarkers, and post-intervention cessation. RESULTS: The RNC (n = 122) versus UNC (n = 123) group had higher attrition (adjusted Hazard Ratio 3.4; 95% confidence interval [CI] 1.99 to 5.81). At the end of the intervention, cotinine levels were 50% lower in the RNC group (mean group difference -137 ng/mL; 95% CI -172, -102). The RNC group smoked fewer CPD (-4.1; 95% CI -6.44, -1.75) and had lower carbon monoxide levels (-4.0 ppm; 95% CI -7.7, -0.4). Forty seven percent (29/62) of the RNC group were biochemically-confirmed compliant with smoking VLNC cigarettes (mean cotinine = 8.9 ng/ml). At three month follow-up, only compliant VLNC smokers quit with an assisted quit attempt (N = 6/22, 27%). CONCLUSIONS: This study supports a VLNC standard in cigarettes. IMPLICATIONS: Differential dropout and noncompliance indicate some smokers had difficulty transitioning to cigarettes with reduced nicotine. These smokers will benefit from supplemental nicotine in medicinal or noncombustible tobacco products if a nicotine reduction standard is established. Other smokers successfully transitioned to very low nicotine content cigarettes exclusively and substantially reduced their exposure to nicotine.

Clinical trial recruitment of adult African American smokers from economically disadvantaged urban communities.

This investigation evaluated the effectiveness and challenges of multiple recruitment methods, described as proactive, reactive, and combination methods, among adult African American smokers (N = 527) from economically disadvantaged urban communities enrolled to test progressively reduced nicotine content investigational cigarettes. The study evaluated success using descriptive statistics to measure the volume of phone calls and percentage of eligible participants per method. Reactive and combination strategies effectively prompted participants to call about the study. Combination methods yielded the highest eligibility rates. Findings demonstrate the unique recruitment successes within this population across a range of recruitment methods and may inform improved methods to recruit and engage African Americans in clinical trials.

Correction to Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized control trial.

CORRECTION: The title of the original publication [1] had an error; furthermore there were errors in Fig. 2. The corrected version of the title and of Fig. 2 can be found below in this Erratum.

Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized control trial.

BACKGROUND: The Family Smoking Prevention and Tobacco Control Act gave the Food and Drug Administration jurisdiction over the regulation of all tobacco products, including their nicotine content. Under this act, a major strategy to reduce harm from cigarette tobacco is lowering the nicotine content without causing unintended adverse consequences. Initial research on reduced nicotine content (RNC) cigarettes has shown that smokers of these cigarettes gradually decrease their smoking frequency and biomarkers of exposure. The effectiveness of this strategy needs to be demonstrated in different populations whose response to RNC cigarettes might be substantially mediated by personal or environmental factors, such as low socioeconomic status (SES) populations. This study aims to evaluate the response to a reduced nicotine intervention in low SES smokers, as defined here as those with less than 16 years of education, by switching smokers from high nicotine commercial cigarettes to RNC cigarettes. METHODS/DESIGN: Adults (N = 280) who have smoked five cigarettes or more per day for the past year, have not made a quit attempt in the prior month, are not planning to quit, and have less than 16 years of education are recruited into a two-arm, double-blinded randomized controlled trial. First, participants smoke their usual brand of cigarettes for 1 week and SPECTRUM research cigarettes containing a usual amount of nicotine for 2 weeks. During the experimental phase, participants are randomized to continue smoking SPECTRUM research cigarettes that contain either (1) usual nicotine content (UNC) (11.6 mg/cigarette) or (2) RNC (11.6 to 0.2 mg/cigarette) over 18 weeks. During the final phase of the study, all participants are offered the choice to quit smoking with nicotine replacement therapy, continue smoking the research cigarettes, or return to their usual brand of cigarettes. The primary outcomes of the study include retention rates and compliance with using only research cigarettes and no use of other nicotine-containing products. Secondary outcomes are tobacco smoke biomarkers, nicotine dependence measures, smoking topography, stress levels, and adverse health consequences. DISCUSSION: Results from this study will provide information on whether low SES smokers can maintain a course of progressive nicotine reduction without increases in incidence of adverse effects. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01928719 . Registered on 21 August 2013.