Differences among cigarette-only smokers compared to dual users of cigarettes and little cigars/cigarillos in the criminal justice population.

INTRODUCTION: The FDA has restrictions on cigarettes; however, little cigars and cigarillos (LCCs) remain largely absent from these regulations. Due to their low prices and flavoring, many engage in dual use of both LCCs and cigarettes. Dual use is particularly prevalent among low income racial/ethnic minority groups. The purpose of this study was to (U.S. Department of Health and Human Services, 2014) conduct an exploratory examination among cigarette users compared to dual users on smoking characteristics; and (Centers for Disease Control and Prevention, 2016) to examine racial differences (White and Black) among cigarette users compared to dual users. METHODS: Participants (N = 500) were recruited from community corrections (i.e., parole/probation) and categorized as either cigarette-only (66.4%) or dual users (33.6%) if they used little cigars or cigarillos over a one-year period during a smoking cessation clinical trial. RESULTS: Dual users were more likely to be younger, Black, males with lower educational attainment compared to cigarette-only smokers. Smokers with increased nicotine dependence were 17% more likely to be cigarette-only smokers compared to dual users. Racial differences revealed that White/cigarette-only smokers were more likely to report non-menthol use and higher cigarette consumption at the end of treatment compared to Black/cigarette-only or Black/dual users. CONCLUSIONS: This study contributes to our understanding of dual use among a disenfranchised group of smokers. Overall, dual users were more likely to be younger, Black, and male with lower reported nicotine dependence compared to cigarette-only users. Racial differences revealed that non-menthol smokers as well as smokers with greater cigarettes smoked at the end of treatment were more likely White/cigarette-only smokers.

Assessment of Cardiovascular Health among Community-Dwelling Men with Incarceration History.

Returning to the community after incarceration is a particularly vulnerable time with significantly increased risk of death in the first 2 weeks. The elevated risk of death persists as long as 2 years, with cardiovascular disease (CVD) among the leading causes. African-Americans, especially African-American men, have higher rates of incarceration and community supervision (e.g., probation and parole) and an earlier onset of hypertension compared to Whites. Few studies have objectively assessed the cardiovascular health profile of criminal justice involved individuals. This study is designed to determine the cardiovascular health profile among men in community corrections and/or transitional housing, identify the prevalence of key CVD risk factors, and assess if risk varies by race/ethnicity. We recruited 100 adult men (mean age = 42.7, SD = 11.35, 60% White, 40% non-Hispanic White) with a history of incarceration in jail or prison of ≥ 6 months during their most recent incarceration and enrolled in a community corrections program. Using the American Heart Association's Life's Simple 7™ (LS-7), measures of each of the LS-7 components (body mass index, blood pressure, lipids, blood glucose, smoking, diet, and physical activity) were obtained, and LS-7 scores were generated for each measure using AHA-defined categories of poor (1 point), intermediate (2 points), and ideal (3 points) and summed to yield a total score ranging from poor for all (7 points) to ideal for all (21 points). Mann-Whitney U tests were performed to assess differences in LS-7 scores (poor, intermediate, ideal) by race/ethnicity. Additionally, an independent samples t test was conducted for race/ethnicity and LS-7 total score. Mann-Whitney U tests for LS-7 categories and race/ethnicity indicated a greater number of non-Whites had poor blood pressure (p < .01) and diet (p < .05) as compared to Whites. The independent samples t test demonstrated significantly lower LS-7 scores for non-Whites compared to Whites. To our knowledge, this is the first study to evaluate cardiovascular health among individuals with a history of incarceration using the LS-7 metric, which included objective measures for four of the seven LS-7 metrics. Non-Whites, which included African-Americans, Hispanics, and American Indians, were more likely than Whites to fall into the poor category for both diet and blood pressure and had significantly lower total LS-7 scores than Whites, indicating they have worse scores across all seven of the LS-7 measures. Similar to what is found among non-incarcerated samples, non-Whites with incarceration histories are at elevated risk for cardiovascular events relative to their White peers.

Medical, psychosocial, and treatment predictors of opioid overdose among high risk opioid users.

INTRODUCTION: Drug overdoses are the leading cause of accidental death in the United States. It is imperative to explore predictors of opioid overdose in order to facilitate targeted treatment and prevention efforts. The present study was conducted as an exploratory examination of the factors associated with having a past opioid overdose. METHODS: Participants (N = 244) from substance treatment facilities, inpatient services following ER admittance, or involved within the drug court system and who reported opioid use in the past 6 months were recruited in this study. Measures of opioid use and history were used to determine characteristics associated with previous experience of a non-fatal opioid overdose. RESULTS: Opioid users who were Caucasian and used a combination of prescription opioids and heroin were more likely to have experienced a prior overdose. Opioid user characteristics associated with greater odds of experiencing a prior overdose included: witnessing a friend overdose (OR 4.21), having chronic hepatitis C virus (HCV) infection (OR 2.44), reporting a higher frequency of buprenorphine treatment episodes (OR 1.55), and having a higher frequency of witnessing others overdose (OR 1.42). Greater frequency of methadone treatment episodes was related to decreased odds of experiencing an overdose (OR 0.67). CONCLUSION: Overall, this study demonstrated certain demographic and drug use factors associated with elevated risk for an overdose. Understanding the risk factors associated with drug overdose can lead to targeted naloxone training and distribution to prevent fatal overdoses.

A pilot trial of In vivo NRT sampling to increase medication adherence in community corrections smokers.

BACKGROUND: Individuals in the criminal justice system demonstrate high rates of cigarette use (70-80%) and low adherence to smoking cessation medication. Educational approaches have not been shown to promote adherence or cessation, though medication sampling has boosted both use and cessation. The objective of the present study was to determine whether In vivo nicotine replacement therapy (NRT) sampling approach increases NRT adherence among criminal justice smokers during a subsequent quit attempt. METHODS: We conducted a pilot study with 43 community corrections smokers randomized to a 4-session (one 30-min session per week) precessation intervention of either In vivo NRT sampling (Session 1: patch; Session 2: gum; Session 3: combination NRT (cNRT); Session 4: review) vs. 4 time-matched sessions of standard smoking cessation with cNRT started after Session 1. Both groups received an additional 8weeks of cNRT following the four intervention sessions. RESULTS: During the in vivo administration of NRT, total withdrawal and craving severity significantly decreased from pre- to post-session compared to Control participants. In vivo participants evinced greater patch use at Session 4 and greater gum use through Week 8 relative to Controls. DISCUSSION: In vivo NRT sampling may increase NRT adherence relative to standard counseling sessions among criminal justice smokers. A larger trial of this novel intervention appears to be warranted.

A CXCR4-targeted site-specific antibody-drug conjugate.

A chemically defined anti-CXCR4-auristatin antibody-drug conjugate (ADC) was synthesized that selectively eliminates tumor cells overexpressing the CXCR4 receptor. The unnatural amino acid p-acetylphenylalanine (pAcF) was site-specifically incorporated into an anti-CXCR4 immunoglobulin G (IgG) and conjugated to an auristatin through a stable, non-cleavable oxime linkage to afford a chemically homogeneous ADC. The full-length anti-CXCR4 ADC was selectively cytotoxic to CXCR4(+) cancer cells in vitro (half maximal effective concentration (EC50 )≈80-100 pM). Moreover, the anti-CXCR4 ADC eliminated pulmonary lesions from human osteosarcoma cells in a lung-seeding tumor model in mice. No significant overt toxicity was observed but there was a modest decrease in the bone-marrow-derived CXCR4(+) cell population. Because CXCR4 is highly expressed in a majority of metastatic cancers, a CXCR4-auristatin ADC may be useful for the treatment of a variety of metastatic malignancies.

In vitro and in vivo evaluation of cysteine and site specific conjugated herceptin antibody-drug conjugates.

Antibody drug conjugates (ADCs) are monoclonal antibodies designed to deliver a cytotoxic drug selectively to antigen expressing cells. Several components of an ADC including the selection of the antibody, the linker, the cytotoxic drug payload and the site of attachment used to attach the drug to the antibody are critical to the activity and development of the ADC. The cytotoxic drugs or payloads used to make ADCs are typically conjugated to the antibody through cysteine or lysine residues. This results in ADCs that have a heterogeneous number of drugs per antibody. The number of drugs per antibody commonly referred to as the drug to antibody ratio (DAR), can vary between 0 and 8 drugs for a IgG1 antibody. Antibodies with 0 drugs are ineffective and compete with the ADC for binding to the antigen expressing cells. Antibodies with 8 drugs per antibody have reduced in vivo stability, which may contribute to non target related toxicities. In these studies we incorporated a non-natural amino acid, para acetyl phenylalanine, at two unique sites within an antibody against Her2/neu. We covalently attached a cytotoxic drug to these sites to form an ADC which contains two drugs per antibody. We report the results from the first direct preclinical comparison of a site specific non-natural amino acid anti-Her2 ADC and a cysteine conjugated anti-Her2 ADC. We report that the site specific non-natural amino acid anti-Her2 ADCs have superior in vitro serum stability and preclinical toxicology profile in rats as compared to the cysteine conjugated anti-Her2 ADCs. We also demonstrate that the site specific non-natural amino acid anti-Her2 ADCs maintain their in vitro potency and in vivo efficacy against Her2 expressing human tumor cell lines. Our data suggests that site specific non-natural amino acid ADCs may have a superior therapeutic window than cysteine conjugated ADCs.

A general approach to site-specific antibody drug conjugates.

Using an expanded genetic code, antibodies with site-specifically incorporated nonnative amino acids were produced in stable cell lines derived from a CHO cell line with titers over 1 g/L. Using anti-5T4 and anti-Her2 antibodies as model systems, site-specific antibody drug conjugates (NDCs) were produced, via oxime bond formation between ketones on the side chain of the incorporated nonnative amino acid and hydroxylamine functionalized monomethyl auristatin D with either protease-cleavable or noncleavable linkers. When noncleavable linkers were used, these conjugates were highly stable and displayed improved in vitro efficacy as well as in vivo efficacy and pharmacokinetic stability in rodent models relative to conventional antibody drug conjugates conjugated through either engineered surface-exposed or reduced interchain disulfide bond cysteine residues. The advantages of the oxime-bonded, site-specific NDCs were even more apparent when low-antigen-expressing (2+) target cell lines were used in the comparative studies. NDCs generated with protease-cleavable linkers demonstrated that the site of conjugation had a significant impact on the stability of these rationally designed prodrug linkers. In a single-dose rat toxicology study, a site-specific anti-Her2 NDC was well tolerated at dose levels up to 90 mg/kg. These experiments support the notion that chemically defined antibody conjugates can be synthesized in commercially relevant yields and can lead to antibody drug conjugates with improved properties relative to the heterogeneous conjugates formed by nonspecific chemical modification.

Site-specific antibody-polymer conjugates for siRNA delivery.

We describe here the development of site-specific antibody-polymer conjugates (APCs) for the selective delivery of small interference RNAs (siRNAs) to target cells. APCs were synthesized in good yields by conjugating an aminooxy-derivatized cationic block copolymer to an anti-HER2 Fab or full-length IgG by means of genetically encoded p-acetyl phenylalanine (pAcF). The APCs all showed binding affinity comparable to that of HER2 as their native counterparts and no significant cellular cytotoxicity. Mutant S202-pAcF Fab and Q389-pAcF IgG polymer conjugates specifically delivered siRNAs to HER2(+) cells and mediated potent gene silencing at both the mRNA and protein levels. However, a mutant A121-pAcF IgG polymer conjugate, despite its high binding affinity to HER2 antigen, did not induce a significant RNA interference response in HER2(+) cells, presumably due to steric interference with antigen binding and internalization. These results highlight the importance of conjugation site on the activity of antibody-polymer-based therapeutics and suggest that such chemically defined APCs may afford a useful targeted delivery platform for siRNAs or other nucleic acid-based therapies.