Development of Novel Pharmacotherapeutics for Tobacco Dependence: Progress and Future Directions

Harmey, Dympna; Griffin, Patrick R.; Kenny, Paul J.

doi:10.1093/ntr/nts201

Cited by 33 publications

(30 citation statements)

References 185 publications

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“…However, no study to our knowledge has explored anti-inflammatory agents as a smoking cessation aid (Table 1). Although our review was primarily focused on repurposing medications approved for other indications, we identified several compounds being tested for their cognitive enhancing properties that may be useful to explore for attenuating nicotine-withdrawal-related cognitive deficits [38,142,143]. To this end, we outline strategies for future research to identify and evaluate novel compounds.…”

Section: Expert Opinionmentioning

confidence: 99%

Optimizing treatments for nicotine dependence by increasing cognitive performance during withdrawal

Ashare

Schmidt

2014

Expert Opinion on Drug Discovery

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Introduction Current FDA-approved smoking cessation pharmacotherapies have limited efficacy and are associated with high rates of relapse. Therefore, there is a clear need to develop novel antismoking medications. Nicotine withdrawal is associated with cognitive impairments that predict smoking relapse. It has been proposed that these cognitive deficits are a hallmark of nicotine withdrawal that could be targeted in order to prevent smoking relapse. Thus, pharmacotherapies that increase cognitive performance during nicotine withdrawal may represent potential smoking cessation agents. Areas covered The authors review the clinical literature demonstrating that nicotine withdrawal is associated with deficits in working memory, attention and response inhibition. They then briefly summarize different classes of compounds and strategies to increase cognitive performance during nicotine withdrawal. Particular emphasis has been placed on translational research in order to highlight areas for which there is strong rationale for pilot clinical trials of potential smoking cessation medications. Expert opinion There is emerging evidence that supports deficits in cognitive function as a plausible nicotine withdrawal phenotype. The authors furthermore believe that the translational paradigms presented here may represent efficient and valid means for the evaluation of cognitive-enhancing medications as possible treatments for nicotine dependence.

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Section: Expert Opinionmentioning

confidence: 99%

Optimizing treatments for nicotine dependence by increasing cognitive performance during withdrawal

Ashare

Schmidt

2014

Expert Opinion on Drug Discovery

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“…Current drug addiction pharmacotherapies exhibit limitations and side effects. Medications for cocaine and methamphetamine abuse are lacking and those for treatment of nicotine and opioid addiction exhibit suboptimal clinical efficacy [2-5]. While vaccines are typically utilized to prevent infection, vaccination against drugs of abuse may offer an alternative to pharmacotherapy for treatment of drug dependence [6,7].…”

Section: Introductionmentioning

confidence: 99%

Hapten-specific naïve B cells are biomarkers of vaccine efficacy against drugs of abuse

Taylor

Laudenbach

Tucker

et al. 2014

Journal of Immunological Methods

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Vaccination against drugs of abuse shows efficacy in animal models, yet few subjects achieve effective serum antibody titers in clinical studies. A barrier to translation is the lack of pre-vaccination screening assays that predict the most effective conjugate vaccines or subjects amenable to vaccination. To address this obstacle, we developed a fluorescent antigen-based enrichment method paired with flow cytometry to characterize hapten-specific B cells. Using this approach, we studied naïve and activated B cells specific for structurally-related model haptens based on derivatization of the morphinan structure at the C6 position on oxycodone or at the C8 position on hydrocodone, and showing different pre-clinical efficacy against the prescription opioid oxycodone. Prior to vaccination, naïve B cells exhibited relative higher affinity for the more effective C6-derivatized oxycodone-based hapten (6OXY) and the 6OXY-specific naïve B cell population contained a higher number of B cells with greater affinity for free oxycodone. Higher affinity of naïve B cells for hapten or oxycodone reflected greater efficacy of vaccination in blocking oxycodone distribution to brain in mice. Shortly after immunization, activated hapten-specific B cells were detected prior to oxycodone-specific serum antibodies and provided earlier evidence of vaccine failure or success. Analysis of hapten-specific naïve and activated B cells may aid rational vaccine design and provide screening tools to predict vaccine clinical efficacy against drugs of abuse or other small molecules.

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“…About 80% of those who attempt to quit smoking relapse within the first month, and only 3% remain abstinent at 6 months (Benowitz, 2009), indicating that new medications are needed to specifically address the problem of relapse (George & O’Malley, 2004; Harmey, Griffin, & Kenny, 2012; Hurt et al, 2003; Irvin, Hendricks, & Brandon, 2003). The rewarding effects of nicotine are mediated, at least in part, by nicotine-evoked dopamine (DA) release leading to sensitization, which is associated with repeated nicotine administration and NIC addiction.…”

Section: Introductionmentioning

confidence: 99%

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

Crooks

Bardo

Dwoskin

2014

Advances in Pharmacology

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Despite the proven efficacy of current pharmacotherapies for tobacco dependence, relapse rates continue to be high, indicating that novel medications are needed. Currently, several smoking cessation agents are available, including varenicline (Chantix®), bupropion (Zyban®), and cytisine (Tabex®). Varenicline and cytisine are partial agonists at the α4β2* nicotinic acetylcholine receptor (nAChR). Bupropion is an antidepressant but is also an antagonist at α3β2* ganglionic nAChRs. The rewarding effects of nicotine are mediated, in part, by nicotine-evoked dopamine (DA) release leading to sensitization, which is associated with repeated nicotine administration and nicotine addiction. Receptor antagonists that selectivity target central nAChR subtypes mediating nicotine-evoked DA release should have efficacy as tobacco use cessation agents with the therapeutic advantage of a limited side-effect profile. While α-conotoxin MII (α-CtxMII)-insensitive nAChRs (e.g., α4β2*) contribute to nicotine-evoked DA release, these nAChRs are widely distributed in the brain, and inhibition of these receptors may lead to nonselective and untoward effects. In contrast, α-CtxMII-sensitive nAChRs mediating nicotine-evoked DA release offer an advantage as targets for smoking cessation, due to their more restricted localization primarily to dopaminergic neurons. Small drug-like molecules that are selective antagonists at α-CtxMII-sensitive nAChR subtypes that contain α6 and β2 subunits have now been identified. Early research identified a variety of quaternary ammonium analogs that were potent and selective antagonists at nAChRs mediating nicotine-evoked DA release. More recent data have shown that novel, non-quaternary bis-1,2,5,6-tetrahydropyridine analogs potently inhibit (IC50<1 nM) nicotine-evoked DA release in vitro by acting as antagonists at α-CtxMII-sensitive nAChR subtypes; these compounds also decrease NIC self-administration in rats.

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Development of Novel Pharmacotherapeutics for Tobacco Dependence: Progress and Future Directions

Cited by 33 publications

References 185 publications

Optimizing treatments for nicotine dependence by increasing cognitive performance during withdrawal

Optimizing treatments for nicotine dependence by increasing cognitive performance during withdrawal

Hapten-specific naïve B cells are biomarkers of vaccine efficacy against drugs of abuse

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

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