Nicotine Difartrate

(-)-Nicotine ditartrate is a potent agonist of AChR (nicotinic acetylcholine recepto). It stimulates autonomic ganglia and skeletal muscle neuromuscular junctions.

Cigarette Nicotine Content as a Moderator of the Relationship Between Negative Affect and Smoking.[Pubmed:28371900]

Nicotine Tob Res. 2017 Sep 1;19(9):1080-1086.

Introduction: Research suggests a strong association between negative affect (NA) and smoking. However, little is known about the association between NA and smoking among individuals who switch to reduced-nicotine cigarettes. The goal of this study was to examine the extent to which cigarette nicotine content moderates the relationship between NA and smoking over time. Methods: Seven hundred and seventeen participants, 237 in the normal nicotine content (NNC; 15.8 mg/g and usual brand) cigarette group and 480 in the very low nicotine content (VLNC; 2.4 mg/g nicotine or less) cigarette group, participated in a randomized trial that examined the effects of cigarette nicotine content on smoking behavior over 6 weeks. We used parallel process latent growth curve modeling to estimate the relationship between changes in NA and changes in the numbers of cigarettes smoked per day (CPD), from baseline to 6 weeks, as a function of cigarette nicotine content. Results: The relationship between NA and investigational CPD reduced over time for those in the VLNC group, but not for those in the NNC group. There was no significant relationship between change in PA and CPD over time for either cigarette group. Conclusions: Smoking VLNC cigarettes disrupts the relationship between smoking and negative affect, which may help reduce nicotine dependence. Implications: This study suggests that the association between NA and smoking behavior is reduced over time among those that smoked reduced-nicotine content cigarettes. This provides additional evidence that smoking reduced-nicotine content cigarettes may help reduce nicotine dependence.

Tobacco-Nicotine Education and Training for Health-Care Professional Students and Practitioners: A Systematic Review.[Pubmed:28371888]

Nicotine Tob Res. 2018 Apr 2;20(5):531-542.

Introduction: The objective of this systematic review was to investigate what education and training characteristics prepares and supports health-care professionals (HCPs) in the delivery of competent and effective care to clients who use tobacco-nicotine. Aims and Methods: A search of eight bibliographic databases for English-language peer-reviewed publications from January 2006 to March 2015. Studies were included if they met the a priori inclusion criteria, which consisted of: (1) quantitative study design and (2) focus on tobacco-nicotine education or training for HCP students and practitioners. All studies were independently screened for inclusion by two reviewers. Data from included studies were extracted for study characteristics and key outcomes then critically appraised for methodological quality. Results: Fifty-nine studies were included for narrative synthesis. Two categories emerged: (1) curriculum characteristics (n = 10) and (2) education and training interventions (n = 49). Included curriculum studies identified the following themes: content, intensity, competencies evaluation, and barriers. Study findings about education and training interventions were grouped by level of education (prelicensure, post-licensure, and faculty training), teaching modality, health discipline, and the associated HCP and client outcomes. Conclusions: This comprehensive review suggests that there is a lack of consistency in HCP tobacco-nicotine education and training characteristics. This paper provides valuable categorization of the most frequently utilized components of academic curriculum and discusses the interventions in relation to HCP and client outcomes. Gaps in the literature are highlighted, and the need for standardization of tobacco-nicotine training competencies and evaluation is discussed. Future research investigating the most effective approaches to training is needed. Implications: This systematic review summarizes existing tobacco-related curriculum components (content, intensity, competency evaluation, and barriers) and training interventions for health-care professionals worldwide and demonstrates that they are associated with positive health-care professional outcomes (knowledge, attitudes, behaviors, and skills) and client outcomes (quit attempts and smoking abstinence).

Restructuring Reward Mechanisms in Nicotine Addiction: A Pilot fMRI Study of Mindfulness-Oriented Recovery Enhancement for Cigarette Smokers.[Pubmed:28373890]

Evid Based Complement Alternat Med. 2017;2017:7018014.

The primary goal of this pilot feasibility study was to examine the effects of Mindfulness-Oriented Recovery Enhancement (MORE), a behavioral treatment grounded in dual-process models derived from cognitive science, on frontostriatal reward processes among cigarette smokers. Healthy adult (N = 13; mean (SD) age 49 +/- 12.2) smokers provided informed consent to participate in a 10-week study testing MORE versus a comparison group (CG). All participants underwent two fMRI scans: pre-tx and after 8-weeks of MORE. Emotion regulation (ER), smoking cue reactivity (CR), and resting-state functional connectivity (rsFC) were assessed at each fMRI visit; smoking and mood were assessed throughout. As compared to the CG, MORE significantly reduced smoking (d = 2.06) and increased positive affect (d = 2.02). MORE participants evidenced decreased CR-BOLD response in ventral striatum (VS; d = 1.57) and ventral prefrontal cortex (vPFC; d = 1.7) and increased positive ER-BOLD in VS (dVS = 2.13) and vPFC (dvmPFC = 2.66). Importantly, ER was correlated with smoking reduction (r's = .68 to .91) and increased positive affect (r's = .52 to .61). These findings provide preliminary evidence that MORE may facilitate the restructuring of reward processes and play a role in treating the pathophysiology of nicotine addiction.

Effect of nicotine on the proliferation and chondrogenic differentiation of the human Wharton's jelly mesenchymal stem cells.[Pubmed:28372298]

Biomed Mater Eng. 2017;28(s1):S217-S228.

BACKGROUND: Osteoarthritis (OA) is a chronic joint disease characterized by a progressive and irreversible degeneration of articular cartilage. Among the environmental risk factors of OA, tobacco consumption features prominently, although, there is a great controversy regarding the role of tobacco smoking in OA development. Among the numerous chemicals present in cigarette smoke, nicotine is one of the most physiologically active molecules. OBJECTIVE: The aim of the study was (i) to measure the impact of nicotine on the proliferation and chondrogenic differentiation of mesenchymal stem cells from the human Wharton's jelly (hWJ-MSCs) into chondrocytes, (ii) to investigate whether the alpha7 nicotinic acetylcholine receptors (nAChRs) was expressed in hWJ-MSCs and could play a role in the process. The project benefits from the availability of an umbilical cord bank from which hWJ-MSCs were originated. METHODS: The hWJ-MSCs were cultured and used up to passage 5. The proliferation of hWJ-MSCs with 5 muM nicotine was measured by the MTT assay on the 1st, 2nd, 3rd, and 6th day. Flow cytometry analysis was used to detect cell apoptosis/necrosis by Annexin V/PI double-staining. The chondrogenic differentiation grade of hWJ-MSCs induced by TGFbeta3 was assessed by the Sirius red and Alcian blue staining. The expression of markers genes was followed by quantitative real-time PCR. The expression of nAChRs was followed by RT-PCR. The functional activity of alpha7 nAChR was evaluated by calcium (Ca2+) influx mediated by nicotine using the Fluo-4 NW Calcium assay. RESULTS: The proliferation of hWJ-MSCs was significantly impaired by nicotine (5 muM) from the 3rd day of treatment, but nicotine did not significantly induce modifications on the viability of hWJ-MSCs. Alcian blue staining indicated that the amount of proteoglycan was more abundant in control group than in the nicotine group, but no difference was observed on the total collagen amount using Sirius red staining. The mRNA expression of Sox9, type II collagen (Col2a1), aggrecan in control group was higher than in the nicotine group. We found that hWJ-MSCs expressed alpha7 nAChR. The receptor agonist nicotine caused calcium (Ca2+) influx into hWJ-MSCs suggesting that the calcium ion channel alpha7 homopolymer could mediate this response. CONCLUSIONS: At the concentration used, nicotine had an adverse effect on the proliferation and chondrogenic differentiation of hWJ-MSCs which was probably impaired through a alpha7 nAChR mediation.

Acute infusion of nicotine potentiates norepinephrine-induced vasoconstriction in the hamster cheek pouch.[Pubmed:10385481]

J Lab Clin Med. 1999 Jan;133(1):48-54.

Although cigarette smoking and the components of cigarette smoke appear to alter nitric oxide synthase-dependent dilation of blood vessels, the effect of these substances on constrictor responses of resistance arterioles has not been examined. Thus the goal of this study was to examine the effect of a major component of cigarette smoke-that is, nicotine-on constrictor responses of cheek pouch arterioles. The diameter of cheek pouch arterioles (approximately 50 microm in diameter) was measured by using intravital microscopy. We examined the responses of arterioles to angiotensin II, arginine vasopressin, norepinephrine, and the thromboxane analog U-46619 before and after treatment with vehicle (saline solution), N(G)-monomethyl-L-arginine (L-NMMA; 1.0 micromol/L), or nicotine (2.0 microg/kg/min i.v. for 30 minutes followed by a maintenance dose of 0.35 microg/kg/min for 30 minutes). Topical application of angiotensin II (0.01 and 0.1 nmol/L), arginine vasopressin (1.0 and 10 pmol/L), norepinephrine (1.0 and 10 nmol/L), and U-46619 (0.01 and 0.1 nmol/L) produced marked reproducible constriction of cheek pouch arterioles in hamsters treated with vehicle. Topical application of L-NMMA potentiated constrictor responses of arterioles to the high dose of arginine vasopressin (28%+/-4% versus 36%+/-4%; P<.05) and to both doses of norepinephrine (14%+/-1% and 24%+/-2% versus 19%+/-1% and 31%+/-3%; P<.05). The infusion of nicotine did not alter responses to angiotensin II, arginine vasopressin, or U-46619 but modestly potentiated vasoconstriction in response to norepinephrine (12%+/-2% and 22%+/-2% versus 14%+/-2% and 26%+/-2%; P<.05). These findings suggest that the synthesis/release of nitric oxide may modulate constrictor responses of cheek pouch resistance arterioles to selected agonists. In addition, nicotine, at levels observed in smokers, may potentiate norepinephrine-induced vasoconstriction. We suggest that preservation/potentiation of vasoconstrictor responses may contribute to the pathogenesis of vascular abnormalities associated with cigarette smoking.

ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization.[Pubmed:9580626]

J Pharmacol Exp Ther. 1998 May;285(2):777-86.

The discovery of (+/-)-epibatidine, a naturally occurring neuronal nicotinic acetylcholine receptor (nAChR) agonist with antinociceptive activity 200-fold more potent than that of morphine, has renewed interest in the potential role of nAChRs in pain processing. However, (+/-)-epibatidine has significant side-effect liabilities associated with potent activity at the ganglionic and neuromuscular junction nAChR subtypes which limit its potential as a clinical entity. ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine] is a novel, potent cholinergic nAChR ligand with analgesic properties (see accompanying paper by Bannon et al., 1998b) that shows preferential selectivity for neuronal nAChRs and a consequently improved in vivo side-effect profile compared with (+/-)-epibatidine. ABT-594 is a potent inhibitor of the binding of [3H](-)-cytisine to alpha 4 beta 2 neuronal nAChRs (Ki = 37 pM, rat brain; Ki = 55 pM, transfected human receptor). At the alpha 1 beta 1 delta gamma neuromuscular nAChR labeled by [125I] alpha-bungarotoxin (alpha-Btx), ABT-594 has a Ki value of 10,000 nM resulting in a greater than 180,000-fold selectivity of the compound for the neuronal alpha 4 beta 2 nAChR. In contrast, (+/-)-epibatidine has Ki values of 70 pM and 2.7 nM at the alpha 4 beta 2 and alpha 1 beta 1 delta gamma nAChRs, respectively, giving a selectivity of only 38-fold. The S-enantiomer of ABT-594, A-98593 has activity at the neuronal alpha 4 beta 2 nAChR identical with ABT-594 (Ki = 34-39 pM), which demonstrates a lack of stereospecific binding similar to that reported previously for (+/-)-epibatidine. A similar lack of stereoselectivity is seen at the human alpha 7 receptor. However, A-98593 is 3-fold more potent at the neuromuscular nAChR (Ki = 3420 nM) and the brain alpha-Btx-sensitive nAChR (Ki = 4620 nM) than ABT-594. ABT-594 has weak affinity in binding assays for adrenoreceptor subtypes alpha-1B (Ki = 890 nM), alpha-2B (Ki = 597 nM) and alpha-2C (Ki = 342 nM), and it has negligible affinity (Ki > 1000 nM) for approximately 70 other receptors, enzyme and transporter binding sites. Functionally, ABT-594 is an agonist. At the transfected human alpha 4 beta 2 neuronal nAChR (K177 cells), with increased 86Rb+ efflux as a measure of cation efflux, ABT-594 had an EC50 value of 140 nM with an intrinsic activity (IA) compared with (-)-nicotine of 130%; at the nAChR subtype expressed in IMR-32 cells (sympathetic ganglion-like), an EC50 of 340 nM (IA = 126%); at the F11 dorsal root ganglion cell line (sensory ganglion-like), an EC50 of 1220 nM (IA = 71%); and via direct measurement of ion currents, an EC50 value of 56,000 nM (IA = 83%) at the human alpha 7 homooligimeric nAChR produced in oocytes. A-98593 is 2- to 3-fold more potent and displays approximately 50% greater intrinsic activity than ABT-594 in all four functional assays. In terms of potency, ABT-594 is 8- to 64-fold less active than (+/-)-epibatidine and also has less IA in these functional assays. ABT-594 (30 microM) inhibits the release of calcitonin gene-related peptide from C-fibers terminating in the dorsal horn of the spinal cord, an effect mediated via nAChRs. Pharmacologically, ABT-594 has an in vitro profile distinct from that of the prototypic nicotinic analgesic (+/-)-epibatidine, with the potential for substantially reduced side-effect liability and, as such, represents a potentially novel therapeutic approach to pain management.

Rat alpha3/beta4 subtype of neuronal nicotinic acetylcholine receptor stably expressed in a transfected cell line: pharmacology of ligand binding and function.[Pubmed:9687574]

Mol Pharmacol. 1998 Aug;54(2):322-33.

We stably transfected human kidney embryonic 293 cells with the rat neuronal nicotinic acetylcholine receptor (nAChR) alpha3 and beta4 subunit genes. This new cell line, KXalpha3 beta4R2, expresses a high level of the alpha3/beta4 receptor subtype, which binds (+/-)- [3H]epibatidine with a Kd value of 304+/-16 pM and a Bmax value of 8942 +/- 115 fmol/mg protein. Comparison of nicotinic drugs in competing for alpha3/beta4 receptor binding sites in this cell line and the binding sites in rat forebrain (predominantly alpha4/beta2 receptors) revealed marked differences in their Ki values, but similar rank orders of potency for agonists were observed, with the exception of anatoxin-A. The affinity of the competitive antagonist dihydro-beta-erythroidine is >7000 times higher at alpha4/beta2 receptors in rat forebrain than at the alpha3/beta4 receptors in these cells. The alpha3/beta4 nAChRs expressed in this cell line are functional, and in response to nicotinic agonists, 86Rb+ efflux was increased to levels 8-10 times the basal levels. Acetylcholine, (-)-nicotine, cytisine, carbachol, and (+/-)-epibatidine all stimulated 86Rb+ efflux, which was blocked by mecamylamine. The EC50 values for acetylcholine and (-)-nicotine to stimulate 86Rb+ effluxes were 114 +/- 24 and 28 +/- 4 microM, respectively. The rank order of potency of nicotinic antagonists in blocking the function of this alpha3/beta4 receptor was mecamylamine > d-tubocurarine > dihydro-beta-erythroidine > hexamethonium. Mecamylamine, d-tubocurarine, and hexamethonium blocked the function by a noncompetitive mechanism, whereas dihydro-beta-erythroidine blocked the function competitively. The KXalpha3 beta4R2 cell line should prove to be a very useful model for studying this subtype of nAChRs.