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Fernando B De Moura - One of the best experts on this subject based on the ideXlab platform.
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unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro β erythroidine in Nicotine tolerant mice
Brain and behavior, 2020Co-Authors: Fernando B De Moura, Jenny L Wilkerson, Lance R McmahonAbstract:OBJECTIVES There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., Nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily Nicotine treatment confers tolerance to some effects of Nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of Nicotine varies as a function of daily Nicotine treatment. METHODS Schedule-controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of Nicotine, and both are sensitive to the development Nicotine tolerance. The rate-decreasing and hypothermic effects of Nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg Nicotine. The nonselective nAChR antagonist mecamylamine and the β2 nAChR antagonist dihydro-β-erythroidine (DHβE) were studied in combination with Nicotine. RESULTS The ED50 values of Nicotine to produce rate-decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily Nicotine treatment. Prior to daily Nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily Nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHβE (up to 5.6 mg/kg) when studied prior to daily Nicotine decreased rectal temperature, but that decrease was abolished during chronic Nicotine treatment. Mecamylamine and DHβE antagonized the rate-decreasing and hypothermic effects of Nicotine before and after daily Nicotine; however, during daily Nicotine, mecamylamine and DHβE antagonized only the hypothermic effects of Nicotine. CONCLUSIONS The differential antagonism of rate-decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHβE to antagonize Nicotine during chronic Nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of Nicotine tolerance and dependence.
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unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro β erythroidine in Nicotine tolerant mice
Brain and behavior, 2020Co-Authors: Fernando B De Moura, Jenny L Wilkerson, Lance R McmahonAbstract:OBJECTIVES: There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., Nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily Nicotine treatment confers tolerance to some effects of Nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of Nicotine varies as a function of daily Nicotine treatment. METHODS: Schedule-controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of Nicotine, and both are sensitive to the development Nicotine tolerance. The rate-decreasing and hypothermic effects of Nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg Nicotine. The nonselective nAChR antagonist mecamylamine and the beta2 nAChR antagonist dihydro-beta-erythroidine (DHbetaE) were studied in combination with Nicotine. RESULTS: The ED50 values of Nicotine to produce rate-decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily Nicotine treatment. Prior to daily Nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily Nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHbetaE (up to 5.6 mg/kg) when studied prior to daily Nicotine decreased rectal temperature, but that decrease was abolished during chronic Nicotine treatment. Mecamylamine and DHbetaE antagonized the rate-decreasing and hypothermic effects of Nicotine before and after daily Nicotine; however, during daily Nicotine, mecamylamine and DHbetaE antagonized only the hypothermic effects of Nicotine. CONCLUSIONS: The differential antagonism of rate-decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHbetaE to antagonize Nicotine during chronic Nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of Nicotine tolerance and dependence.
Neal L. Benowitz - One of the best experts on this subject based on the ideXlab platform.
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Nicotine reduction strategy state of the science and challenges to tobacco control policy and fda tobacco product regulation
Preventive Medicine, 2018Co-Authors: Neal L. Benowitz, Jack E HenningfieldAbstract:Abstract Nicotine addiction is the proximate cause of disease and death from cigarette smoking. In 1994, we proposed reducing the Nicotine content of cigarettes to non-addicting levels to reduce the risk of youth becoming addicted smokers and promoting quitting in established smokers. In 2009, the Family Smoking Prevention and Tobacco Control Act provided the authority to FDA to reduce Nicotine levels as appropriate to benefit public health. Over the past 15 years, considerable research has determined that Nicotine reduction is feasible and safe, resulting in reduced Nicotine dependence with little evidence of compensatory over-smoking. The availability of acceptable non-combusted form of Nicotine would provide support and enhance acceptability of Nicotine reduction in tobacco. Most recently, the FDA promulgated a Nicotine-based regulatory framework, which includes Nicotine reduction combined with ready availability of noncombustible Nicotine products. Nicotine reduction could contribute to a virtual end to the use of cigarette smoking, with enormous benefits to public health.
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cessation of alcohol consumption decreases rate of Nicotine metabolism in male alcohol dependent smokers
Drug and Alcohol Dependence, 2016Co-Authors: Noah R Gubner, Neal L. Benowitz, Peyton Jacob, Aleksandra Kozarkonieczna, Izabela Szoltysekboldys, Ewa Slodczykmankowska, Jerzy Goniewicz, Andrzej Sobczak, Maciej L GoniewiczAbstract:Abstract Background Rate of Nicotine metabolism is an important factor influencing cigarette smoking behavior, dependence, and efficacy of Nicotine replacement therapy. The current study examined the hypothesis that chronic alcohol abuse can accelerate the rate of Nicotine metabolism. Nicotine metabolite ratio (NMR, a biomarker for rate of Nicotine metabolism) and patterns of Nicotine metabolites were assessed at three time points after alcohol cessation. Methods Participants were 22 Caucasian men randomly selected from a sample of 165 smokers entering a 7-week alcohol dependence treatment program in Poland. Data were collected at three time points: baseline (week 1, after acute alcohol detoxification), week 4, and week 7. Urine was analyzed for Nicotine and metabolites and used to determine the Nicotine metabolite ratio (NMR, a biomarker for rate of Nicotine metabolism), and total Nicotine equivalents (TNE, a biomarker for total daily Nicotine exposure). Results and conclusions There was a significant decrease in urine NMR over the 7 weeks after alcohol abstinence (F(2,42) = 18.83, p
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High dose transdermal Nicotine for fast metabolizers of Nicotine: a proof of concept placebo-controlled trial.
Nicotine & Tobacco Research, 2012Co-Authors: Robert A Schnoll, E. Paul Wileyto, Frank T Leone, Rachel F Tyndale, Neal L. BenowitzAbstract:Introduction: Smokers with a faster rate of Nicotine metabolism, estimated using the ratio of 3′-hydroxycotinine (3-HC) to cotinine, have lower plasma Nicotine levels and are more likely to relapse with 21 mg Nicotine patch therapy, than smokers with slower rates of Nicotine metabolism. Thus, faster metabolizers of Nicotine may require a higher Nicotine patch dose to achieve cessation.
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Nicotine intake and dose response when smoking reduced Nicotine content cigarettes
Clinical Pharmacology & Therapeutics, 2006Co-Authors: Neal L. Benowitz, Peyton Jacob, Brenda HerreraAbstract:Objectives The progressive reduction of the Nicotine content of cigarettes has been suggested as a way to wean smokers from Nicotine and tobacco. As a first step in evaluating this strategy, we studied smokers smoking cigarettes containing tobacco with differing Nicotine content. Methods Twelve healthy smokers participated in a semiblinded, within-subject, crossover study. Subjects were asked to smoke 1 of their usual brand of cigarette and then on 5 subsequent occasions to smoke a research cigarette, each with differing Nicotine content. The research cigarettes contained 0.6 to 10.1 mg Nicotine per cigarette. Plasma Nicotine and blood carboxyhemoglobin levels, as well as subjective and cardiovascular responses, were measured after smoking. Systemic Nicotine intake per cigarette was estimated by use of plasma Nicotine concentrations over time and clearance data from the general population. Results Systemic Nicotine intake (0.26-1.47 mg per cigarette) varied with Nicotine content of the cigarette (r = 0.82, P < .001). Compensation when smoking single low–Nicotine content cigarettes ranged from −1% (95% confidence interval, −23% to 21%) to 34% (95% confidence interval, −39% to 107%) for 1-mg to 8-mg research cigarettes. Carbon monoxide intake and estimated tar exposure were similar across cigarettes. Low–Nicotine content cigarettes were rated as being of lower quality and less satisfying than the 12-mg research cigarette or the usual brand (P < .05 for both comparisons). Cigarette smoking increased heart rate and decreased skin temperature, but the Nicotine dose-response curve flattened at higher doses, with a maximal response being observed in cigarettes at a Nicotine content level of about 8 mg. Conclusions Our study suggests that reduced–Nicotine content cigarettes are reasonable candidates for trying to reduce the level of Nicotine addiction in smokers. The flat Nicotine dose–cardiovascular response curve is consistent with other studies demonstrating tolerance to the cardiovascular effects of Nicotine. Clinical Pharmacology & Therapeutics (2006) 80, 703–714; doi: 10.1016/j.clpt.2006.09.007
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arteriovenous differences in plasma concentration of Nicotine and catecholamines and related cardiovascular effects after smoking Nicotine nasal spray and intravenous Nicotine
Clinical Pharmacology & Therapeutics, 1997Co-Authors: Steven G Gourlay, Neal L. BenowitzAbstract:Background and objectives Delivery of a high concentration bolus of Nicotine through the arterial circulation is believed to be an important determinant of the addictive, behavioral, and physiologic effects of Nicotine. To better understand the pharmacologic features of Nicotine with different routes of administration, we measured arterial and venous plasma concentrations of Nicotine, cotinine, epinephrine, and norepinephrine after tobacco smoking, intravenous Nicotine infusion, and use of a Nicotine nasal spray. Subjects and methods Arterial and venous blood samples were drawn simultaneously from 12 male smokers. Six subjects received a single dose of 1 mg Nicotine nasal spray, and six subjects smoked cigarettes, one puff per minute for 10 minutes. All 12 subjects were administered Nicotine as a 30-minute infusion beginning 70 minutes after administration of the Nicotine nasal spray or commencement of smoking. Results The mean peak arterial plasma concentrations of Nicotine (Cmax) after smoking or administration of Nicotine nasal spray, or intravenous Nicotine averaged twofold those of venous plasma. For Nicotine nasal spray, the time to Cmax was much faster for arterial than for venous plasma (median, 5 versus 18 minutes, p < 0.01). Intravenous Nicotine produced the greatest increase in plasma epinephrine concentration, although smoking had a greater chronotropic effect. Acute tolerance to the chronotropic effects of Nicotine was suggested at pharmacodynamic analysis with venous Nicotine concentrations, whereas analysis of arterial concentrations found the opposite—a time lag between plasma concentration and effect. Conclusion Nicotine is rapidly absorbed from Nicotine nasal spray. The Cmax of Nicotine after smoking or administration of Nicotine nasal spray, or intravenous Nicotine is substantially higher in arterial than venous plasma. Acute tolerance to the chronotropic effects of Nicotine is not apparent if arterial plasma concentrations are measured. Clinical Pharmacology & Therapeutics (1997) 62, 453–463; doi:
Lance R Mcmahon - One of the best experts on this subject based on the ideXlab platform.
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unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro β erythroidine in Nicotine tolerant mice
Brain and behavior, 2020Co-Authors: Fernando B De Moura, Jenny L Wilkerson, Lance R McmahonAbstract:OBJECTIVES There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., Nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily Nicotine treatment confers tolerance to some effects of Nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of Nicotine varies as a function of daily Nicotine treatment. METHODS Schedule-controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of Nicotine, and both are sensitive to the development Nicotine tolerance. The rate-decreasing and hypothermic effects of Nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg Nicotine. The nonselective nAChR antagonist mecamylamine and the β2 nAChR antagonist dihydro-β-erythroidine (DHβE) were studied in combination with Nicotine. RESULTS The ED50 values of Nicotine to produce rate-decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily Nicotine treatment. Prior to daily Nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily Nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHβE (up to 5.6 mg/kg) when studied prior to daily Nicotine decreased rectal temperature, but that decrease was abolished during chronic Nicotine treatment. Mecamylamine and DHβE antagonized the rate-decreasing and hypothermic effects of Nicotine before and after daily Nicotine; however, during daily Nicotine, mecamylamine and DHβE antagonized only the hypothermic effects of Nicotine. CONCLUSIONS The differential antagonism of rate-decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHβE to antagonize Nicotine during chronic Nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of Nicotine tolerance and dependence.
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unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro β erythroidine in Nicotine tolerant mice
Brain and behavior, 2020Co-Authors: Fernando B De Moura, Jenny L Wilkerson, Lance R McmahonAbstract:OBJECTIVES: There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., Nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily Nicotine treatment confers tolerance to some effects of Nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of Nicotine varies as a function of daily Nicotine treatment. METHODS: Schedule-controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of Nicotine, and both are sensitive to the development Nicotine tolerance. The rate-decreasing and hypothermic effects of Nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg Nicotine. The nonselective nAChR antagonist mecamylamine and the beta2 nAChR antagonist dihydro-beta-erythroidine (DHbetaE) were studied in combination with Nicotine. RESULTS: The ED50 values of Nicotine to produce rate-decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily Nicotine treatment. Prior to daily Nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily Nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHbetaE (up to 5.6 mg/kg) when studied prior to daily Nicotine decreased rectal temperature, but that decrease was abolished during chronic Nicotine treatment. Mecamylamine and DHbetaE antagonized the rate-decreasing and hypothermic effects of Nicotine before and after daily Nicotine; however, during daily Nicotine, mecamylamine and DHbetaE antagonized only the hypothermic effects of Nicotine. CONCLUSIONS: The differential antagonism of rate-decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHbetaE to antagonize Nicotine during chronic Nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of Nicotine tolerance and dependence.
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unexpected loss of sensitivity to the nachr antagonist activity of mecamylamine and dhβe in Nicotine tolerant c57bl 6j mice
bioRxiv, 2018Co-Authors: Lance R McmahonAbstract:There has always been interest in developing nAChR antagonists as smoking cessation aids, to add to nAChR agonists (e.g., Nicotine replacement) already used for that indication. Previous studies have demonstrated that daily Nicotine treatment confers tolerance to some of the effects of Nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of Nicotine varies as a function of daily Nicotine treatment. The rate-decreasing and hypothermic effects of Nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg Nicotine. The nonselective nAChR antagonist mecamylamine and the β2 nAChR antagonist DHβE were studied in combination with Nicotine. The ED50 values of Nicotine to produce rate-decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily Nicotine treatment. Prior to daily Nicotine treatment, mecamylamine decreased response rate and rectal temperature; however, during daily Nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHβE (up to 5.6 mg/kg) when studied prior to daily Nicotine decreased rectal temperature, but that decrease was abolished during chronic Nicotine treatment. Mecamylamine and DHβE antagonized the rate-decreasing and hypothermic effects of Nicotine before and after daily Nicotine; however, during daily Nicotine, mecamylamine and DHβE antagonized only the hypothermic effects of Nicotine. The differential antagonism of rate-decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHβE to antagonize Nicotine during chronic Nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of Nicotine tolerance and dependence.
Eric C Donny - One of the best experts on this subject based on the ideXlab platform.
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low Nicotine content descriptors reduce perceived health risks and positive cigarette ratings in participants using very low Nicotine content cigarettes
Nicotine & Tobacco Research, 2016Co-Authors: Rachel L Denlingerapte, Danielle L Joel, Andrew A Strasser, Eric C DonnyAbstract:Introduction Understanding how smokers perceive reduced Nicotine content cigarettes will be important if the FDA and global regulatory agencies implement reduced Nicotine product standards for cigarettes. Prior research has shown that some smokers incorrectly believe "light" cigarettes are less harmful than regular cigarettes. Similar misunderstandings of health risk could also apply to reduced Nicotine cigarettes. To date, most studies of reduced Nicotine cigarettes have blinded subjects to the Nicotine content. Therefore, little is known about how smokers experience reduced Nicotine content cigarettes when they are aware of the reduced content, and how use may be impacted. Methods The present study was a within-subjects experiment with 68 adult daily smokers who smoked two identical very low Nicotine content Quest 3 (0.05 mg Nicotine yield) cigarettes. Subjects were told that one cigarette contained "average" Nicotine content, and the other contained "very low" Nicotine content. After smoking each cigarette, subjects completed subjective measures about their smoking experience. Results Subjects rated the "very low" Nicotine cigarette as less harmful to their health overall compared to the "average" Nicotine cigarette; this effect held true for specific smoking-related diseases. Additionally, they rated the "very low" Nicotine cigarette as having less desirable subjective effects than the "average" Nicotine cigarette and predicted having greater interest in quitting smoking in the future if only the "very low" Nicotine cigarette was available. Conclusions Explicit knowledge of very low Nicotine content changes smokers' perceptions of very low Nicotine content cigarettes, resulting in reduced predicted harm, subjective ratings and predicted future use. Implications Before a reduced Nicotine product standard for cigarettes can be implemented, it is important to understand how product information impacts how smokers think about and experience very low Nicotine content cigarettes. Prior research has shown that smokers incorrectly believed light cigarettes were less harmful products. As such, smokers may also misunderstand the health risks associated with smoking very low Nicotine content cigarettes. This study highlights the importance of smokers' perceptions of Nicotine content in cigarettes on the perceived health risks and the subjective effects of smoking very low Nicotine content cigarettes.
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characterizing the relationship between increases in the cost of Nicotine and decreases in Nicotine content in adult male rats implications for tobacco regulation
Psychopharmacology, 2016Co-Authors: Tracy T Smith, Laura E Rupprecht, Alan F Sved, Eric C DonnyAbstract:A large reduction in the Nicotine content of cigarettes may benefit public health by reducing the rate and the prevalence of smoking. A behavioral economics framework suggests that a decrease in Nicotine content may be considered an increase in the unit price of Nicotine (unit price = reinforcer cost/reinforcer magnitude). Increasing the price of cigarettes (i.e., increasing reinforcer cost) would be considered an equivalent change in unit price to reducing Nicotine content (i.e., reducing reinforcer magnitude). The goal of the present experiments was to characterize the relationship between increases in Nicotine cost and decreases in Nicotine dose. A rat self-administration model was used to assess this relationship across three experiments, with an emphasis on very low Nicotine doses to model a potential Nicotine reduction policy. Cost was manipulated via changes in the number of responses required to earn an infusion. Results show that increases in the cost of Nicotine and decreases in Nicotine content were not equivalent manipulations. Nicotine consumption was more sensitive to Nicotine dose than to Nicotine cost. Nicotine consumption was also not equivalent across a variety of cost and dose combinations forming a single unit price. Results of the present studies suggest that Nicotine reduction is likely to have a large impact on Nicotine exposure from cigarettes.
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greater reductions in Nicotine exposure while smoking very low Nicotine content cigarettes predict smoking cessation
Tobacco Control, 2015Co-Authors: Sarah S Dermody, Louise Hertsgaard, Eric C Donny, Dorothy K HatsukamiAbstract:Objective Reducing the Nicotine content of cigarettes is a potential regulatory strategy that may enable cessation. The present study investigated the effect of Nicotine exposure while smoking very low Nicotine content (VLNC) cigarettes on cessation outcomes. The roles of possible sources of Nicotine were also explored, including the VLNC cigarette and co-use of cigarettes with normal Nicotine content. Methods A secondary data analysis of two analogous randomised trials of treatment seeking, adult daily smokers (n=112) who were instructed to smoke VLNC cigarettes for 6 weeks and then make a quit attempt. Controlling for baseline demographic and smoking features, the association between reductions in Nicotine exposure during the 6-week trial, assessed by urinary total cotinine and biomarker-confirmed smoking abstinence 1 month later, was tested. Subsequent analyses controlled for the effects of the frequency of VLNC and normal Nicotine content cigarette use and the Nicotine yield of the VLNC cigarette (0.05 vs 0.09 mg). Results Greater reductions in Nicotine exposure while smoking VLNC cigarettes predicted abstinence independent of individual differences in baseline smoking, cotinine, dependence, gender and study. Nicotine reduction was largest among individuals who were assigned to smoke a VLNC cigarette with lower Nicotine yield and who smoked fewer normal Nicotine content and VLNC cigarettes. Conclusions In the context of Nicotine regulations and corresponding research, factors that undermine Nicotine reduction must be addressed, including the availability and use of cigarettes with normal Nicotine content and not sufficiently reducing the Nicotine yield of cigarettes. Maximising Nicotine reduction may facilitate smoking cessation. Trial registration numbers NCT 101050569 and NCT 00777569.
Peyton Jacob - One of the best experts on this subject based on the ideXlab platform.
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cessation of alcohol consumption decreases rate of Nicotine metabolism in male alcohol dependent smokers
Drug and Alcohol Dependence, 2016Co-Authors: Noah R Gubner, Neal L. Benowitz, Peyton Jacob, Aleksandra Kozarkonieczna, Izabela Szoltysekboldys, Ewa Slodczykmankowska, Jerzy Goniewicz, Andrzej Sobczak, Maciej L GoniewiczAbstract:Abstract Background Rate of Nicotine metabolism is an important factor influencing cigarette smoking behavior, dependence, and efficacy of Nicotine replacement therapy. The current study examined the hypothesis that chronic alcohol abuse can accelerate the rate of Nicotine metabolism. Nicotine metabolite ratio (NMR, a biomarker for rate of Nicotine metabolism) and patterns of Nicotine metabolites were assessed at three time points after alcohol cessation. Methods Participants were 22 Caucasian men randomly selected from a sample of 165 smokers entering a 7-week alcohol dependence treatment program in Poland. Data were collected at three time points: baseline (week 1, after acute alcohol detoxification), week 4, and week 7. Urine was analyzed for Nicotine and metabolites and used to determine the Nicotine metabolite ratio (NMR, a biomarker for rate of Nicotine metabolism), and total Nicotine equivalents (TNE, a biomarker for total daily Nicotine exposure). Results and conclusions There was a significant decrease in urine NMR over the 7 weeks after alcohol abstinence (F(2,42) = 18.83, p
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Nicotine intake and dose response when smoking reduced Nicotine content cigarettes
Clinical Pharmacology & Therapeutics, 2006Co-Authors: Neal L. Benowitz, Peyton Jacob, Brenda HerreraAbstract:Objectives The progressive reduction of the Nicotine content of cigarettes has been suggested as a way to wean smokers from Nicotine and tobacco. As a first step in evaluating this strategy, we studied smokers smoking cigarettes containing tobacco with differing Nicotine content. Methods Twelve healthy smokers participated in a semiblinded, within-subject, crossover study. Subjects were asked to smoke 1 of their usual brand of cigarette and then on 5 subsequent occasions to smoke a research cigarette, each with differing Nicotine content. The research cigarettes contained 0.6 to 10.1 mg Nicotine per cigarette. Plasma Nicotine and blood carboxyhemoglobin levels, as well as subjective and cardiovascular responses, were measured after smoking. Systemic Nicotine intake per cigarette was estimated by use of plasma Nicotine concentrations over time and clearance data from the general population. Results Systemic Nicotine intake (0.26-1.47 mg per cigarette) varied with Nicotine content of the cigarette (r = 0.82, P < .001). Compensation when smoking single low–Nicotine content cigarettes ranged from −1% (95% confidence interval, −23% to 21%) to 34% (95% confidence interval, −39% to 107%) for 1-mg to 8-mg research cigarettes. Carbon monoxide intake and estimated tar exposure were similar across cigarettes. Low–Nicotine content cigarettes were rated as being of lower quality and less satisfying than the 12-mg research cigarette or the usual brand (P < .05 for both comparisons). Cigarette smoking increased heart rate and decreased skin temperature, but the Nicotine dose-response curve flattened at higher doses, with a maximal response being observed in cigarettes at a Nicotine content level of about 8 mg. Conclusions Our study suggests that reduced–Nicotine content cigarettes are reasonable candidates for trying to reduce the level of Nicotine addiction in smokers. The flat Nicotine dose–cardiovascular response curve is consistent with other studies demonstrating tolerance to the cardiovascular effects of Nicotine. Clinical Pharmacology & Therapeutics (2006) 80, 703–714; doi: 10.1016/j.clpt.2006.09.007
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sources of variability in Nicotine and cotinine levels with use of Nicotine nasal spray transdermal Nicotine and cigarette smoking
British Journal of Clinical Pharmacology, 1997Co-Authors: Neal L. Benowitz, Shoshana Zevin, Peyton JacobAbstract:Author(s): Benowitz, NL; Zevin, S; Jacob, P | Abstract: AIMS:Nicotine nasal spray and transdermal Nicotine are effective aids to smoking cessation, and are being evaluated for treatment of other medical diseases. Wide variation in levels of Nicotine and its metabolite, cotinine, have been observed with such therapies. This study aimed primarily to assess sources of individual variability in Nicotine and metabolite plasma levels from these dosing systems and from cigarette smoking. METHODS:Twelve cigarette smokers, studied on a clinical research ward, received four treatments of 5 days duration each, including (1) cigarette smoking, 16 cigarettes/day; (2) transdermal Nicotine, 15 mg/day; (3) Nicotine nasal spray, 24-1 mg doses/day; (4) placebo Nicotine nasal spray, 24 doses/day. On a different occasion, the disposition kinetics of Nicotine and cotinine were determined via infusion of deuterium-labeled Nicotine and continine. Plasma levels of Nicotine, cotinine, and 3'-hydroxycotinine and daily intake of Nicotine during various treatments were examined, as well as pharmacokinetic factors that determined plasma Nicotine and continine levels. RESULTS:There was considerable individual variation in plasma Nicotine and cotinine levels and in the daily of Nicotine absorbed from various delivery systems, with most variability with Nicotine nasal spray (fivefold) and least for transdermal Nicotine (two-to threefold). Plasma Nicotine levels were determined most strongly by Nicotine clearance. Continine levels were determined most strongly by dose of Nicotine and, to a lesser extent, the clearance of cotinine and fractional conversion of Nicotine to continine. CONCLUSIONS:Plasma levels of Nicotine and cotinine produced by Nicotine therapies are highly variable, due to both wide variability in individual pharmacokinetics and in dose delivery from the products. To compensate for individual differences in clearance, individualization of Nicotine dosing based on therapeutic drug monitoring with comparison to Nicotine or continine levels during cigarette smoking prior to treatment may be necessary to optimize Nicotine therapy. This study also validates a recently proposed method for estimating absolute bioavailability of a drug using drug and metabolite pharmacokinetic data, and presents novel data on plasma levels of the metabolite trans-3'-hydroxycotinine in people.