Arterial/venous plasma nicotine concentrations following nicotine nasal spray

Background and objectives: Arterial (A) and venous (V) plasma nicotine and cotinine concentrations were measured after nasal nicotine spray in tobacco smokers of both genders. The hypothesis for this research was that a greater A/V difference in plasma nicotine would be present in males than females because males have greater skeletal muscle mass to bind nicotine. Subjects and methods: Nine male and nine female healthy adult smokers were studied. They all abstained from use of tobacco overnight for 10 h or more prior to the study. Nicotine nasal spray was given in doses of 1–2.5 mg total, with half in each nostril while the subject was supine. Both A and V blood samples were obtained prior to and 3, 6, 10, 15, 20, and 30 min post-nasal nicotine spray. Results and conclusions: Nasal nicotine administration produced greater A than V plasma levels. There were no gender differences in A/V nicotine concentrations, disproving the above hypothesis, suggesting that other physiochemical factors besides skeletal muscle mass must be involved. Heart rate increases correlated well with arterial plasma nicotine levels (r=0.77). Males had less variance than females in the expected increase in arterial plasma nicotine concentrations with increased number of nasal sprays. Although there was considerable overlap, mean A cotinine concentrations were consistently slightly larger than V concentrations. Received: 15 February 1999 / Accepted in revised form: 17 August 1999     

Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: A validation study

Transdermal nicotine is widely used for smoking cessation, but only ~ 20% of smokers quit successfully with this medication. Interindividual variability in nicotine metabolism rate may influence treatment response. This study sought to validate, and extend in a larger sample, our previous finding that the ratio of plasma nicotine metabolites 3′-hydroxycotinine (3-HC)/cotinine, a measure of nicotine metabolism rate, predicts response to nicotine patch. A sample of 568 smokers was enrolled in a study that provided counseling and 8-weeks of 21 mg nicotine patch. Pretreatment 3-HC/cotinine ratio was examined as a predictor of 7-day point prevalence abstinence, verified with breath carbon monoxide (CO), 8 weeks after the quit date. Controlling for sex, race, age, and nicotine dependence, smokers in the upper 3 quartiles of 3-HC/cotinine ratio (faster metabolizers) were ~ 50% less likely to be abstinent vs. smokers in the first quartile (slow metabolizers; 28% vs. 42%; OR = .54 [95% CI:.36-.82], p = .003). Among abstainers, plasma nicotine levels (assessed 1 week after treatment began) decreased linearly across the 3-HC/cotinine ratio (β = − 3.38, t[355] = − 3.09, p < .05). These data support the value of the 3-HC/cotinine ratio as a biomarker to predict success with transdermal nicotine for smoking cessation.     

Long-term nicotine substitution after application of a 16-hour nicotine patch in smoking cessation

Summary The purpose of the study was to examine long-term nicotine substitution and its variability during use of a nicotine patch. In two smoking cessation studies a 16-h nicotine patch, releasing 15 mg nicotine, was applied daily for 16 h over 12 weeks, to 167 smokers. Salivary cotinine was highly correlated with plasma cotinine (r = 0.93), and the concentration of cotinine in a single sample in the afternoon was well correlated with the AUC_cotinine over 24 h (r = 0.94). The salivary cotinine concentration after 1 week in 60 abstainers was 183 ng · ml^–. After 3, 6 and 12 weeks the cotinine concentrations were 86%, 79% and 59% of the 1-week value. The degree of nicotine compensation attained by the patch after 1 week was 52% (SD 24%) in subjects who succeeded in stopping smoking for at least 3 weeks. A quarter of the subjects achieved a compensation of less than 35% of their usual nicotine intake. Nicotine substitution with this 16-h nicotine patch was stable and the risk of overcompensation was small in this group of smokers.     

Plasma nicotine and cotinine levels following intravenous nicotine self-administration in rats

  Rationale: The route of nicotine administration between animal models and humans is very different and further investigation by determining levels of nicotine entering into the circulatory system is warranted. Objective: The present study addresses the validity of the rat self-administration procedure by comparing plasma levels of nicotine in the rat with levels reported in smokers following cigarette consumption. Methods: Plasma levels of nicotine and its metabolite cotinine were measured in 17 rats following intravenous self-administration of a range of nicotine doses (0.015, 0.03 and 0.06 mg/kg per infusion). Results: The two larger unit doses supported reliable self-administration behaviour with no overall difference in the patterns of nicotine intake. However, the total nicotine intake over the 2-h session was related to unit dose and this correlated highly with nicotine and cotinine levels measured in blood collected from the tail vein. On average, cotinine levels (50–200 ng/ml) were approximately 2-fold higher than nicotine levels (40–120 ng/ml) in plasma. Following an extinction test for one session in which saline was substituted for nicotine, no change in behaviour was observed in the two groups, while plasma levels of nicotine and cotinine dropped to nominal levels. Conclusions: The concentrations of nicotine attained following nicotine self-administration appear to be similar to levels reported in smokers after cigarette consumption, providing further validation of this procedure as an animal model of nicotine dependence. Received: 14 November 1998 / Final version: 4 January 1999     

High dose transdermal nicotine therapy for heavy smokers: safety,tolerability and measurement of nicotine and cotinine levels

Transdermal nicotine has been shown to relieve nicotine withdrawal and to double smoking cessation rates compared to placebo in clinical trials. A 21 or 22 mg/day dose provides a steady state serum nicotine that is less than obtained from smoking. Limited information is available about higher nicotine patch doses. To define better the optimal dosing of nicotine patch therapy, we undertook an open-label study to determine the safety and tolerability of 44 mg/day dose for smoking cessation in subjects smoking 20 cigarettes per day. Forty smokers received 44 mg/day of transdermal nicotine for 4 weeks followed by 4 weeks of 22 mg/day. Of the 40 subjects enrolled, 38 (95%) completed the 4 weeks of 44 mg patch therapy and 36 (90%) completed the entire 8 weeks of patch therapy. Non-smokers at week 4 had a mean serum nicotine level of 23.4±11.7 ng/ml and cotinine of 152.2±87.3 ng/ml. Percent replacement was calculated by dividing the steady state level at week 4 by the baseline level while the subjects were smoking their usual number of cigarettes. Percent nicotine replacement for non-smokers at week 4 (while on 44 mg nicotine patch) averaged 158%±108.4, and for cotinine was 112.0±73.8. For nicotine, 33% of non-smokers at week 4 had 100% nicotine replacement and for cotinine 63% 100% replacement. Biochemically confirmed point prevalence smoking cessation rates were 65% and 55% at weeks 4 and 8 of patch therapy, respectively, and self-reported smoking cessation at 3 months was 50%. The most common effect was skin irritation at the patch site. A single subject was admitted for myocardial infarction following step-down from 44 to 22 mg of replacement nicotine. The subject was not smoking and the adverse event was deemed to be not related to the patch therapy. Sleep complaints were reported in 33% of subjects during the 44 mg phase. Other complaints were infrequent. We conclude that 44 mg per 24-h nicotine patch therapy in heavy smokers is safe, tolerable, and without significant adverse events.     

Cotinine: effects with and without nicotine

 The purpose of this study was to examine the effects of the metabolite of nicotine, cotinine, in comparison to the effects of the nicotine patch, and a combination thereof during cigarette abstinence. More specifically, this study examined the effects of cotinine on physiological measures, subjective measures assessing craving, withdrawal symptoms and mood, and performance measures. A between-subject, 2 × 2 factorial design was used, with the daily administration of a 15-mg nicotine patch (Nicotrol) versus placebo patch as one factor and 80 mg of oral cotinine fumarate versus placebo drug as the other factor. Baseline measures were obtained while the subjects smoked cigarettes on an ad lib basis for 1 week. Subjects (n = 106) were then randomly assigned to one of four treatment conditions and for the next 14 days were required to be abstinent from cigarettes and take the study drugs. Cotinine administration, with or without nicotine patch, produced serum cotinine concentrations 3–4 times higher than during ad lib smoking. Results showed a reduction of self-reported tobacco withdrawal symptoms using the nicotine patch alone. Cotinine alone had no effect on withdrawal symptoms. However, when nicotine patch was combined with cotinine, the beneficial effect of the nicotine patch on withdrawal symptoms was absent. Therefore, cotinine appears to antagonize the effects of nicotine in the alleviation of withdrawal symptoms at concentrations higher than that attained from normal smoking. This effect does not appear to be mediated by changes in nicotine disposition. Received: 27 March 1997/Final version: 14 July 1997     

Effects of instructions on responses to the nicotine patch: a laboratory study

Rationale Smokers have weak positive expectancies for nicotine replacement therapies relative to smoking (Juliano and Brandon, Nicotine Tob Res, 6:569–574, 2004). Objectives This study investigated if a manipulation designed to alter expectancies for the nicotine patch was effective in increasing positive expectancies for the patch and influencing smoking cessation outcomes during a 2-day abstinence period. Materials and methods Smokers (n = 72) were randomly assigned to receive information that emphasized either patch benefits (n = 25) or standard patch information including side effects (n = 25). Participants wore placebo patches but were told that the patches contained nicotine. A control condition (n = 22) was informed that they received placebo patches while given standard patch information to independently test the effect of the nicotine-dose instructional set on abstinence outcomes. Results Benefits information significantly increased positive expectancies for the patch and promoted positive mood during the abstinence period relative to the side effects information. Nicotine-dose instructions resulted in fewer lapsed cigarettes and higher ratings of patch helpfulness than placebo instructions. In particular, women’s smoking behavior appeared to be more influenced by nicotine instructions than that of men. Conclusions The results of this preliminary study suggest that information provided to smokers about patch effects and nicotine content may influence behavioral and subjective outcomes of patch use.     

Effect of exercise on transdermal nicotine release in healthy habitual smokers

OBJECTIVE: Transdermal nicotine patches have become a frequently prescribed tool in smoking cessation programs during the past years. However, there is circumstantial evidence that transdermal nicotine release substantially varies with physical activity producing toxic plasma concentrations that may account for severe adverse events. METHODS: We, therefore, compared nicotine release from two different transdermal nicotine systems (TDNS) at rest and during strenuous physical activity in a two-period crossover study in healthy smokers (n = 10). The subjects were randomly assigned to receive either 21 mg/day of formulation A or B on study Day 1 and 2. Patches were applied eight hours before starting standardized physical activity, and nicotine concentrations were measured in plasma and topically in the tissue layers underneath the application site by microdialysis. RESULTS: There was no difference between groups in the mean values for area under the time-concentration curve at rest from 0 - 8 hours AUC(0-8) (p < 0.799) and during exercise from 8 - 11 hours AUC(8-11) (p < 0.878). C(max) values between groups with C(max) values of 16.4 +/- 9.5 ng/ml and 16.0 +/- 10.7 ng/ml at rest (p < 0.919, NS) and 10.05 +/- 6.8 ng/ml and 10.2 +/- 6.9 ng/ml (p < 0.959, NS) during exercise did not differ significantly. Nicotine tissue concentrations increased two-fold during exercise versus baseline (p < 0.878). Skin blood flow increased significantly during exercise compared with baseline (p < 0.001). No adverse events were observed. CONCLUSION: The present study provides evidence that transdermal nicotine release from TDNS increases during exercise. However, this increase has no significant effect on overall plasma pharmacokinetics. Our pharmacokinetic data further indicate that the two TDNS formulations are equivalent during conditions of rest and exercise.     

Temperature dependency of the release and bioavailability of nicotine from a nicotine vapour inhaler; in vitro/ in vivo correlation

Objective: To investigate the temperature dependency of the dose released and the plasma levels of nicotine from a vapour inhaler. Methods: In an open, randomised, three-way cross-over pharmacokinetic study 18 healthy subjects inhaled nicotine for 20 min (80 inhalations) every hour for 10 h (11 administrations) at three different environmental temperatures: 20°, 30° and 40 °C. In the in vitroexperiment, 5, 10, 15 and 20 l air were forced through the inhaler. With a 15 l air volume, the average amount of nicotine released was 1.44, 3.49, 4.80 and 6.99 mg at 10 °C, 22 °C, 29 °C and 40 °C, respectively. The maximum dose released at the highest temperature (40 °C) and the largest air volume investigated (20 l) was approximately 7.5 mg. Results: In vivo peak plasma levels obtained at 30° and 40 °C were 29.7 and 34.0 ng · ml⁻¹, compared with 22.5 ng · ml⁻¹ at ambient room temperature (20 °C). At 20 °C, the area under the plasma concentration–time curve (AUC) of the last dosing interval was 20.5 ng · ml⁻¹ · h. At 30 °C and 40 °C, the AUCs were 26.5 and 30.3 ng · ml⁻¹ · h, respectively. The results thus showed a mean increase of the in vivo AUC by 29% at 30 °C and by 48% at 40 °C compared with the AUC at 20 °C. These increases should be compared to the in vitro results, showing a mean increase of 59% and 122%, respectively, at 30° and 40 °C. The in vitro results also showed that a relatively larger fraction of the dose was released into the first 5 l of air at the higher temperatures, at 40 °C, about 50% of the total amount released into 20 l. Conclusion: It was concluded that the in vitro/in vivo discrepancy was most probably due to increased aversive effects at elevated temperatures, causing the subjects to inhale smaller puff volumes. Further, the inhaler would not produce nicotine plasma levels exceeding those achieved following cigarette smoking, even in a hot climate. Received: 20 September 1996 / Accepted in revised form: 5 March 1997     

A comparison of nicotine dose estimates in smokers between filter analysis, salivary cotinine, and urinary excretion of nicotine metabolites

Rationale Nicotine uptake during smoking was estimated by either analyzing the metabolites of nicotine in various body fluids or by analyzing filters from smoked cigarettes. However, no comparison of the filter analysis method with body fluid analysis methods has been published.Objectives Correlate nicotine uptake estimates between filter analysis, salivary cotinine, and urinary excretion of selected nicotine metabolites to determine the suitability of these methods in estimating nicotine absorption in smokers of filtered cigarettes.Materials and methods A 5-day clinical study was conducted with 74 smokers who smoked 1–19 mg Federal Trade Commission tar cigarettes, using their own brands ad libitum. Filters were analyzed to estimate the daily mouth exposure of nicotine. Twenty-four-hour urine samples were collected and analyzed for nicotine, cotinine, and 3′-hydroxycotinine plus their glucuronide conjugates. Saliva samples were collected daily for cotinine analysis.Results Each method correlated significantly (p < 0.01) with the other two. The best correlation was between the mouth exposure of nicotine, as estimated by filter analysis, and urinary nicotine plus metabolites. Multiple regression analysis implies that saliva cotinine and urinary output are dependent on nicotine mouth exposure for multiple days. Creatinine normalization of the urinary metabolites degrades the correlation with mouth exposure.Conclusions The filter analysis method was shown to correlate with more traditional methods of estimating nicotine uptake. However, because filter analysis is less complicated and intrusive, subjects can collect samples easily and unsupervised. This should enable improvements in study compliance and future study designs.F. K. St.Charles and G. R. Krautter were formerly with Brown & Williamson Tobacco Company, Macon, GA 31202, USA.     

Effectiveness of nicotine patch and nicotine gum as individual versus combined treatments for tobacco withdrawal symptoms

Nicotine gum and transdermal nicotine have been shown to relieve withdrawal and double success rates over placebo in trials of smoking cessation. This study tested whether combining the two methods would relieve withdrawal more effectively compared to either treatment alone. Twenty-eight smokers served as their own controls in each of four conditions: active gum + active patch (double active), active gum + placebo patch (gum only active), placebo gum + active patch (patch active) and placebo gum+placebo patch (double placebo). This double placebo design controls sensory, psychological and ritual variables associated with each drug form. Withdrawal symptoms were rated four times daily for 3 days in each condition. Total baseline (smoking) withdrawal scores using visual analogue scales (VAS) averaged 101.1. During cessation, total withdrawal increased to 187.0 for the double placebo condition, 142.2 for the active gum/placebo patch treatment and 128.3 for the active patch/placebo gum treatment. The double active condition equalled smoking with score 99.2. All pairwise comparisons were significant (P<0.001) except between the two single active conditions and between smoking versus the double active condition. Significant time-of-day effects by treatment on withdrawal were observed for the double placebo condition (P<0.05) with less withdrawal in the morning. The findings suggest: 1) combining nicotine gum with transdermal nicotine may be superior to either treatment alone, 2) more symptoms may be nicotine specific (relieved by replacement) than previously thought.     

The nicotine inhaler: clinical pharmacokinetics and comparison with other nicotine treatments

Nicotine inhaled in smoke is the most rapid form of delivery of the drug. With smoking, arterial boli and high venous blood nicotine concentrations are produced within seconds and minutes, respectively. The potency of nicotine as the primary reinforcement in tobacco addiction is attributed to this rapid rate of delivery. By design, nicotine treatments reduce the rate and extent of drug delivery for weaning from nicotine during smoking cessation. Theoretically, they prevent relapse by reducing withdrawal and craving associated with the abrupt cessation of cigarettes. The nicotine inhaler treats the complexity of smoking through weaning both from the drug and from the sensory/ritual components associated with smoking. The inhaler is 'puffed' but not lit and there is considerable 'puffing' required to achieve slower rising and lower nicotine concentrations. These factors allow it to be used as a nicotine reduction treatment. One inhaler contains 10 mg of nicotine (and 1 mg of menthol) of which 4 mg of nicotine can be extracted and 2mg are systemically available. Shallow or deep 'puffing' results in similar nicotine absorption. Nicotine is delivered mainly to the oral cavity, throat and upper respiratory tract with a minor fraction reaching the lungs. This was confirmed with positron emission tomography and by assessment of arterial concentrations. A single inhaler can be used for one 20-minute period of continuous puffing or periodic use of up to 400 puffs per inhaler. With controlled puffing in laboratory testing, venous plasma nicotine concentrations from a single inhaler puffed 80 times over 20 minutes averaged 8.1 microg/L at 30 minutes. Lower concentrations of 6.4 to 6.9 microg/L have been reported for self-administration under clinical conditions. The time to peak plasma concentrations varies but is always significantly longer than with cigarette delivery. Estimates of nicotine intake from cotinine concentrations were higher than expected (60 to 70% of baseline smoking concentrations). This elevation may be due to the swallowing of nicotine and subsequent first-pass biotransformation to cotinine. In general, venous blood nicotine concentrations are considerably lower than with smoking and are within the range observed for other nicotine reduction therapies. Efficacy trials show consistent superiority of the inhaler over placebo. Despite the 'cigarette-like' appearance of the inhaler and the associated sensory/ritual elements, little treatment dependence or abuse has been reported. This is attributed to the slow rise time and low nicotine blood concentrations. The inhaler is a valuable addition to treatment of tobacco dependence and can be used alone or with other treatments.     

Site of nicotine absorption from a vapour inhaler – comparison with cigarette smoking

Objective: The aim of the study was to assess the site of nicotine absorption during and after use of a nicotine-vapour inhaler compared with that after cigarette smoking. Methods: Using a catheterisation technique, the nicotine plasma concentration–time profiles in arterial and jugular venous blood after using a nicotine inhaler were compared with those achieved after cigarette smoking a in seven healthy habitual smokers. Results: After use of the inhaler, arterial nicotine concentrations rose slowly to a maximum level of 5.9 ± 1.5 ng/ml at a mean time to reach peak concentration (t _max) of 9.0 ± 1.1 min, whereas jugular venous nicotine levels peaked at 25.4 ± 5.4 ng/ml at 6.7 ± 0.3 min. The concentration–time curves indicate that the absorption occurs mainly via the mucosa of the oral cavity and the pharynx, and that there is minimal absorption via the lungs. In contrast, after smoking a cigarette, arterial nicotine plasma concentrations rose quickly to a maximum level of 49.2 ± 9.7 ng/ml after 4.0 ± 0.6 min, while the maximum concentration of nicotine in the jugular vein was 22.4 ± 3.9 ng/ml after 6.4 ± 0.4 min, indicating primarily pulmonary absorption of nicotine. Conclusion: Nicotine absorption after use of the vapour inhaler occurs primarily via the mucosa of the oral cavity; the absorption occurs slowly and the arterial nicotine concentration spike, typical of cigarette smoking, is avoided. Thus, the likelihood for abuse of the nicotine inhaler is probably small. Received: 7 June 1999 / Accepted in revised form: 6 October 1999     

Predictors and timing of adverse experiences during trandsdermal nicotine therapy.

OBJECTIVES: Difficulty sleeping is a recognised tobacco withdrawal symptom, but sleep problems, like application site reactions, are commonly reported as adverse reactions to transdermal nicotine therapy. However, no studies have examined potential predictive factors associated with the occurrence of expected adverse experiences during transdermal nicotine therapy. The subject of skin tolerability among patients with a history of eczema, psoriasis or other skin disorders is of particular interest, as are the relationships between plasma concentrations of nicotine, concurrent smoking, sleep problems and nausea. METHODS: The cohort study involving 1392 participants was designed to assess the timing, severity and predictive factors of adverse experiences reported during 24-hour transdermal nicotine therapy. Data were collected on patients aged 18 to 70 years old who were smokers and who had expressed a strong desire to stop smoking. The intervention consisted of brief behavioural counselling, a booklet containing smoking cessation advice and instructions for use of the patches, and a 12-week course of decreasing transdermal nicotine doses. RESULTS: Follow-up was available on 1392 out of 1481 study participants. The majority of adverse experiences were mild. Sleep problems occurred in 669 out of 1392 (48%) participants and most often commenced on the day of smoking cessation. Application site reactions occurred in 478 out of 1392 (34%) participants and most often occurred after 6 days of therapy. No predictor had an adjusted hazard ratio above 2. Statistically significant (p < 0.05) predictors of sleep problems were successfully quitting smoking and female gender. Predictors of application site reactions were psoriasis or eczema, other skin conditions, age <40 years, female gender, place of birth outside Australasia, and trade or university education level. Substantially increased nicotine intake during therapy compared with baseline smoking occurred in 8% of participants who smoked concurrently, and 4% of participants who did not (p = 0.1). Increased nicotine intake was associated with a modest increase in the overall rate of adverse experiences (89% vs 63%, p = 0.04) and dizziness/lightheadedness (17% vs 3%, p = 0.03), but not with sleep problems or cardiovascular events. CONCLUSIONS: Transdermal nicotine therapy appears to be well tolerated, even if the user smokes concurrently. Sleep disturbance during therapy appeared to be primarily associated with tobacco withdrawal rather than with nicotine excess from treatment with transdermal nicotine. Study participants with pre-existing skin disorders were somewhat more likely to report mild application site reactions than other participants.     

Cotinine replacement levels for a 21 mg/day transdermal nicotine patch in an outpatient treatment setting

This study examined plasma cotinine replacement levels of 56 outpatient smokers administered a 21 mg/day transdermal nicotine patch (Nicoderm CQ ). The percentage of cotinine replacement ranged from 35 to 232% (mean 107%; median 90.5%). Four subject variables were found to be significantly correlated with percentage of cotinine replacement-baseline cotinine level, prior quit attempts, gender, and the Fagerstr?m Tolerance Questionnaire score. A two-variable model consisting of baseline cotinine level and gender provided the most powerful predictor combination. The percentage of cotinine replacement was not predictive of post-treatment smoking. The relatively high levels of cotinine replacement obtained using the Nicoderm CQ 21 mg/day patch suggest cautious use of higher dose treatment with this particular patch.     

Temporal effects of nicotine nasal spray and gum on nicotine withdrawal symptoms

Nicotine nasal spray and nicotine gum have been found to be effective in relieving nicotine withdrawal symptoms. In this randomized single-blind study, 91 cigarette smokers were randomly assigned to a single 1 mg dose of active nicotine nasal spray (n = 29), active 4 mg nicotine gum (n = 31), saline placebo nasal spray (n = 16) or placebo gum (n = 15). Following overnight abstinence, subjects repeatedly completed visual analog scales for assessing nicotine withdrawal symptoms over 30 min preceding (time -30 min to time 0) and 120 min following a single dose of study medication. This sequence was performed 3 times during the day. Nicotine withdrawal symptoms were assessed on a 41-point visual analog scale (1 = no withdrawal, 41 = extreme withdrawal). At the initial session only, blood samples for serum nicotine levels were taken at baseline, then at 5, 10, 30 and 120 min following study drug administration. The mean (± SD) age of the subjects was 38.6 (±10.1) years, 48% were females, smoking rate was 24.5 (±7.8) cigarettes per day, and years of smoking was 19.9 (±10.0). A single 1 mg dose of nicotine nasal spray provided more immediate relief for craving for a cigarette compared to a single 4 mg dose of nicotine gum. Serum venous nicotine levels for the active nicotine nasal spray and nicotine gum were comparable at 5 and 10 min while the levels were higher for nicotine gum at 30 and 120 min. Changes in withdrawal symptoms were not found to be related to serum venous nicotine levels. Our findings provide a rationale for the as needed use of nicotine nasal spray to control withdrawal symptoms, possibly in combination with other medications with longer acting effects. Received: 18 February 1998/Final version: 1 May 1998     

Changes in hemorheological and biochemical parameters following short-term and long-term smoking cessation induced by nicotine replacement therapy (NRT)

OBJECTIVES: Cigarette smoking causes cardiovascular (CV) disease, but the relative roles of nicotine and other components of tobacco smoke remain unclear. We investigated the effect of stopping smoking by using nicotine replacement therapy (NRT) on hemorheology parameters, on the cotinine and thiocyanate plasma concentrations and the exhaled carbon monoxide (CO). DESIGN: Open, parallel-group trial (intervention group and control smokers). SUBJECTS: 197 males, aged 25-45 years, smoking > 20 cigarettes per day (cpd). INTERVENTIONS: 164 subjects were instructed to stop smoking and received NRT for 12 weeks and 33 acted as controls. After 12 weeks, NRT was discontinued and all subjects were followed-up at 26 weeks. Beginning with week 4, the treated subjects were divided into abstainers (self-reported, verified by exhaled CO < 10 ppm) and nonabstainers, not able to stay abstinent since baseline. The group of the nonabstainers was stratified in 2 subgroups, the reducers (smoked < 50% of baseline number of cpd) and relapsers (smoked 50-100% of baseline cpd). MAIN OUTCOME MEASURES: Plasma viscosity, erythrocyte deformability, fibrinogen, transcutaneous partial oxygen tension (tcpO2), hematocrit, white blood cells, cotinine and thiocyanate plasma concentrations and exhaled CO, all assessed at 4, 8, 12 and 26 weeks. RESULTS: After 6 months, plasma fibrinogen (228.2 vs. 275.4 mg/dl at baseline, p < 0.001), tcpO2 (50.4 vs. 34.9 mm mercury at baseline, p < 0.0001) were significantly improved in abstainers, but changes in plasma viscosity and erythrocyte deformability were inconclusive. Cotinine and thiocyanate (abstainers: 6.2 ng/ml at week 26 vs. 10.4 ng/ml at baseline, p < 0.0001) and expired CO (abstainers: 30.4 vs. 4.2 ppm, control vs. week 26, p < 0.0001) accurately followed the changes in smoking and/or NRT use in all of the groups. Other CV risk factors such as hematocrit and white blood cell count decreased to a greater extent in abstainers than in reducers and relapsers. Not only abstainers but also reducers did benefit of the temporarily stop smoking. CONCLUSIONS: Smoking cessation improved CV parameters despite the measured cotinine and thiocyanate plasma levels, and use of nicotine medications did not negate these improvements. A smoking cessation for a short time and smoking of reduced cpd also improved these parameters temporarily.     

Programmable transdermal delivery of nicotine in hairless guinea pigs using carbon nanotube membrane pumps

A compact switchable transdermal nicotine patch device was demonstrated to be effective in vivo in a hairless guinea pig animal model. This required the development and validation of a quantitative method for the simultaneous determination of cotinine and nicotine in hairless guinea pig plasma by liquid chromatography–mass spectrometry. Nicotine metabolism in hairless guinea pigs is rapid and cotinine was found to be the viable nicotine marker. The portable carbon nanotube membrane device, powered by a 1.5 V watch battery, was demonstrated to be a power efficient method to pump nicotine at levels six to eight times that of passive diffusion. Cotinine blood plasma levels in hairless guinea pigs were seen to increase from 6 to 12 ng/mL when the patch was turned from passive diffusion to an active pumping state. These nicotine patch devices are highly promising for potential clinical applications, with programmed delivery based on remote counseling, in order to improve smoking cessation treatments. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3823–3832, 2012     

Depressive symptoms affect changes in nicotine withdrawal and smoking urges throughout smoking cessation treatment: Preliminary results

Background: Individuals who report more depressive symptoms consistently demonstrate higher rates of nicotine dependence and less successful smoking cessation than do individuals who report fewer depressive symptoms. Nicotine withdrawal and smoking urges are two potential factors that may account for the differences observed between these two groups. This study assessed whether elevated depression symptoms among nicotine-dependent smokers are associated with changes in withdrawal and urges to smoke when undergoing smoking cessation treatment. Method: Data on 81 nicotine-dependent smokers were collected as part of a smoking cessation randomized trial that compared standard and contingency management (CM) treatment across one baseline week and four treatment weeks. Linear mixed model analyses were conducted with high and low depression scores predicting changes in withdrawal and urge ratings from a baseline week and four treatment weeks. Results: Participants with elevated depression symptoms reported more intense nicotine withdrawal and smoking urges throughout treatment. Further, participants with greater depressive symptoms exhibited an increase in smoking urges at the start of treatment, compared with a gradual decline in urges among participants with fewer depressive symptoms. Conclusions: Smokers with elevated depressive symptoms experience significantly elevated discomfort during smoking cessation efforts in the form of increased withdrawal and craving. This discomfort has the potential to make quitting smoking more difficult.     

Pharmacokinetics of nicotine in rats after multiple-cigarette smoke exposure

The pharmacokinetics of nicotine and its major metabolites was evaluated in male rats after multiple-cigarette smoke exposure. A smoke-exposure apparatus was used to deliver cigarette smoke to the exposure chamber. The rats were exposed to smoke from a single cigarette every 8 hr for 14 days and to the smoke of a cigarette spiked with radiolabeled nicotine on the 15th day. Blood and urine samples were collected at timed intervals during the 10-min smoke-exposure period of the last cigarette and up to 48 hr thereafter. Nicotine, cotinine, and other polar metabolites were separated by thin-layer chromatography and quantified by liquid scintillation counting. The data were analyzed by computer fitting, and the derived pharmacokinetic parameters were compared to those observed after a single iv injection of nicotine and after a single-cigarette smoke exposure. The results indicated that the amount of nicotine absorbed from multiple-cigarette smoke was approximately 10-fold greater than that absorbed from a single cigarette. Also, unlike the single-cigarette smoke exposure experiment, nicotine plasma levels did not decay monotonically but increased after the 5th hr, and high plasma concentrations persisted for 30 hr. The rate and extent of the formation of cotinine, the major metabolite of nicotine, were decreased as compared with their values following a single-cigarette smoke exposure. It was concluded that nicotine or a constituent of tobacco smoke inhibits the formation of cotinine and may affect the biotransformation of other metabolites. Urinary excretion tended to support the conclusions that the pharmacokinetic parameters of nicotine and its metabolites were altered upon multiple as compared to single dose exposure.