Richmond upon Thames LGBT Forum Appendix 3 - Drug Misuse and the LGBT Community Submission to the Richmond upon Thames Drug Misuse Scrutiny Task Group – 31 January 2011 Introduction The Richmond upon Thames Lesbian, Gay, Bisexual and Trans (LGBT) Forum is a voluntary community group providing a voice for LGBT people who live, work, study or visit in the borough. We were established in 2007 with support from the Community Safety Partnership. We now operate as an independent community group. We work collaboratively with statutory service providers such as Richmond upon Thames Council, Metropolitan Police Service, NHS Richmond and a wide range of voluntary and community groups. Our interests include health, community safety, domestic abuse, housing, homelessness, older people, youth and education. We actively participate in many local community engagement and strategic groups and engage with specialist LGBT organisations across London and nationally. This submission has been prepared at quite short notice and is based upon member's knowledge, discussion with community members and service providers and review of published research.
Healthnz.co.nzS⫽1 9/27/10 8:21 Art: 2010-0409 Experimental and Clinical Psychopharmacology 2010 American Psychological Association 2010, Vol. 18, No. 5, 385–394 DOI: 10.1037/a0020834 Pulmonary Delivery of Nicotine Pyruvate: Sensory and Pharmacokinetic Characteristics Jed E. Rose, James E. Turner, Thangaraju Murugesan, and Health New Zealand Ltd., Christchurch, New Zealand Fre´de´rique M. Behm Duke University Medical Center The aim of this study was to evaluate pharmacokinetic and subjective responses to a prototypenicotine pyruvate (NP) aerosol generation system. In nine healthy adult daily cigarettesmokers, plasma nicotine levels and subjective responses were assessed after double-blindadministration of 10 inhalations of: NP (10 g/puff, 20 g/puff, and 30 g/puff); Nicotrol/Nicorette nicotine vapor inhaler (NV) cartridge; and placebo (room air). Plasma nicotineconcentrations increased to a significantly greater extent after inhalations of 20 g/puff or 30 g/puff NP (by 5.0 ⫾ 3.4 ng/ml and 8.3 ⫾ 3.1 ng/ml) than after placebo and NV conditions.
Satisfaction ratings were higher for all NP conditions than for placebo, and harshness/irritation was lower for the NP 20 condition than for the NV control condition. Pulmonaryfunction showed no adverse changes. These results demonstrate that NP inhalations producerapid increases in plasma nicotine concentrations, provide satisfaction and are well tolerated.
At the 20 g/puff dose, peak nicotine concentrations were higher than with the Nicotrol/Nicorette nicotine vapor inhaler cartridge. Further trials of this promising nicotine inhalationtechnology are warranted to assess its safety and efficacy in smoking cessation treatment orharm reduction approaches.
Keywords: nicotine, smoking cessation, tobacco, aerosol, pyruvic acid The annual death toll from diseases caused by smoking is However, current smoking cessation treatments have lim- estimated to be 440,000/year in the United States (Smoking- ited effectiveness. Long-term (⬎1 year) abstinence rates attributable mortality, 2008) and 5 million/year worldwide are often less than 25%, despite the advent of new phar- (Ezzati & Lopez, 2003). Smoking cessation leads to a macotherapies such as varenicline and bupropion (Fant, substantial reversal of the risks borne by smokers (Kenfield, Buchhalter, Buchman, & Henningfield, 2009; Fiore et al., Stampfer, Rosner, & Colditz, 2008; Papathanasiou et al., 2008). Nicotine replacement therapy (NRT) continues to 2007), and thus, smoking cessation treatment assumes a be one of the mainstays of smoking cessation treatment primary role in the prevention of smoking related disease.
(Schnoll et al., 2009), and is the only pharmacotherapy Jed E. Rose, James E. Turner, Thangaraju Murugesan, and results. JER, TM, and JET are named as inventors on patent Fre´de´rique M. Behm, Department of Psychiatry and Behavioral applications filed by Duke University pertaining to the nicotine Sciences, Duke University Medical Center; Murray Laugesen, inhalation technology; (2) ML has had no relationships with Philip Health New Zealand Ltd., Lyttelton, Christchurch, New Zealand.
Morris U.S.A. that might have an interest in the submitted work; Jed E. Rose contributed to the study design, data analysis, and (3) their spouses, partners, or children have no financial relation- manuscript writing/editing; James E. Turner contributed to the ships that may be relevant to the submitted work, other than those study design and manuscript drafting/editing; Thangaraju Murug- disclosed in (1); and (4) Authors have no nonfinancial interests that esan contributed to the study design, fabrication of the inhalation may be relevant to the submitted work. CJW and ML received system, training technical staff, and manuscript drafting/editing; funding to conduct this work from the Duke University Depart- Frederique M. Behm contributed to the study design, data analysis, ment of Psychiatry. Within the last 3 years, JER has received and manuscript drafting/editing; Murray Laugesen contributed to consulting payments for work unrelated to this study, from the the study design, supervision of study protocol, data analysis, following entities: NIDA, GlaxoSmithKline, Novartis, Philip Mor- manuscript drafting/editing, and the guarantor ensuring scientific ris International, Targacept, Catalyst Pharmaceutical Partners, integrity. All authors, external and internal, had full access to all of Lorillard, University of Kentucky, Medacorp, Pharmalink, and the the data (including statistical reports and tables) in the study and Noble Medical Consulting Group.
can take responsibility for the integrity of the data and the accuracy We thank Chris J. Wynne for preparation of the application for of the data analysis. All authors have completed the Unified ethics committee approval and the supervision of study protocol; Competing Interest form at www.icmje.org/coi_disclosure.pdf and Chris M. A. Frampton for biostatistical support.
(available on request from the corresponding author) and declare Correspondence concerning this article should be addressed to that (1) JER, JET, TM, and FMB have support from Philip Morris Jed E. Rose, Center for Nicotine and Smoking Cessation Research, U.S.A. for the submitted work. The company had no role in the Duke University Medical Center, 2424 Erwin Road, Suite 201, design or execution of the study, data analysis or publication of the Durham, NC 27705. E-mail: email@example.com S⫽1 9/27/10 8:21 Art: 2010-0409 ROSE, TURNER, MURUGESAN, BEHM, AND LAUGESEN approved for over-the-counter (OTC) sales. Nonetheless, amount of nicotine can be delivered in standard 35-ml puffs long term success rates in an OTC setting remain low, than with nicotine vapor alone. Additionally, it was antici- typically less than 10% (Hughes, Shiffman, Callas, & pated that NP aerosol would avoid the irritation associated Zhang, 2003).
with inhalation of pure nicotine base (Caldwell et al., 2009; To overcome the limited effectiveness of NRT, it will be Lee, Gerhardstein, Wang, & Burki, 1993), for two reasons: necessary to recognize and address a major shortcoming of (1) the near-neutral pH of NP was expected to attenuate the current NRT products; that is, these products do not provide irritating effect of pure nicotine base (Armitage & Turner, smokers with rapid absorption of nicotine in conjunction 1970; Lux & Frecker, 1988); and (2) the small diameter of with the unique respiratory tract sensory cues accompany- the NP particles should result in their deposition over the ing nicotine inhalation. These inhalational cues, along with large surface area of the lung rather than being concentrated the delivery of nicotine, are of primary importance in ef- in a small region of the trachea, which can elicit irritation fectively relieving smokers' craving for cigarettes (Rose, and cough (Huchon, 1990; Katz, Schroeter, & Martonen, 1988). Indeed, nicotine administered without airway sen- 2001; Usmani, Biddiscombe, & Barnes, 2005). Lung dep- sory cues only slightly suppresses craving for cigarettes osition is difficult to achieve using metered dose inhalers or (Rose, Behm, Westman, & Johnson, 2000; Rose, Behm, dry powder delivery systems, having particle sizes well Westman, Bates, & Salley, 2003). Moreover, blockade of above 1 m. To gain alveolar entry and deposition of airway sensations during cigarettes smoking markedly re- particles with consequent rapid absorption, we speculated duces the relief of craving after inhaling cigarette smoke particles would need to be similar in size to cigarette smoke (Rose, Tashkin, Ertle, Zinser, & Lafer, 1985; Rose, West- particles (⬍1 m). Particles of the NP aerosol have an man, Behm, Johnson, & Goldberg, 1999). Conversely, pre- average mass median aerodynamic diameter (MMAD) sentation of airway sensory cues has been shown to reduce of 0.62 m, as estimated by cascade impactor measure- craving for cigarettes and facilitate smoking cessation (Rose ments (unpublished data), small enough to be almost totally & Hickman, 1987; Westman, Behm, & Rose, 1995).
inhaled deep into the lung, ensuring rapid absorption.
Current forms of NRT, however, fail to provide these Pyruvate, as sodium pyruvate, has been inhaled at a dose important inhalational components of cigarette smoking, of 0.65 mg pyruvate per day to treat chronic obstructive thereby limiting their efficacy as cessation therapies. For pulmonary disease (Votto, Bowen, Barton, & Thrall, 2008), example, the nicotine nasal spray, although it is a rapid- and in this study 0.76 mg in total was used per subject.
acting NRT, lacks the inhalational cues of cigarette smoke, Pyruvate is rapidly metabolized, and it was unlikely that and has aversive irritating properties; these deficiencies, inhalation in such doses would alter the physiological level along with restrictions in access because of prescription of 0.44 mg/100 ml blood (Landon, Fawcett, & Wynn, requirements, have impeded widespread acceptance by 1962). The acute risk profile of NP was thus assumed to be smokers. Similarly, the nicotine vapor inhaler, while simu- similar to that of nicotine alone.
lating the behavioral components of smoking and presenting This study was an initial investigation in which 9 smokers some sensory cues resembling those of cigarette smoke, were exposed to several doses of NP aerosol administered provides a much lower dose of nicotine, which is slowly by inhalation, and an active control condition, the Nicotrol/ absorbed through the buccal mucosa without reaching the Nicorette nicotine vapor (NV) inhaler cartridge, as well as lung in significant amounts (Lunell, Bergstrom, Antoni, an inactive placebo (air). Venous plasma nicotine levels and Langstrom, & Nordberg, 1996; Lunell, Molander, Ekberg, subjective responses were assessed. The study had three & Wahren, 2000; Schneider, Olmstead, Franzon, & Lunell, main aims: (1) to determine whether NP inhalation would produce higher and more rapid boosts in plasma nicotine Thus, there is a gap in the field of current NRT products concentrations than the control conditions; (2) to evaluate that could be filled with a rapid-acting, lung delivery nico- the efficacy of NP inhalations relative to the control condi- tine inhaler having acceptable sensory properties. Such an tions in providing satisfaction and alleviating subjective inhaler, which does not deliver other toxic smoke constitu- withdrawal symptoms (e.g., craving reduction); and (3) to ents, could hold great promise for assisting smokers in evaluate the safety and tolerability of acute NP administra- breaking their addiction to cigarettes, as well as reducing the tion, based on subjective reports or airway irritation and harm associated with cigarette smoking. This study reports objective measurement of pulmonary function using spi- the completion of the first step in establishing the feasibility of a novel approach to nicotine replacement therapy thatdelivers nicotine to the lung by inhalation (Rose, Rose, Materials and Methods
Turner, & Murugesan, 2008). This approach stems from our Study Design
discovery that nicotine vapor when combined with the va-por of pyruvic acid, a weak organic acid normally present in This was a preliminary, double-blind, placebo controlled, all living cells, forms a stream of submicron airborne par- crossover evaluation of the effects of inhaling NP aerosol on ticles consisting of nicotine pyruvate (NP) salt. Unlike other plasma nicotine concentrations, subjective relief of smoking existing approaches to generating a nicotine aerosol, no withdrawal symptoms and indices of tolerability and safety.
combustion, heat or propellant is necessary to produce the Because the primary pharmacokinetic end point was defined nicotine containing particles. Measurements conducted in as the increase in plasma nicotine in the first 5 min, imme- our laboratory prior to human testing showed that a greater diately after the tenth puff, one condition could feasibly be S⫽1 9/27/10 8:21 Art: 2010-0409 PULMONARY DELIVERY OF NICOTINE PYRUVATE studied every 50 min. This design was consistent with the room air, followed by a 5-s breath hold before exhaling into distributional half life of nicotine (9 min; Feyerabend, Ings, the room air. A total of 10 puffs were taken at 30-s intervals, & Russell, 1985), and with the expectation that maximum requiring a total of 5 min.
plasma levels per dose inhaled would be relatively low, The motorized syringe system and the known dose in minimizing carryover effects.
each prototype were first tested without human subjects to A prototype aerosol delivery system was assembled, measure the average nicotine delivery per puff over 10 puffs loaded, and calibrated to deliver successively to each par- of 35 ml. In these tests, particulate matter or nicotine vapor ticipant five different conditions during the morning of the was collected by filtration through a Cambridge 44-mm study day, a different condition administered every 50 min.
diameter high-efficiency filter contained in a holder. These Three of the conditions involved administering the NP test samples were shipped on ice and analyzed at Duke CNSCRusing Gas Chromatography (Agilent GC-HP6890 series medications: either 10 g, 20 g, or 30 g of NP per 35 ml with Nitrogen Phosphorus Detector (Agilent Technologies puff. In the remaining two conditions, approximately 10 g Inc. Santa Clara, CA). Based on five determinations for each of nicotine per puff was supplied from a Nicotrol/Nicorette condition, the three NP aerosol conditions were found to inhaler cartridge (the active control), or room air was sup- deliver an average of 10.3 g/puff (SD ⫽ 1.66), 23.7 plied (the inactive control or placebo). To minimize the g/puff (SD ⫽ 3.39), and 33.0 g/puff (SD ⫽ 0.63) of likelihood of adverse events, the NP doses were presented in nicotine. These conditions will be referred to below as ascending order from 10 g to 20 g to 30 g per puff, "NP 10," "NP 20," and "NP 30," respectively. Based on whereas the control conditions were arranged in a counter- three determinations, the nicotine vapor condition ("NV") balanced sequence alternating with the 3-sequence block of delivered 9.1 g/puff (SD ⫽ 0.64), which agrees to within NP conditions.
10% of the value reported previously (Schneider et al.,2001).
Pyruvic acid of 97% purity was obtained from Sigma- Aerosol Generation Apparatus
Aldrich Inc. (St. Louis, MO/USA) and stored at 4 °C.
The delivery system used to generate the NP aerosol Nicotine free base USP with a claimed 99.5% purity, re- (Figure 1) consisted of a cylindrical translucent Teflon tube F1
tested at the Center for Nicotine and Smoking Cessation outer housing (11 cm long, 11-mm inside diameter [ID], and Research (CNSCR) at Duke University, was also stored at 4 13-mm outside diameter [OD]) containing three elements °C. For operation of the NP delivery system, all constituents arranged in a series. The first component, where the air- needed to be at room temperature. The prototype compo- stream entered (distal to the mouth), consisted of a porous nents were loaded with NP 10, 20, or 30 or with the NV polypropylene/polyethylene filter loaded with 140 l of cartridge at the CNSCR and tested for stability before pyruvic acid. The second component consisted of a Teflon shipping for assembly at the study site at Christchurch washer (11-mm OD), having one, two, or three cylindrical Clinical Studies Trust (CCST), Christchurch, New Zealand.
openings (3.5-mm ID) that allowed air to flow through the The NV cartridges were purchased in the United States and washer. Depending on the nicotine dose condition, the num- shipped to New Zealand. When assembled before use, the ber of openings that contained a nicotine-loaded membrane seal around the cartridge was punctured in order to allow (60 l Nicotine base) versus empty openings were either: 0 nicotine vapor to be released. CCST staff was trained in the loaded/3 empty (placebo), 1 loaded/1 empty (NP 10), 1 inhalation procedures by means of detailed training dia- loaded/0 empty (NP 20), or all three loaded with nicotine grams and instructions, as well as a site visit from CNSCR (NP 30). These configurations were derived empirically (by coauthor TM).
based on benchtop measurements of nicotine deliveriesfrom the system. The loading was accomplished by insert- Puff Delivery Apparatus
ing a piece of nicotine-loaded membrane (nonwoven poly-ester membrane with an expanded PTFE membrane back- Measured dose inhalations were delivered by an electric ing, 6 cm long and 8 mm wide) into a 3-mm ID, 3.5-mm OD powered motorized syringe pump and 60-ml syringe con- and 6 cm long, thin walled, clear Teflon tube (a support to nected to a 3-way valve. The pump was timed to draw in hold the membranes in place), which was then inserted into 35-ml room air over 2 s and then expel the air out through the designated openings. The ID of the tube with inserted the aerosol delivery system for each condition and every membrane was approximately 2 mm and 60 l of nicotine puff. The subject inhaled through the same mouthpiece for base was added to the membrane. The third component all puffs and conditions. In the placebo condition, when the (proximal to the mouth end) consisted of a 2 cm long participant puffed on the mouthpiece, air was inhaled segment of a charcoal cigarette filter. The first and second through an empty tube, which contained a cigarette filter to components were spaced 1 cm apart and the second and provide draw resistance. Before each inhalation, while the third components were separated by 1 cm. As air entered the motorized syringe pump drew in air, the subject exhaled distal end of the device, pyruvic acid vapor was entrained by into room air. When the pump expelled air into the delivery the airstream. Subsequently, the air stream passed through system the subject inhaled the measured 35-ml volume the nicotine loaded membrane and the nicotine vapor re- through the mouthpiece, and completed the inspiration from acted with the pyruvic acid vapor to form NP particles. As
S⫽1 9/27/10 8:21 Art: 2010-0409 ROSE, TURNER, MURUGESAN, BEHM, AND LAUGESEN Nicotine pyruvate aerosol generation system.
these particles passed through the charcoal filter, excess blood pressure, urinary evidence of illegal drugs or excess vapor of pyruvic acid or nicotine was adsorbed or absorbed, breath alcohol, and recent or current use of other nicotine or along with approximately 20% of the particles. The remain- tobacco products.
ing particle stream exited the filter for inhalation by theresearch participant.
Study Day Procedure
In accordance with the tenets of the Declaration of Hel- sinki, and following receipt of approval from the New Participants were recruited from the Christchurch, New Zealand Ministry of Health, from its Upper South B Re- Zealand area by word of mouth advertising and from a gional Ethics Committee and its Standing Committee on database of volunteers. Eighteen subjects were screened by Therapeutic Trials, informed consent was obtained from a medical practitioner and 10 met requirements for study nine healthy volunteers, who were admitted to the clinic participation, after blood tests, ECG, and smoking history.
overnight, abstaining from tobacco or nicotine while at the Nine of these were enrolled in the study. The Fagerström clinic. On the study day, a baseline expired air carbon test for Nicotine Dependence (FTND; Heatherton, Kozlow- monoxide reading ⬍15 ppm confirmed abstinence from ski, Frecker, & Fagerström, 1991) was also administered.
smoking. Volunteers were studied during a 5 1/2 hour Subjects, male or female, age 18 to 65 morning session presenting five conditions at 50-min inter- years of age, had to be current smokers of at least 10 regular vals, taking 10 puffs of 35 ml after baseline measurements brand cigarettes daily, and with an exhaled CO of 10 ppm or at the start of each condition. Prior to these five experimen- more, to confirm current smoker status, with pulmonary tal conditions, a practice condition presented air inhalations.
function (KoKo Digidoser spirometer Model 323200, Pul- Plasma nicotine responses.
In each condition, 5 ml of monary Data Services, Louisville, CO) values Forced Ex- blood was withdrawn 5 min before inhalation, and at 0, 1, 2, piratory Volume ((FEV1) and Forced Expiratory Flow 5, 10, 20, and 30 min after the tenth puff. Each sample was (FEF) 25–75) at least 75% of the normal values predicted immediately placed on ice, centrifuged within 30 min at 4 °C for that individual based on age, gender, and height. None and aliquoted into separate plasma samples, stored at ⫺70 °C, smoked menthol brands.
and later shipped on dry ice for analysis at Environmental Pregnant women and nursing moth- Science and Research, Porirua, New Zealand. Laboratory ers were excluded, along with subjects with serious cardiac, staff at ESR Porirua were blinded to the sequence of med- respiratory, psychiatric, or other serious disease, particu- ication codes. Plasma nicotine concentrations were quanti- larly cardiac rhythm disorders and abnormally high or low fied by gas chromatography coupled with mass spectropho- S⫽1 9/27/10 8:21 Art: 2010-0409 PULMONARY DELIVERY OF NICOTINE PYRUVATE tometer (GC/MS). Values below the limit of quantification Because the placebo was known to contain no nicotine, (2 ng/ml) were estimated as half of that limit (Duval & one-tailed paired tests were used in these comparisons. As Karlsson, 2002). For one subject, over 50% of the samples reported below, the NP 20 and NP 30 dose conditions were had insufficient volume, and therefore this subject was the only doses found to be superior to placebo. Thus, in omitted from data analysis of plasma nicotine concentra- follow-up analyses, only these two doses were compared to tions. Among the remaining eight subjects, four samples the active NV condition, using two-tailed tests with Holm's could not be assayed because of insufficient volume, and for p value correction and ␣ ⫽ .05.
these samples nicotine concentrations were estimated by Three outlying values were identified in the pre-to-post linear interpolation based on values at adjacent time points.
inhalation nicotine boost: all three showed decreases in Responses were elicited on a Lik- nicotine concentrations after inhalation, one subject's value ert-type scale with responses ranging from 1 to 7 (1 ⫽ not decreasing by 6.9 ng/ml (5.6 SDs from the mean of the other at all, 7 ⫽ extremely). The following questionnaires were subjects) in the NP 10 condition, one decrease of 2.5 ng/ml (3.4 SDs from the mean) in the NP 30 condition, and one The smoking withdrawal symptom reports (9 questions
on an abbreviated version of the Shiffman-Jarvik with- decrease of 3.3 ng/ml in the NV condition (6.2 SDs from the drawal questionnaire (Shiffman & Jarvik, 1976) were elic- mean). The results will be presented excluding these outliers ited 5 min before inhalations began, and again 5 to 10 min from the analysis of plasma nicotine values; however, a after the last (tenth inhalation) in each condition. The an- sensitivity analysis showed that exclusion of these values swers were scored to give composite answers for craving did not affect the conclusions regarding the statistical sig- (urges to smoke, miss a cigarette, and crave a cigarette), nificance of comparisons between conditions.
negative affect (calm vs. tense, irritable), arousal (wide For subjective measures related to efficacy, including awake, able to concentrate), and hunger.
satisfaction and relief of withdrawal symptoms, paired t An inhalation evaluation questionnaire (19 questions)
tests were first conducted comparing each of the three active was completed 5 to 10 min after the tenth inhalation, and the NP dose conditions with the placebo control group. Two- answers scored for ratings of satisfaction ("satisfying," tailed tests (with Holm's correction) were used in these "taste good"), psychological reward ("calm you down," comparisons as it was not known in which direction any "help you concentrate," "more awake," "reduce your hun- detectable differences between NP and other conditions ger," and "less irritable"), nausea/dizziness, enjoyment of would be found. For example, an aversive taste conceivably sensations in the throat and chest, and craving reduction, would result in the NP aerosol being rated worse than which was based on "Do (the puffs) immediately reduce placebo. In follow-up analyses, NP doses showing superi- your craving for cigarettes?" (Cappelleri et al., 2007) The ority over placebo were compared to the active NV control strength of sensations were scored separately for the condition. For measures of tolerability (e.g., harshness/irri- strength of puffs on tongue, in nose, back of throat, wind- tation), only those doses of NP that showed evidence of pipe, and chest, estimated nicotine yield and similarity to efficacy relative to placebo (NP 20 and NP 30) were com- the usual brand of cigarettes. Spirometry (FEV1 and FEF pared against the NV active control condition, again using a 25–75, best of 3 readings) was repeated after all conditions two-tailed alpha criterion of 0.05 with a Holm correction.
had been completed.
When presenting the outcomes of hypothesis testing we will first present corrected p values, which take into account the Holm correction (uncorrected p values will follow inparentheses). Unless explicitly noted, all p values refer to The original analysis plan in the protocol specified a two-tailed tests. A number of other secondary variables not small number of a priori comparisons of interest and no directly related to hypotheses about efficacy or tolerability correction for multiple comparisons. However, to achieve a (e.g., strength of respiratory tract sensations, estimated nic- more comprehensive understanding of the results, we con- otine yield) were tabulated for descriptive purposes (paired ducted a more complete set of comparisons that incorpo- t tests with uncorrected p values only are reported for these rated a correction for multiple testing to limit Type I error.
The Holm's correction procedure for multiple testing atthe 0.05 alpha significance level was adopted, which hasbeen shown to be more powerful than the traditional Bon- ferroni adjustment, while still providing equivalent protec- tion against Type I error (Aickin & Gensler, 1996). To limitthe number of statistical comparisons, a series of condition- Nine smokers (7 men, 2 women) participated in the study; alized comparisons (Keppel, 1982) were conducted to eval- they reported smoking an average of 13.5 cigarettes/day uate efficacy and tolerability of the NP conditions relative to (SD ⫽ 2.85) and had a mean FTND score of 5.2 (SD ⫽ 1.3), the control conditions. For the analysis of plasma nicotine indicating moderate nicotine dependence. Participants' concentrations, the immediate increase in nicotine concen- mean age was 27.4 years (SD ⫽ 7.99), and they reported tration from the preinhalation baseline to the first postinha- having smoked an average of 8.9 years (SD ⫽ 7.8). Expired lation time point (5 min) was first compared between pla- air carbon monoxide at the screening session averaged 20.3 cebo and each of the three active NP dose conditions.
ppm (SD ⫽ 13.4). After overnight abstinence, at the begin-
S⫽1 9/27/10 8:21 Art: 2010-0409 ROSE, TURNER, MURUGESAN, BEHM, AND LAUGESEN ning of the experimental session, expired air CO aver- as significantly more satisfying than placebo: for the composite aged 7.2 ppm (SD ⫽ 2.9). Mean body weight was 78.1 kg scale, t(8) ⫽ 3.01, p ⫽ .017 (uncorrected p ⫽ .017) for NP 10; (SD ⫽ 21.8).
t(8) ⫽ 3.19, p ⫽ .026 (uncorrected p ⫽ .013) for NP 20;t(8) ⫽ 3.25, p ⫽ .036 (uncorrected p ⫽ .012) for NP 30.
Plasma Nicotine Results
Subsequent comparisons with the NV condition showed Figure 2 presents the plasma nicotine concentrations in only nonsignificant trends for the three NP doses to be all conditions and at all time points. Baseline-corrected rated higher. Ratings of immediate craving reduction values are depicted, obtained by subtracting the preinhala- showed a significant difference between the NP 20 dose tion baseline values from the values at each postinhalation condition and placebo: t(8) ⫽ 3.36, p ⫽ .03 (uncorrected time point (baseline values did not differ across conditions, p ⫽ .01). A follow-up comparison with the NV condition mean values ranging from 1.0 –2.7 ng/ml). As the graph did not reach statistical significance. Comparisons be- shows, the NP 20 and NP 30 dose conditions yielded rapid tween active NP conditions and placebo on ratings of increases in nicotine levels, which were apparent at the 5 psychological reward did not reach statistical signifi- min time point, immediately after completion of the inha- lations. Statistical comparisons confirmed that the NP 20 Although not the focus of hypotheses in the present study, and NP 30 conditions produced higher nicotine concentra- descriptive statistics for other subjective ratings are also tions than placebo: For the NP 20 condition, the mean presented in Table 1 (which lists only uncorrected p values increase in nicotine concentration was 5.0 (SD ⫽ 3.4) ng/ml for uniformity). Airway sensations following inhalation of (difference from placebo ⫽ 4.8 ng/ml), t(7) ⫽ 4.85, p NP were generally reported throughout the respiratory tract.
(one-tailed) ⫽ .007 (uncorrected p ⫽ .0035) for the com-parison versus placebo. For the NP 30 condition, the mean Estimated nicotine content also showed higher values in the increase in nicotine concentration was 8.3 (SD ⫽ 3.1) ng/ml nicotine conditions relative to placebo.
(difference from placebo ⫽ 8.0 ng/ml), t(6) ⫽ 7.56, p(one-tailed) ⫽ 0.0004 (uncorrected p ⫽ .00015) for the comparison versus placebo. Follow-up comparisons alsoshowed that the NP 20 and NP 30 dose conditions produced Table 1 (bottom) also displays the change in the craving significantly higher plasma peak nicotine concentrations rating scale of the withdrawal questionnaire from pre- to than the active NV control condition: for the NP 20 condi- postinhalations. The NP 20 dose condition showed a tion, the mean difference from NV in nicotine concentra- marked reduction in craving relative to placebo: t(8) ⫽ 3.51, tions was 4.7 ng/ml, t(6) ⫽ 3.31, p ⫽ .016 (uncorrected p ⫽ p ⫽ .024 (uncorrected p ⫽ .008). The NP 10 condition also .016); for the NP 30 condition, the mean difference from showed a significant difference from placebo: t(8) ⫽ 2.89, NV was 6.6 ng/ml, t(5) ⫽ 5.94, p ⫽ .004 (uncorrected p ⫽ p ⫽ .04 (uncorrected p ⫽ .02). The comparisons with the NV condition, however, did not reach significance. Other Puff Ratings
withdrawal symptoms scales showed no significant effectsof condition.
Table 1 depicts the subjective ratings of the rewarding effects of inhalations. All three NP dose conditions were rated There were no significant adverse reactions to any of the conditions. Of the nine subjects, one had headache afterexposure to the NP 10 condition; one other subject hadheadache and one subject reported loose stool, but theseinstances preceded exposure to any of the inhalation con-ditions. Out of the 45 sets of 10 inhalations, mild coughoccurred during 19 of the exposures: 15 coughs (among 5subjects) in the NP 10 condition, 5 coughs (2 subjects) in theNP 20 condition, 12 coughs (6 subjects) in the NP 30condition, 8 coughs (5 subjects) in the NV condition, and 1cough (1 subject) after the room air placebo.
Based on assessments of efficacy described above (e.g., increases in plasma nicotine), the NP 20 and NP 30 doseconditions were the only conditions demonstrating superi-ority over the NV control condition. Therefore, a statisticalcomparison of harshness/irritation ratings was conductedbetween each of the two NP conditions and NV, which Change in plasma nicotine concentration over time showed the NP 20 condition to be significantly less harsh/ relative to preinhalation baseline for the five experimental condi-tions. After baseline, the first measurement was 5 min after the first irritating than the NV condition: t(8) ⫽ 3.09, p ⫽ .03 puff, at the end of the tenth puff.
(uncorrected p ⫽ .015).
S⫽1 9/27/10 8:21 Art: 2010-0409 PULMONARY DELIVERY OF NICOTINE PYRUVATE Table 1Subjective Evaluation of Puffs on 7-Point Scale, and p Values (Uncorrected) for Comparisons With Placebo andNicotine Vapor Inhaler Cartridge (NV) Did you enjoy the sensations in your mouth and throat? p value vs. placebo p value vs. NV Did they immediately reduce your craving for cigarettes? p value vs. placebo p value vs. NV How high in nicotine? p value vs. placebo p value vs. NV How similar to your cigarette? p value vs. placebo p value vs. NV How harsh or irritating? p value vs. placebo p value vs. NV How harsh or irritating on tongue? p value vs. placebo p value vs. NV How harsh or irritating in nose? p value vs. placebo p value vs. NV How harsh or irritating back of mouth and throat? p value vs. placebo p value vs. NV How harsh or irritating in windpipe? p value vs. placebo p value vs. NV How harsh or irritating in chest? p value vs. placebo p value vs. NV Nausea and dizziness p value vs. placebo p value vs. NV Psychological reward p value vs. placebo p value vs. NV p value vs. placebo p value vs. NV Change in craving ⫺0.44 (0.87) ⫺0.85 (1.03) ⫺0.29 (0.84) ⫺0.59 (0.86) 0.41 (0.80) p value vs. placebo p value vs. NV Unless indicated, values are M (SD). NP 10 ⫽ 10 g/puff of nicotine pyruvate; NP 20 ⫽ 20 g/puff of nicotine pyruvate; NP 30 ⫽ 30 g/puff of nicotine pyruvate.
Indices of pulmonary function showed no significant The findings confirm that NP inhalation at the NP 20 changes from the beginning of the experimental session to and NP 30 dose conditions produced rapid increases in the end (Table 2).
plasma nicotine concentrations assessed after inhalationsended, relative to the placebo and active nicotine vapor control conditions. Although blood samples were not Spirometry Results on Study Day (Best of 3 Readings) collected during the 10 inhalations of each condition, the FEF 25 75 (liters/s) first postinhalation sample showed that blood levels hadalready reached significant levels, averaging over 8 ng/ml Before inhalations 3.87 (3.2–4.32) 3.89 (2.70–5.65) in the NP 30 condition, indicative of rapid pulmonary After inhalations 3.92 (3.23–4.36) 3.98 (2.95–5.5) 1.01 (0.97–1.03) 1.03 (0.90–1.13) absorption of nicotine. This result is consistent withparticle size measurements showing that the mass median Values are mean (range). FEV1 ⫽ forced expiratory vol- ume in one second; FEF ⫽ forced expiratory flow.
aerodynamic diameter is approximately 0.6 m (unpub- S⫽1 9/27/10 8:21 Art: 2010-0409 ROSE, TURNER, MURUGESAN, BEHM, AND LAUGESEN lished data), comparable to that of cigarette smoke plicitly rated, enjoyment of airway sensations received the (Hinds, 1978), and readily able to reach the alveoli of the lowest possible median rating of 1 on a 7-point scale (range ⫽ 1–2) versus a median value of 3 (range ⫽ 1–5) for The absence of detectable peak nicotine concentrations in the NP 20 condition, suggesting greater enjoyment of the the NV and NP 10 dose conditions is not surprising in view NP 20 condition. The present method is also advantageous of the low total dose of nicotine (0.1 mg) delivered in these in not requiring propellants or cumbersome spacer devices.
two conditions. In contrast, a typical cigarette dose of ap- Although the technology evaluated in this study was not proximately 1 mg nicotine typically produces venous presented as a commercial product, in principle the tech- plasma nicotine peaks of 10 to 15 ng/ml (Benowitz, Porchet, nology could be incorporated into a device that can provide & Jacob, 1990). At roughly one tenth of this dose, the NV a smoker with a supply of nicotine, conveniently accessible and NP 10 dose conditions would only have yielded peaks on demand. One can envision two main applications of this of ⬍2 ng/ml, close to the detection threshold of the assay type of lung delivery nicotine inhalation system. First, this method used. Our results thus confirmed the prediction that technology may have promise as an adjunct to smoking a nicotine aerosol delivery system can deliver a higher dose cessation treatment. By providing rapid nicotine delivery than a vapor delivery system.
along with many of the rewarding effects of nicotine inhaled Subjective ratings suggested that all doses of NP were in cigarette smoke, a lung delivery nicotine inhaler could moderately satisfying to smokers, yielding higher ratings of prove more effective than current NRT in weaning smokers satisfaction than placebo. There were trends for ratings to off of cigarettes. In this application, the ultimate goal would exceed those of the NV condition, but these did not reach be to wean smokers gradually off of nicotine altogether.
statistical significance. Craving reduction, assessed by the While inhaled nicotine is likely to be more addictive than some prepost puffing change in the craving scale of the Shiffman- forms of NRT (e.g., patch), it may nonetheless prove to be less Jarvik questionnaire, was greater for the NP 10 and NP 20 difficult to relinquish than cigarettes, for the following reasons: conditions than for placebo. The NP 20 condition was also (1) it would not deliver many of the nonnicotine compounds rated higher than placebo for ratings of how much puffs that are contained in cigarette smoke, such as monoamine "immediately reduced your craving." However, none of the oxidase inhibitors (Fowler et al., 1996a, 1996b) and acetalde- NP conditions was significantly different from the NV con- hyde, which are thought to potentiate the addictive properties dition. With respect to harshness/irritation, NP at the 20 of nicotine (Cao et al., 2007); (2) the dose could be set to a g/puff dose was rated significantly less irritating than the range lower than that obtained from most cigarette brands, nicotine vapor condition; this finding was likely to be the and the inhaler could be used to supplement slow-acting result of the mildly acidic pH of the NP particles along with forms of NRT. In this scenario, the inhaler would be used as their small aerodynamic size, resulting in dispersion of a "rescue" or relapse prevention treatment to address break- particles over the large surface area of the lung.
through craving occurring during use of standard slower- Thus, tolerability of the NP aerosol was excellent, and onset NRT products such as patch, gum or lozenge; and (3) there were no significant adverse events. Pulmonary func- the sensory qualities might be engineered to be less appeal- tion measurements also showed no changes from the begin- ing than cigarettes, while still sufficiently acceptable to ning to the end of the session, supporting the acute safety of promote efficacy.
NP inhalation at the doses used in this study. Future studies A second application of this nicotine inhalation technol- will be needed to assess the safety and tolerability of ex- ogy could be for long term nicotine replacement, to be used tended use of a NP delivery system, and to evaluate its by smokers who would otherwise relapse to smoking; this usefulness in promoting abstinence from cigarettes smok- approach would be analogous to methadone maintenance, which has been demonstrated to be an effective treatment of The results of the present study may also be compared heroin addiction (Strain, Stitzer, Liebson, & Bigelow, with those of a recently published pilot study of a metered 1994). In this harm reduction scenario, ex-smokers would dose inhaler system (Caldwell et al., 2009). In that study, continue to receive the perceived benefits of nicotine while smokers were asked to inhale 10 "puffs" from a metered minimizing the risk of disease from combustion and pyrol- dose inhaler delivering nicotine in an ethanol/hydrofluroal- ysis products, including nitrosamines, polycyclic aromatic kane propellant, using a spacer device attached to facilitate hydrocarbons, carbon monoxide and numerous other toxic pulmonary deposition. Two dose conditions, 50 g/puff and substances contained in tobacco smoke. Accumulating evi- 100 g/puff, were tested, and peak plasma nicotine concen- dence suggests that some smokers may be using cigarettes trations averaged 12.5 ng/ml and 9.4 ng/ml, respectively. In to self medicate a variety of psychiatric disorders, including contrast to the present study results, there was a slight delay depression, anxiety, attention-deficit/hyperactivity disorder of approximately 5 min after inhalations until peak levels (ADHD) and schizophrenia. A major challenge for future were reached. Inhalations were "reasonably well tolerated," research will be to identify smokers who are good candi- although one of 10 subjects could not complete the high dates for long term nicotine maintenance. For these smok- dose condition because of coughing. Ratings of satisfaction, ers, long term use of nicotine replacement may indeed be craving and several other subjective responses were com- warranted if they will not otherwise quit smoking. If the parable to those reported after NP inhalation. However, nicotine inhalation technology evaluated in this study con- initial inhalations from the metered dose inhaler often trig- tinues to prove more acceptable and efficacious than current gered coughing, and while harshness/irritation was not ex- forms of NRT, it could have enormous potential for improv- S⫽1 9/27/10 8:21 Art: 2010-0409 PULMONARY DELIVERY OF NICOTINE PYRUVATE ing public health. The potential for reducing cigarette re- Duval, V., & Karlsson, M. O. (2002). Impact of omission or lated harm was noted by Sumner (2003), who stated: "Even replacement of data below the limit of quantification on param- if used very broadly, clean inhaled nicotine might reduce eter estimates in a two-compartment model. Pharmaceutical public health problems as much as a very successful tobacco Research, 19, 1835–1840.
Ezzati, M., & Lopez, A. D. (2003). Estimates of global mortality control programme." attributable to smoking in 2000. Lancet, 362, 847– 852.
This study had a number of strengths as well as limita- Fant, R. V., Buchhalter, A. R., Buchman, A. C., & Henningfield, tions. Strengths included the repeated measures design J. E. (2009). Pharmacotherapy for tobacco dependence. Hand- (which provided greater sensitivity than a between-groups book of Experimental Pharmacology, 487–510.
comparison), subject and experimenter blinding, and precise Feyerabend, C., Ings, R. M., & Russell, M. A. (1985). Nicotine control over nicotine dosing using machine-controlled puff pharmacokinetics and its application to intake from smoking.
volume and timed breath hold. Additional strengths in- British Journal of Clinical Pharmacology, 19, 239 –247.
cluded the measurement of both pharmacokinetic and sub- Fiore, M. C., Jaen, C. R., Baker, T. B., Bailey, W. C., Bennett, G., jective responses, as well as the use of an active control Benowitz, N. L., . . Williams, C. (2008). Clinical practice condition (NV) in addition to the placebo control. Limita- guideline: Treating tobacco use and dependence: 2008 update. tions included the small sample size and short duration of Rockville, MD: Department of Health and Human Services.
Fowler, J. S., Volkow, N. D., Wang, G.-J., Pappas, N., Logan, J., exposure. In addition, blood sampling began after the com- MacGregor, R. R., . . Cliento, R. (1996a). Inhibition of mono- pletion of inhalations, limiting the precision with which the amine oxidase B in the brains of smokers. Nature, 379, 732– rate of rise in plasma nicotine concentrations could be Fowler, J. S., Volkow, N. D., Wang, G.-J., Pappas, N., Logan, J., In summary, the results of this study indicate that the Shea, C., . . Wolf, A. P. (1996b). Brain monoamine oxidase A novel technology employed to generate nicotine containing inhibition in cigarette smokers. Proceedings of the National particles for inhalation has promise as a potentially more Academy of Sciences, USA, 93, 14065–14069.
Heatherton, T. F., Kozlowski, L. T., Frecker, R. C., & Fagerström, effective form of nicotine replacement. The pharmacoki- K. L. (1991). The Fagerström test for nicotine dependence: A netic and subjective data demonstrated that this technology revision of the Fagerström tolerance questionnaire. British Jour- can be used to administer nicotine by the pulmonary route nal of Addiction, 86, 1119 –1127.
for rapid absorption, coupled with acceptable sensory qual- Hinds, W. C. (1978). Size characteristics of cigarette smoke.
ities, to provide subjective satisfaction and relief of craving.
American Industrial Hygiene Association Journal, 44, 720 –726.
Further controlled trials of this technology are warranted to Huchon, G. (1990). Aerosol deposition in the alveolar space. Lung, fully assess its safety and efficacy in aiding smokers to 168(Suppl.), 672– 676.
Hughes, J. R., Shiffman, S., Callas, P., & Zhang, J. (2003). A relinquish cigarettes and thereby avoid the deadly diseases meta-analysis of the efficacy of over-the-counter nicotine re- caused by smoking.
placement. Tobacco Control, 12, 21–27.
Katz, I. M., Schroeter, J. D., & Martonen, T. B. (2001). Factors affecting the deposition of aerosolized insulin. Diabetes Tech- nology and Therapeutics, 3, 387–397.
Kenfield, S. A., Stampfer, M. J., Rosner, B. A., & Colditz, G. A.
Aickin, M., & Gensler, H. (1996). Adjusting for multiple testing (2008). Smoking and smoking cessation in relation to mortality when reporting research results: The Bonferroni vs Holm meth- in women. Journal of the American Medical Association, 299, ods. American Journal of Public Health, 86, 726 –728.
Armitage, A. K., & Turner, D. M. (1970). Absorption of nicotine Keppel, G. (1982). Design and analysis: A researcher's handbook in cigarette and cigar smoke through the oral mucosa. Nature, (2nd ed.). Englewood Cliffs, NJ: Prentice Hall, Inc.
Landon, J., Fawcett, J. K., & Wynn, V. (1962). Blood pyruvate Benowitz, N. L., Porchet, H., & Jacob, P. I. (1990). Pharmacoki- concentration measured by a specific method in control subjects.
netics, metabolism, and pharmacodynamics of nicotine. In S.
Journal of Clinical Pathology, 15, 579 –584.
Wonnacott, M. A. H. Russell, & I. P. Stolerman (Eds.), Nicotine Lee, L.-Y., Gerhardstein, D. C., Wang, A. L., & Burki, N. K.
psychopharmacology (pp. 112–157). Oxford: Oxford University (1993). Nicotine is responsible for the airway irritation evoked by cigarette smoke inhalation in men. Journal of Applied Phys- Caldwell, B., Dickson, S., Burgess, C., Siebers, R., Mala, S., Parkes, iology, 75, 1955–1961.
A., & Crane, J. (2009). A pilot study of nicotine delivery to Lunell, E., Bergstrom, M., Antoni, G., Langstrom, B., & Nordberg, smokers from a metered-dose inhaler. Nicotine Tobacco Research, A. (1996). Nicotine deposition and body distribution from a 11(4), 342–347. doi: Ntp027 [pii] 10.1093/ntr/ntp027 nicotine inhaler and a cigarette studied with positron emission Cao, J., Belluzzi, J. D., Loughlin, S. E., Keyler, D. E., Pentel, P. R., tomography. Clinical Pharmacology and Therapeutics, 59, & Leslie, F. M. (2007). Acetaldehyde, a major constituent of 593–594. doi: S0009-9236(96)90188 –5 [pii] 10.1016/S0009- tobacco smoke, enhances behavioral, endocrine, and neuronal 9236(96)90188 –5 responses to nicotine in adolescent and adult rats. Neuropsycho- Lunell, E., Molander, L., Ekberg, K., & Wahren, J. (2000). Site of pharmacology, 32(9), 2025–2035. doi: 1301327 [pii] 10.1038/ nicotine absorption from a vapour inhaler– comparison with cigarette smoking. European Journal of Clinical Pharmacol- Cappelleri, J. C., Bushmakin, A. G., Baker, C. L., Merikle, E., ogy, 55, 737–741. doi: 00550737.228 [pii] Olufade, A., & Gilbert, D. G. (2007). Confirmatory factor anal- Lux, J. E., & Frecker, R. C. (1988). Generation of a submicrometre yses and reliability of the modified cigarette evaluation ques- nicotine aerosol for inhalation. Medical and Biological Engi- tionnaire. Addictive Behaviors, 32, 912–923.
neering and Computing, 26, 232–234.
S⫽1 9/27/10 8:21 Art: 2010-0409 ROSE, TURNER, MURUGESAN, BEHM, AND LAUGESEN Papathanasiou, A., Milionis, H., Toumpoulis, I., Kalantzi, K., predicts successful smoking cessation with transdermal nico- Katsouras, C., Pappas, K., . . Goudevenos, J. (2007). Smoking tine: A validation study. Pharmacology Biochemistry and Be- cessation is associated with reduced long-term mortality and the havior, 92, 6 –11. doi: S0091–3057(08)00345– 6 [pii] 10.1016/ need for repeat interventions after coronary artery bypass graft- ing. European Journal of Cardiovascular Prevention and Re- Shiffman, S. M., & Jarvik, M. E. (1976). Smoking withdrawal habilitation, 14, 448 – 450.
symptoms in two weeks of abstinence. Psychopharmacol- Rose, J. E. (1988). The role of upper airway stimulation in smok- ogy, 50, 35–39.
ing. In O. F. Pomerleau & C. S. Pomerleau (Eds.), Nicotine Smoking-attributable mortality, years of potential life lost, and replacement: A critical evaluation (Vol. 261, pp. 95–106). New productivity losses–United States, 2000 –2004. (2008). Morbid- York: Alan R. Liss, Inc.
ity and Mortality Weekly Report, 57, 1226 –1228.
Rose, J. E., Behm, F. M., Westman, E. C., Bates, J. E., & Salley, Strain, E. C., Stitzer, M. L., Liebson, I. A., & Bigelow, G. E.
A. (2003). Pharmacologic and sensorimotor components of sa- (1994). Comparison of buprenorphine and methadone in the tiation in cigarette smoking. Pharmacology Biochemistry and treatment of opioid dependence. American Journal of Psychia- Behavior, 76, 243–250. doi: S0091305703002491 [pii] try, 151, 1025–1030.
Rose, J. E., Behm, F. M., Westman, E. C., & Johnson, M. (2000).
Sumner, W., 2nd. (2003). Estimating the health consequences of Dissociating nicotine and non-nicotine components of cigarette replacing cigarettes with nicotine inhalers. Tobacco Control, 12, smoking. Pharmacology Biochemistry and Behavior, 67, 71– 81.
Rose, J. E., & Hickman, C. S. (1987). Citric acid aerosol as a Usmani, O. S., Biddiscombe, M. F., & Barnes, P. J. (2005).
potential smoking cessation aid. Chest, 92, 1005–1008.
Regional lung deposition and bronchodilator response as a func- Rose, J. E., Rose, S. D., Turner, J. E., & Murugesan, T. (2008).
tion of beta2-agonist particle size. American Journal of Respi- U.S. Patent Application No. 20080241255. Washington, DC: ratory and Critical Care Medicine, 172, 1497–1504. doi: U.S. Patent and Trademark Office.
200410-1414OC [pii] 10.1164/rccm.200410-1414OC Rose, J. E., Tashkin, D. P., Ertle, A., Zinser, M. C., & Lafer, R.
Votto, J. J., Bowen, J. B., Barton, R. W., & Thrall, R. S. (2008).
(1985). Sensory blockade of smoking satisfaction. Pharmacol- Inhaled sodium pyruvate improved FEV1 and decreased expired ogy Biochemistry and Behavior, 23, 289 –293.
breath levels of nitric oxide in patients with chronic obstructive Rose, J. E., Westman, E. C., Behm, F. M., Johnson, M. P., & pulmonary disease. Journal of Aerosol Medicine and Pulmonary Goldberg, J. S. (1999). Blockade of smoking satisfaction using Drug Delivery, 21, 329 –334. doi: 10.1089/jamp.2007.0678 the peripheral nicotinic antagonist trimethaphan. Pharmacology Westman, E. C., Behm, F. M., & Rose, J. E. (1995). Airway Biochemistry and Behavior, 62, 165–172.
sensory replacement combined with nicotine replacement for Schneider, N. G., Olmstead, R. E., Franzon, M. A., & Lunell, E.
smoking cessation: A randomized, placebo controlled trial using (2001). The nicotine inhaler: Clinical pharmacokinetics and a citric acid inhaler. Chest, 107, 1358 –1364.
comparison with other nicotine treatments. Clinical Pharmaco-kinetics, 40, 661– 684.
Received March 7, 2010 Schnoll, R. A., Patterson, F., Wileyto, E. P., Tyndale, R. F., Revision received June 23, 2010 Benowitz, N. L., & Lerman, C. (2009). Nicotine metabolic rate Accepted June 23, 2010 䡲 Online First Publication
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