Nicotine & Tobacco Research, Volume 16, Number 3 (March 2014) 253–262
Review
Clinical Pharmacology Research Strategy for Dissolvable Tobacco Products Elena V. Mishina PhD, Allison C. Hoffman PhD Office of Science, Center for Tobacco Products, Food and Drug Administration, Rockville, MD Corresponding Author: Elena V. Mishina, PhD, Office of Science, Center for Tobacco Products, Food and Drug Administration, 9200 Corporate Boulevard, Rockville, MD 20850, USA. Telephone: 301-796-1579; Fax: 240-276-3655; E-mail:
[email protected] Received May 16, 2013; accepted October 9, 2013
Abstract Introduction: Dissolvable tobacco products (DTPs) are relatively new to the market. Some researchers and manufacturers describe them as finely ground tobacco that has been compressed into sticks, strips, and orbs that dissolve or disintegrate in the mouth and do not require spitting. While the pharmacokinetic profiles of nicotine and other tobacco-associated compounds and pharmacological effects of these products are complex, their clinical pharmacology has not been systematically evaluated. We reviewed the scientific literature regarding the known pharmacokinetic (PK) characteristics and pharmacodynamic (PD) effects of DTPs with the purpose of identifying research gaps and informing future studies. Objectives: To evaluate current knowledge of the pharmacological properties of DTPs; to assess their similarities and differences with other tobacco products, especially smokeless tobacco products, and Food and Drug Administration–approved nicotine replacement therapies; to identify gaps in existing information; and to propose a strategy for future clinical pharmacology studies of DTPs. Methods: We reviewed the peer-reviewed literature and generated research questions for future clinical pharmacology studies. Results and Conclusions: Data on the PK and PD of DTPs are sparse and inconsistent. The results of existing studies are limited and inconclusive, and their interpretation is complicated by methodological and/or study design issues. This review identifies a need for larger, comprehensive, and prospectively designed studies that include PK/PD measurements and data analyses. We propose a research agenda for future DTP studies related to the clinical pharmacology of nicotine, its metabolites, tobaccospecific nitrosamines, and other toxic compounds.
Introduction Dissolvable tobacco products (DTPs) are relatively new to the market. Some researchers and manufacturers have described them as finely ground tobacco that has been compressed into sticks, strips, and orbs that dissolve or disintegrate in the mouth and do not require spitting. Many DTPs may meet the current Food and Drug Administration (FDA) statutory definition of “smokeless tobacco”: “any tobacco product that consists of cut, ground, powdered, or leaf tobacco and that is intended to be placed in the oral or nasal cavity” (Family Smoking Prevention and Tobacco Control Act, 2009, § 900(18)). However, other DTPs may not meet the definitions of “cigarette,” “cigarette tobacco,” “roll-your-own tobacco,” or “smokeless tobacco” and would not currently be subject to FDA regulation. According to some researchers and manufacturers, since DTPs dissolve or disintegrate in the mouth and do not require spitting, it is likely that they are being partially absorbed in the mouth
and partially swallowed, followed by gastrointestinal absorption. Hence, the pharmacological effect of these products is a composite of several simultaneously occurring processes. The scientific knowledge base regarding the pharmacological properties and health effects of these products should be thoroughly evaluated to assess these products’ potential health impacts and to inform future research in this field (Ashley & Backinger, 2012). We examined the peer-reviewed literature related to the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of DTPs, as well as similarities and differences with FDA-approved nicotine replacement therapies and conventional smokeless tobacco products. This review is organized in three parts. First, we describe studies of the chemical composition of DTPs. Second, we evaluate and discuss published clinical studies and identify gaps in existing information. Finally, we propose a research strategy to prospectively address knowledge gaps related to the clinical pharmacology of DTPs.
doi:10.1093/ntr/ntt182 Advance Access publication November 19, 2013 Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2013. This work is written by (a) US Government employee(s) and is in the public domain in the US.
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Methods Given the evolving nature of tobacco product research, this paper utilizes a narrative review approach, which is a qualitative method of summarizing and integrating the literature. A systematic review of the literature was conducted in the PubMed database using the search term “tobacco” in combination with one or more of the following terms: “pharmacokinetics,” “pharmacodynamics,” “clinical,” “pharmacology,” “dissolvable,” “dissolvables,” “Ariva,” “Stonewall,” “Camel Orbs,” “Camel Sticks,” “Camel Strips,” “Viceroy Flex,” “Marlboro Sticks,” or “Skoal Sticks.” The literature search included articles published between 2004 and October 1, 2013. Of the 38 research articles identified, 11 original research papers (six related to clinical pharmacology and five related to chemistry) and two review papers were deemed directly relevant and are included in this assessment. In addition, information related to five U.S. patents (search performed at the U.S. Patent and Trade Office using the internal software and the same key words as the above PubMed search), materials from the 2012 Tobacco Products Scientific Advisory Committee meeting on DTPs, and several additional publications related to the chemical composition of smokeless tobacco and the PK/ PD of tobacco products were included in this review (search performed using PubMed and the following key words: “nicotine,” “metabolism,” “smokeless,” “tobacco,” “clinical,” “pharmacokinetics,” “pharmacodynamics,” “pharmacology”).
Results DTP Formulations Most DTPs appeared on the U.S. market within the last decade. Star Scientific, Inc. was the first tobacco manufacturer to introduce two DTPs, Ariva and Stonewall, in 2001, which are no longer on the market as of January 1, 2013. In 2009, R. J. Reynolds introduced dissolvable Camel products, and in 2011, Altria introduced Marlboro Sticks and Skoal Sticks into test markets (Seidenberg, Rees, & Connolly, 2012). Ingredients used to make Philip Morris USA products, including Marlboro Sticks, are publicly available through http://www.philipmorrisusa.com/en/cms/Products/Smokeless_Tobacco/Ingredients/ Ingredients_By_Brand/Marlboro_Snus/Marlboro_Snus_Rich. aspx. Ingredients used to make U.S. Smokeless products, including Skoal sticks, are publicly available through http:// www.ussmokeless.com/en/cms/Products/Ingredients_Nav/ Ingredients/Ingredients_by_Brand/default.aspx. Tobacco manufacturers have patented several methods for constructing and manufacturing DTPs, including pasteurization, pH control, and moisture control. Patented compositions and processes include the combination of a tobacco component, a binder, humectants, and flavorants, as well as the addition of nontobacco components, followed by compression. For example, U.S. Patent No. 7,946,296, issued to Philip Morris USA Inc. describes a dissolvable tobacco film strip adapted for oral consumption, comprising a tobacco component, optional flavorant(s), at least one binder, and at least one humectant (Wrenn & Marun, 2011). The patent describes the development of the tobacco product, which does not require disposal and is intended to provide tobacco enjoyment. Lozenges, pellets, and film strips completely disintegrate in the mouth, while some
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sticks (e.g., Marlboro and Skoal) may need to be removed after the tobacco product dissolves or disintegrates. Several manufacturers of DTPs have patented products with lower levels of tobacco-specific nitrosamine (TSNA) concentrations compared with the conventional smokeless tobacco products (STPs) (Baskevitch, Le Bec, & Raverdy-Lambert, 2004; Star Scientific Inc., 2012; Thomas, Brandon, Bailey, & Losty, 2010; Williams, 2000; Williams, 2012). However, complete information on DTP constituents is not available to the public. Moreover, while some added ingredients may have the potential to enhance DTPs’ addiction potential, this potential has neither been described nor been evaluated. Chemical Studies TSNA Content The first assessment of TSNAs in DTPs and comparator tobacco products was described about 5 years after the introduction of the first DTP, Ariva, to the U.S. market (Stepanov, Jensen, Hatsukami, & Hecht, 2006). In this study, 19 brands of tobacco products were assayed. These included smokeless spit-free tobacco products (Exalt, Revel), compressed DTP lozenges (Ariva, Stonewall), tobacco-free herbal snuff (Smokey Mountain), new cigarettes with reduced nicotine content (Quest, with less than 0.05, 0.3, and 0.6 mg nicotine yield/cigarette), nicotine replacement therapy products (Nicoderm patch, Nicorette, and Commit with 4, 4, and 2 mg of nicotine, respectively), other STPs (Swedish snus, Copenhagen, Skoal, and Kodiak), and cigarettes (Marlboro, Camel, Winston, and Newport). The concentrations of N′-nitroso-nornicotine (NNN) and 4-(methylnitrosamino)-1(3-pyridyl)-1-butanone (NNK), N′-nitrosoanatabine (NAT), N′nitrosoanabastine (NAB), and total TSNAs were normalized by the tobacco products’ wet weights. The total TSNA concentrations in Ariva and Stonewall were found to be about 10–20 times lower than those in conventional STPs. Differences in TSNA content among various STPs and DTPs (Ariva, Stonewall) and their effects on health were discussed by Hatsukami, Ebbert, Feuer, Stepanov, and Hecht (2007). The authors described a DTP manufacturing process to lower toxicant levels in these products, a method that does not involve chemicals, solvents, or other additives and preserves the nicotine and monoamine oxidase inhibitor content. Star Scientific, Inc. patented several variations of this tobacco curing method in the last decade. The latest, a U.S. patent for “star-curing” (Williams, 2012), claims that the levels of recognized carcinogens NNN and NNK in cured tobacco are below 20 ng/g, which was the limit of detection of the assay used. In contrast, higher levels of TSNA in DTPs were detected very recently (Stepanov et al., 2012). This study measured an array of nitrosamines and nicotine (including unprotonated nicotine) concentrations in Marlboro Snus, Camel Snus, and several flavors of DTPs (Camel Orbs, Strips, and Sticks; Ariva; and Stonewall). The assay results were normalized by the products’ dry weight, a reasonable way to account for the differences in product moisture. While this correction resulted in smaller differences in TSNA concentrations among all tobacco products, TSNA levels remained lower in DTPs compared with STPs. The lowest TSNA concentrations in the tobacco-containing products were found in Ariva followed by Stonewall. Most of the total TSNA content for DTPs consisted of NAT, which has not been shown to be carcinogenic. The concentrations of strongly carcinogenic NNN and NNK were high in Ariva
Nicotine & Tobacco Research (averaging 97 and 71 ng/g of dry weight, respectively) and in Stonewall (averaging 130 and 64 ng/g of dry weight, respectively). In Marlboro and Camel Snus products, NNN concentrations ranged from 440 to 1280 and NNK concentrations ranged from 140 to 609 ng/g of dry weight (Figure 1). Results from a Centers for Disease Control and Prevention (CDC) DTP analysis were presented at the January 19, 2012 FDA Tobacco Products Advisory Committee Meeting (Watson, 2012), and some of these data have been published (Lawler, Stanfill, Zhang, Ashley, & Watson, 2013). The following tobacco products with a variety of flavors were assayed: Stonewall and Ariva tablets, Camel Orbs, Camel Sticks, Camel Strips, Marlboro Tobacco Sticks, and Skoal Tobacco Sticks. Four TSNAs were assayed: NNN, NNK, NAB, and NAT. The average NNK content was 302 ng/g (ranging from 49 [Stonewall Wintergreen] to 529 [Skoal Mint]). The NNN content was, on average, 1070 ng/g (ranging from 74.2 [Ariva Java] to 1933 [Skoal Mint]; Figure 2). Watson (2012) found the NNN, NNK, NAB, and NAT content in Ariva, Stonewall, and Camel products to be similar to that found by Stepanov et al. (2012). The CDC study was first to report the TSNA content in the Altria products (Marlboro and Skoal Sticks). The NNN content in these products was up to 10 times higher than that in Camel Strips and Sticks (Figure 2). Nicotine Content Stepanov et al. (2012) found that the total nicotine content per dry weight of DTPs ranged between 3 mcg/g (Camel Orbs) and 7 mcg/g (Stonewall Java Figure 3). The American Snus products had higher content of nicotine per product (dry weight), ranging from 14 mcg/g in Camel Snus Robust to 25 mg/g in Marlboro Snus Rich (Figure 3). The pH values were lower in Ariva and Stonewall (6.9 and 7.1, respectively) compared with Camel
products (7.8 [Stick and Strips] and 8.1 [Orbs]). Thus, calculated concentrations of unprotonated nicotine in Ariva and Stonewall were about 5 times lower than in the Camel products. Based on the fraction of unprotonated nicotine, its bioavailability may be lower after the use of the Star Scientific DTPs compared with the Camel DTPs. Of note, use behavior (e.g., placement in mouth, length of use, swallowing, number of dissolvables used) may also influence the amount of nicotine delivered. Assays performed by CDC researchers found that pH values of Star, Camel, Marlboro, and Skoal DTPs were similar, ranging from 7.23 to 7.95 (Watson, 2012, Lawler et al., 2013). Calculated unprotonated nicotine content per product weight was, on average, 5.77 mg/g (ranging from 2.17 [Camel Strips Fresh] to 8.74 [Stonewall Java]) and the content of nicotine per unit was, on average, 1.73 mg/unit (ranging from 0.46 [Camel Strips Fresh] to 4.02 [Stonewall Java]; Figure 4). Differences in pH measurements between Watson (2012) and Lawler et al. (2013) versus Stepanov et al. (2012) may be explained by the use of different product lots of Ariva and Stonewall. The qualitative screening of DTPs for volatile and semivolatile components was conducted via gas chromatography with mass-spectroscopy (GC/MS) of the concentrated extract (Watson, 2012). The general classes of identified compounds were carboxylic and fatty acids and their alcohols, esters, amides, sterols, acrylate, and hydrocarbons, as well as humectants, antioxidants, plasticizer, preservatives, ink solvent, and others. In Camel Orbs, for example, the following compounds besides nicotine were identified: menthol, carvone, vanillin, 2,4‐di‐t‐butylphenol, N,N‐dimethyl‐7‐undecenamide, ethyl citrate, menthyl acetate, neophytadiene, beta‐cembrenediol, palmitic and stearic acid and their esters, and vitamin E. Since the nonvolatile or chemically labile compounds were not amenable to this approach, many harmful or potentially harmful
Figure 1. N′-nitroso-nornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone content per dry weight of tobacco product (derived from Stepanov et al., 2012).
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Figure 2. N′-nitroso-nornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone content in dissolvable tobacco products (derived from Watson, 2012).
Figure 3. Total and unprotonated nicotine content in dissolvable tobacco products and snus products (derived from Stepanov et al., 2012). constituents (e.g., heavy metals, heterocyclic amines, aromatic amines) were not evaluated using this method. A two-dimensional GS/time‐of‐flight MS analysis was conducted to identify other compounds in DTPs. In Camel Orbs, this method detected 163 compounds (compared with 32 compounds identified with GC/MS) and made a tentative identification of more than 1,700 compounds in a commercial mass spectral database using a probability-based matching algorithm, confirming the chemical complexity of this DTP formulation. The contents of Camel DTPs (Orbs, Sticks, and Strips) were assessed by ultrasonic and microextraction, derivatization, and
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GC/MS (Rainey, Conder, & Goodpaster, 2011, 2012). The authors stated that the total nicotine content was lower in all products compared with the amount listed on the package, with the largest difference found for Mellow Sticks (found to be 0.91 mg/stick but listed as 3.1 mg/stick). The consequences of these discrepancies are not clear. The pH analyses revealed that the newer products (purchased by the researchers after March 2010) had more stable pH values (7.5–7.6) and content of free nicotine (23%–29%) than the older products (pH 7.5–8.0, nicotine 23%–50%). In addition to commonly used flavorants, humectants and other food additives, the following toxic substances were first reported (although not quantified) in Camel DTPs: ethyl citrate, carvone, cinnamaldehyde, and coumarin. In animal studies, the toxic effects of coumarin have been established (Lake, 1999; Mielke et al., 2011); however, the toxicities of all the above-listed compounds during prolonged buccal exposure in humans have not been evaluated. The health impact of the lower TSNA concentrations in some DTPs, either through exclusive use or in combination with other tobacco products, has not been investigated. The presence of other toxicants in these products may result in negative health consequences (e.g., oral, esophageal, and pancreatic cancer; decreased reproductive health), similar to those recognized for STPs (Boffetta, Hecht, Gray, Gupta, & Straif, 2008). Clinical Studies Several clinical studies have compared human exposures to nicotine, cotinine, and expired carbon monoxide (CO), and responses (e.g., cardiovascular responses and smoking cravings) following administration of DTPs versus STPs or conventional cigarettes. The first study to evaluate PK and the effect of nicotine withdrawal following DTP use was a randomized crossover study that compared nicotine PK and subjective effects among five products: two DTPs (Ariva, Stonewall), two STPs (Revel, Copenhagen), and a medicinal nicotine replacement lozenge (Commit; Kotlyar et al., 2007). Subjects were 10 healthy males, 20–49 years of age. After abstaining from smoking at least 12 hr pretest, subjects used one unit of one tobacco product
Nicotine & Tobacco Research
Figure 4. Unprotonated nicotine content in dissolvable tobacco products (derived from Watson, 2012). for 30 min during each of the treatment sessions and provided blood samples at least 90 min following the dose. After administration of a DTP (either Ariva or Stonewall), the mean exposure to nicotine measured as area under the curve (AUC(0–90)) was reported to be 4–5 times lower than after administration of Copenhagen snuff (192, 292, and 1038 ng∙min/mL, respectively), and it was about 1.5 times lower than after the dose of Commit (467 ng∙min/mL). Only Copenhagen snuff provided a maximum nicotine plasma concentration similar to cigarette smoking (Hukkanen, Jacob, & Benowitz, 2005), while all other products showed lower exposures to nicotine. Use of Copenhagen snuff significantly reduced subjects’ average craving score and withdrawal symptoms at the time of maximal nicotine plasma concentration, while use of the other products showed less pronounced effects. Several study issues were identified. First, with the exception of Commit (at 4 mg), the authors did not list the exact doses of nicotine administered to the subjects. Alpert, Koh, and Connolly (2008) estimated the free nicotine content in Revel at about 1.1 mg/g (about 0.17 mg nicotine per pouch I. Stepanov (personal communication, July 31, 2012)) and in Copenhagen at about 3.2–3.6 mg/g (about 15 mg/pouch). The total nicotine content listed on the DTP and snus packaging is approximate. Moreover, the amount of unprotonated nicotine available for buccal absorption varies, depending on the product’s pH, batch, and manufacturing site (Rainey, Conder, & Goodpaster, 2011; Stepanov et al., 2012). Second, the nicotine plasma concentrations following DTP administration were close to the used assay’s limit of quantification (LOQ; 2 ng/mL). Use of an assay methodology with higher sensitivity might improve the data analysis (Miller, Norris, Rollins, Tiffany, & Wilkins, 2010; Shakleya & Huestis, 2009). Imputing nicotine plasma concentrations below LOQ as 1 ng/mL can introduce bias that could call into question the validity of the parameter estimates. Third, the timing of the blood sampling was too short to capture the full nicotine PK profile. Given imprecise ingested nicotine dose information, less-than-ideal assay sensitivity, and limitations of sampling design, the PK of the tested products could not fully characterized in this study. The reported exposure to nicotine (by both nicotine peak plasma concentration [Cmax] and AUC) after the 4-mg dose received with Commit was twice
as high as the nicotine exposure following a similar nicotine dose from Stonewall. Such a prominent difference in nicotine bioavailability could be the result of a disparity in the nicotine delivery system; however, these differences were not evaluated in this study. The generally low nicotine plasma concentrations and the absence of a pronounced Cmax following DTP ingestion correlated with the PD effects of these products and may partially explain lower consumer satisfaction and acceptance of the DTPs. Blank, Sams, Weaver, & Eissenberg (2008) described nicotine PK and effects of Ariva lozenges in 10 smokers (18– 50 years old; expired air CO levels ≤15 ppm; ≥10 cpd). After overnight cigarette abstinence, one Ariva lozenge was administered at time 0, followed by two lozenges at 1.5 hr and three lozenges at 3 hr, for a total of six lozenges (9 mg of nicotine) over the course of the session. Nicotine plasma concentrations, CO in expired air, and cardiovascular effects (e.g., blood pressure, heart rate) were assessed. Administration of one Ariva lozenge increased the mean nicotine plasma concentrations slightly above the baseline LOQ of 2 ng/mL; a similar result was found by Kotlyar et al. (2007). Nicotine in plasma accumulated over the study course, reaching peaks of 7 ng/mL following the twolozenge dose and 9 ng/mL following the three-lozenge dose. Time to peak nicotine plasma concentrations was not identified over a period of 45 min following the last dose. The total Ariva dose of 9 mg of nicotine over the course of 3 hr produced lower nicotine plasma concentrations than did one cigarette (1 mg of nicotine; Hukkanen et al., 2005). Ariva use suppressed several symptoms of tobacco abstinence (e.g., craving and urges to smoke on the Minnesota Nicotine Withdrawal Scale (MNWS; Hughes & Hatsukami, 1986, 1998), which was most evident after the last dose of three lozenges (p < .05). This withdrawal relief was offset by relatively high nausea symptoms, which significantly peaked (p < .05) at about 10 min following each Ariva dose. Nausea could be a limitation for the simultaneous use of several Ariva lozenges; however, it would be of interest to evaluate whether the use of DTP could produce nicotine exposure similar to that associated with cigarette smoking. A slight increase in heart rate after Ariva use was reported; however, it was not related to the dose. Blood pressure monitoring results were not presented by the authors. This study was
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Dissolvable tobacco research strategy the first attempt to mimic a real-life situation of multiple DTP doses. However, the duration of the observations was too short to describe the full nicotine PK profile and effects and safety of chronic Ariva dosing. A four-condition crossover study (Blank & Eissenberg, 2010) measured toxicant exposure and abstinence symptoms in 21 smokers (18–55 years of age; ≥15 ppm CO in expired air; ≥15 cpd). Subjects were allowed to smoke their own brand of cigarettes during the weekends prior to each of four study conditions (Camel snus, Ariva, own brand cigarettes, or no tobacco) during which participants used the test product for five days. Exposure to nicotine was measured via daily urine cotinine tests. Since only the pattern of change over each 5-day test was assessed, a semiquantitative cotinine test was deemed appropriate for use by the study authors. Expired CO and total (a sum of free and glucuronidated) 4-(methylnitrosamino)-1(3-pyridyl)-1-butanol (NNAL) were measured daily. While these measurements did not change in the “own brand cigarettes” arm, in all other arms urine cotinine concentrations slowly decreased over the 5-day condition and expired air CO levels decreased significantly (p < .05) by Day 2. Mean total NNAL urine levels decreased from Day 1 to Day 5 in the Ariva and “no tobacco” conditions (49% and 63%, respectively). The reported decreases in total NNAL for “no tobacco” arm confirm the previous description of NNAL elimination profile (Goniewicz et al., 2009). Nicotine withdrawal scores were the highest in the “no tobacco” arm, followed by Ariva and snus. The only significant difference between Ariva and “own brand cigarettes” occurred in the increase of craving scores identified on Day 2 (p < .05). Starting from Day 2 (the first assessment), the oral tobacco products were evaluated by the participants as less pleasant and having lower taste ratings and higher “dislike product” ratings compared with their own brand. The researchers concluded that noncombusted products reduced exposure to CO, nicotine, and NNAL and that these products were unable to fully suppress tobacco abstinence symptoms. The methodology and design lacked comprehensive compliance assessment and uncontrolled product use, limiting further interpretation with regard to the PK/PD of the tested products. Two pilot studies compared the TSNA exposure and effects of two noncombusted tobacco products (snus [Exalt] and DTP [Ariva]) versus a nicotine replacement therapy product (Commit, 4 mg; Mendoza-Baumgart et al., 2007). Both studies used a 5-week randomized crossover design with two sequences. The subjects were healthy adult smokers (18– 65 years of age; ≥15 cpd) who committed to smoking cessation and had ≤8 ppm of CO in expired air at baseline. At the end of each study’s baseline period (characterized by ad libitum smoking, defined as variable smoking according to smoker preferences), participants were randomly assigned to one of the two study products for 2 weeks (Period 1) and then crossed over to the other product for 2 weeks (Period 2). Subjects were asked to use the products at least every 2 hr. Participants attended six clinical visits during the 4-week sampling phase and one follow-up visit. Twenty-nine subjects completed the Exalt/Commit study, and 20 subjects completed the Ariva/ Commit study. At these visits, biomarkers for tobacco exposure in urine (cotinine and NNAL), white blood cell (WBC) counts, hemoglobin, CO in the expired air, heart rate, and blood pressure were measured and subjective behavioral responses were assessed using the MNWS and Drug Effects and Liking Visual Analog Scale (VAS). Significant reductions
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in CO levels and in total cotinine levels (nmol/mg creatinine) were observed between baseline and the end of the two study periods. Two weeks following the switch from smoking to Ariva, mean total NNAL urine concentrations decreased by 70%. No significant sequence group, visit, or product effects were found for systolic and diastolic blood pressure, heart rate, WBC count, or hemoglobin (p > .05); however, the period effect was significant for blood pressure (p = .01), with higher values in Period 1 compared with period 2. Tobaccospecific carcinogen uptake was greater with Exalt than with Commit and Ariva (which were similar). For all products, the mean subjective measures of withdrawal scores increased and craving scores decreased in both studies similarly compared with baseline. The total product dosage was assessed by counting the leftover product. Subjects used more Ariva dosage units (7.1–7.8/day) than Commit (5.0–5.3/day). Thus, the “at least every 2-hr” dosing scheme was not maintained. Due to the small sample size, large intra- and intersubject variability, and insufficient control of product administration, a definitive statement regarding PK/PD of the tested products cannot be made. Another crossover study (Cobb, Weaver, & Eissenberg, 2010) compared nicotine and CO exposures, cardiovascular response (i.e., heart rate, blood pressure), and tobacco abstinence symptom suppression in response to Ariva (1.5 mg nicotine), Camel and Marlboro Snus (2.6 nicotine/pouch), Commit (2.0 nicotine/lozenge), own brand cigarette (average of 1.1 mg nicotine yield/cigarette), puffing on an unlit cigarettes (no nicotine yield), and Quest (0.05 mg nicotine yield/ cigarette). After an overnight tobacco abstinence, 28 smokers (mean age 32 years; ≥15 cpd) completed seven 2.5-hr sessions with use of two units of tobacco product separated by 1 hr. Blood was sampled during a period of 45 min after each dose to assay nicotine concentrations. Subjective measurements were assessed using the Questionnaire of Smoking Urges (QSU) Brief (Tiffany & Drobes, 1991), the MNWS (Hughes & Hatsukami, 1986, 1998), and the VAS at 30 min and 1 hr following each dose. Nicotine plasma concentrations were low in all arms compared with the “own tobacco” arm. After the second dose, Cmax of Ariva was 3.4 ng/mL, which was lower than that of both Commit (4.6 ng/mL) and the cigarette (20.7 ng/mL). Low nicotine exposure with Ariva use translated to marginal changes in heart rate, blood pressure, abstinence symptom suppression, and the direct effects associated with nicotine and tobacco. Craving scores were significantly higher with use of the noncombusted products relative to cigarettes. Relative to baseline levels of ≤10 ppm, exposure to CO was elevated after smoking own cigarettes and Quest (mean: 17.5 and 14.4 ppm, respectively) and was unchanged by the other products. This study was similar to previously described studies (Blank & Eissenberg, 2010; Kotlyar et al., 2007) but used a different set of DTPs and STPs. A novel aspect of this study was its attempt to statistically evaluate correlations between the direct effects of nicotine and abstinence symptoms. Since the nicotine plasma concentrations in Ariva and Marlboro snus arms were close to LOQ, it is difficult to interpret the exposure–response relationship for these products. A clinical evaluation of the DTP Stonewall, the STP General moist snus, placebo smokeless Bacc-off (a nontobacco product), and own smokeless tobacco brand was performed in 2 four-arm crossover studies in current users of
Nicotine & Tobacco Research STPs (Gray, Breland, Weaver, & Eissenberg, 2008). In the first study, 13 subjects (mean age 28 years) received four administrations of STPs (2 g) or Stonewall, one dose every hour (with use lasting up to 30 min) during a study observation period of 4.5 hr. The between-sessions wash-out period was 48 hr. Plasma nicotine concentrations were measured prior to use and 30 min following use of the tobacco product. The LOQ for nicotine assay in plasma was 2 ng/mL; this value was imputed to the data for all nicotine concentrations below LOQ. Cardiovascular measurements (i.e., heart rate, blood pressure) were recorded but not reported. Statistical tests compared the first and fourth dose data in each arm. Tobacco abstinence symptoms in both studies were assessed using the QSU (Tiffany & Drobes, 1991) and the VAS. Overnight tobacco abstinence was assumed based on mean presession nicotine levels of 2.2 ng/mL, and the statistical significance criteria to discriminate this value from the LOQ value for nicotine were not described. The authors stated that plasma nicotine concentrations did not increase significantly following the use of placebo or Stonewall. The craving scores slightly decreased following the fourth dose in all arms except for the Stonewall arm. The QSU values significantly decreased (p < .05) in all arms except for the Stonewall arm after the first dose of the product. The QSU values were mixed after the fourth dose. Mean VAS scores related to the direct effect of nicotine for own brand were significantly greater than mean scores for the other conditions (p
