Snus as a smoking cessation aid: a randomized placebo-controlled trial.

INTRODUCTION: Snus is a low-nitrosamine smokeless product that appears to be safer than other smokeless products. Evidence indicates that snus has been used as an effective smoking cessation aid in Scandinavia. No randomized controlled trial has directly tested the efficacy of snus for smoking cessation. METHODS: This randomized, double-blind, placebo-controlled multicentre trial tested the efficacy of snus for smoking cessation. Of the 250 subjects, 125 were randomized to active or placebo snus sachets. Subjects were followed up through 28 weeks after randomization. In total, 5 clinical visits and 8 telephone contacts were scheduled. Primary outcome measure was biologically verified continuous smoking abstinence from Week 6 through 28. RESULTS: The continuous abstinence rate during Weeks 6-28 in the snus and placebo groups was 4.0% and 1.6% (odds ratio [OR]: 2.5, 95% CI: 0.4-27), respectively. The point prevalence abstinence rate at 6 weeks was 18.4% in the snus group versus 8.8% in the placebo group (OR: 2.3, 95% CI: 1.1-5.0, p = .03). At Week 28, the difference in favor of the snus group was not statistically significant (12.8% vs. 7.2%, OR: 1.9, 95% CI: 0.8-4.4). Snus was generally well tolerated. Treatment-related adverse events that were more common in the snus group were generally mild and included nausea, dyspepsia, gingivitis, hiccups, and dizziness. CONCLUSIONS: Although the cessation rates generally were low and, at 28 weeks, did not differ between active and placebo, early quit rates suggested that snus was superior and with similar effect sizes to those with nicotine replacement. These results suggest that snus needs to be further researched as a smoking cessation treatment.

[Smokeless tobacco]. / Tabac non fumé

Use of smokeless tobacco (ST) (chewing tobacco and snuff) can lead to a number of consequences detrimental to health. ST rapidly delivers high doses of nicotine, which can lead to dependence and is also a source of carcinogenic nitrosamines. Changes usually develop in the mouth area where the ST is most often placed. Non-malignant oral lesions include leuko-oedema, hyperkeratotic lesions of the oral mucosa and localised periodontal disease. Oral premalignant lesions are leukoplakia, erythroplakia, submucosal fibrosis and lichen planus. Betel chewing, with or without tobacco, may increase the incidence of oral cancer. There is conflicting evidence with regard to snuff users about the risk of oral and gastro-oesophageal cancer. ST use is a risk factor for pancreatic cancer and may increase the risk of fatal myocardial infarction and ischemic stroke. During pregnancy, ST is associated with an increase in pre-eclampsia, preterm delivery and stillbirth. Nicotine replacement therapy and bupropion reduce withdrawal symptoms and tobacco craving during ST cessation. However, they have not been shown to help long-term abstinence. Information concerning the potential hazards of ST products should be incorporated into educational programmes to discourage its use and to help users to quit. Smokeless tobacco is not recommended to help smoking cessation.

Direct effects of pure nicotine, cigarette smoke extract, Swedish-type smokeless tobacco (Snus) extract and ethanol on human normal endothelial cells and fibroblasts.

UNLABELLED: The adverse health effects of cigarette smoking are well established including the increased risk of various types of cancer. In this study, the direct effects of ethanol, pure nicotine, cigarette smoke extract and Swedish type smokeless tobacco (Snus) extract on normal cells were investigated. MATERIALS AND METHODS: Primary normal adult human endothelial cells and fibroblasts at early passage were used. Upon exposure to pure nicotine, cigarette smoke extract, Snus extract and ethanol, these cells were assessed for DNA synthesis, gene expression profile and cellular morphology. RESULTS: Normal human fibroblasts and endothelial cells have unique gene expression profiles. The effects of treatment with ethanol and nicotine from different sources was more prominent in endothelial cells than fibroblasts. The combination of alterated gene expressions and strongly inhibited DNA synthesis was only detected in cells exposed to smoke extract. In the presence and absence of ethanol, pure nicotine and Snus extract induced abnormalities in the cytoplasm without any significant degree of cell death. With similar doses of nicotine and ethanol, the additional components in smoke extract had a dominant effect. The smoke extract induced vast cellular abnormalities and massive cell death. CONCLUSION: Cigarette smoke induced massive cell death and various abnormalities at cellular and molecular levels in surviving endothelial cells and fibroblasts. The combination of genomic alterations and the chronic inflammatory microenvironment induced from massive cell death, will potentially promote tumourigenesis and various diseases in cigarette smokers.

Guggulsterone targets smokeless tobacco induced PI3K/Akt pathway in head and neck cancer cells.

BACKGROUND: Epidemiological association of head and neck cancer with smokeless tobacco (ST) emphasizes the need to unravel the molecular mechanisms implicated in cancer development, and identify pharmacologically safe agents for early intervention and prevention of disease recurrence. Guggulsterone (GS), a biosafe nutraceutical, inhibits the PI3K/Akt pathway that plays a critical role in HNSCC development. However, the potential of GS to suppress ST and nicotine (major component of ST) induced HNSCC remains unexplored. We hypothesized GS can abrogate the effects of ST and nicotine on apoptosis in HNSCC cells, in part by activation of PI3K/Akt pathway and its downstream targets, Bax and Bad. METHODS AND RESULTS: Our results showed ST and nicotine treatment resulted in activation of PI3K, PDK1, Akt, and its downstream proteins--Raf, GSK3ß and pS6 while GS induced a time dependent decrease in activation of PI3K/Akt pathway. ST and nicotine treatment also resulted in induction of Bad and Bax phosphorylation, increased the association of Bad with 14-3-3ζresulting in its sequestration in the cytoplasm of head and neck cancer cells, thus blocking its pro-apoptotic function. Notably, GS pre-treatment inhibited ST/nicotine induced activation of PI3K/Akt pathway, and inhibited the Akt mediated phosphorylation of Bax and Bad. CONCLUSIONS: In conclusion, GS treatment not only inhibited proliferation, but also induced apoptosis by abrogating the effects of ST/nicotine on PI3K/Akt pathway in head and neck cancer cells. These findings provide a rationale for designing future studies to evaluate the chemopreventive potential of GS in ST/nicotine associated head and neck cancer.

Guggulsterone (GS) inhibits smokeless tobacco and nicotine-induced NF-κB and STAT3 pathways in head and neck cancer cells.

Understanding the molecular pathways perturbed in smokeless tobacco- (ST) associated head and neck squamous cell carcinoma (HNSCC) is critical for identifying novel complementary agents for effective disease management. Activation of nuclear factor-kappaB (NF-κB) and cyclooxygenase-2 (COX-2) was reported in ST-associated HNSCC by us [Sawhney,M. et al. (2007) Expression of NF-kappaB parallels COX-2 expression in oral precancer and cancer: association with smokeless tobacco. Int. J. Cancer, 120, 2545-2556]. In search of novel agents for treatment of HNSCC, we investigated the potential of guggulsterone (GS), (4,17(20)-pregnadiene-3,16-dione), a biosafe nutraceutical, in inhibiting ST- and nicotine-induced activation of NF-κB and signal transducer and activator of transcription (STAT) 3 pathways in HNSCC cells. GS inhibited the activation of NF-κB and STAT3 proteins in head and neck cancer cells. This inhibition of NF-κB by GS resulted from decreased phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha the inhibitory subunit of NF-κB. Importantly, treatment of HNSCC cells with GS abrogated both ST- and nicotine-induced nuclear activation of NF-κB and pSTAT3 proteins and their downstream targets COX-2 and vascular endothelial growth factor. Furthermore, GS treatment decreased the levels of ST- and nicotine-induced secreted interleukin-6 in culture media of HNSCC cells. In conclusion, our findings demonstrated that GS treatment abrogates the effects of ST and nicotine on activation of NF-κB and STAT3 pathways in HNSCC cells that contribute to inflammatory and angiogenic responses as well as its progression and metastasis. These findings provide a biologic rationale for further clinical investigation of GS as an effective complementary agent for inhibiting ST-induced head and neck cancer.

Relationship between semen quality and tobacco chewing in men undergoing infertility evaluation.

OBJECTIVE: Male fertility is affected by a variety of lifestyle habits that include tobacco use. A large population of Indian men is addicted to tobacco chewing. The objective of our study was to assess the relationship between tobacco chewing in these Indian men--who were part of an infertile couple--and their sperm characteristics. DESIGN: Retrospective study. SETTING: Private infertility clinic. PATIENT(S): Six hundred thirty-eight male patients undergoing infertility evaluations were grouped according to the frequency of their tobacco chewing habit: mild (< 3 times/day, n = 177), moderate (3-6 times/day, n = 264), and severe (> 6 times/day, n = 197). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Sperm characteristics (concentration, motility, morphology, and viability). RESULT(S): Sperm concentration, percentage motility, morphology, and percentage viability were significantly higher in the mild group vs. the moderate group and in the moderate group vs. the severe group. The percentage of men with azoospermia rose with the level of addiction (1%, 3%, and 14%) as did the percentage of men with oligoasthenoteratozoospermia (2%, 8%, and 29%), although the differences were not statistically significant. CONCLUSION(S): In our study, use of chewing tobacco by a group of Indian men who were undergoing infertility evaluation was strongly associated with a decrease in sperm quality and to a lesser extent with oligoasthenozoospermia or azoospermia. Infertile men should be counseled about the adverse effects of tobacco chewing on sperm quality.

Serum total sialic acid levels in smokers and users of smokeless tobacco in form of oral powder (Maras powder).

Smokeless tobacco (ST) is widely used as chewing tobacco and as oral snuff in the world. Also, in Kahramanmaras, a city in Southern Turkey, ST used as 'oral powder' or 'Maras Powder' is consumed widely instead of cigarette smoking. The aim of this study was to search the effect of ST use on serum total sialic acid (TSA) and to compare the serum TSA levels in smokers and ST users. The study was performed at the Department of Chemistry-Biochemistry, University of Kahramamaras Sutcu Imam, Turkey, in 2003. Serum samples obtained from smokers (Group I), Maras powder users (Group II), and healthy control subjects (Group III) who were nonsmokers and nonusers ST. Individuals who were smokers and ST users were classified into subgroups with respect to amount of consumed cigarette or oral powder. Serum TSA was measured with the Denny's colorimetric method. The TSA concentrations were significantly higher in the sera of smokers (p < 0.001) and Maras powder users (p < 0.001) than those of control subjects. The mean serum TSA level was found to be lowest in the control group and highest in the Maras Powder users. But, there was no significant difference in serum TSA levels between smokers and Maras powder users (p > 0.05). We can conclude from the results obtained that serum TSA was affected by ST use as seen in smokers. This finding may be an indication of harmful effects of ST use as Maras powder as well as cigarette smoking.

Effect of snuff on nasal mucosa.

PURPOSE: The inhalation of nasal snuff (powdered tobacco) is a common addiction in the Indian subcontinent. In the western world, there is a resurgence of interest in nasal snuff because it does have the morbidity associated with smoked tobacco. Very few studies have reported the long-term effects of snuff on nasal mucosa. The objective of the present study was to investigate the effect of long-term use of snuff on the nasal mucosa. MATERIALS AND METHODS: We conducted a retrospective study on 29 snuff users. We investigated the reasons for initiation of this particular form of addiction along with the clinical signs and symptoms of long-term snuff usage. At the time of the study, all patients complained of one or more nasal symptoms. Nasal obstruction and nasal discharge taken together were reported by 62.5% of patients. Gross mucosal edema of the septum and turbinates was the main finding on nasal examination. The absolute eosinophil count and total serum immunoglobulin E were elevated in 62.5% and 66.7% of patients, respectively. On skin prick test, 41% of patients reacted positively to snuff and 25% to tobacco. Histopathologic examination of the turbinates (16 patients) showed squamous metaplasia, capillary proliferation, capillary and venous dilatation, inflammatory cell reaction, subepithelial edema, and fibrosis. CONCLUSIONS: Much has been written about the advantages of nasal snuff over products that deliver tobacco smoke. Our study shows that snuff users, after long-term abuse, develop a form of chronic rhinitis, as a consequence of which they develop blocked and stuffy noses. We conclude that nasal snuff is not a suitable substitute for smoked tobacco because it does not avoid ill health.

Effects of smokeless tobacco "Maras powder" use on respiratory functions.

In Turkey, "Maras Powder," which is a kind of powder yielded from the shields of tobacco, is widely used as smokeless tobacco through buccal mucosa or together with cigarette. Maras powder, composed of ash and a plant named Nicotiana Rustica Linn, is sometimes used to give up smoking. The present study was aimed to investigate the effects of Maras powder use on respiratory functions of healthy subjects who do not have any chronic disease. We found statistically significant differences in percentage of forced expiratory volume in the first second (FEV(1)%) (p = 0.001), the ratio of FEV(1) to forced vital capacity (FEV(1)/FVC) (p = 0.024), percent of maximum expiratory flow rate (FEF(25-75)%) (p = 0.002) and percent of peak expiratory flow (PEF%) (p = 0.037) between cigarette smokers with Maras powder use (n = 23) and control subjects (n = 24). Likewise, when cigarette smokers (n = 24) and control subjects were compared, the differences for all these parameters were significant (p = 0.022, p = 0.048, p = 0.011 and p = 0.047, respectively). Only FEV(1)% and FEF(25-75)% were significantly lower in cigarette smokers with Maras powder use than in Maras powder users (n = 28) (p = 0.011 and p = 0.022, respectively). There was a negative correlation between forced vital capacity and Maras powder use (r = -0.315, p = 0.03). The present study suggests that Maras powder does not cause serious bronchial obstruction. This may be due to usage of the smokeless tobacco through buccal mucosa but not through inhalation as in case of cigarette smoking.

The effects of Maras powder (smokeless tobacco) on oxidative stress in users.

Maras Powder (MP) is a special kind of smokeless tobacco widely used in the southeast region of Turkey especially in Kahramanmaras and Gaziantep and other southeastern cities. It is obtained from a tobacco species, Nicotiana rustica L and ash of oak or grapevine wood. Tobacco may increase oxidative stress, which is related to the products of the oxygen metabolism taking place in all cells. Cellular antioxidants, e.g. catalase (CAT), superoxide dismutase (SOD) and glucose 6-phosphate dehydrogenase (G6PD) protect the cell against oxidative damage. An imbalance between the ROS and antioxidants in favour of ROS is described as oxidative stress. In this study, we aimed to investigate the effect of MP on antioxidant enzyme levels and lipid peroxidation. We measured malondialdehyde (MDA), CAT, SOD and G6PD levels in blood of 68 MP users and 30 healthy controls who did not use MP. CAT, SOD and G6PD levels were lower in MP users than in the controls. On the other hand, lipid peroxidation levels (MDA), one of the best indicators of cytological damage, was increased in MP users compared with the controls. The present study showed that MP increases oxidative stress, which may cause many systemic disorders, including arteriosclerosis.

Effects of snuff extract on epithelial growth and differentiation in vitro.

Snuff is a locally irritative agent causing hyperkeratinization and hyperplasia of the oral epithelium. The aim of the study was to investigate the effects of snuff on epithelial cell growth and differentiation in vitro. Three-dimensional HaCaT cell cultures were grown for 6, 12, 14, and 18 days in the presence of 1% snuff extract. Ki-67, p53 and cytokeratins (Cks) 5, 13, 10, 19, 18, involucrin and filaggrin were studied by means of immunohistochemistry. Ki-67 indices were assessed, and the results analyzed statistically. Marked morphologic changes were seen with advanced culture time in the snuff group, probably as a result of increased toxic effects. Snuff exposure decreased the percentage of Ki-67 positive cells on days 6, 12, and 14, suggesting that snuff does not stimulate proliferation activity in this in vitro model. Cornification-related Ck 10 decreased after snuff exposure, indicating disturbances in the epithelial differentiation process.

Nasal snuff: historical review and health related aspects.

With cigarette smoking declining in the modern world, the tobacco industry has to look for other products that can keep the old customers and attract new ones. Different forms of smokeless tobacco are currently massively promoted and are gaining in importance. Dry nasal snuff--the oldest known form of tobacco in Europe--is one of them. The health risks associated with it are different to those attributed to smoking and oral wet snuff. The nicotine contained leads to dependency. Its resorption rate is similar to that of smoking, so it could be seen as an adequate substitutional therapy. The risk for cardiovascular diseases is lower, compared to that for smokers. Chronic abuse leads to morphological and functional changes in the nasal mucosa. Although it contains substances that are potentially carcinogenic, at present, there is no firm evidence, relating the use of nasal snuff to a higher incidence of head and neck or other malignancies.

Mitochondrial volume densities in the smokeless tobacco-treated hamster cheek pouch epithelium.

OBJECTIVES: To compare the morphological changes and quantitative distribution of mitochondria in the hamster cheek pouch (HCP) epithelium treated with smokeless tobacco (ST). MATERIALS AND METHODS: Archives of experimental material from previously published studies (Ashrafi et al., 1992) were utilized. Animals in experimental group received moist ST (snuff) in their right pouch, 5 days weekly for 24 months, while no snuff was given to control group. After 24 months, the epithelial tissues were processed for electron microscopy study. Volume densities of mitochondria were assessed by morphometry. MAIN OUTCOME MEASURES: Mitochondrial volume densities in the two groups, experimental vs control. RESULTS: In both control and experimental groups mitochondria were concentrated between the nucleus and basal cell plasma membrane. A decrease in the mean mitochondrial volume density (Vvmit) was observed from the basal layer to the more superficial layers in both groups. The experimental HCP displayed more mitochondria than control, and the granular epithelial cell layer in experimental group showed significantly a higher mean Vvmit than the control group (P = 0.03). It was concluded that greater numbers of mitochondria were retained in ST-treated granular cells of the hyperplastic epithelia than in the normal epithelium.

Preliminary study on reducing oral moist snuff use.

BACKGROUND: Tobacco exposure reduction may be an alternative treatment approach for those tobacco users who are unwilling or unable to quit tobacco use. However, very little information is available on the feasibility of this type of intervention, especially in the area of oral moist snuff tobacco (ST). This pilot study examined whether reducing ST use using various methods can be achieved and whether this reduction results in lower exposure to carcinogens. METHODS: Moist snuff users (N=40 males) were randomly assigned to 4 mg nicotine gum, non-tobacco mint snuff, brand switching, or elimination of ST use in specific situations. These approaches were used to reduce ST use or nicotine exposure by at least 25% for the first 2 weeks and 50% the subsequent 6 weeks of treatment. Follow-up sessions occurred at 12 and 26 weeks. RESULTS: Significant reductions were observed in tins per week and cotinine levels across all conditions. Among the intent-to-treat population, the abstinence rate was 15% at 26 weeks. Reduction in nicotine exposure was associated with reduction in exposure to nitrosamines. CONCLUSION: Reduction in ST use may be a viable approach for those oral moist ST users with no immediate quit plans. Future research in this area is needed.

Snuff synergy: preparation, use and pharmacology of yopo and Banisteriopsis caapi among the Piaroa of southern Venezuela.

Current understanding of the preparation and use of yopo, a hallucinogenic snuff made from the ground seeds of the Anadenanthera peregrina tree, has departed little from the accounts of scientists and travelers made over a century ago. Schultes and others have made refinements to these early accounts. While several scholars have drawn attention to the fact that little ethnographic work has been conducted to assess the ethnobotanical diversity and cultural framework of the snuff hallucinogen complex, few subsequent studies deal with botanical variations in preparation and use. This article contrasts historical accounts of yopo preparation with ethnographic data I have recently collected among the Piaroa of southern Venezuela to demonstrate one way in which yopo preparation and use deviates from the basic model established by Humboldt, Spruce and Safford. Piaroa shamans include B. caapi cuttings in the preparation of yopo and consume doses of B. caapi prior to snuff inhalation concomitant with the strength of visions desired for particular tasks. I argue that the combined use of yopo and B. caapi by Piaroa shamans is pharmacologically and ethnobotanically significant, and substantiates claims of the use of admixtures in snuff; further ethnographic investigation of the snuff hallucinogen complex is necessary.

Effect of non-nicotinic moist snuff replacement and lobeline on withdrawal symptoms during 48-h smokeless tobacco deprivation.

The present study investigated the effects of two herbal components (BACCOFF and DIPSTOP) of a commercially available smokeless tobacco treatment program for reducing subjective withdrawal symptoms during deprivation. One component, BACCOFF, is a non-nicotinic chew. The second component, DIPSTOP, is a liquid containing the alkaloid lobeline, which to some extent mimics peripheral nicotinic effects. All participants (N = 22 males) were placed in four conditions: BACCOFF + DIPSTOP, BACCOFF + placebo control, DIPSTOP, and placebo control only. The conditions involved 48 h of deprivation, and subjects were exposed to one condition per week for 4 weeks. Withdrawal measures were taken at baseline, 24 h, and 48 h of deprivation. Individuals were randomly assigned, and conditions were counterbalanced. Results showed that BACCOFF, as compared with DIPSTOP, significantly reduced withdrawal symptoms but not craving. These data suggest that behavioral/sensory substitutes' influence on withdrawal might be routed through the product's ability to approximate the preferred moist snuff.

Smokeless tobacco extract decreases IL-12 production from LPS-stimulated but increases IL-12 from IFN-gamma-stimulated macrophages.

Modulation of IFN-gamma production from T cells by smokeless tobacco extract (STE) could be a factor in periodontal disease. The major inducer of IFN-gamma from T cells is bioactive IL-12 (p70), a heterodimeric protein composed of p35 and p40 subunits, while homodimeric IL-12 p40 antagonizes bioactive IL-12. Both p70 and p40 are produced by macrophages in response to lipopolysaccharide (LPS), IFN-gamma and/or CD40 ligation. To determine the impact of STE on IL-12 p40, p70 and IFN-gamma, splenic T cells were stimulated with anti-CD3 while splenic macrophages were stimulated with LPS in the presence or absence of STE. Production of IL-12 p40 and p70 from LPS-stimulated splenic macrophages and IL-12 p40, p70 and IFN-gamma from LPS/anti-CD3-stimulated T cells and macrophages was decreased by STE. To determine the impact of STE on macrophage IL-12 production alone, splenic or peritoneal macrophages were enriched and then stimulated. STE significantly diminished production of IL-12 p40 and p70 from LPS-stimulated peritoneal macrophages, LPS/IFN-gamma-stimulated peritoneal and splenic macrophages, but increased production of IL-12 p40 and p70 from IFN-gamma/CD40-stimulated splenic macrophages or IFN-gamma-stimulated peritoneal macrophages. None of the effects of STE on IL-12 was due to nicotine, rutin or chlorogenic acid. In contrast to STE, nicotine at 100 microg/ml significantly elevated production of IL-12 p40 and p70 from splenic macrophages stimulate by IFN-gamma/LPS. The results indicate that STE has a significant overall effect upon IL-12 production. It suppresses p40 and p70 production during responses to LPS or LPS/IFN-gamma but augments p40 and p70 production during responses to IFN-gamma without LPS. This affect could have a major impact on diseases associated with excessive production of IL-12.