altria clinical effects · mechanistic evidence from a pm usa-funded study ... (on behalf of philip...

1 l Altria Client Services (on behalf of Philip Morris USA) l Presentation to the Tobacco Products Scientific Advisory Committee l July 15-16, 2010

Clinical Effects

Jane Y. Lewis, Ph.D.Senior Vice President, Health & Analytical Sciences

Altria Client Services


Clinical Effects

Analytical and Health Sciences Capabilities

Mechanistic Studies on Sensory Effects of Menthol

Health Effects

Dependence and Cessation

Summary


Analytical and Health Sciences Capabilities

Expertise and experience

Evaluation of ingredients– More than 600 studies performed– Many peer-reviewed publications in press or in preparation

Peer-reviewed publications

Presentations and posters

Analysis of published literature


Clinical Effects

Analytical and Health Sciences CapabilitiesAnalytical and Health Sciences CapabilitiesAnalytical and Health Sciences Capabilities


Health EffectsHealth EffectsHealth Effects

Dependence and CessationDependence and CessationDependence and Cessation

SummarySummarySummary



Hundreds of studies have focused on menthol per se

In airways, studies have focused on:– Local anesthetic effects– Cooling sensation– Desensitization to irritation or pain


Mechanistic Studies on the Local Anesthetic Effects of Menthol per se

The salient features of local anesthetics* are:

– blocks Na+ ion movement through Na+ ion channels in nerves

– thereby blocking the action potentials responsible for nerve conduction

Mechanistic evidence from a PM USA-funded study (Hans, publication planned)

– menthol does not block current-induced neuronal action potentials– menthol does not block neuronal sodium channels

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Control recovery 50 µM Menthol

Primary cultures of rat trigeminal neurons

* (Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Catterall & Mackie 2006)


Mechanistic Studies

TRPM8 TRPA1

Menthol per se causes a cooling sensation

Menthol per se causesan irritation / pain sensation

(McKemy, et al. 2002; Peier, et al. 2002; Gerhold and Bautista 2009) (Cliff and Green 1994; Karashima, et al. 2007)


Evidence from cell culture studies– Menthol desensitization of nicotine at the TRPA1 channel

(Karashima, et al. 2007; Talavera, et al. 2009)

– Other compounds can irreversibly bind the TRPA1 channel(Karashima, et al. 2007; Talavera, et al. 2009; Andre, et al. 2008)

Evidence from clinical studies– Menthol pretreatment of the tongue

(Dessirier, et al. 2001)

– Menthol vapor in the nose(Renner, et al. 2008 PM USA-funded study, publication planned)

Mechanistic Studies on the Desensitization Effect of Menthol per se


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Low level of NicotineMeasuring: Burning Pain

Menthol:Cooling level

NicotineMenthol

Mechanistic Studies on the Desensitization Effect of Menthol per se

Study InformationPM USA-funded

study, Renner et al., publication is planned

Stimuli administered as a vapor with an olfactometer

Data represents the average of results from 20 adult smokers

VAS (mean ± SEM)

Menthol 44.8 ± 7.8

Placebo 48.6 ± 7.0

VAS (mean ± SEM)

Menthol 26.0 ± 8.2

Placebo 28.7 ± 8.1

[EU] is Estimation Units

Menthol per se does not desensitize the nose to pain caused by nicotine, even in the presence of a cooling sensation


Summary: Mechanistic Studies on Sensory Effects of Menthol

Study Type Menthol per se Menthol in Smoke

Local anesthetic effect No effect No studies

Desensitization in cell culture

Mixed results No studies

Airway desensitization in clinical studies

Mixed results No studies


Clinical Effects


Mechanistic Studies on Sensory Effects of MentholMechanistic Studies on Sensory Effects of MentholMechanistic Studies on Sensory Effects of Menthol

Health Effects




Health Effects, Dependence and Cessation

Important variables to consider

The proportion of smokers who smoke menthol cigarettes varies by:– race– gender– age groups– socioeconomic status

(Tobacco Use Supplement to the Current Population Survey)

Studies of health effects, dependence and cessation comparing menthol and non-menthol smokers should consider these

potential confounding variables


Epidemiological Studies Comparing Health Effects of Menthol vs. Non-Menthol Cigarettes

Study authors, date, page no. Health outcome investigated Study design Number of subjects Menthol associated with increased risk

Hebert & Kabat, 1988, p.986 Esophageal cancer Case-control Cases = 312; Controls = 462 NO

Hebert & Kabat, 1989, p. 41 Esophageal cancer Case-control Cases = 311; Controls = 462 NO

Kabet & Hebert, 1991, p. 6511 Lung cancer Case-control Cases = 1044; Controls = 1324 NO

Kabet & Hebert, 1994, p. 183 Oropharyngeal cancer Case-control Cases = 276; Controls = 1265 NO

Sidney, et al., 1995, p. 727 Lung cancer Cohort Menthol: 3654 Non-menthol: 8107

YES in men only. (RR=1.45; 95% CI

1.03-2.02)

Friedman, et al., 1998, p. 202Upper aerodigestive, pancreas, renal,

urinary tract, uterine cervix, and all smoking related cancers

Cohort Menthol: 3654 Non-menthol: 8107 NO

Carpenter, et al., 1999, p. 114 Lung cancer Case-control Cases = 337; Controls = 478 NO

Brooks, et al., 2003, p. 609 Lung cancer Case-control Cases = 643; Controls = 4110 NO

Stellman, et al., 2003, p. 294 Lung cancer Case-control Cases = 3448; Controls = 8151 NO

Jockel, et al., 2004, p. 33 Lung cancer Case-control Cases = 1004; Controls = 1004 NO

Pletcher, et al., 2006, p. 1919 Coronary calcification, pulmonary function decline

Longitudinal, prospective Menthol: 972 Non-menthol: 563 NO

Murray et al., 2007, p. 101Mortality from coronary heart disease,

cardiovascular disease, lung cancer, and all causes

Prospective Menthol: 1216 Non-menthol: 4665 NO

Etzel, et al., 2008, p. 261 Lung cancer Case-control Cases = 491; Controls = 497 NO


Health Effects*

Menthol cigarettes do not result in increased toxicity in non-clinical toxicity testing compared with non-menthol cigarettes

Smoking menthol cigarettes produces no consistent effect on human puffing and inhalation behavior

Findings from the PM USA Total Exposure Study (TES) show no difference in biomarkers of exposure (BOE) and biomarkers of potential harm (BOPHs) between menthol and non-menthol cigarette smokers

Findings from the TES suggest no effect of smoking menthol cigarettes on the metabolism of nicotine or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

Epidemiological evidence suggests no effect of menthol on smoking-related disease risks* Refer to ALCS submissions to the TPSAC dated March 22, 2010 and June 30, 2010


Health Effects

Overall, our analysis of the published scientific literature and internal studies concludes that menthol added to cigarettes

does not increase the inherent health risks of smoking


Clinical Effects




Dependence and Cessation



Dependence

Other measures showed no difference in dependence by menthol status:

– DSM-IV criteria for Dependence– Fagerström Tolerance Questionnaire– Nicotine Dependence Syndrome Scale – Minnesota Withdrawal Scale scores

(Kandel & Chen 2000; Mustonen, et al. 2005; Okuyemi, et al. 2007)

Fagerström Test for Nicotine Dependence (FTND)– Most widely reported measurement tool for nicotine dependence

(Heatherton, et al. 1991)

cigarettes per day (CPD)

time to first cigarette (Baker, et al. 2007; Fagerstrom 2003)

– No statistically significant effect of menthol status on the FTND in the TES (Muhammad-Kah, et al. 2010)

– Four other studies using the FTND also found no significant difference between menthol and non-menthol smokers) (Okuyemi, et al. 2004; Okuyemi, et al. 2003; Muscat, et al. 2009; Murray, et al. 2007)


Cessation Treatment

HHS published Clinical Practice Guidelines for Treating Tobacco Use and Dependence: 2008 Update– Comprehensive review of treatment effectiveness for smokers– No mention of menthol in relation to dependence, cessation or

relapse

The weight of evidence from nine published smoking cessation treatment studies show no difference between menthol and non-menthol smokers on cessation outcomes (Bover, et al. 2008, Cropsey,et al. 2009; Foulds, et al. 2006; Fu, et al. 2008; Gandhi, et al. 2009; Harris, et al. 2004; Okuyemi,et al. 2003; Okuyemi, et al. 2004; Okuyemi, et al. 2007)


CessationSix published peer-reviewed studies from national surveys and health risk studies have generally found no difference in cessation outcomes between menthol and non-menthol smokers – higher odds of relapse, but no difference in odds of not currently smoking,

recent quit attempt, cessation if recent quit attempt or sustained smoking cessation (n=1,535) (Pletcher, et al. 2006)

– no significant difference in becoming a sustained quitter, intermittent quitter, or continuing smoker over five years of follow-up (n=5,887)(Murray, et al. 2007)

– no difference in odds of having one or more quit attempts in the last 12 months and no difference in serious intention to quit in the next six months (n=7,912) (Fagan, et al. 2007)

– higher (Whites), lower (Hispanics) and no difference (African-Americans and overall) in odds of cessation (n=7,815) (Gundersen, et al. 2009)

– no difference in relative risk of quitting over five years (n=13,268) (Hyland, et al. 2002)

– no difference in odds of quitting by menthol status among Whites or African-Americans (n=19,545) (Muscat, et al. 2002)


Clinical Effects





Summary


Clinical Effects – Summary

Based on an evaluation of published and unpublished information about menthol we conclude:– Menthol per se has airway sensory effects (cooling and irritation or

pain)

– Menthol per se in desensitization studies showed mixed results– Menthol added to cigarettes does not increase health risks of

smoking as shown in:Non-clinicial studies

Clinical studies

Epidemiology studies

– Menthol does not increase cigarette dependence

– Menthol does not affect smoking cessation


Andre, E., Campi, B., Materazzi, S., Trevisani, M., Amadesi, S., Massi, D., Creminon, C., Vaksman, N., Nassini, R., Civelli, M., Baraldi, P.G., Poole, D.P., Bunnett, N.W., Geppetti, P., & Patacchini, R. (2008). Cigarette smoke-induced neurogenic inflammation is mediated by alpha, beta-unsaturated aldehydes and the TRPA1 receptor in rodents. Journal of Clinical Investigation 118(7):2574-2582.

Baker, R.R., Piper, M., McCarthy, D., Bolt, D., Smith, S., Kim, S.Y., Colby, S., Conti, D., Giovino, G., Hatsukami, D., Hyland, A., Krishnan-Sarin, S., Niaura, R., Perkins, K., & Toll, B. (2007). Time to first cigarette in the morning as an index of ability to quit smoking: Implications for nicotine dependence. Nicotine and Tobacco Research 9(SUPPL. 4):S555-S570.

Catterall, W.A. & Mackie, K. (2006). Local anesthetics. In: Brunton, L.L., Lazo, J.S., & Parker, K.L., editors. Goodman and Gilman's The Pharmacological Basis of Therapeutics.11th ed. pp. 369-386. New York: McGraw Hill.

Cliff, M.A. & Green, B.G. (1994). Sensory irritation and coolness produced by menthol: Evidence for selective desensitization of irritation. Physiology and Behavior 56(5):1021-1029.

Dessirier, J.M., Mahony, M., & Carstens, E. (2001). Oral irritant properties of menthol: Sensitizing and desensitizing effects of repeated application and cross-desensitization to nicotine. Physiology and Behavior 73(1-2):25-36.

Fagan, P., Augustson, E., Backinger, C.L., O'Connell, M.E., Vollinger, J., Kaufman, A., & Gibson, J.T. (2007). Quit attempts and intention to quit cigarette smoking among young adults in the United States. American Journal of Public Health 97(8):1412-1420.

Fagerstrom, K.O. (2003). Time to first cigarette: the best single indicator of tobacco dependence? Monaldi Archives for Chest Disease - Pulmonary Series 59(1):91-94.

Gerhold, K.A. & Bautista, D.M. (2009). Molecular and cellular mechanisms of trigeminal chemosensation. 1170 ed.:184-189.

Gundersen, D.A., Delnevo, C.D., & Wackowski, O. (2009). Exploring the relationship between race/ethnicity, menthol smoking, and cessation, in a nationally representative sample of adults. Preventive Medicine 49(6):553-557.

Hans, M. (2006). Project Report: The Effects of Stimulation with Tobacco Related Compounds (TRCs) on Nicotinic Acetylcholine Receptors in a Model of Sensory Irritation. Project Report: July 2005 - March 2006. Richmond: Philip Morris USA.

Heatherton, T.F., Kozlowski, L.T., Frecker, R.C., & Fagerstrom, K.O. (1991). The Fagerstrom test for nicotine dependence: a revision of the Fagerstrom Tolerance Questionnaire. British Journal of Addiction 86(9):1119-1127.

Hyland, A., Garten, S., Giovino, G.A., & Cummings, K.M. (2002). Mentholated cigarettes and smoking cessation: findings from COMMIT. Tobacco Control 11(2):135-139.

Karashima, Y., Damann, N., Prenen, J., Talavera, K., Segal, A., Voets, T., & Nilius, B. (2007). Bimodal action of menthol on the transient receptor potential channel TRPA1. Journal of Neuroscience 27(37):9874-9884.

Kandel, D.B. & Chen, K. (2000). Extent of smoking and nicotine dependence in the United States: 1991-1993. Nicotine and Tobacco Research 2(3):263-274.

Luo, Z., Alvarado, G.F., Hatsukami, D.K., Johnson, E.O., Bierut, L.J., & Breslau, N. (2008). Race differences in nicotine dependence in the Collaborative Genetic study of Nicotine Dependence (COGEND). Nicotine and Tobacco Research 10(7):1223-1230.

McKemy, D.D., Neuhausser, W.M., & Julius, D. (2002). Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416(6876):52-58.

Muhammad-Kah, R., Liang, Q., Rimmer, L., & Frost-Pineda, K. (2010). The effect of mentholated cigarettes on measures of nicotine dependence [abstract]. Society for Research on Nicotine and Tobacco (SRNT), 16th AnnualMeeting, February 27, 2010, Baltimore, MD .

Murray, R.P., Connett, J.E., Skeans, M.A., & Tashkin, D.P. (2007). Menthol cigarettes and health risks in Lung Health Study data. Nicotine and Tobacco Research 9(1):101-107.

Muscat, J.E., Chen, G., Knipe, A., Stellman, S.D., Lazarus, P., & Richie, J. (2009). Effects of menthol on tobacco smoke exposure, nicotine dependence, and NNAL glucuronidation. Cancer Epidemiology Biomarkers and Prevention 18(1):35-41.

Mustonen, T.K., Spencer, S.M., Hoskinson, J., Sachs, D.P.L., & Garvey, A.J. (2005). The influence of gender, race, and menthol content on tobacco exposure measures. Nicotine and Tobacco Research 7(4):581-590.

Muscat, J.E., Richie, J., & Stellman, S.D. (2002). Mentholated cigarettes and smoking habits in whites and blacks. Tobacco Control 11(4):368-371.

Okuyemi, K.S., Ahluwalia, J.S., Ebersole-Robinson, M., Catley, D., Mayo, M.S., & Resnicow, K. (2003). Does menthol attenuate the effect of bupropion among African American smokers? Addiction 98(10):1387-1393.

Okuyemi, K.S., Ebersole-Robinson, M., Nazir, N., & Ahluwalia, J.S. (2004). African-American menthol and nonmenthol smokers: differences in smoking and cessation experiences. Journal of the National Medical Association96(9):1208-1211.

Okuyemi, K.S., Faseru, B., Sanderson Cox, L., Bronars, C.A., & Ahluwalia, J.S. (2007). Relationship between menthol cigarettes and smoking cessation among African American light smokers. Addiction 102(12):1979-1986.

Peier, A.M., Moqrich, A., Hergarden, A.C., Reeve, A.J., Andersson, D.A., Story, G.M., Earley, T.J., Dragoni, I., McIntyre, P., Bevan, S., & Patapoutian, A. (2002). A TRP channel that senses cold stimuli and menthol. Cell108(5):705-715.

Pletcher, M.J., Hulley, B.J., Houston, T., Kiefe, C.I., Benowitz, N., & Sidney, S. (2006). Menthol cigarettes, smoking cessation, atherosclerosis, and pulmonary function: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Archives of Internal Medicine 166(17):1915-1922.

Renner, B., Besz, D., & Schreiber, K. (2008). Project Report (Final): Trigeminal Interaction of Menthol and Nicotine on Peripheral Chemosensory Responses Using NMP Recordings. Richmond: Philip Morris USA.

Talavera, K., Gees, M., Karashima, Y., Meseguer, V.M., Vanoirbeek, J.A.J., Damann, N., Everaerts, W., Benoit, M., Janssens, A., Vennekens, R., Viana, F., Nemery, B., Nilius, B., & Voets, T. (2009). Nicotine activates the chemosensory cation channel TRPA1. Nature Neuroscience 12(10):1293-1299.

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altria clinical effects · mechanistic evidence from a pm usa-funded study ... (on behalf of philip...

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