State of the Science in the treatment of nicotine dependence 2006 Terry A. Rustin, M.D.
State of the Science Public health issues Effects of nicotine Smoking cessation New chemotherapeutic agents Nicotine as a therapeutic agent Smoking cessation in target populations 2
Public health issues Smoking and PTSD Cost-effectiveness of cessation treatments 3
Smoking among NYC rescue workers after 9/11 15 percent of active rescue workers = current smokers Smoking increased in 29 percent 23 percent of former smokers resumed smoking 11,777 screened; 1,767 smokers; 164 enrolled in the cessation program Bars et al (2006) Tobacco free with FDNY. Chest 129:979-987 4
Smoking among NYC rescue workers after 9/11 Smoking cessation program: inhaler, patch, bupropion, counseling Seven day point prevalence of abstinence at 3, 6 and 12 months Continuous abstinence at 3, 6 and 12 months Bars et al (2006) Tobacco free with FDNY. Chest 129:979-987 5
Smoking among NYC rescue workers after 9/11 Seven day point prevalence 3 months = 53 percent 6 months = 45 percent 12 months = 36 percent Continuous abstinence 3 months = 47 percent 6 months = 36 percent 12 months = 33 percent Bars et al (2006) Tobacco free with FDNY. Chest 129:979-987 6
Smoking among NYC rescue workers after 9/11 Bars et al (2006) Tobacco free with FDNY. Chest 129:979-987 7
Smoking among NYC rescue workers after 9/11 Bars et al (2006) Tobacco free with FDNY. Chest 129:979-987 8
Cessation therapies Comparison of counseling and several pharmacotherapies for effectiveness Measure according to years of life saved Varies according to country Cornuz et al (2006) Cost-effectiveness of pharmacotherapies for nicotine dependence in primary care settings: a multinational 9 comparison. Tobacco Control 2006;15:152 159
Cost (US$) per year of life saved counseling by doctor Men Women Spain 190 288 Switzerland 375 567 Canada 389 588 France 479 724 USA 623 941 UK 773 1168 Cornuz et al (2006). Tobacco Control 2006;15:152 159 10
Cost (US$) per year of life saved counseling by doctor Men Women Spain 190 288 Switzerland 375 567 Canada 389 588 France 479 724 USA 623 941 UK 773 1168 Cornuz et al (2006). Tobacco Control 2006;15:152 159 11
Cost (US$) per year of life saved nicotine gum Men Women Spain 2230 3370 Switzerland 3612 5457 Canada 2820 4260 France 3228 4876 USA 5059 7643 UK 3766 5689 Cornuz et al (2006). Tobacco Control 2006;15:152 159 12
Cost (US$) per year of life saved nicotine patch Men Women Spain 1758 2657 Switzerland 2904 4387 Canada 2527 3817 France 2518 3804 USA 3099 4682 UK 3396 5131 Cornuz et al (2006). Tobacco Control 2006;15:152 159 13
Cost (US$) per year of life saved bupropion Men Women Spain 878 1326 Switzerland 1492 2254 Canada 792 1196 France 1268 1915 USA 1934 2922 UK 1433 2165 Cornuz et al (2006). Tobacco Control 2006;15:152 159 14
Cost (US$) per year of life saved in USA Men Women Counseling only 623 941 Nicotine gum 5059 7643 Nicotine patch 3099 4282 Bupropion 1934 2922 Nicotine nasal spray 5275 7969 Nicotine inhaler 5086 7685 Cornuz et al (2006). Tobacco Control 2006;15:152 159 15
Effects of nicotine Epibatidine a potent nicotine ligand Cardiovascular effects of nicotine 16
Epibatidine Potent ligand at the acetylcholine-n receptor Mimics nicotine effects, but much stronger Naturally occurring chemical Daly et al (2006). Alkaloids from Amphibian Skin: A Tabulation of Over Eight-Hundred Compounds. J. Nat. Prod. 68:1556-1575 Daly (2005) Nicotinic Agonists, Antagonists, and Modulators From Natural Sources. Cellular and Molecular Neurobiology 17 25:513-52
Epibatidine Poison dart frogs Daly et al (2006). J. Nat. Prod. 68:1556-1575 Daly (2005) Cellular and Molecular Neurobiology 25:513-52 18
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Daly (2005) Cellular and Molecular Neurobiology 25:513-52 20
Cardiovascular effects of nicotine Increases formation of free radicals damages blood vessels, leading to arteriosclerosis Impairs ability of large arteries to relax, keeping them in a state of increased tension mediated through nitric oxide Increased contraction of smooth muscle in aorta Hanna (2006) Nicotine Effect on Cardiovascular System and Ion 21 Channels. J Cardiovasc Pharmacol 2006;47:348 358
Cardiovascular effects of nicotine Decreases blood flow in arteries to the penis, causing impairment in erectile function Damages blood vessels in the brain, leading to stroke Nicotine prolongs action potentials and depolarizes membrane potentials in the heart, leading to arrhythmias Hanna (2006) J Cardiovasc Pharmacol 2006;47:348 358 22
Smoking cessation Bupropion Transdermal nicotine Correlation between smoking and acne, depression, alcohol 23
Bupropion for cessation Trial of extending treatment with bupropion Combined counseling, bupropion, nicotine replacement, group support for 11 weeks 14 weeks further treatment with either bupropion or placebo Killen (2006) Extended Treatment With Bupropion SR for Cigarette Smoking Cessation. Journal of Consulting and Clinical Psychology 24 74:286 294
Bupropion for cessation End of first 11 weeks 52 percent abstinent End of one year Bupropion extended treatment: 33 percent Men 39 percent Women 27 percent Placebo extended treatment: 34 percent Killen (2006) J Consulting and Clinical Psychology 74:286 294 25
Nicotine transdermal systems Nicotine metabolized by CYP 2A6 Standard treatment with nicotine patch produces varying blood levels of nicotine Differences due primarily to rate of nicotine metabolism Lerman (2006) Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation. Clin Pharmacol Ther 26 79:600-8
Nicotine transdermal systems Smoking cessation program, including counseling and nicotine replacement (patch or spray) 8 weeks active treatment 6 month followup Lerman (2006) Clin Pharmacol Ther 79:600-8 27
Nicotine transdermal systems Rapid metabolizers = lower nicotine levels Rapid metabolizers = lower quit rates Lerman (2006). Clin Pharmacol Ther 79:600-8 28
Lerman (2006). Clin Pharmacol Ther 79:600-8 29
Smoking and severe acne 27,083 military men examined for acne at discharge 43 percent smokers 237 had severe acne (0.88 percent) Klaz (2006) Severe Acne Vulgaris and Tobacco Smoking in Young Men. Journal of Investigative Dermatology advance online 30 publication, 27 April 2006
Smoking and severe acne 237 had severe acne (0.88 percent) Among smokers: 0.71 percent Among nonsmokers: 1.01 percent Klaz (2006) Journal of Investigative Dermatology advance online 31 publication, 27 April 2006
New chemotherapeutic agents Varenicline Immunological agents 32
Varenicline 33
Varenicline Nicotine 34
Varenicline Approved May 11, 2006 by FDA (Pfizer) Partial agonist at the nicotine receptor High affinity for the α4β2 subtype Trade name: Chantix Derived from natural chemical cytisine, found in the plant false tobacco 35
Varenicline Excretion is primarily in unchanged form (81 percent) Remainder glucuronidated Minimal metabolism T ½ excretion = 17 ± 3 hours Orbach et al (2006) Metabolism and disposition of varenicline, a selective alph4-beta2 acetylcholine receptor partial agonist, in vivo and in vitro.. Drug Metabolism and Distribution 36 http://dmd.aspetjournals.org/cgi/content/abstract/34/1/121
Orbach et al (2006) Drug Metabolism and Distribution http://dmd.aspetjournals.org/cgi/content/abstract/34/1/121 37
Varenicline Partial agonist at AchN site Very high affinity for the α4β2 receptor Foulds (2006) The neurobiological basis for partial agonist treatment of nicotine dependence: varenicline. J Clin Pract 60: 38 571 576
Nicotine receptor 39 Powledge TM (2004) Nicotine as therapy.plos Biol 2(11): e404.
Nicotine receptor (electron micrograph) http://www.sdsc.edu/ 40
Foulds (2006) J Clin Pract 60: 571 576 41
Foulds (2006) J Clin Pract 60: 571 576 42
N N = Nicotine 43
N 44
N Na+ 45
N V V = Varenicline N = Nicotine 46
N V V = Varenicline N = Nicotine 47
N V 48
N V 49
N V 50
N V 51
N V 52
N V 53
N V Na+ 54
Varenicline Partial agonist at the N-acetylcholine site targets the α4β2 receptor Reduced craving and withdrawal symptoms The most common adverse effects included nausea, headache, trouble sleeping, and abnormal dreams Pfizer: data on file 55
Varenicline Abstinence at 12 weeks of treatment Varenicline 44 % Bupropion 30 % Placebo 17.7 % Pfizer: data on file 56
Varenicline Abstinence at 12 months of treatment Varenicline 22.1% Bupropion 16.4% Placebo 8.4% Pfizer: data on file 57
Immunological agents Nicotine monoclonal antibodies Nicotine vaccine Kosten & Owens (2005) Immunotherapy for the treatment of 58 drug abuse. Pharmacology & Therapeutics 108: 76 85
Anti-nicotine monoclonal antibodies Bind to nicotine in the circulation Prevent nicotine from crossing the blood-brain barrier Subject get the peripheral response to nicotine without the central response Passive once the antibodies are bound, there are no more 59
Nicotine vaccine Active immunization the body produces the antibodies Highly specific for nicotine 60
images.clinicaltools.com/images/gene/igg.jpg 61
IgG Structure people.cryst.bbk.ac.uk 62
Tobacco smoke contains nicotine 63
Smokeless tobacco contains nicotine 64
Circulation (pulmonary vein) Tobacco smoke, inhaled by the smoker, enters the alveoli of the lungs; nicotine (and numerous toxins) diffuse into the circulation Lungs 65
Circulation Nicotine, contained in smokeless tobacco, crosses the oral mucosa and enters the circulation, along with numerous toxins Mouth and oral mucosa 66
Nicotine is carried by arterial blood into the brain, where it diffuses into brain cells 67
Nicotine antibodies are administered passively as monoclonal antibodies, or are produced by the individual following vaccination 68
Nicotine antibodies bind nicotine in the circulation 69
Antibody-bound nicotine remains in the circulation; only a small amount of nicotine enters brain cells 70
Nicotine antibodies Target the drug, not the receptor Some peripheral nicotine effects Vasoconstriction Tachycardia Minimal central effects Alertness Decreased hunger Relief of withdrawal symptoms 71
Nicotine vaccine Nicotine normally activates the acetylcholine-n receptor Nicotine is not antigenic How can a vaccine be prepared against something that is not antigenic? 72
Nicotine vaccine Bind the antibody to a carrier protein Colera toxin is highly antigenic and easily binds other chemicals 73
Recombinent cholera toxin www.rctb.net 74
Recombinent cholera toxin with nicotine molecules bound to it www.rctb.net 75
http://www.xenova.co.uk 76
Anti-PCP IgG reduces brain PCP concentrations after a single dosing PCP (ng/g) 1000 500 IgG monoclonal antibodies injected 0 0 1 7 14 21 28 Time after IgG (days) Proksh (2000) J Pharmacol Exp Ther 292, 831 837 77
Human nicotine vaccines Cytos product (CYT002-NicQb) Xenova product (TA-NIC) 78
Effects of antibody titer on brain nicotine concentrations 1.5 Antibody titer 1.0 Hieda 1999 50 100 150 Brain nicotine (ng/g) 79
Nicotine vaccine Nicotine (ug/g) 250 200 150 100 50 0 ** Control Vaccine ** Serum Brain Pentel 2000 80
Anti-nicotine antibodies prevent nicotine from relieving withdrawal Abstinence signs (% of pre-treatment) 80 60 40 20 0 Malin 2001 Control IgG +Saline * * Control IgG +Nicotine Nicotine IgG +Nicotine 81
Nicotine withdrawal relief IgG anti-nicotine antibodies bind nicotine in the circulation Nicotine does not cross the blood-brain barrier Nicotine withdrawal symptoms are not relieved by nicotine 82
Cytos Phase I study 40 healthy, non-smoking volunteers, ten in each of four groups Different doses and formulations of CYT002-NicQb were compared In each group, 8 received two intramuscular injections of CYT002- NicQb at an interval of 4 weeks and 2 received placebo www.smokersvaccine.com 83
Cytos Phase I study CYT002-NicQb was safe and well tolerated All the participants who received CYT002- NicQb produced high levels of nicotinespecific antibodies Participants who received placebo showed no nicotine-specific antibody response Peak IgG antibody titers were observed at day 42 in most participants and declined over time www.smokersvaccine.com 84
Nicotine antibodies produced by nicotine vaccine www.smokersvaccine.com 85
www.smokersvaccine.com 86
Cytos Phase II study 341 Swiss smokers desiring to quit smoking 159 given active vaccine, 80 given placebo All participants received individualized tobacco cessation counseling 5 intramuscular injections of the vaccine or placebo at monthly intervals www.smokersvaccine.com 87
Cytos Phase II study Point prevalence and continuous abstinence from smoking determined Self-report and biochemical validation Antibody levels measured www.smokersvaccine.com 88
Cytos Phase II study Antibody levels measured in vaccinetreated participants Vaccine-treated participants categorized as high, medium, or low antibody producers Point prevalence and continuous abstinence from smoking determined Self-report and biochemical validation www.smokersvaccine.com 89
www.smokersvaccine.com 90
Xenova TA-NIC study Anti-Nic Ab (units/ml) 1800 1600 1400 1200 1000 800 600 400 200 0 Booster 0 10 20 30 40 50 Weeks 50µg 250µg 1000µg Placebo 91
Xenova Phase II study Point-prevalence of abstinence at 12 months Placebo = 8 percent (1/12) 250 mcg vaccine = 19 percent (3/16) 1000 mcg vaccine = 38 percent (6/16) http://www.xenova.co.uk 92
Antigen therapy for tobacco dependence Potential for long-term treatment Does not target the receptor Does not require daily doses of medication Effective against relapse 93
Antigen therapy for tobacco dependence Expensive Difficult to produce in quantity Could cause allergic reactions Does not change cognitions the individual may switch drugs 94
Nicotine as a therapeutic agent Use of nicotine ligand for treatment of schizophrenia Nicotine protects against lesions in the striatum in rats (possible protective effect from Parkinson s disease) A nicotine ligand suppresses amphetamine-seeking behavior in rats 95
Nicotine in schizophrenia 12 patients with schizophrenia evaluated Tested with the Repeatable Battery for the Assessment of Neuropsychological Status Improved with administration of a nicotine ligand Olinsky (2006) Proof-of-Concept Trial of an alpha-7 Nicotinic Agonist in Schizophrenia. Arch Gen Psychiatry 63:630-638 96
Olinsky (2006) Arch Gen Psychiatry 63:630-638 97
Olinsky (2006) Arch Gen Psychiatry 63:630-638 98
If you would like a copy of these slides, email me at terry.rustin @ gmail.com and I will send you a copy