State of the Science in the treatment of nicotine dependence Terry A. Rustin, M.D.

Transcription

1 State of the Science in the treatment of nicotine dependence 2006 Terry A. Rustin, M.D.

2 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

3 Public health issues Smoking and PTSD Cost-effectiveness of cessation treatments 3

4 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:

5 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:

6 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:

7 Smoking among NYC rescue workers after 9/11 Bars et al (2006) Tobacco free with FDNY. Chest 129:

8 Smoking among NYC rescue workers after 9/11 Bars et al (2006) Tobacco free with FDNY. Chest 129:

9 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:

10 Cost (US$) per year of life saved counseling by doctor Men Women Spain Switzerland Canada France USA UK Cornuz et al (2006). Tobacco Control 2006;15:

11 Cost (US$) per year of life saved counseling by doctor Men Women Spain Switzerland Canada France USA UK Cornuz et al (2006). Tobacco Control 2006;15:

12 Cost (US$) per year of life saved nicotine gum Men Women Spain Switzerland Canada France USA UK Cornuz et al (2006). Tobacco Control 2006;15:

13 Cost (US$) per year of life saved nicotine patch Men Women Spain Switzerland Canada France USA UK Cornuz et al (2006). Tobacco Control 2006;15:

14 Cost (US$) per year of life saved bupropion Men Women Spain Switzerland Canada France USA UK Cornuz et al (2006). Tobacco Control 2006;15:

15 Cost (US$) per year of life saved in USA Men Women Counseling only Nicotine gum Nicotine patch Bupropion Nicotine nasal spray Nicotine inhaler Cornuz et al (2006). Tobacco Control 2006;15:

16 Effects of nicotine Epibatidine a potent nicotine ligand Cardiovascular effects of nicotine 16

17 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: Daly (2005) Nicotinic Agonists, Antagonists, and Modulators From Natural Sources. Cellular and Molecular Neurobiology 17 25:513-52

18 Epibatidine Poison dart frogs Daly et al (2006). J. Nat. Prod. 68: Daly (2005) Cellular and Molecular Neurobiology 25:

19 19

20 Daly (2005) Cellular and Molecular Neurobiology 25:

21 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:

22 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:

23 Smoking cessation Bupropion Transdermal nicotine Correlation between smoking and acne, depression, alcohol 23

24 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:

25 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:

26 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

27 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:

28 Nicotine transdermal systems Rapid metabolizers = lower nicotine levels Rapid metabolizers = lower quit rates Lerman (2006). Clin Pharmacol Ther 79:

29 Lerman (2006). Clin Pharmacol Ther 79:

30 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

31 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

32 New chemotherapeutic agents Varenicline Immunological agents 32

33 Varenicline 33

34 Varenicline Nicotine 34

35 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

36 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

37 Orbach et al (2006) Drug Metabolism and Distribution 37

38 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:

39 Nicotine receptor 39 Powledge TM (2004) Nicotine as therapy.plos Biol 2(11): e404.

40 Nicotine receptor (electron micrograph) 40

41 Foulds (2006) J Clin Pract 60:

42 Foulds (2006) J Clin Pract 60:

43 N N = Nicotine 43

44 N 44

45 N Na+ 45

46 N V V = Varenicline N = Nicotine 46

47 N V V = Varenicline N = Nicotine 47

48 N V 48

49 N V 49

50 N V 50

51 N V 51

52 N V 52

53 N V 53

54 N V Na+ 54

55 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

56 Varenicline Abstinence at 12 weeks of treatment Varenicline 44 % Bupropion 30 % Placebo 17.7 % Pfizer: data on file 56

57 Varenicline Abstinence at 12 months of treatment Varenicline 22.1% Bupropion 16.4% Placebo 8.4% Pfizer: data on file 57

58 Immunological agents Nicotine monoclonal antibodies Nicotine vaccine Kosten & Owens (2005) Immunotherapy for the treatment of 58 drug abuse. Pharmacology & Therapeutics 108: 76 85

59 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

60 Nicotine vaccine Active immunization the body produces the antibodies Highly specific for nicotine 60

61 images.clinicaltools.com/images/gene/igg.jpg 61

62 IgG Structure people.cryst.bbk.ac.uk 62

63 Tobacco smoke contains nicotine 63

64 Smokeless tobacco contains nicotine 64

65 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

66 Circulation Nicotine, contained in smokeless tobacco, crosses the oral mucosa and enters the circulation, along with numerous toxins Mouth and oral mucosa 66

67 Nicotine is carried by arterial blood into the brain, where it diffuses into brain cells 67

68 Nicotine antibodies are administered passively as monoclonal antibodies, or are produced by the individual following vaccination 68

69 Nicotine antibodies bind nicotine in the circulation 69

70 Antibody-bound nicotine remains in the circulation; only a small amount of nicotine enters brain cells 70

71 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

72 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

73 Nicotine vaccine Bind the antibody to a carrier protein Colera toxin is highly antigenic and easily binds other chemicals 73

74 Recombinent cholera toxin 74

75 Recombinent cholera toxin with nicotine molecules bound to it 75

76 76

77 Anti-PCP IgG reduces brain PCP concentrations after a single dosing PCP (ng/g) IgG monoclonal antibodies injected Time after IgG (days) Proksh (2000) J Pharmacol Exp Ther 292,

78 Human nicotine vaccines Cytos product (CYT002-NicQb) Xenova product (TA-NIC) 78

79 Effects of antibody titer on brain nicotine concentrations 1.5 Antibody titer 1.0 Hieda Brain nicotine (ng/g) 79

80 Nicotine vaccine Nicotine (ug/g) ** Control Vaccine ** Serum Brain Pentel

81 Anti-nicotine antibodies prevent nicotine from relieving withdrawal Abstinence signs (% of pre-treatment) Malin 2001 Control IgG +Saline * * Control IgG +Nicotine Nicotine IgG +Nicotine 81

82 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

83 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 83

84 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 84

85 Nicotine antibodies produced by nicotine vaccine 85

86 86

87 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 87

88 Cytos Phase II study Point prevalence and continuous abstinence from smoking determined Self-report and biochemical validation Antibody levels measured 88

89 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 89

90 90

91 Xenova TA-NIC study Anti-Nic Ab (units/ml) Booster Weeks 50µg 250µg 1000µg Placebo 91

92 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) 92

93 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

94 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

95 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

96 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:

97 Olinsky (2006) Arch Gen Psychiatry 63:

98 Olinsky (2006) Arch Gen Psychiatry 63:

99 If you would like a copy of these slides, me at gmail.com and I will send you a copy