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In the name of GOD Decreasing smoking behavior and risk through CYP2A6 inhibition Shadi Sarahroodi (Pharm.D) Ahvaz Jondishapour University of medical.

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Presentation on theme: "In the name of GOD Decreasing smoking behavior and risk through CYP2A6 inhibition Shadi Sarahroodi (Pharm.D) Ahvaz Jondishapour University of medical."— Presentation transcript:

1

2 In the name of GOD

3 Decreasing smoking behavior and risk through CYP2A6 inhibition Shadi Sarahroodi (Pharm.D) Ahvaz Jondishapour University of medical sciences (AJUMS)

4 PrevalencePrevalence 1.2 billion people worldwide are known to smoke tobacco daily. 5.6 trillion cigarettes are smoked per year. 4.2 million people die annually from tobacco-related disease. Tobacco-related diseases will be about 10 million in billion people worldwide are known to smoke tobacco daily. 5.6 trillion cigarettes are smoked per year. 4.2 million people die annually from tobacco-related disease. Tobacco-related diseases will be about 10 million in 2020.

5 Smoking prevalence and reason for concern  Health consequences of smoking Respiratory disease Cardiovascular disease Cerebrovascular disease  Health consequences of smoking Respiratory disease Cardiovascular disease Cerebrovascular disease   Cancers Lung Oral cavity Pharynx Pancreas Kidney Urinary tract   Cancers Lung Oral cavity Pharynx Pancreas Kidney Urinary tract cancer  15% of all cancers  80-90%of lung cancers

6 GeneticsGenetics Initiation of smoking, 50% Maintenance, 70% Number of cigarettes smoked, 80% Initiation of smoking, 50% Maintenance, 70% Number of cigarettes smoked, 80%

7 Current treatment for tobacco dependence  NRT (nicotine replacement therapy) Nicotine gums Transdermal patches Inhalers Lozenges Sprays  NRT (nicotine replacement therapy) Nicotine gums Transdermal patches Inhalers Lozenges Sprays   Bupropion (non-nicotinic pharmacological agent) Antidepressant Used in more than 50 countries as treatment of tobacco dependency.   Bupropion (non-nicotinic pharmacological agent) Antidepressant Used in more than 50 countries as treatment of tobacco dependency.

8 Existing NRTs fail for several reasons Existing NRTs fail for several reasons Inadequate extent of replaced nicotine compared to the nicotine of cigarette. NRT dos not mimic the rapid rise and fall in plasma like cigarette nicotine. Wide variation in nicotine metabolism among individuals leads to variation of nicotine concentration when an standard dose is taken. Dermal or gastric irritation. … Inadequate extent of replaced nicotine compared to the nicotine of cigarette. NRT dos not mimic the rapid rise and fall in plasma like cigarette nicotine. Wide variation in nicotine metabolism among individuals leads to variation of nicotine concentration when an standard dose is taken. Dermal or gastric irritation. …

9 Novel treatment strategies based on genetic manipulation  CYP2A6 Hepatic enzyme 90% of inactivation of nicotine to cotinine 17 allelic variants The allelic variants vary in the ability to metabolize CYP2A6 substances The metabolic ratio of cotinine to nicotine is also grater in Korean than Japanese population.  CYP2A6 Hepatic enzyme 90% of inactivation of nicotine to cotinine 17 allelic variants The allelic variants vary in the ability to metabolize CYP2A6 substances The metabolic ratio of cotinine to nicotine is also grater in Korean than Japanese population.

10 Public health implications of CYP2A6 polymorphism Decreases risk of smoking initiation and dependence Decreases amount smoked Decreases risk of tobacco-related cancers and mutations Decreases risk of smoking initiation and dependence Decreases amount smoked Decreases risk of tobacco-related cancers and mutations

11 Risk of smoking initiation and tobacco dependence  Null or defective CYP2A6 allele(s) or slow metabolizers [SMs]. CYP2A6*2 & CYP2A6*4 Use of grater levels of tobacco when they learn smoking. Feeling of nicotine overdose. Slower acquisition of withdrawal and tolerance.  Null or defective CYP2A6 allele(s) or slow metabolizers [SMs]. CYP2A6*2 & CYP2A6*4 Use of grater levels of tobacco when they learn smoking. Feeling of nicotine overdose. Slower acquisition of withdrawal and tolerance.   Extensive metabolizers [EMs]. CYP*1/*1 Use as much as SMs use but it is normal for them. don’t feel nicotine overdose. faster tolerance and withdrawal.   Extensive metabolizers [EMs]. CYP*1/*1 Use as much as SMs use but it is normal for them. don’t feel nicotine overdose. faster tolerance and withdrawal.

12 The number of cigarettes smoked and other smoking indices  SMs Fewer cigarettes/day lower CO breath conc. lower plasma cotinine  (low metabolism of nicotine to cotinine)  SMs Fewer cigarettes/day lower CO breath conc. lower plasma cotinine  (low metabolism of nicotine to cotinine)   EMs or FMs more cigarettes/day more CO breath conc. more plasma cotinine   (high metabolism of nicotine to cotinine) smoke each cigarette more intensely   EMs or FMs more cigarettes/day more CO breath conc. more plasma cotinine   (high metabolism of nicotine to cotinine) smoke each cigarette more intensely

13 SMs Start smoking 3 years later. smoke for shorter duration. have an increased probability of quitting than EMs. Start smoking 3 years later. smoke for shorter duration. have an increased probability of quitting than EMs.

14 Risk of tobacco-related cancers and mutations  carcinogen components in cigarette Tobacco specific nitrosamines  4-(methylnitrosamino)-1-(3-pyridyl)-1-butanon (NNK)  N’-nitrosonornicotine (NNN) Polycyclic aromatic hydrocarbons (PAHs) Aromatic amines(5-200ng/cigarette) procarcinogen that specifically activates by CYP2A6

15 Risk of tobacco-related cancers and mutations  Carriers of one or more defective CYP2A6 alleles are in lower risk of lung cancer development Decreased ability to bioactivate certain tobacco–specific pro- carcinogens. Decreased risk of becoming tobacco-dependent. Smoke less  Carriers of one or more defective CYP2A6 alleles are in lower risk of lung cancer development Decreased ability to bioactivate certain tobacco–specific pro- carcinogens. Decreased risk of becoming tobacco-dependent. Smoke less   Carriers of active CYP2A6 alleles are in higher risk of lung cancer development Increased ability to bioactivate certain tobacco–specific pro- carcinogens. Increased risk of becoming tobacco- dependent. Smoke more   Carriers of active CYP2A6 alleles are in higher risk of lung cancer development Increased ability to bioactivate certain tobacco–specific pro- carcinogens. Increased risk of becoming tobacco- dependent. Smoke more

16 Clinical implications of CYP2A6 inhibition as a treatment for tobacco dependence Facilitates oral nicotine as a form of NRT. Reduces exposure to the harmful components of tobacco smoke. Enhances the efficacy of nicotine gum, nicotine patches and other NRTs. Decreases the load of carcinogens in the body. Facilitates oral nicotine as a form of NRT. Reduces exposure to the harmful components of tobacco smoke. Enhances the efficacy of nicotine gum, nicotine patches and other NRTs. Decreases the load of carcinogens in the body.

17 Facilitating oral nicotine as a form of NRT  Maximum tolerable dose of oral nicotine is about 4mg.  Up one first pass through the liver 70% of it will be metabolized to cotinine  Intestinal disturbances.  Maximum tolerable dose of oral nicotine is about 4mg.  Up one first pass through the liver 70% of it will be metabolized to cotinine  Intestinal disturbances. Bioavailability=30%

18 Facilitating oral nicotine as a form of NRT  Methoxsalen Psoriasis Inhibits CYP2A6  Tranylcypromine Monoamine oxidase Antidepressant Inhibits CYP2A6

19 Facilitating oral nicotine as a form of NRT 10mg Methoxsalen+ 4mg oral nicotine 30mg Methoxsalen+ 4 mg oral nicotine 2.5mg Tranylcypromine+ 4 mg oral nicotine 10mg Tranylcypromine+ 4 mg oral nicotine Increased mean plasma nicotine concentration by 72% Increased mean plasma nicotine concentration by 83% Increased mean plasma nicotine concentration by 43% Increased mean plasma nicotine concentration by 65%

20 Exposure reduction Methoxsalen + Oral nicotine 50% reduction in breath CO 83%increase in latency to the second cigarettes 24%decrease in the number of cigarettes smoked 24%decrease in grams of burned tobacco 25%decrease in the total number of puffs taken 50% reduction in breath CO 83%increase in latency to the second cigarettes 24%decrease in the number of cigarettes smoked 24%decrease in grams of burned tobacco 25%decrease in the total number of puffs taken

21 Enhancing the efficacy of nicotine gum, nicotine patches and other NRTs  Inhibition of CYP2A6 Prolonging the duration of action of NRTs Decreasing the variation in nicotine metabolism between and within individuals.  Inhibition of CYP2A6 Prolonging the duration of action of NRTs Decreasing the variation in nicotine metabolism between and within individuals.

22 Decreasing body load of carcinogens Smokers were told to maintain their smoking levels while receiving oral Methoxsalen 10mg three times a day for 3 days 29% increase in the ratio of plasma nicotine conc./breath CO conc. More NNK was metabolized to the inactive 4-(methylnitroamino)-1-(3-pyridyl)-1-butanol(NNAL)-glucuronide Re-routing of NNK from its CYP2A6-mediated mutagenic hydroxylation pathway to a non-mutagenic glucuronidation pathway.

23 Strategies to shorter development of drug for tobacco dependence Target risk factors associated with smoking or relapse ;e.g. mood, triggers. Use of any array of markers related to tobacco use and smoke exposure. Target withdrawal, inhibition of abstinence, relapse prevention and exposure reduction. Employ short-term proof-of-concern studies as either clinical trails or experimental design. Consider genetic-based source of variation in response. Target risk factors associated with smoking or relapse ;e.g. mood, triggers. Use of any array of markers related to tobacco use and smoke exposure. Target withdrawal, inhibition of abstinence, relapse prevention and exposure reduction. Employ short-term proof-of-concern studies as either clinical trails or experimental design. Consider genetic-based source of variation in response.

24 Thank you for your attention


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