In the name of GOD

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

• 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 2020.

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Smoking prevalence and reason for concern

• 15 of all cancers
• 80-90of lung
• cancers

• Cancers
• Lung
• Oral cavity
• Pharynx
• Pancreas
• Kidney
• Urinary tract

• Health consequences of smoking
• Respiratory disease
• Cardiovascular disease
• Cerebrovascular disease

cancer
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Genetics

• Initiation of smoking, 50
• Maintenance, 70
• Number of cigarettes smoked, 80

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Current treatment for tobacco dependence

• 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.

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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.

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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.

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Public health implications of CYP2A6 polymorphism

• Decreases risk of smoking initiation and
  dependence
• Decreases amount smoked
• Decreases risk of tobacco-related cancers and
  mutations

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Risk of smoking initiation and tobacco dependence

• Null or defective CYP2A6 allele(s) or slow
  metabolizers SMs.
• CYP2A62 CYP2A64
• Use of grater levels of tobacco when they learn
  smoking.
• Feeling of nicotine overdose.
• Slower acquisition of withdrawal and tolerance.

• Extensive metabolizers EMs.
• CYP1/1
• Use as much as SMs use but it is normal for them.
• dont feel nicotine overdose.
• faster tolerance and withdrawal.

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The number of cigarettes smoked and other smoking
indices

• EMs or FMs
• more cigarettes/day
• more CO breath conc.
• more plasma
• cotinine
• (high metabolism of nicotine to cotinine)
• smoke each cigarette more intensely

• SMs
• Fewer cigarettes/day
• lower CO breath conc.
• lower plasma cotinine
• (low metabolism of nicotine to cotinine)

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SMs

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

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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

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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
  tobaccospecific 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
  tobaccospecific pro-carcinogens.
• Increased risk of becoming tobacco-dependent.
• Smoke more

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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.

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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.

Bioavailability30
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Facilitating oral nicotine as a form of NRT

• Methoxsalen
• Psoriasis
• Inhibits CYP2A6
• Tranylcypromine
• Monoamine oxidase
• Antidepressant
• Inhibits CYP2A6

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

• 50 reduction in breath CO
• 83increase in latency to the second cigarettes
• 24decrease in the number of cigarettes smoked
• 24decrease in grams of burned tobacco
• 25decrease in the total number of puffs taken

Methoxsalen Oral nicotine
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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.

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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.

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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.

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Thank you for your attention