CYP2A enzymes and their use in therapeutic and diagnostic method

A technology of enzyme activity and substances, applied in the field of regulating nicotine metabolism in the individual body, can solve the problems of low effect, unknown oral nicotine replacement therapy, etc.

Inactive Publication Date: 2001-06-13
NICOGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because first-pass metabolism of nicotine is very efficient and it is impossible to use high concentrations of nicotine without irritating the digestive system, oral administration (such as pills) is a poorly effective nicotine delivery system
For this reason, no effective oral nicotine replacement therapy is known

Method used

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  • CYP2A enzymes and their use in therapeutic and diagnostic method
  • CYP2A enzymes and their use in therapeutic and diagnostic method
  • CYP2A enzymes and their use in therapeutic and diagnostic method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0175] Epidemiological studies

[0176] We examined the prevalence of CYP2A6 gene mutations in 126 tobacco-dependent Caucasian smokers and 143 Caucasian individuals who had smoked but were not addicted (eg, exposed controls). There are two purposes. The first is to determine the incidence of individuals with insufficient CYP2A6 activity (eg, homozygous for a null CYP2A6 allele). The second is to determine whether slowed CYP2A6-mediated nicotine metabolism due to having a null CYP2A6 allele reduces the chance of becoming a dependent smoker.

[0177] In this example, a study was conducted to evaluate the CYP2A6 genotype in a group of individuals and the effect of CYP2A6 on the smoking behavior of the individuals.

[0178] The subjects were unrelated healthy individuals, each with 4 Caucasian grandparents, who were divided into three groups. The first group comprised only tobacco dependent (TD, DSM-IV (“DSM” = Diagnostic Statistical Manual of the American Psychiatric Associati...

Embodiment 2

[0200] Coumarin Phenotype Test and CYP2A6 Genotype Test

[0201] A. Coumarin test

[0202] Coumarin is a selective and specific substrate of human CYP2A6, which can be used to: (1) identify individuals who may be therapeutically resistant to CYP2A6 inhibitors; (2) fine-tune the dose based on the initial concentration of CYP2A6 activity; and (3) conduct a risk assessment to identify individuals who will not benefit from treatment or who may be at risk of toxicity due to inhibitors or CYP2A6 substrates themselves. Coumarin trials fall into two categories:

[0203] (1) Coumarin test only available in urine

[0204] Coumarin 5mg is made into capsules or other dosage forms, and is given orally to fasting patients after emptying the residual bladder. Urine was collected for the first 2 hours and the subsequent 6 hours. Urinary excretion of the coumarin metabolite 7-hydroxycoumarin (free and bound) was measured by HPLC as described in the previous example. The relative activity ...

Embodiment 3

[0220] in vivo phenotyping

[0221] The plasma kinetics of nicotine and coumarin were compared after oral administration to 10 smokers and 9 non-smokers (12 males, 7 females) with known CYP2A6 genotypes. The dose of nicotine was 4.0 mg (expressed as base) and the dose of coumarin was 50 mg. Plasma concentrations of nicotine, cotinine, coumarin and 7-hydroxycoumarin were determined as described above.

[0222] By determining the metabolite of coumarin, 7-hydroxycoumarin (7-hydroxycoumarin [μM] * 1 / * 1=5.6±2.9; * 1 / * 2 or * 1 / * 3-3.8+1.1, p=0.04), found that coumarin makes * 1 / * 1 (wild-type homozygous, n=13) and heterozygous ( * 1 / * 2; * 1 / * 3,n=4) and homozygous ( * 2 / * 2, n=2) had optimal separation at 45 minutes. Optimal separation was found with nicotine at 90 minutes (nicotine [nM] * 1 / * 1=24±15; * 1 / * 2 or * 1 / * 3=29±12; * 2 / * 2=52±3; * 2 / * 2 pairs * 1 / * 2 or * 1 / * 3, p=0.01; * 2 / * 2 pairs * 1 / * 1, p=0.0001). Separation di...

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PUM

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Abstract

A method of regulating the activity of human cytochrome P450 isozyme CYP2A6 to control nicotine metabolism or decrease the production of carcinogens from procarcinogens, such as those present in tobacco smoke, in an individual by selectively inhibiting CYP2A6. Various prophylactic (i.e., prevention and treatment) compositions and methods are also described, including an improved oral nicotine composition and method comprising the use of nicotine together with an inhibitor of the CYP2A6 enzyme. Furthermore, it has been discovered that the presence in an individual of a mutant allele of human cytochrome P450 enzyme CYP2A6 (referred to throughout this specification as 'CYP2A6' for brevity) is predictive of an individual who: (1) has a decreased risk of becoming a smoker, (ii) will smoke less if he / she becomes dependent, and / or (iii) may be at relatively lower risk for cancer due to both decreased smoke exposure and decreased CYP2A6 -mediated activation of tobacco smoke and other procarcinogenic substrates. This invention provides diagnostic methods for predicting tobacco dependence risk and risk for cancers related to CYP2A6 substrates in an individual by analyzing for the presence of a mutant genotype for human cytochrome P450 enzyme CYP2A6 in an individual, ranging from gene duplication (multiple copies of CYP2A6) to single or even no copies due to null alleles or gene deletion.

Description

field of invention [0001] The present invention relates to methods and compositions for modulating nicotine metabolism in an individual; methods and compositions for enhancing nicotine replacement therapy; methods and compositions for diagnosing tobacco risk dependence and likelihood of cancer, and methods for treating or preventing cancer. Background technique [0002] Nicotine (nicotine) is one of the most widely used psychoactive drugs in the world. The World Health Organization reports that there are currently more than 1 billion smokers in the world, or about 1 / 3 of people aged 15 and over in the global population are smokers. It is well known that smoking is associated with a higher incidence of many diseases, including various cancers, respiratory diseases, cardiovascular diseases, gastrointestinal diseases, and many other medical complications (Lee et al., Arch. Intern. Med., "Cigarette Smoking, Nicotine Addiction, and Pharmacotherapy" 153(1):34-48 (1993)). [0003...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/00A61K31/12A61K31/122A61K31/13A61K31/131A61K31/137A61K31/27A61K31/35A61K31/351A61K31/365A61K31/37A61K31/415A61K31/4178A61K31/44A61K31/4439A61K31/465A61K31/70A61K36/28A61P25/34A61P35/00A61P43/00
CPCA61K31/131A61K31/7032A61K31/122A61K31/4439A61K31/351A61K31/37A61K31/27A61K31/4178A61P25/34A61P35/00A61P43/00A61K2300/00
Inventor 爱德华M·赛勒斯瑞雪F·汀达尔
Owner NICOGEN
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