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Novel nicotine cessation therapeutics

Institution: Human BioMolecular Research Institute
Investigator(s): John Cashman, Ph.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0196H Award: $802,840
Subject Area: Nicotine Dependence
Award Type: Research Project Awards

Initial Award Abstract
There are many people in California and the United States that would like to give up smoking. Some have used counseling or other self-help programs to wean themselves from the habit of smoking but these programs have only been somewhat effective. One of the reasons, we believe, that more success has not been achieved with these programs is that the chemicals in tobacco are very powerful and equally powerful medicines will be required to be used jointly with self-help programs before a vast improvement in smoking cessation is observed. This is an important problem. One out of every four American adults smoke tobacco despite clear evidence that smoking is the leading cause of lung cancer and the number one cause of preventable death in the United States.

The major biologically active chemical in tobacco is nicotine. People smoke cigarettes to obtain a certain level of nicotine in the blood stream and the brain. Some individuals ingest a great deal of tobacco from smoking to get the amount of nicotine in their blood stream that they require while others need considerably less. For example, men metabolize nicotine much more rapidly than women and on the whole, men consequently smoke more cigarettes per person than women. This type of difference in smoking behavior has also been seen in different ethnic groups as well. For example, Mexican Americans and white smokers appear to have lower blood levels of the major metabolite of nicotine (i.e., cotinine) than do African Americans. The amount of cotinine in the blood is dependent on the rate it is formed or eliminated in the body. Some of the differences in the way men and women smoke or the way different ethnic groups smoke may be due to socio-cultural factors. Major differences, however, are undoubtedly related to the inherited genetic material that different ethnic groups and men and women possess.

It is becoming clear from phenotypic studies that some individuals are more efficient at removing nicotine from the body than others. This information has provided powerful insight into ways to make new medications that could help prevent people from smoking in the first place or decrease the number of cigarettes smokers use per day. By treating smokers with medicines that decrease tobacco consumption and at the same time provide counseling and self-help programs, individuals would be given an opportunity to decrease smoking altogether. In the long run, this would improve the health of smokers and non-smokers. In addition, a decrease in smoking or a decrease in the number of cigarettes smoked per person could result in fewer smoking-related diseases. This could result in enormous social and economic cost savings for the State of California as well as the Nation.

We plan to use a new approach to chemically synthesizing large numbers of anti-smoking medications. The compounds will be individually synthesized in small amounts by a process called combinatorial chemistry. The compounds will be screened for biological activity and, if active, further elaborated into medicines that could be developed further. The new medications developed will provide a new approach to aid in the prevention of smoking addiction.

Population distribution of human flavin-containing monoxygenase form 3: Gene polymorphisms.
Periodical: Drug Metabolism and Disposition Index Medicus:
Authors: Cashman JR, Zhang J, Leushner J, and Braun A ART
Yr: 2001 Vol: 29 Nbr: Abs: Pg: 1629-1637

Human and plant flavin-containing monooxygenase N-oxygenation of amines: Detoxication vs. bioactivation.
Periodical: Drug Metabolism Reviews Index Medicus:
Authors: Cashman, JR ART
Yr: 2002 Vol: 34 Nbr: Abs: Pg: 509-517

Inhibition of human liver mocrosomal (S)-nicotine oxidation by (-)-menthol and analogs.
Periodical: Chemical Research in Toxicology Index Medicus:
Authors: MacDougall JM, Fandrick K, Zhang X, Serafin S, Cashman JR ART
Yr: 0 Vol: Nbr: Abs: Pg:

Nicotine-related alkaloids and metabolites as inhibitors of human cytochrome P-450 2A6.
Periodical: Biochemical Pharmacology Index Medicus:
Authors: Denton TT, Zhang X, Cashman JR ART
Yr: 2004 Vol: 67 Nbr: Abs: Pg: 751-756

Inhibition of human liver microsomal (S)-nicotine oxidation by (-) methol and analogues.
Periodical: Chemical Research in Toxicology Index Medicus:
Authors: MacDougall JM, Fandrick K, Zhang X, Serafin SV, Cashman JR ART
Yr: 2003 Vol: 16 Nbr: Abs: Pg: 988-993

Two new polymorphisms of the FM03 gene in Caucasian and African-American populations comparative genetic and functional studies.
Periodical: Drug Metabolism and Disposition Index Medicus:
Authors: Lattard V, Zhang J, Tran Q, Furnes B, Schlenk D, Cashman JR ART
Yr: 2003 Vol: 31 Nbr: Abs: Pg: 854-860

Interindividual differences of human flavin-containing monoxygenase 3: Genetic polymorphisms and functional variation.
Periodical: Drug Metabolism and Disposition Index Medicus:
Authors: Cashman JR, Zhang J ART
Yr: 2002 Vol: 30 Nbr: Abs: Pg: 1043-1052