PATENTS:

Jirkovsky, I., King, G., Reinhart, B. and DeNoble, V. J. 6, 7, 8, 9-tetrahydro-10methyl-pyrido [1,2-A] indol-9-amines and derivatives thereof, useful for the treatment of cognitive impairments. US Patent 4,624,954-11-25-86, 1986.

DeNoble, V. J., DeNoble, K. F., Eart, R. A. Use of serotonin-two type receptor antagonists in combination with neurotransmitter release enhancers (e.g. DuP 996) for treating cognition dysfunction. Case No. BP-6459, 1990.

Chiu, A., DeNoble, V., Duncia, J., Wong, P. Treatment of central nervous system disorders with imidazole angiotensin-Il receptor antagonists. Case No. BP-6439, 1990.

Chiu, A., DeNoble, V., Duncia, J., Wong, P. Treatment of central nervous system.
disorders with benzimidazole angiotensin-Il receptor antagonists. Case No.
BP-6456, 1990.

Chiu, A., DeNoble, V., Duncia, J., Wong, P. Treatment of central nervous system disorders with pyrazole, pyrrole and triazole angiotensin-ll receptor antagonists. Case No. BP-6457, 1990.

Chiu, A., DeNoble, V., Duncia, J., Wong, P. Treatment of central nervous disorders with imidazole compounds. Case No. BP-6458, 1990.

Johnson, A., Christos, T., Schmidt, W., Pottorf, R., Smyser, T., DeNoble, V., Stewart, J., Gilligan, P., Cain, G., Maduskuie, T., Arvanitis, A. Partially protected C-terminal neurotensin fragments and bond modified fragments as analgesics. Case No. BP-6843, 1990.

Boswell, G. A., DeNoble, V. J. Bicyclo[2:2:2]oct-1-yl amines as therapeutic agents to treat cognition dysfunction and Parkinsonism. Case No. BP-6515, 1991.

DeNoble, V. J. The use of neurotransmitter release enhancers (e.g. DuP 921) in combination with monoamine oxidase B inhibitors for treating cognitive dysfunction. MOI submitted, 1991.

Earl, R. A., DeNoble, V.J. 4,4'-(9H-fluoren-9-ylidenebis (methylene)]

-bispyrimidine for treating neurological disorders. Case No. BP-6444, 1992.

Mr. WAXMAN. Dr. Mele, we are also pleased that you are able to be here. And although you didn't present a formal statement, could you tell us about your training, education, and employment background?

Mr. MELE. Yes. First, Mr. Chairman, let me thank you and the members of the committee for allowing me to be here today. I received my Ph.D. degree in experimental psychology in 1980 from Adelphi University, in the field of behavioral pharmacology. That work focused on the effects of amphetamine on complex behavior in rats.

Following that work, I spent 2 years at the University of Wisconsin at Madison, funded under a National Institute of Health research service award, where I studied the behavioral toxicology of lead and polychlorinated biphenyls in non-human primates.

Following that, I went to the Philip Morris Research Center, to work with Dr. DeNoble. That was in November of 1981, and I was there until its closing in April of 1984.

Since leaving Philip Morris, I have been with the Department of Defense, at the Armed Forces Radiobiology Research Institute, in Bethesda, studying effects of ionizing radiation and radioprotectant compounds on the behavior of laboratory animals.

Mr. WAXMAN. Thank you very much, Dr. Mele.

Dr. DeNoble, I assume that you are aware that a month ago Dr. David Kessler, the Commissioner of the Food and Drug Administration, testified before this subcommittee about nicotine manipulation. He referred to your article on nicotine self-administration in rats and to the fact that Philip Morris ordered the article withdrawn after it had been accepted for publication. Subsequent to his testimony, I released your article.

Then just 2 weeks ago, the executives from the largest tobacco companies appeared before this subcommittee and testified that nicotine is not addictive. For example, William Campbell, the president and CEO of Philip Morris, U.S.A., testified, and I quote, "Cigarette smoking is not addictive. Nicotine contributes to the taste of cigarettes and the pleasure of smoking."

Now, you ran a laboratory that was charged with identifying the essential characteristics of nicotine so that a synthetic form of nicotine could be developed, yet you didn't test for the taste of nicotine. Did you ever hear of any serious discussion to the effect that Philip Morris leaves nicotine in cigarettes for taste?

Mr. DENOBLE. No, sir, none at all.

Mr. WAXMAN. As I understand it, you were charged with developing a rat model to test nicotine analogues for the effects on the brain in an effort to develop a nicotine substitute. Did anyone at Philip Morris ever suggest to you during the course of your analogue work that you should develop an analogue that would duplicate the taste of nicotine?

Mr. DENOBLE. No, not at all.

Mr. WAXMAN. Are you aware of anyone else doing work on this at Philip Morris?

Mr. DENOBLE. Our laboratory didn't do any work in taste. That could have been done in the other areas of the Research Center, but I don't have any knowledge of that.

Mr. WAXMAN. Prior to your employment at Philip Morris, what sort of scientific work had you done?

Mr. DENOBLE. I was working at the University of Minnesota, under a sponsorship of the National Institute of Drug Abuse. My work was with drug self-administration in non-human primates and rodents.

Mr. WAXMAN. You were doing animal tests on alcohol and barbiturates?

Mr. DENOBLE. That is correct, yes.

Mr. WAXMAN. OK. You were previously doing work on drugs for which there is a concern about both dependence and abuse?

Mr. DENOBLE. That's correct.

Mr. WAXMAN. And at Philip Morris you did similar types of animal research on nicotine, is that correct?

Mr. DENOBLE. Very similar, yes.

Mr. WAXMAN. Can you compare the tests you did on nicotine with the tests that the National Institute on Drug Abuse would do to determine if a drug has an abuse potential?

Mr. DENOBLE. Well, they are exactly the same tests. We did not do drug comparisons, but the test models are exactly the same.

Mr. WAXMAN. As I understand it, in order to test nicotine analogues, you had to understand the brain effects of nicotine itself. How did you approach this task? Where did you start?

Mr. DENOBLE. When the lab existed, we already had one test which identified whether rats could tell us whether they were given an injection of nicotine peripherally in the systemically. Our first model, to get to a direct effect of the pleasurable effects, if you will, of nicotine, was to look at a self-administration model. That was the primary screen.

Mr. WAXMAN. I suppose that there are many brain effects that a substance might have, and many tests that could be done. It is my understanding that there are certain tests that qualify as hallmarks of potential drug abuse or addiction.

Am I correct that in the early 1980's, the three animal tests that would be done to identify whether a substance was potentially addictive would be self-administration, tolerance, and physical withdrawal?

Mr. DENOBLE. That is correct.

Mr. WAXMAN. And isn't it true that you did all these tests and that they were a central part of your work at the laboratory? Mr. DENOBLE. That is also correct.

Mr. WAXMAN. Now, would you briefly describe for us how you tested for self-administration, tolerance, and physical dependence? Mr. DENOBLE. Well, for self-administration, the animals were surgically prepared with a catheter that lodged itself just above the heart. The animals, after surgical recovery, could be hooked up to an infusion pump. If the animal pressed one of two levers, one lever didn't do anything, the other lever would deliver a nicotine solution into the vein.

If nicotine is a reinforcing agent, then the pressing of the lever would increase, and that is what we found. We did several manipulations and several investigations to clearly show that the animal was pressing the lever to obtain nicotine.

In terms of tolerance, a study design that Paul put together was to repeatedly inject animals with nicotine over several days, and then test to determine whether or not the animal was tolerant to the disruptive effects of nicotine.

When you inject nicotine in an animal and he is working on a lever for food, the performance of the animal becomes impaired. That performance impairment goes away as the animal has exposure to nicotine. We also demonstrated in that experiment that part of that tolerance was physiological and part of the tolerance was behavioral, that is, a learned tolerance.

In physical dependence, we conducted two large experiments in which we chronically administered nicotine to rats over several days, if not weeks. We challenged the nicotine in the animals with an antagonist, mecamylamine. Or in another experiment we let the simply the nicotine, took it away from the animal. We did not observe any withdrawal syndrome as evidenced by changes in foodmotivated behavior.

Mr. WAXMAN. So of the three hallmarks of dependence, you did find that there was self-administration and tolerance, but you did not find that there was a physical dependence?

Mr. DENOBLE. That is correct.

Mr. WAXMAN. OK. And did the studies that you did also indicate that nicotine has a potential for drug liability?

Mr. DENOBLE. Yes. The self-administration study is a classical hallmark to indicate that a solution or drug substance has a potential for abuse, yes.

Mr. WAXMAN. And what does "drug liability" mean?

Mr. DENOBLE. It essentially means that if you find it in an animal, it has the potential to be a drug of abuse in humans. You need to then go on to do other species, and other strains of animals, and also go into the human to determine the final factor.

Mr. WAXMAN. Now, on March 31, I released a version of your self-administration study. On that same day Philip Morris issued a statement, which I'd like entered into the record, without objection, as Exhibit 2.

RESPONSE OF PHILIP MORRIS U.S.A. TO CONGRESSMAN WAXMAN'S PRESS

CONFERENCE

Dr. Victor DeNoble was employed by Philip Morris from April 1980 to March 1984 as a research scientist in the Research and Development Department. Dr. DeNoble conducted nicotine-related research and concluded that nicotine is a reinforcer in the class of nonaddictive chemical compounds such as saccharin, or water, and that he did not believe nicotine fit the accepted criteria for drug dependence. He also concluded that nicotine self-administration cannot be viewed as a form of drug "abuse" or as an "addiction."

Contrary to the suggestions that Dr. DeNoble's research has been somehow withheld from the scientific community and the public, we find dozens of publications authored by him, including five based on his nicotine-related research conducted while at Philip Morris.

At no time did Philip Morris seek an injunction, legal or otherwise, against the publication of any of Dr. DeNoble's research. As with virtually all industries, publication of research done while an employee must be reviewed and approved prior to such publication. We are aware of one instance when Dr. DeNoble failed to go through the Philip Morris manuscript review process and thus was told not to publish Philip Morris research until completing the process. An abstract based on that research was published.

Mr. WAXMAN. And they said, and I quote, "Dr. DeNoble concluded that nicotine self-administration cannot be viewed as a form of drug abuse."

On the basis of your work at Philip Morris, did you reach such a conclusion?

Mr. DENOBLE. No, sir, I did not.

Mr. WAXMAN. At this time, I'd like to show you Exhibit 3, which is a letter from Dr. Alan Leschner, director of the National Institute on Drug Abuse. That letter states that the findings in your study, quote, "indicate that nicotine has reinforcing properties, one of the hallmark characteristics of an addictive drug." Do you agree with that characterization of your work?

Mr. DENOBLE. Yes, I do.

[Exhibit No. 3 follows:]