Tobacco Documents Online

MEETING-OF. PHARMACOLOGIC AED CLINICAL APPROACHES IN SMOKING WORKING GROUP Atlantic City, April 15, 1973 Dr Kensler opened the meetinl~ by notin~ that it was the fifth meeting of the ~roup in ~he somewhat more than a year since it has been foxed. Dr. Gio Gori of the NCl,.Chairman; T.B. ~en, Manage~ ~f ~he Tobacco Se~en% in . the Carcinogenesis Section of the NCI Executive See~etamy" D~. E:-F. Domi,..o, Phm~oologist of the Univemsity of Michigan; Dr. G.A. Dens.u, Pharmacolcgis$ at ~he University of California at Davis, California D~. John ~ng, Pha~eologist at the University of Iowa ; Dr. Claude L'Enfant, of the National Heart and Institute ; D~. Charles Kensler of A. D. Little & Co, any; . D~. Murray. Jarv~, Pharmacologist at U.C.L.A.; Dr. George Koelle, Pharmacologist at %be University of Pennsylvania ; D~. William K. Riker, Pharmacologist at the University of Oregon; and ~. T. Hill, of Wynder's American Health Foundation All of.the above were either meters of the co~ft%ee (p~es~ably in the case of Dr. Hill) representing meters. Also present by invltation were Drs. Morley K~re and Brand of ~he Monell Chemlcal Senses Center of the University of Pennsylvania. Dr. Golf noted that the meetfn~ was, according to law~ open to the p~lfe. He sa!i that their meetings were always open CONFIDENTIAL: MINNESOTA TOBACCO LITIGATION TIMN 418881 F

and that he was pleased to welcome two visitors, a reporter from the Blue Sheet (a newsletter on subscription to various ~nstltutions and researchers, etc.), and' myself. Chamlie Kenslem had intmodueed me to Dr. Gori.before the meetir~ started; .and we had had a short but pleasant eonversatlon. The minutes of the last meeting were approved, Including the outline of the areas of investiEatlon the ~oup felt worthy of pursuit. [Apparently, the ~oup proceeds by developing pro- tocols for research in various fields whleh, ~t ~s planned, well .~ be open %o publlc bid.] '4 In substance, the laPeas for eonslderation and research ~.~.~ ~:p~ p~otoools were as follows: ~., ?:'~; ,.:;:.~"~ ~.~, I. Clinical eval'uat~on of agents for ellnieal ~-, ~'- ."-..:~ use in disoou~aging smoking. r~:~.....:.Y".~ :~ [In general, apparently %his a~a was ~o eove~ ~hose ~ ~:=~ ~.:~ .~.~ s~stances which had already been s~ficiently screened ~ ~J ~! ,-~ so that they could be used in tests on h~ns.] ~ ~, ~ ~. Bfoassay and evaluation of the above in lab0ra~o~ ~ ~ ~ antis. .~.~, ~ B. Nicotine agonists to be evaluated in laboratory ~ an~Is ~elf~naPy sePeenfn~ to dete~ine whether the s~s%anee is suit~le fop eo~idePa%ion fo~ testln~ in h~ns). CONFIDENTIAL: TIMN 418882 MINNESOTA TOBACCO LITIGATION

W. Nicotine antagonists to be evaluated in laboratory animals. 5. Modification of organoleptic responses. 6. I~munologie approach. Dr. Gorl mentioned that Dr. Hill's p~o~eet had been revised after review by statisltieians at the NCI. He mentioned that the p~eet dealt with antaEon~s of nleot~e. At this poi~,-D~. Kensle~ began to take ove~ and or~nize the d~seussion. He seemed fo~ the ~est of the day the de facto ehai~a~ of the ~oup. [At one point, someone referred to h~ as having been p~evlously elected as charon and he jowlly stated that he had not yet accepted.] The~e was a discussion of eo~o~ds to be included as antagonists of nicotine This began with a p~otocol Pelating to the effects of s~kln~ on the pmoteln bind~g of nieotlne. The ~eport of a Boston ~oup that propoxylane is less effective smokers was discussed, with the question being raised as to how it couldbe less effective there than an~here else (since, appa~ntly, everyone thought it to be generally ineffective) .D~. Go~i ~epo~ted tha~, ~der contract to Brandeis, the NCI has developed a ~adioi~unoassay of nicotine. The sensitivity was at the pieo~am level and the ~eseareh was Helen Vanacees -- (spelling?). : The pmepamem of the proto~l ~. Rike~) mentioned that the Barkos couple were locking for something which might be a mo~e sensitive area than what everyone had previously been led to ~der- CO.DEnIAL: -3- MI SOV TOS CCO UTm TmN -- - TIMN 418883

stand had been developed st Brandeis. It was, after discussion, suEgested that Riker should review what has been done at Brandeis %o see whether the Barko~ should use a different method or whethem the Brandeis technique should be incorporated into the protocol. Apparently everyone considered that the news of the Brandeis results was potentially of Ereat value in dete~mininE nicotine levels in the blood and was a eonside~ble advance ove~ what had been previously reported. ~ R~kem stated that, after assay, he wanted to consider ~-' ,- both passive and active immunization. He wanted to have nicotine ~ ~~ "soaked up" so that it did hot do what it otherwise would in such •- _ a~eas as pressor response, free fatty aclds,.cateeholam~nes, •.,~ tachycardia, etc. Apparently this work was to be done in rabbits. ~. Jarv~.k mentioned that Dr. Kreuzer of Bell Laboratories <.., ~:~ ~ had developed an infrared speettoE~eaphy technique that could detect ~i!~ '.i~ ~- parts per billion of nicotine in exhaled air. ~g~:=,:: }i Other techniques of mass spectrometry could find ~o~ ~.:~ 200 molecules of nicotine, but it was felt that they were neither >. t~ sensitive not specific enouEh. ~ ~ Dr. Gori said that someone should collect the information, % ~£~ pPobe it and mev~ew ~t to see what should be done in this a~ea. ¢ Dr. Kensle~ was selected to do so. Kensler noted that Riker's ~munization approach appea~ed Eood and should be followed through. CONFIDENTIAL: MINNESOTA TOBACCO LITIGATION 418884

Riker observed that the trouble with examining why hepatitis patients were reluctant to smoke was that it was difficult to get controls. Koelle pointed out that the recovery of the desire to smoke by sueh patients came very soon. Riker observed that more than n.~cot£ne is involved, so it is misleading to talk of nicotine. ~here are at least 55 drugs shown m~lecularly in the mass spectvttm, and he wondered whether investigation of ~he other 55 should be taken. Kensler observed that some 1500 or so co~onents of smoke ~ad been Several ~f those present see~d to be ~aware of this and expressed sunrise that the~e were mo~e than a fe~. I~ was decided that a lls*.of eo~onents and of their levels should be co~iled fo~ Gor~ refer~ed to the effort ~o years ago to ~dentify eo~onents. Ke~lee ~efe~ed favorably to it, and pointed out - that it had been published in the 1971 edition of "Health.Consequences of Smoking." He suggested that the others could ~efe~ to it there. Gorl pointed out that ofthe components identified, perhaps were p~esent £n parts per billion. Kensle~ observed.that the objective of this ~oup was .to deal with nicotine, and that the Tobacco Wo~ing Group had responsibility fo~ othe~ components. .Go~ said that everyone should ~ what else was involved. Kensler agreed, but pointed out that p~am to dete~ine co~os/Tion of smoke and that vePy few of the -5- CONFIDENTIAL: TIMN 418885 MINNESOTA TOBACCO LITIGATION

components were related to nicotine. Jarvik asked whether any of the other components had the pha~macologlc activity of nicotine. In one voice, Gorl and Kensler said "carbon monoxide." Kensler went on to say cyanide and acPolein. Domino said that it would be useful to show that the levels of nicotine present in the lowest n~eotine clgaPettes that were eo~emcial successes were pha~colog~cally active. Gori observed that it depended on the method of smoking aS to whether ~iven levels of nicotine were pha~cologically active. Also, s~ce how the nicotine was presented is ~ortant, data in ~n is needed. Japv~k suggested that the pba~colo~ie effects of smoke PefePable ~o nicotine alone be listed. KensleP Pefe£,Ped pul~nary f~ction and blood flow. Gori again mentioned carbon monoxide. JaPv~k observed that i% was possible %hat the effects wePe potentiated by other smoke co~onents. KensleP indicated that this was a co~lex d~g ~te.raction problem. Jarvlk - observed %hat if all 1500 components were active, it would be a tough pPobl~. It was a~eed that the focus should be on nicotine as ~he point of. departure. Go~i suggested that Rikem should s~dy what other com- ponents weme involved so that They could be meas~ed in ~n. They sa~d That they weme st~ll %~ing %o get the tools as they do not TIMN 418886 CONFIDENTIAL: MINNESOTA TOBACCO LITIGATION

have methodoloKy for this purpose. Denau said that they should eonslder not only hepatitis patients, but also pregnant women who also lose The desire to smoke. Cori observed that psyehologlc effects were involved. Kensler observed that many of these women were told not to smoke. Denau said that nevertheless such women should be studied, since the ones ~nvolved are Those that get morning s~ckness. Jarvik referred to the s~k~g ~nkeys and wondered whether, they could be given hepatit~s. Gorl said ~t ~s not ~own whether the-b~n v~rus could be-glven to ani~Is [a newspape~ ~epo~t that ve~ day indicated Gomi observed that t.he loss of ~esi~e to smoke ~ p~e~nant . ~aetieal to ~ke people nauseate~ so Chat they would not s~ke. He also questioned, not jocularly, how to get a man pregnant?: Jamvlk again suggested that p~lot work could be done with monkeys ~o see ~f they could get hepatitis. Kensle~ obsePved that the hepatitis phenomenon could involve othe~ s~ke eo~onen%s than n~eotine, om taste factors • Dr. B~and said ~hat they were wo~kin~ on %be pemeeption of b~tter taste factors. He said ~% was pmobably ~e complicated than nicotine alone when wo~kln~ ~n the ~aste aspect of smokinK, particularly when refer~Jn~ to some of the co~o~ds mentioned to -7- CONFIDENTIAL: TIMN 418887 MINNESOTA TOBACCO LITIGATION

h~m, which were taste antagonists to smoke. Reference was made to .dentists' f~ndings that silver nitrate administration also lessened the desire to smoke. In considering the use of either a lozenge or a drug to give smoking a bad taste, it should be. remembered that the use of taste antagonists is not unusual. Fbr example, MSG,: and nucleltides, are strong kelators. A glycoprotein. <> ~ is more exotic. It is of high chendcal weight and acts at the .... :? ~ cell surface, Zu~n~ng the sou~ taste of acids to sweet.. The ~ . ~ ~. ~;~ ~ntensit9 of ~he sweeZness ~s eo~mela%ed w~Zh the ~ , ~.~,:~-~-~ Acids extracted f~om %he leaves o£ a t~opiual plant p~oduce ~ ~ .... ::'~ taste antagonism by ~on~e washi~, whereby ~he abil~Ty to taste :. ~ " ~:" sweetness ~s lost. .... ., .~.~ ~ Thus, one could ~nwsti~a~e the c: :.:.:: ~ wlth othe~ e~ga~ette smoke antagonlsts ~om the point of v~ew of ~ ~.~ ...... taste b5oehe~stmy. One could look fo~ any d~ect 5nte~aetion ~, ":~ w~th nicotine oD othem s~ke v01atiles. Then one could investigate the p~operties with recently developed isolated cell p~epamations from the ~aste buds, using cow tongue. The problem here is not ~usual and fluorescence changes can be used. Any pmomlsing smoke antagonist or s~stanees on the G~S PDA l~st can be clinically tested ~ediately slnee the Monell Center has available psycholo- gists who can evaluate clinically the taste and smell approsches. CONFIDENTIAL: TIMN 418888 I INNESOTA TOBACCO LITIGATION

So Brand hopes that someone has a class of antagonists available for smoke taste investigation. He also ~bserved that hepatic patients were available at the VA hospital where Dr. Vesor (the psyehologlst) is located. Kessler observed that a lot of work on flavor had been done by the industry. He sa~d ~ha~ it was clear %ha~ nleo%~ne was not per se dete~native~ s~ce the Same a~unt can be in c~ga~ettes w~%h both zood and awful ¢astes. Brand pointed out ~t one needn't taste n~eotine for n~eot~ne antason~sm to work. R~ker asked about selee¢iv~, poin¢~g out that the s~stanee ~¢ abolish other tastes as well and that he didn't know of any which were s~f~eien¢ly selective Go~i observed that the proposal related ¢o a research approach for basics and that the question for the group was one of priorities. Kensler observed that a cl~cal psychol-og~st could be b~uEht ~n early and without a basic ~esea~eh p~Eram. Ja~vlk observed that the mole of n~eotine ~n taste must be eonse~ential, since it is a bitte~ alkaloid, and he ~estioned whethem people s~ke fo~ o~ in sp~Te of taste. He said he thins they smoke ~n spite of taste as do opi~ smokems. Go~ said he ¢hou~ht the area was womth explo~in~ and asked ~f Dr. Brand would ~ke a specific proposal which could be sent to ¢he meters of the ~oup before %he next mee%in~ so it could be acted upon at the next meeting. Kate obse~ed ¢hat you can't skip f~om species ¢o species CONFIDENTIAL: MINNESOTA TOBACCO LITIGATION - TIMN 418889

with respect to taste, and That the~e were no freely available animal models for humans, since natume ha, s p~ovided that all species do not compete for the same food material. Kensler observed that the need is for data referable to man. Jarv~k and Gori then asked about tobacco plant parasites, which must be able. TO counter- act nicotine, and about parasites whichI resist nicotine preparations used as pesticides. Dm. Hill's pPoposal was then c~roulated and, when the Blue Shee~ ~epom~e~ souEh~ to take a copy, Kensle~ ~efused to let h~, say~nE that i~ was not p~lie i~o~aZion since a potential ~ant. [Since it Pelated to a p~toool fore a p~lio bid, I did not thi~ Kenslem's pos~t~on well take. Indeed, I have question whether even ~ant applications which a~e circulated at open meetings can be kept eonfidentlal.] The Hill proposal is said to be designed to help people who want to st~ smoking but can't. They w~sh to follow physic- logical ehanEes ~n people copmelated w~th ehan~es ~n smok~nE ~ the context of co, fete smok~ and medical ~sto~ies. They wish to put people on various d~uEs for periods of t~ and see ~f the~e age eha~es in vamious pamameters. This. is to be done do~le as suggested by the NCI. One.test ~eferred to was tunnel yislon acuity, said to affected by smokinE. Some expressed surprise that smok~E would affee~ t~nel vision, but Hill said tha~ "his om~anlzat~on had data on th~s. CON~DE~AL: ~~SOTA TOBACCO TIMN 41889