Tobacco Documents Online

it.t( •4•4) I:r> May 19, 1981 NDDRAND[..'M 70: Dr. W. U. Gardner and Staff HK91165021 FROM: D. H. Ford and D. Stone SUR7DCT: Site Visit with Dr. C. K. Erickson, University of 7txas, College of Phannacy, Austin, Ttxas, May il, 1981 Grant Nuvnb:r 1208B "Blood-Brain Monitoring of Sustained Nicotine Levels in Rats" Dr. Ericksord reviewed the current status of their progran (see appended interim report). A report by Dr. Stavchansky (page 2) was based 'dn calcularions he made based on a report in the literature by Miller on the effect of varied nicotine dose levels on the pharmokinetics of nicotine following intravenous in- jection in rats, using labeled niootine. Doses injected varied fnon 0.08 to 0.8 mg/kg. Despite a ten fold difference in dose, estimated release only increased slightly (page 3). However, no estimate was made on how much was nicotine or met:abolite. khile Dr. Stavchansky made a number of asstmptions in making these calculations, the rate of release (based on clearance) was very oonparable to the 14 mg/day which they record with their nicotine release device. Figure 1 illustrates that separation of nicotine and standards in water and blood or from blood obtained from animals with inplanted nicotine release de- vices all give sharp peaks. Figure 2 illustrates that the standard curves for nicotine rreasured in water or 10 of blood follow a close relationship to each other. Figure 3 illustrates that nicotine release from the device (in water) varies with, the temperature of the water. Figzu-e 4 demonstrates that nicbtine release in vitro is more rapid during the first ten days than thereafter. (Feels the slow dv,m in release is due to formation of a bubble in the capsule which creates a vacuum and slows release. ) (41hen nicotine release devices are imp.lanted in ani- mal.so it is done after a pre-release period'with the device in wafer to eliminate the period of early rapid release.) Ficnere 5 demonstrates the lack of change in body weight in female Spr'ague Dawley rats for a period of 14 days after irrplanta- tion, in 60 to 70 day old rats. Ficrure 6 allustrates that, in vivo, even when the device is irg?lanted in the rat after a pre-release period in ~ao ter to elimi- nate the early surge of niootine release, blood levels of nicotine are much higher in the first few days and then plateau at a lower level. Dr. Erickson feels that the early high nicotine levels may relate to a period in which liver enzyme levels for nicotine degradation are low, thus allowing for higher blood nicotine levels. Plans to follow a group wherein a new device is implanted after 14 days to see if blood nicotine levels remain low (confirming the concept that the higher early levels were due to a need for a short period to induce liver nicotine degrading enzynies). Figure 7 merely represents the same data as in Figure 6; but adjusted for body weight. ~Fi 8 compares blood nicotine levels in male and female rats, but unadjusted for o~~y c,w~ight. Since release rate was the sane for both sexes and since males were significantly heavier, the effect was to achieve a louer anount of nicotine present/unit weight. Will repeat this using animals of the sane weight. Saline not used in capsules as controls because it is not released. No progress in devising a capsule for release of nicotine sulfate.

C. K. ERIC3iSON PA(E 2 NWY 19, 1981 Tcn: CorNc•tL FOn TuBiaccO Rrar..itcii-L':S.A.. I.Nc•: N KE1 165022 Future Plans: Will oar,pare the blood levels of nicotine in male and femle rats of tlie six strains of rat oamonly used for cancer studies, using animals of eomparable weight. There has been some delay in this, since the animal source for the rats has ceased breeding and selling then. Dr. Erickson was, howeve.r, able to obtain two ma].es and eight females of each strain, which he has now set up in breeding groups. Expects first animals to be available for testing on July lst. 2hey will not be doina the assay of nicotine in brain. The initial probXefis Ahich they had encaowntered in the appearance of peaks of contaminants were apparently not as easily solved as they had anticipated. Dr. Erickson will not be resuhnitting for a new grant. Plans only to finish up the current study with the animals used for canoer studies. Seste: time in the future he rray submit a new grant pertaining to the effects of nicotine exposure in uterd on the developing fetus, as well as studies exposi.ng rales or females to nicotine prior to matialg. Wbuld pl<:n to have some preliminary data on thi s project before sulxnittixig. liesults obtained so fir will be sutinitted for publication and copies sent to us. Achievement: Dr. Erickson fEels that they have successfully created a release de forvice' pure nieotine which can deliver nicotine at a given rate for a prolonged period in vitro and in vivo (after a preliminary in vitro period to eliminate a large pulse of nicotine wh.ich is emitt:ed). Crnmrnt: wbuld agree with Dr. Erickson, this particular project has reached the esid of the road, and the primary objective sought by CTR appears to have been obtained. How useful the release device will be for others remains to be seen. D. H. F'ORD D. SI'CtE jagm