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I I I I I I I I I I I I I I wiZ3MiSi9U/I54lil1XW3uY.l1JN TNC JOl'RNAL Oe P//ARMACOLOfy AND EXPCRIMCNTAI. T/ICRAPCLT1CR Copyneht 2 1990 by The Amencan Jocletv for Pharmacoloay and Eaperlmental Therapeutic. VOI, ISI. N0 PnntNW US A Intravenous Nicotine Replacement Suppresses Nicotine Intake from Cigarette Smoking NEAL L. BENOWITZ and PEYTON JACOB III The Clinical Pharmacology Unit of the Medical Service, San Francisco General Hospital Medical Center and the Depanment of Medicine and Langley Porter Psychiatric /nstitute, University of California at San Francisco, San Francisco, California Accepted for publication May 29, 1990 ABSTRACT Insofar as smokers regulate body levels of nicotine, nicotine replacement is expected to suppress the desire to smoke a cigarette. Our study was designed to test the hypothesis that i.v. replacement of nicotine will suppress daily intake of nicotine from ad libitum cigarette smoking and to compare the physiolog- ical effects of prolonged exposure to nicotine infused i.v. to the effect of smoking cigarettes throughout the day. Eight subjects received a 14-hr infusion of deuterium-labeled nicotine dosed to achieve levels of nicotine similar to those while smoking ciga- rettes for each individual (average, 33.1 mg: range, 17.7-49.9 mg) or saline (placebo). Cigarette smoking was permitted as desired. Nicotine infusion did not significantly affect the number of cigarettes smoked or the amount of tobacco burned, but nicotine intake from cigarette smoking was suppressed in all but one subject by an average of 24.6% (range, 4.0-51.2%), Down- regulation of levels of nicotine while smoking in response to infusion of nicotine was imprecise, which may be a resutt pf psychosocial factors influencing smoking behavior along with the development of tolerance to toxic effects of nicotine as a con, sequence of prolonged exposure to nicotine. Intravertotu rw_ otine and cigarette smoking increased average heart rate arta blood pressure throughout the day and 24-hr urinary epineptytrk excretion to a similar extent. Despite higher levels of rticotre when subjects smoked during infusion of nicotine, there were no additional nicotine-related effects. No adverse effects were noted; most subjects could not distinguish nicotine from saine Our data indicate that sustained delivery of nicotine tfxotxgt>ottt the day is safe and may suppress self-determined rticobne car} sumption in cigarette smokers, There is abundant evidence that tobacco use is maintained by nicotine, and that cigarette smokers adjust their smoking behavior to regulate levels of nicotine in the body (Benowitz, 1988). Analogous to the use of methadone in treating opiate addiction, nicotine replacement therapy in the form of nicotine gum has been shown to be an effective adjunct to smoking cessation therapy (Lam et a1., 1987). However, the benefit is realized by only a small fraction of smokers. The primary effect of nicotine gum is to relieve nicotine withdrawal symptoms, with relatively little effect on the desire for cigarettes and only a small effect on ad libitum cigarette consumption (Russell et al., 1976; West et al., 1984). Chewing nicotine gum results in an intake of nicotine and resultant blood levels of nicotine that are usually less than those achieved from cigarette smoking (Benowitz et al., 1987; Russell et al., 1976). Attempts to increase nicotine consumption by chewing more gum are often limited by jaw fatigue and gastrointestinal side effects. Received for publication October 5. 1989. ' This work was supported by Grants DA 02277 and DA 01696 from the National Institute on Drug Abuse and carried out in part in the General Clinical Research Center at San Francisco General Hospital Medical Center (RR-00083) with support of the Division of Research Resources, National Institutes of Health. Nicotine is absorbed through the skin, and tranadermal nic. otine delivery systems are being developed as a method of nicotine replacement for smoking cessation (Abelin et a1.,19891 Transdermal delivery systems have the potential to achieve and maintain a level of nicotine in the body similar to that achieved during cigarette smoking. Insofar as smokers regulate body levels of nicotine, nicotine replacement is expected to suppress the desire to smoke a cigarette. If so, such therap. might be effective not only in ameliorating nicotine withdnw•al symptoms but also in reducing ad libitum cigarette smoking. Assuming that absorption of nicotine from tranadermal sys• tems will occur at a constant rate, it is possible to simulate the systemic effects of transdermal nicotine by administering nic• otine i.v. by constant infusion. In our study we examined the hypothesis that i.v. replacement of nicotine administered tt, achieve levels of nicotine similar to those resulting from ciga rette smoking in an individual will suppress daily intake of nicotine from ad libitum cigarette smoking in that individual At the same time, we were able to compare the phyaiologicai effects of prolonged exposure to nicotine infused i.v. to the effects of smoking cigarettes throughout the day. ABBREVIATIONS: nicotine-d2, 3',3'-didenteroS-nicotine; nicotine-do, unlabeled S-nicotine; nlcotine-d. 3',3'-didentero-N'-didenterometttyf•rrooarve AUC area under the concentration-time curve. _ - _v 1000

I I Methods Suppression of Cigarette Smoking 1001 subjects. The subjects were eight healthy male volunteers, 27 to 62 r f age, recruited by newspaper advertisement.a. The subjects an average of 22 cigarettes per day (range, 12-30) and had for an average of 23 years (range, 12-44). Machine-determined ...S (Federal Trade Commission) of cigarettes averaged 1.1 mg of o and 16.6 mg of tar. Admission blood cotinine concentration 315 ng/ml (range, 143-681), whereas the mean score on the tom questionnaire, a questionnaire to assess degree of nicotine tuence, averaged 8.6 (range, 7-11) out of a maximum score of 11, h.6 points indicating maximal physical dependence (Fagerstrom. By design. Subjects were admitted to the Clinical Study Center Francisco General Hospital on two occasions. The first admis- n t hase 1) was to determine intake of nicotine during ad libiturn a e smoking, and lasted for 3 days. One day was allowed for the to become acclimatized to the research ward. On the 2nd day )ject smoked his chosen brand of cigarettes as desired. Blood ..ampied from an indwelling i.v. catheter every 2 hr for measure• n concentrations of nicotine and carboxyhemoglobin. On the 3rd R etermine clearance of nicotine, subjects received an i.v. infusion ine•d, (Jacob et aL, 1988), 2 µg base/kg/min for 30 min with sampling before and every 10 min during and at 30- to 60•min ls for 6 hr after the infusion. The clearance of deuterium•labeled e has been shown in a previous study to be similar to that of e•do (manuscript in preparation). Infusions were administered morning. On the day of the infusion, the subjects were allowed 9moke cigarettes as desired so that the measured clearance of e would be representative of clearance during cigarette smoking. is studies have indicated that tobacco abstinence may affect the lic clearance of nicotine (Lee et al., 1987). ..e blood level data from studies conducted during the first admis- re analyzed as described below to determine the daily intake of le from cigarette smoking for each subject. On another occasion 2), usually 2 weeks (range, 9-41 days) later, subjects were utted to the research ward for 8 days. On alternate days (total of [ions), between 7:00 and 8:00 A.M. in the morning, an i.v. was placed in a forearm vein to administer a 14-hr infusion of or saline. The infusion was administered between 8:00 A.M. ..00 P.M., the hours in which subjects typically smoke most of I igarettes. The total dose of nicotine infused was that dose ed to be the daily intake of nicotine from smoking for that jal as measured during the first admission. During two of the n sessions (one while receiving nicotine-d2 and the other while ,.ing saline), subjects could smoke their cigarettes as desired from I M. (when the infusion started) for the remainder of the day and 00 A.M. the next morning. Subjects were instructed to smoke as shed without any suggestion that the infusions might reduce their consumption. Subjects were told that they would be receiving an infusion containing nicotine or salt water, but would not be told which. The nursing staff who made the cardiovascular measurements and administered the questionnaires were also blind to the nature of the infusion. Subjects were required not to smoke from 11:00 P.M. the previous night until the start of the infusion so as to standardize the pretreatment nicotine exposure among subjects. During the other two infusions (unlabeled nicotine and saline), no smoking was allowed. The purpose of these infusions was to assess the pharmacologic activity of nicotine infusion in the absence of cigarette smoking. All cigarette butts were collected and weighed to determine how many cigarettes were smoked and how much tobacco was burned. On infusion days, venous blood samples were obtained from the arm opposite the infusion catheter every 2 hr for measurement of blood nicotine and carbozyhemoglobin concentrations. Urine was collected each 24 hr for measurement of concentrations of catecholamines. Heart rate and blood pressure were measured by ward nurses in subjects in the recumbent position every 4 hr while subjects were awake. Subjective questionnaires were administered 5 times per day: before, 1, 3, 8 and 13 hr after beginning of the infusion. The questionnaire had 12 items that inquired about effects that might be anticipated to result from exposure to nicotine, as well as an item asking about desire to smoke a cigarette. The following statements were rated on a 0 to 4 scale from "not at all" to "extremely": 1, 1 feel lightheaded or dizzy; 2, I feel high; 3, I feel nauseated: 4, I feel alert and awake; 5, I feel calm and relazed; 6, I feel stimulat.ed; 7, my heart is beating faster, 8, 1 feel satisfied: 9, I feel anxious or tense; 10, 1 would like a cigarette now; 11, how similar are the effects produced by this infusion to those produced by smoking a regular cigarette? and 12, how strong is the dose of the infusion? Analytical methods. Plasma samples (collected in study blocks during which no deuterium•labeled nicotine had been infused) were assayed for concentrations of nicotine by gas liquid chromatography and nitrogen phosphorus detection, using the assay of Jacob et al (1981) modified for use of a capillary column and using 5-methylnico• tine as the internal standard. Concentrations of nicotine and nicotine• dz (after infusion of labeled nicotine) were measured by selected ion monitoring gas chromatography-mass spectrometry using nicotine•d, as an internal standard (manuscript in preparation). Carboxyhemoglo- bin concentrations were measured using an IL 280 Co-oximeter. Urine catecholamines were measured by high-performance liquid chromatog- raphy using a coulometric electrochemical detector (Higa et al., 1977). Data analysis. The area under the AUCs for 24 hr for nicotine and carboxyhemoglobin were computed by the trapezoidal rule. Total plasma clearance of nicotine was computed as infused dose + AUC, extrapolating the area under the terminal log-linear portion to infinity. Assuming that the clearance (CL) of nicotine was the same on the infusion and the circadian blood sampling days, daily intake of nicotine during cigarette smoking (Dose, D) was computed as D=(AUC) x 1 ae and nicotine consumption and clearance of nicotine, measured during phase 1 of the study i. Federal Trade Commissron: Nic, nicoLne; C1g, cgarettes. Adnstqn F Ad I. drtum Cgarme Smohng (2e tT) &Oset No Plssti FTC NKOa+e FTC Ta• aqentran Raong cierena Sr cru" 9" Hic/Cg . ~ Cotrrx AUC- Dose - N/Ry rtg ng m/rmn par 24 Nr np/m+•nr mg 1 311.7 1.1 16 7 1214 24 413 32.7 1.36 2 143.3 1.0 17 7 1492 12 219 19.7 1.64 I 3 288.8 1.1 16 8 1125 20 534 35.3 1.77 4 232.0 1.4 17 9 1912 24 426 49.9 2.08 5 154.8 1.1 16 8 1730 15 165 17.0 1.15 6 478.5 1.1 16 11 1013 30 734 44.5 1,48 7 681.0 1.0 15 8 933 28 858 48.0 1.71 8 122.8 1.2 20 11 1287 27 229 17.7 0.66 Mean 315.5 1.1 16.6 8.6 1338 22.5 447 33.1 1.48 S.D. 181.3 0.1 1.5 1.6 316 6.4 250 13.7 0.44 I

1002 Benowitt and Jacob III vor. 254 I TABLE 2 Cigarette consumption and nicotine/carbon monoxide exposure during infusion of deuterium-tabeled nicotine or satin. (phas. 2 of the study) Nic. naotne: COHb, carboxyhert'wqbbuAnn Cgvsttes SnipcN TcOacca B&mee AUC,e A11C CdHD kw I No S&k NtirobrM Saw N4rotrK SakK NKarn satie Nroerw pv 21 rv q/24 Ar nG/ml' M p %'M 1 21 11 11.4 5.7 387 189 154 95 2 30 11 14.5 4,2 268 158 123 109 3 26 15 16.0 9.2 656 540 158 68 I 4 19 19 13 2 13 2 332 232 119 104 5 13 11 . 8.2 . 7.0 134 140 104 90 6 43 25 34.1 19.5 651 479 224 160 7 22 29 16.4 21.4 721 613 166 175 I 8 30 38 14,2 17.6 523 423 120 130 Mean 25.5 19.9$ 16.0 12.2t 459 347" 146 116' S.D. 9.1 9.9 7.8 6.7 211 188 38 36 I I I I I I I I I I I 1 SlQruficarttty different from salinE condition: ' P<.05; " P<.001; ; P<.10, NICOTINE TIME -W Nicotlna-d 2 (IV Infusion) 4 Nicotine-d p (Ciqarette Smoking, phasel) (CL). Average nicotine intake per cigarette was computed by dividing D by the number of cigarettes smoked. Measures of cigarette smoking in phase 2 of the study included the number of cigarettes smoked, the weight of tobacco burned, the area under the unlabeled nicotine blood concentration-time curve, daily intake of nicotine from smoking (computed using the AUC of nicotine while smoking cigarettes and the clearance determined by infusion of labeled nicotine in phase 1 of the study) and area under the carboxy- hemoglobin concentration time curve. Data were compared on nicotine and saline infusion days by paired Student's t tests with P < .05 considered significant. One-sided tests were used to test suppression of cigarette smoking with i.v. nicotine as the direction of difference was hypothesized a priori. Other comparisons used two-tailed t tests. The extent of suppression, that is, reduction of nicotine intake from cigarette smoking, was computed from the 24-hr AUCs for unlabeled nicotine as: (AUCs - AUCN) + AUCs, where AUCs and AUCk are the areas under the blood concentration-time curve during i.v. infusion of saline and of nicotine, respectively. Physiological measurements including blood pressure and heart rate were averaged over the day and compared across treatments, as well as urine catecholamine data, by repeated measures analysis of variance. Results Results from the first phase of the study, describing cigarette consumption, clearance and other pharmacokinetic parameters for nicotine and nicotine intake from cigarette smoking are shown in table 1. The total dose of nicotine infused over 14 hr during phase 2 of the study averaged 33.1 mg (range, 17.0-49.9 1NFUSION Fig. 1. Plasma concentrations of nicotine measurec throughout the day during ad libitum smoking (phase 1) and during 14-hr i.v. infusion of deuterium-labebc nicotine (phase 2). Note that during i.v. infusion a nicotirle-d2, cigarette smoking was allowed, but tt>E figure shows nicotineHyz concentrations only. Mean (Y S.E.M.) of eight subjects. mg), the same as that estimated from ad libitum smoking iu phase 1. The number of cigarettes smoked and blood nicotine concen trations (AUC) over 24 hr were similar comparing phase I o the circadian study during cigarette smoking and phase 2 durim infusion of saline (tables I and 2). The 24-hr AUC was 447 : 250 ng/ml-hr (mean t S.D.) us. 459 ± 211 ng/ml•hr for phas, 1 and phase 2, respectively. Area under the blood concentration-time curves were simils for nicotine-d2 administered by infusion and natural nicotin during cigarette smoking while receiving an infusion of salir (488 ± 269 us. 459 ± 211, respectively), validating the estimi tion procedure and the intent to fully replace nicotine frot cigarette smoking. The temporal pattern of concentrations r nicotine were somewhat different for infusion compared wit smoking (fig. 1), because during infusion nicotine was admit istered over 14 hr, whereas during smoking nicotine could 1 consumed ad libiturn over 24 hr. Infusion of nicotine-d2 suppressed cigarette consumption ar the amount of tobacco burned in five of the eight subjec although the effects were not significant (table 2). Nicoti infusion did significantly suppress nicotine intake from cif rette smoking by an average of 24.6% (figs. 2 and 3); carb monoxide was similarly decreased, consistent with a reduc level of smoking. However, the total concentration of nicoti that is, combined from smoking and infusion; was substantif 0

I + Nicotine-d 2 Infusion 4 Saline Infusion TIME I 2. Ptasma concentrations of nicotine and blood concentrations of irboxytfemogkobin (COHB) measured throughout the day during ad ttum smoking on days during which 14hr i.v. Infusions of saline or ~terium-Iabeled nicotine (32.7 mg) were administered 'n one subject. I roetttrations of deutenum-labeled nicotine are not shown. reater during nicotine infusion, indicating incomplete down- at,.on (fig. 4). It is noteworthy that the one subject whose ottne intake from smoking was not suppressed by i.v. nic- .ne is the subject (No. 5) who had the lowest daily intake of icotine at base line. To examine the temporal aspects of suppression of nicotine ake from smoking, area under the blood concentration-time rves of nicotine-do were examined at different times of day: ~ the morning as nicotine-d2 levels from the infusion were .~iefng (8:00 A.M. to 12:00 NOON), in the afternoon and evening, fen nicotine-d2 levels were near or at plateau values (12:00 ~)ON to 12:00 A.M.), and overnight, when nicotine-d2 levels I 80-1 60'1 40'i 20- r 0 IV SAL IV NIC-d 2 1 Suppression of Cigarette Smokinp 1003 were falling (12:00 A.M. to 8:00 A.M.). The greatest suppression of nicotine derived from cigarettes by infused nicotine occurred in the afternoon, when levels of i.v. nicotine were the greatest (average suppression, 27.8%) with a lesser degree of suppression in the morning (22.2%) and overnight (18.4%). Cardiovascular responses to i.v. nicotine and cigarette smok- ing are shown in figure 5 and table 3. Heart rate was similar during smoking with saline or nicotine infusion and nonsmok- ing with nicotine infusion sessions. All were higher than non- smoking saline infusion. The combination of smoking and i.v. nicotine produced no additional heart rate acceleration. Blood pressure tended to be highest during the smoking with i.v. nicotine and lowest during the nonsmoking with saline condi- tions, but the magnitude of differences between conditions was small. Urine epinephrine secretion was significantly higher during nicotine infusion in both the smoking and nonsmoking condi- tions. Dopamine excretion tended to be lower during the non- smoking/saline infusion condition compared with all nicotine conditions. The 14-hr infusion of nicotine produced no adverse subjective effects. Comparing nonsmoking days during which saline or nicotine were infused, there were no differences in responses to any of the questionnaire items; that is, subject could not tell whether they were receiving nicotine or saline. Two subjects (numbers 1 and 6) spontaneously reported less of a desire to smoke cigarettes while receiving the infusion of nicotine. Discussion Our study confirms the hypothesis that full replacement of nicotine suppresses the intake of nicotine from cigarette smok- ing. The extent of suppression was incomplete, averaging only 25%, indicating that down-regulation is imprecise. Down-reg- ulation was observed in all subjects except for the subject with the lowest habitual intake of nicotine. The greatest suppression was by 51%. Our subjects were mostly heavy cigarette smokers who rated high on a dependence scale; none was interested in trying to stop smoking. Two of our subjects reported less of a desire for cigarettes, even though not trying to stop smoking. Our study describes the physiological effects of prolonged Fig. 3. Twenty-four hour area under the plasma nicotine concentratbn time curve (reNecting intake of nicotine) durmg ad libitum cigarette smoking on days during which subjects received a 14-hr i.v. infusion of saline (SAL) or deutenum-Iabeled nicotine. Concentrations of deutenum-labeled nicotine are not included in the Al1C computation. Mean ± S.D. values are shown in the margins. The AUC during infusion of nicotine was sig- nificantly bwer than that measured during infusion of saline as indicated by the * (P < .05). 0

I I I I I I I I I I I I I I I I I I 1004 ° E ENnowitz and Jacob III INFUSION ; M1cCtM" , (N,c • = InfYfienl 4 NICOIIM.r 5 (SUIn1 InfuuOn) } NICa1 . NIC-At (NiC4t InfuslOn) Voi. 254 cigarette smoking. That administration of nicotine from a source other than smoking should influence smoking behavior has been felt to be critical to supporting the argument that nicotine is the main determinant of cigarette smoking. Lucches, et al. (1967) reported that infusion of 2 to 4 mg of nicotine per hour reduced the number of cigarettes smoked and the amount of each cigarette smoked. In contrast, Kumar et aL (1977) founc no changes in cigarette puffing after 1.7 mg of nicotine giver by intermittent bolus injection over 10 min. Russell (1988 recently reported that pretreatment with i.v. nicotine to achievc blood levels comparable to those achieved during cigarettf smoking markedly suppressed nicotine intake from a singlc cigarette. Russell (1988) found precise down-regulation of nic otine intake from cigarettes such that the levels of nicotinl after smoking a cigarette were nearly the same in nicotine o saline pretreatment conditions. Suppression of cigarette smoking with other forms of nicotinf treatment has also been reported. Nicotine taken p.o. in cap sules produces small reductions in number of cigarettes smokef (Jarvik et al., 1970). Russell and coworkers (1976) found tha smokers (recruited from a smokers' clinic) had similar plasmr nicotine levels while smoking and chewing 2-mg nicotine gum 10 pieces per day, as they had while smoking without the us, of gum. That the concentrations of nicotine were not increase, by the combination indicated down-regulation of smoking, al though a decrease in nicotine intake from cigarette smokin could not be directly measured. Although our data support the idea that exogenous nicotin can suppress cigarette smoking, they do not support the ide. of precise down-regulation of nicotine. It has been assume that down-regulation of nicotine intake serves to avoid th development of nicotine intoxication. Such regulation would b most likely to occur after relatively brief periods of exposure t nicotine, such as was the case in the Russell (1988) study. I contrast, our subjects were exposed to a gradually increasin level of nicotine over many hours, allowing for the developmen of tolerance. Pharmacodynamic studies suggest a half-life c regression of tolerance to nicotine effects on heart rate of 3 min (Porchet et aL, 1988). If such a half-life is also relevant t the acquisition of tolerance (as is implied by the pharmacod.% namic model), and if the half-life applies to toxic effects c nicotine, it is expected that after several hours of nicotin .o _ 0 41. NlCollnla " Infusion 'o- SaIIfN Infusion 0 oaoo 1600 2400 1./E 0800 Fig. 4. Plasma ooncentrations of nicotine and biood carboxyhemogiobin (COHB) measured throughout the day during ad libitum smoking on days during which subjects received 14-hr infusions of saline or deuterium- Iabeled nicotine. Two curves from the nicotine infusion day are presented, one shows natural nicotine derived from smoking: the other shows total nicotine (natural + deuterium-Iabeled). Mean (±S.E.M.) of eight subjects. nicotine exposure, even at levels of nicotine substantially higher than those derived from usual cigarette smoking. No subjects became ill. Cardiovascular data indicate that i.v, nicotine and smoking had similar effects, and that there was only a slight suggestion of additive effects when both were combined. These findings are consistent with a previously published study show- ing similar cardiovascular responses to smoking cigarettes that resulted in low or high blood levels of nicotine (Benowitz et aL, 1984). Our study has theoretical relevance to a longstanding contro- versy as to whether administration of nicotine per se affects INFUSION _ 60 A ~ 0 0 1200 0800 t Nicotina Infusion, NS] -0* Salin• Infusion, C IS ~ Salin• Infusion, NS 0 1600 2000 2400 TIME Fig. 5. Heart rate measured throughout the day dun ad librtum cigarette smoking (CS) with i.v. infusion saline and on no-smoking days (NS) dtrcing which sc )ects received a 14-hr infusion of saline or r>+cob Mean (±S.E.M.) of eight subjects.

I IIM TABL E 3 t:ardiovascular effscts of i,v. nicotine and cigarette smoking Men x S.D. Suppression of Cigarette Smoking 1005 I No Srtwueq 8rt~++0 S~ SaHe eMncn (1) Nootre nfwnn (2) Sune edus+on (3) N~cofne nhw (4) Or~~ rate (bpm, mean)e 70.4±8.2 77.0t8.1 75.9±9.4 77.1±7.6 1-2, 3. 4 I Systolic t>{ood pressure (mm Hg, mean) 122.1 t6.4 124.7±7.5 124.7±9.8 127.9±12.2 (P < .10) Diastobc blood pressure (mm Hg, mean) 67.4±6.8 70.2t6.1 69.6t7.1 72.0t8.6 (P <.10) Urirro rtorepinephnne (µg/24 hr) 39.9t14.6 39.4±16.4 37.2±15.5 40.6t13.0 - fU nne epinephnne (Kg/24 hr) 6.2±3.1 9.5±5.8 7.0±5.8 9.8±4.3 1, 3-2, 4 Urine tlopanxne ()ug/24 hr) 223.4±39.0 267.7±50.3 286.7±79.3 274.0±75.6 (P < .10) • AnNysis of vanance: oashes klGicate s+gniflcant differenoes whereas commas ind+cete no siqnificant Gifferences Detween treatments by Tukey post hoc tests. ' Merl anC S.D. of fiw measur.ments taken over 16 Ix. tretreatment the development of tolerance to toxic effects of nicotine would be maximized, at which point precise down- regulation would become irrelevant. Cigarrette smoking might hen be motivated more by psychosocial factors than by regu- ation of the level of nicotine in the body. This is the likely :zplanation for the different findings with regard to down• regulation in our study and the study of Russell (1988). Despite the development of tolerance to subjective (and Iresumably to toxic) effects, prolonged nicotine infusion pro- luced mazimal suppression of nicotine intake from cigarettes in the afternoon and evening. Thus, although a high degree of olerance to toxic effects of nicotine appears to develop, com- lete tolerance does not seem to develop to nicotine actions hat influence smoking behavior. As predicted by pharmaco- dynamic modeling (Porchet et aL, 1988), i.v. nicotine and/or Imoking had similar and persistent effects on heart rate iroughout the day. Our data suggest that some of the psycho- Aical effects of nicotine may behave similarly to heart rate in this regard. In summary, we have shown that prolonged infusions of icotine suppress nicotine intake from cigarette smoking and, +en when nicotine from cigarettes is superimposed, are well tolerated. The results suggest that administration of nicotine a sustained release manner, such as would occur with trans- trmal delivery systems, shows promise as a safe and effective .ijunct to smoking cessation therapy and/or as a medication t treat human disease. know{sdtmenta Tbe authors are grateful to Clarissa Ramatead for .ssistance in conducting +clinical studies, Liu Yu, Chin Savanapridi and Lila Glogowaky for assistance biocMmieal analyses, Gunnatd Modin for statistical analysis and Kaye Welch r Pceparation of the manuscript. ~ ferencea 1 tLIN, T., BUEHLER, A., MULLER, P., VE8ANEN, K. AND IMHOF, P. R.: Controlled trial of transdermal nicotine patch in tobacco withdrawal. Lancet. I: 7-9, 1989. NOWrrz, N. L.: Pharmacologic aspects of cigarette smoking and nicotine ddiction. N. Engt. J. Med. 319: 1318-1330, 1988. BENowrrz, N. L.. JACOB, P. III AND SAVANAPRIDI, C.: Determinanu of nicotine intake while chewing nicotine polacrilex gum. Clin. Pharmacol. Ther. 41: 467- 473, 1987. BENowrrz, N. L., KUYT. F. AND JACOB, P. III: Influence of nicotine on cardio- vaacular and hormonal effects of cigarette smoking. Clin. Pharmacol. Ther. 38: 74-81, 1984. FAGERerROM, K. 0.: Measuring degree of physical dependence to tobacco smoke with reference to individualization of treatment. Addict. Behav. 3: 235-241, 1978. HIGA, S. T., SULUKI, T., HAYASHI, A., PBUGE, I. AND YAMAMURA, Y.: Isolation of catecholaminea in biological fluids by boric acid gel. AnaL Biochem. 77: 18- 24, 1977. JACOB, P. I1:I, BENOWR'z, N. L., AND SHULGIN, A. T.: Synthesis of optically pure deuterium-labelled nicotine, nornicotine, and cotinine. J. Labelled Comp. Phar- maceu t. 2 6: 1117-1128, 1988. JACOB, P. III, WILaON, M. AND BENOWITZ, N. L.: Improved gas chromatographic method for the determination of nicotine and cotinine in biologic fluida. J. Chromatogr. 222: 61-70, 1981. JARVIK, M. E., GLtcK, S. D. AND NAKAMURA, R. K.: Inhibition of cigarette smoking by orally administered nicotine. Clin. Pharmacol. Ther. 11: 574-576, 1970. KuMAR, R., COOKE, E. C., LADER, M. H. AND RUSSELL, M. A. H.: Is nicotine important in tobacco smoking" Clin. Pharmacol. Ther. 21: 520-529, 1977. LAM, W., SZE. P. C., SACKS. H. S. AND CHALMERS, T. C.: Meta-analysis of randomised controlled trials of nicotine chewing-gum. Lancet 2: 27-30, 1987. LEE, B. L., BENOwrrz, N. L. AND JACOB, P. IfI: Influence of tobacco abstinence on the disposition kinetics and effects of nicotine. Clin. Pharmacol. Ther. 41: 474-478,1987. LucCHESt, B. R., SCHUS7ER, C. R. AND EMLEY, G. S.: The role of nicotine as a determinant of cigarette smoking frequency in man with observations of certain catdiovaacular effects associated with the tobacco alkaloid. Clin. Pharmacol. Ther. 8: 789-796, 1967. PORCHE-r, H. C., BENowrrz, N. L. AND SHEINER, L. B.: Pharmacodynamic model of tolerance: Application to nicotine. J. Pharmacol. E:p. Ther. 244: 231-236,1988. RUSSELL, M. A. H.: Nicotine intake by smokers: Are rates of absorption or steady state levels more important? In The Pharmacology of Nicotine, ed by J. J. Rand and K. Thurau, pp. 375-403, IRL Preu, Washington, DC, 1988. RUSSELL, M. A. H., FEYLRABEND, C. AND COLE, P. V.: Plasma nicotine leveb after cigarette smoking and chewing nicotine gum. Br. Med. J. 1: 1043-1046, 1976. WEsT, R. J., JARvIs, M. J., RUSSELL, M. A. H., CARRUTHERS, M. E. AND FEYERABEND, C.: Effect of nicotine replacement on the cigarette withdrawal syndrome. Br. J. Addict. 79: 215-219, 1984. Sead reprint requests to: Dr. Neal L. Benowitz, San Francisco General Hospital Medical Center. Bldg. 30, 5th Floor, 1001 Potrero Ave., San Francisco, CA 94110. I I I