Nicotine chewing gum as a substitute for smoking.

The capacity of nicotine-containing chewing gum to produce plasma nicotine levels comparable to heavy cigarette smoking was tested in 21 subjects. On a fixed schedule of one piece of gum (4 mg nicotine) per hour, the average peak plasma nicotine concentration was 175-7 nmol/l (28-5 ng/ml) compared to 189-3 nmol/l (30-7 ng/ml) obtained from normal ad libitum smoking. Unpleasant side effects were common and in some cases plasma nicotine concentrations were two and even three times as high as with smoking; The chewing gum provided some satisfaction to all but four subjects, but its degree was not related to the concentration of plasma nicotine it produced, neither was there an inverse relation between the plasma nicotine concentration while taking the gum and the subjective sense of missing cigarettesmthis suggests that the capacity of the gum to act as a substitute for smoking is not necessarily related to its capacity to provide nicotine. Flexible dosage dictated by individual needs would probably lower the incidence of side effects and might secure closer approximation to smoking concentrations of plasma nicotine.     

Effect of cigar smoking on carboxyhaemoglobin and plasma nicotine concentrations in primary pipe and cigar smokers and ex-cigarette smokers

Five ex-cigarette smokers and five primary pipe and cigar smokers each smoked a large cigar. Carboxyhaemoglobin (COHb) and plasma nicotine levels were measured. In the ex-cigarette smokers mean COHb rose from 2·9% to 9·6% and plasma nicotine from 79·0 nmol/l to 281 nmol/l (12·8-45·6 ng/ml). This response was similar to that of cigarette smokers smoking cigarettes, which indicated that the subjects had inhaled and absorbed significant amounts of nicotine. In the primary pipe and cigar smokers the mean COHb rose from 0·8% to 1·0% and the plasma nicotine from 21 nmol/l to 32 nmol/l (3·4-5·2 ng/ml), indicating neither significant inhalation nor significant nicotine absorption.Since ex-cigarette smokers do not seem to lose their habit of inhaling when they change to cigars, measures aimed at persuading smokers to switch to cigars will have little effect on their health. Pipe and cigar smokers who have never smoked cigarettes do not inhale, which probably accounts for their reduced incidence of coronary heart disease and lung cancer. But they also appear not to absorb nicotine, which suggests that nicotine is absorbed largely from the lung and that the buccal mucosa is unimportant. It also raises the interesting question of why primary pipe and cigar smokers do smoke.     

Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers.

Blood nicotine and carboxyhaemoglobin (COHb) concentrations were studied in 330 smokers (206 women and 124 men). Blood nicotine concentrations in individual smokers varied from 25 to 444 nmol/l (4 to 72 ng/ml). The average concentration, 203 nmol/l (33 ng/ml), was the same in the men and the women, although cigarette consumption was higher in the men. Despite large differences in nicotine yield, there was no relation between blood nicotine concentration and the type of cigarette smoked: smokers of plain, untipped cigarettes (1.9 mg nicotine), cigarettes with unventilated filters (1.3 mg nicotine), and cigarettes with ventilated filters (0.8 mg nicotine) had similar blood nicotine concentrations. Cigarette consumption was also similar in these three groups. The correlation between blood nicotine concentration and nicotine yield of cigarette, though significant, was low (0.21, p < 0.001), showing that the nicotine yield of the cigarettes accounted for only 4.4% of the variation in blood nicotine concentrations. Similarly, the low correlation of 0.30 between COHb concentration and cigarette consumption suggests that cigarette consumption accounted for only 9% of the variation in the amount of smoke taken into the smokers'' lungs. These results suggest that the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation. The findings of epidemiological studies showing lower risks with filter-tipped cigarettes may be attributable to other factors such as biases in the samples and changes in the quality and carcinogenicity of tobacco tar, rather than to reduced tar intake.     

Absorption and metabolism of nicotine from cigarettes.

Eight men volunteers each smoked a single cirgarette containing 14C-nicotine and gave arterial blood samples during and for 50 minutes after smoking. The maximum concentration of nicotine in the arterial blood ranged from 31 to 41 mug/l in four regular cigarette smokers who inhaled. Two non-smokers achieved maximum levels of 2 and 4 mug/l. On a separate occasion two of the inhalers received 1 mg. 14C-nicotine in 10 divided doses injected intravenously. In both cases the peak arterial nicotine concentrations bore a similar relationship to the intravenous dose, as did the peak nicotine concentrations to the retained doses during smoking.     

Tobacco and myocardial infarction: is snuff less dangerous than cigarettes?

OBJECTIVE--To estimate the risk of myocardial infarction in snuff users, cigarette smokers, and non-tobacco users in northern Sweden, where using snuff is traditional. DESIGN--Case-control study. SETTING--Northern Sweden. SUBJECTS--All 35-64 year old men who had had a first myocardial infarction and a population based sample of 35-64 year old men who had not had an infarction in the same geographical area. MAIN OUTCOME MEASURE--Tobacco consumption (regular snuff dipping, regular cigarette smoking, non-tobacco use) and risk of acute myocardial infarction. RESULTS--59 of 585 (10%) patients who had a first myocardial infarction and 87 of 589 (15%) randomly selected men without myocardial infarction were non-smokers who used snuff daily. The age adjusted odds ratio for myocardial infarction was 0.89 (95% confidence interval 0.62 to 1.29) for exposure to snuff and 1.87 (1.40 to 2.48) for cigarette smoking compared with non-tobacco users, showing an increased risk in smokers but not in snuff dippers. Regular cigarette smokers had a significantly higher risk of myocardial infarction than regular snuff dippers (age adjusted odds ratio 2.09; 1.39 to 3.15). Smoking, but not snuff dipping, predicted myocardial infarction in a multiple logistic regression model that included age and level of education. CONCLUSIONS--In middle aged men snuff dipping is associated with a lower risk of myocardial infarction than cigarette smoking.     

Cigarette smoking may reduce plasma leptin concentration via catecholamines

BACKGROUND: Leptin might influence body weight among smokers. DESIGN: (A) Screening of plasma leptin levels in 222 sedentary, smoking and non-smoking middle-aged men. (B) Double-blind, placebo-controlled smoking intervention on smokers (n=31). (C) Non-smokers (n=40) received chewing gum with nicotine (2mg nicotine, n=23) or without nicotine (n=19). (D) The effects of nicotine (0.05 and 0.5 microg/mL) were monitored on leptin secretion and mRNA levels in a human placental cell line (BeWo) expressing leptin, a murine adipocyte cell line (3T3-L1) and human adipose tissue explants. RESULTS: (A) Plasma leptin levels in smoking men (8.4+/-8.4 ng/mL, n=100) was lower as compared to non-smokers (10.3+/-7.3 ng/mL, n=122) (P<0.001), even when adjusted for differences in body mass index (BMI) (P<0.001). (B) A significant reduction (P=0.02) in plasma concentration of leptin was found already after smoking one cigarette. Concomitant with the 3-5 fold increase in plasma nicotine concentration after the first cigarette, we observed increased plasma adrenaline levels (P=0.005). (C) There was no effect of nicotine on plasma leptin levels in non-smokers receiving nicotine-containing chewing gum, and plasma concentrations of catecholamines were unaltered. (D) There was no effect of nicotine on leptin mRNA expression after incubation with cells or adipose tissue. CONCLUSION: Cigarette smoking reduced plasma leptin concentration in vivo, whereas nicotine had no direct effect on leptin expression in vitro. Nicotine might indirectly reduce leptin secretion via enhanced plasma catecholamine concentration.     

Relationship between cigarette yields,puffing patterns,and smoke intake: evidence for tar compensation?

The relationship between cigarette yields (of nicotine, tar, and carbon monoxide), puffing patterns, and smoke intake was studied by determining puffing patterns and measuring blood concentrations of nicotine and carboxy-haemoglobin (COHb) in a sample of 55 smokers smoking their usual brand of cigarette. Regression analyses showed that the total volume of smoke puffed from a cigarette was a more important determinant of peak blood nicotine concentration than the nicotine or tar yield of the cigarette, its length, or the reported number of cigarettes smoked on the test day. There was evidence of compensation for a lower tar yield over and above any compensation for nicotine. When nicotine yield was controlled for, smokers of lower-tar cigarettes not only puffed more smoke from their cigarettes than smokers of higher-tar cigarettes but they also had higher plasma nicotine concentrations, suggesting that they were compensating for the reduced delivery of tar by puffing and inhaling a greater volume of smoke. The results based on the COHb concentrations were consistent with this interpretation. If an adequate intake of tar proves to be one of the main motives for smoking, then developing a cigarette that is acceptable to smokers and also less harmful to their health will be much more difficult.     

Effect of nicotine chewing gum on smoking behaviour and as an aid to cigarette withdrawal.

In a double-blind, placebo-controlled, crossover trial the effect of 2-mg nicotine chewing gum was studied in 43 smokers when they were smoking as inclined and when they were trying to stop smoking. Although 70% of the smokers stopped smoking during treatment, only 23% were still abstinent after one year. The effect of the nicotine, though significant, was small compared with the overall reduction in smoking. When the subjects were smoking as inclined cigarette consumption was reduced by an average of 37% on the nicotine gum compared with 31% on placebo gum, while avergage carboxyhaemoglobin (COHb) levels were reduced by 26% and 15% on the active and placebo gums respectively. When subjects tried to stop smoking there was a further considerable reduction in cigarette consumption, but no longer any difference between the two gums. Nevertheless, average COHb was still lower on the active gum. Plasma nicotine levels on the nicotine gum averaged only 10-7 ng/ml compared with 27-4 ng/ml after smoking. Better results could be expected with 4-mg nicotine gums.     

Simultaneous estimation of nicotine and cotinine levels in biological fluids using high-resolution capillary-column gas chromatography combined with solid phase extraction work-up

A rapid and sensitive capillary gas-chromatographic method with nitrogen-sensitive detection is reported for the simultaneous analysis of nicotine and cotinine levels occurring in the plasma, saliva, and urine of regular tobacco smokers. The proposed assay has a linear output, has satisfactory accuracy over the range of concentrations of both amines encountered in active smokers, and has also been successful in the analysis of the urine samples of passive smokers. Its lower limit of sensitivity is 0.2 ng of nicotine and 0.5 ng of cotinine per ml of plasma or saliva or per 100 l of urine.The beneficial characteristics of the presented method were achieved by the combination of solid phase extraction of 0.1–1.0 ml of fluid specimens, capillary column gas chromatography with splitless injection and nitrogen sensitive detection, and the use of separate, structurally analogous compounds as internal standards for nicotine. The suitability of the assay is shown by plasma concentration-time curves of nicotine and cotinine in a steady smoker during a 24 hours period.     

Should intake of carbon monoxide be used as a guide to intake of other smoke constituents?

The relation between blood carboxyhaemoglobin (COHb) and plasma nicotine concentrations was studied in a group of 12 smokers smoking cigarettes of three levels of standard delivery. While the intake of carbon monoxide from a single cigarette was unrelated to the intake of nicotine, presmoking "trough" concentrations of the two substances (reflecting longer-term exposure) were highly correlated. Various other measures of nicotine exposure were at best only moderately correlated with blood nicotine concentrations. Thus trough COHb concentrations might be used to provide a reliable indication of the exposure to nicotine of individual smokers smoking the same type of cigarette, and of the relative exposure to nicotine of populations smoking cigarettes of different standard deliveries.     

Absorption and metabolism of oral progesterone.

The absorption, metabolism, and clearance of progesterone from the peripheral circulation were investigated in five postmenopausal women after oral administration of 100 mg daily for five consecutive days. Maximal plasma concentrations of progesterone were observed within four hours after ingestion of the last dose, when the range (22.11-34.18 nmol/l; 696-1077 ng/100 ml) was comparable with that observed during the mid-luteal phase of the ovarian cycle. The surge in values lasted six hours, and progesterone concentrations remained raised for at least 96 hours. Of the three metabolites studied, the plasma concentrations of pregnanediol-3 alpha-glucuronide were most raised by treatment, the peak values ranging from 1097 nmol/l (54.9 microgram/100 ml) to over 2000 nmol/l (100 microgram/100 ml), which was the upper limit of the assay used. Concentrations of 17-hydroxyprogesterone were least raised, and the peak values ranged from 4.32 to 9.68 nmol/l (143-319 ng/100 ml). The plasma profile of 20 alpha-dihydroprogesterone most closely approximated that of progesterone, although the range of maximal values was lower (7.11-16.06 nmol/l; 228-514 ng/100 ml). Plasma concentrations of oestradiol were unchanged by giving progesterone. It is concluded that the increases in circulating concentrations of progesterone and the biologically active metabolite 20 alpha-dihydroprogesterone, and the duration of these increases, were sufficient to modulate the biochemistry of responsive tissues. Oral progesterone may thus have a therapeutic role, and this route of administration merits further investigation.     

Passive exposure to tobacco smoke: saliva cotinine concentrations in a representative population sample of non-smoking schoolchildren.

Saliva cotinine concentrations in 569 non-smoking schoolchildren were strongly related to the smoking habits of their parents. When neither parent smoked the mean concentration was 0.44 ng/ml, rising to 3.38 ng/ml when both parents were cigarette smokers. Mothers'' smoking had a stronger influence than did fathers'' (p less than 0.01). In addition, there was a small independent effect of number of siblings who smoked (p less than 0.01). The dose of nicotine received from fathers'' smoking was estimated as equivalent to the active smoking of 30 cigarettes a year, that from mothers'' smoking as equivalent to smoking 50 cigarettes a year, and that from both parents smoking as equivalent to smoking 80 cigarettes a year. This unsolicited burden may be prolonged throughout childhood and poses a definite risk to health.     

Plasma cocaine concentrations during cocaine paste smoking

Cigarettes containing cocaine paste were administered to experienced volunteer smokers in Peru, and plasma concentrations of cocaine were measured. Cocaine concentrations as high as 462 ng/ml were obtained after only three minutes of smoking cocaine paste. Subjects titrated their rate of consumption so as to achieve remarkably constant plasma concentrations during the smoking period. Areas under curve (AUC), adjusted for dose, were approximately 70% that obtained with oral or intranasal administration of cocaine to different subjects in previous experiments.     

Products of 5-lipoxygenase and myeloperoxidase activities are increased in young male cigarette smokers

Abstract The significance of 5-lipoxygenase and myeloperoxidase activities has not been extensively studied among young male smokers. Leukotriene B(4), 20-hydroxy-leukotriene B(4), 20-carboxy-leukotriene B(4) and 3-chlorotyrosine were measured in plasma and urinary samples of young male smokers at 8 hours following cigarette abstinence and an hour after cigarette smoking. Leukotriene B(4) and 3-chlorotyrosine were determined in neutrophils isolated from these individuals. The levels of these markers were compared with those of age-matched controls. In vitro studies were performed to evaluate the production of leukotriene B(4) and 3-chlorotyrosine from human neutrophils following exposure to nicotine and cotinine. Thirty male smokers (mean age, 27.4 years) and 28 male non-smokers (mean age, 28.7 years) were studied. Plasma levels of leukotriene B(4), 20-carboxy-leukotriene B(4) and 3-chlorotyrosine were higher in smokers than in non-smokers; leukotriene B(4) and 20-carboxy-leukotriene B(4) levels increased further an hour after cigarette smoking. Peripheral neutrophils isolated from smokers showed greater expressions of myeloperoxidase and 5-lipoxygenase activities compared with non-smokers, while plasma leukotriene B(4) and 3-chlorotyrosine were correlated significantly with high-sensitivity C-reactive protein and plasma nicotine concentrations. Exposure of human neutrophils to nicotine and cotinine resulted in a higher production of leukotriene B(4) and 3-chlorotyrosine. To conclude, leukotriene B(4) and 3-chlorotyrosine levels are increased in young male cigarette smokers. These results suggest that cigarette smoking aggravates neutrophil-mediated inflammation by modulating the activities of myeloperoxidase and 5-lipoxygenase pathways.     

男性吸烟者体重对烟碱引起的生热作用和儿茶酚胺释放的影响

本研究的目的是在中年男子中观察禁食情况下吸烟后烟碱对安静时能量消失（resting energy expenditure,REE)和血浆儿茶酚胺浓度的影响,并且在正常体重（BMI≤25kg/m^2),和超重（BMI＞25kig/m^2)吸烟者之间比较吸烟引起的REE和血浆儿茶酚胺的急性反应是否有差别,对32名禁食的男性吸烟者用间接测热法分别在吸烟前和吸2支含0．16mg烟碱（低烟碱）或2支含1．74mg烟碱（高烟碱）香烟30min后测定REE,同时测定血浆中烟碱和去甲肾上腺素浓度,正常体重组在吸低烟碱烟后和超重组不认在吸低烟碱烟或高烟碱烟后,REE和血浆儿茶酚胺均无明显改变,而在正常体重组中,吸高烟碱烟后血浆去甲肾上腺素浓度升,时REE增加7．2％,如果将血浆烟碱水平作为一个共变量进行分析,则吸烟后血浆去甲肾上腺素浓度和REE的改变也不明显,表明吸烟后的生热效应是因血浆烟碱浓度升高而引起的,体重对烟碱的生热效应能发生影响,在超重的吸烟者中烟碱的生热效应减弱,由此推测,正常体重的吸烟者在戒烟后,由于不再有吸烟引起的耗能生热,可能导致体重增加。     

Increased plasma concentrations of C9, C1-inhibitor and alpha 1-protease inhibitor associated with cigarette smoking

The association between various parameters of acute and chronic smoking status and plasma levels of three proteins, C9, C1-inhibitor (C1-INH) and alpha 1-protease inhibitor (alpha 1-PI) were determined for 49 male cigarette smokers and 49 age-matched nonsmokers (mean age = 32.2 years). The mean number of cigarettes smoked was 28.7 per day while the cumulative consumption was only 18.1 pack-years. Plasma levels of all three proteins were significantly higher in the smokers than nonsmokers. Plasma C9 and alpha 1-PI concentrations correlated with cumulative cigarette consumption and plasma nicotine concentrations. While C1-INH concentration did not correlate with either cumulative cigarette consumption or plasma nicotine concentration, it correlated significantly with serum thiocyanate concentration. No consistent correlation was found between plasma concentration of these proteins and parameters of pulmonary function.     

Chewing nicotine gum for 3 months: what happens to plasma nicotine levels?

Techniques that help patients stop smoking should also reduce their exposure to agents such as nicotine. The mean plasma nicotine levels in 50 subjects while they were still smoking and then while they were chewing pieces of gum containing either 2 or 4 mg of nicotine over a 12-week period of abstinence were 35, 9 and 23 ng/mL (217, 56 and 143 nmol/L) respectively. A small number of subjects given an unlimited supply of gum used 14 to 24 pieces of 4-mg gum daily and had plasma nicotine levels exceeding the levels achieved while smoking. There were no acute symptoms necessitating medical intervention associated with these excessive levels. Side effects were uncommon and usually controllable. When simple dosage rules are followed people who chew nicotine gum for a few months to stop smoking lower their exposure to nicotine.     

A Rat Model of Cigarette Smoke Abuse Liability

We sought to develop a rat model of cigarette smoke exposure (CSE) that created cotinine serum levels comparable to those of smokers and induced conditioned place preference (CPP) suggestive of cigarette smoke abuse liability. Rats were exposed to sidestream cigarette smoke delivered semicontinuously for 2 periods of 20 (group S20), 40 (group S40), or 60 (group S60) min daily for 12 wk. Serum cotinine concentration in blood samples was determined at 1 and 20 h after CSE. A biased (black versus white chamber) CPP paradigm was used. In the high CSE group (group S60), serum cotinine at 1 h (250 to 300 ng/mL) was comparable to average cotinine levels reported for addicted smokers (around 300 ng/mL). Cotinine levels at 20 h after CSE were higher than the smoker–nonsmoker cut-off value (greater than 14 ng/mL) in all smoking groups, with the S60 group having the highest levels. All rats preferred the black chamber to the white chamber during the preexposure CPP test. The time spent in the white chamber was increased compared with 0-wk values in group S40 at 8 wk, group S60 at 4 and 8 wk, and the control group at 4 and 8 wk but not at 12 wk; however, the shift in CPP was significantly higher at 8 wk in group S60 compared with other groups. In conclusion, interrupted 2-h daily CSE for 8 wk induced serum cotinine levels in rats comparable to those of smokers and induced CPP suggestive of cigarette smoke abuse liability.Abbreviations: CPP, conditioned place preference; CSE, cigarette smoke exposureThe devastating consequences of smoking on health have been studied extensively in numerous clinical and animal studies over time. This chronic habit leads to dependence on tobacco smoke, with nicotine, a main active ingredient of tobacco products, being recognized as the basic addictive substance.³²The known health benefits of smoking cessation motivate smokers to quit tobacco use. However, unaided efforts usually are unsuccessful, resulting in smoking relapse. The fight against nicotine addiction may be undermined by potential weight gain after smoking cessation, potentially discouraging those attempting to quit smoking and contributing to relapse. During the past few years, research has been focused on 2 main areas of interest toward this direction: understanding the underlying biologic mechanisms related to nicotine addiction to effectively design therapeutic strategies to support those who wish to quit smoking and investigating the hormonal and molecular mechanisms responsible for weight gain after smoking cessation.So far, animal models used to study the consequences of smoking cessation involved the administration of nicotine as a sole agent until addiction was achieved.²³ However, nicotine-administration models do not completely represent the toxic and addictive effects of cigarette smoke, given that smoke contains more than 4000 chemicals whose actions or coactions have not been thoroughly evaluated yet.¹ Cigarette smoke exposure (CSE) animal models have been used in studies investigating the metabolic changes conferred by smoking^10-12 but not in those after its cessation. In toxicity studies, animals are exposed to tobacco smoke for various periods, which depend on the side effect under investigation.^18,25,27 Smoke exposure timetables usually do not involve weekends for practical reasons, and addiction of animals to tobacco smoke is not assessed in current models.In our opinion, an ideal animal model of cigarette smoke abuse liability suitable for the study of smoking cessation resembles the clinical situation in terms of chronic daily inhalation of cigarette smoke sufficient to attain blood nicotine levels comparable to those of smokers and in cessation of the CSE period after achieving tobacco smoke abuse liability. In the present project, we sought to establish such a model in rats by defining the daily timetable of CSE to induce serum levels of cotinine, nicotine''s major proximate metabolite, comparable to those of smokers and by determining the minimum total CSE period required to induce abuse liability to cigarette smoke. We assessed the CSE period by using a biased conditioned place preference (CPP) paradigm.⁸     

Blood carboxyhaemoglobin,plasma thiocyanate,and cigarette consumption: implications for epidemiological studies in smokers.

Carboxyhaemoglobin and plasma thiocyanate concentrations were found to be significantly correlated with self-reported daily cigarette consumption in 360 smokers (r = 0.416 and 0.412 respectively; p less than 0.001). The extent to which inhalation patterns affected the intake of cigarette smoke constituents was determined from the partial correlation between carboxyhaemoglobin and plasma thiocyanate concentrations after the number of cigarettes smoke per day had been allowed for (r = 0.48). Thus 23% of the variation in carboxyhaemoglobin and thiocyanate concentrations was accounted for by the was a cigarette was smoked and a further 21% by the number smoked a day. Furthermore, the relation between carboxyhaemoglobin or plasma thiocyanate and daily cigarette consumption was not linear but reached an asymptote at consumption rates above 25 cigarettes a day. These results suggest that by itself daily cigarette consumption will not identify those smokers most at risk and will also underestimate and dose-response relationship between smoking and selected diseases.     

Pathogenesis of ischemic necrosis in random-pattern skin flaps induced by long-term low-dose nicotine treatment in the rat

The objectives of the present experiments were to study the effects of long-term low-dose nicotine treatment on skin hemodynamics, viability, and microvascular morphology in 4 x 10 cm dorsally based acute random-pattern skin flaps in the rat. In addition, the reversibility of the nicotine-induced detrimental effects on skin-flap viability following cessation of nicotine treatment also was investigated. Low-dose nicotine (0.6 mg/kg) administered twice daily and subcutaneously for 24 weeks significantly (p less than 0.05) decreased skin-flap capillary blood flow, distal perfusion, and length and area of skin viability compared with the saline-treated control (n = 15). However, these same parameters in rats (n = 15) whose nicotine treatment had been withheld for 2 weeks prior to skin-flap surgery were not significantly different from the control, thus indicating that the detrimental effects of this long-term, low-dose nicotine treatment were reversible. The mean plasma level of nicotine in the nicotine-treated rats was 8.1 +/- 0.4 micrograms/dl and was within the range of plasma nicotine levels reported for human heavy cigarette smokers. Light and electron microscopic studies did not show evidence of histologic damage to the cutaneous microvasculature in acute random-pattern skin flaps and samples of normal (nonoperated) skin in nicotine-treated rats. It is concluded that long-term plasma levels of nicotine similar to those of heavy cigarette smokers are detrimental to the capillary blood flow and viability of random-pattern skin flaps in the rat. These deleterious effects can be avoided if skin flaps are raised 2 weeks after cessation of nicotine treatment. This low-dose nicotine treatment does not cause histologic damage to the microvasculature. Other pathogenic mechanisms of nicotine-induced skin flap ischemia are discussed.