Smoke-free homes in England: prevalence, trends and validation by cotinine in children.

OBJECTIVE: To examine the prevalence of smoke-free homes in England between 1996 and 2007 and their impact on children's exposure to second-hand smoke via a series of annual cross-sectional surveys: the Health Survey for England. These comprised nationally representative samples of non-smoking children aged 4-15 (n = 13 365) and their parents interviewed in the home. Main outcome measures were cotinine measured in saliva, smoke-free homes defined by "no" response to "Does anyone smoke inside this house/flat on most days?", self-reported smoking status of parents and self-reported and cotinine validated smoking status in children. RESULTS: The proportion of homes where one parent was a smoker that were smoke free increased from 21% in 1996 to 37% in 2007, and where both parents were smokers from 6% to 21%. The overwhelming majority of homes with non-smoking parents were smoke free (95% in 1996; 99% in 2007). For children with non-smoking parents and living in a smoke-free home the geometric mean cotinine across all years was 0.22 ng/ml. For children with one smoking parent geometric mean cotinine levels were 0.37 ng/ml when the home was smoke free and 1.67 ng/ml when there was smoking in the home; and for those with two smoking parents, 0.71 ng/ml and 2.46 ng/ml. There were strong trends across years for declines in cotinine concentrations in children in smoke-free homes for the children of smokers and non-smokers. CONCLUSIONS: There has been a marked secular trend towards smoke-free homes, even when parents themselves are smokers. Living in a smoke-free home offers children a considerable, but not complete, degree of protection against exposure to parental smoking.

Nicotine yield from machine-smoked cigarettes and nicotine intakes in smokers: evidence from a representative population survey.

BACKGROUND: The relevance of nicotine yields from machine-smoked cigarettes for quantifying smokers' nicotine intakes and exposure to cigarette toxins has been called into question. However, most studies of the relationship between nicotine yield and nicotine intake have been on relatively small and unrepresentative samples and have included few smokers of "ultra-low" brands (i.e., those yielding around 1 mg of tar and 0.1 mg of nicotine). METHODS: We examined the relationship between salivary cotinine (a major metabolite of nicotine) concentrations and nicotine yields of machine-smoked cigarettes in a nationally representative sample of 2031 adult smokers of manufactured cigarettes surveyed in the 1998 Health Survey for England. We used standard linear regression techniques to examine associations and two-sided tests of statistical significance. RESULTS: Cotinine concentrations varied widely between smokers at any level of nominal brand nicotine yield. On average, cotinine levels were slightly lower in smokers of lower nicotine-yielding brands, but these smokers differed in terms of sex, socioeconomic profile, and cigarette consumption. After we controlled for potential confounders, nicotine yield from the brand smoked accounted for only 0.79% of the variation in saliva cotinine concentrations. Nicotine intake per cigarette smoked, as estimated from salivary cotinine level, did not correspond with machine-smoked yields at any level of nicotine yield. Nicotine intake per cigarette was about eight times greater than machine-smoked yields at the lowest deliveries (1.17 mg estimated nicotine intake per cigarette from brands averaging 0.14-mg delivery from machine smoking) and 1.4 times greater for the highest yield cigarettes (1.31-mg estimated nicotine intake per cigarette from brands averaging 0.91 mg from machine smoking). CONCLUSIONS: Smokers' tendency to regulate nicotine intake vitiates potential health gains from lower tar and nicotine cigarettes. Current approaches to characterizing tar and nicotine yields of cigarettes provide a simplistic guide to smokers' exposure that is misleading to consumers and regulators alike and should be abandoned.

Adjustment of smokers to dilution of tobacco smoke by ventilated cigarette holders.

This study was designed to examine the extent to which smokers would compensate for the dilution of smoke produced by ventilated cigarette holders. Peak plasma nicotine and carboxyhemoglobin levels were measured in 18 smokers when they had been smoking normally and when they had been using holders which dilute the smoke by about 20% (holder 1) and 60% (holder 2) for periods of 2 days and 7 days. Comparison of the observed blood levels with the "expected" levels estimated from the dilution factors of the holders showed that subjects partially compensated on holder 2 but showed little or no compensation on holder 1. There were no changes in the number of cigarettes smoked when using the holders so any compensation achieved must have been due to increasing the intake from each cigarette. There was wide individual variation in the amount of compensation with about 50% of subjects compensating fairly consistently on both holders. Degree of compensation was not significantly associated with usual cigarette consumption, plasma nicotine and carboxyhemoglobin levels when smoking without a holder, the nicotine yields of the subjects' cigarettes, or the experience of withdrawal symptoms and the degree of satisfaction when using the holders. It cannot be determined from this study whether the compensation observed was mediated by a need to regulate the intake of nicotine rather than some other factor.

Smokers' response to shortened cigarettes: dose reduction without dilution of tobacco smoke.

This study was designed to examine the response of smokers to shortening their usual brand of cigarettes. The shortening reduces the dose of smoke available from each cigarette without affecting concentration and therefore differs from dose reduction by dilution, which occurs when smokers switch to cigarettes with lower tar and nicotine deliveries. Measures of smoking behavior (e.g., cigarette consumption, puff rate), mouth-level nicotine intake (calculated from butt content), and intake to the lungs (plasma nicotine and COHb) were made in 10 smokers after 48 hr ad libitum smoking of full, three-quarter, and half-length cigarettes in a Latin square design. Mouth-level smoke intake was maintained on shortened cigarettes due to a combination of 2 types of compensatory maneuver: (1) by increasing the intensity of puffing and thereby extracting proportionately more of the smoke available from each cigarette and (2) by smoking more cigarettes. The amount of smoke inhaled, on the other hand, was only partially maintained (58% compensation). This was achieved by increase in cigarette consumption alone. There was achieved by increase in cigarette consumption alone. There was no evidence of any compensatory increase in the amount of smoke inhaled from each cigarette. Increase in consumption was thus the only maneuver that contributed to maintaining smoke intake at lung level; mouth-level intake was regulated by increasing intake per cigarette as well as consumption.

Pharmacokinetics of nicotine carbomer enemas: a new treatment modality for ulcerative colitis.

BACKGROUND: Ulcerative colitis is largely a disease of nonsmokers, and transdermal nicotine is of therapeutic value in the active disease. Because side effects are common, we developed a topical enema formulation of nicotine. OBJECTIVE: To study the pharmacokinetics of nicotine complexed with a polyacrylic carbomer and administered by enema to eight healthy volunteers and to eight patients with active ulcerative colitis, verified sigmoidoscopically. PATIENTS AND METHODS: All 16 subjects were nonsmokers. The mean age for normal subjects was 33 years; the mean for patients with ulcerative colitis was 60 years. Median stool frequency for patients with ulcerative colitis was four daily. Patients were taking 5-amino salicylic acid compounds and five were taking oral prednisolone (median dose, 12 mg daily). Nicotine, 6 mg, complexed with carbomer 974P, 400 mg, was administered in a 100 ml enema after an overnight fast, with serial blood measurements taken over 8 hours. Serum nicotine and cotinine were measured by gas liquid chromatography. Area under the concentration-time curves were calculated by the trapezoidal method, and the terminal elimination half-life was derived by extrapolation of the log-linear terminal phase. RESULTS: With the exception of nicotine time to reach peak concentration, which was longer in patients (median of 60 minutes compared with 45 minutes; p < 0.005), other comparisons between normal subjects and patients showed no statistically significant difference, although there was considerable inter-subject variation. Maximum concentration of nicotine, 8.1 +/- 3.5 ng/ml, in the 16 subjects occurred after a median of 60 minutes (range, 30 to 180 minutes); maximum cotinine concentrations of 60.4 +/- 11.5 ng/ml occurred after 4 hours. Side effects in five subjects were mild (four subjects) or moderate (one subject) and included lightheadedness, nausea, and headache; these five subjects were female lifelong nonsmokers of low body weight. CONCLUSION: Because most of the active ingredient of nicotine is converted to continine on the first pass through the liver, substantial concentrations can be achieved at the site of disease with only modest rises in serum nicotine, which are responsible for side effects; cotinine has low pharmacologic activity. Topical administration of nicotine may be useful treatment for distal ulcerative colitis.

Nicotine enemas for treatment of ulcerative colitis: a study of the pharmacokinetics and adverse events associated with three doses of nicotine.

BACKGROUND: Transdermal nicotine is of value in active ulcerative colitis but causes adverse events because of systemic absorption. Nicotine enemas may give rise to fewer adverse events. AIM: To assess the pharmacokinetics of nicotine enemas in three doses. METHODS: Thirteen volunteers, all non-smokers but three ex-smokers, were given enemas on separate occasions containing 3, 6 and 9 mg of nicotine, in ascending dose order. Adverse events were recorded and blood samples taken over 8 h for measurement of serum nicotine and cotinine. RESULTS: Enemas were retained by most subjects. Eleven of 14 adverse events were 'early'--30-105 min after the enema, corresponding to maximum plasma nicotine concentrations; three events were later, 4-8 h after the enema and unrelated to the tmax. 'Early' adverse events occurred in eight subjects--six with 9 mg. The three highest plasma nicotine concentrations were with 9 mg and associated with headache, nausea and sweating. Only one had adverse events with 3 mg and withdrew from the study. Nicotine Cmax with 6 and 9 mg doses were respectively two and three times the value with 3 mg. Peak nicotine concentrations occurred 44-50 min after the enema. CONCLUSION: The 6 mg dose of nicotine probably represents the dose to use in clinical practice - for the highest therapeutic dose with a low risk of adverse events.

Nicotine enemas for active ulcerative colitis--a pilot study.

BACKGROUND: Since transdermal nicotine is of value in the treatment of active ulcerative colitis but is often associated with side-effects, an alternative in the form of topical therapy with nicotine enemas has been developed. METHODS: In an open study, 22 patients with active colitis, all non-smokers, were asked to take a 100 mL enema containing 6 mg of nicotine every night for 4 weeks. Pre-trial treatment using mesalazine (n = 16), oral prednisolone (8), cyclosporin (1) and azathioprine (1) was kept constant for the month prior to assessment and during the study period. Symptoms, with stool frequency, were recorded on a diary card and an endoscopy was performed with rectal biopsy at the beginning of the study and after 4 weeks. RESULTS: Seventeen of the 22 patients completed 1 month of treatment. Mean duration of relapse was 29 weeks, range 3-94. Sixteen of 17 improved their St Mark's score. Urgency and stool frequency improved in 12 patients, sigmoidoscopic and histological scores in 10. Three patients had a full remission of symptoms with normal sigmoidoscopy. Six of 10 with a partial response continued with the enemas for a second month and five showed further improvement with full remission in two. The enema appeared effective when added to conventional treatment and produced few side-effects. CONCLUSION: Topical nicotine therapy for ulcerative colitis may have a place in future management, but controlled studies are needed.

Assessment of environmental tobacco smoke exposure in children with asthmatic symptoms by questionnaire and cotinine concentrations in plasma, saliva, and urine.

To validate a detailed questionnaire for assessment of environmental tobacco smoke (ETS) exposure by the biomarker cotinine in various media, a population-based study in the urban area of Malmö, Sweden was performed in children aged 8-13 years with and without asthmatic symptoms. There were strong correlations between urinary and saliva cotinine concentrations and also, though to a lesser extent, between these media and plasma. Even a detailed questionnaire gave only a rough picture of the ETS exposure, as indicated by the biomarkers. In a multivariate model, the most significant questionnaire-derived predictor of the cotinine levels was the maternal smoking habits; other questionnaire variables gave only a minimal explained variance. Children with a history of asthmatic symptoms had statistically significantly lower median cotinine levels in urine and saliva compared to referent children, most likely because of the antismoking information to their parents. This should be considered in epidemiological studies of ETS risks.

Naltrexone, smoking behaviour and cigarette withdrawal.

In order to examine the role of endogenous opioids in the reinforcing effects of nicotine, a double-blind, placebo-controlled, cross-over design was used to study the effects of the opiate antagonist, naltrexone, on smoking behaviour and cigarette withdrawal in 12 heavy smokers. Although naltrexone (50 mg) appeared to reduce the perceived difficulty of abstaining during 24-h cigarette withdrawal, other withdrawal symptoms were unaffected. Naltrexone also had no effect on a variety of biochemical and behavioural measures of nicotine intake or on subjective satisfaction and enjoyment from the first cigarette smoked after 24-h abstinence. Similarly naltrexone (100 mg) had no effect on smoking behaviour, nicotine intake or satisfaction from smoking during a 48-h period of ad libitum smoking. However, during the ad libitum smoking period naltrexone caused mood changes of the kind that occur during tobacco withdrawal. Since nicotine intake and smoking behaviour were unaffected, the mood changes are unlikely to have been mediated by blockade or any other form of opioid interaction with nicotinic mechanisms. These findings provide evidence against the notion that the endogenous opioids are involved in mediating the reinforcing properties of nicotine in smokers under normal conditions.

Nicotine availability from Eclipse tobacco-heating cigarette.

A cigarette which heats rather than burns tobacco (Premier) was introduced in 1988, but was unacceptable due to unpleasant taste and low nicotine intake. We examined availability of nicotine from a new version (Eclipse), in the same four subjects as our earlier Premier study. Average blood nicotine boosts of 23.7 and 17.8 ng/ml were obtained from smoking a first and second Eclipse. This substantially exceeds intake from Premier (boost 13 ng/ml) and that obtained by heavy smokers from conventional brands (boost 12-15 ng/ml). Eclipse (or similar product) may be the best option for averting Peto's dire warnings of rising millions of annual smoking deaths in the 2020s, and its potential for large-scale, long-term switching warrants further study.

Non-smokers show acute tolerance to subcutaneous nicotine.

Plasma nicotine concentrations following subcutaneous (SC) injection were measured in six subjects who included three life-long nonsmokers. On average, a peak plasma level of 8.5 ng/ml (SD = 3.1) was reached 15 min after the mean dose of 13.25 micrograms/kg nicotine base. Subjective effects were reported by five subjects. The peak heart rate response (mean boost 11 beats per min at 10 min) preceded and was already declining by the time plasma nicotine concentrations peaked. Hysteresis plots showed clear evidence of acute nicotine tolerance in subjects who had never smoked, indicating that acute tolerance is not an acquired phenomenon. The acquisition by smokers of chronic tolerance to nicotine has not yet been systematically demonstrated. Reliable dose-response studies in smokers and nonsmokers are needed, and use of the SC route for this purpose is discussed.

Effect of smoke-free cigarettes on 24 h cigarette withdrawal: a double-blind placebo-controlled study.

In a double-blind randomised trial, 40 cigarette smokers used either nicotine-containing or placebo smoke-free cigarettes during 24 h abstinence from smoking. Subjects in the nicotine group experienced smaller increases in irritability and difficulty concentrating and fewer urges to smoke than those who received placebo. Nicotine smoke-free cigarettes were rated as more satisfying, more helpful and more effective in relieving craving than placebo. After 24 h use nicotine smoke-free cigarettes provided average blood nicotine levels of 6.3 ng/ml, i.e., 29.2% of smoking levels. The most frequent side effects were irritation of the throat and coughing. Overall, side effects were rated as not serious. Although the smoke-free cigarette in its present form is not very efficient in delivering nicotine, it was effective in alleviating initial tobacco withdrawal. It is possible that by providing both nicotine and "behavioural" replacement it may be particularly useful in the first stages of stopping smoking. The product is worth further investigation.

Nicotine intake and dependence in Swedish snuff takers.

Two studies examining nicotine intake in users of Swedish moist oral snuff are reported. Absorption form a single pinch (2 g) in ten users after overnight abstinence was fairly rapid. The increment in plasma nicotine concentrations averaged 9.9 ng/ml (SD 6.5) after 10 min and peaked at 14.5 ng/ml (SD 4.6) shortly after discarding at 30 min. Among groups of habitual snuff takers (n = 27) and cigarette smokers (n = 35) studied on a day of normal snuffing/smoking, peak blood nicotine levels after use were similar [averaging 36.6 ng/ml (SD 14.4) and 36.7 ng/ml (SD 16.1), respectively], but there was a tendency to higher cotinine levels in the snuffers (399.2 ng/ml versus 306.3 ng/ml). The snuff takers and cigarette smokers reported similar levels of subjective dependence on tobacco. Epidemiological study of Swedish snuff users could clarify whether the cardiovascular risks of tobacco are attributable to nicotine or to other smoke components, as in their case nicotine intake is not accompanied by combustion products.

Nasal nicotine spray: a rapid nicotine delivery system.

Plasma nicotine concentrations following administration by two types of nasal nicotine spray were compared in ten subjects. Absorption was particularly rapid during the first 2.5 min, the average rise in blood nicotine concentrations during this time being 8.6 ng/ml for the two products, followed by a small further rise to an average peak increase of 10.5 ng/ml 5 min after the dose of 2 mg nicotine base (mean 27.8 micrograms/kg). Despite a four-fold Cmax variation between subjects, the levels of individual subjects were fairly consistent across the two products. There were no significant differences between the two products in blood nicotine concentrations or cardiovascular responses, and the correlation between the AUCs from the two products was 0.68 (P = 0.01). Eight subjects reported subjective feelings of light-headedness or slight dizziness, which are not typical after slower absorption from nicotine gum or skin patches. Blood nicotine levels within the smoking range were soon built up with repeated doses, even in the subject with the least efficient nasal absorption. In a second study of ad libitum use under clinical conditions both products appeared sufficiently acceptable for therapeutic use as an aid to smoking cessation. There was no tendency to escalate to excessive use over 4 weeks, and blood nicotine concentrations in nine subjects averaged only 44% of their prior smoking levels. Only one subject had levels equivalent to prior smoking and possible reasons why this was not more common are discussed.

Does switching to an ultra-low nicotine cigarette induce nicotine withdrawal effects?

Twenty-six smokers took part in a study which examined subjective and physiological effects of switching to an ultra-low yielding cigarette (0.1 mg nicotine) for 10 days. Subjects were randomly assigned to one of two groups. One group continued smoking their usual brand while the other group switched to the low yielding cigarette. Subjective ratings and physiological measures were taken at baseline, then after 1, 3 and 10 days in the respective conditions. Plasma nicotine concentrations dropped by some 60% after switching. Although substantial, this drop was considerably less than the drop in nominal yield of the cigarettes (around 90%), indicating marked compensation on the part of these smokers. Switching to the low yielding cigarette was accompanied by a significant increase in hunger and a drop in heart rate. These effects typically occur following cigarette withdrawal. However, other common cigarette withdrawal symptoms, such as irritability, depression, and inability to concentrate, were not detected.

Effect of subcutaneous nicotine injections of EEG alpha frequency in non-smokers: a placebo-controlled pilot study.

The effect of two subcutaneous injections of 0.6 mg nicotine, administered 40 min apart, was compared with placebo in four non-smoking subjects in a counter-balanced double-blind crossover design. The nicotine injections produced mean peak plasma nicotine concentrations of 5.3 ng/ml 10 min after the first injection and 8.5 ng/ml 10 min after the second injection. The nicotine injections produced an increase in mean dominant alpha frequency on the electroencephalogram (EEG) which was 2 Hz greater than the effect of placebo (P = 0.049) and also produced a heart-rate boost which was 8 beats per minute greater than that produced by placebo (P = 0.022). These effects on dominant alpha frequency and heart rate were most apparent in the 10 min following each nicotine injection. The increase in dominant alpha frequency found in non-smokers in this study was similar to that following nicotine inhalation in abstinent smokers in previous studies, and suggests that this is a primary effect of nicotine, rather than simply a reversal of withdrawal-induced EEG slowing.

Sensitivity and tolerance to nicotine in smokers and nonsmokers.

We studied the responses of smokers and lifelong non-smokers to transdermal nicotine patches over 24 h in three groups of subjects: non-smokers on a 15 mg patch (n = 8), non-smokers on a 30 mg patch (n = 8) and smokers on a 30 mg patch (n = 8). Unexpectedly, the non-smokers appeared to absorb nicotine more rapidly. The increase in blood nicotine concentrations of non-smokers over the first 2 h of patch use was double that of the smokers, with mean increases of 4.5 (SD = 3.7), 10.9 (SD = 4.2) and 4.1 (SD = 2.7) ng/ml in the three groups, respectively (P less than 0.005). The smokers had no pleasant or unpleasant effects from the 30 mg patch (X Cmax 13.9 ng/ml, SD = 4.9; Tmax 8.75 h) but all eight non-smokers experienced mild nausea and lightheadedness (P less than 0.01) within the first hour, and seven dropped out (P less than 0.01) at 3-8 h due mainly to severe nausea, vomiting or headache (X Cmax 18.4 ng/ml, SD = 4.9; Tmax 5.25 h). Only one non-smoker dropped out on the 15 mg patch, but five had transient nausea in the first hour (X Cmax 7.9 ng/ml, SD = 3.0; Tmax 8.0). Our study provides evidence of chronic pharmacodynamic nicotine tolerance in smokers, but does not address whether this is acquired or innate. The higher rate of transdermal nicotine absorption in non-smokers is unexplained and requires replication.

Discriminative stimulus properties of nicotine: further evidence for mediation at a cholinergic receptor.

Rats were trained to discriminate nicotine (0.4 mg/kg SC) from saline in a standard two-bar operant conditioning procedure with food reinforcement. The response to nicotine was dose-related and at the ED50 of 0.14 mg/kg, plasma nicotine concentrations were similar to those reported previously for cigarette smokers who inhale. The nicotine analogues anabasine and cytisine increased nicotine-appropriate responding in a dose-related manner. Animals predominantly responded on the saline-associated lever when administered drugs from a range of pharmacological classes, even at doses that were sufficiently large to reduce the overall numbers of responses. The results confirm that the nicotine discriminative stimulus is highly specific. Previous work has shown anabasine and cytisine to be active at nicotinic-cholinergic binding sites in rat brain. The finding that there is some correlation between the behavioural effects of these compounds and their actions at the nicotine binding site may indicate that the nicotine cue is mediated through a cholinergic receptor.

Effect of transdermal nicotine patches on cigarette smoking: a double blind crossover study.

The effect of transdermal nicotine patches on ad libitum cigarette smoking was examined in 30 subjects by measuring behavioural, biochemical and subjective aspects of smoking during a week of smoking without patches, and then a week each of nicotine and placebo patches in a randomised double blind crossover design. While wearing nicotine patches the subjects did not reduce the number of cigarettes smoked, but their expired carbon monoxide was reduced by 14%, they obtained less satisfaction from their cigarettes, and reported fewer and weaker urges to smoke. Down-regulation of nicotine intake from cigarettes was imprecise, such that when subjects wore nicotine patches their post-cigarette plasma nicotine concentration increased to an average of 45 ng/ml compared with 37 ng/ml in both no patch and placebo patch conditions. As the nicotine patches produced a plasma nicotine concentration of 15.9 ng/ml in abstinent subjects, this suggests a 22% reduction in nicotine intake from cigarettes while wearing nicotine patches. No serious symptoms of nicotine overdose were reported. It is suggested that the continuous absorption of nicotine from the patch may cause a build-up of acute tolerance to both toxic and pleasant subjective effects from smoking.

The effect of nicotine on fetal breathing movements in conscious pregnant ewes.

Nicotine (0.14--0.25 mg/kg), injected intravenously or intraarterially into conscious pregnant ewes, caused a decrease in fetal PaO2 within 5 minutes, persisting for up to 30 minutes. There was a significant fall in the incidence of fetal breathing movements. These changes did not occur if the ewe was treated with an alpha-blocking agent (phentolamine) or if the nicotine was infused for 30 minutes at 0.27 to 0.85 mg/minute. Nicotine crossed the placenta; fetal concentrations equaled those in the ewe 5 minutes after the injection and remained at or above maternal levels for 1 hour. Nicotine given directly to the fetus (0.005--0.03 mg/kg estimated fetal weight) stimulated fetal breathing movements in a dose-related manner. We suggest that the maternal injection of nicotine results in a fall of uterine blood flow by a sympathomimetic action, leading to transient fetal hypoxemia and a reduction of fetal breathing movements and that a similar phenomenon may occur when a pregnant woman smokes cigarettes.