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Biomedical subjects

J E Henningfield

Publications and source records attributed to J E Henningfield.

At least 19 recordsLinked to original sources

Brand differences of free-base nicotine delivery in cigarette smoke: the view of the tobacco industry documents.

The recent availability of internal tobacco industry documents provides significant insight into industry knowledge and manipulation of tobacco smoke delivery. One critical area of research is the role of smoke chemistry in determining the absorption and effects of smoke constituents, especially harm producing or pharmacologically active compounds. Independent scientific research has suggested that the nicotine dosing characteristics, hence the addiction potential of cigarettes, may be determined in part by the amount of free-base nicotine in cigarette smoke and its effects on the location, route, and speed of absorption in the body and on the sensory perception effects of the inhaled smoke. Tobacco industry documents describe the use of a number of methods internally for measuring free-base nicotine delivery. These include the common use of cigarette "smoke pH" as a means to estimate the fraction of free-base nicotine in the particulate matter (PM) in cigarette smoke, as well as efforts to measure free-base nicotine directly. Although these methods do not provide accurate absolute measures of free-base nicotine in smoke, consistencies observed in the findings across the various manufacturers indicate: (1) real relative differences in the acid/base chemistry of the smoke from different brands of cigarettes; (2) a connection between differences in free-base levels and brand-dependent differences in sensory perception and smoke "impact"; and (3) levels of free-base nicotine that are greater than have typically been publicly discussed by the industry. Furthermore, the results of these methods are generally consistent with those of a recent study from the Centers for Disease Control and Prevention which directly measured the free-base fraction of nicotine across a range of cigarette types. Consideration of the likely fundamental importance of free-base nicotine levels in cigarette smoke, together with the efforts discussed in the tobacco industry documents to measure such levels, indicates that the public health community would benefit from additional research to assess directly the delivery of free-base nicotine in cigarette smoke across brands. This may be especially useful for those products ("light", "ultralight", "reduced carcinogen", etc) that have been promoted, either explicitly or implicitly, as "harm reducing".

Documentation↗

Toward a comprehensive long term nicotine policy.

Global tobacco deaths are high and rising. Tobacco use is primarily driven by nicotine addiction. Overall tobacco control policy is relatively well agreed upon but a long term nicotine policy has been less well considered and requires further debate. Reaching consensus is important because a nicotine policy is integral to the target of reducing tobacco caused disease, and the contentious issues need to be resolved before the necessary political changes can be sought. A long term and comprehensive nicotine policy is proposed here. It envisages both reducing the attractiveness and addictiveness of existing tobacco based nicotine delivery systems as well as providing alternative sources of acceptable clean nicotine as competition for tobacco. Clean nicotine is defined as nicotine free enough of tobacco toxicants to pass regulatory approval. A three phase policy is proposed. The initial phase requires regulatory capture of cigarette and smoke constituents liberalising the market for clean nicotine; regulating all nicotine sources from the same agency; and research into nicotine absorption and the role of tobacco additives in this process. The second phase anticipates clean nicotine overtaking tobacco as the primary source of the drug (facilitated by use of regulatory and taxation measures); simplification of tobacco products by limitation of additives which make tobacco attractive and easier to smoke (but tobacco would still be able to provide a satisfying dose of nicotine). The third phase includes a progressive reduction in the nicotine content of cigarettes, with clean nicotine freely available to take the place of tobacco as society's main nicotine source.

Health Policy↗

Regulatory strategies to reduce tobacco addiction in youth.

Preventing tobacco addiction and achieving cessation in established users are the cornerstones of efforts to reduce tobacco use and disease. It has been increasingly recognised that reducing tobacco toxin exposure has theoretical potential to reduce disease in continuing tobacco users. This has been controversial because such approaches also carry the potential to undermine prevention and cessation. As complicated as harm reduction issues are for adults, they are still more complicated for youth. Harm reduction is not a singular approach, but rather a concept that encompasses an extremely diverse array of potential approaches. These carry equally diverse potential risks and benefits. The regulatory framework (for example, whether or not the Food and Drug Administration regulates the approach) is also predicted to be a major factor in determining the consequences of harm reduction approaches. This paper examines the various issues and potential approaches concerning the application of harm reduction to youth. We conclude that although some carry great risk, others may actually support broader tobacco control efforts to prevent tobacco use and foster cessation in youth and adults.

Adolescent↗

Effect of nicotine on brain activation during performance of a working memory task.

Nicotine influences cognition and behavior, but the mechanisms by which these effects occur are unclear. By using positron emission tomography, we measured cognitive activation (increases in relative regional cerebral blood flow) during a working memory task [2-back task (2BT)] in 11 abstinent smokers and 11 ex-smokers. Assays were performed both after administration of placebo gum and 4-mg nicotine gum. Performance on the 2BT did not differ between groups in either condition, and the pattern of brain activation by the 2BT was consistent with reports in the literature. However, in the placebo condition, activation in ex-smokers predominated in the left hemisphere, whereas in smokers, it occurred in the right hemisphere. When nicotine was administered, activation was reduced in smokers but enhanced in ex-smokers. The lateralization of activation as a function of nicotine dependence suggests that chronic exposure to nicotine or withdrawal from nicotine affects cognitive strategies used to perform the memory task. Furthermore, the lack of enhancement of activation after nicotine administration in smokers likely reflects tolerance.

Adult↗

Correlates of expired air carbon monoxide: effect of ethnicity and relationship with saliva cotinine and nicotine.

AIMS: To assess the accuracy of expired air carbon monoxide (CO) measurement vs. saliva cotinine and nicotine and to estimate the degree of misclassifications of smoking status as a function of ethnicity. DESIGN AND MEASUREMENTS: Comparison for accuracy of expired air CO, saliva nicotine and cotinine in simultaneously collected specimens. SETTING: Outpatient clinic of a clinical research ward. PARTICIPANTS: 228 current African-American and Caucasian cigarette smokers. RESULTS: Expired-air CO concentration was significantly associated with saliva cotinine, but not with saliva nicotine. Saliva cotinine but not expired CO or saliva nicotine showed a significant between-ethnic difference when adjusted for number of cigarettes smoked and for time since last cigarette. Agreement between expired air CO and saliva cotinine was substantial at expired CO < or = 8 ppm but only moderate at < or = 10 ppm. False negative rates were twice as high at < or = 10 ppm than at < or = 8 ppm at each saliva cotinine cut-off tested. At saliva cotinine of < or = 15 ng/ml, more African-Americans were classified as false negative. CONCLUSIONS: Expired CO is strongly associated with saliva cotinine but not with saliva nicotine. Despite this association, misclassifications for no smoking are frequent if true classification is based on saliva cotinine. False negative results occur more frequently in African-Americans.

Adolescent↗

Tobacco addiction and pharmacological interventions.

Even though its health consequences are well known, tobacco use continues to kill millions of smokers worldwide every year. In the US alone, tobacco use kills > 430,000 people each year. The global mortality toll is approximately 5 million annually and this is increasing. It is the powerful grip of tobacco addiction that sustains high levels of daily smoke intake and persistent smoking, with > 90% of all cigarette smokers who quit, resuming smoking within 1 year. Tobacco addiction, which places tremendous health and economic burdens on individual societies, is also becoming a global epidemic. Although tobacco addiction is a complex phenomenon, it is treatable and several effective medications are now available. In the mid-1980s, the US FDA approved nicotine gum, the first of these effective pharmacological aids. Other effective medications have subsequently become available, including nicotine transdermal patches, nasal spray, oral vapour inhaler, sublingual nicotine tablets and bupropion. These medications and the potential for development of new medications will be reviewed.

Antidepressive Agents, Second-Generation↗

Combination nicotine replacement therapy for smoking cessation: rationale, efficacy and tolerability.

Currently available nicotine replacement therapy (NRT) medications provide effective treatment for tobacco dependence, typically doubling success rates compared with placebo. A strategy for further improving the efficacy of NRT is to combine one medication that allows for passive nicotine delivery (e.g. transdermal patch) with another medication that permits ad libitum nicotine delivery (e.g. gum, nasal spray, inhaler). The rationale for combining NRT medications is that smokers may need both a slow delivery system to achieve a constant concentration of nicotine to relieve cravings and tobacco withdrawal symptoms, as well as a faster acting preparation that can be administered on demand for immediate relief of breakthrough cravings and withdrawal symptoms. This article reviews 5 published studies that have examined the effectiveness of combination NRT compared with monotherapy in providing withdrawal relief and smoking cessation, and examines other factors relevant to the promotion of combination NRT for treating tobacco dependence. The data show that there are conditions under which combinations of NRT products provide greater efficacy in relieving withdrawal and enabling cessation than monotherapy, but the findings are not robust and additional research is warranted to better understand the magnitude and generality of the benefits of combination therapy. There are also regulatory and commercial obstacles that must be considered. Nonetheless, combination NRT has the potential to provide effective treatment of tobacco dependence in persons whose dependence is refractory to currently available treatments.

Humans↗

Health risks associated with cigar smoking.

This article summarizes principal findings from a conference convened by the American Cancer Society in June 1998 to examine the health risks of cigar smoking. State-of-the-science reports were presented and 120 attendees (representing government and private agencies, academia, health educators, and tobacco control experts) participated in panels and summary development discussions. The following conclusions were reached by consensus: (1) rates of cigar smoking are rising among both adults and adolescents; (2) smoking cigars instead of cigarettes does not reduce the risk of nicotine addiction; (3) as the number of cigars smoked and the amount of smoke inhaled increases, the risk of death related to cigar smoking approaches that of cigarette smoking; (4) cigar smoke contains higher concentrations of toxic and carcinogenic compounds than cigarettes and is a major source of fine-particle and carbon monoxide indoor air pollution; and (5) cigar smoking is known to cause cancers of the lung and upper aerodigestive tract. JAMA. 2000;284:735-740

Humans↗

Nalmefene: blockade of intravenous morphine challenge effects in opioid abusing humans.

No studies have assessed the dose-effect or duration of opioid blockade in opioid abusers produced by oral nalmefene, a micro-opioid antagonist. The present study examined the profile and time course of oral nalmefene blockade of subjective and physiological effects produced by intravenous morphine. To assess these effects, seven opioid abusers received oral nalmefene (0, 50 and 100 mg) followed by intravenous morphine (0, 10 and 20 mg) challenges every 24 h for 96 h using a Latin square randomized cross-over design. The duration of blockade varied by measure and dose. Both 50 and 100 mg nalmefene blocked morphine's effects up to 48 h.

Adult↗

Tolerance to repeated nicotine administration on performance, subjective, and physiological responses in nonsmokers.

RATIONALE: When administered acutely to nonsmokers, nicotine's effects on performance are inconsistent, perhaps because of suboptimal dosing or initial dysphoria that could interfere with performance. OBJECTIVE: The purpose of this study was to determine if a range of nicotine doses administered for 8 days to nonsmokers would enhance psychomotor and cognitive abilities and to document the development of nicotine tolerance or sensitization. METHODS: Twelve male volunteers, who reported ever smoking five cigarettes or less, participated in 8 consecutive experimental days in which they were administered four doses of nicotine polacrilex gum each day in this order: 0, 2, 4, and 8 mg. Performance, subjective, and physiological measures were assessed before and after each dose. RESULTS: Plasma nicotine concentration ranged from 6.9 to 11.5 ng/ml following the 8 mg dose. Nicotine increased rate of responding and decreased response time on working memory (digit recall); however, accuracy was impaired. Nicotine also decreased accuracy on visual scanning and attention (two-letter search), and the 8 mg dose impaired gross motor coordination (circular lights). Tolerance did not develop to the performance impairing effects of nicotine. Nicotine produced dose-related increases in ratings of dysphoria and negative mood, including tension, anxiety, nervousness, turning of stomach, and sedation. Tolerance developed to some, but not all, of these aversive effects. Tolerance also was not observed to the increased cardiovascular measures. CONCLUSION: Although tolerance developed to some of the aversive effects of nicotine, performance enhancement was not observed. These data do not support the hypothesis that nicotine-induced performance enhancement contributes to the reinforcing effects of tobacco use during the early stages of dependence development.

Adult↗

Reinforcing and subjective effects of morphine in human opioid abusers: effect of dose and alternative reinforcer.

RATIONALE: Although most opioid self-administration research has been conducted with laboratory animals, such research with humans is necessary to answer questions unique to human drug-taking behavior. OBJECTIVE: We investigated the influence of morphine dose and an alternative non-drug reinforcer on choice between morphine versus money and examined the relationship between drug-reinforced behavior and subjective euphoria. METHODS: Five male opioid users participated in the 7-week study. During the first 5 weeks, a single dose of morphine (0, 4, 8, 16, or 32 mg/70 kg) was available each week. On Monday, subjects received an IM injection of the dose tested that week. On Tuesday, Thursday, and Friday, subjects could work for morphine or money under a second-order, progressive ratio schedule. For each primary ratio completed on the drug lever, subjects earned one-ninth of the available drug dose, and for each ratio completed on the money lever, subjects earned $1. Total amount of drug earned was administered in a single IM injection at the end of the session; money earned was credited to the subject's account. RESULTS: As morphine dose increased, responding for drug increased in an orderly manner and responding for money decreased. During the final phase of the study, the lowest and highest doses that maintained drug responding for each subject were repeated, and the value of the alternative reinforcer was increased to $2 per ratio. This manipulation was associated with decreased drug-maintained responding at the lowest, but not the highest, reinforcing dose of morphine. CONCLUSION: The progressive ratio, concurrent access procedure may be useful in predicting the outcome of drug abuse treatment interventions that use alternate reinforcement strategies.

Adult↗

Mecamylamine blockade of both positive and negative effects of IV nicotine in human volunteers.

The ganglionic blocker mecamylamine blocks the positive reinforcing effects of IV nicotine, but has been shown to increase cigarette smoking behavior under some conditions. The effects of mecamylamine on subjective and physiologic responses to IV nicotine were evaluated in seven healthy male volunteer cigarette smokers who provided informed consent and resided on a clinical pharmacology research unit. On four separate days, each subject was given a different oral dose of mecamylamine (placebo, 5, 10, or 20 mg). One hour later subjects received the first of four doses of IV nicotine (placebo, 0.75, 1.5, and 3.0 mg); the remaining injections were given at 1-h intervals. Both the positive effects following 0.75 mg and negative effects following 3.0 mg of nicotine were significantly reversed by mecamylamine. Thus, the mecamylamine-induced increase in smoking may be due both to competitive blockade of nicotinic receptors and nicotine's reversal of aversive effects.

Adult↗

A pharmacokinetic crossover study to compare the absorption characteristics of three transdermal nicotine patches.

We compared the pharmacokinetic profiles of the highest marketed doses of three different patch systems using a crossover study design. Specifically, each of the 25 subjects was assigned to receive the Pharmacia-Upjohn (McNeil) 15-mg, 16-h patch, the Novartis 21-mg, 24-h patch, and the Alza (SmithKline Beecham) 21-mg, 24-h patch. Subjects used each patch for 3 consecutive days, applying a new patch each morning. Plasma nicotine concentrations were measured 15 times during the first 24-h period and at 48, 48.5, 49.5, and 51 h following initial patch application. Measures of total nicotine absorbed (AUC), maximum plasma nicotine concentration (C(max)) and minimum plasma nicotine concentration (C(min)), were higher for the 21-mg, 24-h patches than for the 15-mg, 16-h patch during both the first day of dosing and during the modeled steady-state period (48-72 h after initial application). Within the 21-mg, 24-h patch systems, the Alza patch produced significantly higher AUC and C(max) values during acute dosing and during steady state, but there was no difference between C(min) values. The time to reach C(max) (T(max)) was fastest for the Alza patch system; the Pharmacia-Upjohn patch produced a faster T(max) than the Novartis patch. These results indicate that there are significant differences between the pharmacokinetics of the currently marketed patch systems, which may be important for effective relief of withdrawal symptoms and cigarette craving.

Administration, Cutaneous↗

A review of tobacco smoking in adolescents: treatment implications.

OBJECTIVE: To review current data on the tobacco epidemic in adolescents that impact treatment decisions. METHOD: Epidemiological and pharmacological data, risk factors, characteristics of nicotine use in adolescents, and treatment intervention reports from the literature are discussed. RESULTS: Of students in grades 9 to 12, 42.7% have used tobacco; 75% of teenage smokers will smoke as adults. Environmental and biological factors influence adolescent smoking, including sociodevelopmental aspects of adolescence, psychiatric history, genetic background, ethnic and gender characteristics, drug effects, and regulatory factors. Criteria for nicotine dependence are currently based on the experience with adult smokers. Overall, smoking cessation treatment for adolescents has been disappointing because of low participation, high attrition, and low quit rates. CONCLUSION: Characterization of nicotine dependence and further assessment of the safety and efficacy of pharmacological treatment interventions in adolescents are needed given the formidable challenge of the tobacco epidemic in adolescents.

Adolescent↗