Pharmacokinetics and pharmacodynamic effects of nicotine nasal spray devices on cardiovascular and pulmonary function.

BACKGROUND: A nasal spray form of nicotine replacement therapy (Nicotrol NS, McNeil Consumer Products Co, Fort Washington, Pa) has been approved and, because of its rapid absorption across the nasal mucosa, may be more effective than nicotine gum or transdermal patches. We tested the hypothesis that the nicotine absorbed into the nasal mucosa would produce significant changes in hemodynamics and pulmonary function in 20 healthy, nonsmoking men and women. METHODS: In this double-blind, randomized study of Nicotrol NS versus placebo, we measured serum nicotine concentrations, blood pressure, heart rate, and indices of pulmonary function at timed intervals before and after nasal spray administration of 3 mg of nicotine. RESULTS: A peak serum nicotine concentration of 4.71 +/- 3.16 ng/mL occurred 10 minutes after drug administration. The maximum change in systolic blood pressure occurred 5 minutes after dosing and was significantly related to nicotine administration (7.1 +/- 9.4% for the nicotine group vs -1.6 +/- 7.3% for the placebo; P = 0.03). In contrast, neither diastolic blood pressure (P = 0.8) nor heart rate (P = 0.07) changed significantly after nicotine administration, when compared with placebo. Pulmonary function was not altered acutely by a single inhalation of nicotine. Pharmacokinetic modeling revealed a classic one-compartment model in which nicotine is absorbed into the systemic circulation by a zero-order process and eliminated by a first-order process. CONCLUSIONS: In this population of nonsmokers, hemodynamic effects of the nicotine nasal spray were observed shortly after administration and before the peak serum nicotine concentration.     

Transdermal nicotine reduces cigarette craving and nicotine preference

The effects of transdermal nicotine in 10 cigarette smokers were studied in a within-subjects, double-blind design. Either 8 mg nicotine base in a 30% aqueous solution or an inactive placebo solution was applied to intact skin under a polyethylene patch. Subjective reports of cigarette craving were collected every 30 minutes during a 90-minute smoking abstinence period. Immediately before and after this abstinence period subjects smoked through a smoke mixing device that allowed them to select their desired nicotine intake with each puff. Transdermal nicotine significantly increased saliva nicotine levels within 30 minutes after application. Cigarette craving was significantly lower in the nicotine condition than in the placebo condition. Nicotine preference during the initial puffs of the smoke mixer test at the end of 90 minutes of deprivation was also decreased by transdermal nicotine. In contrast, measures of cumulative smoke intake were not affected by the nicotine dose used. Our results suggest that transdermal nicotine may enhance success in smoking cessation by preventing the rise in cigarette craving usually observed after cessation. Transdermal nicotine may be preferable to other routes of nicotine administration because of the relative absence of adverse side effects.     

Prolonged absorption with development of tolerance to toxic effects after cutaneous exposure to nicotine

This report describes a patient who developed nicotine poisoning after cutaneous application of nicotine sulfate. Measurement of nicotine and metabolite levels in the blood demonstrated prolonged absorption of nicotine despite vigorous skin decontamination. This suggests that the skin may be a reservoir for slow release of nicotine into the circulation. Despite extraordinarily high levels of nicotine, the patient had full resolution of signs and symptoms of intoxication, indicating rapid and profound development of tolerance.     

Future drug delivery research in South Korea.

According to the Science Citation Index database, over 50 papers related to drug delivery have been published from South Korea during the last 3 years. For the purpose of this presentation, some of the recently carried out research in our department will be introduced and future research directions presented. Proliposomes are free flowing particles which are composed of drugs, phospholipids and a water soluble porous powder, and immediately form a liposomal dispersion upon hydration. The preparation can be stored sterilized in a dried state and, by controlling the size of the porous powder in proliposomes, relatively narrow range of reconstituted liposome size can be obtained. Because of these properties, proliposomes appear to be a potential alternative to liposomes in design and fabrication of liposomal dosage forms. Thus, we tested the feasibility of this preparation as a sustained transdermal dosage form. Proliposomes containing varying amount of nicotine, a model drug, were prepared using sorbitol and lecithin. Microscopic observation revealed that this preparation is converted to liposomes almost completely within minutes following contact with water. The release pattern of the model drug from this preparation was apparently similar to that of the Exodus((R)) patch, a commercially available transdermal nicotine formulation. Compared with nicotine powder, the nicotine flux across rat skin from proliposomes was initially retarded, and appeared to remain constant. This observation indicated that sustained transdermal delivery of nicotine is feasible using proliposomal formulations under occluded condition. In addition to the investigation of the potential application of proliposomes, we were also interested in the role of the stratum corneum (SC) in the enhanced delivery of drugs from liposomes. Thus, liposome-gel formulation containing hydrocortisone (HC), a model hydrophobic drug, was prepared and used in this study. The study was carried out on both normal and stratum corneum removed skins. Percutaneous absorption of HC across SC removed skin was significantly faster than that across normal skin, suggesting that SC behaves as a penetration barrier for the liposome-bound drugs. Interestingly, the liposome-gel in this study reduced the skin absorption of HC, compared with the conventional ointment formulation. The amount of HC absorbed from the liposome-gel after 8 h into the SC-removed skin was less than one third of that from the conventional ointment. Despite the reduced absorption, a higher and sustained skin concentrations of HC were achieved for the liposome-gel. Drug concentration in both viable and deep skin reached a maximum within 0.5 h. However, drug concentrations in these tissues declined as a function of time for conventional ointment, while those from the liposome-gel were greatly sustained, resulting in a 5-fold higher viable skin drug level was obtained at 8 h after the application. In contrast, plasma concentration of HC at 4 h from the liposome-gel was only one-fourth the value from the conventional ointment in the SC-removed skin. Therefore, the higher and sustained drug concentration in the viable skin appeared not to be due to the enhanced percutaneous absorption but due to retarded diffusion of the drug from the skin.     

Expert consensus of the Chinese Association for the Study of Pain on pain treatment with the transdermal patch

Chronic pain lasting more than 3 mo, or even several years can lead to disability. Treating chronic pain safely and effectively is a critical challenge faced by clinicians. Because administration of analgesics through oral, intravenous or intramuscular routes is not satisfactory, research toward percutaneous delivery has gained interest. The transdermal patch is one such percutaneous delivery system that can deliver drugs through the skin and capillaries at a certain rate to achieve a systemic or local therapeutic effect in the affected area. It has many advantages including ease of administration and hepatic first pass metabolism avoidance as well as controlling drug delivery, which reduces the dose frequency and side effects. If not required, then the patch can be removed from the skin immediately. The scopolamine patch was the first transdermal patch to be approved for the treatment of motion sickness by the Food and Drug Administration in 1979. From then on, the transdermal patch has been widely used to treat many diseases. To date, no guidelines or consensus are available on the use of analgesic drugs through transdermal delivery. The pain branch of the Chinese Medical Association, after meeting and discussing with experts and based on clinical evidence, developed a consensus for promoting and regulating standard use of transdermal patches containing analgesic drugs.     

Apparent tolerance to the acute effect of nicotine results in part from distribution kinetics.

Persons exposed to nicotine develop tolerance to many of its effects. When heart rate and forearm venous blood concentration are plotted against time after intravenous administration of nicotine, a greater increase in heart rate is seen for a given nicotine concentration during the rising phase of nicotine concentrations than during the decreasing phase. This could be due to acute tolerance or to more rapid distribution of drug to effect site (brain) than to venous blood. To distinguish between these possibilities, six rabbits were given nicotine intravenously. Blood samples were taken from the internal jugular vein (reflecting brain concentration), and the femoral vein and artery. Brain concentrations peaked before femoral venous concentrations. Seven men received intravenous infusions of nicotine. Peripheral venous blood concentrations and cardiovascular responses were measured. Heart rate peaked before venous concentrations. A physiological kinetic model, fit to the rabbit data, was scaled to humans and used to predict "brain" concentrations in them. Heart rate and predicted brain concentrations peaked simultaneously. We conclude that the rapid development of tolerance to the cardioaccelerating effect of nicotine can be attributed, at least in part, to its distribution kinetics.     

Therapeutic vaccines for nicotine dependence

Smoking remains the leading cause of preventable death worldwide. Despite the development of a number of drugs for smoking cessation, overall efficacy of these substances is limited and the majority of smokers fail to quit smoking long-term. These drugs aim to help people quit by either replacing nicotine with an alternative source of nicotine (eg, patches or gums) or by reducing the withdrawal symptoms. A vaccine against nicotine has a different strategy: by inducing sufficient nicotine-specific antibodies, it is possible to sequester the drug in the blood and prevent it from entering the brain. In this way, the addictive properties of cigarettes are eliminated and smokers attempting to quit may be able to smoke one or two cigarettes without becoming hooked again. Essentially, a vaccine against nicotine targets the progression from lapses to full relapse rather than withdrawal symptoms. Recent research with vaccines against nicotine has clearly demonstrated in animals that antibodies can interfere with the addictive properties of nicotine in different settings. The first phase II clinical trial has confirmed the validity of the concept and shown that a vaccine against nicotine can be efficacious for smoking cessation in humans provided anti-nicotine antibody levels are sufficiently high.     

低频超声波对双氯芬酸钠体外经皮渗透的影响

背景：双氯芬酸钠是临床上常用的强效非类固醇抗炎镇痛药物,经皮渗透可以避免肝的首过作用和胃肠道破坏,但受角质层影响,渗透量小;低频超声波能够改善皮肤通透性,促进药物经皮吸收。目的：通过对低频超声对促进双氯芬酸钠药物经皮的吸收效果研究,确定适合该类药物的低频超声经皮渗透物理参数。方法：30只大鼠随机均分为10组,9组用于正交试验,1组用于不加超声波时的对照试验。取大鼠背部皮肤进行透皮实验,以超声波的频率、强度及作用时间为影响因素,渗透量为指标,采用正交试验法,对双氯芬酸钠进行大鼠离体皮肤体外渗透试验,考察双氯芬酸钠渗透效果最好时,低频超声波各个参数值最优配比,并与空白组对比,观察其显著意义。结果与结论：渗透量随着超声波的作用时间的延长而增加,且超声波频率和强度都对渗透量有一定的影响。正交试验筛选的低频超声波最佳配比的参数为频率20kHz,强度0.75W/cm2,作用时间15min。结果提示,低频超声波频率、强度、作用时间均对渗透量的影响显著（P〈0.01）,三者相比较,作用时间对双氯芬酸钠渗透性的影响最大。     

低频超声波对双氯芬酸钠体外经皮渗透的影响

背景:双氯芬酸钠是临床上常用的强效非类固醇抗炎镇痛药物,经皮渗透可以避免肝的首过作用和胃肠道破坏,但受角质层影响,渗透量小;低频超声波能够改善皮肤通透性,促进药物经皮吸收。目的:通过对低频超声对促进双氯芬酸钠药物经皮的吸收效果研究,确定适合该类药物的低频超声经皮渗透物理参数。方法:30只大鼠随机均分为10组,9组用于正交试验,1组用于不加超声波时的对照试验。取大鼠背部皮肤进行透皮实验,以超声波的频率、强度及作用时间为影响因素,渗透量为指标,采用正交试验法,对双氯芬酸钠进行大鼠离体皮肤体外渗透试验,考察双氯芬酸钠渗透效果最好时,低频超声波各个参数值最优配比,并与空白组对比,观察其显著意义。结果与结论:渗透量随着超声波的作用时间的延长而增加,且超声波频率和强度都对渗透量有一定的影响。正交试验筛选的低频超声波最佳配比的参数为频率20kHz,强度0.75W/cm2,作用时间15min。结果提示,低频超声波频率、强度、作用时间均对渗透量的影响显著(P<0.01),三者相比较,作用时间对双氯芬酸钠渗透性的影响最大。     

Metabolism and biochemical effects of nicotine for primary care providers

Nicotine is a colorless and volatile liquid alkaloid naturally occurring in the leaves and stems of Nicotiana tabacum and Nicotiana rustica. Nicotine, the primary component of tobacco, is responsible for both tobacco product addiction (with chronic exposure) and the odor associated with tobacco. In addition to cigarettes, nicotine is found in chewing gum, transdermal patches, nasal spray, and sublingual tablets. Following its inhalation and absorption, nicotine and its metabolic products exert diverse physiologic and pharmacologic effects. This article covers the absorption and metabolism of nicotine, nicotine toxicity, pharmacologic effects of nicotine, nicotine-drug interactions, and the use of nicotine for the treatment of disease.     

Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation

BACKGROUND: Nicotine is metabolized to cotinine, and cotinine is metabolized to 3'-hydroxycotinine (3-HC) by the liver enzyme cytochrome P450 (CYP) 2A6. More rapid metabolism of nicotine may result in lower nicotine blood levels from nicotine replacement products and poorer smoking cessation outcomes. This study evaluated the utility of the 3-HC/cotinine ratio as a predictor of the efficacy of nicotine replacement therapy as an aid for smoking cessation. METHODS: By use of an open-label design, 480 treatment-seeking smokers were randomly assigned to 8 weeks of transdermal nicotine or nicotine nasal spray use, plus behavioral group counseling. Assessments included demographics, smoking history, body mass index, and plasma nicotine, cotinine, and 3-HC concentrations, as well as CYP2A6 genotypes. Smoking cessation was biochemically verified at the end of treatment and at 6-month follow-up. RESULTS: The rate of nicotine metabolism, as indicated by pretreatment 3-HC/cotinine ratio derived from cigarette smoking, predicted the effectiveness of transdermal nicotine at both time points. The odds of abstinence were reduced by almost 30% with each increasing quartile of metabolite ratio (odds ratio, 0.72 [95% confidence interval, 0.57-0.90]; P=.005). Higher metabolite ratios also predicted lower nicotine concentrations (beta=-1.72, t(179)=-3.31, P<.001), as well as more severe cravings for cigarettes after 1 week of treatment (beta=0.32, t(190)=2.91, P=.004). The metabolite ratio did not predict cessation with use of nicotine nasal spray (odds ratio, 1.05 [95% confidence interval, 0.83-1.33]; P=.68). CONCLUSION: The nicotine metabolite ratio might be useful in screening smokers to determine likely success with a standard dose of transdermal nicotine.     

Abuse liability and pharmacodynamic characteristics of intravenous and inhaled nicotine

The potential role of nicotine in tobacco dependence was investigated using the strategies of abuse liability assessment. Eight male volunteer cigarette smokers with histories of drug abuse resided on a research ward for the duration of the study. Each subject was tested with three doses of i.v. nicotine (0.75, 1.5 and 3.0 mg/10-sec infusion) and placebo each test day, and with three doses of inhaled nicotine, in the form of research cigarette smoke (0.4, 1.4 and 2.9 mg estimated yield) and placebo (sham-smoking), given on alternate test days. Each subject was tested on 4 days with both routes of administration, according to identical experimental protocols. Physiologic, subjective and observer data were collected at intervals ranging from 15 sec to 10 min beginning 10 min before drug administration and continuing for 30 min after administration. Both i.v. and inhaled nicotine produced dose-related increases in heart rate and blood pressure, and i.v. nicotine produced a transient bradycardia in four subjects during the first 30 sec after drug administration. Skin temperature was decreased by nicotine and pupil diameter was not consistently changed. Ratings of drug dose "strength" and drug "liking" were directly related to dose level whereas "desire to smoke cigarettes" was inversely related. Scores on the Morphine-Benzedrine Group (or Euphoria) scale of the Addiction Research Center Inventory were elevated by nicotine, and i.v. doses were identified frequently as cocaine. Signs and symptoms were similar for nicotine across the two routes of administration and included coughing, dizziness, nausea and relaxed feelings. Nicotine shared the pharmacologic profile of prototypic drugs of abuse. The study supports the hypothesis that the role of nicotine in tobacco dependence is equivalent to the role of other psychoactive drugs in substance abuse, e.g., to the role of cocaine in coca leaf use.     

Influence of tobacco abstinence on the disposition kinetics and effects of nicotine

Habitual tobacco smoking accelerates the metabolism of many drugs. With tobacco abstinence, it was expected that nicotine metabolism would be slower than when smoking. To test this hypothesis, the disposition kinetics of intravenous nicotine were studied in 20 healthy smokers while smoking, after abstaining from smoking for 1 week, and (in six subjects) when smoking again. Cardiovascular responses to nicotine were also measured. Unexpectedly, total and nonrenal clearance of nicotine increased by 36% and 39%, respectively, during abstinence. The increase in clearance after brief abstinence suggests that nicotine or its metabolites or another component of cigarette smoke inhibits nicotine metabolism in smokers. Cardiovascular responses to nicotine were greater after 1 week compared with overnight abstinence, consistent with loss of tolerance.     

Determinants of nicotine intake while chewing nicotine polacrilex gum

Nicotine polacrilex gum is widely used as substitution therapy during cigarette smoking cessation. We studied circadian blood nicotine concentrations, daily intake of nicotine, and extraction of nicotine from gum in smokers switched experimentally to 2 or 4 mg nicotine gum, 12 pieces per day. Nicotine levels and intake were much lower while chewing gum than during ad libitum smoking. Extraction of nicotine from gum by the chewer was incomplete, averaging 53% and 72% for 2 and 4 mg gum, and variable (more than twofold) among individuals. The systemic dose of nicotine was less than expected based on analysis of nicotine in the chewed gum. Disproportionately higher metabolite-to-nicotine ratios while chewing gum compared with smoking suggested that some nicotine was swallowed and underwent first-pass metabolism. Nicotine and metabolite data were used to estimate buccal vs. gastrointestinal absorption. Relative buccal absorption vs. swallowing of nicotine appears to be an important determinant of systemic nicotine intake.     

Stable isotope studies of nicotine kinetics and bioavailability

The stable isotope-labeled compound 3',3'-dideuteronicotine was used to investigate the disposition kinetics of nicotine in smokers, the systemic absorption of nicotine from cigarette smoke, and the bioavailability of nicotine ingested as oral capsules. Blood levels of labeled nicotine could be measured for 9 hours after a 30-minute intravenous infusion. Analysis of disposition kinetics in 10 healthy men revealed a multiexponential decline after the end of an infusion, with an elimination half-life averaging 203 minutes. This half-life was longer than that previously reported, indicating the presence of a shallow elimination phase. Plasma clearance averaged 14.6 ml/min/kg. The average intake of nicotine per cigarette was 2.29 mg. A cigarette smoke-monitoring system that directly measured particulate matter in smoke was evaluated in these subjects. Total particulate matter, number of puffs on the cigarette, total puff volume, and time of puffing correlated with the intake of nicotine from smoking. The oral bioavailability of nicotine averaged 44%. This bioavailability is higher than expected based on the systemic clearance of nicotine and suggests that there may be significant extrahepatic metabolism of nicotine.     

Nicotine absorption and cardiovascular effects with smokeless tobacco use: comparison with cigarettes and nicotine gum

Because of recent resurgence in its consumption, the effects and health consequences of smokeless tobacco are of considerable public health interest. We studied the extent and time course of absorption of nicotine and cardiovascular effects of smokeless tobacco (oral snuff and chewing tobacco) and compared it with smoking cigarettes and chewing nicotine gum in 10 healthy volunteers. Maximum levels of nicotine were similar but, because of prolonged absorption, overall nicotine exposure was twice as large after single exposures to smokeless tobacco compared with cigarette smoking. All tobacco use increased heart rate and blood pressure, with a tendency toward a greater overall cardiovascular effect despite evidence of development of some tolerance to effects of nicotine with use of smokeless tobacco. Relatively low levels of nicotine and lesser cardiovascular responses were observed with use of nicotine gum. Adverse health consequences of smoking that are nicotine related would be expected to present a similar hazard with the use of smokeless tobacco.     

Spatial distribution of cutaneous microvasculature and local drug clearance after drug application on the skin.

We analysed quantitatively blood microvessels distribution in normal skin. We conclude that the segmental area of blood vessels peaks approximately 0.1 mm below the skin surface, where the upper cutaneous blood plexus resides. Total blood vessels area then decreases quasi-exponentially to a depth of approx. -0.75 mm, with a decay length of approximately 0.1 mm, which is site and skin condition dependent, but at greater depths the decrease is approx. 6-times less steep. The corresponding permeability sink exhibits a similar, but superficially steeper, depth-profile. The lateral localisation of superficial blood vessels is such that ensures maximum diffusion from and into the capillaries, which affects transdermal drug delivery: each hairpin-like loop is in the centre of a papilla that corresponds to a cluster of corneocytes surrounded by main diffusion pathways. The aggregate area of blood vessels in the skin is >or=2.5-fold greater than total organ surface area under normal physiological conditions. The molecules diffusing through the skin barrier are thus largely cleared in outermost 20% of the organ, which may create a drug concentration maximum in the dermis, if clearance increases significantly with time. Skin microdialysis data are therefore extremely sensitive to cutaneous blood flow (distribution) and sampling. Skin microvasculature and its distribution must consequently be considered in all topical or transdermal drug transport studies, for example, by including suitably formulated clearance term into generalised diffusion equation.     

Clinical and pharmacokinetic properties of a transdermal nicotine patch

We examined the pharmacokinetics of a transdermal nicotine patch and evaluated the usefulness of such a patch in a pilot smoking-cessation program. Use of the patch was associated with plasma nicotine concentrations that were comparable to smoking or to the use of other smoking-cessation devices. However, these plasma concentrations were maintained for 24 hours, and the patch appeared to be suitable for use once a day. Its use in a 6-week placebo-controlled double-blind study resulted in a significant degree of smoking cessation or in reduction of smoking activity. The findings suggest that it may be valuable to extend investigations to a larger population and that transdermal nicotine may have a useful role in smoking-cessation therapy.     

Mentholated cigarette smoking inhibits nicotine metabolism

Smoking mentholated cigarettes has been suggested to convey a greater cancer risk compared with smoking nonmentholated cigarettes. Two of the possible mechanisms by which mentholated cigarette smoking could increase risk are by increasing systemic exposure to tobacco smoke toxins and by affecting the metabolism of nicotine or tobacco smoke carcinogens. To examine these possibilities, we performed a crossover study in 14 healthy smokers, one-half of whom were African-Americans and one-half whites. Subjects were randomly assigned to smoke mentholated or nonmentholated cigarettes for 1 week, then to cross over to the other type of cigarettes for another week. Subjects were confined to a Clinical Research Center for 3 days of each week, during which time blood levels of nicotine and carbon monoxide were measured throughout the day and an intravenous infusion of deuterium-labeled nicotine and cotinine was administered to determine the rate and pathways of nicotine metabolism. The systemic intake of nicotine and carbon monoxide was, on average, not affected by mentholation of cigarettes. Mentholated cigarette smoking did significantly inhibit the metabolism of nicotine (clearance: 1289 versus 1431 ml/min, two sided, p = 0.02). Inhibition of nicotine metabolism occurred both by slower oxidative metabolism to cotinine and by slower glucuronide conjugation. Our data do not support the hypothesis that mentholated cigarette smoking results in a greater absorption of tobacco smoke toxins. Our finding of impaired metabolism of nicotine while mentholated cigarette smoking suggests that mentholated cigarette smoking enhances systemic nicotine exposure.     

Intravenous nicotine and caffeine: subjective and physiological effects in cocaine abusers

The subjective and physiological effects of intravenously administered caffeine and nicotine were compared in nine subjects with histories of using caffeine, tobacco, and cocaine. Subjects abstained from tobacco cigarette smoking for at least 8 h before each session. Dietary caffeine was eliminated throughout the study; however, to maintain consistency with the nicotine intake, subjects were administered caffeine (150 mg/70 kg b.i.d.) in capsules, with the last dose administered 15 to 18 h before each session. Under double-blind conditions, subjects received placebo, caffeine (100, 200, and 400 mg/70 kg), and nicotine (0.75, 1.5, and 3.0 mg/70 kg) in mixed order. Physiological and subjective data were collected before and repeatedly after drug or placebo administration. Compared with the highest dose of caffeine, the highest dose of nicotine produced greater subjective ratings on a number of scales. At doses that produced comparable ratings of drug effect (1.5 mg/70 kg of nicotine and 400 mg/70 kg of caffeine), both drugs produced similar increases in ratings of good effect, liking, high, stimulated, and bad effect. Nicotine showed a somewhat faster time to peak subjective effects than caffeine (2 versus 4 min). Subjective ratings that differentiated caffeine and nicotine were ratings of rush, blurry vision, and stimulant identification (elevated by nicotine) and ratings of unusual smell and/or taste (elevated by caffeine). Both caffeine and nicotine decreased skin temperature and increased diastolic blood pressure; however, caffeine decreased whereas nicotine increased heart rate. The study documents both striking similarities and some notable differences between caffeine and nicotine, which are among the most widely used mood-altering drugs.