Nicotine: A Targeted Therapy for Epilepsy Due to nAChR Gene Variants.

OBJECTIVE: Genetic variants of the neuronal nicotinic acetylcholine receptor (nAChR) cause autosomal dominant sleep-related hypermotor epilepsy. Approximately 30% of autosomal dominant sleep-related hypermotor epilepsy patients are medically intractable. In preclinical models, pathogenic nAChR variants cause a gain of function mutation with sensitivity to acetylcholine antagonists and agonists. Nicotine modifies the activity of nAChRs and can be used as targeted therapy. METHODS: We reviewed next-generation sequencing epilepsy panels from a single laboratory (GeneDx) from patients at Children's Medical Center Dallas between 2011 and 2015 and identified patients with nAChR variants. Retrospective review of records included variant details, medical history, neuroimaging findings, and treatment history. RESULTS: Twenty-one patients were identified. Four patients were prescribed nicotine patches for intractable seizures. Three of 4 patients had a clinical response, with >50% seizure reduction. CONCLUSIONS: Treatment with a nicotine patch can be an effective therapy in epilepsy patients with nAChR gene variants. We propose consideration of transdermal nicotine treatment in intractable epilepsy with known nAChR variants as an experimental therapy. Further clinical trials are needed to fully define therapeutic effects.

Nicotine nasal spray as an adjuvant analgesic for third molar surgery.

PURPOSE: To determine the efficacy of preoperatively administered nicotine nasal spray (3 mg) for analgesia after third molar (TM) surgery. MATERIALS AND METHODS: A single-center, prospective, randomized, double-blind, crossover trial was conducted. The study population consisted of 20 nonsmoking patients referred to the Department of Oral and Maxillofacial Surgery of Columbia University College of Dental Medicine for extraction of all 4 TMs. Each patient received nicotine nasal spray or placebo spray before TM surgery. At a subsequent visit the contralateral TMs were removed with prior administration of the alternate treatment. For an hour postoperatively, subjects reported information on pain and nausea, and hemodynamic variables were recorded at 15-minute intervals. Telephone follow-up was recorded for 5 days postoperatively, where patients reported information on pain, nausea, and use of hydrocodone/acetaminophen as rescue analgesia. RESULTS: Nicotine treatment was associated with a highly significant decrease in pain reported during the 5 days after TM surgery. There was no difference in the amount of hydrocodone/acetaminophen used or amount of nausea reported. There was a small but significant increase in heart rate after nicotine treatment compared with placebo during the first hour after surgery. There was no difference in blood pressure between groups. CONCLUSION: Pain is well controlled by hydrocodone/acetaminophen in most patients after TM surgery. However, there is significant variability in pain reported. Nicotinic agonists represent a new class of analgesic that can be considered for patients who are expected to have significant opioid-resistant pain after TM surgery. Caution should be used with patients in whom a small increase in heart rate would be deleterious.

Chronic nicotine restores normal Aß levels and prevents short-term memory and E-LTP impairment in Aß rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by increased deposition of beta-amyloid (Aß) peptides and progressive cholinergic dysfunction in regions of the brain involved in learning and memory processing. In AD, progressive accumulation of Aß peptide impairs nicotinic acetylcholine receptor (nAChR) function by an unknown mechanism believed to involve α(7)- and α(4)ß(2)-nAChR blockade. The three approaches of the current study evaluated the effects of chronic nicotine treatment in the prevention of Aß-induced impairment of learning and short-term memory. Rat AD model was induced by 14-day i.c.v. osmotic pump infusion of a 1:1 mixture of 300 pmol/day Aß(1-40)/Aß(1-42) or Aß(40-1) (inactive peptide, control). The effect of nicotine (2 mg/(kg day)) on Aß-induced spatial learning and memory impairments was assessed by evaluation of performance in the radial arm water maze (RAWM), in vivo electrophysiological recordings of early-phase long-term potentiation (E-LTP) in urethane-anesthetized rats, and immunoblot analysis to determine changes in the levels of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), Aß and memory-related proteins. The results indicate that 6 weeks of nicotine treatment reduced the levels of Aß(1-40) and BACE1 peptides in hippocampal area CA1 and prevented Aß-induced impairment of learning and short-term memory. Chronic nicotine also prevented the Aß-induced inhibition of basal synaptic transmission and LTP in hippocampal area CA1. Furthermore, chronic nicotine treatment prevented the Aß-induced reduction of α(7)- and α(4)-nAChR. These effects of nicotine may be due, at least in part, to upregulation of brain derived neurotropic factor (BDNF).

Nicotine exerts an anti-inflammatory effect in a murine model of acute lung injury.

Activation of the cholinergic anti-inflammatory pathway through direct activation of nicotinic acetylcholine receptors on immune cells can inhibit pro-inflammatory chemokine and cytokine release and thereby protect in a variety of inflammatory diseases. The aim of this study was to investigate whether nicotine treatment protected against acute lung inflammation. Mice challenged with intratracheal lipopolysaccharide (LPS, 50 µg) were treated with nicotine (0.2 or 0.4 mg/kg, sc). After 24 h, bronchoalveolar lavage fluid (BALF) was obtained to measure leukocyte infiltration, lung edema, and pro-inflammatory chemokine (MIP-1α, MIP-2, and eotaxin) and cytokine (IL-1, IL-6, and TNF-α) levels. Nicotine treatment reduced the LPS-mediated infiltration of leukocytes and edema as evidenced by decreased BALF inflammatory cells, myeloperoxidase, and protein. Nicotine also downregulated lung production of pro-inflammatory chemokines and cytokines. These data support the proposal that activation of the cholinergic anti-inflammatory pathway may represent a useful addition to the therapy of acute respiratory distress syndrome.

Intensification of long-term memory deficit by chronic stress and prevention by nicotine in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cholinergic dysfunction and deposition of beta-amyloid (Aß) in regions of the brain associated with learning and memory. The sporadic nature and late onset of most AD cases suggests that aside from biological determinants, environmental factors such as stress may also play a role in the progression of the disease. Behavioral and molecular studies were utilized to evaluate the effects of chronic nicotine treatment in the prevention of impairment of long-term memory. The rat model of AD was induced by i.c.v. osmotic pump infusion of Aß peptides. Chronic psychosocial stress and chronic nicotine treatment were instituted for 6weeks. Spatial memory testing in the Radial Arm Water Maze revealed that, although stress, by itself, did not affect long-term memory, the combination of chronic stress and Aß infusion impaired long-term memory significantly more than Aß peptides infusion alone. Chronic nicotine treatment completely prevented Aß- and stress/Aß combination-induced memory impairment. Furthermore, molecular findings in hippocampal CA1 region of stress/Aß rats indicated marked reduction in the protein levels of phosphorylated cAMP response element binding (p-CREB) and calcium-calmodulin-dependent protein kinase IV (CaMKIV), with significant increases in the levels of brain-derived neurotrophic factor (BDNF). These disturbances in signaling pathways, which may be the underlying mechanisms of impairment of long-term memory in these rats, were totally prevented by chronic nicotine treatment.

Toll-like receptor 4 modulation as a strategy to treat sepsis.

Despite a decrease in mortality over the last decade, sepsis remains the tenth leading causes of death in western countries and one of the most common cause of death in intensive care units. The recent discovery of Toll-like receptors and their downstream signalling pathways allowed us to better understand the pathophysiology of sepsis-related disorders. Particular attention has been paid to Toll-like receptor 4, the receptor for Gram-negative bacteria outer membrane lipopolysaccharide or endotoxin. Since most of the clinical trial targeting single inflammatory cytokine in the treatment of sepsis failed, therapeutic targeting of Toll-like receptor 4, because of its central role, looks promising. The purpose of this paper is to focus on the recent data of various drugs targeting TLR4 expression and pathway and their potential role as adjunctive therapy in severe sepsis and septic shock.

Exploring the views of women on using nicotine replacement therapy in pregnancy.

OBJECTIVE: to explore women's views surrounding the use of nicotine replacement therapy (NRT) to aid smoking cessation. DESIGN AND SETTING: a qualitative approach using semi-structured interviews undertaken on 10 pregnant women in a semi-rural area of England. FINDINGS: the two main themes that emerged from the study were that NRT was an important component in stopping smoking, but this was in conjunction with support given by the midwife advisor. Both themes appeared to be equally important to the women in aiding their attempts at smoking cessation. Also, the importance of tailored interventions should not be dismissed when aiding women in smoking cessation. CONCLUSIONS: exploring the views of women enabled the researchers to gain a greater understanding of the problems and achievements that women encountered when using NRT as an aid to stop smoking during pregnancy. The study also demonstrated that smoking cessation strategies can be successful if they are tailored to the individual needs of each woman, taking into account her dependency, domestic circumstances and willingness to change. IMPLICATIONS FOR PRACTICE: the findings of this study add to the available research surrounding the efficacy of NRT in pregnancy. There is little evidence that the views of pregnant women have been taken into account prior to this study; as such, this report offers a different dimension to the available evidence. Although these findings could be adopted and utilized by practitioners, there is still the need for further research in this area on a larger scale.

Women's use of nicotine replacement therapy in pregnancy-a structured review of the literature.

OBJECTIVE: to review the literature of women's use of nicotine replacement therapy (NRT) during pregnancy. The review will examine NRT and nicotine, interventions and barriers to smoking cessation and the literature exploring women's views on using NRT in pregnancy. METHOD: a structured review of the literature was undertaken by accessing internet and library sources, restricted to English written articles between 1989 and 2003. Keywords were used to refine the search: pregnancy, smoking, NRT and smoking cessation. FINDINGS: several papers had examined interventions employed to aid pregnant women in smoking cessation and the efficacy of NRT. However, papers exploring the views of women on the use of NRT during pregnancy were limited. CONCLUSIONS: smoking cessation is unique to individual women; as such, appropriate support and advice should be tailored accordingly. Further research is needed to explore the views of women using NRT during pregnancy to aid smoking cessation. IMPLICATIONS FOR PRACTICE: the findings from this structured review raise awareness of the importance of smoking cessation during pregnancy, and the inclusion of women's views when discussing the use of NRT. Understanding women's views may enhance the care and advice given by midwives, thus improving smoking cessation rates in pregnancy.

'Breathe': the stop smoking service for pregnant women in Glasgow.

OBJECTIVE: to develop a pragmatic service for pregnant smokers. DESIGN: identification and referral of pregnant smokers to specialist services using self-report gathered on routine pregnancy booking questionnaire augmented by a carbon monoxide breath test. Engagement by specialist smoking cessation midwives using telephone contact with the offer of clinic-based counselling for women who want help. Telephone support and pharmacy provision of nicotine replacement therapy for women who decide to quit. SETTING: three maternity units serving Glasgow in the West of Scotland. PARTICIPANTS: a relatively deprived population of 12,000 pregnant women each year in Glasgow. INTERVENTIONS: at maternity booking, women with either a carbon monoxide breath test result >7 parts per million or self-reporting to be a current smoker during the routine pregnancy booking questionnaire were identified as smokers. All smokers were referred on to the specially trained midwives who provided an opt-out smoking cessation intervention. This involved motivational interviewing to engage pregnant smokers during telephone contact. Women considering quitting were invited for a follow-up face-to-face meeting in a clinic setting. Women who set a quit date were offered withdrawal oriented therapy augmented by pharmacy-based nicotine replacement therapy. FINDINGS: booking midwives found it difficult to approach all pregnant women to talk about smoking. This was not made easier by the service requirement that all pregnant women should provide a carbon monoxide breath test at maternity booking. In one hospital, auxiliary nurses performed the carbon monoxide breath test and 2879 of 3219 (89%) women booking for antenatal care provided a sample, allowing most smokers to be identified. In another hospital where the carbon monoxide test was administered by midwives, only 1968 of 5570 (35%) women provided a carbon monoxide breath test sample; 61% of pregnant smokers were not identified and referred to specialist services. Of the 1936 pregnant smokers referred from all three hospitals, 386 (20%) attended a face-to-face appointment with specialist smoking cessation midwives, 370 (19%) set a quit date and 117 (6%) had quit 4 weeks after their quit date. IMPLICATIONS FOR PRACTICE: this service development provides a pragmatic approach to identify nearly all pregnant smokers at maternity booking, and an opt-out model to refer them to specialist smoking cessation services. Further research is required to establish if extra auxiliary staff in maternity booking clinics can optimise the identification and referral of pregnant smokers to specialist smoking cessation services. This telephone- and clinic-based specialist service engaged 20% of referred pregnant smokers to attend a face-to-face appointment with a specialist smoking cessation midwife. Further research is required to assess if home-based support would engage a greater proportion of pregnant smokers, or if an incentive scheme would achieve the same aim. In total, 117 of 370 (32%) women who set a quit date had quit smoking 4 weeks later, which compares fairly well with a figure of 40% for pregnant smokers in the English smoking treatment services.

A comparison of abstinence outcomes among gay/bisexual and heterosexual male smokers in an intensive, non-tailored smoking cessation study.

INTRODUCTION: Smoking rates are higher among lesbian/gay/bisexual (LGB) than heterosexual (HT) individuals. However, there is scant information regarding smoking cessation treatments and outcomes in LGB populations. This study examined abstinence outcome in response to a high intensity smoking cessation program not specifically tailored to LGB smokers. METHODS: A total of 54 gay/bisexual (GB) and 243 HT male smokers received 8-week open treatment with nicotine patch, bupropion, and counseling. Participants reported biologically verified abstinence at multiple time points during the study. RESULTS: Demographic, smoking, and psychological characteristics at baseline were similar according to sexual orientation. During the first 2 weeks after quit day, abstinence rates were higher among GB smokers (Week 1: GB = 89%, HT = 82%; Week 2: GB = 77%, HT = 68%; ps < .05); abstinence rates converged subsequently, becoming nearly identical at the end of treatment (Week 8, GB = 59% vs. HT = 57%). In mixed effects longitudinal analysis of end-of-treatment outcome, sexual orientation (b = 1.40, SEM = 0.73, p = .056) and the Sexual Orientation x Time interaction (b = -0.146; SEM = 0.08, p = .058) approached statistical significance, reflecting the higher initial abstinence rates among GB smokers and the later convergence in abstinence rates by sexual orientation. DISCUSSION: This first report comparing smoking cessation treatment response by sexual orientation found higher initial and similar end-of-treatment abstinence rates in GB and HT smokers. Further work is needed to determine whether these observations from GB smokers who displayed a willingness to attend a non-tailored program and broad similarity with their HT counterparts in many baseline characteristics will replicate in other groups of GB smokers.

Heterogeneity in preferences for smoking cessation.

Promoting cessation is a cornerstone of tobacco control efforts by public-health agencies. Economic information to support cessation programs has generally emphasized cost-effectiveness or the impact of cigarette pricing and smoking restrictions on quit rates. In contrast, this study provides empirical estimates of smoker preferences for increased efficacy and other attributes of smoking cessation therapies (SCTs). Choice data were collected through a national survey of Canadian smokers. We find systematic preference heterogeneity for therapy types and SCT attributes between light and heavy smokers, as well as random heterogeneity using random parameters logit models. Preference heterogeneity is greatest between length of use and types of SCTs. We estimate that light smokers would be willing to pay nearly $500 ($CAN) to increase success rates to 40% with the comparable figure for heavy smokers being near $300 ($CAN). Results from this study can be used to inform research and development for smoking cessation products and programs and suggest important areas of future inquiry regarding heterogeneity of smoker preferences and preferences for other health programs.

Postintervention effect of nicotine replacement therapy for smoking reduction: a randomized trial with a 5-year follow-up.

We tested whether a reduction of cigarette consumption obtained after 6 months of nicotine replacement therapy was maintained 5 years after the end of this treatment. Heavy smokers (mean = 30 cigarettes per day) who had no intention of quitting smoking were randomly assigned to a 6-month treatment of nicotine (15-mg patch, 4-mg gum, and/or 10-mg inhaler, n = 265), placebo (n = 269), or no intervention (n = 389). Products were sent by mail, and education was limited to a booklet. Of 923 participants, 879 (95%) were followed after 6 months and 671 (73%) after 5 years. After 6 months, smoking reduction was larger for nicotine (-10.9 cigarettes per day) than for placebo (-8.7) and no treatment (-4.9, all P or= 0.2) and smoking cessation rates (17% to 21%, all P > 0.2) were similar in all groups. In smokers, 5-year continuous abstinence was higher in those who had reduced their cigarette consumption by at least 50% between baseline and 6 months than in those who did not reduce (11.9% vs 5.6%; P = 0.011; odds ratio, 2.3; 95% confidence interval, 1.2-4.2). Thus, the initial effect of the treatment on smoking reduction was not maintained after 5 years. However, reducing cigarette consumption was associated with a higher chance of subsequently quitting smoking. Nicotine replacement therapy in unmotivated smokers had no deleterious effect on dependence levels and smoking behavior.

Nicotine, cotinine, withdrawal, and craving patterns during smoking and nicotine nasal spray use: results from a pilot study with African American men.

Nicotine intake via smoking is highly variable. Individualized dosing of nicotine replacement therapy (NRT) may improve product efficacy, but a better understanding of the within-day and within-subject relationships between smoking, NRT use, nicotine and cotinine concentrations in blood, and cravings and withdrawal symptoms is needed to inform dosing algorithms. A pilot study was undertaken to collect data on these relationships and to assess the feasibility of the methods needed for this type of research, including a sophisticated statistical modeling technique (a two-part mixed-effects model with correlated random effects that accounts for clumping at zero). Because nicotine metabolism varies by gender and race, the sample was homogeneous with respect to these characteristics. In a within-subjects study, 27 African American adult male smokers carried a computerized cigarette dispenser for 1 week, capturing the time each cigarette was smoked. Subjects then entered an inpatient setting for 1 day of scheduled smoking (matched to data from the cigarette dispenser to create an ecologically valid schedule) and 4 days of ad libitum nicotine nasal spray use, while tobacco abstinent. Eight times per day, at 2-hour intervals, blood was drawn and ratings of cigarette cravings and withdrawal symptoms were obtained. On average, subjects used less than half of the manufacturer's recommended minimum daily dose of nicotine nasal spray. Large differences in nicotine and cotinine levels were observed between individuals. When predicting nicotine, cotinine, withdrawal, and cravings, we observed significant interactions between route of nicotine intake and a variety of independent variables.

Cognitive effects of adjunctive 24-weeks Rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind investigation.

Cognitive impairment has the greatest impact on illness outcome in schizophrenia. The most significant challenge in schizophrenia therapeutics, thus, is to develop an efficacious treatment for cognitive impairments. Acetylcholinesterase inhibitors, such as Physostigmine and Rivastigmine, are considered effective treatments for cognitive decline in Alzheimer's Disease, where the loss of cholinergic neurons is thought to be responsible for various cognitive deficits. The current study investigated the cognitive effects of Rivastigmine given as an add-on therapy to antipsychotic-treated schizophrenia patients in a placebo-controlled double-blind design. The study initially involved 40 patients, of which 21 patients (11 assigned to Rivastigmine and 10 assigned to placebo) agreed to continued participation, remained on the study drug, and underwent assessment of executive functioning, verbal skills, verbal and spatial working memory, attention and psychomotor speed on three occasions: (i) at baseline, and then (ii) after 12 weeks and (iii) 24 weeks of treatment with placebo or Rivastigmine. The results failed to reveal significant improvement on any cognitive measure with Rivastigmine treatment, compared with the placebo treatment. Some cognitive variables showed significant practice effects in both the placebo and Rivastigmine groups. No effects were noted in symptoms or side effects ratings. The beneficial cognitive effects of Rivastigmine seen in an open-label preliminary study are not substantiated by this study. Future studies should investigate the effects of other procholinergic drugs, such as Galantamine, which also act on the nicotine receptors and may produce stronger cognitive effects in schizophrenia.

Smoking cessation program and CYP2A6 polymorphism.

The relationship between CYP2A6 genotype and smoking status remains unclear although several studies have been reported. In this study, we have investigated the significance of CYP2A6 genotype on smoking habit and treatment of nicotine patch. Sixty-one smokers (1.7%) working in a Japanese company (n = 3585) participated in this smoking cessation program. Forty-four of 61 (72.1%) smokers were treated by nicotine patch. A genotyping analysis was carried out for 41 (40 men and 1 women) of 61 participants (67.2%). The smoking cessation rate at 90 days was 54.1% (33/61). Age and smoking years in re-smoking group are significantly lower than those in smoking cessation group. The smoking cessation rate of participants treated with nicotine patch (63.6%; 28/44) was significantly higher than that of the group non-treated with nicotine patch (29.4%; 5/17) at 90 days (p < 0.05). The incidence of homozygotes of CYP2A6 gene deletion (CYP2A619934/19934) in 41 cases (9.8%; 4/41) could be higher than that in 894 healthy controls (3.7%; 33/894) (p = 0.12), while no other variant alleles (CYP2A619932, CYP2A619933 and CYP2A619936) were found. Age and smoking years of participants with CYP2A619934/19934 are significantly higher than those with CYP2A619931 positive. The scores of Fagerstrom test, an analysis for nicotine-dependence, were slightly different between participants with CYP2A619934/19934 and CYP2A619931 positive. Although treatment of nicotine patch is efficacious to smoking cessation, cases with CYP2A619934/19934 might be more sensitive to nicotine adverse effects and more difficult to quit smoking once they have smoking habit.

Adolescents' perceptions about quitting and nicotine replacement therapy: findings from the California Tobacco Survey.

We collected data from 5,857 adolescent (12-17 y) respondents in California to assess their perception about quitting smoking and nicotine replacement therapy use. In multivariate models, never smokers were less likely than established or experimenter smokers to believe that if they were to smoke they could quit anytime but were more likely to believe that nicotine replacement therapy is a sure way to quit.