FDA对开发尼古丁替代疗法药品的要求

美国食品药品管理局（FDA）于2019年2月发布了"供企业用戒烟及相关适应症：开发尼古丁替代疗法药品的指导原则"（草案）。该指导原则介绍了FDA对尼古丁替代疗法（NRT）药品总体开发方案的建议，而我国目前尚无类似指导原则。介绍该指导原则的主要内容，期待对我国这类药的研发有益。     

Learning and memory performance following acute intranasal insulin administration in abstinent smokers

The highest incidence of relapse to smoking occurs within the first 2 weeks of a cessation attempt. In addition to enhanced nicotine craving, this phase of smoking cessation is also marked by learning and memory dysfunction. Many smokers are not able to overcome these symptoms, and they relapse to smoking shortly after trying to quit. In two clinical studies, we evaluated intranasal insulin for efficacy in improving learning and memory function during nicotine withdrawal. Our first study was a crossover evaluation (N = 19) following 20 hr of smoking abstinence. Study 2 was a parallel design study (N = 50) following 16 hr of abstinence. Intranasal insulin (60 IU) dose was administered in both studies and cognitive function was measured using California Verbal Learning Test‐II. Intranasal insulin did not improve learning over the 5 verbal learning trials. In addition, intranasal insulin did not improve either short‐ or long‐delay recall in either study. In summary, the one‐time administration of intranasal insulin does not improve verbal learning and memory in smokers. Whether longer administration schedules may be of benefit should be evaluated in future studies.     

Study of the relationship between anxiety sensitivity,smoking abstinence expectancies,nicotine withdrawal,and cigarette dependence among daily smokers

Introduction: Anxiety sensitivity (AS) is the fear of anxiety symptoms related to physical, cognitive, and social concerns. AS has been implicated in amplifying negative emotional states and maintaining smoking behavior. Aims: The current cross-sectional study evaluated the lower-order facets of AS (Physical, Cognitive, Social concerns) in relation to current nicotine withdrawal symptoms, short-term consequences of abstaining from smoking, and cigarette dependence. Methods: 331 adult Italian smokers were recruited from the general population and asked to fill in scales assessing AS, nicotine withdrawal symptoms, and cigarette dependence. Results: All ASI-3 subscales were associated with psychological symptoms of nicotine abstinence (β?=?0.30–0.10; p?≥?0.001), whereas ASI-3 physical concerns (β?=?0.62; p?≥?0.001) and ASI-3 cognitive concerns (β?=?0.25; p?≥?0.001) were associated with physical symptoms of nicotine abstinence. No ASI-3 subscales were associated with short-term smoking abstinence expectancies. ASI-3 physical concerns (β?=?0.72; p?≥?0.001) and ASI-3 cognitive concerns (β?=?0.25; p?≥?0.001) were associated with cigarette dependence. Discussion: ASI-3 physical concerns and ASI-3 cognitive concerns could amplify withdrawal-related factors, thereby increasing the negative reinforcement processes which might motivate smoking.     

Black Light Smokers: How Nicotine Intake and Carcinogen Exposure Differ Across Various Biobehavioral Factors

ObjectiveThe study objective was to identify biobehavioral variables associated with greater intake of nicotine and a tobacco carcinogen among Black light smokers who smoke 1 to 10 cigarettes per day (CPD).MethodsWe analyzed baseline data collected from 426 Black light smokers enrolled in Kick It at Swope III (KIS III), a smoking cessation trial for Black smokers. We examined differences in concentrations of tobacco biomarkers, including urinary total nicotine equivalents (TNE) and total 4-(methylnitrosamino)-1-(3)pyridyl-1-butanonol (NNAL; a human carcinogen), across gender, age, plasma nicotine metabolite ratio (NMR), CPD, and measures of tobacco dependence, including time to first cigarette (TFC), using ANOVA.ResultsTobacco biomarker levels were significantly higher among those who smoked more CPD (6–10 vs 1–5 CPD) and those with greater reported physical dependence on tobacco. Concurrently, those who smoked 1–5 CPD smoked each cigarette more intensely than those who smoked 6–10 CPD. While we found no gender differences overall, among those who smoked 1–5 CPD, women had higher NNAL levels compared to men. The rate of nicotine metabolism, measured by the nicotine metabolite ratio, was not significantly related to TNE or NNAL levels.ConclusionAmong Black Light smokers, higher cigarette consumption and greater physical dependence—but not rate of nicotine metabolism, menthol use, or socioeconomic status—were associated with greater toxicant exposure and thus a likely increased risk of tobacco-related diseases. The lack of data on light smokers, and specifically on Blacks, make this observation important given the disproportionate burden of lung cancer in this population.     

Electronic cigarette use in New South Wales,Australia: reasons for use,place of purchase and use in enclosed and outdoor places

Objective: To monitor patterns of use of e‐cigarettes to understand their potential impact on the New South Wales (NSW) population in Australia. Methods: A cross‐sectional online survey was carried out with a sample of adults in NSW in February 2016. Ever and past 30‐day use of e‐cigarettes, reasons for use, place of purchase and use within outdoor and enclosed public places were assessed along with sociodemographic characteristics. Results: Ever and past 30‐day use was reported by 13% and 4% of the sample, respectively. More than one‐third of participants did not purchase their own e‐cigarette (36.3%). The most frequently reported reason for using an e‐cigarette for smokers and ex‐smokers was to help quit smoking (45.3% and 44.7%, respectively) while for non‐smokers it was novelty (40%). E‐cigarettes were most commonly used at home (59.4%), in outdoor dining areas (36.8%) and in the workplace (27.8%). Conclusions: E‐cigarettes are being used by a small percentage of the NSW population. Reasons for e‐cigarette use varied with smoking status. Different sociodemographic characteristics were associated with ever and past 30‐day use of e‐cigarettes. E‐cigarettes are being used in areas that are covered by smoke‐free legislation. Implications for public health: Given e‐cigarettes are being used in smoke‐free areas, policy‐makers could take a precautionary approach by including e‐cigarette use under smoke‐free legislation.     

Nicotine effects on PGE2 and IL-1β release by LPS-treated human monocytes

Cigarette smoking is a major risk factor in the development and further progression of periodontitis. However, little is known regarding the pathogenesis of smoking-related periodontal diseases. The purpose of this study was to examine the effects of nicotine, alone and in combination with lipopolysaccharide (LPS), on monocyte secretion of bone-resorbing factors, PGE₂ and IL-1β. Peripheral blood monocytes (PBM) were isolated by counterflow centrifugal elutriation from 15 healthy, non-smoking donors. PBM were incubated for 24 h in RPMI 1640 containing nicotine (0, 50 μg/ml, I μg/ml, 10 μg/ml and 100 μg/ml) with or without 10 μg/ml Porphyromonas gingivalis LPS or Escherichia coli LPS. Culture supernatants were assayed for PGE₂ and IL-1β by ELISA. None of the nicotine preparations resulted in significant PBM secretion of PGE₂ and IL-1β above that of unstimulated cultures. However, PGE₂ release was potentiated 1.7-fold by the combination of P. gingivalis LPS and 10 μg/ml nicotine relative to P. gingivalis LPS alone (p<0.05, one-way ANOVA). Prostaglandin E₃ release also was potentiated 3.5-fold by P. gingivalis LPS and 100 μg/ml nicotine relative to P. gingivalis LPS alone (p<0.00001, one-way ANOVA) and 3.1-fold by E. coli LPS and 100 μg/ml nicotine relative to E. coli LPS alone (p<0.00001, I. one-way ANOVA). IL-1β secretion was lower for either LPS plus 100 μg/ml nicotine relative to LPS alone, although not significantly. These data demonstrate upregulation of LPS-mediated monocyte secretion of PGE₂ by nicotine and suggest a potential role for nicotine in periodontal disease pathogenesis.     

Effects of nicotine and tobacco-specific nitrosamines on hamster cheek pouch and gastric mucosa

Fifty-two hamsters were divided into 6 groups and their cheek pouches treated with either 0.01% NNN, 0.01% NNN and 6% nicotine, 0.01%. NNK, 0.01% NNK and 6% nicotine, 6%i nicotine, or sesame oil. After painting each pouch 3 times per week for 13 months, the animals were killed and specimens from the cheek pouch and forestomach examined. Cheek pouch epithelium showed more frequent histologic changes, including hyperplasia, hyperkeratosis and, in one animal, moderate dysplasia, when nicotine was combined with NNN than after treatment with NNN (or nicotine) alone. There was a higher frequency of hyperplasia with hyperkeratosis in the forestomach when nicotine was combined with NNK than following NNK, or nicotine treatment alone, and squamous cell papillomas were evident in animals treated with both NNK and nicotine. These results suggest that in mucosal tissues nicotine may enhance the effect of weak carcinogens such as the nitrosamines.     

Nicotine-induced damage affects gingival fibroblasts in the gingival tissue of rats

Background: Very limited information is available from in vivo studies about whether smoking and/or nicotine affect gingival tissues in the absence of plaque. The purpose of this study is to evaluate the effect of the systemic administration of nicotine in the proliferation and counting of fibroblast‐like cells in the gingival tissue of rats. Methods: Thirty adult male Wistar rats were randomly assigned into two groups to receive subcutaneous injections of a saline solution (control group = group C) or nicotine solution (group N; 3 mg/kg) twice a day. The animals were euthanized 37, 44, or 51 days after the first subcutaneous injection. Specimens were routinely processed for serial histologic sections. Five fields of view in the connective tissue adjacent to the gingival epithelium and above the alveolar bone crest of the maxillary first molar were selected for the counting of fibroblast‐like cells. Data were statistically analyzed (P <0.05). Results: The intergroup analysis detected a lower number of fibroblast‐like cells in group N compared to group C on days 37 (2.65 ± 1.41 and 6.67 ± 3.25, respectively), 44 (2.70 ± 1.84 and 8.57 ± 2.37, respectively), and 51 (2.09 ± 1.41 and 7.49 ± 2.60, respectively) (P <0.05). The quantification of fibroblast‐like cells showed no significant difference (P >0.05) in the intragroup analysis of control and nicotine throughout experimental periods. In the intergroup analysis, group N had reduced proliferating cell nuclear antigen–positive fibroblasts compared to group C in all periods (P <0.05). Conclusion: The daily systemic administration of nicotine negatively affected, in vivo, the number and proliferation of fibroblast‐like cells in the gingival tissue of rats.     

Social nicotine dependence in Australian dental undergraduate students

Objectives: This study aimed to investigate dental undergraduate students’ tobacco usage and social nicotine dependence in Australia. A special interest was to identify the role of factors such as age, gender, year of dental education and cohabitants’ smoking status for social nicotine dependence. Materials and methods: A sample of 252, first‐to‐fifth year undergraduate students in an Australian dental school was used. Each completed a self‐administered questionnaire. Results: The smoking rate was 4.8%. Current smokers displayed higher social nicotine dependence than those that had never smoked (t = 3.1, df = 244, P = 0.002). Dental undergraduate students that showed higher social nicotine dependence (P = 0.001, OR = 1.3, 95% CI: 1.1–1.6), or that had smoking cohabitants (P = 0.016, OR = 4.8, 95% CI: 1.3–17.0), were more likely to smoke. Students’ social nicotine dependence increased with year of dental study (P = 0.043, β = 0.4, t = 2.0). Social nicotine dependence enhanced tobacco usage among Year‐1‐to‐4 students (P = 0.005, OR = 1.4, 95% CI: 1.1–1.7) but not Year‐5 undergraduates (P = 0.432). Conclusions: Social nicotine dependence has become a developing issue in dental education. Tobacco control should be highlighted in the dental curriculum. Future investigations into the effects of dental education on social nocotine dependence and tobacco usage are indicated.     

The up-regulation of heme oxygenase-1 expression in human gingival fibroblasts stimulated with nicotine

BACKGROUND: Cigarette smoking is a major risk factor in the development and further progression of periodontal diseases. Heme oxygenase-1 (HO-1) is known as a stress-inducible protein and functions as an antioxidant enzyme. There is limited information on the expression of HO-1 in smoking-associated periodontal disease. OBJECTIVES: The aim of the present study was to investigate the effects of nicotine on the expression of HO-1 protein in cultured human gingival fibroblasts in vitro and further to compare HO-1 expression in gingival tissues obtained from cigarette smokers and non-smokers in vivo. METHODS: Western blot assay was used to investigate the effects on human gingival fibroblasts exposed to nicotine. In addition, antioxidants catalase, superoxide dismutase (SOD), and N-acetyl-l-cysteine (NAC) were added to test how they modulated the effects on nicotine-induced HO-1 expression. Gingival biopsies taken from the flap surgery of 20 male patients with periodontal disease (10 cigarette smokers and 10 non-smokers) were examined by immunohistochemistry. RESULTS: The exposure of quiescent human gingival fibroblasts to 10 mm nicotine resulted in the induction of HO-1 protein expression in a time-dependent manner (p < 0.05). The addition of glutathione (GSH) precursor NAC inhibited the nicotine-induced HO-1 protein expression (p < 0.05). However, SOD and catalase did not decrease the nicotine-induced HO-1 protein expression (p > 0.05). The results from immunohistochemistry demonstrated that HO-1 expression was significantly higher in cigarette smokers (p < 0.05). HO-1 was noted in the basal layers of epithelium, inflammatory cells, and fibroblasts in specimens from cigarette smoking. CONCLUSIONS: Taken together, these results suggest that HO-1 expression is significantly up-regulated in gingival tissues from cigarette smokers, and nicotine may, among other constituents, be responsible for the enhanced HO-1 expression in vivo. The regulation of HO-1 expression induced by nicotine is critically dependent on the intracellular GSH concentration.