Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal

Smoking is the largest preventable cause of death in the United States. Furthermore, a recent study found that <10% of quit attempts resulted in continuous abstinence for 1 year. With the introduction of pharmacotherapies like Chantix (varenicline), a selective α4β2 nicotinic partial agonist, successful quit attempts have significantly increased. Therefore, novel subtype-specific nicotinic drugs, such as sazetidine-A, present a rich area for investigation of therapeutic potential in smoking cessation. The present studies examine the anxiety-related behavioral and functional effects of the nicotinic partial agonists varenicline and sazetidine-A during withdrawal from chronic nicotine in mice. Our studies indicate that ventral hippocampal-specific infusions of sazetidine-A, but not varenicline, are efficacious in reducing nicotine withdrawal-related anxiety-like phenotypes in the novelty-induced hypophagia (NIH) paradigm. To further investigate functional differences between these partial agonists, we utilized voltage-sensitive dye imaging (VSDi) in ventral hippocampal slices to determine the effects of sazetidine-A and varenicline in animals chronically treated with saline, nicotine, or undergoing 24 h withdrawal. These studies demonstrate a functional dissociation of varenicline and sazetidine-A on hippocampal network activity, which is directly related to previous drug exposure. Furthermore, the effects of the nicotinic partial agonists in VSDi assays are significantly correlated with their behavioral effects in the NIH test. These findings highlight the importance of drug history in understanding the mechanisms through which nicotinic compounds may be aiding smoking cessation in individuals experiencing withdrawal-associated anxiety.     

Hippocampal and Insular Response to Smoking-Related Environments: Neuroimaging Evidence for Drug-Context Effects in Nicotine Dependence

Environments associated with prior drug use provoke craving and drug taking, and set the stage for lapse/relapse. Although the neurobehavioral bases of environment-induced drug taking have been investigated with animal models, the influence of drug–environments on brain function and behavior in clinical populations of substance users is largely unexplored. Adult smokers (n=40) photographed locations personally associated with smoking (personal smoking environments; PSEs) or personal nonsmoking environment (PNEs). Following 24-h abstinence, participants underwent fMRI scanning while viewing PSEs, PNEs, standard smoking and nonsmoking environments, as well as proximal smoking (eg, lit cigarette) and nonsmoking (eg, pencil) cues. Finally, in two separate sessions following 6-h abstinence they viewed either PSEs or PNEs while cue-induced self-reported craving and smoking behavior were assessed. Viewing PSEs increased blood oxygen level-dependent signal in right posterior hippocampus (pHPC; F_2,685=3.74, p<0.024) and bilateral insula (left: F_2,685=6.87, p=0.0011; right: F_2,685=5.34, p=0.005). In the laboratory, viewing PSEs, compared with PNEs, was associated with higher craving levels (F_2,180=18.32, p<0.0001) and greater ad lib smoking (F_1,36=5.01, p=0.032). The effect of PSEs (minus PNEs) on brain activation in right insula was positively correlated with the effect of PSEs (minus PNEs) on number of puffs taken from a cigarette (r=0.6, p=0.001). Our data, for the first time in humans, elucidates the neural mechanisms that mediate the effects of real-world drug-associated environments on drug taking behavior under conditions of drug abstinence. These findings establish targets for the development and evaluation of treatments seeking to reduce environment provoked relapse.     

The Effects of Social Support on Alcohol Consumption During Pregnancy: Situational and Ethnic/Cultural Considerations

While the effects of alcohol consumption during pregnancy have been well documented, variables associated with drinking during pregnancy have received little attention. This study sought to determine the importance of situational and ethnic/cultural-specific support on alcohol consumption during pregnancy among Black and White women in a U.S. southern urban prenatal population. A consecutive sample of 311 prenatal patients were interviewed during both the fourth month and the eighth month of pregnancy. Using standard regressions, the two components of expressive support-general support and pregnancy support—were found to be working in opposite directions, with pregnancy support showing a negative association with alcohol consumption during pregnancy. Pregnancy support was found to contribute signiflcantly to the variance in alcohol consumption among Whites but was not found to be a significant contributor among Blacks. These findings suggest that social support, specifically pregnancy support, is a significant variable in accounting for alcohol consumption during pregnancy, but this association may not be consistent across ethnic groups.     

Substance Use During Pregnancy and Postnatal Outcomes

Substance exposure in utero has been associated with physical birth defects and increased risk of regulatory and neuropsychological difficulties. The aims of this study were to describe women who use substances and are in treatment with respect to the type and number of substances used during pregnancy, as well as their background, and to examine the effect substance use has on gestational age, birth weight, and the development of neonatal abstinence syndrome at birth. A sample of 161 pregnant women and their 163 newborn children were included. The results indicate that the children whose mothers continued to use substances throughout their pregnancies were born at a lower gestational age (Chi-Square = 15.1(2), P < .01); children exposed to poly-substances in utero were more affected than those exposed to only alcohol and those with no substance exposure. The same children were more vulnerable to the development of neonatal abstinence syndrome at birth (Chi-Square = 51.7(2), P < .001). Newborns who were exposed primarily to alcohol in utero were at a significant risk of being born with low birth weight (Chi-Square = 8.8(2), P < .05) compared with those exposed to other types of substances. More than 50% of the mothers ceased using any substances (with the exception of tobacco) by birth, indicating that the treatment program did have an interventional effect on the mothers. The mothers’ ability to either cease or decrease the use of substances during pregnancy appears to have direct positive effect on their newborns.     

Nicotine and smoking: Effects upon subjective changes in mood

A Mood Adjective Check List and an activation scale were used to measure subjective reports on mood changes in 24 male habitual smokers before and after smoking cigarettes with known content of nicotine, at different times of day and rates of puffing. Ratings on pleasantness were dose related. Aggression and anxiety showed effects attributable to circadian influence and slight decreases in both factors occurred after smoking the highest nicotine cigarette. The MACL scores were greatly affected by the experimental procedure. Levels of inner tension were found related to the nicotine inhaled. The heuristic value of the concept of activation in these studies is suggested.This work was supported by the Tobacco Research Council, and carried out at the Institute of Psychiatry, London.     

左甲状腺素对甲状腺功能减退症患者妊娠结局和甲状腺素、游离三碘甲状腺原氨酸、抗甲状腺过氧化物酶的影响

目的:研究不同剂量左甲状腺素对妊娠期甲状腺功能减退症患者妊娠结局和甲状腺素(TSH)、游离三碘甲状腺原氨酸(FT3)、抗甲状腺过氧化物酶(TPOAb)的影响.方法:选取天津北大医疗海洋石油医院2018年6月至2020年1月收治的98例妊娠期甲状腺功能减退症患者,分为对照组和试验组,各49例.两组患者均根据血清TSH值给...     

反向离子对高效液相色谱法测定人血浆中尼古丁浓度

目的建立一种简便、准确的高效液相色谱法测定人血浆中尼古丁浓度。方法采用反向离子对高效液相色谱法,Kromasil C18色谱柱（250mm×4.6mm,5μm）,缓冲液（30mmol.L-1磷酸二氢钠,30mmol.L-1柠檬酸三钠,4mmol.L-1辛烷磺酸钠,pH 4.5）-乙腈（85∶15）,流速1.0mL.min-1,紫外检测波长260nm,柱温35℃,以2-苯基咪唑为内标。结果尼古丁在0.04～2.56mg.L-1范围内线形关系良好,标准曲线为Y=0.0009X-0.007,r=0.99995,相对回收率95.2～106.36%,提取回收率67.5～77.3%,日内RSD≤3.1%,日间RSD≤6.8%。血样在-20℃下保存30d后尼古丁含量无明显降低。结论本法具有灵敏度高、准确性好、色谱峰分离良好等特点,适用于人血浆样本中尼古丁浓度的测定。     

妊娠和哺乳期降压药物选择

目的:了解评估妊娠和哺乳期降压药物使用的风险/效益,为妊娠和哺乳期高血压妇女的降压治疗提供帮助。方法:检索近10余年国内外相关研究文献,筛选部分文献进行总结和分析。结果:通过分析显示:中枢性降压药、受体拮抗剂、钙拮抗剂类中一些药物在妊娠和哺乳期使用的风险/效益较低;利尿剂在妊娠伴发全身水肿且无先兆子痫时使用风险/效益较低;ACEI和ARB类可导致胎儿畸形、肾功能衰竭和死胎等,妊娠期药物使用的风险/效益高,但在哺乳期一些药物如依那普利、卡托普利无明确的禁忌。结论:拉贝洛尔、硝苯地平、甲基多巴等在妊娠和哺乳期使用的安全性和有效性较为肯定,并且受到越来越多的指南推荐。     

105例妊娠合并卵巢肿瘤的临床分析

目的探讨妊娠合并卵巢肿瘤的诊断、临床特征、处理方法和对妊娠结局的影响。方法回顾性分析东莞市人民医院2007年1月至2012年12月期间收治妊娠合并卵巢肿瘤105例病例的临床诊治及妊娠结局。结果 105例妊娠合并卵巢肿瘤患者中62例(59.0%)于孕早中期发现,孕期发生蒂扭转14例(13.3%),破裂6例(5.7%)。其中良性肿瘤102例(97.1%),交界性肿瘤2例(1.9%),恶性肿瘤1例(0.1%)。105例均行手术治疗,1例早孕终止妊娠,1例流产,103例婴儿均健康。结论在孕期选择适宜的手术时机及手术方式治疗妊娠合并卵巢肿瘤的患者不影响母婴预后。     

减少奥卡西平对妊娠小鼠不良作用的实验研究

摘要目的观察奥卡西平单次给药与分次给药对妊娠小鼠的影响及叶酸对其诱发小鼠发生妊娠意外的干预效果,探讨减少奥卡西平所致不良作用的干预措施。方法将150只小鼠随机分为5组（每组30只,雌雄比例2：1）,分别为：①对照组（灌胃纯化水10 mL&#8226;kg－1）,②奥卡西平单次给药组（单次灌胃奥卡西平150 mg&#8226;kg－1）,③奥卡西平单次给药＋叶酸组（单次灌胃奥卡西平150 mg&#8226;kg－1 ＋叶酸0.07 mg&#8226;kg－1）,④奥卡西平分次给药组（分次灌胃奥卡西平,上、下午各75 mg&#8226;kg－1）,⑤奥卡西平分次给药＋叶酸组（分次灌胃奥卡西平,上、下午各75 mg&#8226;kg－1 ＋叶酸0.07 mg&#8226;kg－1）。观察小鼠受孕率、流产率、死胎吸收胎率、畸形率、每窝正常仔鼠的数目、妊娠期增重、小鼠血清叶酸含量等指标。结果奥卡西平单次给药组、单次给药＋叶酸组、分次给药组、分次给药＋叶酸组小鼠受孕分别为4,6,8,10只;死胎和吸收胎分别为3,4,5,6只;小鼠妊娠期增重、血清叶酸含量依次升高;奥卡西平无明显致畸作用。结论奥卡西平可导致妊娠小鼠妊娠意外的增加,但无明显致畸作用,小剂量分次给药及补充适量叶酸可降低其不良作用。     

The Effects of Nicotine Replacement on Cognitive Brain Activity During Smoking Withdrawal Studied with Simultaneous fMRI/EEG

Impaired attention (‘difficulty concentrating'') is a cognitive symptom of nicotine withdrawal that may be an important contributor to smoking relapse. However, the neurobiological basis of this effect and the potentially beneficial effects of nicotine replacement therapy both remain unclear. We used functional MRI with simultaneous electroencephalogram (EEG) recording to define brain activity correlates of cognitive impairment with short-term smoking cessation in habitual smokers and the effects of nicotine replacement. We found that irrespective of treatment (ie nicotine or placebo) EEG α power was negatively correlated with increased activation during performance of a rapid visual information processing (RVIP) task in dorsolateral prefrontal, dorsal anterior cingulate, parietal, and insular cortices, as well as, caudate, and thalamus. Relative to placebo, nicotine replacement further increased the α-correlated activation across these regions. We also found that EEG α power was negatively correlated with RVIP-induced deactivation in regions comprising the ‘default mode'' network (ie angular gyrus, cuneus, precuneus, posterior cingulate, and ventromedial prefrontal cortex). These α-correlated deactivations were further reduced by nicotine. These findings confirm that effects of nicotine on cognition during short-term smoking cessation occur with modulation of neuronal sources common to the generation of both the blood oxygen-level-dependent and α EEG signals. Our observations thus demonstrate that nicotine replacement in smokers has direct pharmacological effects on brain neuronal activity modulating cognitive networks.     

Reward Sensitization: Effects of Repeated Nicotine Exposure and Withdrawal in Mice

Tobacco dependence is an addiction with high rates of relapse, resulting in multiple quit attempts in individuals who are trying to stop smoking. How these multiple cycles of smoking and withdrawal contribute to nicotine dependence, long-term alterations in brain reward systems, and nicotine receptor regulation is unknown. Therefore, to evaluate how multiple exposures of nicotine and withdrawal periods modulate rewarding properties of nicotine, we used intracranial self-stimulation to measure alterations in the threshold of brain stimulation reward. In addition, we employed the conditioned place preference (CPP) paradigm to evaluate positive context conditioning following each withdrawal period and measured levels of neuronal nicotinic receptors in cortex, striatum, and hippocampus. We found that repeated nicotine exposure and withdrawal enhanced brain stimulation reward and reward sensitivity to acute injections of nicotine. This increased reward was reflected by enhanced CPP to nicotine. Chronic nicotine is known to up-regulate nAChRs (nicotinic acetylcholine receptors) and we found that this up-regulation was maintained for up to 8 days of withdrawal in the striatum and in the hippocampus, but not in the cortex, of animals exposed to multiple nicotine exposure and withdrawal periods. These results demonstrate that repeated exposures to nicotine, followed by withdrawal, induce a persistent increase in both brain reward function and sensitivity to the hedonic value of nicotine and long-lasting up-regulation of neuronal nicotinic receptors. Together, these data suggest that a continuing increase in brain reward function and enhanced sensitivity to nicotine reward following repeated withdrawal periods may be one reason why smokers relapse frequently.     

妊娠及哺乳期应用抗生素的研究现状

抗生素是妊娠及哺乳期最常用的药物之一.妊娠及哺乳期抗生素的药动学与药效学可能发生改变,从而影响疗效.此外,抗生素对发育中的胎儿或新生儿可能存在致畸或毒性作用.对妊娠及哺乳期常用的11种广谱抗生素的文献资料进行综述.11种抗生素均能穿过胎盘进入胎儿体内,均能分泌至乳汁.阿莫西林、庆大霉素、青霉素G、青霉素V钾、环丙沙星,左氧氟沙星的血药浓度妊娠期较未妊娠妇女偏低,表明若需达到未妊娠妇女的血药浓度,必须缩短用药间隔和(或)加大给药剂量.妊娠期克林霉素药动学无改变.妊娠期应用氯霉素、庆大霉素或万古霉素时,建议检测血药峰-谷浓度.根据"致畸因子信息服务分类系统",上述11种抗生素可被分为:无致畸危险(如青霉素G及青霉素V钾)、不大可能致畸(如阿莫西林、氯霉素、环丙沙星、多西环素、左氧氟沙星及利福平)、不确定是否致畸(如克林霉素、庆大霉素及万古霉素)3类.根据美国FDA制定的"妊娠期药物危险分级"标准,阿莫西林、克林霉素、青霉素G、青霉素V钾及万古霉素均属于B级;氯霉素、环丙沙星、庆大霉素、左氧氟沙星及利福平皆为C级,多西环素为D级.     

Effects of HIV and Methamphetamine on Brain and Behavior: Evidence from Human Studies and Animal Models

Methamphetamine (Meth) use is frequent among HIV-infected persons. Combined HIV and Meth insults may exacerbate neural injury in vulnerable neuroanatomic structures or circuitries in the brain, leading to increased behavioral disturbance and cognitive impairment. While acute and chronic effects of Meth in humans and animal models have been studied for decades, the neurobehavioral effects of Meth in the context of HIV infection are much less explored. In-depth understanding of the scope of neurobehavioral phenotypes and mechanisms in HIV/Meth intersection is needed. The present report summarizes published research findings, as well as unpublished data, in humans and animal models with regard to neurobehavioral disturbance, neuroimaging, and neuropathology, and in vitro experimental systems, with an emphasis on findings emerging from the National Institute on Drug Abuse (NIDA) funded Translational Methamphetamine AIDS Research Center (TMARC). Results from human studies and animal (primarily HIV-1 gp120 transgenic mouse) models thus far suggest that combined HIV and Meth insults increase the likelihood of neural injury in the brain. The neurobehavioral effects include cognitive impairment and increased tendencies toward impaired behavioral inhibition and social cognition. These impairments are relevant to behaviors that affect personal and social risks, e.g. worse medication adherence, riskier behaviors, and greater likelihood of HIV transmission. The underlying mechanisms may include electrochemical changes in neuronal circuitries, injury to white matter microstructures, synaptodendritic damage, and selective neuronal loss. Utilization of research methodologies that are valid across species is instrumental in generating new knowledge with clinical translational value.     

Neuronal Responses to Systemic Nicotine in the Solitary Tract Nucleus: Origin and Possible Relation with Nutritional Effects of Nicotine

Single-unit activity was recorded extracellularly in the caudal part of the solitary tract nucleus of anesthetized rats. Of 60 recorded neurons, 44 (73.3%) responded to intravenous (IV) nicotine. The incidence of response was significantly greater in the cells sensitive to moderate changes in blood glucose level, suggesting that the effects of nicotine on food intake and body weight are partly mediated by the glycemia-sensitive neurons in the caudal nucleus tractus solitarius. Only one-fourth of the neurons affected by IV nicotine responded in the same direction to iontophoretic nicotine application, suggesting that sensitivity to systemic nicotine results mainly from an indirect mechanism. Based on the observed effects of nicotinic agonists and antagonists unable to cross the blood–brain barrier, a majority of indirect unit responses to IV nicotine might be mediated by peripheral receptors, while the remaining ones might involve central or both central and peripheral receptors.     

Accumulation of Nicotine in Human Hair during Long-Term Controlled Exposure to a Low Concentration of Nicotine Vapour

Abstract: Hair from 5 subjects were exposed in dynamic exposure chambers to air nicotine vapour for 72 hr or 12 months at concentrations of 200 or 5μg/m³, respectively. Nicotine in the chamber air and human hair was determined by GC/ MS. A linear accumulation of nicotine in hair was found with time for all hairs during the long-term, low concentration exposure, with individual hair nicotine uptake rate constants ranging from 0.70 to 3.75×10^?3 m³/gxhr. The corresponding hair nicotine uptake rate constants during short-term, high concentration exposure, were significantly higher, ranging from 1.35 to 15.11×10^?3 m³/gxhr, showing, however, a highly significant linear correlation with the individual long-term exposure rate constants, r²=0.9961. It is indicated that long-term hair nicotine uptake rate constants calculated from controlled exposure experiments with pure nicotine vapour are adequate for estimation of individual long-term hair accumulation of nicotine from environmental tobacco smoke even at variable and intermittent exposure. Although higher than the long-term uptake rate constants, the short-term uptake rate constants seem well fitted for a differentiation between different types of hair in their ability to adsorb nicotine also during long-term exposures. The short-term uptake rate constants might also be useful parameters for establishing a reliable cut-off limit in the hair concentration of nicotine between smokers and non-smokers which otherwise seems to be overlapping.     

Nicotine and tetrahydroaminoacradine: Evidence for improved attention in patients with dementia of the Alzheimer type

A placebo-controlled, single-blind study investigated the effects of administering three acute doses of nicotine (0.4, 0.6, and 0.8 mg) to a group of patients suffering from dementia of the Alzheimer type (DAT), and to young and aged normal controls. Performance on objective computerised tests provided evidence for improvements in attentional function rather than memory, in patients with mild to moderate DAT. Despite the lack of drug effect on mnemonic ability, these results demonstrate that DAT patients have significant attentional deficits which can be remediated by nicotine administration. They add to the growing body of evidence that the cholinergic system is involved in the control of attentional processes; and are substantiated by the findings of a second study examining the use of a chronic dose of the cholinesterase inhibitor THA, as a treatment for DAT. In this study, effects on both subjective clinical rating scales and objective computerised tests were assessed. In regard to the former, analysis of the three main clinical outcome measures showed statistically significant effects of the drug on the Mini-Mental State Examination (MMSE) and the Abbreviated Mental Test Score (AMTS), but not on the Activities of Daily Living scale (ADL). Using objective computerised CANTAB tests, sensitive to specific aspects of memory and attention, evidence was found for improvements in attentional function rather than memory, in patients with mild to moderate DAT. These data will clearly provide important comparative data for future investigations of putative cognitive enhancing drugs in DAT sufferers. © 1994 Wiley-Liss, Inc.     

Effects of Chronic Varenicline Treatment on Nicotine,Cocaine, and Concurrent Nicotine+Cocaine Self-Administration

Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal treatment medication would reduce both cigarette smoking and cocaine abuse. Varenicline is a clinically available, partial agonist at α4β2* and α6β2* nicotinic acetylcholine receptors (nAChRs) and a full agonist at α7 nAChRs. Varenicline facilitates smoking cessation in clinical studies and reduced nicotine self-administration, and substituted for the nicotine-discriminative stimulus in preclinical studies. The present study examined the effects of chronic varenicline treatment on self-administration of IV nicotine, IV cocaine, IV nicotine+cocaine combinations, and concurrent food-maintained responding by five cocaine- and nicotine-experienced adult rhesus monkeys (Macaca mulatta). Varenicline (0.004–0.04 mg/kg/h) was administered intravenously every 20 min for 23 h each day for 7–10 consecutive days. Each varenicline treatment was followed by saline-control treatment until food- and drug-maintained responding returned to baseline. During control treatment, nicotine+cocaine combinations maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05–0.001). Varenicline dose-dependently reduced responding maintained by nicotine alone (0.0032 mg/kg/inj) (P<0.05), and in combination with cocaine (0.0032 mg/kg/inj) (P<0.05) with no significant effects on food-maintained responding. However, varenicline did not significantly decrease self-administration of a low dose of nicotine (0.001 mg/kg), cocaine alone (0.0032 and 0.01 mg/kg/inj), or 0.01 mg/kg cocaine combined with the same doses of nicotine. We conclude that varenicline selectively attenuates the reinforcing effects of nicotine alone but not cocaine alone, and its effects on nicotine+cocaine combinations are dependent on the dose of cocaine.