Sex Differences and Drug Dose Influence the Role of the α7 Nicotinic Acetylcholine Receptor in the Mouse Dextran Sodium Sulfate-Induced Colitis Model

<span class=”paragraphSection”><div class=”boxTitle”>Abstract</div><div class=”boxTitle”>Introduction:</div>α7 nicotinic acetylcholine receptors (nAChRs) play an important role in vagus nerve-based cholinergic anti-inflammatory effects. This study was designed to assess the role of α7 nAChRs in dextran sodium sulfate (DSS)-induced colitis in male and female mouse. We first compared disease activity and pathogenesis of colitis in α7 knockout and wild-type mice. We then evaluated the effect of several α7 direct and indirect agonists on the severity of disease in the DSS-induced colitis.<div class=”boxTitle”>Methods:</div>Male and female adult mice were administered 2.5% DSS solution freely in the drinking water for 7 consecutive days and the colitis severity (disease activity index) was evaluated as well as colon length, colon histology, and levels of tumor necrosis factor-alpha colonic levels.<div class=”boxTitle”>Results:</div>Male, but not female, α7 knockout mice displayed a significantly increased colitis severity and higher tumor necrosis factor-alpha levels as compared with their littermate wild-type mice. Moreover, pretreatment with selective α7 ligands PHA-543613, choline, and PNU-120596 decreased colitis severity in male but not female mice. The anti-colitis effects of these α7 compounds dissipated when administered at higher doses.<div class=”boxTitle”>Conclusions:</div>Our results suggest the presence of a α7-dependent anti-colitis endogenous tone in male mice. Finally, our results show for the first time that female mice are less sensitive to the anti-colitis activity of α7 agonists. Ovarian hormones may play a key role in the sex difference effect of α7 nAChRs modulation of colitis in the mouse.<div class=”boxTitle”>Implications:</div>Our collective results suggest that targeting α7 nAChRs could represent a viable therapeutic approach for intestinal inflammation diseases such as ulcerative colitis with the consideration of sex differences.</span>

Association of TAS2R38 Haplotypes and Menthol Cigarette Preference in an African American Cohort

<span class=”paragraphSection”>In a recent publication in <span style=”font-style:italic;”>Nicotine & Tobacco Research</span>, Oncken <span style=”font-style:italic;”>et al.</span><sup><a href=”#CIT0001″ class=”reflinks”>1</a></sup> examined 323 pregnant female Caucasian cigarette smokers, including menthol and nonmenthol users, and genotyped three <span style=”font-style:italic;”>TAS2R38</span> bitter taste receptor gene polymorphisms (<span style=”font-style:italic;”>rs713598</span>, <span style=”font-style:italic;”>rs1726866</span>, and <span style=”font-style:italic;”>rs10246939</span>). These polymorphisms specify whether an individual is a taster (associated with the PAV haplotype) or a nontaster (associated with the AVI haplotype) for a variety of bitter compounds, including the well-known phenylthiocarbamide and propylthiouracil.<sup><a href=”#CIT0002″ class=”reflinks”>2–3</a></sup> The rationale behind this study was to test whether variations in the well-studied <span style=”font-style:italic;”>TAS2R38</span> bitter taste receptor gene could contribute to the preference of smokers for menthol cigarettes, because menthol could mask the bitter taste of nicotine or other components of cigarette smoke. Oncken <span style=”font-style:italic;”>et al.</span> reported the frequency of the PAV taster haplotype to be greater in menthol smokers than in nonmenthol smokers in both non-Hispanic (54% vs. 30%, respectively, <span style=”font-style:italic;”>p</span> < 0.001) and Hispanic (53% vs. 25%, respectively, <span style=”font-style:italic;”>p</span> = 0.016) women, confirming this initial hypothesis.</span>

A Novel Tobacco Use Phenotype Suggests the 15q25 and 19q13 Loci May be Differentially Associated With Cigarettes per Day and Tobacco-Related Problems

<span class=”paragraphSection”><div class=”boxTitle”>Abstract</div><div class=”boxTitle”>Introduction:</div>Tobacco use is associated with variation at the 15q25 gene cluster and the cytochrome P450 (CYP) genes CYP2A6 and CYP2B6. Despite the variety of outcomes associated with these genes, few studies have adopted a data-driven approach to defining tobacco use phenotypes for genetic association analyses. We used factor analysis to generate a tobacco use measure, explored its incremental validity over a simple indicator of tobacco involvement: cigarettes per day (CPD), and tested both phenotypes in a genetic association study.<div class=”boxTitle”>Methods:</div>Data were from the University of California, San Francisco Family Alcoholism Study (<span style=”font-style:italic;”>n =</span> 1942) and a Native American sample (<span style=”font-style:italic;”>n</span> = 255). Factor analyses employed a broad array of tobacco use variables to establish the candidate phenotype. Subsequently, we conducted tests for association with variants in the nicotinic acetylcholine receptor and CYP genes. We explored associations with CPD and our measure. We then examined whether the variants most strongly associated with our measure remained associated after controlling for CPD.<div class=”boxTitle”>Results:</div>Analyses identified one factor that captured tobacco-related problems. Variants at 15q25 were significantly associated with CPD after multiple testing correction (rs938682: <span style=”font-style:italic;”>p</span> = .00002, rs1051730: <span style=”font-style:italic;”>p</span> = .0003, rs16969968: <span style=”font-style:italic;”>p</span> = .0003). No significant associations were obtained with the tobacco use phenotype; however, suggestive associations were observed for variants in CYP2B6 near CYP2A6 (rs45482602: <span style=”font-style:italic;”>p</span>s = .0082, .0075) and CYP4Z2P (rs10749865: <span style=”font-style:italic;”>p</span>s = .0098, .0079).<div class=”boxTitle”>Conclusions:</div>CPD captures variation at 15q25. Although strong conclusions cannot be drawn, these finding suggest measuring additional dimensions of problems may detect genetic variation not accounted for by smoking quantity. Replication in independent samples will help further refine phenotype definition efforts.<div class=”boxTitle”>Implications:</div>Different facets of tobacco-related problems may index unique genetic risk. CPD, a simple measure of tobacco consumption, is associated with variants at the 15q25 gene cluster. Additional dimensions of tobacco problems may help to capture variation at 19q13. Results demonstrate the utility of adopting a data-driven approach to defining phenotypes for genetic association studies of tobacco involvement and provide results that can inform replication efforts.</span>

How to Quit Smoking A Guide to Kicking the Habit for Good

 How to Quit Smoking

Whether you’re a teen smoker or a lifetime pack-a-day smoker, quitting can be tough. But the more you learn about your options and prepare for quitting, the easier the process will be. With the right game plan tailored to your needs, you can break the addiction, manage your cravings, and join the millions of people who have kicked the habit for good.

Why quitting smoking can seem so hard

Smoking tobacco is both a physical addiction and a psychological habit. The nicotine from cigarettes provides a temporary—and addictive—high. Eliminating that regular fix of nicotine will cause your body to experience physical withdrawal symptoms and cravings. Because of nicotine’s “feel good” effect on the brain, you may also have become accustomed to smoking as a way of coping with stress, depression, anxiety, or even boredom.

At the same time, the act of smoking is ingrained as a daily ritual. It may be an automatic response for you to smoke a cigarette with your morning coffee, while taking a break from work or school, or during your commute home at the end of a long day. Perhaps friends, family members, and colleagues smoke, and it has become part of the way you relate with them.

To successfully quit smoking, you’ll need to address both the addiction and the habits and routines that go along with it.

Your personal stop smoking plan

While some smokers successfully quit by going cold turkey, most people do better with a plan to keep themselves on track. A good plan addresses both the short-term challenge of quitting smoking and the long-term challenge of preventing relapse. It should also be tailored to your specific needs and smoking habits.

Questions to ask yourself

Take the time to think of what kind of smoker you are, which moments of your life call for a cigarette, and why. This will help you to identify which tips, techniques or therapies may be most beneficial for you.

  • Do you feel the need to smoke at every meal?
  • Are you more of a social smoker?
  • Is it a very bad addiction (more than a pack a day)? Or would a simple nicotine patch do the job?
  • Do you reach for cigarettes when you’re feeling stressed or down?
  • Are there certain activities, places, or people you associate with smoking?
  • Is your cigarette smoking linked to other addictions, such as alcohol or gambling?
  • Are you open to hypnotherapy and/or acupuncture?
  • Are you someone who is open to talking about your addiction with a therapist or counselor?
  • Are you interested in getting into a fitness program?

Start your stop smoking plan with START

S = Set a quit date.

Choose a date within the next two weeks, so you have enough time to prepare without losing your motivation to quit. If you mainly smoke at work, quit on the weekend, so you have a few days to adjust to the change.

T = Tell family, friends, and co-workers that you plan to quit.

Let your friends and family in on your plan to quit smoking and tell them you need their support and encouragement to stop. Look for a quit buddy who wants to stop smoking as well. You can help each other get through the rough times.

A = Anticipate and plan for the challenges you’ll face while quitting.

Most people who begin smoking again do so within the first three months. You can help yourself make it through by preparing ahead for common challenges, such as nicotine withdrawal and cigarette cravings.

R = Remove cigarettes and other tobacco products from your home, car, and work.

Throw away all of your cigarettes (no emergency pack!), lighters, ashtrays, and matches. Wash your clothes and freshen up anything that smells like smoke. Shampoo your car, clean your drapes and carpet, and steam your furniture.

T = Talk to your doctor about getting help to quit.

Your doctor can prescribe medication to help with withdrawal and suggest other alternatives. If you can’t see a doctor, you can get many products over the counter at your local pharmacy or grocery store, including the nicotine patch, nicotine lozenges, and nicotine gum.

How to quit smoking: Identify your smoking triggers

One of the best things you can do to help yourself quit is to identify the things that make you want to smoke, including specific situations, activities, feelings, and people.

Keep a craving journal

A craving journal can help you zero in on your patterns and triggers. For a week or so leading up to your quit date, keep a log of your smoking. Note the moments in each day when you crave a cigarette:

  • What time was it?
  • How intense was the craving (on a scale of 1-10)?
  • What were you doing?
  • Who were you with?
  • How were you feeling?
  • How did you feel after smoking?

Do you smoke to relieve unpleasant or overwhelming feelings?

Managing unpleasant feelings such as stress, depression, loneliness, fear, and anxiety are some of the most common reasons why adults smoke. When you have a bad day, it can seem like cigarettes are your only friend. As much comfort as cigarettes provide, though, it’s important to remember that there are healthier (and more effective) ways to keep unpleasant feelings in check. These may include exercising, meditating, using sensory relaxation strategies, and practicing simple breathing exercises.

For many people, an important aspect of quitting smoking is to find alternate ways to handle these difficult feelings without smoking. Even when cigarettes are no longer a part of your life, the painful and unpleasant feelings that may have prompted you to smoke in the past will still remain. So, it’s worth spending some time thinking about the different ways you intend to deal with stressful situations and the daily irritations that would normally have you reaching for a cigarette.

Tips for avoiding common smoking triggers

  • Alcohol. Many people have a habit of smoking when they drink. TIP: switch to non-alcoholic drinks or drink only in places where smoking inside is prohibited. Alternatively, try snacking on nuts and chips, or chewing on a straw or cocktail stick.
  • Other smokers. When friends, family, and co-workers smoke around you, it is doubly difficult to quit or avoid relapse. TIP: Your social circles need to know that you are changing your habits so talk about your decision to quit. Let them know they won’t be able to smoke when you’re in the car with them or taking a coffee break together. In your workplace, don’t take all your coffee breaks with smokers only, do something else instead, or find non-smokers to have your breaks with.
  • End of a meal. For some smokers, ending a meal means lighting up, and the prospect of giving that up may appear daunting. TIP: replace that moment after a meal with something such as a piece of fruit, a (healthy) dessert, a square of chocolate, or a stick of gum.

How to quit smoking: Coping with nicotine withdrawal symptoms

Once you stop smoking, you will experience a number of physical symptoms as your body withdraws from nicotine. Nicotine withdrawal begins quickly, usually starting within thirty minutes to an hour of the last cigarette and peaking about two to three days later. Withdrawal symptoms can last for a few days to several weeks and differ from person to person.

Common nicotine withdrawal symptoms include:

  • Cigarette cravings
  • Irritability, frustration, or anger
  • Anxiety or nervousness
  • Difficulty concentrating
  • Restlessness
  • Increased appetite
  • Headaches
  • Insomnia
  • Tremors
  • Increased coughing
  • Fatigue
  • Constipation or upset stomach
  • Depression
  • Decreased heart rate

Unpleasant as these withdrawal symptoms may be, they are only temporary. They will get better in a few weeks as the toxins are flushed from your body. In the meantime, let your friends and family know that you won’t be your usual self and ask for their understanding.

Coping with Nicotine Withdrawal Symptoms

Symptom Duration Relief
Craving for cigarette Most intense during first week but can linger for months Wait out the urge; distract yourself; take a brisk walk.
Irritability, impatience Two to four weeks Exercise; take hot baths; use relaxation techniques; avoid caffeine.
Insomnia Two to four weeks Avoid caffeine after 6 p.m.; use relaxation techniques; exercise; plan activities (such as reading) when sleep is difficult.
Fatigue Two to four weeks Take naps; do not push yourself.
Lack of concentration A few weeks Reduce workload; avoid stress.
Hunger Several weeks or longer Drink water or low-calorie drinks; eat low-calorie snacks.
Coughing, dry throat, nasal drip Several weeks Drink plenty of fluids; use cough drops.
Constipation, gas One to two weeks Drink plenty of fluids; add fiber to diet; exercise.

Adapted with permission from Overcoming Addiction: Paths Toward Recovery, a special health report from Harvard Health Publications.

How to quit smoking: Manage cigarette cravings

Avoiding smoking triggers will help reduce the urge to smoke, but you can’t avoid cravings entirely. But cigarette cravings don’t last long, so if you’re tempted to light up, remember that the craving will pass and try to wait it out. It also helps to be prepared in advance. Having a plan to cope with cravings will help keep you from giving in.

  • Distract yourself. Do the dishes, turn on the TV, take a shower, or call a friend. The activity doesn’t matter as long as it gets your mind off of smoking.
  • Remind yourself why you quit. Focus on your reasons for quitting, including the health benefits, improved appearance, money you’re saving, and enhanced self-esteem.
  • Get out of a tempting situation. Where you are or what you’re doing may be triggering the craving. If so, a change of scenery can make all the difference.
  • Reward yourself. Reinforce your victories. Whenever you triumph over a craving, give yourself a reward to keep yourself motivated.

Coping with Cigarette Cravings in the Moment

Find an oral substitute Keep other things around to pop in your mouth when cravings hit. Good choices include mints, hard candy, carrot or celery sticks, gum, and sunflower seeds.
Keep your mind busy Read a book or magazine, listen to some music you love, do a crossword or Sudoku puzzle, or play an online game.
Keep your hands busy Squeeze balls, pencils, or paper clips are good substitutes to satisfy that need for tactile stimulation.
Brush your teeth The just-brushed, clean feeling can help get rid of cigarette cravings.
Drink water Slowly drink a large, cold glass of water. Not only will it help the craving pass, but staying hydrated helps minimize the symptoms of nicotine withdrawal.
Light something else Instead of lighting a cigarette, light a candle or some incense.
Get active Go for a walk, do some jumping jacks or pushups, try some yoga stretches, or run around the block.
Try to relax Do something that calms you down, such as taking a warm bath, meditating, reading a book, or practicing deep breathing exercises.

Preventing weight gain after you’ve stopped smoking

Weight gain is a common concern when quitting smoking. Some people even use it as a reason not to quit. While it’s true that many smokers put on weight within six months of stopping smoking, the gain is usually small—about five pounds on average—and that initial gain decreases over time. It’s also important to remember that carrying a few extra pounds for a few months won’t hurt your heart as much as smoking will. Of course, gaining weight is NOT inevitable when you quit smoking.

Smoking acts as an appetite suppressant. It also dampens your sense of smell and taste. So after you quit, your appetite will likely increase and food will seem more appealing. Weight gain can also happen if you replace the oral gratification of smoking with eating, especially if you turn to unhealthy comfort foods. So it’s important to find other, healthy ways to deal with stress and other unpleasant feelings rather than mindless, emotional eating.

  • Nurture yourself. Instead of turning to cigarettes or food when you feel stressed, anxious, or depressed, learn new ways to soothe yourself.
  • Eat healthy, varied meals. Eat plenty of fruits and vegetables and limit your fat intake. Seek out low-fat options that look appetizing to you and you will actually eat. Avoid alcohol, sugary sodas, and other high-calorie drinks.
  • Drink lots of water. Drinking lots of water—at least six to eight 8 oz. glasses—will help you feel full and keep you from eating when you’re not hungry. Water will also help flush toxins from your body.
  • Take a walk. Walking is a great form of exercise. Not only will it help you burn calories and keep the weight off, but it will also help alleviate feelings of stress and frustration that accompany smoking withdrawal.
  • Snack on low-calorie or calorie-free foods. Good choices include sugar-free gum, carrot and celery sticks, sliced bell peppers or jicama, or sugar-free hard candies.

Medication and therapy to help you quit smoking

There are many different methods that have successfully helped people to quit smoking, including:

  • Quitting smoking cold turkey.
  • Systematically decreasing the number of cigarettes you smoke.
  • Reducing your intake of nicotine gradually over time.
  • Using nicotine replacement therapy or non-nicotine medications to reduce withdrawal symptoms.
  • Utilizing nicotine support groups.
  • Trying hypnosis, acupuncture, or counseling using cognitive behavioral techniques.

You may be successful with the first method you try. More likely, you’ll have to try a number of different methods or a combination of treatments to find the ones that work best for you.

Medications to help you stop smoking

Smoking cessation medications can ease withdrawal symptoms and reduce cravings, and are most effective when used as part of a comprehensive stop smoking program monitored by your physician. Talk to your doctor about your options and whether an anti-smoking medication is right for you. U.S. Food and Drug Administration (FDA) approved options are:

Nicotine replacement therapy. Nicotine replacement therapy involves “replacing” cigarettes with other nicotine substitutes, such as nicotine gum or a nicotine patch. It works by delivering small and steady doses of nicotine into the body to relieve some of the withdrawal symptoms without the tars and poisonous gases found in cigarettes. This type of treatment helps smokers focus on breaking their psychological addiction and makes it easier to concentrate on learning new behaviors and coping skills.

Non-nicotine medication. These medications help you stop smoking by reducing cravings and withdrawal symptoms without the use of nicotine. Medications such as bupropion (Zyban) and varenicline (Chantix) are intended for short-term use only.

Alternative therapies to help you stop smoking

There are several things you can do to stop smoking that don’t involve nicotine replacement therapy or prescription medications: Ask your doctor for a referral or see Resources and References below for help finding qualified professionals in each area.

  • Hypnosis – A popular option that has produced good results. Forget anything you may have seen from stage hypnotists, hypnosis works by getting you into a deeply relaxed state where you are open to suggestions that strengthen your resolve to quit smoking and increase your negative feelings toward cigarettes.
  • Acupuncture – One of the oldest known medical techniques, acupuncture is believed to work by triggering the release of endorphins (natural pain relievers) that allow the body to relax. As a smoking cessation aid, acupuncture can be helpful in managing smoking withdrawal symptoms.
  • Behavioral Therapy – Nicotine addiction is related to the habitual behaviors (the “rituals”) involved in smoking. Behavior therapy focuses on learning new coping skills and breaking those habits.
  • Motivational Therapies – Self-help books and websites can provide a number of ways to motivate yourself to quit smoking. One well known example is calculating the monetary savings. Some people have been able to find the motivation to quit just by calculating how much money they will save. It may be enough to pay for a summer vacation.

Smokeless or spit tobacco is NOT a healthy alternative to smoking

Smokeless tobacco, otherwise known as spit tobacco, is not a safe alternative to smoking cigarettes. It contains the same addictive chemical, nicotine, contained in cigarettes. In fact, the amount of nicotine absorbed from smokeless tobacco can be 3 to 4 times the amount delivered by a cigarette.

What to do if you slip or relapse

Most people try to quit smoking several times before they kick the habit for good, so don’t beat yourself up if you start smoking again. Turn the relapse into a rebound by learning from your mistake. Analyze what happened right before you started smoking again, identify the triggers or trouble spots you ran into, and make a new stop-smoking plan that eliminates them.

It’s also important to emphasize the difference between a slip and a relapse. If you slip up and smoke a cigarette, it doesn’t mean that you can’t get back on the wagon. You can choose to learn from the slip and let it motivate you to try harder or you can use it as an excuse to go back to your smoking habit. But the choice is yours. A slip doesn’t have to turn into a full-blown relapse.

I started smoking again, now what?

Having a small setback doesn’t mean you’re a smoker again. Most people try to quit smoking several times before they kick the habit for good. Identify the triggers or trouble spots you ran into and learn from your mistakes.

  • You’re not a failure if you slip up. It doesn’t mean you can’t quit for good.
  • Don’t let a slip become a mudslide. Throw out the rest of the pack. It’s important to get back on the non-smoking track now.
  • Look back at your quit log and feel good about the time you went without smoking.
  • Find the trigger. Exactly what was it that made you smoke again? Decide how you will cope with that issue the next time it comes up.
  • Learn from your experience. What has been most helpful? What didn’t work?
  • Are you using a medicine to help you quit? Call your doctor if you start smoking again. Some medicines cannot be used if you are smoking at the same time.

Evaluation of a Novel Difficulty of Smoking Cessation Phenotype Based on Number of Quit Attempts

<span class=”paragraphSection”><div class=”boxTitle”>Abstract</div><div class=”boxTitle”>Background:</div>Numerous studies have sought to identify genes that influence the ability to quit smoking, but none found any that are consistently associated with smoking cessation.<div class=”boxTitle”>Methods:</div>We developed a novel difficulty of quitting smoking phenotype based on the extremes of the number of quit attempts needed to achieve successful abstinence: Easy quitters were defined as having achieved long-term (>1 year) abstinence after their first quit attempt and difficult quitters as having reported 10 or more quit attempts. We conducted a two-stage study to determine if this phenotype could be useful for identifying single nucleotide polymorphisms (SNPs) that influence smoking cessation. In stage 1, 82 SNPs in 26 genes involved in nicotine signaling and metabolism were genotyped in 1357 easy quitters and 1321 difficult quitters from Cancer Prevention Study 3 (CPS-3). In stage 2, the 11 SNPs associated with difficult quitting in stage 1 (<span style=”font-style:italic;”>p</span> < .1) were genotyped in an independent sample of 1300 easy quitters and 1299 difficult quitters from CPS-3.<div class=”boxTitle”>Results:</div>Three of 11 SNPs (<span style=”font-style:italic;”>HTR1B</span> rs6298, <span style=”font-style:italic;”>NR4A2</span> rs834829, and <span style=”font-style:italic;”>CYP2A65</span> rs8192729) were significantly associated with the difficult quitting phenotype in stage 2 (<span style=”font-style:italic;”>p</span> < .05). In addition, a polygenic risk score based on the 11 SNPs identified in stage 1 was significantly associated with the difficult quitting phenotype in stage 2 (odds ratio = 1.08, 95% confidence interval: 1.03–1.14 per quintile, <span style=”font-style:italic;”>p</span> trend = 4.5×10<sup>–3</sup>).<div class=”boxTitle”>Conclusions:</div>Using a novel difficulty of quitting phenotype, three gene variants and a polygenic risk score based on 11 SNPs were found to be significantly associated with smoking cessation.<div class=”boxTitle”>Implications:</div>Our results provide evidence that a difficulty of quitting smoking phenotype based on the extremes of number of quit attempts could be a useful tool for identifying genetic variants that influence difficulty of smoking cessation. Knowledge of these genetic variants will indicate biological pathways that could be targeted for the development of novel smoking cessation aids and could be used to determine which smokers are most likely to benefit from such smoking cessation aids.</span>

The Influence of a Mouthpiece-Based Topography Measurement Device on Electronic Cigarette User’s Plasma Nicotine Concentration, Heart Rate, and Subjective Effects Under Directed and Ad Libitum Use Conditions

<span class=”paragraphSection”><div class=”boxTitle”>Abstract</div><div class=”boxTitle”>Introduction:</div>Electronic cigarettes e-cigarettes aerosolize a liquid solution often containing nicotine. e-cigarette nicotine delivery may be influenced by user puffing behaviors (“puff topography”). E-cigarette puff topography can be recorded using mouthpiece-based computerized systems. The present study sought to examine the extent to which these systems influence e-cigarette nicotine delivery and other e-cigarette associated acute effects under ad libitum use conditions.<div class=”boxTitle”>Methods:</div>Plasma nicotine concentration, heart rate, and subjective effects were assessed in 29 experienced e-cigarette users using their preferred e-cigarette battery and liquid (≥12mg/mL nicotine) in two sessions differing only by the presence of a mouthpiece-based device. In both sessions, participants completed a directed e-cigarette use bout (10 puffs, 30-s interpuff interval) and a 90-min ad libitum bout. Puff topography was recorded in the session with the topography mouthpiece.<div class=”boxTitle”>Results:</div>Plasma nicotine, heart rate, and subjective effects, aside from “Did the e-cigarette Taste Good?” were independent of topography measurement (higher mean taste ratings were observed in the no topography condition). Mean (SEM) plasma nicotine concentration following the ad libitum bout was 34.3ng/mL (4.9) in the no topography condition and 35.7ng/mL (4.3) in the topography condition. Longer puff durations, longer interpuff intervals, and larger puff volumes were observed in the ad libitum relative to the directed bout.<div class=”boxTitle”>Conclusions:</div>E-cigarette use significantly increased plasma nicotine concentration and heart rate while suppressing abstinence symptoms. These effects did not differ when a topography mouthpiece was present. Future studies using ad libitum e-cigarette use bouts would facilitate understanding of e-cigarette toxicant yield.<div class=”boxTitle”>Implications:</div>No prior study has examined whether mouthpiece-based topography recording devices influence e-cigarette associated nicotine delivery, heart rate, or subjective effects under ad libitum conditions or assessed ad libitum puff topography in experienced individuals using their preferred e-cigarette battery and liquid with a mouthpiece-based computerized device. E-cigarette use significantly increased plasma nicotine concentration and heart rate while suppressing abstinence symptoms. These effects did not differ when a topography mouthpiece was present. Ad libitum puff topography differed from puff topography recorded during directed puffing. These findings suggest that future studies using ad libitum use bouts would facilitate better understanding of e-cigarette toxicant yield.</span>

Single-Dose and Multiple-Dose Pharmacokinetics of Nicotine 6 mg Gum

<span class=”paragraphSection”><div class=”boxTitle”>Abstract</div><div class=”boxTitle”>Introduction:</div>Under-dosing is a recognized problem with current nicotine replacement therapy (NRT). Therefore, a new 6mg nicotine gum has been developed. To compare the nicotine uptake from the 6mg gum versus currently available NRT products, two pharmacokinetic studies were performed.<div class=”boxTitle”>Methods:</div>In one randomized crossover study, 44 healthy adult smokers received single doses of 6, 4, and 2mg nicotine gum, and 4mg nicotine lozenge on separate occasions. In a separate randomized crossover multiple-dose study over 11 hours, 50 healthy adult smokers received one 6mg gum every hour and 90 minutes, respectively, one 4mg gum every hour, and one 4mg lozenge every hour. In both studies, blood samples were collected over 12 hours to determine single-dose and multiple-dose pharmacokinetic variables.<div class=”boxTitle”>Results:</div>In the single-dose study, the amount of nicotine released from the 2, 4, and 6mg gums (1.44, 3.36, and 4.94mg) as well as the resulting maximum concentration and area under the curve (5.9, 10.1, and 13.8ng/mL, and 17.1, 30.7, 46.2ng/mL × h, respectively) increased with dose. The maximum concentration and area under the curve of the 6mg gum were 44% and 30% greater, respectively, than those for 4mg lozenge. Upon hourly administration, the steady-state average plasma nicotine concentration with 6mg gum (37.4ng/mL) was significantly higher than those for 4mg lozenge (28.3ng/mL) and 4mg gum (27.1ng/mL).<div class=”boxTitle”>Conclusions:</div>Nicotine delivery via the 6mg gum results in higher plasma nicotine concentrations after a single dose and at steady state than with currently available oral NRT.<div class=”boxTitle”>Implications:</div>Under-dosing is a recognized problem with current NRT. Therefore, a new 6mg nicotine gum has been developed. Our studies show that upon single-dose and multiple-dose administration, the 6mg gum releases and delivers more nicotine to the systemic circulation than 2mg gum, 4mg gum, and 4mg lozenge. Thus, each 6mg nicotine gum provides a higher degree of nicotine substitution and/or lasts for a longer period of time than currently available nicotine gums and lozenges.</span>

Smoking’s Toll on Health Is Even Worse Than Previously Thought, a Study Finds

However bad you thought smoking was, it’s even worse.OK

A new study adds at least five diseases and 60,000 deaths a year to the toll taken by tobacco in the United States. Before the study, smoking was already blamed for nearly half a million deaths a year in this country from 21 diseases, including 12 types of cancer.

The new findings are based on health data from nearly a million people who were followed for 10 years. In addition to the well-known hazards of lung cancer, artery disease, heart attacks, chronic lung disease and stroke, the researchers found that smoking was linked to significantly increased risks of infection, kidney disease, intestinal disease caused by inadequate blood flow, and heart and lung ailments not previously attributed to tobacco.

Even though people are already barraged with messages about the dangers of smoking, researchers say it is important to let the public know that there is yet more bad news.

“The smoking epidemic is still ongoing, and there is a need to evaluate how smoking is hurting us as a society, to support clinicians and policy making in public health,” said Brian D. Carter, an epidemiologist at the American Cancer Society and the first author of an article about the study, which appears in The New England Journal of Medicine. “It’s not a done story.”

In an editorial accompanying the article, Dr. Graham A. Colditz, from Washington University School of Medicine in St. Louis, said the new findings showed that officials in the United States had substantially underestimated the effect smoking has on public health. He said smokers, particularly those who depend on Medicaid, had not been receiving enough help to quit.

About 42 million Americans smoke — 15 percent of women and 21 percent of men — according to the Centers for Disease Control and Prevention. Research has shown that their death rates are two to three times higher than those of people who have never smoked, and that on average, they die more than a decade before nonsmokers. Smokers are more than 20 times as likely as nonsmokers to die of lung cancer. Poorpeople and those with less formal education are the most likely to smoke.

Mr. Carter said he had been inspired to dig deeper into the causes of death in smokers after taking an initial look at data from five large health surveys being conducted by other researchers. The participants were 421,378 men and 532,651 women 55 and older, including nearly 89,000 current smokers.

As expected, death rates were higher among the smokers. But diseases known to be caused by tobacco accounted for only 83 percent of the excess deaths in people who smoked.



Researchers have found that smoking is linked to significantly increased risks of infection, kidney disease, intestinal disease, and heart and lung ailments not previously attributed to tobacco.CreditKarsten Moran for The New York Times

“I thought, ‘Wow, that’s really low,’ ” Mr. Carter said. “We have this huge cohort. Let’s get into the weeds, cast a wide net and see what is killing smokers that we don’t already know.”

The research was paid for by the American Cancer Society, and Mr. Carter worked with scientists from four universities and the National Cancer Institute.

The study was observational, meaning that it looked at people’s habits, like smoking, and noted statistical correlations between their behavior and their health. Correlation does not prove a cause-and-effect relationship, so this kind of research is not considered as strong as experiments in which participants are assigned at random to treatments or placebos and then compared. But people cannot ethically be instructed to smoke for a study, so a lot of the data on smoking’s effects on people comes from observational studies.

Analyzing deaths among the participants from 2000 to 2011, the researchers found that, compared with people who had never smoked, smokers were about twice as likely to die from infections, kidney disease, respiratory ailments not previously linked to tobacco, andhypertensive heart disease, in which high blood pressure leads to heart failure. Smokers were also six times more likely to die from a rare illness caused by insufficient blood flow to the intestines.

Mr. Carter said he had confidence in the findings because, biologically, it made sense that those conditions were related to tobacco. Smoking can weaken the immune system, increasing the risk of infection, he said. It is also known to cause diabetes, high blood pressure and artery disease, all of which can lead to kidney problems. Artery disease can also choke off the blood supply to the intestines. Lung damage from smoke, combined with increased vulnerability to infection, can lead to multiple respiratory illnesses.

Two other observations supported the findings, he said. One was that the more heavily a person smoked, the greater the added risks. The second was that among former smokers, the risks diminished over time. In general, such effects, known as a dose response, suggest that an observed correlation is more than a coincidence.

The study also found small increases in the risks of breast and prostate cancer among smokers. Mr. Carter said those findings were not as strong as the others, adding that additional research could help determine whether there were biological mechanisms that would support a connection.

A 2014 report by the surgeon general’s office said the evidence for a causal connection between smoking and breast cancer was “suggestive but not sufficient.” The same report found no evidence that smoking caused prostate cancer, but it noted that in men who did have prostate cancer, smoking seemed to worsen the outcome.

The diseases that had previously been established by the surgeon general as caused by smoking were cancers of the esophagus, stomach, colon, liver, pancreas, larynx, lung, bladder, kidney, cervix, lip and oral cavity; acute myeloid leukemia; diabetes; heart disease; stroke;atherosclerosis; aortic aneurysm; other artery diseases; chronic lung disease; pneumonia; influenza; and tuberculosis.

Secondhand Tobacco Smoke Exposure Associations With DNA Methylation of the Aryl Hydrocarbon Receptor Repressor

<span class=”paragraphSection”><div class=”boxTitle”>Abstract</div><div class=”boxTitle”>Introduction:</div>Cigarette smoking is inversely associated with DNA methylation of the aryl hydrocarbon receptor repressor (<span style=”font-style:italic;”>AHRR</span>; cg05575921). However, the association between secondhand tobacco smoke (SHS) exposure and <span style=”font-style:italic;”>AHRR</span> methylation is unknown.<div class=”boxTitle”>Methods:</div>DNA methylation of <span style=”font-style:italic;”>AHRR</span> cg05575921 in CD14+ monocyte samples, from 495 never-smokers and 411 former smokers (having quit smoking ≥15 years) from the Multi-Ethnic Study of Atherosclerosis (MESA), was cross-sectionally compared with concomitantly ascertained self-reported SHS exposure, urine cotinine concentrations, and estimates of air pollutants at participants’ homes. Linear regression was used to test for associations, and covariates included age, sex, race, education, study site, and previous smoking exposure (smoking status, time since quitting, and pack-years).<div class=”boxTitle”>Results:</div>Recent indoor SHS exposure (hours per week) was inversely associated with cg05575921 methylation (β ± <span style=”font-style:italic;”>SE</span> = −0.009 ± 0.003, <span style=”font-style:italic;”>p</span> = .007). The inverse effect direction was consistent (but did not reach significance) in the majority of stratified analyses (by smoking status, sex, and race). Categorical analysis revealed high levels of recent SHS exposure (≥10 hours per week) inversely associated with cg05575921 methylation (β ± <span style=”font-style:italic;”>SE</span> = −0.28 ± 0.09, <span style=”font-style:italic;”>p</span> = .003), which remained significant (<span style=”font-style:italic;”>p</span> < .05) in the majority of stratified analyses. cg05575921 methylation did not significantly (<span style=”font-style:italic;”>p</span> < .05) associate with low to moderate levels of recent SHS exposure (1–9 hours per week), urine cotinine concentrations, years spent living with people smoking, years spent indoors (not at home) with people smoking, or estimated levels of air pollutants.<div class=”boxTitle”>Conclusions:</div>High levels of recent indoor SHS exposure may be inversely associated with DNA methylation of <span style=”font-style:italic;”>AHRR</span> in human monocytes.<div class=”boxTitle”>Implications:</div>DNA methylation is a biochemical alteration that can occur in response to cigarette smoking; however, little is known about the effect of SHS on human DNA methylation. In the present study, we evaluated the association between SHS exposure and DNA methylation in human monocytes, at a site (<span style=”font-style:italic;”>AHRR</span> cg05575921) known to have methylation inversely associated with current and former cigarette smoking compared to never smoking. Results from this study suggest high levels of recent SHS exposure inversely associate with DNA methylation of <span style=”font-style:italic;”>AHRR</span> cg05575921 in monocytes from nonsmokers, albeit with weaker effects than active cigarette smoking.</span>