Nilsen

Курение

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Услышал информацию, что в штатах запущенна в клиническую апробацию вакцина против курения табака.

Smoking vaccine being tested locally: NicVAX builds antibodies against nicotine [The Capital, Annapolis, Md.]

May 10--A drug that aims to keep smokers from developing an addiction to nicotine by eliminating the good feeling they get from cigarettes is being tested in Annapolis.

The city is one of 20 sites testing NicVAX, a vaccine that produces antibodies that could keep smokers away from cigarettes for one year. Researchers from Community Clinical Research in Annapolis are giving the vaccine to area smokers, in addition to counseling, and noting their reactions.

Rockville-based Nabi Biopharmaceuticals produces NicVAX, which is now in its third phase of testing. Each of the 20 sites is aiming to get 50 people to use the drug to study how it affects their desire to smoke. This is the last test before federal approval is sought, said Dr. Henrik Rasmussen, a cardiologist working on the study.

"Despite everybody knowing it's dangerous and can kill you if you smoke the rest of your life, 25 percent of the adult population is still smoking," said Rasmussen, who is also president and chief executive officer of Texas-based Community Clinical Research. "Nicotine is more addictive than heroin, (but) people think that if you can't stop smoking you have a weak character."

The county Health Department's 2007 behavioral health survey found that about 17 percent of Anne Arundel County's adult population smokes. Each year, the department had been providing programing grants ranging from $3,000 to $9,000 to offer smoking cessation programs.

But the department had to cut $600,000 from its budget last year, and reduced those classes and activities in the process.

With fiscal 2011 approaching, it is unclear whether cessation programs at Baltimore Washington Medical Center will be funded beyond June 30.

Anne Arundel Medical Center has exhausted its grant funding through the department, but will continue to offer a seven-week smoking cessation course for $85, said Justin Paquette, media relations coordinator for AAMC. The department also provided programming grants to Owensville Primary Care and Harbor Hospital.

Since March, CCR officials have been working with area physicians to reach smokers between the ages of 18 and 65 who do not have any acute illnesses. They are given doses of the vaccine and enrolled in smoking counseling programs.

NicVAX is supposed to be good for one year, but in the early phases participants will have to get multiple injections of the drug to build up antibodies.

When cigarette smoke is inhaled through the lungs, nicotine enters the bloodstream, eventually releasing dopamine and serotonin into the brain. This gives smokers an addictive rush, one that often makes them return for more cigarettes, Rasmussen said.

NicVAX creates antibodies that prevent the smokers from getting this high, effectively immunizing them against the effect of nicotine. The vaccine should be taken once a year. By the end of that year, smokers would be former smokers and wouldn't need it anymore. If they did try to smoke, they wouldn't get the customary good feeling from a cigarette, making it unlikely that they'd return to their nicotine habit.

"You can smoke, but it'll be like sticking your tongue out a window," Rasmussen said. "If you don't smoke for a year, it's extremely unlikely (for a smoker) to fall back into the smoking habit. People relapse within the first couple of months. If they're able to abstain for a year, the likelihood of relapse is very small."

CCR is looking for smokers between the ages of 18 and 65 to participate in the trial. Call 410-224-4887, Ext. 460, to participate.

To see more of The Capital or to subscribe to the newspaper, go to http://www.hometownannapolis.com.

Copyright © 2010, The Capital, Annapolis, Md.

Distributed by McClatchy-Tribune Information Services.

For reprints, email [email protected] , call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.

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и вот еще: В Европе также тестировалась вакцина (непонятно, та же или модификация?)

Background

Tobacco dependence is the leading cause of preventable death and disabilities worldwide and nicotine is the main substance responsible for the addiction to tobacco. A vaccine against nicotine was tested in a 6-month randomized, double blind phase II smoking cessation study in 341 smokers with a subsequent 6-month follow-up period.

Methodology/Principal Findings

229 subjects were randomized to receive five intramuscular injections of the nicotine vaccine and 112 to receive placebo at monthly intervals. All subjects received individual behavioral smoking cessation counseling. The vaccine was safe, generally well tolerated and highly immunogenic, inducing a 100% antibody responder rate after the first injection. Point prevalence of abstinence at month 2 showed a statistically significant difference between subjects treated with Nicotine-Qβ (47.2%) and placebo (35.1%) (P=0.036), but continuous abstinence between months 2 and 6 was not significantly different. However, in subgroup analysis of the per-protocol population, the third of subjects with highest antibody levels showed higher continuous abstinence from month 2 until month 6 (56.6%) than placebo treated participants (31.3%) (OR 2.9; P=0.004) while medium and low antibody levels did not increase abstinence rates. After 12 month, the difference in continuous abstinence rate between subjects on placebo and those with high antibody response was maintained (difference 20.2%, P=0.012).

Conclusions

Whereas Nicotine-Qβ did not significantly increase continuous abstinence rates in the intention-to-treat population, subgroup analyses of the per-protocol population suggest that such a vaccination against nicotine can significantly increase continuous abstinence rates in smokers when sufficiently high antibody levels are achieved. Immunotherapy might open a new avenue to the treatment of nicotine addiction.

Trial Registration

Swiss Medical Registry 2003DR2327; ClinicalTrials.gov NCT00369616

Despite the known health risks, people continue to smoke and use tobacco primarily as a result of their addiction to nicotine [1]. Most smokers trying to quit on their own fail on the long term [2]. Different types of counseling and behavioral therapies can increase abstinence rates [2]. Similarly, pharmacotherapies prescribed in smoking cessation interventions, such as nicotine replacement products, bupropion and the recently approved varenicline, help smokers quit, but all current therapies have only modest efficacy [2]. Consequently, there is a need for alternative and improved treatments [3].

One novel approach is provided by immunization against nicotine. The rationale is to induce antibodies which bind nicotine in the blood, thereby preventing it from crossing the blood-brain barrier [4], [5]. Thus, the reinforcing action of nicotine in the brain, which is the driving force in nicotine addiction and tobacco smoking, should be reduced. Nicotine is a small non-immunogenic molecule and must be conjugated to a carrier protein to induce antibodies. Such nicotine conjugates have been shown to induce enough antibodies in animals to sequester the drug in the blood [4], [6] attenuate nicotine addiction [7] and prevent reinstatement of nicotine seeking behavior in vaccinated animals [8].

A candidate vaccine against nicotine has been developed based on a virus-like particle (VLP)-nicotine conjugate [9]. The presentation of an antigen in a highly ordered, repetitive array, such as protein shells or coats of certain viruses, provokes strong antibody responses [10]. The coat protein of the bacteriophage Qβ forms non-infectious VLPs when expressed recombinantly in Escherichia coli [11]. Using chemical cross-linkers, any antigen can be placed directionally onto the VLP surface, rendering it highly immunogenic. Antigens coupled to such VLPs induce potent and long-lived antibody responses in mice [12] as well as humans [9], [13], [14]. Specific antibodies of the IgG but not IgE isotype can be detected, demonstrating that potent antibody responses may be induced in the absence of isotypes causing allergic problems. For the present vaccine, a nicotine derivative was chemically linked to VLPs formed by the coat protein of the bacteriophage Qβ. In pre-clinical animal studies, this Nicotine-Qβ vaccine induced strong and specific IgG antibody responses [9].

In a phase I study 32 healthy non-smokers were immunized with the Nicotine-Qβ vaccine at doses of 50 µg and 100 µg in presence or absence of Alum, one of the adjuvants approved for use in humans [9]. A single injection induced an anti-nicotine response in 100% of subjects, antibody levels were boosted by either a second injection or by the addition of Alum, and the vaccine was well tolerated. Based on these encouraging results, we performed an exploratory phase II randomized trial in smokers ready to quit.

We present the results of the 6-month randomized double blind trial and the subsequent 6-month follow-up period of this trial assessing immunogenicity, efficacy, safety and tolerability of the vaccine against nicotine.

Design overview

The protocol synopsis for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1.

We performed a phase II randomized, double blind, placebo-controlled trial. The study subjects were recruited through public advertisements on billboards posted in the three clinical study centers in Switzerland (Kantonsspital, St. Gallen, University Hospital Center, Lausanne, and Hirslanden Lung Center, Zurich) where the study was performed. Interested participants were asked to call the study center. The trial was explained and a pre-screening interview was undertaken. If the subjects met the initial screening criteria, they were scheduled for a visit to provide informed consent and to undergo a screening of their health and a medical examination including standard clinical laboratory and electrocardiogram. Participants did not receive any compensation.

We considered three main objectives. First, to assess the clinical efficacy of Nicotine-Qβ in smokers willing to quit, second, to evaluate the safety and tolerability of Nicotine-Qβ in smokers and third, to determine the immunogenicity of Nicotine-Qβ.

Participants

Participants were required to be between 18 and 70 years, to have been smoking at least 10 but no more than 40 cigarettes/day for more than 3 years, have a Fagerström Score of at least 5 at screening [15], and willing to quit smoking. Women of childbearing potential had to agree to use an effective form of contraception during treatment and up to 12 months after the last dose of the vaccine. Exclusion criteria were the following: cardiovascular, renal, pulmonary, endocrine, or neurological disorders, ulcers, skin disorders, autoimmune diseases or severe allergies; risk behavior to acquire HIV; an active liver infectious disease; a current diagnosis or a history of major depressive episodes, of panic attacks, psychosis, bipolar or eating disorders; use of other smoking-cessation treatments, like bupropion or nicotine replacement therapy within 6 months before study enrollment or at the time of screening; pregnancy or lactation; abuse of alcohol or other recreational drugs; use of a psychoactive drug (excluding sleeping pills) within one month before enrollment; and regular use of any non-cigarette tobacco product.

We obtained written informed consent from all subjects before they were enrolled in the study. The Ethics Committees of the three centers (i.e., Lausanne Medical School Ethics Committee, St Gallen: Ethics Committee of the Canton St. Gallen, Hirslanden: Ethics Committee of the Canton Zurich) approved the study. The Swiss health authorities were notified of its conduct and the study protocol has been registered in the Swiss Medical Registry (Swissmedic # 2003DR2327) and at www.clinicaltrials.org (NCT 00369616).

Randomization and Interventions

Two thirds of the subjects were scheduled to receive five intra-muscular injections of 100 µg Nicotine-Qβ in Alum and one third to receive indistinguishable placebo (Alum alone) at monthly intervals, i.e., on months 0, 1, 2, 3, and 4. After having fulfilled the eligibility criteria, investigators sent the subject's identification number to the local pharmacist, who assigned subjects to treatment according to a randomization list, prepared using standard software, with a block size of 15. All study personnel, participants, study statisticians and data monitoring committee were blinded to treatment assignment for the duration of the study. A “target quitting date” was set at 1 month after the first vaccination. Individual standardized counseling was provided weekly to all study participants starting at week 3 after the first vaccination until week 16 by health care professionals and physicians trained through an effective smoking cessation program [16]. The initial phase ended at month 6 and was followed by an additional 6-month period of follow-up with two visits at months 9 and 12. Neither additional injections nor counseling was given during the follow-up phase.

The active pharmaceutical agent was Nicotine-Qβ, i.e., a nicotine derivative coupled to the VLP Qβ as a carrier. The VLP is produced by recombinant expression of the coat protein of the bacteriophage Qβ in E. coli. The adjuvant used with Nicotine-Qβ was Alum (Alhydrogel: Brenntag Biosector A/S, Frederikssund, Denmark), and the placebo consisted of Alhydrogel alone. All materials for the clinical trial were produced to current good manufacturing principles according to the International Conference on Harmonization guidelines. An injection volume of 2 ml was given intramuscularly at the upper arm. The vaccine dose was selected based on the results from the Phase I study which showed an early onset, a maximal immune response with 100 µg Nicotine-Qβ and an about twofold increase of titers by the addition of Alum. Additional information on the product, pre-clinical toxicological safety studies, animal efficacy studies and the ELISA are published elsewhere [9].

Outcomes and follow-up

The first primary outcome was abstinence from smoking defined as self-reported abstinence from smoking, confirmed by a carbon monoxide concentration in expired air of less than 10 ppm. Carbon monoxide was measured pre-study, at each monthly visit after vaccination and during follow-up at months 9 and 12 with a Micro Smokerlyzer® (Bedfont). Study participants were considered to be continuously abstinent when at all monthly visits from month 3 until month 6 they declared themselves as being non-smokers during that period and when the carbon monoxide concentration in their exhaled air was below 10 ppm. We did not use cotinine as a second confirmation means of abstinence because the binding of nicotine to antibodies might prolong the elimination of nicotine and its metabolite cotinine [17]. Point prevalence of smoking or of abstinence was defined at each assessment visit as the smoking status (self-report confirmed by CO below 10 ppm) of a study participant at that visit, irrespective of his/her smoking status on the visits before or after. Self-reported cigarette consumption was recorded daily in paper and pencil diaries. Subjects with missing visits or who were lost to follow-up at any time during the study were considered as smokers. Given the exploratory nature of this Phase II trial, the study protocol stipulated that additional evaluations guided by the results might be considered, in particular the correlation between the clinical outcome and anti-nicotine antibody titers could be assessed.

The other primary outcomes were immunogenicity, safety and tolerability of Nicotine-Qβ. The immunogenicity was assessed by determination of specific anti-nicotine antibodies of IgG isotype by ELISA using an RNAse-nicotine conjugate [9] in sera before vaccination and then at monthly intervals up to month 6 and at months 9 and 12. Since a human anti-nicotine monoclonal IgG reference standard was not available, nicotine-specific IgG levels are reported as titers. The ELISA titer for each serum specimen corresponds to the dilution needed to achieve an optical density of 50% of the optical density reached at saturation. An antibody responder was defined as a subject who had an anti-nicotine IgG titer, which was larger than the unspecific background reactivity (average plus three standard deviations) of the ELISA. Background reactivity of the ELISA was determined using preimmune sera. Sub-group analyses were performed by using the area under the curve (AUC) of log-transformed titers from month 3 to month 6.

Safety and tolerability were assessed through systematic collection of vital signs and all reported symptoms, as well as standard clinical laboratory and injection site examination in all subjects. A specific safety check-up was performed one week after each injection. Subjects also kept a diary for self-assessment of local reactions. Information was collected about adverse events that occurred during the double blind and follow-up periods. An adverse event was any new undesirable medical occurrence, which did not necessarily have to have a causal relationship with this treatment. The classification of the severity was based on the following scale. Mild: the adverse event was noticeable to the individual; it did not require modification of the dose but may have required additional therapy, such as paracetamol. Moderate: the adverse event interfered with the individual's daily activities; it may have required additional therapy, but did not require discontinuation of the study agent. Severe: the adverse event was intolerable and necessitated additional therapy or discontinuing the study agent. A serious adverse event was any untoward medical occurrence that at any dose resulted in death, in persisting or significant disability/incapacity, was life-threatening, required in-patient hospitalization, or any significant medical event as judged by the investigators.

To assess craving and withdrawals symptoms, we used two questionnaires, the Questionnaire on Smoking Urges [18] addressing two conditions (i.e., intention to smoke and anticipation of relief from the urgent desire to smoke) and the Wisconsin Withdrawal Scale [19] addressing craving, concentration, sleeplessness, anger, anxiety, sadness and hunger.

Statistical analyses

Statistical analyses were performed with SAS for Microsoft Windows® 9.1.3. Pearson Chi-Square test without correction was used to calculate the statistical significance of the effect of vaccination (active versus placebo) and the effect of antibody titer levels (high, medium, low versus placebo) on continuous abstinence and on point prevalence abstinence. For continuous variables differences between two groups were analyzed with the two-sample t-test or with the Mann-Whitney test as nonparametric test, and, for more than two groups, with analysis of variance or the Kruskal-Wallis test as nonparametric test. The influence of baseline parameters on the abstinence rate was tested by means of a logistic regression analysis (SAS ProcLogistic using the binary logit model). Outcomes were considered significant if p values of the respective statistical tests were smaller than 0.05. Nicotine replacement users were excluded from the per-protocol analysis.

We powered our study on rates of continuous abstinence and calculated a sample size that would detect a difference of at least 15% (smoking abstinence rates of at least 30% compared to 15% on placebo) with an alpha error of 5% or less and a power of 90% or more. We chose unbalanced group sizes with a ratio of 21 for active vs. placebo treatment to allow as many study participants as possible to potentially benefit from the active treatment and to permit sub-group analyses of efficacy by antibody response. Based on theses parameters, the required sample size was 300 subjects (200 in the active group vs. 100 in the placebo group). Considering the exploratory nature of this Phase II study, additional participants were considered as valuable source of information.

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