Levshin V.F., Slepchenko N.I. Radkevich N.V. RONC named after. N.N. Blokhin RAMS
Introduction
Tobacco and tobacco smoking (TS) are one of the leading causes of morbidity and mortality in the modern population (2, 7). At the same time, according to the World Health Organization, the development and implementation of methods to reduce the prevalence of smoking and, in particular, assistance in quitting smoking, are recognized, based on the criteria of cost and effectiveness, as the most promising area for the prevention of many chronic non-communicable diseases (12). The need to develop methods and introduce medical assistance in cessation of tobacco use into health care practice is due, first of all, to the fact that the vast majority of regular smokers suffer from a certain type of disorder, tobacco addiction. Therefore, only 3-5 out of 100 people who want to quit smoking manage to quit smoking on their own without any help (10). Other smokers require some medical care. Among the various methods of helping to quit smoking and treating tobacco addiction, drug therapy plays a significant role. The number of drugs offered for the treatment of tobacco addiction is growing, but not all of them undergo sufficient testing and objective assessment of their effectiveness.
In particular, there are only three drugs on the Russian market that have undergone proper clinical trials on a larger or smaller scale to evaluate their effectiveness in the treatment of tobacco addiction : Nicorette (nicotine replacement therapy drug), Tabex (cytisine) and Chantix (varenicline). Of these drugs, Tabex has the longest history of use in the treatment of tobacco addiction, at the same time, the least number of special clinical studies have been devoted to this drug. There are a relatively small number of publications devoted to controlled studies of Tabex, and all of them indicate greater or lesser effectiveness of the drug in the treatment of tobacco dependence (6, 13). However, due to the lack of relevant research, the effectiveness and indications for the use of Tabex continue to be discussed and studied. In particular, to our knowledge, a randomized, double-blind controlled study of the use of Tabex in the treatment of tobacco dependence has not yet been conducted in Russia.
Tabex
Tabex (cytisine) is a drug for the treatment of tobacco dependence of the n-cholinomimetics group from the Bulgarian pharmaceutical. The active ingredient of the drug is the alkaloid cytisine, extracted from broom. It interacts with n-cholinergic receptors, acting as an antagonist to nicotine. Cytisine stimulates the receptors of the ganglia of the autonomic nervous system, excites chemoreceptors located at the site of the expansion of the internal carotid artery (the so-called carotid sinus) and promotes more intense secretion of epinephrine by the adrenal cortex. Increases blood pressure and stimulates the respiratory reflex. A special feature of Tabex is that it provides the opportunity to systematically quit smoking for a person who does not have sufficient willpower to give up the bad habit once and for all. Smoking must be stopped no later than the fifth day from the start of pharmacotherapy. The effectiveness of the drug was tested in randomized clinical trials involving patients with an impressive smoking history. About 60% of them completely gave up smoking; in 30% of cases, a partial result was achieved, which consisted in reducing the number of smoking episodes during the day from 20-30 to 4-5. Only in 11% of cases a negative result was obtained, which in most situations was caused by an unmotivated refusal of pharmacotherapy until the required saturation of the body with the active substance of the drug. The pharmacological effect of Tabex is based on its ability to cause unpleasant sensations of nicotine overdose against the background of smoking, which motivates a person to either completely give up this habit or reduce the number of cigarettes smoked per day.
The Tabex package contains 100 tablets of 1.5 mg of active ingredient. The course of treatment is 25 days, the average number of tablets per course is 100. The dosage is determined by the doctor individually. For people with low smoking intensity, it may be lower: its selection is carried out based on the patient’s well-being. The drug does not affect the psychophysical state and does not impair the ability to engage in activities that require concentration and attention. With a mechanism of action similar to nicotine, cytisine has a much higher toxicity threshold. Tabex is prescribed only to those patients who have seriously decided to work towards completely quitting smoking. For persons with a smoking history of more than 40 years, the drug is prescribed only after an interview with a doctor. Drug therapy with Tabex against the background of continued smoking can cause potentiation of the negative effects of nicotine and, ultimately, provoke nicotine intoxication. Provided the prescribed doses are followed and the doctor's recommendations are followed, the drug has no serious side effects. During treatment and upon its completion, there is an improvement in the patient's general condition due to the elimination of nicotine intoxication.
Instructions for use TABEX
Tabex should be prescribed only when the patient has a serious intention to quit smoking. Treatment with the drug and continued smoking may lead to increased side effects of nicotine (nicotine intoxication).
There is not enough clinical experience with the use of Tabex in patients with coronary artery disease, heart failure, arterial hypertension, cerebrovascular diseases, obliterating arterial diseases, hyperthyroidism, peptic ulcers, diabetes, renal or liver failure. The use of Tabex in this category of patients should be carried out after a thorough assessment by the attending physician.
There is not enough clinical experience with the safe use of Tabex in children under 18 years of age and in adults over 65 years of age, therefore its use in these age groups is not recommended.
The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption should not use this medicinal product.
Impact on the ability to drive vehicles and operate machinery
Tabex does not affect the ability to drive vehicles or operate machines.
Preclinical data
Toxicological studies of the drug on rats for 30 and 90 days show good resorption and the absence of toxic effects on hematopoiesis and internal organs. Oral administration of the drug in mice for 45 days and in rats and dogs for 180 days does not cause toxic changes in hematopoiesis and internal organs, with the exception of dystrophic changes in the liver of varying degrees. Single oral doses of cytisine (1 and 5 mg/kg) and nicotine (1 and 5 mg/kg) did not cause changes in heart rate or prolongation of the QT interval in male and female guinea pigs.
Cytisine at doses of 1 mg/kg and 5 mg/kg has a better safety profile in relation to the gastric mucosa compared to nicotine when used at the same dose in rats. When studying cytisine and nicotine at equimolar concentrations in isolated hepatocytes, it was established that cytisine causes significantly weaker toxicity in relation to hepatocyte viability and GSH depletion compared to nicotine. At the same time, cytisine shows a more pronounced toxic effect on the lipid peroxidation product, MDA.
Cytisine (6.25-200 µM) shows extremely low nephrotoxic potential in in vitro studies on human embryonic renal epithelial cells compared to nicotine and other nephrotoxic drugs.
With 5-day use of cytisine and nicotine in rats, significant changes were found in the walls of the renal blood vessels in the group that used nicotine at a dose of 5 mg/kg, followed by the groups that used nicotine at a dose of 1 mg/kg and cytisine at a dose of 5 mg/kg , in the group of animals treated with cytisine at a dose of 1 mg/kg, there are minor changes.
A comparative study of the genotoxic potential of cytisine, nicotine and well-known genotoxic substances (mitomycin C and cyclophosphamide) shows that cytisine does not exhibit clastogenic activity in therapeutic doses. There is no data on the carcinogenic potential of cytisine.
Cytisine at doses of 3 mg/kg and 4 mg/kg does not cause embryotoxic effects in rats. In chicken embryos, the use of cytisine in therapeutic doses does not cause embryotoxic or teratogenic effects; however, in high doses the drug has an embryotoxic effect.
Reviews about Tabex
Hello!
I want to share my experience of quitting... I smoked for 13 years, now I am 28 years old. I quit of my own accord because I was just tired of it. I understand that this is unconvincing. In general, it all started like this. I went in and bought a pack of Tabex and bought a pack of cigarettes. I smoked a pack and a half a day. On this day I decided to smoke less because of how I felt. On the second day, when smoking, my heart began to feel like it was tingling. This happened sometimes, so I didn’t attach much importance. But I wanted to smoke less on the second day. As a result, in 4 days I smoked a pack of cigarettes and didn’t understand why... Of course I tried, but not really. Before this I had not been able to smoke even for one day. On the fifth day, as expected, I quit. I wanted to smoke, well, 5 times a day.. In general, I lived to see the 13th day and things began to get rough... Next, I am attaching my question that I addressed to the site: “Hello! I smoked for 13 years, now I’m 28. I’ve been taking the drug for 13 days, I haven’t smoked for 9 days. I feel like I've collected all the extra stuff. Now the head is terribly aching, worse over the nose and side of the body, the whole left side of the body hurts, like a heart, but like neurogia - it’s not clear, it radiates to the elbow and all over the left arm, the left leg is pulled, there is pain in the back under the left shoulder blade, both eyelids are swollen , my eye hurts on the left side. Against the background of these symptoms, it seems to me that he became very irritable. Constant internal dialogue - I’m scolding someone, it’s difficult to stop. Not to say that before this I was a sportsman all my life? ?oym, even on the contrary, but the feeling intensified. I also don’t sleep much. I started taking glycine. It seemed like he was starting to sleep, but there was no feeling of sleep, as if he was dozing, even without seeming... I stopped glycine after several days of such “sleep”. Again there is no sleep, or rather, at least no nap. I'm freaking out. I don’t really want to smoke. I want everything to stop hurting. Never in my life have I been able to avoid smoking for even a couple of days. And then I was happy. There is a great desire to quit once and for all. I want to finish the pills, but it’s already becoming unbearable. I feel sorry for myself and my family. Tell me what to do, please?” Next, I will say that everything I had continued, only severe sweating and insomnia have increased. I haven't taken the drug for a week now. I change three T-shirts a night because it’s simply impossible to lie in a wet T-shirt anymore. There is no sleep, a feeling of constant drowsiness... By the way, I finished the drug, because while I was waiting for an answer from a specialist (5 days) I took the drug. When I saw the answer, the HARDNESS was already over. I want to tell those who decided that everything will be simple and unpretentious - don’t even think about it. Everything that hurts me hurts, but less and less often. Periodically I want to smoke, but the thought only enters my head for a minute or two. Now I’m worried about my health and don’t want to go back at all. By the way, my wife was unable to take the drug; she also began to experience severe pain, but her jaw and teeth hurt unbearably. I didn’t quit and didn’t feel any effect. Good luck to all! Think about whether to throw it or not, the engine will have to be supported - that’s for sure. Vitaly
The active ingredient of Tabex is the alkaloid cytisine.
It is a natural extract of the seeds of the Cytisus Laburnum plant. As an agonist of acetylcholinergic receptors, cytisine blocks them from attaching nicotine, reduces dependence on it and at the same time stimulates the release of dopamine. A drug. Tabex is licensed and approved for use in Russia as a prescription drug.
The purpose of this study is to study the therapeutic effectiveness of the drug TABEX in the treatment of tobacco dependence in smokers who quit smoking and to assess the possible side effects of the drug in a controlled and randomized trial.
Material and methods for studying the effectiveness of Tabex
The study was conducted on the basis of the prevention department of the Russian Oncological Scientific Center named after. N.N. Blokhina. For more than 5 years, the department has had a permanent service to help you refuse TC. Information about the work of the assistance service in refusing TC is disseminated through medical institutions in Moscow and their medical personnel, as well as through some local media and the Internet. Advisory assistance in quitting smoking, as well as provision of the drug TABEX under the research program were provided free of charge.
Recruitment of individuals into groups for the clinical trial was carried out from among smokers who sought help in quitting smoking during 2008. Persons were included in the study taking into account the following conditions:
— age 18-60 years; - experience of regular smoking for at least 3 years; - smoke 10 or more cigarettes per day; — motivated to quit smoking; — living in Moscow and available for contact by phone; — no contraindications to taking the drug specified by the manufacturer of the drug; — those who agree to participate in the study and with its terms (signed the Information Agreement).
All persons included in the study underwent a certain examination and psychological support before prescribing the drug.
Standard examination of smokers included:
— filling out a standardized questionnaire clarifying demographic data, smoking history and smoking behavior of the smoker, the degree of tobacco dependence and the level of motivation to quit smoking; — a survey regarding previous and concomitant diseases, current well-being and existing complaints; — measurement of height, weight, pulse, blood pressure, apnea (time of holding your breath while exhaling); — measuring the level of CO in exhaled air using a CO detector.
Standard psychological support for smoking cessation included:
— strengthening motivation to quit TC, — training in methods of psychological preparation for quitting TC, — training in methods of overcoming the desire to smoke after quitting TC, — explanation of the basic principles of treating tobacco addiction and the purpose of this clinical trial. — prescribing a course of medication and instructions on the regimen of drug use, a plan for quitting TC and subsequent consultations.
Individuals included in the study received TABEX or placebo. The tested drug TABEX contains the alkaloid Cytizin, which is an active agonist of nicotine neuroreceptors, reduces nicotine addiction, and alleviates withdrawal symptoms and depression. One tablet of Tabex contains 1.5 mg of Cytisine. The drug is intended for oral administration (per os).
The placebo drug completely copies the Tabex drug in appearance, but does not contain its active pharmacological component. The placebo drug is also intended for oral administration (per os). The standard course of medication, the same for Tabex and placebo, is 100 tablets for 25 days.
The distribution of smokers into groups (receiving TABEX or Placebo) was carried out randomly and double-blind. Randomization was performed using a randomization code generated by an external statistician, who kept it and made it available to the investigators only at the end of the study during the evaluation phase.
To track study participants and assess the results of tobacco dependence treatment, all patients were offered a minimum of 2 follow-up visits to a smoking cessation service at 1 and 4 weeks after starting medication, and a minimum of 2 telephone contacts at 3 and 6 months. from the start of treatment.
Control examinations included
— control of the treatment regimen and administration of study drugs; — assessment of changes in smoking behavior with mandatory measurement of CO levels in exhaled air; — determination of the nature and degree of manifestation of withdrawal syndrome and clarification of the dynamics in subjective complaints and sensations of patients during the period of taking drugs; — objective examination and examination of patients, taking into account possible dynamics in objective examination data (weight-height index, pulse rate, blood pressure, apnea); — psychological support and recommendations for preventing relapse in cases of continued abstinence and motivation for a new attempt to quit in case of relapse of TS.
The analysis of the collected data included a study of the comparability of two groups taking Tabex and placebo, based on a set of anamnestic and status indicators and characteristics, and an assessment of the effectiveness of tobacco addiction therapy by groups and subgroups of the test population of smokers.
The criterion for abstinence status (successful cessation of TC) was the patient’s own report of complete cessation of TC for a period of more than a week at the time of the last contact with him and assessment of his smoking status. During control examinations, abstinence status was necessarily confirmed by measuring the level of CO in exhaled air, not more than 9 ppm.
Statistical processing and analysis were carried out on a computer database using statistical programs.
