Cytisine for smoking cessation

 Cytisine for smoking cessation

Abstract

Cigarette smoking is the one of the major risk factor for human health. The treatment of smoking addiction is changing rapidly through different natural and artificial substances. Among them Cytisine is playing one of the major role. Cytisine, also known as baptitoxine and sophorine , is an alkaloid that occurs naturally in several plant genera , such as Laburnum and Cytisus of family Fabaceae and usually extracted from the seeds of those plants. Cytisine is an acetylcholine  agonist , and has strong binding affinity for the nicotinic acetylcholine receptor. Cytisine plays the part of a nicotine- substitute substance which decreases the period of interaction between nicotine and the corresponding receptors. This in turn leads to a gradual decrease and interruption of the smoker’s psychic and physical nicotine dependence. The use of cytisine for smoking cessation remains relatively unknown outside Eastern Europe. This review is about the source, nature, mode of action and usage of Cytisine for smoking cessation.

Keywords: 

Cytisine , Alkaloid , Acetylcholine agonist, Nicotine, dopamine.

Introduction:

Tobacco smoking is one of the main threats to human health and is the biggest single factor of premature mortality in Poland and worldwide. It is estimated that in XXI century 1 million smokers

will die because of their smoking [1,2]. Despite attempts to control tobacco use covering a broad

spectrum of interventions, breaking the nicotine habit remains difficult

The best results in the treatment of nicotine addiction are achieved when a combination of

pharmacotherapy and non-pharmacological treatments, including additional behavioural support, is

applied. The current most effective pharmacological tools are nicotine replacement therapy (NRT)

and bupropion [1,3], and in some countries recently approved varenicline . NRT increases 12-month

continuous abstinence rate in smokers about 1.5 to 2 times in comparison to placebo [1,4]. Bupropion

doubles the chances of success of quit attempts [1,5]. Despite their advantages, current

pharmacotherapies are too expensive for many smokers, especially in developing countries, and are

not widely disseminated to the general population of smokers. It is supposed that new medicines, like

varenicline, rimonabant, and nicotine vaccines will be expensive and unaffordable for many smokers.

Thus, there is an urgent need for identification and evaluation of other forms of pharmacotherapy

which would be effective, safe and less expensive for health care systems and smokers [1,6].

These guidelines of mimicking the biochemical effects of nicotine yet lacking addictive or positive

rewarding properties led us to focus on cytisine, an alkaloid of plant origin marketed for over 40 years

in Central and Eastern Europe (CEE) [1,7, 8, 9, 10, 11].In addition, our recent trial confirming its

efficacy and safety and potential low cost of the therapy encouraged us to propose cytisine as an

attractive drug for smoking cessation that should receive wider awareness[1].

Tobacco use and nicotine dependence

History of tobacco use

Tobacco and traces of nicotine were discovered in human remains, as early as the prehistoric era,

although there was no clear evidence of the use of tobacco and smoking as a regular activity. The

ancient Mayan civilization commonly used tobacco, as it was native to virtually all areas of the two

Americas. Perhaps one of the most notable events in the history of tobacco was its discovery by

Columbus in1492. However, a couple thousand years before Columbus arrived the indigenous

peoples of the Americas were already cultivating tobacco on a large scale, by careful hand farming.

Pipes existed even in those ancient times, as clay pipes have been unearthed as archaeological finds.

During the 16th and 17 th centuries, tobacco gained widespread popularity, especially in the form of

snuffing tobacco. Tobacco became even more popular and more affordable in the 19th and 20th

century, but the widespread tobacco consumption revealed the negative effects of tobacco

smoking[12].

Nicotine tolerance and dependence

Nicotine is responsible for the effects of tolerance and dependence, and for the development of

withdrawal syndrome in both animals and humans (12,13,14 ). The neurochemical, anatomical and

molecular basis of nicotine dependence is very similar to the other drugs of abuse, particularly the

psychostimulants. Nicotine acts on nicotinic acetylcholine receptors (nAChRs) in both central and

autonomic nervous systems. The stimulation ofacetylcholine receptors increases the transmitter

release. Nicotine, like other drugs of abusetriggers the dopamine reward system and increases the

extracellular level of dopamine in nucleus accumbens, which is thought to be responsible for the

reinforcing behavior, stimulant and dependence properties of nicotine. Nicotine also exerts its effect

in the brain on non-dopaminergic structures that may account for its positive rewarding effects and

some of the symptoms of nicotine withdrawal. Moreover, the actions of nicotine on many systems,

including brain stem cholinergic, GABAergic, noradrenergic, and serotonergic nuclei, may also

help to mediate nicotine effects related to addiction[12].

Origin of cytosine

Cytisine is a quinolizidine alkaloid originating from seeds and many other parts of plants of the

Leguminosae (Fabaceae) family, including Laburnum, Sophora, Baptisia and Ulex spp. [1,15, 16].

The greatest amount of the alkaloid is found in the seeds of the common garden decorative plant

Laburnum anagyroides (Cytisus laburnum; Golden Rain accacia) (about 1–5%). In 1912, Dale and

Laidlaw [1,17] have described cytisine to be the toxic component of this plant.

History of the use in medicine

The extracts from the Laburnum seeds and flowers have been used in traditional medicine for

hundreds of years. However, a historical clock for cytosine started thousands years ago in America

where Indians have consumed the seeds for their emetic and purgative effects during rites and magical

practices [1,18,19,20]. In Europe, traditional medicine has recommended alcoholic extracts containing

cytisine for constipation, migraine, insomnia, cough and neuralgias. About 100 years ago, cytisine

was used as an antiasthmatic agent and an insecticide.

During the Second World War the leaves of Laburnum anagyroides were used as a tobacco substitute

[1,21]. There are also reports indicating that cytisine or cytisine-containing plants have been

administered as a diuretic in Western Europe [1,22], an analeptic in the former Soviet Union [1,24,25]

as well as an agent replacing NIC in smokers making a quit attempt in Central and Eastern Europe

[1,25,26].

Cytisine as a smoking cessation aid has been used since the 1960s in Bulgaria. The first clinical study

using cytisine for smoking cessation was carried out by Stoyanov and Yanachkova in 1965 [1,27]. In

the next 10 years, other pharmacological and clinical studies in Bulgaria, Poland, Russia, East and

West Germany were performed, demonstrating good efficacy and safety of the drug [1,28–31,

32,33,34,35,36,37,38,39,40]. Since the results of those studies were promising, cytisine was

developed, and has been manufactured and marketed from 1964 as Tabex® (Sopharma, Bulgaria),

and has been widely distributed in Central and Eastern Europe

Chemistry

Although cytisine was isolated already in 1863 by Husemann and Marme, its chemical structure was

described only in the 1930s [66–68]

Fig. 1. Chemical

structure of cytisine and nicotine .

Reprinted from[43]

Chemically, cytisine is (1R-cis)-

1,2,3,4,5,6-hexahydro- 1,5-

methano-8H-pyrido[1,2-

a][1,5]diazocin-8-

one(C11H14ON2). The structural formula is depicted in Figure 1. X-ray crystal structure analysis

indicates thatits chemical structure closely resembles that of NIC [1,44]. The quasi-aromatic ring in

cytisine and the pyridine ring of nicotine are associated in a similar way in relationship to the nitrogen

atom in the bispidine ring and the nitrogen atom in the pyrrolidine ring, respectively[1,44].

Cytisine crystallizes as big colorless crystals, easily soluble in water, chloroform and ethanol, less

soluble in benzene, ethyl acetate and acetone, and insoluble in ether [1,45].

Cytisine is a compound with a relatively rigid conformation.The rigidity of the molecule makes it

an attractive template for structure-activity studies. In recent years, the studies on the structural

modificationof cytisine have led to the development of novel compounds of potential therapeutic

interest [1, 18, 19, 21,31, 34, 50]. One of such compounds, varenicline has recently been approved by

the US Food and Drug Administration for the treatment of nicotine addiction [31–33, 54, 73, 102,

145].

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