TABEX FOR CLEAN LUNGS, FOR A HEALTHY HEARTH!

Tabex is an original Bulgarian drug of vegetal origin for treatment of nicotinism and to help quit smoking. It is developed on the basis of the alkaloid contained in the plant Citisus laborinum L., also called Golden Rain, widespread in the southern areas of Central Europe and Italy. All parts of the plant contain the alkaloid Cytisine, the greatest amount (up to 3%) being found in the seeds.

Fig. 1 Structural formula of cytisine

Fig. 1 Structural formula of cytisine

(1R-cis)-1,2,3,4,5,6-hexahidro-1,5-metano-8h-pyrido[1,2a][1,5]diazocin-8-on

Chemical characteristics and content of Tabex

Each tablet contains 0.0015 g cytisine

Empirical formula of cytisine: C11H 14ON 2

Ensuing from the molecular orbital calculations after Kier(1969), it is evident that the molecular configurations of nicotine and acetylcholine have a quaternary nitrogen atom which is with a negative charge and located at 4.85 +/- 0.1 A, considered to be responsible for the nicotine-like activity. In cytisine the nitrogen atom in ring C appears at 4.8-9 A from the oxygen atom of the pyridine group and is also negatively charged.

The prolonged clinical and toxicological studies in many countries all over the world have proved the enormous harm of smoking on all organs and systems of the human organism. Did you know that just a few minutes after the last cigarette the body begins to recover? Stopping smoking immediately boosts physical regeneration – this effect lasts for years (Read “What happens after you quit smoking“). The danger of cardiovascular incidents (myocardial infarction, stenocardia, peripheral vascular diseases), diseases of the respiratory system (lung cancer, tracheobronchitis, etc.), as well as psychic and physiological dependence of addictive type is mostly emphasized.

Fig. 2 Stereoisomeric formulae of cytisine and nicotine (after Barlow, R.B. and McLeod, L.J.)

Fig. 2 Stereoisomeric formulae of cytisine and nicotine (after Barlow, R.B. and McLeod, L.J.)

The treatment of nicotine addiction is a complex process in which drug therapy occupies an important part. Sopharma produces the drug Tabex, developed on the basis of the alkaloid Cytisine, which has an action similar to that of nicotine.

PHARMACODYNAMICS OF CYTISINE

Cytisine is an agonist of the cholinoreceptors in the vegetative ganglia and belongs to the group of the gangliostimulating drugs. It excites the nicotine-sensitive cholinoreceptors of the postsynaptic membranes in the vegetative ganglia, chromaffin cells in the molecular part of the suprarenal gland and sinocarotid reflexogenic zone, which results in excitation of the respiratory center, predominantly through the reflexes, simulation of adrenaline release by the medullar part of the suprarenal glands and a rise in the blood pressure. After its absorption in the gastrointestinal tract, 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 smokers’ psychic and physical nicotine dependence.

Many researchers confirm in different pharmacological experiments the similarity between the pharmacological properties of cytisine and nicotine, as described by Dale & Laidlaw (1912) and confirmed also by the conclusions of Zachowsky (1937), Anichkov (1937), Dobrev and Paskov (1953), Daleva (1963), etc., in whose opinion cytisine is more potent as a gangliostimulating than as a ganglioblocking agent.

Fig. 3 Mechanism of action of cytisine. Creation of the vicious cycle of tobacco addiction and the way to exit from it by means of Tabex

Fig. 3 Mechanism of action of cytisine. Creation of the vicious cycle of tobacco addiction and the way to exit from it by means of Tabex 

This similarity between the peripheral effects of cytisine and nicotine is more quantitative than qualitative. Comparable effects of both drugs have been obtained in experiments on cats and rats (studies on the blood pressure), or on guinea-pig ileum and rat diaphragm, the doses of cytisine being 1/4 to 2/3 from the nicotine dose.

As regards the effects on the central nervous system, Cytisine has a weaker effect on the respiration of anesthetized rabbits, compared to the effects on the peripheral nervous system.

TOXICITY OF CYTISINE

Tabex was experimentally studied for its toxicological action on different kinds of experimental animals. The acute LD50 toxicity, the subchronic (30 days) and the chronic (80-180 days) toxicity were determined. The acute toxicity was determined on line H albino mice (intravenously, subcutaneously and orally); rats (intraperitoneally, subcutaneously and orally); dogs (subcutaneously and orally).

Table 1 Acute LD50 toxicity in mice, rats and dogs with different nodes of administration

Mice
Intravenously Female sign 2.3 (1.3-3.6)
Male sign 3.1 (1.8-5.2)
Subcutaneously Female sign 13 (11-15.3)
Orally Male sign 13 (8.5-19.9)
29 (22.37)
Rats
Intraperitoneally 9 (8.9-10.3)
Subcutaneously 11 (7.7-15.6)
Orally 38 (17-83.6)
Dogs
LD0 4 mg/kg
LD0 25 mg/kg

The mice and the rats were divided in groups of six animals and the dogs in groups of 2 animals for each dose used. The behavior of the animals and the lethality were observed daily for 7 days after the drug was applied. All the results obtained were statistically processed according to Litchfield-Wilcoxon’s method. During the experiments the animals received standard food and water ad libitum (Angelova, O.).

During the observation the following toxic symptoms were found: accelerated respiration, clonic and toxic convulsions, motility disturbances in the hind legs, lower muscle tonus. The absorption index in rats was 4.2. In dogs, injected subcutaneously with 4 mg/kg, the changes occurred one hour after the treatment. The animals began vomiting, colonic and tonic convulsions of body and limbs muscles appeared. The movement was slow and phlegmatic. When stimulated by force, they became aggressive. On the following day the animals restored their normal behavior. No lethality was noted. After oral administration of doses of 15-25 mg/kg, the dogs showed no external symptoms of toxicity.

The results of the acute toxicity studies showed that Cytisine was much less toxic than intravenously applied nicotine, but it was more toxic after intraperitoneal and oral administration.

Table 2 Comparison between acute toxicity of Cytisine and nicotine

Mode of administration
i.v. i.p. p.o.
Nicotine LD50 mmoles/kg 1.92 59.0 1.425
1.75 – 2.12 53.6 – 65.0 1.370 – 1.486
LD50 mg/kg 0.3 9.5 230
(6) (7) (9)
Time of death 32.0 +/- 0.8 2.42 +/- 0.1 2.86 +/- 0.1
sec (28) min (38) min (45)
Equipotential molar ration 1 1 1
Cytisine LD50 mmoles/kg 9.10 49.5 535
7.9 – 10.5 46.6 – 57.5 411-696
LD50 mg/kg 1.73 9.4 101
(6) (6) (7)
Time of death 37.2 +/- 3.1 5.32 +/- 0.4 12.7 +/- 0.6
sec (36) min (28) min (46)
Equipotential molar ration 4.75 0.84 0.37

 

SUBACUTE TOXICITY

The experiments for subacute toxicity were carried out on line H albino mice and Wistar rats of both sexes equally, treated orally with aqueous solution of Tabex with the following terms and doses: mice – for 45 days with a dose of 3.3 mg/kg and rats – for 30 days with a dose of 7.6 mg/kg.

The chronic toxicity was studied on Wistar rats and on dogs treated orally with aqueous solution for the rats and substance in the feed – for dogs, at the following terms and doses:

  • Rats – for 90 days with doses: 1.36, 0.45, 0.90 mg/kg
  • Rats – for 180 days with doses: 0.45, 0.90 mg/kg
  • Dogs – for 180 days with doses: 0.45 mg/kg

The control groups of animals were treated with equivalent amounts of water. All the animals received standard feed and water ad libitum. The behavior and lethality of the animals were observed daily. The following clinical-laboratory and pathoanatomical examinations were carried out:

Hematological:

Hb, RBC, WBC, platelets, leukocyte formula, prothrombin index

Biochemical:

serum bilirubin, blood sugar, blood urea

Urine:

albumin and sediment

Pathoanatomical:

examination of internal organs

The data obtained were statistically processed according to Student-Fisher’s method.

No changes in the behavior of the experimental animals were observed during the experiment carried out. No changes were likewise noted in the clinical-laboratory indices studied. The pathoanatomical examinations showed a different degree of dystrophic changes in the liver of the mice treated with 3.3 mg/kg and in the dogs treated with 0.45 mg/kg.

The following enzyme indices were examined: transaminases – SGOT and SGPT, and alkaline phosphatase in chronic experiment on white Wistar rats and dogs treated orally with the following doses and terms:

  • Rats – for 90 days with a dose of 1.35 mg/kg
  • Rats – for 180 days with doses of 0.45 and 0.90 mg/kg
  • Dogs – for 180 days with a dose of 0.45 mg/kg

A statistically significant increase of SGOT was found in the group treated with 1.35 mg/kg for 90 days. The SGOT level was twice higher than that of the control group. The results obtained showed hyperenzynemia of SGOT and coincided with the data of Veress and Rengei about the influence of nicotine on the level of this enzyme.

On the basis of the toxicological studies we can make the following conclusions:

  1. According to Hodge and Sterner’s classification for oral administration to rats, Tabex belongs to the group of strongly toxic drugs with a good absorption index.
  2. When given orally to rats for 30 and 90 days, Tabex shows no toxic changes in the hemopoiesis and internal organs of the experimental animals.
  3. When applied orally to mice for 45 days and to rats and dogs for 180 days, Tabex does not cause any toxic changes in the hemopoiesis and in the internal organs, except different degrees of dystrophic changes in the liver.

THERAPUETIC RANGE AND TOLERANCE

The therapeutic range of cytisine is much greater than of nicotine.

The daily therapeutic saturating doses of Tabex is 1.5 to 9 mg. The pharmacodynamic results obtained by Barlow et al. show that when applied at much higher concentrations in comparison with those of nicotine, Cytisine causes parasympathetic block of N-cholinergic receptors. Thus, for instance, the upper cervical ganglion of cat is blocked with 1.17+/-0.07 against 100 nmol for nicotine.

Tabex is very well tolerated, it does not provoke anorexia, nausea and vomiting in therapeutic doses. When applied according to appropriate schedule, it enables smokers to give up smoking gradually, without developing abstinence symptoms.

Cytisine substance

Item # EB0280-103-11

CYTISINE DESCRIPTION

Cytisine substance has a mechanism of action similar to the effect of nicotine, but with rather low toxicity. It can substitute nicotine substance, which shortens the period of interaction of nicotine with the respective receptors and hence leads to a gradual reduction and elimination of existing psychic nicotine dependence in smokers.

MOLECULAR MASS: 190.24

PHYSICOCHEMICAL INDICES OF THE FINISHED PRODUCT

¤ Appearance crystalline powder
¤ Color white or lightly yellowish
¤ Odor odorless
¤ Taste very bitter
¤ Melting temperature (C°) 154-157
¤ Solubility
in water slightly soluble
in chloroform slightly soluble
in ether practically insoluble
in alcohol slightly soluble
in acetone slightly soluble
in benzene poorly soluble
in amyl alcohol poorly soluble
in benzine practically insoluble
¤ Specific rotation (2% aqueous solution) 120.0 – 123.0
¤ Purity indices

¤ Limpidity and color of solution

the solution of the drug (1:20) should be limpid and colorless
sulfates content (%) not more than 0.04
chlorides content (%) not more than 0.02
¤ Sulfate ash (%) should not exceed 0.1

 

CYTISINE SUPPLIED

The substance is filled in tightly closed orange glass flasks of 500 g and placed in cardboard barrels

QUALITY

Bulgarian State Standard

EXPIRATION TERM

Five years