Cytisine

190.24

190.24

207-616-0

53S5U404NU

407282

Orthorhombic prisms from acetone|Solid

N - Nervous system

2933990090

32.3

0.2

light yellow powder

1.2±0.1 g/cm3

152-153 °C

218 °C @ Press: 2 Torr

203.6±25.7 °C

1.623

439g/L(16 ºC)

Store at RT

7.61X10-6 mm Hg at 25 deg C (est)

LD50 in mice (mg/kg): 1.73 i.v.; 9.4 i.p.; 101 orally (Barlow, McLeod)

D17 -120°

Henry's Law constant = 4.01X10-12 atm-cu m/mol at 25 °C (est)

pK1 = 6.11; pK2 = 13.08

137.9 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Deliquescent crystals, soluble in water and alchol. pH of 0.1 molar aqueous solution = 4.3 /Cytisine hydrochloride/|Hydroxyl radical reaction rate constant = 8.59X10-11 cu cm/molec-sec at 25 °C (est)

Ⅲ

6.1(b)

UN 2811 6.1/PG 3

3

25-36/37/38

26-28-36/37-45

HA4025000

T

P305 + P351 + P338

H301-H315-H319-H335

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal and plant life; and conformance with environmental and public health regulations.

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P310, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 46 companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The therapeutic index of cytisine is wide. -Large doses can interfere with breathing and cause death. From MSDS: orl-mus LD50:101 mg/kg ipr-mus LD50:8550 ug/kg ivn-mus LD50:1730 ug/kg scu-rat LD50:8750 ug/kg

The analeptic effect of cytisine decreases during combined therapy with antituberculosis drugs (PASA, streptomycin, etc.).|The effect of various drugs on the acute toxicity of cytisine, the toxic constituent of Laburnum anagyroides Med, was studied in mice. Drugs were tested which have been recommended for symptomatic treatment of laburnum poisoning. Drugs which influence the CNS reduce the acute toxicity of cytisine more effectively than those with predominantly peripheral site of action.

LD50 Cat iv 400 ug/kg|LD50 Mouse iv 1730 ug/kg|LD50 Mouse ip 9400 ug/kg|LD50 Mouse oral 101 mg/kg

Cytisine is a toxin found in some plants(1,2). It is the toxic principle in seed of Laburnum anagyroides Medik /golden chain tree/, and other Leguminosae(3).|Nicotinic receptor in the nervous system of organisms

Indicated for use in smoking cessation.

Nicotine/antagonists and inhibitors|/Cytisine is indicated for/ treatment of chronic nicotinism. It is particularly appropriate for treatment of risk groups of smokers with health problems on the part of the cardiovascular and respiratory systems, as well as smokers professionally subjected to tension and stress that are predisposed to seek a "false comfort" in nicotine or other drugs causing dependence. /NOT included in US product label/|/Investigators/ conducted a single-center, randomized, double-blind, placebo-controlled trial. Participants were randomly assigned to receive cytisine or matching placebo for 25 days; participants in both groups received a minimal amount of counseling during the study. The primary outcome measure was sustained, biochemically verified smoking abstinence for 12 months after the end of treatment. Of 1542 adult smokers screened, 740 were enrolled and 370 were randomly assigned to each study group. The rate of sustained 12-month abstinence was 8.4% (31 participants) in the cytisine group as compared with 2.4% (9 participants) in the placebo group (difference, 6.0 percentage points; 95% confidence interval (CI), 2.7 to 9.2; P=0.001). The 7-day point prevalence for abstinence at the 12-month follow-up was 13.2% in the cytisine group versus 7.3% in the placebo group (P=0.01). Gastrointestinal adverse events were reported more frequently in the cytisine group (difference, 5.7 percentage points; 95% CI, 1.2 to 10.2). ...|Cytisine, a natural plant alkaloid, has been marketed in Central and Eastern Europe for over 40 years for the clinical management of smoking cessation. Despite the fact that cytisine has been used by millions of smokers, its characteristics have not been reviewed in scientific literature in English, and presently existing clinical studies on its effectiveness and safety are insufficient to warrant licensing by modern standards. Understanding of the mechanism of cytisine action as a smoking cessation aid provides a necessary basis for conducting clinical trials to confirm its efficacy as an optimal antismoking therapy. ... /Investigators/ present a review of current knowledge about the pharmacokinetics, pharmacodynamics, toxicity, therapeutic efficacy and safety of cytisine, and about its derivatives that are under development. Recent pharmacological research has elucidated that the drug is a low efficacy partial agonist of alpha4beta2 nicotinic acetylcholine receptors, which are believed to be central to the effect of nicotine (NIC) on the reward pathway. The drug reduces the effects of NIC on dopamine release in the mesolimbic system when given alone, while simultaneously attenuating NIC withdrawal symptoms that accompany cessation attempts. Clinical studies on cytisine as a smoking cessation aid have demonstrated that the drug is effective and safe. /The/ recent uncontrolled trial has shown that a 12-month carbon monoxide-verified continuous abstinence rate following a standard course of treatment with cytisine with minimal behavioral support is similar (13.8%; N = 436) to that observed following treatment with NIC replacement therapy. Since cytisine exhibits a desirable pharmacological profile which makes it an attractive smoking cessation drug, it should be advanced to randomized clinical trials. However, more detailed preclinical studies on its pharmacokinetics and safety profile are required.

/Contraindications for cytisine include:/ Advanced atherosclerosis, some forms of schizophrenia, pheochromocytome, conditions connected with severe impairment of the cardiovascular system and malignant hypertension.|The following adverse effects are rather often observed at the beginning of /Cytisine/ treatment: changes in both taste and appetite, dryness in the mouth, headache, irritability, nausea, constipation, tachycardia, light elevation of the arterial pressure.|The drug should be administered carefully to patients with exacerbated peptic ulcer. After completing the treatment course, the patients should refrain from smoking...|The physicians should warn the patients that the simultaneous administration of the drug and smoking could lead to aggravated adverse effects of nicotine (nicotine intoxication). The drug should be used in all cases when the patient has a honest and firm intention to give up smoking.|For more Drug Warnings (Complete) data for CYTISINE (8 total), please visit the HSDB record page.

Various models have been run where the affinity of nAChR agonists to the receptor subtype are tested to help identify the molecules, groups and steric conformation that are vital to greater affinity. By using a nAChR muscle receptor subtype (α1)2β1δγ model the following results were obtained: anatoxin > epibatidine > acetylcholine > DMPP >> CYTISINE > pyrantel > nicotine > coniine > tubocurare > lobeline, where anatoxin had the highest activity efficacy and tubocurare the lowest. Acetylcholine on the other hand induced a much longer opening time of the receptor though anatoxin is more potent. The results suggest that anatoxin derivatives would be helpful in understanding structure-activity relationships (SAR) for muscle nAChRs (Cooper et al., 1996).

Oral: 6.2 l/kg Oral (5 mg/kg; tested in rabbits).|Renal: 43 mL/min.|The pharmacokinetic behavior of cytisine was studied in mice by means of tritiated cytisine after intravenous and oral administration of a sublethal dose of 2 mg/kg. After oral administration the maximum blood level is reached after 2 hr. The absorption rate is approximately 42%. From the blood level after intravenous administration a half-life of 200 min was calculated. Within 24 hr after intravenous administration 32% and after oral administration 18% of the administered radioactivity was excreted into urine. Following intravenous administration 3% of the dose was found in the feces within 6 hr. Among the examined organs and tissues the highest concentrations were reached in the liver, adrenals and kidneys. In the bile the highest concentration after intravenous administration was 200 times that in the blood.|Experimental study of pharmacokinetics of transdermal system with cytisine in rabbits showed a possibility of controlled intake of the drug over a 4-day period. The two stages of attaining the stationary levels of cytisin concentrations are revealed. The first stage lasted during first 24 hr and the second stage during succeeding 3 days. Using the data on intravenous cytisine injection we found that the stationary concentrations and the rate of cytisine intake in the first stage is twice as large as in the second stage. Thus cytisine can be classed as a short-living drug.

4.8 hours.|... The absorption rate is approximately 42%. From the blood level after intravenous administration a half-life of 200 min was calculated.

Cytisine is a low efficacy partial agonist of ⍺4-β2 nicotinic acetylcholine receptors. These which are believed to be central to the effect of nicotine (NIC) on the reward pathway and facilitate addiction. Cytisine reduces the effects of NIC on dopamine release in the mesolimbic system when given alone, while simultaneously attenuating NIC withdrawal symptoms that accompany cessation attempts.|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.|A family of genes has been identified that encodes subunits of nicotinic acetylcholine receptors (nAChRs) and is expressed in the nervous system. Functional neuronal nAChRs can be expressed in Xenopus oocytes by injection of RNA encoding 1 of 2 different beta-subunits (beta 2, beta 4) in pairwise combination with RNA encoding 1 of 3 different alpha-subunits (alpha 2, alpha 3, alpha 4). We examined the sensitivity of these 6 different alpha- beta-subunit combinations to the nicotinic agonists ACh, nicotine, cytisine, and 1,1-dimethyl-4-phenylpiperazinium (DMPP). Each subunit combination displayed a distinct pattern of sensitivity to these 4 agonists. The alpha 2 beta 2 combination was 5-fold more sensitive to nicotine than to acetylcholine, while the alpha 3 beta 2 combination was 17-fold less sensitive to nicotine than to ACh, and the alpha 3 beta 4 combination was equally sensitive to both nicotine and ACh. nAChRs composed of alpha 2, alpha 3, or alpha 4 in combination with beta 2 were 14-100-fold less sensitive to cytisine than to ACh. In contrast, nAChRs composed of alpha 2, alpha 3, or alpha 4 in combination with beta 4 were 3-17-fold more sensitive to cytisine than to ACh. The alpha 2 beta 2, alpha 3 beta 2, and alpha 3 beta 4 combinations were each equally sensitive to DMPP and ACh, while the alpha 2 beta 4, alpha 4 beta 2, and alpha 4 beta 4 combinations were 4-24-fold less sensitive to DMPP than to ACh. We also demonstrated that these differences are neither a consequence of variation in the relative amounts of RNA injected nor an artifact of oocyte expression. The oocyte system can accurately express ligand-gated ion channels because mouse muscle nAChRs expressed in oocytes display pharmacological properties similar to those reported for these receptors expressed on BC3H-1 cells. We conclude that both the alpha- and the beta-subunits contribute to the pharmacological characteristics of neuronal nAChRs.|Neuronal nicotinic acetylcholine receptors subserve predominantly modulatory roles in the brain, making them attractive therapeutic targets. Natural products provide key leads in the quest for nicotinic receptor subtype-selective compounds. Cytisine, found in Leguminosae spp., binds with high affinity to alpha4beta2* nicotinic receptors. We have compared the effect of C3 and C5 halogenation of cytisine and methylcytisine (MCy) on their interaction with native rat nicotinic receptors. 3-Bromocytisine (3-BrCy) and 3-iodocytisine (3-ICy) exhibited increased binding affinity (especially at alpha7 nicotinic receptors; Ki approximately 0.1 microM) and functional potency, whereas C5-halogenation was detrimental. 3-BrCy and 3-ICy were more potent than cytisine at evoking (3)H dopamine release from striatal slices (EC50 approximately 11 nM), (3)H noradrenaline release from hippocampal slices (EC50 approximately 250 nM), increases in intracellular Ca2+ in PC12 cells and inward currents in Xenopus oocytes expressing human alpha3beta4 nicotinic receptor (EC50 approximately 2 microM). These compounds were also more efficacious than cytisine. C3-halogenation of cytisine is proposed to stabilize the open conformation of the nicotinic receptor but does not enhance subtype selectivity.|Cytisine, a partial agonist that binds with high affinity to the alpha4beta2 nicotinic acetylcholine receptor...|For more Mechanism of Action (Complete) data for CYTISINE (7 total), please visit the HSDB record page.

Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat seizures, coma, hypotension, hypertension, and arrhythmias if they occur. Observe for at least 4 to 6 hours to rule out delayed toxicity, especially after skin exposure. For ingestion of intact gum, tablets, or transdermal patches, observe for a longer period (up to 12-24 hours). Mecamylamine (Inversine) is a specific antagonist of nicotine actions; however it is available only in tablets, a form not suitable for a patient who is vomiting, convulsing, or hypotensive. Signs of muscarinic stimulation (eg, bradycardia, salivation, wheezing), if they occur, may respond to atropine. /Nicotine/|Decontamination. Caution: Rescuers should wear appropriate skin protective gear when treating patients with oral or skin exposures to liquid nicotine. Skin and eyes. Remove all contaminated clothing and wash exposed skin with copious soap and water. Ingestion. Administer activated charcoal only if conditions are appropriate. Gastric lavage is not necessary after tobacco ingestion if activated charcoal can be given promptly. Consider gastric lavage for large recent ingestions of liquid nicotine. For asymptomatic small-quantity cigarette ingestions, no gut decontamination is necessary. For ingestion of transdermal patches or large amounts of gum, consider repeat doses of charcoal and whole-bowl irrigation. Enhanced elimination. These procedures are not likely to be useful because the endogenous clearance of nicotine is high., its half-life is relatively short (2 hours), and the volume of distribution is large. /Nicotine/|As antidotes at overdose /for/ cytisine one may use tranquilizers (anticonvulsive effect) and antihypertensive drugs (decrease of the blood pressure).|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|For more Antidote and Emergency Treatment (Complete) data for CYTISINE (6 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Symptoms of nicotine intoxication are observed in /cytisine/ overdose. The toxic effects are manifested in nausea, vomiting, pupil dilation, tachycardia, general weakness, clonic convulsions, paralysis of respiration. The communications of overdose with the drug are scarce.|/ALTERNATIVE and IN VITRO TESTS/ The nicotinic receptor proteins and gene transcripts for the different nicotinic receptor subunits exist in human prenatal brain already at 4-5 weeks of gestation. The early presence of nicotinic receptors suggests an important role for these receptors in modulating dendritic outgrowth, establishment of neuronal connections and synaptogenesis during development. When measurements of nicotinic receptors using [(3)H]epibatidine (labelling both the alpha3 and alpha4 subtype) and [(3)H]cytisine (labelling the alpha4 subtype) were performed in intact cells from the cortex, subcortical forebrain and mesencephalon (7.5-11 weeks of gestation), the highest specific binding for both ligands was detected in cells from mesencephalon, followed by subcortical forebrain and cortex. The effects of nicotine exposure were studied in primary cultures of prenatal brain (7.5-11 weeks of gestation). Treatment with nicotine (1-100 microM) for 3 days significantly increased the specific binding of [(3)H]epibatidine and [(3)H]cytisine in cortical cells but not in cells from subcortical forebrain and mesencephalon brain regions, indicating region-specific differences in the sensitivity to nicotine exposure. Relative quantification of mRNA showed that the expression of the nicotinic receptor subunits alpha3 and alpha7, but not alpha4, was increased in cortical cells after nicotine treatment. These findings support the assumption of a potential risk of disturbance in the functional role of nicotinic receptors during brain development as a consequence of maternal smoking during pregnancy.|/OTHER TOXICITY INFORMATION/ Cytisine has a molecular structure somewhat similar to that of nicotine and varenicline. The concept for the new smoking cessation drug varenicline was based partly on cytisine. Like varenicline, cytisine is a partial agonist of nicotinic acetylcholine receptors, with high affinity for alpha4beta2 receptors. Cytisine has been used since the 1960s as a smoking cessation drug in Eastern and Central Europe, but has remained largely unnoticed elsewhere. Three placebo-controlled trials, conducted in East and West Germany in the 1960s and 1970s, suggest that cytisine, even with minimal behavioural support, may be effective in aiding smoking cessation. Cytisine tablets are very inexpensive to produce and could be a more affordable treatment than nicotine replacement, bupropion and varenicline. There is however a dearth of scientific research on the properties of cytisine, including safety, abuse liability and efficacy. This paper seeks to identify research priorities for molecular, animal and clinical studies. In particular, new studies are necessary to define the nicotinic receptor interaction profile of cytisine, to establish its pharmacokinetics and pharmacodynamics in humans, to determine whether animals self-administer cytisine, and to ascertain whether cytisine is safe and effective as a smoking cessation drug. Potentially, this research effort, contributing to wider use of an inexpensive drug, could save many lives.

3-hydroxy-11-norcytisine

Tabex: Film tablets of 1.5 mg in packages of 100.

1,5-Methano-8H-pyrido[1,2-a][1,5]diazocin-8-one, 1,2,3,4,5,6-hexahydro-, (1R,5S)-: INACTIVE|Toxic principle in seed of Laburnum anagyroides Medik /golden chain tree/, and other Leguminosae.|Tabex contains cytisine and is used to aid chronic smokers in abstaining from smoking. Total abstentation occurred in 65.1% of the subjects.

A new screening method for the simultaneous determination of thirteen plant alkaloids (aconitine, anabasine, atropine, brucine, colchicine, cotinine, cytisine, harmine, ibogaine, nicotine, scopolamine, strychnine, yohimbine) in a human specimen was developed based on solid-phase extraction and reversed-phase liquid chromatography with photodiode array detection. The validated method enables selective identification as well as accurate and sensitive quantification. The analysis of forensic and clinical samples emphasizes the applicability for intoxications and drug abuse, as well as for compliance control.|Cytisine was determined in tabex tablets and cytiton injections by using uv spectrophotometry at 307 nm.|The resolution and identification of 12 lupine alkaloids are demonstrated using capillary gas chromatography & gas chromatography-mass spectrometry.