In HepG2 cells, cytosinicline (Cytisine) at 2.5, 5 and 10 mM can cause apoptosis [4]. Phase G1 (P<0.01). The population of sub-G1 cells is greatly increased when HepG2 cells are preincubated with Cytisinicline (Cytisine) at concentrations of 2.5, 5, and 10 mM [4].

Compared to those receiving vehicle, individuals on cytisinicline (5 mg/kg, ip) ate less and gained less weight [2]. Animals self-administered Cytisine substantially less than nicotine, and total particle intake rose with Cytisinicline (Cytisine) substitution compared with nicotine [2].

Absorption, Distribution and Excretion
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.

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

Interactions
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.

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Non-Human Toxicity Values
LD50 Cat iv 400 ug/kg
LD50 Mouse iv 1730 ug/kg
LD50 Mouse ip 9400 ug/kg
LD50 Mouse oral 101 mg/kg

[1]. [3H]cytisine binding to nicotinic cholinergic receptors in brain. Mol Pharmacol. 1991 Jan;39(1):9-12.

[2]. The effects of noncontingent and self-administered cytisine on body weight and meal patterns in male Sprague-Dawley rats. Pharmacol Biochem Behav. 2013 Sep;110:192-200.

[3]. Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014 Dec 18;371(25):2353-62.

[4]. Cytisine induces endoplasmic reticulum stress caused by calcium overload in HepG2 cells. Oncol Rep. 2018 Mar;39(3):1475-1484.

Therapeutic Uses
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.

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Drug Warnings
/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.

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Pharmacodynamics
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).

C11H14N2O

190.24

190.11

485-35-8

10235

White to off-white solid powder

1.2±0.1 g/cm3

413.0±34.0 °C at 760 mmHg

154-156ºC

203.6±25.7 °C

0.0±1.0 mmHg at 25°C

1.623

0.07

1

2

0

14

332

2

C1[C@H]2CNC[C@@H]1C3=CC=CC(=O)N3C2

ANJTVLIZGCUXLD-DTWKUNHWSA-N

InChI=1S/C11H14N2O/c14-11-3-1-2-10-9-4-8(5-12-6-9)7-13(10)11/h1-3,8-9,12H,4-7H2/t8-,9+/m0/s1

(1R,5S)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (10.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (10.93 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (10.93 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)