Cytisine

The herb of Genista tinctoria L.

Cytisine versus nicotine for smoking cessation.[Pubmed:25517706]

N Engl J Med. 2014 Dec 18;371(25):2353-62.

BACKGROUND: Placebo-controlled trials indicate that Cytisine, a partial agonist that binds the nicotinic acetylcholine receptor and is used for smoking cessation, almost doubles the chances of quitting at 6 months. We investigated whether Cytisine was at least as effective as nicotine-replacement therapy in helping smokers to quit. METHODS: We conducted a pragmatic, open-label, noninferiority trial in New Zealand in which 1310 adult daily smokers who were motivated to quit and called the national quitline were randomly assigned in a 1:1 ratio to receive Cytisine for 25 days or nicotine-replacement therapy for 8 weeks. Cytisine was provided by mail, free of charge, and nicotine-replacement therapy was provided through vouchers for low-cost patches along with gum or lozenges. Low-intensity, telephone-delivered behavioral support was provided to both groups through the quitline. The primary outcome was self-reported continuous abstinence at 1 month. RESULTS: At 1 month, continuous abstinence from smoking was reported for 40% of participants receiving Cytisine (264 of 655) and 31% of participants receiving nicotine-replacement therapy (203 of 655), for a difference of 9.3 percentage points (95% confidence interval, 4.2 to 14.5). The effectiveness of Cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months. In a prespecified subgroup analysis of the primary outcome, Cytisine was superior to nicotine-replacement therapy among women and noninferior among men. Self-reported adverse events over 6 months occurred more frequently in the Cytisine group (288 events among 204 participants) than in the group receiving nicotine-replacement therapy (174 events among 134 participants); adverse events were primarily nausea and vomiting and sleep disorders. CONCLUSIONS: When combined with brief behavioral support, Cytisine was found to be superior to nicotine-replacement therapy in helping smokers quit smoking, but it was associated with a higher frequency of self-reported adverse events. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12610000590066.).

Cytisine inhibits the anticonvulsant activity of phenytoin and lamotrigine in mice.[Pubmed:23563038]

Pharmacol Rep. 2013;65(1):195-200.

BACKGROUND: Cytisine (CYT), the most commonly used drug for smoking cessation in Poland, was experimentally found to induce convulsions. There is a lack of studies on the influence of CYT on the anticonvulsant activity of antiepileptic drugs (AEDs). METHODS: The effects of CYT on the anticonvulsant activity of six AEDs were examined in maximal electroshock (MES)-induced seizures in mice. RESULTS: Single intraperitoneal (ip) administration of CYT in a subthreshold dose of 2 mg/kg antagonized the protective activity of ip phenytoin and lamotrigine against MES-induced seizures in mice. A dose of 1 mg/kg did not reverse the protective activity of phenytoin and lamotrigine. CYT in a dose of 2 mg/kg had no effect on the anticonvulsive activity of carbamazepine, oxcarbazepine, phenobarbital, and valproate magnesium. CONCLUSION: CYT ability to antagonize the anticonvulsive activity of phenytoin and lamotrigine can be of serious concern for epileptic smokers, who might demonstrate therapeutic failure to these drugs resulting in possible breakthrough seizure attacks.

Cytisine-based nicotinic partial agonists as novel antidepressant compounds.[Pubmed:19164465]

J Pharmacol Exp Ther. 2009 Apr;329(1):377-86.

Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the beta2 subunit (beta2(*)), results in antidepressant-like effects. Previous studies have shown that Cytisine, a partial agonist at alpha4/beta2(*) nAChRs, and a full agonist at alpha3/beta4(*) and alpha7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models. We tested Cytisine and two derivatives, 5-bromo-Cytisine (5-Br-Cyt) and 3-(pyridin-3'-yl)-Cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at alpha4/beta2(*) nAChRS but had no agonist effects at other nAChRs normally targeted by Cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly. These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders.

Agonist and antagonist effects of cytisine in vivo.[Pubmed:25839895]

Neuropharmacology. 2015 Aug;95:206-14.

Varenicline, the most successful smoking cessation aid, is a selective partial agonists at alpha4beta2* nicotinic receptors. Its efficacy is likely to be shared by other drugs with similar receptor action, including Cytisine. The present study aimed to characterize behavioral effects of Cytisine compared with nicotine using locomotor activity tests, intracranial self-stimulation of ventral tegmental area (discrete-trial threshold current intensity titration procedure), drug discrimination (0.6 mg/kg nicotine from vehicle), physical dependence (osmotic minipumps delivering 6 mg/kg/day of nicotine) and intravenous nicotine self-administration (0.01 mg/kg per infusion) in adult Wistar rats. Cytisine (1-3 mg/kg) partially substituted for nicotine and at the highest dose tended to antagonize nicotine's discriminative stimulus effects. Nicotine (0.05-0.4 mg/kg), but not Cytisine (0.3-3 mg/kg), lowered ICSS thresholds and Cytisine dose-dependently reversed effects of nicotine. Nicotine (0.15-0.6 mg/kg), but not Cytisine (0.3-3 mg/kg), stimulated locomotor activity and Cytisine (3 mg/kg) fully reversed these effects of nicotine. Acute pretreatment with nicotine (0.15-0.6 mg/kg), but not Cytisine (0.3-3 mg/kg), reinstated extinguished nicotine self-administration. Continuous infusion of nicotine induced physical dependence, as indicated by reduced rates of food-reinforced responding induced by a challenge dose of mecamylamine. At the highest tested dose (3 mg/kg), Cytisine tended to reduce response rates irrespective of whether the rats were continuously exposed to nicotine or saline. Cytisine behaves like a weak partial agonist, mimicking effects of nicotine to a limited degree. Although Cytisine reversed several effects of nicotine, it seemed to have a reduced potential to produce withdrawal signs in nicotine-dependent subjects.

Cytisine confers neuronal protection against excitotoxic injury by down-regulating GluN2B-containing NMDA receptors.[Pubmed:23022271]

Neurotoxicology. 2013 Jan;34:219-25.

Cytisine (CYT), one of the principal bioactive components derived from the seeds of Cytisus laborinum L, has been widely used for central nervous system (CNS) diseases treatment. The present study investigated the protective effect of CYT on cultured cortical neural injury induced by N-methyl-d-aspartate (NMDA). Our data showed that CYT conferred protective effect against loss of cellular viability induced by brief exposure to 200 muM NMDA in a concentration-dependent manner. CYT significantly inhibited the neuronal apoptosis induced by NMDA exposure by reversing intracellular Ca(2+) overload and balancing Bcl-2 and Bax expression levels. Furthermore, CYT significantly reversed the up-regulation of GluN2B-containing NMDA receptors by exposure to NMDA, but it did not affect the level of GluN2A-containing NMDA receptors. These findings suggest that CYT protects cortical neurons, at least partially, by inhibiting the level of GluN2B-containing NMDA receptors and regulating Bcl-2 family.

Localization of nicotinic cholinergic receptors in rat brain: autoradiographic studies with [3H]cytisine.[Pubmed:7870314]

Neuroscience. 1994 Oct;62(3):929-44.

There is a great deal of interest in the role of nicotinic acetylcholine receptors in the central nervous system, although their function is not well understood at present. Currently, central nicotinic receptors can be classified broadly as either alpha-bungarotoxin binding sites with low affinity for acetylcholine agonists, or as high-affinity agonist binding sites with low affinity for alpha-bungarotoxin. Neuronal nicotinic receptors with a high affinity for agonists are distributed widely in the central nervous system. Evidence from molecular biology and electrophysiology suggests that multiple nicotinic receptor types exist in the brain. In this study we have used the agonist [3H]Cytisine as a ligand for autoradiography to generate a detailed quantitative map of the high-affinity agonist binding nicotinic receptor in the rat brain. Optimized binding conditions, characterization of the kinetic and equilibrium binding properties, and demonstration of the nicotinic pharmacology of this binding site in tissue sections confirm the usefulness of [3H]Cytisine as a ligand for nicotinic receptor autoradiography. [3H]Cytisine autoradiography provides excellent anatomic resolution with very low non-specific binding. This property has allowed us to describe variations in receptor density within subnuclei and gradients of receptor density in larger brain regions. Data from several studies suggest that the predominant high-affinity agonist binding nicotine receptor in the central nervous system is composed of the alpha 4 and beta 2 subunits. The data in the current study are consistent with the suggestion that [3H]Cytisine labels only the alpha 4 beta 2 nicotinic receptor with high affinity, offering the possibility of localizing a specific nicotinic receptor subtype in the central nervous system. In summary, we characterize the optimum experimental conditions for the use of [3H]Cytisine in tissue section autoradiography. [3H]Cytisine proves to be an excellent marker for nicotinic cholinergic receptors with a very high affinity and very low background. We provide a detailed quantitative characterization of nicotinic receptor density in the rat central nervous system and we find there are significant variations and gradients in receptor density within specific brain regions, including subregions previously thought to be homogeneous.

Partial agonist properties of cytisine on neuronal nicotinic receptors containing the beta 2 subunit.[Pubmed:8302273]

Mol Pharmacol. 1994 Jan;45(1):142-9.

As previously reported by Luetje and Patrick [J. Neurosci. 11:837-845 (1991)], the nicotine-like alkaloid Cytisine is relatively ineffective in evoking current responses from nicotinic receptors containing the beta 2 subunit. In our experiments, the responses of alpha 4 beta 2- and alpha 3 beta 2-injected oocytes to the application of 1 mM Cytisine were only 14.7 +/- 4% and 2.5 +/- 0.8% of the responses to 1 mM acetylcholine (ACh), respectively. Concentration-response relationships for ACh were examined in the presence and absence of Cytisine. Although Cytisine was relatively ineffective in stimulating current, the coapplication of Cytisine and ACh reduced the responses to ACh. For alpha 4 beta 2 receptors, 3 microM Cytisine shifted the dose-response curve for ACh to the right, resulting in a 60-fold increase in the apparent EC50 for ACh. For alpha 3 beta 2 receptors, 30 microM Cytisine shifted the apparent EC50 for ACh from approximately 150 microM to 1 mM. Although the efficacy of Cytisine for alpha 3 beta 2 receptors was very low, Cytisine could effectively inhibit the responses of these receptors, with an IC50 of approximately 10 microM. The efficacy of Cytisine for alpha 4 beta 2 receptors was greater than that for alpha 3 beta 2 receptors, and it was possible to evaluate the partial agonist properties of Cytisine for these receptors. Although the EC50 of Cytisine for stimulating current through alpha 4 beta 2 receptors was about 1 microM, concentrations of Cytisine as low as 20 nM were able to inhibit 50% of the response to 1 microM ACh. The inhibitory effects of Cytisine were reversible over a period of 5 min. Our analysis suggests that Cytisine is a true partial agonist for beta 2-containing ACh receptors and as such can inhibit the response of these receptors to ACh through a competitive mechanism. In the case of alpha 4 beta 2 receptors Cytisine binds with high apparent affinity and low efficacy to a site shared with ACh, and for alpha 3 beta 2 receptors both the apparent affinity and efficacy of Cytisine are relatively low.

Behavioural and pharmacokinetic studies on nicotine, cytisine and lobeline.[Pubmed:2385332]

Neuropharmacology. 1990 Jul;29(7):619-24.

Previous work has suggested that Cytisine and lobeline are of low potency in producing nicotine-like behavioural effects, despite having some nicotine-like peripheral effects and potently inhibiting the binding of tritiated nicotine to the brain of the rat. Rats were trained to discriminate nicotine from saline in a two-bar operant conditioning procedure with food reinforcement. It was confirmed that Cytisine had a nicotine-like discriminative effect, but it was much less potent than nicotine itself. Lobeline failed to produce a nicotine-like discriminative effect, even at doses that greatly reduced overall rates of responding. Neither drug attenuated discriminative responses to nicotine. The concentrations of drugs in plasma and brain were determined by HPLC in rats of the same sex, strain and age as those used in the behavioural experiments. The rank order of the ratios of concentrations in brain to plasma was lobeline greater than nicotine greater than Cytisine, which was directly proportional to their lipophilicity determined by reversed-phase HPLC. Based on the concentrations in brain and known affinities for high-affinity nicotine binding sites, in vivo tests should show Cytisine to be slightly more potent than nicotine and lobeline to have nicotine effects in the doses used. These predictions were not fulfilled and thus, the behavioural effects of Cytisine and lobeline cannot be correlated with their effects at the binding site for tritiated nicotine. Since pharmacokinetic factors do not account for this discrepancy, a pharmacodynamic explanation will be necessary.

Cytisinicline (Cytisine) is an alkaloid that occurs naturally in several plant genera, such as Laburnum and Cytisus. Cytisinicline (Cytisine) is a partial agonist of α4β2 nAChRs, and partial to full agonist at β4 containing receptors and α7 receptors. Has been used medically to help with smoking cessation.

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