Systematic review and meta-analyses of cytisine to support tobacco cessation.

BACKGROUND AND AIMS: Cytisine (also known as cytisinicline) is a low-cost partial agonist of nicotinic acetylcholine receptors used to assist tobacco cessation. We aimed to review the effectiveness of cytisine for tobacco cessation and the effects of dose and co-use of behavioural or other pharmacological interventions on cessation outcomes. METHODS: We searched seven databases, Google Scholar, and reference lists of included publications for randomised controlled trials investigating use of cytisine as a tobacco cessation aid. Studies were eligible if participants were ≥15 years old and used tobacco upon study enrolment. We conducted four random effects meta-analyses and sensitivity analyses with fixed effects models. We used the Cochrane risk-of-bias tool for randomised trials version 2 to assess risk of bias in included studies, with adjustments recommended by the Cochrane Tobacco Addiction Group. RESULTS: Participants using cytisine were significantly more likely to quit tobacco than participants who received placebo/no intervention/usual care (risk ratio [RR] = 2.65, 95% confidence interval [CI] = 1.50-4.67, 6 trials, 5194 participants) or nicotine replacement therapy (RR = 1.36, 95% CI = 1.06-1.73, p = 0.0152, 2 trials, 1511 participants). The difference in cessation rates among participants receiving cytisine versus varenicline was not statistically significant (RR = 0.96, 95% CI 0.63-1.45, P = 0.8464, 3 trials, 2508 participants). Two trials examined longer versus shorter treatment duration, finding higher abstinence rates with longer treatment (RR = 1.29, 95% CI = 1.02-1.63, 2 trials, 1009 participants). The differences in the number of adverse events reported by participants who received cytisine versus placebo (RR = 1.19, 95% CI = 0.99-1.41, P = 0.0624; 6 trials; 4578 participants) or cytisine versus varenicline (RR = 1.37, 95% CI = 0.57-3.33, P = 0.4835; 2 trials; 1345 participants) were not statistically significant. Most adverse events were mild (e.g. abnormal dreams, nausea, headaches). CONCLUSIONS: Cytisine is an effective aid for tobacco cessation and appears to be more effective for tobacco cessation than placebo, no intervention, usual care and nicotine replacement therapy.

Efficacy and safety of cytisine versus nortriptyline for smoking cessation: A multicentre, randomized, double-blinded and placebo-controlled trial.

BACKGROUND AND OBJECTIVE: Cytisine serves as an affordable smoking cessation aid with acceptable safety profile. However, data comparing its efficacy and safety to standard therapies are limited. We aimed to examine efficacy and safety of cytisine compared to nortriptyline, which is the only approved smoking-cessation medication in Thailand. METHODS: A 12-month, multicentre, randomized, double-blinded, placebo-controlled trial was conducted. Participants aged ≥20 years who smoked ≥10 cigarettes/day were randomly assigned to receive a 25-day cytisine or a 12-week nortriptyline treatment course. Brief interventions (BI) for smoking cessation were provided to all participants. The primary outcome was biochemically verified continuous abstinence rate (CAR) at 12 months. Additionally, self-reported abstinence, verified by exhaled carbon monoxide (CO) ≤ 10 ppm, was collected at 2 weeks, 1, 3, 6 and 12 months to assess both CAR and 7-day point prevalence abstinence rate (PAR). RESULTS: A total of 1086 participants were recruited and randomized into cytisine (n = 540) and nortriptyline (n = 546) groups. The 12-month CAR was 12.22% for cytisine and 9.52% for nortriptyline. The relative difference was 0.03 (95% confidence interval [CI]; -0.01 to 0.06) and the relative risk was 1.28 (95% CI; 0.91-1.81). No differences were observed in secondary outcomes between both groups. The incidence of adverse effects from cytisine appeared to be lower than that of nortriptyline. CONCLUSION: At 12 months, cytisine plus BI was as effective as nortriptyline plus BI for smoking cessation. The adverse events for both cytisine and nortriptyline were minimal and well-tolerated.

Alkaloid-Based Isoxazolylureas: Synthesis and Effect in Combination with Anticancer Drugs on C6 Rat Glioma Model Cells.

Alkaloid-based urea derivatives were produced with high yield through the reaction of anabasine and cytisine with isoxazolylphenylcarbamates in boiling benzene. Their antitumor activity, in combination with the commonly used five anticancer drugs, namely cyclophosphane, fluorouracil, etoposide, cisplatin, ribomustine with different mechanisms of action, was investigated. Based on the quantum chemical calculations data and molecular docking, hypotheses have been put forward to explain their mutual influence when affecting C6 rat glioma model cells.

[Prescription of drugs for smoking cessation. Retrospective analysis of the health area of Zamora]. / Prescripción de fármacos para la deshabituación tabáquica. Análisis retrospectivo del área de salud de Zamora.

OBJECTIVE: To analyze the prescription of drugs to aid smoking cessation and to detect whether there are differences by age or sex. DESIGN: Retrospective cohort study. SITE: Zamora Health Area. PARTICIPANTS: Persons with smoking cessation attempts employing drugs funded in the period from 2020 to 2023. INTERVENTIONS: Request of pharmaceutical consumption of varenicline, bupropion and cytisine to the Pharmacy Information System of the Regional Health Management of Castilla y León. MAIN MEASUREMENTS: Number of quit attempts per person, treatment drug, number of medication containers per attempt, year, age and sex. Descriptive and statistical analysis using SPSS© v. 20. RESULTS: 2581 people tried to quit smoking with drugs, 2206 made one attempt and 375 made several attempts. Mean age was 50.7 years (95% CI: 50.2-51.1). No significant differences were found for age (P=.71) or sex (P=.74). There was a preference for prescribing varenicline over bupropion and low drug compliance, with only one container of medication being collected in about 50% of cases. A total of 1680 attempts were made to quit using cytisine in 2023, equivalent to 55.4% of the total number of treatment drugs used in the four years. The estimated cumulative incidence rate of drug withdrawal attempts in smokers between 18 and 65 years of age was 11.9%. CONCLUSIONS: The drug intervention had a low reach and poor compliance with the recommended treatment. It is essential to emphasize patient follow-up and drug adherence.

The efficacy and acceptability of pharmacological monotherapies and e-cigarette on smoking cessation: a systemic review and network meta-analysis.

Background and aims: Several pharmacological interventions, such as nicotine replacement therapy (NRT), varenicline, and bupropion, have been approved for clinical use of smoking cessation. E-cigarettes (EC) are increasingly explored by many RCTs for their potentiality in smoking cessation. In addition, some RCTs are attempting to explore new drugs for smoking cessation, such as cytisine. This network meta-analysis (NMA) aims to investigate how these drugs and e-cigarettes compare regarding their efficacy and acceptability. Materials and methods: This systematic review and NMA searched all clinical studies on smoking cessation using pharmacological monotherapies or e-cigarettes published from January 2011 to May 2022 using MEDLINE, COCHRANE Library, and PsychINFO databases. NRTs were divided into transdermal (TDN) and oronasal nicotine (ONN) by administrative routes, thus 7 network nodes were set up for direct and indirect comparison. Two different indicators measured the efficacy: prevalent and continuous smoking abstinence. The drop-out rates measured the acceptability. Results: The final 40 clinical studies included in this study comprised 77 study cohorts and 25,889 participants. Varenicline is more effective intervention to assist in smoking cessation during 16-32 weeks follow-up, and is very likely to prompt dropout. Cytisine shows more effectiveness in continuous smoking cessation but may also lead to dropout. E-cigarettes and oronasal nicotine are more effective than no treatment in encouraging prevalent abstinence, but least likely to prompt dropout. Finally, transdermal nicotine delivery is more effective than no treatment in continuous abstinence, with neither significant effect on prevalent abstinence nor dropout rate. Conclusion: This review suggested and agreed that Varenicline, Cytisine and transdermal nicotine delivery, as smoking cessation intervention, have advantages and disadvantages. However, we had to have reservations about e-cigarettes as a way to quit smoking in adolescents.

Cytisine for smoking cessation: A 40-day treatment with an induction period.

INTRODUCTION: Cytisine is a smoking cessation drug now used worldwide. Most of the data available in the literature predict a 25-day treatment, accepted on the basis of previous clinical experience in Eastern Europe. There are few studies on dosing, and only recently some researchers have tried a longer treatment period. METHODS: This real-world retrospective cross-sectional study analyzed data collected consecutively from 2015 to 2021, in seven smoking cessation centers in north-central Italy. The aim of this study is to evaluate the effectiveness and tolerability of a 40-day cytisine treatment with an induction phase and a slower reduction schedule. Data were collected from a group of 871 patients treated with cysteine, varenicline, and nicotine replacement therapy (NRT). The sample was not randomized. Behavioral support (4-6 sessions, each lasting 20-30 min, plus the evaluation session) was delivered to all patients. RESULTS: Subgroups taking cytisine (n=543 for 40 days), varenicline (n=281 for 12 weeks), and NRT (n=47 for eight weeks) showed biochemically confirmed smoking abstinence at 6 months of 50.5%, 55.9%, and 51.0%, respectively, with a statistically significant difference between cytisine versus varenicline (p<0.01) but not between cytisine versus NRT (p=0.5597). Adverse events were 4.4% with cytisine and 33.3% with varenicline. Behavioral support was an important factor in effectiveness. CONCLUSIONS: This study produced preliminary evidence that the 40-day regimen of cytisine, appears to have less effectiveness in comparison to varenicline but the magnitude of the effect is comparable. The results and tolerability seem to be better than in most other studies.

Exploring the mechanism of cytisine in treating respiratory depression following venomous snake bites based on network pharmacology and molecular docking.

OBJECTIVE: To investigate the antivenom mechanism of cytisine through network pharmacology and molecular docking (MD) techniques, with the intention of exploring its clinical applications. METHODS: The cytisine target and the snakebite respiratory inhibition target were obtained using the Swiss Target Prediction platform and the Gene Cards database. The two target sets were overlapped to form a protein interaction network. Additionally, pathway enrichment analysis was conducted on cross targets, and the related pathways for the treatment of snake venom-induced respiratory failure were obtained. Verification of the MD between cytisine and its related targets was performed using the Autodock 1.5.7 software. The respiratory depression model of rats bitten by venomous snakes was established, and the expression of key target genes in the rat model was verified by western blot (WB). RESULT: A total of 16 targets of cytisine and 9 potential targets of cytisine in treating snake venom-induced respiratory depression were obtained. Core targets including CHRNA7, CHRNG, CHRNB1, CHRND, CHRNA1 and DRD2 were obtained. These targets are mainly enriched in neuroactive ligand-receptor interaction pathway and cholinergic synaptic pathway. The MD results demonstrated favorable docking activity of cytisine with its related targets. WB experiments showed that snake venom reduced the levels of CHRNA7 and CHRNG. Treatment with serum and cytisine could slow down this decline. CONCLUSION: Cytisine may synergistically target CHRNA7, CHRNG, CHRNB1, CHRND, CHRNA1, DRD2 and other proteins, modulating cholinergic and neuroactive pathways to alleviate neuromuscular block and protect acetylcholine receptors.

Cytisine eye drops for benzalkonium chloride-induced dry eye: safety and efficacy evaluation.

This experiment aimed to investigate the feasibility of cytisine (CYT) in treating eye diseases with ocular topical application. An in vitro cytotoxicity test, a hen's egg test-chorioallantoic membrane (HET-CAM), and a mouse eye tolerance test were used to fully reveal the ocular safety profiles of CYT. For the efficacy evaluations, CYT's effects on cell wound healing, against H2O2-induced oxidative stress damages on cells, and on benzalkonium chloride (BAC)-induced dry eye disease (DED) in mice were evaluated. Results showed that CYT did not show any cytotoxicities at concentrations no higher than 250 µg/ml, while lipoic acid (α-LA) at 250 µg/ml and BAC at 1.25 µg/ml showed significant cytotoxicities within 48 h incubation. The HET-CAM and mouse eye tolerance test confirmed that 0.5% CYT eye drops demonstrated good safety characteristics. Efficacy evaluations showed that CTY significantly promoted cell migration and wound healing. CYT significantly improved cell survival against H2O2-induced oxidative stress damage by reversing the imbalance between the reactive oxygen species (ROS) and antioxidant defense mechanisms. The animal evaluation of the BAC-induced dry eye model revealed that CYT demonstrated a strong treatment effect, including reversing ocular surface damages, recovering corneal sensitivity, and inhibiting neovascularization; HMGB1/NF-κB signaling was involved in this DED treatment by CTY. In conclusion, CYT had strong experimental treatment efficacy against DED with good ocular safety profiles, and it might be a novel and promising drug for DED.

Cytisine-N-methylene-(5,7,4'-trihydroxy)- isoflavone ameliorates ischemic stroke-induced brain injury in mouse by regulating the oxidative stress and BDNF-Trkb/Akt pathway.

BACKGROUND: A novel compound Cytisine-N-methylene-(5,7,4'-trihydroxy)- isoflavone (LY01) found in the Sophora alopecuroides L is a neuroprotective agent. However, the effect and potential mechanism of LY01 treatment for ischemic stroke (IS) have not been fully elucidated. AIM OF THE STUDY: The aim of this study is to demonstrate whether LY01 can rescue ischemic stroke-induced brain injury and oxygen-glucose deprivation/reperfusion (OGD/R). RESULTS: Our results show that intragastric administration of LY01 improves ischemic stroke behaviors in mice, as demonstrated by neurological score, infarct volume, cerebral water content, rotarod test for activity. Compared with the model group, the ginkgo biloba extract (EGb) and LY01 reversed the neurological score, infarct volume, cerebral water content, rotarod test in model mice. Further analysis showed that the LY01 rescued oxidative stress in the model mice, which was reflected in the increased levels of catalase, superoxide dismutase, total antioxidant capacity and decreased levels of malondialdehyde in the serum of the model mice. Moreover, the expression of the brain-derived neurotrophic factor brain-derived neurotrophic factor (BDNF), phosphorylated protein kinase B (p-Akt), Bax, Bcl-2, (p)-tropomysin related kinase B (p-Trkb) was restored and the expression of Bax, glial fibrillary acidic protein (GFAP) in the brains of the model mice was inhibited through LY01 treatment. In the polymerase chain reaction (PCR) data, after giving LY01, the expression in the brains of model mice was that, IL-10 increased and IL-1ß, Bax, Bcl-2 decreased. Furthermore, the results indicated that LY01 improved cell viability, reactive oxygen species content, and mitochondrial membrane potential dissipation induced by OGD/R in primary culture of rat cortical neurons. Bax and caspase-3 activity was upregulated compared to the before after treatment with LY01. CONCLUSIONS: Our study suggests that LY01 reversed ischemic stroke by reducing oxidative stress and activating the BDNF-TrkB/Akt pathway and exerted a neuroprotective action against OGD/R injury via attenuation, a novel approach was suggested to treat ischemic stroke. Our observations justify the traditional use of LY01 for a treatment of IS in nervous system.

Evaluation of the effectiveness of cytisine for the treatment of smoking cessation: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Smoking is considered the main cause of preventable death world-wide. This study aimed to review the efficacy and safety of cytisine for smoking cessation. METHODS: This review included an exhaustive search of databases to identify randomized controlled trials (RCTs) in health centers of any level with smokers of any age or gender investigating the effects of cytisine at standard dosage versus placebo, varenicline or nicotine replacement therapy (NRT). RESULTS: We identified 12 RCTs. Eight RCTs compared cytisine with placebo at the standard dose covering 5922 patients, 2996 of whom took cytisine, delivering a risk ratio (RR) of 2.25 [95% confidence interval (CI) = 1.42-3.56; I2  = 88%; moderate-quality evidence]. The greater intensity of behavioral therapy was associated directly with the efficacy findings (moderate-quality evidence). The confirmed efficacy of cytisine was not evidenced in trials conducted in low- and middle-income countries. We estimate a number needed to treat (NNT) of 11. Two trials compared the efficacy of cytisine versus NRT, and the combination of both studies yields modest results in favor of cytisine. Three trials compared cytisine with varenicline, without a clear benefit for cytisine. Meta-analyses of all non-serious adverse events in the cytisine group versus placebo groups yielded a RR of 1.24 (95% CI = 1.11-1.39; participants = 5895; studies = 8; I2 = 0%; high-quality evidence). CONCLUSIONS: Cytisine increases the chances of successful smoking cessation by more than twofold compared with placebo and has a benign safety profile, with no evidence of serious safety concerns. Limited evidence suggests that cytisine may be more effective than nicotine replacement therapy, with modest cessation rates.

Cytisine: State of the art in pharmacological activities and pharmacokinetics.

Cytisine is a naturally occurring bioactive compound, an alkaloid mainly isolated from legume plants. In recent years, various biological activities of cytisine have been explored, showing certain effects in smoking cessation, reducing drinking behavior, anti-tumor, cardiovascular protection, blood sugar regulation, neuroprotection, osteoporosis prevention and treatment, etc. At the same time, cytisine has the advantages of high efficiency, safety, and low cost, has broad development prospects, and is a drug of great application value. However, a summary of cytisine's biological activities is currently lacking. Therefore, this paper summarizes the pharmacological action, mechanism, and pharmacokinetics of cytisine by referring to numerous databases, and analyzes the new and core targets of cytisine with the help of computer simulation technology, to provide reference for doctors.

Anti-smoking drugs cytisine and varenicline reduce cardiac reperfusion injury in rat model of myocardial ischemia.

Evidence to date indicates that activation of nicotinic acetylcholine receptors (nAChRs) can reduce cardiac injury from ischemia and subsequent reperfusion. The use of nAChR agonists in various animal models leads to a reduction in reperfusion injury. Earlier this effect was shown for the agonists of α7 nAChR subtype. In this work, we demonstrated the expression of mRNA encoding α4, α6 and ß2 nAChR subunits in the left ventricle of rat heart. In a rat model of myocardial ischemia, we studied the effect of α4ß2 nAChR agonists cytisine and varenicline, medicines used for the treatment of nicotine addiction, and found them to significantly reduce myocardium ischemia-reperfusion injury, varenicline manifesting a higher protection. Dihydro-ß-erythroidine, antagonist of α4ß2 nAChR, as well as methyllycaconitine, antagonist of α7 and α6ß2-containing nAChR, prevented protective effect of varenicline. This together with the presence of α4, α6 and ß2 subunit mRNA in the left ventricule of rat heart raises the possibility that the varenicline effect is mediated by α4ß2 as well as by α7 and/or α6ß2-containing receptors. Our results point to a new way for the use of cytisine and varenicline as cardioprotective agents.

Cytisine as a smoking cessation aid: Preliminary observations with a modified therapeutic scheme in real life.

INTRODUCTION: Cigarette smoke accounts for over 90,000 deaths each year in Italy. Tobacco dependence treatment guidelines suggest adopting an integrated pharmacological-behavioral model of intervention. Cytisine is a partial agonist of nicotinic receptors. Trials conducted to date have demonstrated its good efficacy in promoting smoking cessation. The cytisine scheme of treatment consists of 25 days of treatment. A 40-day regimen, with an escalating dose and an extended duration of the treatment, has been in use in many anti-smoking centers in Italy for several years, but to date there are no reports on the use of cytisine with this scheme. METHODS: A retrospective, real-life, observational study was conducted between January 2016 and September 2022. The 300 patients who had received at least one dose of study medication were selected. Continuous variables were compared by the Wilcoxon-Mann-Whitney test. Univariate and multivariate logistic regression models were implemented for self-reported seven-day point prevalence for abstinence at three, six and 12 months. RESULTS: The median age of the patients was 59 years, 57% were women. The median smoking exposure was 33.8 pack-years. Self-reported smoking abstinence at three, six and 12 months was 68.7%, 56.3% and 47.3% respectively. 84% completed the cytisine treatment, 31.3% reported adverse events and in 8.3% these led to dropping out of the treatment. CONCLUSION: Cytisine, administered with a novel therapeutic scheme in the real-life setting of a specialized anti-smoking center, significantly promotes smoking abstinence. However, more studies are needed to assess the tolerability and efficacy of this new regimen.

Obstructive Sleep Apnea and Smoking Increase the Risk of Cardiovascular Disease: Smoking Cessation Pharmacotherapy.

Tobacco smoking has been a recognized risk factor for cardiovascular diseases (CVD). Smoking is a chronic relapsing disease and pharmacotherapy is a main component of smoking cessation. Obstructive sleep apnea (OSA) and smoking both increase the risk of CVD and are associated with significant morbidity and mortality. There are few existing data examining how pharmacological treatment, such as nicotine replacement therapy (NRT), bupropion, and varenicline, affect smokers suffering with OSA and especially their cardiovascular effects. The aim of this review was to evaluate the effects of smoking cessation pharmacotherapy on OSA with a special emphasis on the cardiovascular system. Results: Only small studies have assessed the effect of NRTs on OSA. Nicotine gum administration showed an improvement in respiratory events but with no permanent results. No specific studies were found on the effect of bupropion on OSA, and a limited number evaluated varenicline's effects on sleep and specifically OSA. Varenicline administration in smokers suffering from OSA reduced the obstructive respiratory events, especially during REM. Studies on second-line medication (nortriptyline, clonidine, cytisine) are even more limited. There are still no studies evaluating the cardiovascular effects of smoking cessation medications on OSA patients. Conclusions: Sleep disturbances are common withdrawal effects during smoking cessation but could be also attributed to pharmacotherapy. Smokers should receive personalized treatment during their quitting attempts according to their individual needs and problems, including OSA. Future studies are needed in order to evaluate the efficacy and safety of smoking cessation medications in OSA patients.

Assessment of cytisine as an insecticide candidate for Hyphantria cunea management: Toxicological, biochemical, and control potential insights.

In the present study, the toxicological effects of cytisine on the H. cunea larvae were investigated, and the potential of cytisine as a botanical insecticide through field simulation experiments was evaluated. The results showed that cytisine treatment (0.25-2.5%) exerted significant biotoxic effects on the H. cunea larvae, including diminished weight, disruption of both positive (HcCKS1, HcPLK, HcCCNA) and negative (HcGADD and HcCDKN) regulatory genes associated with larval growth, increased mortality, and heightened oxidative damage (H2O2 and MDA). Cytisine treatment significantly reduced glucose content and inhibited the expression of key rate-limiting enzyme genes (HcPFK, HcPK, HcHK1, HcCS, and HcIDH2) within glycolysis and the tricarboxylic acid cycle pathways. Under cytisine treatment, detoxification enzyme activities (CarE and GST) and expression of detoxification genes (HcCarE1, HcCarE2, HcCarE3, HcGST1, and HcGST3) were inhibited in H. cunea larvae. An increased contents of SOD, CAT, ASA and T-AOC, as well as expression of antioxidant enzyme genes HcSOD1 and HcCAT2, was found in cytisine-treated H. cunea larvae. Simultaneously, this is accompanied by a significant reduction in the expression of four antioxidant enzyme genes (e.g., HcPOD1 and HcPOD2). In the field experiment, a cytisine aqueous solution (25 g/L) with pre-sprayed and directly sprayed ways demonstrated potent insecticidal activity against H. cunea larvae, achieving a mortality rate of 53.75% and 100% at 24 h, respectively. Taken together, cytisine has significantly weight inhibition and lethal toxicity on the H. cunea larvae, and can be developed as a botanical insecticide for H. cunea control.

Development and Validation of LC-MS/MS Method for Determination of Cytisine in Human Serum and Saliva.

Cytisine (CYT) is a quinolizidine alkaloid used for nicotine addiction treatment. Recent clinical trial data regarding cytisine confirm its high effectiveness and safety as a smoking cessation treatment. CYT's popularity is growing due to its increased availability and licensing in more countries worldwide. This increased use by smokers has also resulted in an urgent need for continued drug research, including developing appropriate analytical methods for analyzing the drug in biological samples. In this study, a simple, fast, and reliable method combining hydrophilic interaction liquid chromatography and electrospray ionization quadrupole time of flight mass spectrometry (HILIC/ESI-QTOF-MS) for the determination of CYT in human serum and saliva was developed and validated. This was undertaken after the previous pre-treatment of the sample using solid-phase extraction (SPE). A hydrophilic interaction liquid chromatography (HILIC) column with a silica stationary phase was used for chromatographic analysis. In a linear gradient, the mobile phase consisted of acetonitrile (ACN) and formate buffer at pH 4.0. The proposed method was fully validated and demonstrated its sensitivity, selectivity, precision, and accuracy. The method was successfully applied to determine CYT in serum and, for the first time, in saliva. The findings indicate that saliva could be a promising non-invasive alternative to measure the free concentration of CYT.

Further Quinolizidine Derivatives as Antiarrhythmic Agents- 3.

Fourteen quinolizidine derivatives, structurally related to the alkaloids lupinine and cytisine and previously studied for other pharmacological purposes, were presently tested for antiarrhythmic, and other cardiovascular effects on isolated guinea pig heart tissues in comparison to well-established reference drugs. According to their structures, the tested compounds are assembled into three subsets: (a) N-(quinolizidinyl-alkyl)-benzamides; (b) 2-(benzotriazol-2-yl)methyl-1-(quinolizidinyl)alkyl-benzimidazoles; (c) N-substituted cytisines. All compounds but two displayed antiarrhythmic activity that was potent for compounds 4, 1, 6, and 5 (in ascending order). The last compound (N-(3,4,5-trimethoxybenzoyl)aminohomolupinane) was outstanding, exhibiting a nanomolar potency (EC50 = 0.017 µM) for the increase in the threshold of ac-arrhythmia. The tested compounds shared strong negative inotropic activity; however, this does not compromise the value of their antiarrhythmic action. On the other hand, only moderate or modest negative chronotropic and vasorelaxant activities were commonly observed. Compound 5, which has high antiarrhythmic potency, a favorable cardiovascular profile, and is devoid of antihypertensive activity in spontaneously hypertensive rats, represents a lead worthy of further investigation.

Cytisine for smoking cessation: A systematic review and meta-analysis.

BACKGROUND: Cytisine is a smoking cessation medication. This systematic review incorporates recently published randomized controlled trials (RCTs) to provide an updated evidence-based assessment of cytisine's efficacy and safety. METHODS: We searched Cochrane Library, MEDLINE, and EMBASE, for RCTs comparing cytisine to other smoking cessation treatments in adults who smoke. PRIMARY OUTCOME: 6-month biochemically verified continuous abstinence. Other outcomes: abstinence at longest follow-up, adverse events, mortality, and health-related quality of life (HRQOL). We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess evidence certainty. RESULTS: We included 14 RCTs involving 9953 adults. Cytisine was superior to placebo (risk ratio [RR] 2.25, 95% confidence interval [CI] 1.13-4.47; 5 RCTs, 4325 participants), but not varenicline (RR 1.13, 95% CI 0.65-1.95; 2 RCTs, 2131 participants) for the primary outcome. Cytisine was superior to placebo (RR 2.78, 95% CI 1.64-4.70; 8 RCTs, 5762 participants) and nicotine replacement therapy [NRT] (RR 1.39, 95% CI 1.12-1.73; 2 RCTs, 1511 participants), but not varenicline (RR 1.02, 95% CI 0.72-1.44; 4 RCTs, 2708 participants) for abstinence at longest follow-up. Cytisine increased mostly gastrointestinal adverse events compared to placebo (RR 1.15; 95% CI 1.06-1.25; 8 RCTs, 5520 participants) and NRT (RR 1.52, 95% CI 1.26-1.84; 1 RCT, 1310 participants) but less adverse events compared to varenicline (RR 0.67; 95% CI 0.48-0.95; 3 RCTs, 2484 participants). CONCLUSION: Cytisine shows greater efficacy than placebo and NRT, but more adverse events. It is comparable to varenicline, with fewer adverse events. This can inform clinicians and guidelines on cytisine for smoking cessation.