In-cell NMR suggests that DNA i-motif levels are strongly depleted in living human cells.

I-Motifs (iM) are non-canonical DNA structures potentially forming in the accessible, single-stranded, cytosine-rich genomic regions with regulatory roles. Chromatin, protein interactions, and intracellular properties seem to govern iM formation at sites with i-motif formation propensity (iMFPS) in human cells, yet their specific contributions remain unclear. Using in-cell NMR with oligonucleotide iMFPS models, we monitor iM-associated structural equilibria in asynchronous and cell cycle-synchronized HeLa cells at 37 °C. Our findings show that iMFPS displaying pHT < 7 under reference in vitro conditions occur predominantly in unfolded states in cells, while those with pHT > 7 appear as a mix of folded and unfolded states depending on the cell cycle phase. Comparing these results with previous data obtained using an iM-specific antibody (iMab) reveals that cell cycle-dependent iM formation has a dual origin, and iM formation concerns only a tiny fraction (possibly 1%) of genomic sites with iM formation propensity. We propose a comprehensive model aligning observations from iMab and in-cell NMR and enabling the identification of iMFPS capable of adopting iM structures under physiological conditions in living human cells. Our results suggest that many iMFPS may have biological roles linked to their unfolded states.

Effect of moxibustion combined with intraperitoneal injection of benazepril on endoplasmic reticulum stress-related protein phosphorylation in rats with chronic heart failure. / è‰¾ç¸è”åˆè´é‚£æ™®åˆ©å¯¹æ ¢æ€§å¿ƒåŠ›è¡°ç«­å¤§é¼ å¿ƒè‚Œå† è´¨ç½‘åº”æ¿€ç›¸å ³è›‹ç™½ç£·é ¸åŒ–è¡¨è¾¾çš„å½±å“.

OBJECTIVES: To observe the effect of moxibustion at "Xinshu"(BL15) and "Feishu"(BL13) combined with intraperitoneal injection of benazepril on cardiac function and phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2α (elF2α) proteins in myocardium of rats with chronic heart failure (CHF), so as to explore its potential mechanism underlying improvement of CHF. METHODS: A total of 42 male SD rats were randomly assigned to blank control (n=10), CHF model (n=7), medication (benazepril, n=8), moxibustion (n=8) and moxibustion+benazepril (n=9) groups, after cardiac ultrasound model identification and elimination of the dead. The CHF model was established by intraperitoneal injection of doxorubicin hydrochloride (DOX), once every week for 6 weeks. Mild moxibustion was applied to bilateral BL15 and BL13 regions for 20 min, once daily for 3 weeks. The rats of the medication group and moxibustion+benazepril group (benazepril was given first, followed by moxibustion) received intraperitoneal injection of benazepril (0.86 mg/kg) solution once daily for 3 weeks . The cardiac ejection fraction (EF) and left ventricular fractional shortening (FS) were measured using echocardiography. Histopathological changes of the cardiac muscle tissue were observed under light microscope after hematoxylin-eosin (H.E.) staining. Serum contents of B-type brain natriuretic peptide (BNP) and angiotensin Ⅱ (AngⅡ) were measured by enzyme-linked immunosorbent assay (ELISA). The expressions of phospho-PERK (p-PERK) and phospho-elF2α (p-elF2α) in the myocardium were detected by Western blot. RESULTS: Compared with the blank control group, the EF and FS of the left cardiac ventricle were significantly decreased (P<0.01), while the contents of serum BNP and AngⅡ, and expression levels of p-PERK and p-eIF2α significantly increased in the model group (P<0.01). In comparison with the model group, both the decreased EF and FS and the increased BNP and AngⅡ contents as well as p-PERK and p-elF2α expression levels were reversed by moxibustion, medication and moxibustion+benazepril (P<0.01). The effects of moxibustion+benazepril were markedly superior to those of simple moxibustion and simple medication in raising the levels of EF and FS rate and in down-regulating the contents of BNP, Ang Ⅱ, levels of p-PERK and p-elF2α (P<0.01, P<0.05). Outcomes of H.E. staining showed irregular arrangement of cardiomyocytes, cell swelling, vacuole and inflammatory infiltration in the model group, which was relatively milder in the 3 treatment groups. The effects of moxibustion+benazepril were superior to those of moxibustion or benazepril. CONCLUSIONS: Moxibustion combined with Benazepril can improve the cardiac function in CHF rats, which may be related to its functions in down-regulating the expression levels of myocardial p-PERK and p-elF2α to inhibit endoplasmic reticulum stress response.

Blocking the dopaminergic receptors within the hippocampal dentate gyrus reduced analgesic responses induced by restraint stress in the formalin test.

Previous studies have shown that various receptors, including dopamine receptors, are expressed in the hippocampal dentate gyrus (DG). Besides, indicatively, dopamine receptors play an essential role in the modulation of pain perception. On the other hand, stressful experiences can produce analgesia, termed stress-induced analgesia (SIA). The current study examined the probable role of dopamine receptors within the DG in antinociception induced by restraint stress (RS). Ninety-seven male albino Wistar rats were unilaterally implanted with a cannula in the DG. Animals received intra-DG microinjections of SCH23390 or Sulpiride (0.25, 1, and 4 µg/rat) as D1-and D2-like dopamine receptor antagonists, respectively, five minutes before RS. Ten minutes after the end of the induction of RS for three hours, 50 µl 2.5% formalin was injected subcutaneously into the plantar surface of the hind paw to induce persistent inflammatory pain. Pain scores were evaluated at 5-minute intervals for 60 minutes. These findings showed that; exposure to RS for three hours produced SIA in both phases of the formalin test, while this RS-induced analgesia was attenuated in the early and late phases of the formalin test by intra-DG microinjection of SCH23390 and Sulpiride. The results of the present study suggested that both D1- and D2-like dopamine receptors in the DG have a considerable role in the induced analgesia by RS.

Long-Term Effects of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Predictors of Treatment Response and Safety over 6 Years of Continuous Therapy.

Tolvaptan, an oral vasopressin V2 receptor antagonist, reduces renal volume expansion and loss of renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Data for predictive factors indicating patients more likely to benefit from long-term tolvaptan are lacking. Data were retrospectively collected from 55 patients on tolvaptan for 6 years. Changes in renal function, progression of renal dysfunction (estimated glomerular filtration rate [eGFR], 1-year change in eGFR [ΔeGFR/year]), and renal volume (total kidney volume [TKV], percentage 1-year change in TKV [ΔTKV%/year]) were evaluated at 3-years pre-tolvaptan, at baseline, and at 6 years. In 76.4% of patients, ΔeGFR/year improved at 6 years. The average 6-year ΔeGFR/year (range) minus baseline ΔeGFR/year: 3.024 (-8.77-20.58 mL/min/1.73 m2). The increase in TKV was reduced for the first 3 years. A higher BMI was associated with less of an improvement in ΔeGFR (p = 0.027), and family history was associated with more of an improvement in ΔeGFR (p = 0.044). Hypernatremia was generally mild; 3 patients had moderate-to-severe hyponatremia due to prolonged, excessive water intake in response to water diuresis-a side effect of tolvaptan. Family history of ADPKD and baseline BMI were contributing factors for ΔeGFR/year improvement on tolvaptan. Hyponatremia should be monitored with long-term tolvaptan administration.

Antitumoral Potential of the Histone Demethylase Inhibitor GSK-J4 in Retinoblastoma.

Purpose: The purpose of this study was to investigate the antitumor effects of GSK-J4 on retinoblastoma, as well as its related biological functions and molecular mechanisms. Methods: The antitumor effect of GSK-J4 on retinoblastoma was evaluated by in vitro and in vivo assays. CCK-8, EdU incorporation, and soft agar colony formation assays were performed to examine the effect of GSK-J4 on cell proliferation. Flow cytometry was used to evaluate the effect of GSK-J4 on the cell cycle and apoptosis. RNA-seq and Western blotting were conducted to explore the molecular mechanisms of GSK-J4. An orthotopic xenograft model was established to determine the effect of GSK-J4 on tumor growth. Results: GSK-J4 significantly inhibited retinoblastoma cell proliferation both in vitro and in vivo, arrested the cell cycle at G2/M phase, and induced apoptosis. Mechanistically, GSK-J4 may suppress retinoblastoma cell growth by regulating the PI3K/AKT/NF-κB signaling pathway. Conclusions: The antitumor effects of GSK-J4 were noticeable in retinoblastoma and were at least partially mediated by PI3K/AKT/NF-κB pathway suppression. Our study provides a novel strategy for the treatment of retinoblastoma.

No major effect of dopamine receptor 1/5 antagonist SCH-23390 on epileptic activity in the Tg2576 mouse model of amyloidosis.

The excitation-inhibition imbalance manifesting as epileptic activities in Alzheimer's disease is gaining more and more attention, and several potentially involved cellular and molecular pathways are currently under investigation. Based on in vitro studies, dopamine D1-type receptors in the anterior cingulate cortex and the hippocampus have been proposed to participate in this peculiar co-morbidity in mouse models of amyloidosis. Here, we tested the implication of dopaminergic transmission in vivo in the Tg2576 mouse model of Alzheimer's disease by monitoring epileptic activities via intracranial EEG before and after treatment with dopamine antagonists. Our results show that neither the D1-like dopamine receptor antagonist SCH23390 nor the D2-like dopamine receptor antagonist haloperidol reduces the frequency of epileptic activities. While requiring further investigation, our results indicate that on a systemic level, dopamine receptors are not significantly contributing to epilepsy observed in vivo in this mouse model of Alzheimer's disease.

Effectiveness and safety of ivabradine in Chinese patients with chronic heart failure: an observational study.

AIMS: A therapeutic strategy for chronic heart failure (HF) is to lower resting heart rate (HR). Ivabradine is a well-known HR-lowering agent, but limited prospective data exist regarding its use in Chinese patients. This study aimed to evaluate the effectiveness and safety of ivabradine in Chinese patients with chronic HF. METHODS AND RESULTS: This multicentre, single-arm, prospective, observational study enrolled Chinese patients with chronic HF. The primary outcome was change from baseline in HR at 1 and 6 months, measured by pulse counting. Effectiveness was also evaluated using laboratory tests, the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS) and overall summary score (OSS), and New York Heart Association (NYHA) class. Treatment-emergent adverse events (TEAEs) were assessed. A post hoc analysis examined the effectiveness and safety of ivabradine combined with an angiotensin receptor-neprilysin inhibitor (ARNI) or beta-blocker. A total of 1003 patients were enrolled [mean age 54.4 ± 15.0 years, 773 male (77.1%), mean baseline HR 88.5 ± 11.3 b.p.m., mean blood pressure 115.7/74.4 ± 17.2/12.3 mmHg, mean left ventricular ejection fraction 30.9 ± 7.6%, NYHA Classes III and IV in 48.8% and 22.0% of patients, respectively]. HR decreased by a mean of 12.9 and 16.1 b.p.m. after 1 and 6 months, respectively (both P < 0.001). At Month 6, improvements in the KCCQ CSS and OSS of ≥5 points were observed in 72.1% and 74.1% of patients, respectively (both P < 0.001). Left ventricular ejection fraction increased by 12.1 ± 11.6 (P < 0.001), and 66.7% of patients showed improvement in NYHA class (P < 0.001). At Month 6, the overall proportion of patients in NYHA Classes III and IV was reduced to 13.5% and 2.1%, respectively. Serum brain natriuretic peptide (BNP) and N-terminal pro-BNP changed by -331.9 ng/L (-1238.6, -134.0) and -1113.8 ng/L (-2202.0, -297.2), respectively (P < 0.001). HR reductions and improvements in NYHA and KCCQ scores with ivabradine were similar with and without use of ARNIs or beta-blockers. Of 498 TEAEs in 296 patients (29.5%), 73 TEAEs in 55 patients (5.5%) were considered related to ivabradine [most frequent sinus bradycardia (n = 7) and photopsia (n = 7)]. TEAEs were reported in a similar number of patients in ARNI and beta-blocker subgroups (21.9-35.6%). CONCLUSIONS: Ivabradine treatment reduced HR and improved cardiac function and health-related quality of life in Chinese patients with chronic HF. Benefits were seen irrespective of whether or not patients were also taking ARNIs or beta-blockers. Treatment was well tolerated with a similar profile to previous ivabradine studies.

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.

A randomized, double-blind, placebo-controlled, multicentre trial on the efficacy of varenicline and bupropion in combination and alone for treatment of alcohol use disorder: Protocol for the COMB study.

BACKGROUND: Alcohol Use Disorder (AUD) is a major cause of premature death, disability and suffering. Available treatments are of modest efficacy and under-prescribed so there is a pressing need for a well-tolerated and effective treatment option for AUD. Dopamine is hypothesized to be involved in the development of alcohol dependence. To challenge the low-dopamine hypothesis of addiction, this randomized, double-blind, placebo-controlled, 13-week, multicentre clinical trial with four parallel arms is designed to evaluate the efficacy of two substances raising dopamine levels, varenicline and bupropion, alone and in combination vs. placebo on alcohol consumption in AUD. Varenicline, a partial agonist at brain nicotinic acetylcholine receptors increases dopamine release, whereas bupropion is a centrally-acting, norepinephrine-dopamine reuptake inhibitor. Varenicline is previously shown to reduce alcohol intake in individuals with AUD. We hypothesize that the effect size of a combination of two drugs affecting dopamine levels in the brain will exceed that of approved AUD therapies. METHODS: Consenting individuals with AUD will be recruited via media advertisements. Those fulfilling the eligibility criteria (N = 380) will be randomized to one of four interventions (n = 95 per arm). Treatment will comprise one week of titration (varenicline 0.5‒2 mg; bupropion SR 150‒300 mg) plus 12 weeks at steady state. Efficacy will be evaluated using two primary endpoints of alcohol consumption: Heavy Drinking Days and blood levels of phosphatidylethanol. Secondary objectives, exploratory and subgroup analyses will be also performed. The modified Intention-to-Treat and Per Protocol datasets will be evaluated using Analysis of Covariance. Last patient out is estimated to occur in December, 2022. DISCUSSION: The COMB Study aims to evaluate the efficacy of the combination of varenicline and bupropion, two drugs affecting dopamine, on alcohol consumption, and to challenge the low-dopamine hypothesis of addiction. Study Code COMB-BO8, EudraCT 2018-000048-24, Version 3.2, Lidö & deBejczy, 2020-06-16; https://clinicaltrials.gov identifier NCT04167306.

Hyperpolarization-activated cyclic nucleotide-gated channel inhibitor in myocardial infarction: Potential benefits beyond heart rate modulation.

Myocardial infarction (MI) and its associated complications including ventricular arrhythmias and heart failure are responsible for a significant incidence of morbidity and mortality worldwide. The ensuing cardiomyocyte loss results in neurohormone-driven cardiac remodeling, which leads to chronic heart failure in MI survivors. Ivabradine is a heart rate modulation agent currently used in treatment of chronic heart failure with reduced ejection fraction. The canonical target of ivabradine is the hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in cardiac pacemaker cells. However, in post-MI hearts, HCN can also be expressed ectopically in non-pacemaker cardiomyocytes. There is an accumulation of intriguing evidence to suggest that ivabradine also possesses cardioprotective effects that are independent of heart rate reduction. This review aims to summarize and discuss the reported cardioprotective mechanisms of ivabradine beyond heart rate modulation in myocardial infarction through various molecular mechanisms including the prevention of reactive oxygen species-induced mitochondrial damage, improvement of autophagy system, modulation of intracellular calcium cycling, modification of ventricular electrophysiology, and regulation of matrix metalloproteinases.

Results of a randomized, double-blind, placebo-controlled trial of lorcaserin in cocaine use disorder.

BACKGROUND: Cocaine use disorder (CUD) is a major public health problem for which there is no approved pharmacotherapy. The primary purpose of this study was to evaluate the ability of lorcaserin, a 5-hydroxytryptamine2 C (5-HT2 C) receptor agonist, to facilitate abstinence in individuals seeking treatment for CUD. METHODS: This was a 12-site, randomized, parallel arm study with a 13-week Treatment Phase that included a 1-week, single-blind run-in period when all participants received twice daily 15mg acetazolamide capsules (a medication adherence marker), followed by randomization to either twice daily 10mg lorcaserin or placebo capsules for the remaining 12 weeks. Pre-randomization data were utilized in an enrichment strategy aimed at achieving high levels of medication adherence and low placebo response rates in a subgroup of participants that qualified for the "efficacy population." For lorcaserin vs. placebo, the primary efficacy endpoint was the proportion of participants in the efficacy population achieving abstinence during the last three weeks of treatment, as evidenced by self-report of no cocaine use, confirmed by urine testing. RESULTS: Within the efficacy population, 1.1% of 91 participants receiving lorcaserin and 4.3% of 92 receiving placebo achieved abstinence during the last 3 weeks of treatment. Among all randomized participants, 2.5% of 118 receiving lorcaserin and 5.6% of 124 receiving placebo achieved similar abstinence. Study participants receiving lorcaserin exhibited significantly greater reductions in body weight and BMI, indicating that medication adherence was sufficient to produce a pharmacological effect. CONCLUSIONS: Twice daily 10mg lorcaserin failed to demonstrate efficacy in the treatment of CUD.

Lorcaserin: Worthy of Further Insights? Results from Recent Research.

Lorcaserin is a 3-benzazepine that binds 5-HT2C serotonin receptors in the hypothalamus, where it mediates lack of hunger and/or satiety, and in the ventral tegmental area, the site of origin of the mesolimbic and mesocortical dopaminergic projections, which mediate pleasure and reward. The drug has been first developed for the treatment of obesity, where it has shown efficacy, and subsequently trialed to counter substance use (mostly cocaine, cannabis, opioids, and nicotine) and craving, but showed inconsistent effects. Since 2020, the US Food and Drug Administration obtained that the drug was voluntarily withdrawn from the US market on the grounds that its long-term use was found to be associated with a greater incidence of some types of cancer. Provided it can show to be free from cancerogenic effects, ongoing research suggests that lorcaserin may have therapeutic potential for a variety of disorders and conditions beyond obesity. Since 5-HT2C receptors are involved in many diversified physiological functions (mood, feeding, reproductive behavior, neuronal processes related to impulsiveness, and modulating reward-related mechanisms) this drug has the potential to treat different central nervous system conditions, such as depression and schizophrenia.

Interactions between lorcaserin and opioids: Ventilation and food-versus-drug choice.

Lorcaserin, a selective serotonin 2C (5-HT2C) receptor agonist, was approved for treating obesity and has been investigated for treating substance use disorders including those involving opioids. Although lorcaserin was withdrawn from the market, interest in the therapeutic potential of drugs acting at 5-HT2C receptors continues, supporting the need to further characterize potential adverse effects especially when combined with drugs of abuse. This study examined acute effects of lorcaserin on opioid-induced ventilatory depression, which is the primary cause of overdose, and opioid self-administration, which models factors contributing to opioid abuse, in male and female rhesus monkeys. In one group (n = 4), effects of morphine (0.178 to 5.6 mg/kg, s.c.), fentanyl (0.0032 to 0.1 mg/kg, s.c.), and lorcaserin (0.1 to 1.78 mg/kg, s.c.) alone as well as effects of lorcaserin with each opioid on ventilation were determined using head plethysmography. Another group (n = 5) responded under a food versus fentanyl (0.1 to 3.2 µg/kg/infusion, i.v.) choice procedure, and lorcaserin (0.32 to 1.78 mg/kg, i.v.) was given as a pretreatment. Lorcaserin dose-dependently decreased minute volume to below 70 % of baseline when administered alone and increased the potency of morphine and fentanyl. Consistent with previous studies, lorcaserin failed to alter choice of fentanyl over food. This study demonstrates the novel finding that lorcaserin alone decreases ventilation and enhances the ventilatory-depressant effects of opioids. Taken together with previous studies, these results suggest that combining a 5-HT2C receptor agonist such as lorcaserin with an opioid could increase the risk of ventilatory depression without the benefit of decreasing abuse.

Patient interest in acupuncture for smoking cessation: a survey.

BACKGROUND/OBJECTIVE: Tobacco use remains the leading cause of preventable death in the United States. The most widely available treatment options to assist patients in smoking cessation are limited by side effects and moderate efficacy at best. Acupuncture may be an effective option for smoking cessation. The goal of this study was to establish the need for and interest in acupuncture therapy to potentially assist with smoking cessation from a patient perspective. METHODS: We conducted a cross-sectional survey study among patients aged 18 years or older whose medical record reported current tobacco use with English as their preferred language. REDCap surveys were administered to patients during office visits and included questions regarding opinions and use of all treatments available for smoking cessation (including acupuncture) as well as perceived barriers to acupuncture treatment. RESULTS: A total of 57 surveys were distributed, and 42 (74%) were completed. Most patients reported previous attempts at quitting (76%) and had tried a variety of treatments including nicotine replacement (45%), Chantix (varenicline; 23%), Wellbutrin (bupriopion; 19%), "cold turkey" (65%) and hypnosis (3%). No respondents reported having tried acupuncture for smoking cessation. CONCLUSION: When comparing treatment options, patients reported more interest in acupuncture than other treatment options with a statistically significant difference in the level of interest between acupuncture and bupropion. All barriers (cost, time and effectiveness) were equally rated on a Likert-type scale with a median of 50 on a 101-point scale.

Acute and chronic glutamate NMDA antagonist treatment attenuates dopamine D1 antagonist-induced reduction of nicotine self-administration in female rats.

Multiple interacting neural systems are involved in sustaining nicotine reinforcement. We and others have shown that dopamine D1 receptors and glutamate NMDA receptors both play important roles in nicotine reinforcement. Blockade of D1 receptors with the antagonist SCH-23390 (0.02 mg/kg) both acutely and chronically significantly decreased nicotine self-administration in rats. Blockade of NMDA receptors (10 mg/kg) acutely with memantine significantly increased nicotine self-administration, but chronic blockade of NMDA receptors with memantine significantly decreased nicotine self-administration. The current study examined the interactions of acute and chronic administration of SCH-23390 and memantine on nicotine self-administration in female rats. Replicating earlier studies, acute and chronic SCH-23390 significantly decreased nicotine self-administration and memantine had a biphasic effect with acute administration increasing nicotine self-administration and chronic memantine showed a non-significant trend toward decreasing it. However, chronic interaction study showed that memantine significantly attenuated the decrease in nicotine self-administration caused by chronic SCH-23390. These studies provide important information that memantine attenuates the efficacy of D1 antagonist SCH 23390 in reducing nicotine-self-administration. These two drugs do not appear to have mutually potentiating effects to aid tobacco cessation.

Smoking Cessation Pharmacotherapy Efficacy in Comorbid Medical Populations: Secondary Analysis of the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) Randomized Clinical Trial.

INTRODUCTION: This study sought to compare medication efficacy in participants with medical comorbidities who smoke in the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) trial, a double-blind, triple-dummy, placebo- and active-controlled randomized controlled trial. AIMS AND METHODS: Participants were from the U.S. cohort of the main trial and randomized (1:1:1:1) to varenicline, bupropion, nicotine replacement therapy (NRT) patch, or placebo for 12 weeks with follow-up through week 24. Medical comorbidity data were derived from the baseline medical screening questionnaire and categorized into four subgroups (cardiac, respiratory, vascular, and diabetes). Within each comorbidity, generalized linear mixed models were used to assess the association between treatment and continuous abstinence rates from weeks 9-12 to 9-24. Similar models were used to test the effect of number of comorbidities on abstinence. RESULTS: Varenicline resulted in the highest week 12 abstinence rates across all pharmacotherapies and compared to placebo in all comorbidity subgroups: Cardiac (40.0% vs. 3.6%; odds ratios [OR] = 23.3 [5.1-107.1]), respiratory (24.7% vs. 12.8%; OR = 2.2 [1.3-3.8]), vascular (29.1% vs. 10.4%; OR = 3.6 [2.3-5.7]), and diabetes (30.9% vs. 8.3%; OR = 6.5 [2.3-19.0]). This was maintained at week 24 for those with cardiac (23.3% vs. 1.8%; OR = 21.7 [2.7-178.2]), vascular (18.9% vs. 7.1%; OR = 3.1 [1.8-5.3]), and diabetes (20.6% vs. 4.2%; OR = 8.4 [2.1-33.7]) comorbidities. Treatment contrasts within some comorbidity subgroups revealed superior efficacy of varenicline over other pharmacotherapies. All pharmacotherapies increased the odds of abstinence regardless of number of comorbidities. CONCLUSIONS: Varenicline is the most efficacious option for patients with manageable cardiac, respiratory, vascular, and diabetes conditions to quit smoking, supporting recent clinical practice guidelines that recommend varenicline as first-line pharmacotherapy. Bupropion and NRT demonstrated efficacy for some comorbidity subgroups. IMPLICATIONS: This secondary analysis of the EAGLES trial demonstrated that varenicline is the most efficacious option for patients with cardiac, respiratory, vascular, and diabetes diagnoses to quit smoking. This demonstration of varenicline efficacy among individuals with comorbid medical conditions supports recent clinical practice guidelines that recommend varenicline as a first-line pharmacotherapy for smoking cessation.

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.