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Drugs of Today (Barcelona, Spain : 1998) Dec 2010Obesity is a worldwide epidemic and there is an urgent need for the development of effective pharmacological therapies that target the metabolic and behavioral factors... (Review)
Review
Obesity is a worldwide epidemic and there is an urgent need for the development of effective pharmacological therapies that target the metabolic and behavioral factors of body weight regulation. Serotonin (5-HT) has been implicated as a critical factor in the short-term (meal-by-meal) regulation of food intake and pharmaceutical companies have invested millions of dollars to discover and develop drug targets for the serotonergic pathway. Lorcaserin is a novel selective agonist of the 5-HT(2C) receptor for weight loss therapy. Preclinical and clinical studies indicate lorcaserin is well tolerated and not associated with cardiac valvulopathy or pulmonary hypertension suggesting that lorcaserin is a selective 5-HT(2C) receptor agonist and has little or no activation of the 5-HT(2B) and 5-HT(2A) receptors, respectively. Lorcaserin acts to alter energy balance through a reduction in energy intake and without an increase in energy expenditure and achieved the U.S. Food and Drug Administration guidelines for weight loss efficacy. It remains to be determined whether or not lorcaserin will be approved for the long-term management of obesity.
Topics: Benzazepines; Clinical Trials as Topic; Humans; Obesity; Serotonin 5-HT2 Receptor Agonists
PubMed: 21589947
DOI: 10.1358/dot.2010.46.12.1556433 -
The New England Journal of Medicine Dec 2012
Topics: Antidiuretic Hormone Receptor Antagonists; Benzazepines; Female; Humans; Kidney; Male; Polycystic Kidney, Autosomal Dominant; Tolvaptan
PubMed: 23121376
DOI: 10.1056/NEJMe1211857 -
Neuropharmacology Nov 2018Substance abuse is serious public health problem for which there are few effective pharmacotherapies. Traditional strategies for drug development have focused on... (Review)
Review
Substance abuse is serious public health problem for which there are few effective pharmacotherapies. Traditional strategies for drug development have focused on antagonists to block the abuse-related effects of a drug at its site of action, and agonists to replace/mimic the effects of the abused substance. However, recent efforts have targeted receptors, such as serotonin (5-HT) receptors, that can indirectly modulate dopamine neurotransmission with the goal of developing a pharmacotherapy that might be effective at reducing the abuse-related effects of drugs more generally. Lorcaserin is a 5-HT receptor-preferring agonist that is approved by the US Food and Drug Administration for the treatment of obesity. Mounting evidence from preclinical and clinical studies suggests that lorcaserin might also be effective at reducing the abuse-related effects of drugs with different pharmacological mechanisms (e.g., cocaine, heroin, ethanol, and nicotine). Lorcaserin represents a promising and important first step towards the development a new class of pharmacotherapies that have the potential to dramatically improve the treatment of substance abuse. This article will review the behavioral pharmacology of 5-HT receptor-preferring agonists, with a focus on lorcaserin, and evaluate the preclinical evidence supporting the development of lorcaserin for treating substance abuse. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.
Topics: Animals; Benzazepines; Humans; Psychotropic Drugs; Substance-Related Disorders
PubMed: 29246856
DOI: 10.1016/j.neuropharm.2017.12.023 -
Therapeutic Advances in Respiratory... Oct 2008Tobacco dependence is a chronic relapsing disease that needs continuous treatment. In combination with behavioural support, pharmacotherapy is a proven key component for... (Review)
Review
Tobacco dependence is a chronic relapsing disease that needs continuous treatment. In combination with behavioural support, pharmacotherapy is a proven key component for supporting smoking cessation. Effective drugs are available and recommended: nicotine replacement therapy (NRT), bupropion and varenicline. Much research into new pharmacological approaches is ongoing, combining 'old' and 'new' drugs and personalizing a pharmacological treatment for a single smoker/patient; other new medications and vaccines are in development. Overall, pharmacotherapy seems to have efficacy and cost-effectiveness in real life, thus physicians should become familiar with these medicines. Further efforts should be aimed at optimizing treatment management and increasing smoking cessation rates in the general population.
Topics: Adrenergic Uptake Inhibitors; Antidepressive Agents, Tricyclic; Benzazepines; Bupropion; Humans; Nortriptyline; Piperidines; Pyrazoles; Quinoxalines; Randomized Controlled Trials as Topic; Rimonabant; Smoking Cessation; Treatment Outcome; Varenicline
PubMed: 19124379
DOI: 10.1177/1753465808096136 -
Nicotine & Tobacco Research : Official... Oct 2022Negative reinforcement models posit that relapse to cigarette smoking is driven in part by changes in affect and craving during the quit attempt. Varenicline may aid... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Negative reinforcement models posit that relapse to cigarette smoking is driven in part by changes in affect and craving during the quit attempt. Varenicline may aid cessation by attenuating these changes; however, this mediational pathway has not been formally evaluated in placebo-controlled trials. Thus, trajectories of negative affect (NA), positive affect (PA), and craving were tested as mediators of the effect of varenicline on smoking cessation.
AIMS AND METHODS
Secondary data analysis was conducted on 828 adults assigned to either varenicline or placebo in a randomized controlled trial for smoking cessation (NCT01314001). Self-reported NA, PA, and craving were assessed 1-week pre-quit, on the target quit day (TQD), and 1 and 4 weeks post-TQD.
RESULTS
Across time, NA peaked 1-week post-quit, PA did not change, and craving declined. Less steep rises in NA (indirect effect 95% CI: .01 to .30) and lower mean craving at 1-week post-quit (CI: .06 to .50) were mediators of the relationship between varenicline and higher cessation rates at the end of treatment. PA was associated with cessation but was not a significant mediator.
CONCLUSIONS
These results partially support the hypothesis that varenicline improves smoking cessation rates by attenuating changes in specific psychological processes and supported NA and craving as plausible treatment mechanisms of varenicline.
IMPLICATIONS
The present research provides the first evidence from a placebo-controlled randomized clinical trial that varenicline's efficacy is due, in part, to post-quit attenuation of NA and craving. Reducing NA across the quit attempt and craving early into the attempt may be important treatment mechanisms for effective interventions. Furthermore, post-quit NA, PA, and craving were all associated with relapse and represent treatment targets for future intervention development.
Topics: Adult; Humans; Varenicline; Craving; Smoking Cessation; Cigarette Smoking; Recurrence; Quinoxalines; Benzazepines
PubMed: 35639828
DOI: 10.1093/ntr/ntac138 -
International Journal of Molecular... Feb 2023Cardiac remodeling can cause ventricular dysfunction and progress to heart failure, a cardiovascular disease that claims many lives globally. Ivabradine, a funny channel... (Review)
Review
Cardiac remodeling can cause ventricular dysfunction and progress to heart failure, a cardiovascular disease that claims many lives globally. Ivabradine, a funny channel (I) inhibitor, is used in patients with chronic heart failure as an adjunct to other heart failure medications. This review aims to gather updated information regarding the therapeutic use and mechanism of action of ivabradine in heart failure. The drug reduces elevated resting heart rate, which is linked to increased morbidity and mortality in patients with heart failure. Its use is associated with improved cardiac function, structure, and quality of life in the patients. Ivabradine exerts several pleiotropic effects, including an antiremodeling property, which are independent of its principal heart-rate-reducing effects. Its suppressive effects on cardiac remodeling have been demonstrated in animal models of cardiac remodeling and heart failure. It reduces myocardial fibrosis, apoptosis, inflammation, and oxidative stress as well as increases autophagy in the animals. It also modulates myocardial calcium homeostasis, neurohumoral systems, and energy metabolism. However, its role in improving heart failure remains unclear. Therefore, elucidating its molecular mechanisms is imperative and would aid in the design of future studies.
Topics: Animals; Ivabradine; Ventricular Remodeling; Quality of Life; Benzazepines; Heart Rate; Heart Failure
PubMed: 36769115
DOI: 10.3390/ijms24032801 -
Journal of Biological Inorganic... Aug 2010The synthesis of ruthenium(II) and osmium(II) arene complexes with the closely related indolo[3,2-c]quinolines N-(11H-indolo[3,2-c]quinolin-6-yl)-ethane-1,2-diamine (L (... (Comparative Study)
Comparative Study
The synthesis of ruthenium(II) and osmium(II) arene complexes with the closely related indolo[3,2-c]quinolines N-(11H-indolo[3,2-c]quinolin-6-yl)-ethane-1,2-diamine (L ( 1 )) and N'-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (L ( 2 )) and indolo[3,2-d]benzazepines N-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-ethane-1,2-diamine (L ( 3 )) and N'-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-N,N-dimethylethane-1,2-diamine (L ( 4 )) of the general formulas [(eta(6)-p-cymene)M(II)(L ( 1 ))Cl]Cl, where M is Ru (4) and Os (6), [(eta(6)-p-cymene)M(II)(L ( 2 ))Cl]Cl, where M is Ru (5) and Os (7), [(eta(6)-p-cymene)M(II)(L ( 3 ))Cl]Cl, where M is Ru (8) and Os (10), and [(eta(6)-p-cymene)M(II)(L ( 4 ))Cl]Cl, where M is Ru (9) and Os (11), is reported. The compounds have been comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, spectroscopy (IR, UV-vis, and NMR), and X-ray crystallography (L ( 1 ).HCl, 4.H(2)O, 5, and 9.2.5H(2)O). Structure-activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells as well as cyclin-dependent kinase (cdk) inhibition and DNA intercalation in cell-free settings have been established. The metal-free indolo[3,2-c]quinolines inhibit cancer cell growth in vitro, with IC(50) values in the high nanomolar range, whereas those of the related indolo[3,2-d]benzazepines are in the low micromolar range. In cell-free experiments, these classes of compounds inhibit the activity of cdk2/cyclin E, but the much higher cytotoxicity and stronger cell cycle effects of indoloquinolines L ( 1 ) and 7 are not paralleled by a substantially higher kinase inhibition compared with indolobenzazepines L ( 4 ) and 11, arguing for additional targets and molecular effects, such as intercalation into DNA.
Topics: Animals; Antineoplastic Agents; Benzazepines; Cell Cycle; Cell Line, Tumor; Crystallography, X-Ray; Cyclin-Dependent Kinases; DNA; Humans; Inhibitory Concentration 50; Intercalating Agents; Ligands; Organometallic Compounds; Quinolines; Spectrum Analysis
PubMed: 20369265
DOI: 10.1007/s00775-010-0653-y -
Journal of the American College of... Aug 2022
Topics: Benzazepines; Cardiovascular Agents; Heart Failure; Heart Failure, Systolic; Heart Rate; Humans; Ivabradine; Treatment Outcome
PubMed: 35926932
DOI: 10.1016/j.jacc.2022.05.028 -
Nicotine & Tobacco Research : Official... Mar 2020Understanding study characteristics' influence on treatment efficacy could improve interpretation of trials' outcomes. We examined study characteristics as predictors of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Understanding study characteristics' influence on treatment efficacy could improve interpretation of trials' outcomes. We examined study characteristics as predictors of outcomes in clinical trials of medications for tobacco use.
METHODS
We obtained and analyzed data on 44 trials of nicotine gum, 37 trials of nicotine patch, 27 trials of varenicline, and 43 trials of bupropion from Cochrane reviews. We extracted and analyzed data for 15 study characteristics, odds ratios (ORs), and percent abstinent in control and medication conditions. We used general linear models to determine which study characteristics explained the variability among outcomes after controlling for medication characteristics.
RESULTS
Study characteristics accounted for 12% of the variance in odds ratios among patch trials, 16% among gum trials, 16% among varenicline trials, and 34% among bupropion trials above and beyond medication characteristics. Patch and gum trials with industry funding had larger odds ratios than those without. Among patch trials, this appeared to be due to less abstinence in industry-funded trials' control conditions. Bupropion trials published earlier had larger odds ratios, which appeared to be due to less abstinence in control conditions. The reason for study characteristics' influence on varenicline trials was unclear.
DISCUSSION
Study characteristics influenced the assessment of treatment efficacy above and beyond medication characteristics in smoking cessation trials. Our findings that study characteristics are associated with higher or lower efficacy does not suggest that the effect size under one versus another condition is the more valid outcome. Future studies are needed to determine which study characteristics reliably influence efficacy because this would help investigators and clinicians interpret trials.
IMPLICATIONS
Study characteristics influenced the estimates of treatment efficacy but individual characteristics' influence on efficacy appeared to differ among different medications for smoking cessation. We encourage researchers to report study characteristics to improve interpretation of findings and systematic reviews, and to account for nontreatment-related variables to better estimate the efficacy of treatments.
Topics: Benzazepines; Bupropion; Clinical Trials as Topic; Humans; Smoking Cessation; Smoking Cessation Agents; Substance-Related Disorders; Tobacco Use Cessation Devices; Treatment Outcome; Varenicline
PubMed: 30380134
DOI: 10.1093/ntr/nty225 -
International Journal of Chronic... 2009Chronic obstructive pulmonary disease (COPD) is a costly and deadly disease afflicting an estimated 210 million people and accounting for 5% of all global deaths.... (Review)
Review
Chronic obstructive pulmonary disease (COPD) is a costly and deadly disease afflicting an estimated 210 million people and accounting for 5% of all global deaths. Exposure to cigarette smoke is the greatest risk factor for COPD in the developed world. Smoking cessation improves respiratory symptoms and lung function and reduces mortality among patients with COPD. Cigarette smokers with COPD and other co-morbid conditions such as cardiovascular disease and psychiatric illnesses should receive comprehensive tobacco treatment interventions incorporating efficacious pharmacotherapies. Varenicline, an alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist, is the newest and most effective drug currently available to promote smoking cessation. In conjunction with behavioral interventions and clinical monitoring for potential side effects, varenicline offers great hope for reducing smoking-attributable death and disability.
Topics: Benzazepines; Cardiovascular Diseases; Drug Labeling; Humans; Mental Disorders; Nicotinic Agonists; Pulmonary Disease, Chronic Obstructive; Quinoxalines; Smoking; Smoking Cessation; Tobacco Use Disorder; Treatment Outcome; Varenicline
PubMed: 20037681
DOI: 10.2147/copd.s6300