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William R. Shanahan - One of the best experts on this subject based on the ideXlab platform.
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Lorcaserin: A review of its preclinical and clinical pharmacology and therapeutic potential.
Pharmacology & therapeutics, 2019Co-Authors: Guy A Higgins, Paul J Fletcher, William R. ShanahanAbstract:The selective 5-HT2C receptor agonist Lorcaserin, in conjunction with lifestyle modification, was approved by the FDA in 2012 for weight management. It has been marketed in the US as Belviq® since 2013. This article provides a review of the preclinical and clinical pharmacology of Lorcaserin, including its pharmacokinetic and safety profiles. Preclinical studies with Lorcaserin initially focused on simple measures of food intake and body weight gain, but have now expanded to include studies on its effects on appetitive aspects of feeding behaviour and models of binge-eating. A significant number of studies have also shown that Lorcaserin alters behaviours related to drug use and addiction, in rodents and non-human primates. Potential clinically-relevant effects of Lorcaserin have also been reported in models of pain and seizure-like activity. Not surprisingly, the majority of clinical work with Lorcaserin has focused on its effects on weight gain, and on physiological processes related to energy intake. However, results of clinical trials and experimental laboratory studies involving Lorcaserin are now appearing which describe effects on a range of other behaviours and physiological functions. These include smoking cessation, cocaine self-administration, and behavioural and brain responses to food cues. All of this work suggests that Lorcaserin may have therapeutic potential for a variety of disorders and conditions beyond obesity. Based on clinical experience, including the outcomes from several, large, well-powered clinical obesity trials at the approved 10mg BID dose both pre and post approval, a priori concerns about cardiac valvulopathy have largely been allayed. However, as with any recently approved first-in-class pharmacotherapy, there may be yet-unknown risks, as well as benefits, associated with use of Lorcaserin. Nonetheless, the current safety profile and an expanding post approval safety data base should encourage further experimental laboratory-based and clinical trial-based research with Lorcaserin in targeted populations to investigate its full therapeutic potential.
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effect of Lorcaserin on glycemic parameters in patients with type 2 diabetes mellitus
Obesity, 2017Co-Authors: Faidon Magkos, Sharon Zhou, Randi Fain, Elena Nikonova, William R. ShanahanAbstract:Objective Lorcaserin, a 5-HT2C receptor agonist approved for chronic weight management, is also associated with improvements in glycemic parameters in patients with/without type 2 diabetes mellitus (T2DM), but the extent to which these effects are mediated by weight loss is unknown. This post hoc analysis further examines glycemic data from the Phase III BLOOM-DM study stratified by weight changes. Methods Patients with T2DM were randomized to Lorcaserin 10 mg twice daily or placebo. Glycemic parameters were reported by Week (W) 12 weight loss status ≥5% (Group ≥5%) or <5% (Group <5%). Glycemic parameter changes were analyzed using ANCOVA; the relationship between glycemic parameter changes and percent weight loss was assessed by simple regression modeling. Results Group ≥5% receiving Lorcaserin had greater improvements in fasting plasma glucose (FPG) at W2 (prior to significant weight loss) and greater improvements in glycated hemoglobin (HbA1c) at W12 versus placebo. These improvements were maintained through W52 (FPG, −29.3 mg/dL vs. −24.2 mg/dL; HbA1c, −1.2% vs. −1.1%). Group <5% treated with Lorcaserin also had larger decreases in FPG (−28.3 mg/dL vs. −10.0 mg/dL) and HbA1c (−0.8% vs. −0.4%) at W52 versus placebo despite limited weight loss. Conclusions Lorcaserin may have beneficial effects on glycemic control with or without weight loss.
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Effects of Lorcaserin on pre-existing valvulopathy: A pooled analysis of phase 3 trials.
Obesity (Silver Spring Md.), 2016Co-Authors: Neil J. Weissman, Steven R. Smith, Randi Fain, Nancy Hall, William R. ShanahanAbstract:Objective To evaluate the effects of Lorcaserin in patients with pre-existing Food and Drug Administration (FDA)-defined valvulopathy. Methods This is a pooled, post hoc analysis of three Phase 3 studies. BLOOM and BLOSSOM patients were 18 to 65 years of age without diabetes and with a body mass index (BMI) of 27 to 29.9 kg/m2 and ≥1 weight-related comorbidity or a BMI of 30 to 45 kg/m2. BLOOM-DM patients had a BMI of 27 to 45 kg/m2 and type 2 diabetes. Patients were treated with placebo, Lorcaserin 10 mg once daily, or Lorcaserin 10 mg twice daily. Serial echocardiographs were obtained at baseline and every 6 months. Results Included patients (N = 169) had FDA-defined valvulopathy at baseline and a week 52 echocardiogram. At week 52, 35.5% and 52.7% of patients experienced changes from baseline in aortic and mitral regurgitation, respectively. Numerically greater proportions of patients taking Lorcaserin versus placebo had decreases in aortic (33.0% vs. 28.3%) or mitral (41.3% vs. 36.7%) regurgitation. Fewer patients taking Lorcaserin versus placebo had increases in aortic (2.8% vs. 6.7%) or mitral (8.3% vs. 21.7%) regurgitation. No adverse event-related discontinuation was due to a valve problem. Conclusions These data suggest that Lorcaserin does not adversely affect valvular disease in patients with pre-existing FDA-defined valvulopathy.
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Single- and Multiple-dose Pharmacokinetics of a Lorcaserin Extended-release Tablet.
Clinical therapeutics, 2016Co-Authors: Ronald J. Christopher, Michael Morgan, Jim Ferry, Bhaskar Rege, Yong Tang, Allan Kristensen, William R. ShanahanAbstract:Abstract Purpose Lorcaserin is a serotonin 2C receptor agonist indicated for chronic weight management as an adjunct to diet and exercise. The initial approved formulation is a 10-mg, immediate-release (IR) tablet for administration BID. These studies investigated the single- and multiple-dose pharmacokinetic properties of a new, recently US Food and Drug Administration–approved, extended-release, 20-mg once-daily formulation. Methods We performed 2 separate 2-period, 2-sequence crossover studies in 36 healthy adults: a study comparing the IR formulation to the extended-release formulation under fasting conditions and a study comparing the extended-release formulation under fed and fasted conditions. Findings Compared with Lorcaserin IR, the T max after a single dose of Lorcaserin extended-release was greater (median, 12 vs 3 hours), and the C max was 26% lower (38.8 vs 52.3 ng/mL). AUC data were bioequivalent for the 2 formulations in both single- and multiple-dose regimens, confirming no formulation effect on Lorcaserin bioavailability. In fasted and fed conditions, T max after a single dose was identical (median, 12 hours), but C max was approximately 45% higher in the fed state (mean, 38.5 ng/mL fasted vs 56.1 ng/mL fed). However, at steady state, C max and AUC were determined to be bioequivalent between the fasted and fed states, indicating no clinically relevant food effect on the pharmacokinetic properties of Lorcaserin extended-release. The safety profile was consistent between the 2 formulations. Implications Overall, the results indicate that Lorcaserin extended-release is a suitable once-daily alternative to the approved IR BID formulation.
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Safety and tolerability review of Lorcaserin in clinical trials
Clinical obesity, 2016Co-Authors: Frank L. Greenway, William R. Shanahan, Randi Fain, D. RubinoAbstract:Summary Lorcaserin is a novel selective serotonin 2C receptor agonist indicated by the US Food and Drug Administration for chronic weight management in adults with obesity or overweight with ≥1 comorbidity. The safety and efficacy of Lorcaserin were established during two Phase III clinical trials in patients without diabetes (BLOOM and BLOSSOM) and one Phase III clinical trial in patients with type 2 diabetes (BLOOM-DM). Headache was the most common adverse event experienced by patients during all Phase III trials. Additional adverse events occurring in >5% of patients receiving Lorcaserin included dizziness, fatigue, nausea, dry mouth and constipation in patients without diabetes, and hypoglycaemia, back pain, cough and fatigue in patients with diabetes. In a pooled analysis of echocardiographic data collected during the three Lorcaserin Phase III trials, the incidence of FDA-defined valvulopathy was similar in patients taking Lorcaserin and the placebo. Here, the safety profile of Lorcaserin at the FDA-approved dose of 10 mg twice daily is reviewed using data from the Lorcaserin Phase III programme, with a focus on theoretical adverse events commonly associated with agonists of the serotonin receptor family. Based on the Lorcaserin Phase III clinical trial data, Lorcaserin is safe and well tolerated in the indicated patient populations.
Paul J Fletcher - One of the best experts on this subject based on the ideXlab platform.
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The serotonin 2C receptor agonist Lorcaserin, alone and in combination with the opioid receptor antagonist naltrexone, attenuates binge-like ethanol drinking.
Addiction biology, 2021Co-Authors: Rayane I Tabbara, Paul J FletcherAbstract:The serotonin (5-HT) system has been implicated in the pathophysiology of alcohol (ethanol; EtOH) use disorders. Lorcaserin, a 5-HT2C receptor agonist, attenuates drug self-administration in animal models. We investigated the effects of Lorcaserin on EtOH intake using the drinking-in-the-dark (DID) procedure, an animal model of binge-like drinking. We compared the effects of Lorcaserin to those of the Food and Drug Administration (FDA)-approved drug naltrexone and examined the effects of combining Lorcaserin and naltrexone. To examine whether effects were specific for EtOH, we examined the effects of Lorcaserin and naltrexone, administered alone and in combination, on saccharin intake. Adult male C57BL/6J mice received EtOH access (20% v/v) for 2 h in the home-cage during the first 3 days of the DID procedure, beginning 3 h into the dark cycle. On day 4, mice were injected with Lorcaserin, naltrexone, or a combination of Lorcaserin and naltrexone prior to a 4-h EtOH access. Intake was measured at 2 and 4 h. Lorcaserin reduced EtOH intake in a dose-dependent fashion over the 2- and 4-h measurement periods. Naltrexone also reduced EtOH intake when administered alone, with dose-dependent effects being more pronounced over 2 h rather than the full 4-h session. Combining Lorcaserin and naltrexone reduced binge-like EtOH drinking to a greater extent than either drug alone. A similar pattern of results was obtained for saccharin intake. These results suggest that Lorcaserin and naltrexone can have additive effects on binge-like EtOH drinking. They also support continued research into the therapeutic potential of Lorcaserin for alcohol use disorders.
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Lorcaserin: A review of its preclinical and clinical pharmacology and therapeutic potential.
Pharmacology & therapeutics, 2019Co-Authors: Guy A Higgins, Paul J Fletcher, William R. ShanahanAbstract:The selective 5-HT2C receptor agonist Lorcaserin, in conjunction with lifestyle modification, was approved by the FDA in 2012 for weight management. It has been marketed in the US as Belviq® since 2013. This article provides a review of the preclinical and clinical pharmacology of Lorcaserin, including its pharmacokinetic and safety profiles. Preclinical studies with Lorcaserin initially focused on simple measures of food intake and body weight gain, but have now expanded to include studies on its effects on appetitive aspects of feeding behaviour and models of binge-eating. A significant number of studies have also shown that Lorcaserin alters behaviours related to drug use and addiction, in rodents and non-human primates. Potential clinically-relevant effects of Lorcaserin have also been reported in models of pain and seizure-like activity. Not surprisingly, the majority of clinical work with Lorcaserin has focused on its effects on weight gain, and on physiological processes related to energy intake. However, results of clinical trials and experimental laboratory studies involving Lorcaserin are now appearing which describe effects on a range of other behaviours and physiological functions. These include smoking cessation, cocaine self-administration, and behavioural and brain responses to food cues. All of this work suggests that Lorcaserin may have therapeutic potential for a variety of disorders and conditions beyond obesity. Based on clinical experience, including the outcomes from several, large, well-powered clinical obesity trials at the approved 10mg BID dose both pre and post approval, a priori concerns about cardiac valvulopathy have largely been allayed. However, as with any recently approved first-in-class pharmacotherapy, there may be yet-unknown risks, as well as benefits, associated with use of Lorcaserin. Nonetheless, the current safety profile and an expanding post approval safety data base should encourage further experimental laboratory-based and clinical trial-based research with Lorcaserin in targeted populations to investigate its full therapeutic potential.
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Preclinical evidence for combining the 5-HT2C receptor agonist Lorcaserin and varenicline as a treatment for nicotine dependence.
Addiction biology, 2018Co-Authors: Paul J Fletcher, Leo B. Silenieks, Cam Macmillan, Ines Delannoy, Guy A HigginsAbstract:Varenicline, a nicotinic acetylcholine receptor partial agonist, is used to treat nicotine dependence. Lorcaserin, a 5-HT2C receptor agonist has been approved in some countries to treat obesity. Based on preclinical and preliminary clinical evidence, Lorcaserin may have potential to treat nicotine dependence. These experiments examined in rats the effects of combining varenicline (0.5 or 1 mg/kg) and Lorcaserin (0.3, 0.6 and 1 mg/kg) on nicotine self-administration, reinstatement of nicotine seeking, responding for food and impulsive action. Both drugs alone reduced nicotine self-administration. Combining varenicline and 0.6 mg/kg Lorcaserin reduced responding to a greater extent than either drug alone. In a relapse model, extinguished nicotine seeking was reinstated by a priming injection of nicotine and nicotine-associated cues. Reinstatement was reduced by varenicline (1 mg/kg) and by Lorcaserin (0.3 mg/kg). Combining Lorcaserin (0.3 mg/kg) with varenicline (0.5 or 1 mg/kg) reduced reinstatement to a greater degree than either drug alone. Both drugs had minimal effects on responding for food, alone or in combination. In the five-choice serial reaction time test, varenicline (0.5 or 1 mg/kg) increased impulsivity, measured as increased premature responding. This effect was reduced by Lorcaserin (0.3 mg/kg). Plasma levels of varenicline or Lorcaserin were not altered by co-administration of the other drug. Varenicline and Lorcaserin have additive effects on nicotine self-administration, and on nicotine seeking. Lorcaserin prevents impulsivity induced by varenicline. This pattern of effects suggests that co-administration of varenicline and Lorcaserin has potential as a treatment for nicotine dependence that may exceed the value of either drug alone.
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The 5-HT(2C) receptor agonist Lorcaserin reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced locomotor activity.
Neuropharmacology, 2015Co-Authors: Colin Harvey-lewis, Guy A Higgins, Paul J FletcherAbstract:Lorcaserin (Lorqess, Belviq(®)) is a selective 5-HT(2C) receptor agonist that has received FDA approval for the treatment of obesity. 5-HT(2C) receptor agonists are also efficacious in decreasing multiple aspects of cocaine motivation and reward in preclinical models. This would suggest that Lorcaserin is a clinically available therapeutic with the potential to treat cocaine addiction. Here we report the effects of Lorcaserin (0.1 mg/kg-1.0 mg/kg) on multiple aspects of cocaine-related behaviours in rats. We find that Lorcaserin dose-dependently decreases cocaine self-administration on progressive and fixed ratio schedules of reinforcement. Lorcaserin also reduces reinstatement of cocaine-seeking behaviour in response to priming injections of cocaine and/or reintroduction of cocaine-associated cues. Finally, Lorcaserin dose-dependently decreases cocaine-induced hyperlocomotion. Our results, when considered in concert with similar emergent findings in non-human primates, strongly support continued research into the potential of Lorcaserin as a clinical treatment for cocaine addiction.
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the serotonin 2c receptor agonist Lorcaserin attenuates intracranial self stimulation and blocks the reward enhancing effects of nicotine
ACS Chemical Neuroscience, 2015Co-Authors: Fiona D Zeeb, Guy A Higgins, Paul J FletcherAbstract:Lorcaserin, a serotonin (5-hydroxytryptamine, 5-HT) 2C receptor agonist, was recently approved for the treatment of obesity. We previously suggested that 5-HT2C receptor agonists affect reward processes and reduce the rewarding effects of drugs of abuse. Here, we determined whether Lorcaserin (1) decreases responding for brain stimulation reward (BSR) and (2) prevents nicotine from enhancing the efficacy of BSR. Rats were trained on the intracranial self-stimulation (ICSS) paradigm to nosepoke for BSR of either the dorsal raphe nucleus or left medial forebrain bundle. In Experiment 1, Lorcaserin (0.3–1.0 mg/kg) dose-dependently reduced the efficacy of BSR. This effect was blocked by prior administration of the 5-HT2C receptor antagonist SB242084. In Experiment 2, separate groups of rats received saline or nicotine (0.4 mg/kg) for eight sessions prior to testing. Although thresholds were unaltered in saline-treated rats, nicotine reduced reward thresholds. An injection of Lorcaserin (0.3 mg/kg) prior to ni...
Gregory T. Collins - One of the best experts on this subject based on the ideXlab platform.
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Effects of Lorcaserin and Buspirone, Administered Alone and as a Mixture, on Cocaine Self-Administration in Male and Female Rhesus Monkeys
Experimental and clinical psychopharmacology, 2018Co-Authors: Gregory T. CollinsAbstract:Cocaine use disorder is a serious public health issue for which there is no effective pharmacotherapy. One strategy to speed development of medications for cocaine use disorder is to repurpose drugs already approved for use in humans based on their ability to interact with targets known to be important for addiction. Two such drugs, Lorcaserin (Belviq; a drug with serotonin [5-HT]2C receptor agonist properties) and buspirone (Buspar; a drug with 5-HT1A receptor partial agonist and dopamine D3/D4 receptor antagonist properties) can produce modest decreases in cocaine self-administration in rhesus monkeys. The current study evaluated the effectiveness of mixtures of Lorcaserin and buspirone (at fixed dose ratios of 3:1, 1:1, and 1:3 relative to each drug's ID50) to reduce responding for 0.032 mg/kg/inf cocaine under a progressive ratio schedule of reinforcement in 2 male and 2 female rhesus monkeys. Dose addition analyses were used to determine if the effects of the drug mixtures differed from those predicted for an additive interaction between Lorcaserin and buspirone. Dose-dependent reductions of cocaine self-administration were observed when Lorcaserin and buspirone were administered alone, as well as when they were administered as 3:1, 1:1, and 1:3 fixed ratio mixtures of Lorcaserin + buspirone. The effects of the 1:1 mixture of Lorcaserin + buspirone on cocaine self-administration were supraadditive, whereas the effects of 3:1 and 1:3 mixtures were additive. Together, these results indicate that a combination therapy containing a mixture of Lorcaserin and buspirone might be more effective than either drug alone at treating cocaine use disorder. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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The behavioral pharmacology and therapeutic potential of Lorcaserin for substance use disorders.
Neuropharmacology, 2017Co-Authors: Gregory T. Collins, Lisa R GerakAbstract: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)2 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-HT2C 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-HT2C 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'.
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Inhibition of Cocaine and 3,4-Methylenedioxypyrovalerone (MDPV) Self-Administration by Lorcaserin Is Mediated by 5-HT2C Receptors in Rats.
The Journal of pharmacology and experimental therapeutics, 2017Co-Authors: Brenda M. Gannon, Kenner C Rice, Agnieszka Sulima, Gregory T. CollinsAbstract:Lorcaserin is a serotonin (5-HT)2C receptor-preferring agonist approved by the US Food and Drug Administration to treat obesity. Lorcaserin decreases cocaine self-administration in rats and monkeys. Although this effect is partially inhibited by a 5-HT2C receptor antagonist (SB242084), Lorcaserin also has effects at 5-HT2A and 5-HT1A receptors, and the relative contribution of these receptors to its anti-cocaine effects has not been investigated. The goals of this study were to determine 1) the potency and effectiveness of Lorcaserin to decrease self-administration of cocaine and 3,4-methylenedioxypyrovalerone (MDPV), a common "bath salts" constituent; and 2) the receptor(s) mediating the effects of Lorcaserin on cocaine and MDPV self-administration. Male Sprague-Dawley rats (n = 6) were trained to self-administer MDPV under a progressive ratio schedule of reinforcement and maintained under this schedule with daily access to 0.32 mg/kg per infusion of cocaine or 0.032 mg/kg per infusion of MDPV. Dose-response curves for the effects of Lorcaserin on cocaine and MDPV self-administration were generated by administering Lorcaserin (0.1-5.6 mg/kg) 25 minutes before the start of the session. To assess the effects of 5-HT2C (SB242084, 0.1 mg/kg), 5-HT2A (MDL100907, 0.1 mg/kg), and 5-HT1A (WAY100635, 0.178 mg/kg) receptor antagonists, they were administered 15 minutes before Lorcaserin. Lorcaserin decreased cocaine and MDPV self-administration with equal potency. Antagonism of 5-HT2C (but not 5-HT1A or 5-HT2A) receptors blocked the effects of Lorcaserin on cocaine and MDPV self-administration. Taken together, these data provide additional support for further development of 5-HT2C receptor agonists, such as Lorcaserin, for the treatment of stimulant abuse.
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Effects of Lorcaserin on Cocaine and Methamphetamine Self-Administration and Reinstatement of Responding Previously Maintained by Cocaine in Rhesus Monkeys.
The Journal of pharmacology and experimental therapeutics, 2016Co-Authors: Lisa R Gerak, Gregory T. CollinsAbstract:Stimulant abuse is a serious public health issue for which there is no effective pharmacotherapy. The serotonin2C [5-hydroxytryptamine2C (5-HT2C)] receptor agonist Lorcaserin decreases some abuse-related effects of cocaine in monkeys and might be useful for treating stimulant abuse. The current study investigated the effectiveness of Lorcaserin to reduce self-administration of either cocaine or methamphetamine and cocaine-induced reinstatement of extinguished responding. Four rhesus monkeys responded under a progressive-ratio (PR) schedule in which the response requirement increased after each cocaine infusion (32–320 μg/kg/infusion). A separate group of four monkeys responded under a fixed-ratio (FR) schedule for cocaine (32 μg/kg/infusion) and reinstatement of extinguished responding was examined following administration of noncontingent infusions of cocaine (0.1–1 mg/kg) that were combined with response-contingent presentations of the drug-associated stimuli. Finally, three monkeys responded under a FR schedule for methamphetamine (0.32–100 μg/kg/infusion). Lorcaserin (3.2 mg/kg) significantly decreased the final ratio completed (i.e., decreased break point) in monkeys responding under the PR schedule and reduced the reinstatement of responding for drug-associated stimuli following a noncontingent infusion of cocaine; these effects did not appear to change when Lorcaserin was administered daily. The same dose of Lorcaserin decreased responding for methamphetamine in two of the three monkeys, and the effect was maintained during daily Lorcaserin administration; larger doses given acutely (10–17.8 mg/kg) significantly decreased responding for methamphetamine, although that effect was not sustained during daily Lorcaserin administration. Together, these results indicate that Lorcaserin might be effective in reducing cocaine and methamphetamine abuse and cocaine relapse at least in some individuals.
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Lorcaserin reduces the discriminative stimulus and reinforcing effects of cocaine in rhesus monkeys
Journal of Pharmacology and Experimental Therapeutics, 2015Co-Authors: Gregory T. Collins, Lisa R Gerak, Martin A JavorsAbstract:Cocaine abuse and obesity are serious public health problems, and studies suggest that both dopamine and serotonin systems are involved in regulating the consumption of drugs and food. Lorcaserin has serotonin (5-HT)2C receptor agonist actions, is approved by the U.S. Food and Drug Administration for treating obesity, and might be effective for treating cocaine abuse. These studies characterized the pharmacokinetic and behavioral profiles of Lorcaserin (intragastric administration) and determined the effectiveness of Lorcaserin to alter discriminative stimulus and reinforcing effects of cocaine (intravenous administration) in rhesus monkeys. Administered acutely, Lorcaserin dose-dependently increased the occurrence of yawning while decreasing spontaneous activity and operant responding for food. These effects appeared within 30-60 minutes of administration and began to dissipate by 240 minutes, a time course closely matching plasma concentrations of Lorcaserin. In monkeys discriminating cocaine from saline, Lorcaserin alone did not occasion cocaine-appropriate responding but shifted the cocaine dose-response curve to the right and down in two of three monkeys. When administered acutely, Lorcaserin dose-dependently decreased the rate at which monkeys responded for infusions of cocaine. When administered chronically, 3.2 mg/kg Lorcaserin reduced the rate of cocaine-maintained responding by 50% for the duration of a 14-day treatment period. Together, these results show that Lorcaserin attenuates the discriminative stimulus effects of cocaine after acute administration and the reinforcing effects of cocaine after acute and repeated administration, consistent with the view that it might have utility in treating cocaine abuse.
Guy A Higgins - One of the best experts on this subject based on the ideXlab platform.
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Lorcaserin: A review of its preclinical and clinical pharmacology and therapeutic potential.
Pharmacology & therapeutics, 2019Co-Authors: Guy A Higgins, Paul J Fletcher, William R. ShanahanAbstract:The selective 5-HT2C receptor agonist Lorcaserin, in conjunction with lifestyle modification, was approved by the FDA in 2012 for weight management. It has been marketed in the US as Belviq® since 2013. This article provides a review of the preclinical and clinical pharmacology of Lorcaserin, including its pharmacokinetic and safety profiles. Preclinical studies with Lorcaserin initially focused on simple measures of food intake and body weight gain, but have now expanded to include studies on its effects on appetitive aspects of feeding behaviour and models of binge-eating. A significant number of studies have also shown that Lorcaserin alters behaviours related to drug use and addiction, in rodents and non-human primates. Potential clinically-relevant effects of Lorcaserin have also been reported in models of pain and seizure-like activity. Not surprisingly, the majority of clinical work with Lorcaserin has focused on its effects on weight gain, and on physiological processes related to energy intake. However, results of clinical trials and experimental laboratory studies involving Lorcaserin are now appearing which describe effects on a range of other behaviours and physiological functions. These include smoking cessation, cocaine self-administration, and behavioural and brain responses to food cues. All of this work suggests that Lorcaserin may have therapeutic potential for a variety of disorders and conditions beyond obesity. Based on clinical experience, including the outcomes from several, large, well-powered clinical obesity trials at the approved 10mg BID dose both pre and post approval, a priori concerns about cardiac valvulopathy have largely been allayed. However, as with any recently approved first-in-class pharmacotherapy, there may be yet-unknown risks, as well as benefits, associated with use of Lorcaserin. Nonetheless, the current safety profile and an expanding post approval safety data base should encourage further experimental laboratory-based and clinical trial-based research with Lorcaserin in targeted populations to investigate its full therapeutic potential.
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Preclinical evidence for combining the 5-HT2C receptor agonist Lorcaserin and varenicline as a treatment for nicotine dependence.
Addiction biology, 2018Co-Authors: Paul J Fletcher, Leo B. Silenieks, Cam Macmillan, Ines Delannoy, Guy A HigginsAbstract:Varenicline, a nicotinic acetylcholine receptor partial agonist, is used to treat nicotine dependence. Lorcaserin, a 5-HT2C receptor agonist has been approved in some countries to treat obesity. Based on preclinical and preliminary clinical evidence, Lorcaserin may have potential to treat nicotine dependence. These experiments examined in rats the effects of combining varenicline (0.5 or 1 mg/kg) and Lorcaserin (0.3, 0.6 and 1 mg/kg) on nicotine self-administration, reinstatement of nicotine seeking, responding for food and impulsive action. Both drugs alone reduced nicotine self-administration. Combining varenicline and 0.6 mg/kg Lorcaserin reduced responding to a greater extent than either drug alone. In a relapse model, extinguished nicotine seeking was reinstated by a priming injection of nicotine and nicotine-associated cues. Reinstatement was reduced by varenicline (1 mg/kg) and by Lorcaserin (0.3 mg/kg). Combining Lorcaserin (0.3 mg/kg) with varenicline (0.5 or 1 mg/kg) reduced reinstatement to a greater degree than either drug alone. Both drugs had minimal effects on responding for food, alone or in combination. In the five-choice serial reaction time test, varenicline (0.5 or 1 mg/kg) increased impulsivity, measured as increased premature responding. This effect was reduced by Lorcaserin (0.3 mg/kg). Plasma levels of varenicline or Lorcaserin were not altered by co-administration of the other drug. Varenicline and Lorcaserin have additive effects on nicotine self-administration, and on nicotine seeking. Lorcaserin prevents impulsivity induced by varenicline. This pattern of effects suggests that co-administration of varenicline and Lorcaserin has potential as a treatment for nicotine dependence that may exceed the value of either drug alone.
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The 5-HT(2C) receptor agonist Lorcaserin reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced locomotor activity.
Neuropharmacology, 2015Co-Authors: Colin Harvey-lewis, Guy A Higgins, Paul J FletcherAbstract:Lorcaserin (Lorqess, Belviq(®)) is a selective 5-HT(2C) receptor agonist that has received FDA approval for the treatment of obesity. 5-HT(2C) receptor agonists are also efficacious in decreasing multiple aspects of cocaine motivation and reward in preclinical models. This would suggest that Lorcaserin is a clinically available therapeutic with the potential to treat cocaine addiction. Here we report the effects of Lorcaserin (0.1 mg/kg-1.0 mg/kg) on multiple aspects of cocaine-related behaviours in rats. We find that Lorcaserin dose-dependently decreases cocaine self-administration on progressive and fixed ratio schedules of reinforcement. Lorcaserin also reduces reinstatement of cocaine-seeking behaviour in response to priming injections of cocaine and/or reintroduction of cocaine-associated cues. Finally, Lorcaserin dose-dependently decreases cocaine-induced hyperlocomotion. Our results, when considered in concert with similar emergent findings in non-human primates, strongly support continued research into the potential of Lorcaserin as a clinical treatment for cocaine addiction.
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the serotonin 2c receptor agonist Lorcaserin attenuates intracranial self stimulation and blocks the reward enhancing effects of nicotine
ACS Chemical Neuroscience, 2015Co-Authors: Fiona D Zeeb, Guy A Higgins, Paul J FletcherAbstract:Lorcaserin, a serotonin (5-hydroxytryptamine, 5-HT) 2C receptor agonist, was recently approved for the treatment of obesity. We previously suggested that 5-HT2C receptor agonists affect reward processes and reduce the rewarding effects of drugs of abuse. Here, we determined whether Lorcaserin (1) decreases responding for brain stimulation reward (BSR) and (2) prevents nicotine from enhancing the efficacy of BSR. Rats were trained on the intracranial self-stimulation (ICSS) paradigm to nosepoke for BSR of either the dorsal raphe nucleus or left medial forebrain bundle. In Experiment 1, Lorcaserin (0.3–1.0 mg/kg) dose-dependently reduced the efficacy of BSR. This effect was blocked by prior administration of the 5-HT2C receptor antagonist SB242084. In Experiment 2, separate groups of rats received saline or nicotine (0.4 mg/kg) for eight sessions prior to testing. Although thresholds were unaltered in saline-treated rats, nicotine reduced reward thresholds. An injection of Lorcaserin (0.3 mg/kg) prior to ni...
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the 5 ht2c receptor agonist Lorcaserin reduces nicotine self administration discrimination and reinstatement relationship to feeding behavior and impulse control
Neuropsychopharmacology, 2012Co-Authors: Guy A Higgins, Paul J Fletcher, Leo B. Silenieks, Anne Rossmann, Zoe Rizos, Kevin Noble, Ashlie D SokoAbstract:Lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl) is a selective 5-HT2C receptor agonist with clinical efficacy in phase-III obesity trials. Based on evidence that this drug class also affects behaviors motivated by drug reinforcement, we compared the effect of Lorcaserin on behavior maintained by food and nicotine reinforcement, as well as the stimulant and discriminative stimulus properties of nicotine in the rat. Acutely administered Lorcaserin (0.3–3 mg/kg, subcutaneous (SC)) dose dependently reduced feeding induced by 22-h food deprivation or palatability. Effects up to 1 mg/kg were consistent with a specific effect on feeding motivation. Lorcaserin (0.6–1 mg/kg, SC) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement. In this dose range Lorcaserin also reversed the motor stimulant effect of nicotine, reduced intravenous self-administration of nicotine, and attenuated the nicotine cue in rats trained to discriminate nicotine from saline. Lorcaserin also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement. Lorcaserin did not reinstate nicotine-seeking behavior or substitute for a nicotine cue. Finally, Lorcaserin (0.3–1 mg/kg) reduced nicotine-induced increases in anticipatory responding, a measure of impulsive action, in rats performing the five-choice serial reaction time task. Importantly, these results indicate that Lorcaserin, and likely other selective 5-HT2C receptor agonists, similarly affect both food- and nicotine-motivated behaviors, and nicotine-induced impulsivity. Collectively, these findings highlight a therapeutic potential for 5-HT2C agonists such as Lorcaserin beyond obesity into addictive behaviors, such as nicotine dependence.
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effect of Lorcaserin on prevention and remission of type 2 diabetes in overweight and obese patients camellia timi 61 a randomised placebo controlled trial
The Lancet, 2018Co-Authors: Erin A Bohula, Steven R. Smith, Benjamin M. Scirica, Sabina A. Murphy, Silvio E Inzucchi, Darren K Mcguire, Anthony C Keech, Estella Kanevsky, Lawrence A Leiter, Jamie P DwyerAbstract:Summary Background There is a direct relationship between bodyweight and risk of diabetes. Lorcaserin, a selective serotonin 2C receptor agonist that suppresses appetite, has been shown to facilitate sustained weight loss in obese or overweight patients. We aimed to evaluate the long-term effects of Lorcaserin on diabetes prevention and remission. Methods In this randomised, double-blind, placebo-controlled trial done in eight countries, we recruited overweight or obese patients (body-mass index ≥27 kg/m 2 ) with or at high risk for atherosclerotic vascular disease. Eligible patients were aged 40 years or older; patients at high risk for atherosclerotic vascular disease had to be aged 50 years or older with diabetes and at least one other risk factor. Patients were randomly assigned to receive either Lorcaserin (10 mg twice daily) or matching placebo. Additionally, all patients had access to a standardised weight management programme based on lifestyle modification. The prespecified primary metabolic efficacy endpoint of time to incident diabetes was assessed in patients with prediabetes at baseline. The prespecified secondary outcomes for efficacy were incident diabetes in all patients without diabetes, achievement of normoglycaemia in patients with prediabetes, and change in glycated haemoglobin (HbA 1c ) in patients with diabetes. Hypoglycaemia was a prespecified safety outcome. Analysis was by intention to treat, using Cox proportional hazard models for time-to-event analyses. This trial is registered with ClinicalTrials.gov, number NCT02019264. Findings Between Feb 7, 2014, and Nov 20, 2015, 12 000 patients were randomly assigned to Lorcaserin or placebo (6000 patients in each group) and followed up for a median of 3·3 years (IQR 3·0–3·5). At baseline, 6816 patients (56·8%) had diabetes, 3991 (33·3%) prediabetes, and 1193 (9·9%) normoglycaemia. At 1 year, patients treated with Lorcaserin had a net weight loss beyond placebo of 2·6 kg (95% CI 2·3–2·9) for those with diabetes, 2·8 kg (2·5–3·2) for those with prediabetes, and 3·3 kg (2·6–4·0) for those with normoglycaemia (p vs 204 [10·3%] of 1976; hazard ratio 0·81, 95% CI 0·66–0·99; p=0·038) and by 23% in patients without diabetes (174 [6·7%] of 2615 vs 215 [8·4%] of 2569; 0·77, 0·63–0·94; p=0·012). Lorcaserin resulted in a non-significant increase in the rate of achievement of normoglycaemia in patients with prediabetes (185 [9·2%] vs 151 [7·6%]; 1·20, 0·97–1·49; p=0·093). In patients with diabetes, Lorcaserin resulted in a reduction of 0·33% (95% CI 0·29–0·38; p 1c compared with placebo at 1 year from a mean baseline of 53 mmol/mol (7·0%). In patients with diabetes at baseline, severe hypoglycaemia with serious complications was rare, but more common with Lorcaserin (12 [0·4%] vs four [0·1%] events; p=0·054). Interpretation Lorcaserin decreases risk for incident diabetes, induces remission of hyperglycaemia, and reduces the risk of microvascular complications in obese and overweight patients, supporting the role of Lorcaserin as an adjunct to lifestyle modification for chronic management of weight and metabolic health. Funding Eisai.
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effect of Lorcaserin on prevention and remission of type 2 diabetes in overweight and obese patients camellia timi 61 a randomised placebo controlled trial
The Lancet, 2018Co-Authors: Erin A Bohula, Steven R. Smith, Benjamin M. Scirica, Sabina A. Murphy, Silvio E Inzucchi, Darren K Mcguire, Anthony C Keech, Estella Kanevsky, Lawrence A Leiter, Jamie P DwyerAbstract:BACKGROUND: There is a direct relationship between bodyweight and risk of diabetes. Lorcaserin, a selective serotonin 2C receptor agonist that suppresses appetite, has been shown to facilitate sustained weight loss in obese or overweight patients. We aimed to evaluate the long-term effects of Lorcaserin on diabetes prevention and remission. METHODS: In this randomised, double-blind, placebo-controlled trial done in eight countries, we recruited overweight or obese patients (body-mass index ≥27 kg/m2) with or at high risk for atherosclerotic vascular disease. Eligible patients were aged 40 years or older; patients at high risk for atherosclerotic vascular disease had to be aged 50 years or older with diabetes and at least one other risk factor. Patients were randomly assigned to receive either Lorcaserin (10 mg twice daily) or matching placebo. Additionally, all patients had access to a standardised weight management programme based on lifestyle modification. The prespecified primary metabolic efficacy endpoint of time to incident diabetes was assessed in patients with prediabetes at baseline. The prespecified secondary outcomes for efficacy were incident diabetes in all patients without diabetes, achievement of normoglycaemia in patients with prediabetes, and change in glycated haemoglobin (HbA1c) in patients with diabetes. Hypoglycaemia was a prespecified safety outcome. Analysis was by intention to treat, using Cox proportional hazard models for time-to-event analyses. This trial is registered with ClinicalTrials.gov, number NCT02019264. FINDINGS: Between Feb 7, 2014, and Nov 20, 2015, 12 000 patients were randomly assigned to Lorcaserin or placebo (6000 patients in each group) and followed up for a median of 3·3 years (IQR 3·0-3·5). At baseline, 6816 patients (56·8%) had diabetes, 3991 (33·3%) prediabetes, and 1193 (9·9%) normoglycaemia. At 1 year, patients treated with Lorcaserin had a net weight loss beyond placebo of 2·6 kg (95% CI 2·3-2·9) for those with diabetes, 2·8 kg (2·5-3·2) for those with prediabetes, and 3·3 kg (2·6-4·0) for those with normoglycaemia (p<0·0001 for all analyses). Lorcaserin reduced the risk of incident diabetes by 19% in patients with prediabetes (172 [8·5%] of 2015 vs 204 [10·3%] of 1976; hazard ratio 0·81, 95% CI 0·66-0·99; p=0·038) and by 23% in patients without diabetes (174 [6·7%] of 2615 vs 215 [8·4%] of 2569; 0·77, 0·63-0·94; p=0·012). Lorcaserin resulted in a non-significant increase in the rate of achievement of normoglycaemia in patients with prediabetes (185 [9·2%] vs 151 [7·6%]; 1·20, 0·97-1·49; p=0·093). In patients with diabetes, Lorcaserin resulted in a reduction of 0·33% (95% CI 0·29-0·38; p<0·0001) in HbA1c compared with placebo at 1 year from a mean baseline of 53 mmol/mol (7·0%). In patients with diabetes at baseline, severe hypoglycaemia with serious complications was rare, but more common with Lorcaserin (12 [0·4%] vs four [0·1%] events; p=0·054). INTERPRETATION: Lorcaserin decreases risk for incident diabetes, induces remission of hyperglycaemia, and reduces the risk of microvascular complications in obese and overweight patients, supporting the role of Lorcaserin as an adjunct to lifestyle modification for chronic management of weight and metabolic health. FUNDING: Eisai.
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design and rationale for the cardiovascular and metabolic effects of Lorcaserin in overweight and obese patients thrombolysis in myocardial infarction 61 camellia timi 61 trial
American Heart Journal, 2018Co-Authors: Erin A Bohula, Steven R. Smith, Benjamin M. Scirica, Silvio E Inzucchi, Darren K Mcguire, Anthony C Keech, Christina L Fanola, Tim Abrahamsen, Bruce Francis, Wenfeng MiaoAbstract:Abstract Objectives Lorcaserin, a selective serotonin 2C receptor agonist, is an effective pharmacologic weight-loss therapy that improves several cardiovascular risk factors. The long-term clinical cardiovascular and metabolic safety and efficacy in patients with elevated cardiovascular risk are unknown. Research design and methods CAMELLIA-TIMI 61 ( NCT02019264 ) is a randomized, double-blind, placebo-controlled, multinational clinical trial designed to evaluate the safety and efficacy of Lorcaserin with regard to major adverse cardiovascular events and progression to diabetes in overweight or obese patients at high cardiovascular risk. Overweight or obese patients either with established cardiovascular disease or with diabetes and at least 1 other cardiovascular risk factor were randomized in a 1:1 ratio to Lorcaserin 10 mg twice daily or matching placebo. The primary safety objective is to assess for noninferiority of Lorcaserin for the composite end point of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular event [MACE]) (with noninferiority defined as the upper bound of a 1-sided 97.5% CI excluding a hazard ratio of 1.4) compared with placebo assessed at an interim analysis with 460 adjudicated events. The efficacy objectives, assessed at study completion, will evaluate the superiority of Lorcaserin for the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or any coronary revascularization (MACE+) and the key secondary end point of conversion to diabetes. Recruitment began in January 2014 and was completed in November 2015 resulting in a total population of 12,000 patients. The trial is planned to continue until at least 1,401 adjudicated MACE+ events are accrued and the median treatment duration exceeds 2.5 years. Conclusion CAMELLIA-TIMI 61 is investigating the safety and efficacy of Lorcaserin for MACEs and conversion to diabetes in overweight or obese patients with established cardiovascular disease or multiple cardiovascular risk factors.
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Effects of Lorcaserin on pre-existing valvulopathy: A pooled analysis of phase 3 trials.
Obesity (Silver Spring Md.), 2016Co-Authors: Neil J. Weissman, Steven R. Smith, Randi Fain, Nancy Hall, William R. ShanahanAbstract:Objective To evaluate the effects of Lorcaserin in patients with pre-existing Food and Drug Administration (FDA)-defined valvulopathy. Methods This is a pooled, post hoc analysis of three Phase 3 studies. BLOOM and BLOSSOM patients were 18 to 65 years of age without diabetes and with a body mass index (BMI) of 27 to 29.9 kg/m2 and ≥1 weight-related comorbidity or a BMI of 30 to 45 kg/m2. BLOOM-DM patients had a BMI of 27 to 45 kg/m2 and type 2 diabetes. Patients were treated with placebo, Lorcaserin 10 mg once daily, or Lorcaserin 10 mg twice daily. Serial echocardiographs were obtained at baseline and every 6 months. Results Included patients (N = 169) had FDA-defined valvulopathy at baseline and a week 52 echocardiogram. At week 52, 35.5% and 52.7% of patients experienced changes from baseline in aortic and mitral regurgitation, respectively. Numerically greater proportions of patients taking Lorcaserin versus placebo had decreases in aortic (33.0% vs. 28.3%) or mitral (41.3% vs. 36.7%) regurgitation. Fewer patients taking Lorcaserin versus placebo had increases in aortic (2.8% vs. 6.7%) or mitral (8.3% vs. 21.7%) regurgitation. No adverse event-related discontinuation was due to a valve problem. Conclusions These data suggest that Lorcaserin does not adversely affect valvular disease in patients with pre-existing FDA-defined valvulopathy.
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Early weight loss while on Lorcaserin, diet and exercise as a predictor of week 52 weight-loss outcomes.
Obesity (Silver Spring Md.), 2014Co-Authors: Steven R. Smith, Patrick M. O'neil, Randi Fain, Arne Astrup, Nick Finer, Matilde Sanchez-kam, Kyle Fraher, William R. ShanahanAbstract:Objective To identify an early treatment milestone that optimizes sensitivity and specificity for predicting ≥5% weight loss at Week (W) 52 in patients with and without type 2 diabetes on Lorcaserin or placebo. Methods Post hoc area under the curve for receiver operating characteristic analyses of data from three phase 3 trials comparing lifestyle modification+placebo with lifestyle modification+Lorcaserin. A total of 6897 patients (18–65 years; BMI, 30–45 or 27–29.9 kg/m2 with ≥1 comorbidity) were randomized to placebo or Lorcaserin 10 mg bid. Changes (baseline to W52) in cardiometabolic parameters were assessed. Results Response (≥5% weight loss from baseline) at W12 was a strong predictor of W52 response. Lorcaserin patients with a W12 response achieved mean W52 weight losses of 10.6 kg (without diabetes) and 9.3 kg (with diabetes). Proportions achieving ≥5% and ≥10% weight loss at W52 were 85.5% and 49.8% (without diabetes), and 70.5% and 35.9% (with diabetes). Lorcaserin patients who did not achieve a W12 response lost 3.2 kg (without diabetes) and 2.8 kg (with diabetes) at W52. Responders had greater improvements in cardiometabolic risk factors than the modified intent-to-treat (MITT) population, consistent with greater weight loss. Conclusions ≥5% weight loss by W12 predicts robust response to Lorcaserin at 1 year.
