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Alexandros Makriyannis - One of the best experts on this subject based on the ideXlab platform.
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Central mediation and differential blockade by cannabinergics of the discriminative stimulus effects of the cannabinoid CB_1 receptor antagonist Rimonabant in rats
Psychopharmacology, 2011Co-Authors: Torbjörn U. C. Järbe, Subramanian K. Vadivel, Brian J. Lemay, V. Kiran Vemuri, Alexander Zvonok, Alexandros MakriyannisAbstract:Rationale Discovery of an endocannabinoid signaling system launched the development of the blocker Rimonabant, a cannabinoid CB1 receptor (CB_1R) antagonist/inverse agonist. Due to untoward effects, this medication was withdrawn and efforts have been directed towards discovering chemicals with more benign profiles. Objective This study aims to comparatively evaluate new ligands using a Rimonabant discriminated drinking aversion procedure. Methods Rats discriminated between Rimonabant (5.6 mg/kg) and vehicle. The 30 min saccharin (0.1%) drinking after Rimonabant pretreatment was followed by injection of lithium chloride (120 mg/kg) in the experimental animals. After vehicle pretreatment, experimental animals were given i.p. NaCl (10 ml/kg). Postdrinking treatment for controls was NaCl, irrespective of pretreatment condition (Rimonabant or vehicle). Results The centrally acting neutral CB_1R antagonist AM4113, but not the limited brain penetrating CB_1R neutral antagonist AM6545, substituted for Rimonabant. The CB_1R agonists THC (1–10 mg/kg), AM1346 (1–10 mg/kg) did not substitute. The Rimonabant-induced conditioned suppression of saccharin drinking was attenuated when CB_1R agonists AM5983 (0.01–1 mg/kg) and THC (10 mg/kg), but not the CB_1R agonist AM1346 (0.1–18 mg/kg), were combined with Rimonabant (5.6 mg/kg). By varying the injection-to-test interval, we gauged the relative duration of the cueing effects of Rimonabant, and the in vivo functional half-life was estimated to be approximately 1.5 h. Conclusion A neutral CB_1R antagonist (AM4113) produced cueing effects similar to those of Rimonabant and generalization likely was centrally mediated. The functional cueing effects of Rimonabant are relatively short-acting, pharmacologically selective, and differentially blocked by cannabinergics.
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Antagonism of ∆⁹-THC induced behavioral effects by Rimonabant: time course studies in rats.
European journal of pharmacology, 2010Co-Authors: Torbjörn U. C. Järbe, Roger S Gifford, Alexandros MakriyannisAbstract:The objective was to examine the time course of the cannabinoid 1 receptor antagonist/inverse agonist Rimonabant's ability to antagonize in vivo cannabinergic agonist effects. We used two behavioral procedures sensitive to the effects of ∆⁹-tetrahydrocannabinol (∆⁹-THC): rat drug discrimination (EXP-1) and suppression of fixed-ratio responding (FR) for food reinforcement (EXP-2). Two training doses of ∆⁹-THC (1.8 and 3 mg/kg) served as discriminative cues in two groups discriminating ∆⁹-THC from vehicle; injections were i.p. 20 min before session onset. Tests assessed the dose-response functions of ∆⁹-THC and the time course for Rimonabant in its ability to block the discriminative stimulus effects of ∆⁹-THC. For antagonism testing, the training doses of ∆⁹-THC were used and the Rimonabant dose was 1mg/kg. Tests were 20, 60, 120, and 240 min post Rimonabant administration; ∆⁹-THC was always administered 20 min prior to testing. For EXP-2, only one response lever was activated and every 10th (FR-10) press on that lever resulted in food delivery. Once the response rate stabilized, tests occurred with ∆⁹-THC, Rimonabant and combinations of the drugs. The ED(50) estimates for the dose-response functions were 0.38 (±0.28-0.51) and 0.50 (±0.40-0.63) mg/kg for the training doses of 1.8 and 3 mg/kg ∆⁹-THC, respectively. The time course studies suggested functional half-life estimates of 128.4 (±95.7-172.2) and 98.4 (±64.2-150.7) min by Rimonabant for the two groups in EXP-1, respectively. Similarly, the functional half-life of Rimonabant was 118.9 (±66.1-213.9) min in EXP-2. Thus, antagonism of ∆⁹-THC by Rimonabant is relatively short lasting.
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Antagonism of Δ9-THC induced behavioral effects by Rimonabant: time-course studies in rats
European Journal of Pharmacology, 2010Co-Authors: Torbjörn U. C. Järbe, Roger S Gifford, Alexandros MakriyannisAbstract:Abstract The objective was to examine the time course of the cannabinoid 1 receptor antagonist/inverse agonist Rimonabant's ability to antagonize in vivo cannabinergic agonist effects. We used two behavioral procedures sensitive to the effects of ∆ 9 -tetrahydrocannabinol (∆ 9 -THC): rat drug discrimination (EXP-1) and suppression of fixed-ratio responding (FR) for food reinforcement (EXP-2). Two training doses of ∆ 9 -THC (1.8 and 3 mg/kg) served as discriminative cues in two groups discriminating ∆ 9 -THC from vehicle; injections were i.p. 20 min before session onset. Tests assessed the dose–response functions of ∆ 9 -THC and the time course for Rimonabant in its ability to block the discriminative stimulus effects of ∆ 9 -THC. For antagonism testing, the training doses of ∆ 9 -THC were used and the Rimonabant dose was 1 mg/kg. Tests were 20, 60, 120, and 240 min post Rimonabant administration; ∆ 9 -THC was always administered 20 min prior to testing. For EXP-2, only one response lever was activated and every 10th (FR-10) press on that lever resulted in food delivery. Once the response rate stabilized, tests occurred with ∆ 9 -THC, Rimonabant and combinations of the drugs. The ED 50 estimates for the dose–response functions were 0.38 (± 0.28–0.51) and 0.50 (± 0.40–0.63) mg/kg for the training doses of 1.8 and 3 mg/kg ∆ 9 -THC, respectively. The time course studies suggested functional half-life estimates of 128.4 (± 95.7–172.2) and 98.4 (± 64.2–150.7) min by Rimonabant for the two groups in EXP-1, respectively. Similarly, the functional half-life of Rimonabant was 118.9 (± 66.1–213.9) min in EXP-2. Thus, antagonism of ∆ 9 -THC by Rimonabant is relatively short lasting.
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Discriminative stimulus effects of the cannabinoid CB_1 receptor antagonist Rimonabant in rats
Psychopharmacology, 2008Co-Authors: Torbjörn U. C. Järbe, Subramanian K. Vadivel, Alexandros MakriyannisAbstract:Objective To examine the discriminative stimulus effects of the cannabinoid CB_1 receptor (CB_1R) antagonist/inverse agonist Rimonabant (SR141716A) using a discriminated taste aversion (DTA) procedure. Materials and methods Groups of rats were trained to discriminate between drug (5.6 or 3 mg/kg) and vehicle in DTA ( t ′ = 20 min). The 30-min drinking opportunity after Rimonabant pretreatment was followed by injection of lithium chloride (120 mg/kg) in the experimental (EXP) animals. When offered fluid after vehicle pretreatment, EXP animals subsequently were given intraperitoneal saline (NaCl, 10 ml/kg). Post-drinking treatment for controls (CONT) was NaCl irrespective of the pretreatment condition (Rimonabant or vehicle). Tests examined other doses and drugs ( t ′ = 20 min). Results The Rimonabant analog AM251 (1 to 5.6 mg/kg) substituted for Rimonabant. AM281 also appeared to substitute, but interpretation is complicated by unconditioned effects (drinking suppressed also in the CONT group). The CB_2R antagonists SR144528 (18 and 30 mg/kg), AM630 (1 to 10 mg/kg), and the CB_1R agonist methanandamide (mAEA, 3 and 10 mg/kg) did not substitute. There was a dose-related attenuation of the Rimonabant-induced suppression of saccharin drinking when Δ9-tetrahydrocannabinol (Δ9-THC; 0.3 to 5.6 mg/kg), but not mAEA (1 to 10 mg/kg), was given together with Rimonabant (3 mg/kg). Unconditioned effects occurred with the mAEA–Rimonabant combination, not evident for combinations of Rimonabant and Δ9-THC. mAEA (10 mg/kg) plus AM251 (5.6 mg/kg) resulted in strong unconditioned effects. Conclusion Rimonabant induces a discriminative stimulus in DTA that continues to show potential for further examination of cannabinoid receptor antagonism.
Brad Allen Fremming - One of the best experts on this subject based on the ideXlab platform.
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Rimonabant a selective cb1 antagonist
Annals of Pharmacotherapy, 2005Co-Authors: Steven Thomas Boyd, Brad Allen FremmingAbstract:OBJECTIVE:To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of Rimonabant, a new selective cannabinoid receptor antagonist.DATA SOURCES:Primary literature and review articles were obtained via a MEDLINE search (1966–November 2004) using the key terms obesity, smoking cessation, cannabinoid, Rimonabant, SR 141716, and SR 141716a. Additional studies and abstracts were identified from the bibliographies of reviewed literature.STUDY SELECTION AND DATA EXTRACTION:Studies and review articles related to Rimonabant and the endocannabinoid system were reviewed. Data pertinent to this article were included.DATA SYNTHESIS:Rimonabant is a selective cannabinoid receptor antagonist. Recent data have demonstrated beneficial effects of Rimonabant in obesity, smoking cessation, and metabolic syndrome. Animal studies using Rimonabant have shown a positive role for reducing hunger, caloric intake, and body weight and in increasing satiety. In humans, Rimonabant appears to be effective for treatment...
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Rimonabant—A Selective CB1 Antagonist
The Annals of pharmacotherapy, 2005Co-Authors: Steven Thomas Boyd, Brad Allen FremmingAbstract:OBJECTIVE:To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of Rimonabant, a new selective cannabinoid receptor antagonist.DATA SOURCES:Primary literature and review articles were obtained via a MEDLINE search (1966–November 2004) using the key terms obesity, smoking cessation, cannabinoid, Rimonabant, SR 141716, and SR 141716a. Additional studies and abstracts were identified from the bibliographies of reviewed literature.STUDY SELECTION AND DATA EXTRACTION:Studies and review articles related to Rimonabant and the endocannabinoid system were reviewed. Data pertinent to this article were included.DATA SYNTHESIS:Rimonabant is a selective cannabinoid receptor antagonist. Recent data have demonstrated beneficial effects of Rimonabant in obesity, smoking cessation, and metabolic syndrome. Animal studies using Rimonabant have shown a positive role for reducing hunger, caloric intake, and body weight and in increasing satiety. In humans, Rimonabant appears to be effective for treatment...
Andre Scheen - One of the best experts on this subject based on the ideXlab platform.
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long term effect of cb1 blockade with Rimonabant on cardiometabolic risk factors two year results from the rio europe study
European Heart Journal, 2008Co-Authors: Luc Van Gaal, Andre Scheen, Aila Rissanen, Stephan Rossner, Corinne Hanotin, O ZieglerAbstract:Aims Rimonabant, the first selective cannabinoid type 1 receptor blocker, has been shown to produce weight loss and improvements in several cardiometabolic risk factors over 1 year. We report the 2 year efficacy and tolerability data of Rimonabant. Methods and results Patients with a body mass index ≥30 or >27 kg/m2 with treated/untreated hypertension, dyslipidaemia, or both, were randomized to double-blind treatment with placebo, Rimonabant 5 or 20 mg once daily plus a calorie-restricted diet for 2 years. Weight loss from baseline to 2 years in the intention-to-treat population was significantly greater with Rimonabant 20 mg (mean ± SD: −5.5 ± 7.7 kg; P 11) were similar in all treatment groups. Conclusion Rimonabant 20 mg over 2 years promoted clinically relevant and durable weight loss and improvements in cardiometabolic risk factors.
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cb1 receptor blockade and its impact on cardiometabolic risk factors overview of the rio programme with Rimonabant
Journal of Neuroendocrinology, 2008Co-Authors: Andre ScheenAbstract:Rimonabant, the first selective CB 1 receptor antagonist in clinical use, has been extensively investigated in the Rimonabant in Obesity (RIO) programme, comprising four 1-2 year placebo-controlled randomised clinical trials recruiting more than 6600 overweight/obese patients with or without co-morbidities. Rimonabant 20 mg daily consistently reduced body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels, and increased HDL cholesterol concentrations in both non-diabetic and type-2 diabetic overweight/obese patients. Adiponectin levels were increased, an effect that correlated with HDL cholesterol augmentation, while small dense LDL cholesterol levels were decreased in patients receiving Rimonabant 20 mg compared with those receiving placebo in RIO Lipids. Furthermore, in RIO Diabetes, a 0.7% reduction in glycated haemoglobin (HbA1c) levels was observed in metformin- or sulphonylurea-treated patients with type-2 diabetes, an effect recently confirmed in the 6-month SERENADE (Study Evaluating Rimonabant Efficacy in drug-NAive DiabEtic patients) trial in drug-naive diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. The positive effects observed after 1 year were maintained after 2 years. Rimonabant was generally well-tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared with placebo. In clinical practice, Rimonabant has to be prescribed to the right patient, i.e. overweight/obese subjects with cardiometabolic risk factors and with no major depressive illness and/or ongoing antidepressive treatment, in order to both maximise efficacy and minimise safety issues. New trials are supposed to confirm the potential role of Rimonabant in patients with abdominal adiposity, atherogenic dyslipidaemia and/or type-2 diabetes, i.e. at high cardiometabolic risk.
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effect of Rimonabant on blood pressure in overweight obese patients with without co morbidities analysis of pooled rio study results
Journal of Hypertension, 2008Co-Authors: Luis M Ruilope, Jeanpierre Despres, Andre Scheen, Xavier Pisunyer, G Mancia, Alberto Zanchetti, Luc Van GaalAbstract:OBJECTIVE Rimonabant, the first selective cannabinoid type 1 (CB1) receptor blocker, has been shown to improve multiple cardiometabolic risk factors in overweight/obese patients. This analysis assessed the impact of Rimonabant on blood pressure in the pooled population from four large trials with similar design - the Rimonabant-In-Obesity (RIO) programme. METHODS RIO-Europe (n = 1507) and RIO-North America (n = 3040) recruited overweight/obese patients, and RIO-Lipids (n = 1033) and RIO-Diabetes (n = 1045) recruited overweight/obese patients with untreated dyslipidaemia or type 2 diabetes, respectively. At study entry (screening), 37.2% (n = 2463) of patients had hypertension, 71.4% (n = 1757) of whom were taking an antihypertensive treatment. RESULTS After 1 year of treatment, mean change in systolic blood pressure (SBP) from baseline was -0.8 mmHg for Rimonabant 20 mg versus +0.3 mmHg for placebo (P = 0.007); diastolic blood pressure (DBP) decreased by -0.8 versus -0.3 mmHg (P = 0.029) respectively. In the subgroup of patients with high blood pressure at baseline, SBP change was -7.5 mmHg for Rimonabant 20 mg versus -4.7 mmHg for placebo (P = 0.005); DBP change was -5.2 versus -3.0 mmHg (P < 0.001). Reductions were more pronounced in patients with dyslipidaemia and type 2 diabetes. There was no effect of Rimonabant 20 mg on blood pressure beyond that expected from weight loss alone. Overall, there was a similar incidence of adverse events (AEs) at 1 year in the placebo (81.8%) and Rimonabant 20 mg (86.0%). The most common AEs occurring with Rimonabant were nausea, dizziness, arthralgia and diarrhoea. A slightly higher proportion of patients in the Rimonabant 20 mg group discontinued as a result of AEs (13.8%) versus placebo (7.2%). CONCLUSIONS Rimonabant 20 mg led to modest, but significant SBP and DBP reductions in overweight/obese patients. The effect of Rimonabant on blood pressure appears to be mediated by weight loss.
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efficacy and tolerability of Rimonabant in overweight or obese patients with type 2 diabetes a randomised controlled study
The Lancet, 2006Co-Authors: Andre Scheen, Priscilla Hollander, N Finer, Michael Dennis Jensen, Luc Van GaalAbstract:Summary Background Rimonabant, a selective cannabinoid type 1 receptor blocker, reduces bodyweight and improves cardiovascular and metabolic risk factors in non-diabetic overweight or obese patients. The aim of the RIO-Diabetes trial was to assess the efficacy and safety of Rimonabant in overweight or obese patients with type 2 diabetes that was inadequately controlled by metformin or sulphonylureas. Methods 1047 overweight or obese type 2 diabetes patients (body-mass index 27–40 kg/m 2 ) with a haemoglobin A 1c (HbA 1c ) concentration of 6·5–10·0% (mean 7·3% [SD 0·9] at baseline) already on metformin or sulphonylurea monotherapy were given a mild hypocaloric diet and advice for increased physical activity, and randomly assigned placebo (n=348), 5 mg/day Rimonabant (360) or 20 mg/day Rimonabant (339) for 1 year. Two individuals in the 5 mg/day group did not receive double-blind treatment and were thus not included in the final analysis. The primary endpoint was weight change from baseline after 1 year of treatment. Analyses were done on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov, number NCT00029848. Findings 692 patients completed the 1 year follow-up; numbers in each group after 1 year were much the same. Weight loss was significantly greater after 1 year in both Rimonabant groups than in the placebo group (placebo: −1·4 kg [SD 3·6]; 5 mg/day: −2·3 kg [4·2], p=0·01 vs placebo; 20 mg/day: −5·3 kg [5·2], p vs placebo). Rimonabant was generally well tolerated. The incidence of adverse events that led to discontinuation was slightly greater in the 20 mg/day Rimonabant group, mainly due to depressed mood disorders, nausea, and dizziness. Interpretation These data indicate that 20 mg/day Rimonabant, in combination with diet and exercise, can produce a clinically meaningful reduction in bodyweight and improve HbA 1c and a number of cardiovascular and metabolic risk factors in overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas.
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Rimonabant improves cardiometabolic risk profile in obese or overweight subjects: overview of RIO studies
Revue medicale suisse, 2006Co-Authors: Andre Scheen, Jeanpierre Despres, Luc Van Gaal, Alain Golay, Xavier Pi-sunyer, Corinne HanotinAbstract:RIO (Rimonabant In Obesity and related disorders) is a large phase 3 programme (>6600 patients) evaluating the efficacy and safety of Rimonabant (5 or 20 mg/day), a CBI receptor antagonist of endocannabinoid system, in obese or overweight patients with or without comorbidities (RIO-Europe and RIO-North America), with untreated dyslipidaemia (RIO-Lipids) or with type 2 diabetes treated with metformin or sulfonylurea (RIO-Diabetes). Compared to placebo, Rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. Almost half of the metabolic effects, including adiponectin increase, occur beyond weight loss, suggesting a direct peripheral effect of Rimonabant.
Torbjörn U. C. Järbe - One of the best experts on this subject based on the ideXlab platform.
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Central mediation and differential blockade by cannabinergics of the discriminative stimulus effects of the cannabinoid CB_1 receptor antagonist Rimonabant in rats
Psychopharmacology, 2011Co-Authors: Torbjörn U. C. Järbe, Subramanian K. Vadivel, Brian J. Lemay, V. Kiran Vemuri, Alexander Zvonok, Alexandros MakriyannisAbstract:Rationale Discovery of an endocannabinoid signaling system launched the development of the blocker Rimonabant, a cannabinoid CB1 receptor (CB_1R) antagonist/inverse agonist. Due to untoward effects, this medication was withdrawn and efforts have been directed towards discovering chemicals with more benign profiles. Objective This study aims to comparatively evaluate new ligands using a Rimonabant discriminated drinking aversion procedure. Methods Rats discriminated between Rimonabant (5.6 mg/kg) and vehicle. The 30 min saccharin (0.1%) drinking after Rimonabant pretreatment was followed by injection of lithium chloride (120 mg/kg) in the experimental animals. After vehicle pretreatment, experimental animals were given i.p. NaCl (10 ml/kg). Postdrinking treatment for controls was NaCl, irrespective of pretreatment condition (Rimonabant or vehicle). Results The centrally acting neutral CB_1R antagonist AM4113, but not the limited brain penetrating CB_1R neutral antagonist AM6545, substituted for Rimonabant. The CB_1R agonists THC (1–10 mg/kg), AM1346 (1–10 mg/kg) did not substitute. The Rimonabant-induced conditioned suppression of saccharin drinking was attenuated when CB_1R agonists AM5983 (0.01–1 mg/kg) and THC (10 mg/kg), but not the CB_1R agonist AM1346 (0.1–18 mg/kg), were combined with Rimonabant (5.6 mg/kg). By varying the injection-to-test interval, we gauged the relative duration of the cueing effects of Rimonabant, and the in vivo functional half-life was estimated to be approximately 1.5 h. Conclusion A neutral CB_1R antagonist (AM4113) produced cueing effects similar to those of Rimonabant and generalization likely was centrally mediated. The functional cueing effects of Rimonabant are relatively short-acting, pharmacologically selective, and differentially blocked by cannabinergics.
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Antagonism of ∆⁹-THC induced behavioral effects by Rimonabant: time course studies in rats.
European journal of pharmacology, 2010Co-Authors: Torbjörn U. C. Järbe, Roger S Gifford, Alexandros MakriyannisAbstract:The objective was to examine the time course of the cannabinoid 1 receptor antagonist/inverse agonist Rimonabant's ability to antagonize in vivo cannabinergic agonist effects. We used two behavioral procedures sensitive to the effects of ∆⁹-tetrahydrocannabinol (∆⁹-THC): rat drug discrimination (EXP-1) and suppression of fixed-ratio responding (FR) for food reinforcement (EXP-2). Two training doses of ∆⁹-THC (1.8 and 3 mg/kg) served as discriminative cues in two groups discriminating ∆⁹-THC from vehicle; injections were i.p. 20 min before session onset. Tests assessed the dose-response functions of ∆⁹-THC and the time course for Rimonabant in its ability to block the discriminative stimulus effects of ∆⁹-THC. For antagonism testing, the training doses of ∆⁹-THC were used and the Rimonabant dose was 1mg/kg. Tests were 20, 60, 120, and 240 min post Rimonabant administration; ∆⁹-THC was always administered 20 min prior to testing. For EXP-2, only one response lever was activated and every 10th (FR-10) press on that lever resulted in food delivery. Once the response rate stabilized, tests occurred with ∆⁹-THC, Rimonabant and combinations of the drugs. The ED(50) estimates for the dose-response functions were 0.38 (±0.28-0.51) and 0.50 (±0.40-0.63) mg/kg for the training doses of 1.8 and 3 mg/kg ∆⁹-THC, respectively. The time course studies suggested functional half-life estimates of 128.4 (±95.7-172.2) and 98.4 (±64.2-150.7) min by Rimonabant for the two groups in EXP-1, respectively. Similarly, the functional half-life of Rimonabant was 118.9 (±66.1-213.9) min in EXP-2. Thus, antagonism of ∆⁹-THC by Rimonabant is relatively short lasting.
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Antagonism of Δ9-THC induced behavioral effects by Rimonabant: time-course studies in rats
European Journal of Pharmacology, 2010Co-Authors: Torbjörn U. C. Järbe, Roger S Gifford, Alexandros MakriyannisAbstract:Abstract The objective was to examine the time course of the cannabinoid 1 receptor antagonist/inverse agonist Rimonabant's ability to antagonize in vivo cannabinergic agonist effects. We used two behavioral procedures sensitive to the effects of ∆ 9 -tetrahydrocannabinol (∆ 9 -THC): rat drug discrimination (EXP-1) and suppression of fixed-ratio responding (FR) for food reinforcement (EXP-2). Two training doses of ∆ 9 -THC (1.8 and 3 mg/kg) served as discriminative cues in two groups discriminating ∆ 9 -THC from vehicle; injections were i.p. 20 min before session onset. Tests assessed the dose–response functions of ∆ 9 -THC and the time course for Rimonabant in its ability to block the discriminative stimulus effects of ∆ 9 -THC. For antagonism testing, the training doses of ∆ 9 -THC were used and the Rimonabant dose was 1 mg/kg. Tests were 20, 60, 120, and 240 min post Rimonabant administration; ∆ 9 -THC was always administered 20 min prior to testing. For EXP-2, only one response lever was activated and every 10th (FR-10) press on that lever resulted in food delivery. Once the response rate stabilized, tests occurred with ∆ 9 -THC, Rimonabant and combinations of the drugs. The ED 50 estimates for the dose–response functions were 0.38 (± 0.28–0.51) and 0.50 (± 0.40–0.63) mg/kg for the training doses of 1.8 and 3 mg/kg ∆ 9 -THC, respectively. The time course studies suggested functional half-life estimates of 128.4 (± 95.7–172.2) and 98.4 (± 64.2–150.7) min by Rimonabant for the two groups in EXP-1, respectively. Similarly, the functional half-life of Rimonabant was 118.9 (± 66.1–213.9) min in EXP-2. Thus, antagonism of ∆ 9 -THC by Rimonabant is relatively short lasting.
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Discriminative stimulus effects of the cannabinoid CB_1 receptor antagonist Rimonabant in rats
Psychopharmacology, 2008Co-Authors: Torbjörn U. C. Järbe, Subramanian K. Vadivel, Alexandros MakriyannisAbstract:Objective To examine the discriminative stimulus effects of the cannabinoid CB_1 receptor (CB_1R) antagonist/inverse agonist Rimonabant (SR141716A) using a discriminated taste aversion (DTA) procedure. Materials and methods Groups of rats were trained to discriminate between drug (5.6 or 3 mg/kg) and vehicle in DTA ( t ′ = 20 min). The 30-min drinking opportunity after Rimonabant pretreatment was followed by injection of lithium chloride (120 mg/kg) in the experimental (EXP) animals. When offered fluid after vehicle pretreatment, EXP animals subsequently were given intraperitoneal saline (NaCl, 10 ml/kg). Post-drinking treatment for controls (CONT) was NaCl irrespective of the pretreatment condition (Rimonabant or vehicle). Tests examined other doses and drugs ( t ′ = 20 min). Results The Rimonabant analog AM251 (1 to 5.6 mg/kg) substituted for Rimonabant. AM281 also appeared to substitute, but interpretation is complicated by unconditioned effects (drinking suppressed also in the CONT group). The CB_2R antagonists SR144528 (18 and 30 mg/kg), AM630 (1 to 10 mg/kg), and the CB_1R agonist methanandamide (mAEA, 3 and 10 mg/kg) did not substitute. There was a dose-related attenuation of the Rimonabant-induced suppression of saccharin drinking when Δ9-tetrahydrocannabinol (Δ9-THC; 0.3 to 5.6 mg/kg), but not mAEA (1 to 10 mg/kg), was given together with Rimonabant (3 mg/kg). Unconditioned effects occurred with the mAEA–Rimonabant combination, not evident for combinations of Rimonabant and Δ9-THC. mAEA (10 mg/kg) plus AM251 (5.6 mg/kg) resulted in strong unconditioned effects. Conclusion Rimonabant induces a discriminative stimulus in DTA that continues to show potential for further examination of cannabinoid receptor antagonism.
Jeanpierre Despres - One of the best experts on this subject based on the ideXlab platform.
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effect of Rimonabant on carotid intima media thickness cimt progression in patients with abdominal obesity and metabolic syndrome the auditor trial
Heart, 2011Co-Authors: Daniel H Oleary, Jeanpierre Despres, Anne Q Reuwer, Steven Nissen, John E Deanfield, Michael W Brown, Rong Zhou, Salvatore M Zabbatino, Bernard Job, John J P KasteleinAbstract:Objective The aim of this trial was to determine whether obese patients benefit from treatment with Rimonabant in terms of progression of carotid atherosclerosis. Rimonabant, a selective cannabinoid-1 receptor blocker, reduces body weight and improves cardiometabolic risk factors in patients who are obese. Design, setting, patients, interventions and results A prospective, double-blind, placebo-controlled trial (Atherosclerosis Underlying Development assessed by Intimaemedia Thickness in patients On Rimonabant (AUDITOR)) randomised 661 patients with abdominal obesity and metabolic syndrome to Rimonabant or placebo for 30 months of treatment. The absolute change in the average value for six segments of far wall carotid intimaemedia thickness from baseline to month 30 was 0.01060.095 mm in the Rimonabant group and 0.01260.091 mm in the placebo group (p¼0.67). The annualised change was an increase of 0.00560.042 mm for the Rimonabant-treated group and 0.00760.043 mm for the placebo-treated group (p¼0.45). Conclusions There was no difference in atherosclerosis progression between patients receiving Rimonabant for 30 months and those receiving placebo for the primary efficacy measure (absolute change in carotid intimaemedia thickness). These findings are consistent with a similar study using coronary intravascular ultrasound and another study evaluating the occurrence of cardiovascular events. Our findings suggest that a 5% loss of body weight over a 30-month period with Rimonabant is insufficient to modify atherosclerosis progression in the carotid artery in obese patients with metabolic syndrome. Clinical trial registration information clinicaltrials.gov Identifier: NCT00228176.
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effect of Rimonabant on the high triglyceride low hdl cholesterol dyslipidemia intraabdominal adiposity and liver fat the adagio lipids trial
Arteriosclerosis Thrombosis and Vascular Biology, 2009Co-Authors: Jeanpierre Despres, Robert Ross, Gabor Boka, Natalie Almeras, Isabelle LemieuxAbstract:Background— Rimonabant, the first selective cannabinoid type 1 (CB 1 ) receptor antagonist, improves cardiometabolic risk factors in overweight/obese patients. ADAGIO-Lipids assessed the effect of Rimonabant on cardiometabolic risk factors and intraabdominal and liver fat. Methods and Results— 803 abdominally obese patients with atherogenic dyslipidemia (increased triglycerides [TG] or reduced high-density lipoprotein–cholesterol [HDL-C]) were randomized to placebo or Rimonabant 20 mg/d for 1 year. HDL-C and TG were coprimary end points. Intraabdominal (visceral) and liver fat were measured by computed tomography in a subgroup of 231 patients. In total, 73% of Rimonabant- and 70% of placebo-treated patients completed the study treatment. Rimonabant 20 mg produced significantly greater changes from baseline versus placebo in HDL-C (+7.4%) and TG levels (−18%; P 2 , HDL 3 , C-reactive protein, and adiponectin levels (all P P P P P P Conclusions— In abdominally obese patients with atherogenic dyslipidemia, Rimonabant 20 mg significantly improved multiple cardiometabolic risk markers and induced significant reductions in both intraabdominal and liver fat.
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effect of Rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease the stradivarius randomized controlled trial
JAMA, 2008Co-Authors: Steven E Nissen, Christopher P. Cannon, Jeanpierre Despres, John E Deanfield, John J P Kastelein, Stephen J Nicholls, Kathy Wolski, Josep Rodescabau, Steven R Steinhubl, Samir R KapadiaAbstract:Context: Abdominal obesity is associated with metabolic abnormalities and increased risk of atherosclerotic cardiovascular disease. However, no obesity management strategy has demonstrated the ability to slow progression of coronary disease. Objective: To determine whether weight loss and metabolic effects of the selective cannabinoid type 1 receptor antagonist Rimonabant reduces progression of coronary disease in patients with abdominal obesity and the metabolic syndrome. Design, Setting, and Patients: Randomized, double-blinded, placebo-controlled, 2-group, parallel-group trial (enrollment December 2004-December 2005) comparing Rimonabant with placebo in 839 patients at 112 centers in North America, Europe, and Australia. Interventions: Patients received dietary counseling, were randomized to receive Rimonabant (20 mg daily) or matching placebo, and underwent coronary intravascular ultrasonography at baseline (n=839) and study completion (n=676). Main Outcome Measures: The primary efficacy parameter was change in percent atheroma volume (PAV); the secondary efficacy parameter was change in normalized total atheroma volume (TAV). Results: In the Rimonabant vs placebo groups, PAV (95% confidence interval [CI]) increased 0.25% (-0.04% to 0.54%) vs 0.51% (0.22% to 0.80%) (P=.22), respectively, and TAV decreased 2.2mm3 (-4.09 to -0.24) vs an increase of 0.88mm3 (-1.03 to 2.79) (P=.03). In the Rimonabant vs placebo groups, imputing results based on baseline characteristics for patients not completing the trial, PAV increased 0.25% (-0.04% to 0.55%) vs 0.57% (0.29% to 0.84%) (P=.13), and TAV decreased 1.95mm3 (-3.8 to -0.10) vs an increase of 1.19 mm3 (-0.73 to 3.12) (P=.02). Rimonabant-treated patients had a larger reduction in body weight (4.3 kg [-5.1 to -3.5] vs 0.5 kg [-1.3 to 0.3]) and greater decrease in waist circumference (4.5 cm [-5.4 to -3.7] vs 1.0 cm [-1.9 to -0.2]) (P<.001 for both comparisons). In the Rimonabant vs placebo groups, high-density lipoprotein cholesterol levels increased 5.8mg/dL (4.9 to 6.8) (22.4%) vs 1.8mg/dL (0.9 to 2.7) (6.9%) (P<.001), and median triglyceride levels decreased 24.8mg/dL (-35.4 to -17.3) (20.5%) vs 8.9mg/dL (-14.2 to -1.8) (6.2%) (P<.001). Rimonabant-treated patients had greater decreases in high-sensitivity C-reactive protein (1.3 mg/dL [-1.7 to -1.2] [50.3%] vs 0.9 mg/dL [-1.4 to -0.5] [30.9%]) and less increase in glycated hemoglobin levels (0.11%[0.02% to 0.20%] vs 0.40% [0.31% to 0.49%]) (P<.001 for both comparisons). Psychiatric adverse effects were more common in the Rimonabant group (43.4% vs 28.4%, P<.001). Conclusions: After 18 months of treatment, the study failed to show an effect for Rimonabant on disease progression for the primary end point (PAV) but showed a favorable effect on the secondary end point (TAV). Determining whether Rimonabant is useful in management of coronary disease will require additional imaging and outcomes trials, which are currently under way. Trial Registration: clinicaltrials.gov Identifier: NCT00124332.
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effect of Rimonabant on blood pressure in overweight obese patients with without co morbidities analysis of pooled rio study results
Journal of Hypertension, 2008Co-Authors: Luis M Ruilope, Jeanpierre Despres, Andre Scheen, Xavier Pisunyer, G Mancia, Alberto Zanchetti, Luc Van GaalAbstract:OBJECTIVE Rimonabant, the first selective cannabinoid type 1 (CB1) receptor blocker, has been shown to improve multiple cardiometabolic risk factors in overweight/obese patients. This analysis assessed the impact of Rimonabant on blood pressure in the pooled population from four large trials with similar design - the Rimonabant-In-Obesity (RIO) programme. METHODS RIO-Europe (n = 1507) and RIO-North America (n = 3040) recruited overweight/obese patients, and RIO-Lipids (n = 1033) and RIO-Diabetes (n = 1045) recruited overweight/obese patients with untreated dyslipidaemia or type 2 diabetes, respectively. At study entry (screening), 37.2% (n = 2463) of patients had hypertension, 71.4% (n = 1757) of whom were taking an antihypertensive treatment. RESULTS After 1 year of treatment, mean change in systolic blood pressure (SBP) from baseline was -0.8 mmHg for Rimonabant 20 mg versus +0.3 mmHg for placebo (P = 0.007); diastolic blood pressure (DBP) decreased by -0.8 versus -0.3 mmHg (P = 0.029) respectively. In the subgroup of patients with high blood pressure at baseline, SBP change was -7.5 mmHg for Rimonabant 20 mg versus -4.7 mmHg for placebo (P = 0.005); DBP change was -5.2 versus -3.0 mmHg (P < 0.001). Reductions were more pronounced in patients with dyslipidaemia and type 2 diabetes. There was no effect of Rimonabant 20 mg on blood pressure beyond that expected from weight loss alone. Overall, there was a similar incidence of adverse events (AEs) at 1 year in the placebo (81.8%) and Rimonabant 20 mg (86.0%). The most common AEs occurring with Rimonabant were nausea, dizziness, arthralgia and diarrhoea. A slightly higher proportion of patients in the Rimonabant 20 mg group discontinued as a result of AEs (13.8%) versus placebo (7.2%). CONCLUSIONS Rimonabant 20 mg led to modest, but significant SBP and DBP reductions in overweight/obese patients. The effect of Rimonabant on blood pressure appears to be mediated by weight loss.
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Rimonabant improves cardiometabolic risk profile in obese or overweight subjects: overview of RIO studies
Revue medicale suisse, 2006Co-Authors: Andre Scheen, Jeanpierre Despres, Luc Van Gaal, Alain Golay, Xavier Pi-sunyer, Corinne HanotinAbstract:RIO (Rimonabant In Obesity and related disorders) is a large phase 3 programme (>6600 patients) evaluating the efficacy and safety of Rimonabant (5 or 20 mg/day), a CBI receptor antagonist of endocannabinoid system, in obese or overweight patients with or without comorbidities (RIO-Europe and RIO-North America), with untreated dyslipidaemia (RIO-Lipids) or with type 2 diabetes treated with metformin or sulfonylurea (RIO-Diabetes). Compared to placebo, Rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. Almost half of the metabolic effects, including adiponectin increase, occur beyond weight loss, suggesting a direct peripheral effect of Rimonabant.
