piperidines and Obesity

Adiponectin, an adipokine secreted by adipocytes, exerts favorable effects in the milieu of diabetes and metabolic syndrome through its anti-inflammatory, antifibrotic, and antioxidant effects. It mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor (PPAR)-α expression through adiponectin receptor (AdipoR)1 and AdipoR2, respectively, which in turn activate PPAR gamma coactivator 1 alpha (PGC-1α), increase the phosphorylation of acyl CoA oxidase, and upregulate the uncoupling proteins involved in energy consumption. Moreover, adiponectin potently stimulates ceramidase activity associated with its two receptors and enhances ceramide catabolism and the formation of its anti-apoptotic metabolite, sphingosine 1 phosphate (S1P), independently of AMPK. Low circulating adiponectin levels in obese patients with a risk of insulin resistance, type 2 diabetes, and cardiovascular diseases, and increased adiponectin expression in the state of albuminuria suggest a protective and compensatory role for adiponectin in mitigating further renal injury during the development of overt diabetic kidney disease (DKD). We propose AdipoRon, an orally active synthetic adiponectin receptor agonist as a promising drug for restoration of DKD without inducing systemic adverse effects. Its renoprotective role against lipotoxicity and oxidative stress by enhancing the AMPK/PPARα pathway and ceramidase activity through AdipoRs is revealed here.

Topics: Adiponectin; Animals; Diabetes Mellitus, Type 2; Humans; Kidney; Lipid Metabolism; Obesity; Oxidative Stress; Piperidines; Receptors, Adiponectin

The use of conventional pharmacokinetic parameters sets 'models' derived from nonobese patients has proven inadequate to administer intravenous anesthetics in the obese population and is commonly associated with higher than anticipated plasma propofol concentrations when used with target (plasma or effect site) controlled infusion pumps. In this review we will describe recent modeling strategies to characterize the disposition of intravenous anesthetics in the obese patient and will show clinically relevant aspects of new model's performance in the obese population.. Because clearance of a drug increases in a nonlinear manner with weight, nonlinear relationships better scale infusion rates between lean and obese individuals. Allometric concepts have been successfully used to describe size-related nonlinear changes in clearances. Other nonlinear scaling options include the use of descriptors such as body surface area, lean body weight, fat-free mass, and normal fat mass. Newer pharmacokinetic models, determined from obese patient data, have been developed for propofol and remifentanil using allometric concepts and comprehensive size descriptors.. Pharmacokinetic models to perform target-controlled infusion in the obese population should incorporate descriptors that reflect with greater precision the influence of body composition in volumes and clearances of each drug. It is our hope that commercially available pumps will soon incorporate these new models to improve the performance of this technique in the obese population.

Topics: Anesthetics, Intravenous; Body Composition; Body Mass Index; Body Weight; Humans; Obesity; Patient-Specific Modeling; Piperidines; Propofol; Remifentanil

Neuraxial labor analgesia can be initiated via combined spinal-epidural (CSE) or stand-alone epidural. Pros and cons of these techniques are outlined in this review. In recent years computer-integrated patient-controlled epidural analgesia (CI-PCEA) and programed intermittent epidural boluses (PIEB) have been developed, adding to continuous infusion and PCEA for the maintenance of neuraxial analgesia. Postdural puncture headache (PDPH) and fever can occur secondary to labor epidural that both have clinical relevance for the care givers. Insights into the mechanism of epidural fever and treatment strategies for PDPH are outlined. Due to the increase in obesity the specific considerations for this patient group are discussed. New data have been presented for remifentanil, an ultra-shortly acting opioid, that is used in obstetric analgesia. Without breaking new data, the use of nitrous oxide especially by midwives has a kind of renaissance, and this will be discussed, too.

Topics: Analgesia, Epidural; Analgesia, Obstetrical; Analgesia, Patient-Controlled; Analgesics; Female; Fever; Humans; Nitrous Oxide; Obesity; Piperidines; Pregnancy; Pregnancy Complications; Punctures; Remifentanil

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Antagonists (inverse agonists) of the cannabinoid-1 (CB1) receptor showed promise as new therapies for controlling obesity and related metabolic function/liver disease. These agents, representing diverse chemical series, shared the property of brain penetration due to the initial belief that therapeutic benefit was mainly based on brain receptor interaction. However, undesirable CNS-based side effects of the only marketed agent in this class, rimonabant, led to its removal, and termination of the development of other clinical candidates soon followed. Re-evaluation of this approach has focused on neutral or peripherally restricted (PR) antagonists. Supporting these strategies, pharmacological evidence indicates most if not all of the properties of globally acting agents may be captured by molecules with little brain presence. Methodology that can be used to eliminate BBB penetration and the means (in vitro assays, tissue distribution and receptor occupancy determinations, behavioral paradigms) to identify potential agents with little brain presence is discussed. Focus will be on the pharmacology supporting the contention that reported agents are truly peripherally restricted. Notable examples of these types of compounds are: TM38837 (structure not disclosed); AM6545 (8); JD5037 (15b); RTI-12 (19).

Topics: Animals; Brain; Cocaine; Drug Discovery; Humans; Liver Diseases; Metabolic Diseases; Morpholines; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Sulfonamides

Obesity is a chronic disease, and it requires chronic therapy. Hypertension, dyslipidemia, diabetes and cardiovascular diseases are leading causes of mortality in the modern world. All of them are strongly linked to obesity. While treating obesity, those conditions are also managed. Obese patients should always be treated through lifestyle interventions, though the results of such interventions are modest. Pharmacotherapy is a second step in the treatment of obesity, approved only when weight loss targets were not reached through lifestyle intervention. During the history of antiobesity drugs, many of them were withdrawn because of their side effects. Various guidelines recommend prescribing drug therapy for obesity through consideration of the potential benefits and limitations. Orlistat deactivates intestinal lipase and inhibits intestinal fat lipolysis. It is actually the only drug on the European market approved for the treatment of obesity. Orlistat therapy reduces weight to a modest extent, but it reduces the incidence of diabetes beyond the result achieved with lifestyle changes. Recently, some effective antiobesity drugs like sibutramine and rimonabant have been removed from the market due to their side effects. The new combination of topimarate and fentermine is approved in the US but not in Europe. The cost effectiveness of long-term pharmacotherapy of obesity is still an unresolved question.

Topics: Anti-Obesity Agents; Appetite; Combined Modality Therapy; Comorbidity; Cost-Benefit Analysis; Cyclobutanes; Diabetes Mellitus, Type 2; Diet, Diabetic; Drug Combinations; Exercise Therapy; Fructose; Gastrointestinal Hormones; Humans; Incretins; Insulin; Insulin Secretion; Intestines; Lactones; Leptin; Life Style; Models, Biological; Neuropeptides; Obesity; Orlistat; Phentermine; Phytotherapy; Piperidines; Plant Preparations; Pyrazoles; Rimonabant; Topiramate

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively.

Topics: Benzazepines; Diabetes Mellitus, Type 2; Heart Valve Diseases; Humans; Molecular Structure; Obesity; Parkinson Disease; Piperidines; Receptors, Serotonin; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Urea

The study aims to compare anti-obesity interventions in a single evidence synthesis framework. Electronic databases were searched for randomized controlled trials of orlistat, rimonabant or sibutramine reporting weight or body mass index (BMI) change from baseline at 3, 6 or 12 months. A mixed treatment comparison was used to combine direct and indirect trial evidence. Ninety-four studies involving 24,808 individuals were included; 83 trials included data on weight change and 41 on BMI change. All results are in comparison with placebo. The active drugs were all effective at reducing weight and BMI. At 3 months, orlistat reduced weight by -2.65 kg (95% credibility interval -4.00 kg, -1.31 kg). For sibutramine, 15 mg gave a greater reduction than 10 mg at 12 months, -6.35 kg versus -5.42 kg, respectively. Rimonabant reduced weight by -11.23 kg at 3 months and -4.55 kg at 12 months. Lifestyle advice alone also reduced weight at 6 and 12 months, but was less effective than the pharmacological interventions. In conclusion, modest weight reductions were seen for all pharmacological interventions. Those interventions which have now been withdrawn from use (sibutramine and rimonabant) seem to be the most effective, implying that there may be a place in clinical practice for similar drugs if side effects could be avoided.

Topics: Anti-Obesity Agents; Body Mass Index; Cyclobutanes; Humans; Lactones; Life Style; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome; Weight Loss

Obesity [defined as a body mass index (BMI) ≥ 30 kg/m(2)] represents a considerable public health problem and is associated with a significant range of comorbidities and an increased mortality risk. The primary aim of the management of obesity is to achieve weight reduction in the interests of health. For obese patients who cannot achieve or maintain a healthy weight by non-pharmacological means, drug therapy is recommended in combination with non-pharmacological interventions such as dietary modifications and exercise.. To evaluate the clinical effectiveness and cost-effectiveness of three pharmacological interventions in obese patients.. Clinical effectiveness data used in the meta-analysis were sourced from articles identified in a systematic review of the literature. Data used to inform transitions to obesity-related comorbidities were derived from the General Practice Research Database (GPRD). The results of the meta-analysis and GPRD analyses informed the economic model supplemented by data from the Health Survey for England and other UK-specific data sourced from the literature.. A systematic literature review was conducted of the clinical effectiveness and cost-effectiveness of orlistat, sibutramine and rimonabant within their licensed indications for the treatment of obese patients. Electronic bibliographic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched in January 2009, and the reference lists of relevant articles were checked. Studies were included if they compared orlistat, sibutramine or rimonabant with lifestyle and/or exercise advice (standard care), placebo or metformin.. Overall, 94 studies involving 24,808 individuals were included in the clinical meta-analysis. Eighty-three trials included data on weight change, 41 included data on BMI change and 45 and 36 studies reported on 5% and 10% body weight loss, respectively. Overall, the results show that the active drug interventions are all effective at reducing weight and BMI compared with placebo. In the case of sibutramine, the higher dose (15 mg) resulted in a greater reduction than the lower dose (10 mg). Generally, the data quality of the trials included was low with poor reporting of standard errors and standard deviations. Results from the BMI risk models derived from the GPRD showed consistent increases in risk with increasing BMI. Adjustments for key confounders, such as age, sex and smoking status, were found to be statistically significant at the 5% level, in all risk models. Applying linear models to estimate BMI trajectories, for the diabetic cohort, an average increase in BMI of 0.040 per year for both men and women was observed. The non-diabetic cohort model showed an increase in BMI of 0.175 per year for women and 0.145 per year for men. The results of the cost-effectiveness analyses suggest that sibutramine 15 mg dominates the other three active interventions and the net benefit analyses show that sibutramine 15 mg is the most cost-effective alternative for thresholds > £2000 per quality-adjusted life-year (QALY). However, both sibutramine and rimonabant have been withdrawn because of safety concerns relating to potential treatment-induced fatal adverse events. If the proportion of patients who experienced a fatal adverse event was > 1.8% (1.5%, 1.0%) for sibutramine 15 mg (sibutramine 10 mg, rimonabant) the treatment would not be considered cost-effective when using a threshold of £20,000 per QALY.. The clinical review did not include all possible lifestyle comparators, with the inclusion limited to only those trials included one of the active drug interventions. We also excluded all studies not reported in English. Although the clinical review included data from 94 studies, the quality of data was generally low, particularly in terms of the reporting of standard deviation. There was also inconsistency between the results of the mixed-treatment comparison (MTC) and the pair-wise analyses.. The MTC of anti-obesity treatments shows that all the active treatments are effective at reducing weight and BMI. The economic results show that, compared with placebo, the treatments are all cost-effective when using a threshold of £20,000 per QALY, and, within the limitations of the data available, sibutramine 15 mg dominates the other three interventions. This work has highlighted many areas of methodological research that could be explored, including assessing inconsistencies within a network to determine differences between the results of pair-wise and MTC analyses; the use of meta-regression methods to look for effect modifiers; exploring the effect of local publication bias; and the use of joint models to analyse the repeated measures of BMI and the time-to-event processes simultaneously.. The National Institute for Health Research Health Technology Assessment programme.

Topics: Anti-Obesity Agents; Cost-Benefit Analysis; Cyclobutanes; Drug Costs; Exercise; Female; Humans; Lactones; Male; Middle Aged; Obesity; Orlistat; Piperidines; Primary Health Care; Pyrazoles; Rimonabant; Risk Reduction Behavior; Treatment Outcome

Currently, obesity presents one of the biggest health problems. Management strategies for weight reduction in obese individuals include changes in life style such as exercise and diet, behavioral therapy, and pharmacological treatment, and in certain cases surgical intervention. Diet and exercise are best for both prevention and treatment, but both require much discipline and are difficult to maintain. Drug treatment of obesity offer a possible adjunct, but it may only have modest results, limited by side effects; furthermore, the weight lowering effects last only as long as the drug is being taken and, unfortunately, as soon as the administration is stopped, the weight is regained. These strategies should be used in a combination for higher efficacy. Drugs used to induce weight loss have various effects: they increase satiety, reduce the absorption of nutrients or make metabolism faster; but their effect is usually moderate. In the past, several drugs were used in the pharmacological therapy of weight reduction including thyroid hormone, dinitrophenol, amphetamines and their analogues, e.g. fenfluramine, At present, only orlistat is available in the long term treatment (≥ 24 weeks) of obesity as sibutramine and rimonabant were withdrawn form the market. Several new anti-obesity drugs are being tested at present, and liraglutide, a GLP-1 analogue (incretin mimetic), is the most promising one.

Topics: Amides; Anti-Obesity Agents; Anticonvulsants; Antidepressive Agents; Basal Metabolism; Benzazepines; Benzoxazines; Body Mass Index; Bridged Bicyclo Compounds, Heterocyclic; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Combined Modality Therapy; Cyclobutanes; Dexfenfluramine; Fatty Acids; Female; Fenfluramine; Glucagon-Like Peptide 1; Human Growth Hormone; Humans; Intestinal Absorption; Lactones; Leptin; Life Style; Liraglutide; Male; Norepinephrine; Obesity; Obesity, Morbid; Orlistat; Piperidines; Pyrazoles; Pyridines; Receptor, Melanocortin, Type 4; Rimonabant; Satiation; Serotonin; Sodium-Glucose Transport Proteins; Sucrose; Thyroid Hormones

Cannabidiol, a cannabinoid and serotonin receptor antagonist, may alleviate hyperphagia without the side effects of rimonabant (for example depression and reduced insulin sensitivity). Similar to the peroxisome proliferator-activated receptor-gamma agonists, it may also help the differentation of adipocytes. Cannabidiol has an immunomodulating effect, as well, that helps lessen the progression of atherosclerosis induced by high glucose level. It may also be effective in fighting ischaemic diseases, the most harmful complications of metabolic syndrome. However, it can only be administered as an adjuvant therapy because of its low binding potency, and its inhibiting effect of cytochrome P450 enzymes should also be considered. Nevertheless, it may be beneficially used in adjuvant therapy because of its few side effects.

Topics: Adipocytes; Appetite Depressants; Atherosclerosis; Cannabidiol; Cannabinoid Receptor Antagonists; Disease Progression; Humans; Hyperphagia; Ischemia; Metabolic Syndrome; Obesity; Piperidines; PPAR gamma; Pyrazoles; Rimonabant

CB(1) receptor antagonists were among the most promising drug targets in the last decade. They have been explored and found to be effective as therapeutic agents for obesity and related cardiometabolic problems; however, use of rimonabant, the first marketed CB(1) receptor antagonist, has been suspended because of its anxiogenic and depressogenic side effects. Because some other antiobesity drugs, like dexfenfluramine or sibutramine, were also suspended, the unmet need for drugs that reduce body weight became enormous. One approach that emerged was the use of CB(1) receptor antagonists that poorly cross the blood brain barrier, the second, the development of neutral antagonists instead of inverse agonists, and the third, use of personalized medicine, namely the selection of the patient population without psychiatric side effects. In this review, we dissect the peripheral and central mechanisms involved in the effects of CB(1) receptor antagonists and argue that central mechanisms are more or less involved in most cardiometabolic therapeutic effects and thus, among patients with unsatisfactory therapeutic response to compounds with peripheral action, centrally acting antagonists may be needed. An analysis of pharmacogenetic factors may help to identify persons who are at no or low risk for psychiatric adverse effects. Here, we present the models and identify molecular mechanisms and receptors involved in the effects of stress-, anxiety- and depression-related neurocircuitries sensitive to CB(1) receptor antagonists, like the serotonergic, noradrenergic and dopaminergic systems, which are not only regulated by CB(1) receptors, but also regulate the synthesis of the endocannabinoid 2-arachidonoyl-glycerol.

Topics: Anti-Obesity Agents; Anxiety Disorders; Depressive Disorder; Humans; Obesity; Piperidines; Precision Medicine; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Topics: Animals; Cyclobutanes; Diabetes Mellitus; Female; Humans; Incretins; Insulin; Lactones; Male; Metformin; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Sex Characteristics; Sulfonylurea Compounds

Rimonabant, a cannabinoid receptor blocker, has recently been used in clinical practice for weight loss and weight maintenance. Our aim was to review the results of trials of the drug in relation to weight loss and maintenance, and its impact on cardio-metabolic risk factors.. Randomized controlled trials with rimonabant were selected, through a Medline search, using the terms: rimonabant, endocannabinoid antagonist and obesity. Reports of studies on large numbers of patients and covering the topics related to this review were included.. In all the trials, there was a considerable reduction in body weight in subjects taking 20 mg rimonabant daily varying from 2.6 to 6.3 kg (placebo-subtracted changes). Rimonabant was also associated with haemoglobin A(₁c) (HbA(₁c) ) reduction. In the Rimonabant in obesity (RIO)-diabetes study, diabetic patients taking metformin or sulphonylureas showed decrease in HbA(₁c) levels by 0.5-0.6 ± 0.8% when rimonabant was added, whereas in the Serenade trial patients with untreated diabetes showed a reduction in HbA(₁c) of 0.8% vs. 0.3% with placebo. Similar results were obtained in diabetic patients under insulin treatment. The lipidemic profile also improved in patients taking rimonabant 20 mg daily; levels of high density lipoprotein cholesterol (HDL-c) increased significantly while levels of triglycerides (TRG) decreased in all trials, and positive effects were also observed in patients with atherogenic or untreated dyslipidaemia. In all the RIO studies, prevalence of the metabolic syndrome decreased significantly. In addition, patients treated with 20 mg rimonabant daily exhibited increase in adiponectin. The metabolic changes observed were partly independent of the weight loss and could be attributed to independent peripheral effect of rimonabant. All these beneficial metabolic effects of rimonabant could lead to progress in the prevention of cardiovascular disease. However, in all the trials the incidence of adverse events leading to discontinuation was greater in the rimonabant treated patients than placebo, mainly because of psychiatric disorders (depression and anxiety), nausea and dizziness.. Rimonabant is effective in reducing weight in the obese but may lead to intolerable adverse effects most notably psychiatric effects, which make it unsuitable for routine use. However, the drug provides useful proof of principle for this approach to weight loss. Novel cannabinoid type 1 receptor blockers with selectivity for peripheral receptors, may achieve similar metabolic results with decreased prevalence of psychiatric adverse effects.

Topics: Anti-Obesity Agents; Humans; Molecular Targeted Therapy; Mood Disorders; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant

The pharmaceutical search to induce weight loss was precipitated by the United States Food and Drug Administration's (FDA) 1959 formal approval of phentermine for short-term weight loss despite limited research supporting its assertions of weight loss. In addition to sympathomimetic amine products like phentermine, other medications considered in this article include herbal products, sibutramine, orlistat, metformin, and rimonabant. The use of pharmacotherapy for morbidly obese adolescents should be part of a comprehensive weight-loss program that recommends diet, exercise, and behavioral modification. Side effects and the possibility of major adverse effects should be remembered when considering use of these products.

Topics: Adolescent; Amphetamines; Anti-Obesity Agents; Anticonvulsants; Antidepressive Agents; Central Nervous System Stimulants; Ciliary Neurotrophic Factor; Herbal Medicine; Humans; Hypoglycemic Agents; Metformin; Obesity; Piperidines; Pyrazoles; Rimonabant

Obesity is a world wide epidemic; it is becoming more usual to be overweight or obese than to be normal weight. Obesity increases the risk of an extensive range of diseases such as cardiovascular disease, diabetes mellitus type 2, hypertension, depression and some types of cancer. Adipose tissue is more than a storage organ for surplus energy - it is also a setting for complex metabolic processes and adipose tissue releases substances that interact with other parts of the body to influence several systems including food intake and energy metabolism. The endocannabinoid system (ECS) is one of the signalling systems that control feeding behaviour. The ECS is implicated in many functions, such as pain, memory, addiction, inflammation, and feeding, and could be considered a stress recovery system. It also seems to integrate nutrient intake, metabolism and storage maintaining homeostatic balance. The ECS is a recently discovered system, and research indicates hyperactivity in obesity. The aim of this thesis is to elaborate on the relationships of this widespread system and its elements in adipose tissue in obesity. Study I is a 4 weeks rat intervention study to investigate whether weight independent effect of Rimonabant treatment exists. We found that food intake-tolerance development could be circumvented by cyclic administration of Rimonabant and implications of weight independent effects of treatment. Study II is a cross-sectional study to establish the expression of cannabinoid receptor 1 from various adipose tissue depots of lean and obese persons. In this study we conclude, that the subcutaneous adipose tissue express more CBR1 than the visceral depot in lean, but comparable levels in obese. Study III is a 10 weeks human intervention study to asses the effects on the ECS of 10% weight loss. We found reduction in the ECS in obesity that normalised with weight loss. Our results clearly show the presence of all the components of the ECS in human adipose tissue, and suggest that the ECS is reduced in adipose tissue in obesity. Our results do not support the hypothesis of hyperactivity of the ECS in human obesity. Possible future treatment of obesity with CBR1 antagonist could involve cyclic treatment of specific peripheral compounds.

Topics: Adiponectin; Adipose Tissue; Animals; Body Mass Index; Body Weight; C-Reactive Protein; Cannabinoid Receptor Modulators; Case-Control Studies; Endocannabinoids; Fatty Acids, Nonesterified; Feeding Behavior; Female; Genetic Variation; Humans; Inflammation; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Reference Values; Rimonabant; Risk Factors; Weight Loss

Topics: Animals; Appetite Depressants; Cannabinoid Receptor Modulators; Dexfenfluramine; Drug Design; Drug Inverse Agonism; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Serotonin Receptor Agonists

Antagonists of cannabinoid type-1 (CB₁) receptors have been explored as therapeutic agents for obesity and addiction. However, use of rimonabant (the first marketed CB₁ receptor antagonist) has been suspended due to its anxiogenic and depressive side effects (including suicide risk). Recent genomic studies provide evidence that variants of the CB₁ receptor gene (CNR1) alone or in combination with the gene of the serotonin transporter (SLC6A4) contribute to the development of anxiety and/or depression, suggesting that high-risk individuals could be identified through genetic testing. In this review, we argue that identification of high-risk individuals by a combination of genomic screening, previous risk phenotype, and environmental risk factors offers a promising method for the safe use of centrally acting CB₁ receptor antagonists. We summarize endocannabinoid signaling in pathways related to anxiety and depression, identify the serotonergic system as the most likely candidate to mediate the side effects of CB₁ receptor antagonists, and propose that poloymorphisms in CNR1, SLC6A4 and certain CYP 450 enzymes could help to identify individuals who may benefit from treatment with CB₁ receptor antagonist without psychiatric side effects.

Topics: Animals; Anti-Obesity Agents; Genetic Testing; Humans; Obesity; Piperidines; Polymorphism, Genetic; Precision Medicine; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Substance-Related Disorders

Topics: Adverse Drug Reaction Reporting Systems; Appetite Depressants; Body Weight; Brain; Combined Modality Therapy; Cyclobutanes; Diet, Reducing; Drug Approval; Drug Combinations; Drug Recalls; Drugs, Investigational; Forecasting; Humans; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant

Successful management of type 2 diabetes mellitus (T2DM) requires attention to additional conditions often associated with hyperglycemia including overweight or obesity, dyslipidemia and hypertension, as each has some relationship with microvascular or macrovascular complications. Because control of cardiovascular risk factors is as important as glucose control in T2DM, these risk factors need to be addressed, and it is critical that antidiabetes medications do not exacerbate these risk factors. A patient-centered approach to treatment in which clinicians maximize patient involvement in the selection of antidiabetes therapy may lead to increased adherence and improved clinical outcomes. The incretin hormones, which include glucagon-like peptide-1 (GLP-1), are involved in glucoregulation and have become an important focus of T2DM research and treatment. Incretin-based therapies, such as the glucagon-like peptide-1 receptor agonists and the dipeptidyl peptidase-IV inhibitors, have shown beneficial effects on hyperglycemia, weight, blood pressure and lipids with a low incidence of hypoglycemia.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Liraglutide; Nitriles; Obesity; Patient Compliance; Peptides; Piperidines; Precision Medicine; Primary Health Care; Pyrazines; Pyrrolidines; Risk Factors; Sitagliptin Phosphate; Triazoles; Uracil; Venoms; Vildagliptin

Cardiometabolic risk factors affect more than 47 million adults in the United States today. Although certain risk factors (e.g., obesity, dyslipidemia, hypertension, and hyperglycemia) contribute independently to the global risk, dyslipidemia is one of the most important risk factors for cardiovascular disease. Successful treatment requires a well-coordinated multifaceted approach, with commitment to a long-term program for disease management. Although initial attempts should focus on dietary changes and increased physical activity, most patients also need effective, safe, and well-monitored pharmacotherapy. Experimental studies have shown that overactivation of the endocannabinoid system-a physiologic signaling system involved in regulating energy intake, fatty acid synthesis and storage, and glucose and lipid metabolism-is associated with obesity, dyslipidemia, and insulin resistance. In clinical trials, selective blockade of CB1 receptors has resulted in substantial weight loss and significant improvement in lipid profiles. The effects of rimonabant, the first selective CB1 receptor blocker, were evaluated in 6600 obese or overweight adults who participated in one of 4 multicenter, placebo-controlled, randomized clinical trials for at least 1 year. Significant improvement in lipid profiles (specifically HDL and triglyceride levels and ratio of total cholesterol to HDL cholesterol) was seen in the 2503 patients taking rimonabant 20 mg/day, independent of its substantial effects on weight loss. No significant changes in LDL or total cholesterol were observed. Results of clinical trials with rimonabant are promising. Additional long-term controlled studies with appropriate follow-up are warranted to confirm the clinical potential of this drug, particularly its effects on dyslipidemia and other cardiovascular endpoints.

Topics: Cannabinoid Receptor Modulators; Cardiovascular Diseases; Dyslipidemias; Endocannabinoids; Humans; Insulin Resistance; Lipid Metabolism; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Signal Transduction

Obesity, currently associated with metabolic syndrome is characterized by an excessive fat storage in different organs, in particular adipose tissue, inducing the loss of its structural and functional integrity. Being aware of the importance of adipose tissue endocrine function and the key role of adipocytokines, such as adiponectin, in obesity and metabolic syndrome drives the necessity to develop new drugs that can exert a specific action on adipose tissue and on adiponectin levels. Rimonabant, an antiobesity drug, presents a dual effect by decreasing food intake and importantly increasing adiponectin. This review focuses on the key role of adiponectin regulation in the success of rimonabant and suggests that this adipohormone may be considered as a therapeutic target to design innovative and promising antiobesity and anti-metabolic syndrome drugs.

Topics: Adiponectin; Adipose Tissue; Animals; Anti-Obesity Agents; Body Fat Distribution; Clinical Trials as Topic; Drug Delivery Systems; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant

Topics: Animals; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Disease Models, Animal; Endocannabinoids; Energy Metabolism; Humans; Mice; Obesity; Piperidines; Pyrazoles; Rats; Rimonabant; Risk Factors

Obesity is one of the greatest public health challenges of the twenty-first century. The World Health Organization (WHO) reports that in 2005 approximately 1.6 billion adults were overweight and at least 400 million adults were obese. The prevalence of obesity is still continuing to increase dramatically. Overweight and obese people carry a higher risk for a variety of cardiovascular diseases including hypertension, coronary heart disease, stroke and peripheral occlusive artery disease. Weight loss is considered to be the initial step which helps to prevent or to control the clinical consequences of obesity. In a great number of patients who are not able to reduce weight by means of non-pharmacological measures, drug therapy can assist in reaching the weight management targets. Drug treatment should only be considered as part of a systematic weight management program including dietary and lifestyle changes. This review summarizes current pharmacotherapeutic concepts for the treatment of obesity in adults focusing on efficacy and safety of anti-obesity drugs.

Topics: Adult; Anti-Obesity Agents; Appetite Depressants; Combined Modality Therapy; Cyclobutanes; Enzyme Inhibitors; Humans; Lactones; Lipase; Obesity; Orlistat; Piperidines; Prevalence; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Reduction Behavior; Treatment Outcome; Weight Loss

Obesity is considered a worldwide epidemic. Weight reduction by means of lifestyle changes is difficult to achieve, and pharmacotherapy is frequently needed. Although all currently approved anti-obesity agents have proven to be effective to achieve some degree of weight reduction and improve cardiometabolic risk factors, different compounds differ in their mechanism of action and safety profile. However, it is still difficult to achieve and maintain therapeutic objectives along time. The aim of the present article is to summarize the main characteristics of available anti-obesity agents and to explore novel agents that may provide significant clinical benefits in the future.

Topics: Animals; Anti-Obesity Agents; Cardiovascular Diseases; Cyclobutanes; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant

Abdominal obesity (high waist circumference) is more strongly associated with cardiovascular disease and type 2 diabetes than generalized adiposity (high body mass index). Recent research has highlighted the role of chronic overactivation of the endogenous endocannabinoid system, acting through its CB(1) receptor, as a key factor involved in the development of abdominal obesity and related cardiometabolic risk abnormalities such as insulin resistance, low HDL-cholesterol, hypertriglyceridemia, inflammation and low adiponectin. Evidence suggests that these cardiometabolic risk factors/markers are not optimally managed by current treatments. Improving the nutrition and physical activity/exercise habits of patients remains the cornerstone of management of elevated global cardiometabolic risk. Antagonism of the endocannabinoid system provides a novel strategy to target several unaddressed cardiometabolic risk markers/factors. Randomized trials of rimonabant in patients with overweight or obesity and/or type 2 diabetes have demonstrated marked and significant improvements in body weight, waist circumference, glycemic control (in patients with type 2 diabetes), features of atherogenic dyslipidemia, insulin resistance, adipose tissue-derived cytokines (leptin and adiponectin) and C-reactive protein (a marker of systemic inflammation). Further analyses suggested that about half of the improvements of several cardiometabolic risk markers were independent from concomitant weight loss. Blood pressure also improved with rimonabant treatment, this effect being consistent with the blood pressure lowering effect of weight loss. The tolerability and safety of rimonabant have been extensively studied and most transient side effects include some gastrointestinal side effects, anxiety, mood changes and incidence of depressive disorders, particularly in patients with previous history of depression. Rimonabant is a useful option for patients with abdominal obesity and with related cardiometabolic risk abnormalities such as an atherogenic dyslipidemia and/or type 2 diabetes.

Topics: Abdominal Fat; Animals; Anti-Obesity Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Risk Factors

Obesity is considered as a major health problem, as its prevalence continuously rises worldwide. One of the common health consequences of obesity is type 2 diabetes mellitus. Therefore, antiobesity management is a prerequisite in treating diabetic patients. Lifestyle modifications combined with pharmacological agents appear to be an effective approach. Sibutramine is a serotonin-noradrenaline reuptake inhibitor, which acts centrally by promoting the feeling of satiety and decreasing caloric intake, thus resulting in weight loss. A potential association with cardiovascular side effects has been noted. Orlistat, a gastric and pancreatic lipase inhibitor, also achieves significant weight loss and improves glycaemic status, but it has gastrointestinal side effects. Rimonabant, the first endocannabinoid CB1 antagonist, is associated with weight reduction and it improves diabetic parameters; nevertheless, it is associated with psychiatric disorders; indeed, a recently conducted safety review led to the temporal suspension of its commercialization. The above-mentioned medications seem to be currently useful agents for treating obesity in patients with type 2 diabetes mellitus. Other medications used for diabetes management, such as exenatide, liraglutide and pramlintide, have also shown body weight reduction. Ongoing research is needed to scrutinize the precise impact of these agents in the daily clinical practice of management of obesity in patients with type 2 diabetes mellitus.

Topics: Adolescent; Adult; Aged; Anti-Obesity Agents; Appetite Depressants; Body Weight; Cyclobutanes; Diabetes Mellitus, Type 2; Female; Humans; Lactones; Male; Middle Aged; Obesity; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant; Treatment Outcome; Weight Loss; Young Adult

Type 2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a high incidence of cardiovascular complications. Several animal and human observations suggest that the endocannabinoid (EC) system is overactivated in presence of abdominal obesity and/or diabetes, and contributes to disturbances of energy balance and metabolism. Not only it regulates the intake of nutrients through central mechanisms located within the hypothalamus and limbic area, but it also intervenes in transport, metabolism and deposit of the nutrients in the digestive tract, liver, adipose tissue, skeletal muscle, and possibly pancreas. Activation of both central and peripheral CB1 receptors promotes weight gain and associated metabolic changes. Conversely, rimonabant, the first selective CB(1) receptor antagonist in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels, and to increase HDL cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in glycated hemoglobin (HbA1c) levels was observed in metformin- or sulfonylurea-treated patients with type 2 diabetes and in drug-naive or insulin-treated diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. Rimonabant was generally well-tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared to placebo. New trials are supposed to confirm the potential role of rimonabant (and other CB1 neutral antagonists or inverse agonists) in overweight/obese patients with type 2 diabetes and high risk cardiovascular disease.

Topics: Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Endocannabinoids; Humans; Hypoglycemic Agents; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Abdominal obesity is associated with numerous metabolic abnormalities, including insulin resistance, impaired glucose tolerance/type-2 diabetes, and atherogenic dyslipidaemia with low high-density lipoprotein (HDL) cholesterol, high triglycerides, and increased small dense low-density lipoprotein (LDL) cholesterol. A proportion of these metabolic disorders may be attributed to increased endocannabinoid activity. The selective cannabinoid 1 (CB1) receptor antagonist rimonabant has been shown to reduce body weight, waist circumference, insulin resistance, triglycerides, dense LDL, C-reactive protein (CRP), and blood pressure, and to increase HDL and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. Besides an improvement in glucose tolerance in non-diabetic subjects, a reduction of 0.5-0.7% in haemoglobin A1C (HbA(1c)) levels was consistently observed in various groups of patients with type-2 diabetes. Almost half the metabolic changes could not be explained by weight loss, supporting direct peripheral effects of rimonabant. Ongoing studies should demonstrate whether improved metabolic disorders with CB1 receptor antagonists (rimonabant, taranabant, etc.) would translate into fewer cardiovascular complications among high-risk individuals.

Topics: Atherosclerosis; Blood Glucose; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Fasting; Glucose; Glycated Hemoglobin; Humans; Lipid Metabolism; Metabolic Diseases; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors

Topics: Animals; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Endocannabinoids; Humans; Mice; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant

Being a great threaten for human health, obesity has become a pandemic chronic disease. There have been several therapeutic treatments for this social health issue, including diet and exercise therapy, medication and surgery, among which the diet is still the most common way. However, none of these therapeutic measures available is ideal, making it necessary to find an effective medical treatment. The endocannabinoid system, which is well known for its contributions in certain mental processes such as relaxation, amelioration of pain and anxiety, and sedation initiation, has been recently reported to play an essential role in regulating appetite and metabolism to maintain energy balance, leading to the belief that endocannabinoid system is closely related to obesity. This new discovery deepens our understanding of obesity, and provides us with a new direction for clinical obesity treatment. Rimonabant is an antagonist for CB1, and has entered the market in some countries. However, although effective as an anti-obesity drug, rimonabant also causes obviously adverse side-effects, thus is being doubted and denied for medical usage.

Topics: Animals; Anti-Obesity Agents; Cannabinoid Receptor Modulators; Endocannabinoids; Humans; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant

Experimental evidence has suggested that drugs that enhance cannabinoid type-1 (CB1) receptor activity may induce anxiolytic and antidepressant effects, whilst the opposite has been reported with antagonists. Thus, the objective of the present review is to discuss the potential psychiatric side-effects of CB1 receptor antagonists, such as rimonabant, which has been recently marketed in several countries for the treatment of smoking cessation, obesity and associated metabolic disorders.. Literature searches were performed in PubMed and SciELO databases up to February 2009. The terms searched were 'obesity', 'rimonabant', 'cannabinoids', 'unwanted effects', 'diabetes', 'smoking cessation' and 'side-effects'.. Clinical trials have revealed that rimonabant may promote weight loss in obese patients, although it may also induce symptoms of anxiety and depression.. Patients taking CB1 receptor antagonists should be carefully investigated for psychiatric side-effects. These drugs should not be prescribed for those already suffering from mental disorders. Nevertheless, the development of new compounds targeting the endocannabinoid system for the treatment of several conditions would be necessary and opportune.

Topics: Anxiety Disorders; Appetite Depressants; Cannabinoid Receptor Modulators; Depressive Disorder; Humans; Metabolic Diseases; Obesity; Piperidines; Placebo Effect; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant; Smoking; Smoking Cessation

Rimonabant and taranabant are two extensively studied cannabinoid-1 receptor (CB1R) inverse agonists. Their effects on in vivo peripheral tissue metabolism are generally well replicated. The central nervous system site of action of taranabant or rimonabant is firmly established based on brain receptor occupancy studies. At the whole-body level, the mechanism of action of CB1R inverse agonists includes a reduction in food intake and an increase in energy expenditure. At the tissue level, fat mass reduction, liver lipid reduction and improved insulin sensitivity have been shown. These effects on tissue metabolism are readily explained by CB1R inverse agonist acting on brain CB1R and indirectly influencing the tissue metabolism through the autonomic nervous system. It has also been hypothesized that rimonabant acts directly on adipocytes, hepatocytes, pancreatic islets or skeletal muscle in addition to acting on brain CB1R, although strong support for the contribution of peripherally located CB1R to in vivo efficacy is still lacking. This review will carefully examine the published literature and provide a perspective on what new tools and studies are required to address the peripheral site of action hypothesis.

Topics: Aged; Amides; Anti-Obesity Agents; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Female; Humans; Male; Obesity; Piperidines; Pyrazoles; Pyridines; Receptor, Cannabinoid, CB1; Rimonabant

The discovery of cannabinoid receptors led to the development of several compounds targeted against these receptors. In particular, CB1 receptor antagonists have been described to possess key functions in the treatment of obesity and obesity-related pathologies. Numerous clinical trials revealed the advantage of strategies designed to block CB1 receptor but also evidenced the limitations due to side effects exerted by these substances. Recent studies have highlighted that CB1 antagonists could have other effects and find applications even in other pathologies like hepatic fibrosis, chronic inflammatory conditions, diabetes, and cancer. Since the suspending sales of the lead compound, rimonabant, and the discontinuation of all ongoing clinical trials of CB1 blockers, alternative strategies could emerge and lead to the development of further basic research studies to redirect these compounds.

Topics: Animals; Cannabinoid Receptor Modulators; Clinical Trials as Topic; Energy Metabolism; Humans; Models, Animal; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of rimonabant for the treatment of obese or overweight patients based upon a review of the manufacturer's submission to the National Centre for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's main evidence came from four randomised controlled trials. Rimonabant resulted in a significantly greater benefit than placebo for all primary weight loss outcomes. At 1 year, rimonabant had a statistically significant beneficial effect on systolic blood pressure, high-density lipoprotein cholesterol, triglycerides and fasting plasma glucose in diabetics and non-diabetics, and glycosylated haemoglobin in diabetics. Improvements were maintained over 2 years with rimonabant; withdrawal of rimonabant at 1 year resulted in a reduction in weight loss until there was no difference from placebo at 2 years. Psychiatric adverse events were experienced by 26% and 14% of rimonabant and placebo patients respectively; figures for symptoms of depression were 9% and 5% respectively. Pairwise comparisons of orlistat, sibutramine and rimonabant showed beneficial effects of rimonabant over orlistat and sibutramine for weight loss outcomes; however, response hurdles imposed on orlistat or sibutramine in clinical practice may not have been applied in the orlistat and sibutramine trials. The manufacturer's Markov cohort model evaluated rimonabant versus orlistat, sibutramine and diet and exercise alone for three base-case populations. The incremental cost-effectiveness ratio (ICER) of rimonabant varied from 10,534 pounds to 13,236 pounds per quality-adjusted life-year (QALY) versus diet and exercise, to 8977 pounds to 12,138 pounds per QALY versus orlistat, to 1463 pounds to 3908 pounds per QALY versus sibutramine. In subgroup analysis there was a wider variation in the ICER estimates although none exceeded 20,000 pounds per QALY. The ICER of rimonabant remained under 20,000 pounds per QALY in reanalyses by the manufacturer and the ERG, with the results sensitive to the source of health-related quality of life (HRQoL) benefits in the model. Four treatment strategies were modelled in comparisons of rimonabant versus diet and exercise alone and orlistat and sibutramine in which rimonabant was continued only in patients achieving 5% weight loss at 3, 6, 9 or 12 months. In pairwise comparisons rimonabant remained bel

Topics: Anti-Obesity Agents; Cost-Benefit Analysis; Humans; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Adipose tissue is an endocrine organ secreting more than 30 various adipokines which regulate wide spectrum of metabolic and immune processes. Obesity is associated with development of adipose tissue inflammation. This inflammation is characterized by infiltration with macrophages, alterations of adipokine secretion, development of insulin resistance. All these factors promote atherosclerosis. Inflammation of perivascular adipose tissue is especially important. Adipokines damage vascular endothelium via paracrine pathway. Cytokines released by macrophages as well as changes of adipokine secretion lead to endothelial dysfunction - the first stage of atherogenesis. Besides specific action curative factors used in obesity, metabolic syndrome, and diabetes mellitus also produce anti-inflammatory effect and thus diminish risk factors of cardiovascular diseases, rate of their development, and alleviate manifestations of atherosclerosis. Inflammation of adipose tissue is a connecting link between obesity and atherosclerosis. This review contains an outline of roles of various major adipokines in development of atherosclerosis as well as synopsis of anti-inflammatory and antiatherogenic effects of glytazones , metformin, rimonabant, statins, and of lowering of body weight.

Topics: Adipokines; Adipose Tissue; Atherosclerosis; Chemotaxis; Cytokines; Endothelium, Vascular; Humans; Hypoglycemic Agents; Inflammation; Insulin Resistance; Macrophages; Metformin; Obesity; Piperidines; Pyrazoles; Rimonabant; Vasoconstrictor Agents

Weight gain, during and after the menopause is common. Contributing factors include ethnicity, reduced physical activity, reduced lean mass, reduced resting metabolic rate and treatment with certain drugs, e.g. steroids, insulin, glitazones. Excess body weight increases the risk of medical conditions including type 2 diabetes, hypertension, osteoarthritis, certain cancers and is associated with increased mortality. This review examines pharmacological approaches to promote weight loss. Pharmacological therapy should be considered as an adjunct to diet and lifestyle changes. The licensed drugs orlistat, sibutramine and rimonabant are discussed. Obesity increases the risk of type 2 diabetes. Thus, the effects of metformin and exenatide are examined.

Topics: Anti-Obesity Agents; Bariatric Surgery; Cyclobutanes; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Hypoglycemic Agents; Lactones; Menopause; Metformin; Obesity; Orlistat; Peptides; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Venoms

Abdominal obesity is closely related to type 2 diabetes and overactivity of the endocannabinoid system. The present review aims at evaluating the role of endocannabinoid system in glucose dysregulation and the effects of cannabinoid 1 receptor blockade on glucose metabolism in both animal models and overweight/obese humans, especially with type 2 diabetes.. Cannabinoid 1 receptors have been identified not only in the brain, but also in the adipose tissue, the gut, the liver, the skeletal muscle and even the pancreas, all organs playing a key role in glucose metabolism and type 2 diabetes. Rimonabant, the first selective cannabinoid 1 receptor blocker in clinical use, has been shown to reduce body weight, waist circumference, glycated haemoglobin, triglycerides, insulin resistance index, and to increase HDL cholesterol and adiponectin concentrations in patients with type 2 diabetes, confirming data on nondiabetic overweight/obese patients. Almost half of the metabolic changes, including glycated haemoglobin reduction, could not be explained by weight loss, in agreement with direct peripheral effects.. Cannabinoid 1 blockade reduces food intake and body weight and improves metabolic regulation beyond just weight loss. Because of its positive effect on glucose metabolism, rimonabant deserves consideration in the treatment of overweight/obese patients with type 2 diabetes.

Topics: Animals; Blood Glucose; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid; Rimonabant

The endocannabinoid system (ECS) is a complex physiologic system that affects metabolic pathways. A dysregulated ECS has been demonstrated in animal models of obesity and the expression of the cannabinoid type 1 (CB(1)) receptor in both brain and peripheral tissues suggests that selective antagonism at this receptor could target multiple tissues involved in metabolic homeostasis. In clinical trials with obese patients, treatment with the CB(1) receptor antagonist rimonabant was associated with clinically meaningful weight loss, as well as improved serum lipids and glycemic control. The biological basis for the metabolic effects of rimonabant (SR141716) appears to involve the modulation of metabolism through antagonism at a single receptor with several target organs.

Topics: Animals; Clinical Trials as Topic; Disease Models, Animal; Drug Delivery Systems; Gene Expression Regulation; Homeostasis; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The prevalence of obesity and the metabolic syndrome (MS) is on the rise, and subsequently the hepatic manifestation of MS, nonalcoholic fatty liver disease (NAFLD), has become a common entity in clinical practice. Most patients with NAFLD face medical complications related to their underlying MS in other organ systems; however, a small but significant group of patients with the more aggressive form of fatty liver, nonalcoholic steatohepatitis (NASH), are at risk of developing cirrhosis and hepatocellular carcinoma. As patients are generally asymptomatic, often their disease goes unrecognized. This is particularly true for NASH, where liver biopsy is currently required to make the diagnosis. Once diagnosed, no one treatment has been shown to be universally efficacious and those that are of benefit are not without side effects. Effective treatment regimens directed at both decreasing insulin resistance as well as the processes leading to necroinflammation and hepatic fibrosis have been investigated and include lifestyle modification, surgical therapies, and pharmacotherapy. This review focuses on current and potential future therapies for NASH.

Topics: Animals; Antioxidants; Bariatric Surgery; Body Mass Index; Cannabinoids; Cholagogues and Choleretics; Comorbidity; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin Resistance; Lactones; Life Style; Metformin; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Thiazolidinediones; Treatment Outcome; Ursodeoxycholic Acid; Weight Loss

To review economic evaluations of weight loss drugs and compare reported incremental cost-effectiveness ratios (ICERs).. A literature search was conducted for cost-effectiveness (CEAs) and cost-utility analyses (CUAs) of sibutramine, orlistat and rimonabant.. Fourteen unique articles were identified (11 CUAs and 3 CEAs; 9 orlistat, 4 sibutramine and 1 rimonabant). All used diet and exercise as comparator, whereas none included indirect costs. Time horizons varied from treatment period only (1-4 years) to 80 years (median 7.5 years). Longer studies modeled effects on diabetes, micro- and macrovascular complications, coronary heart disease and death. Of the CUAs, the median ICER was 16,000 euro(2007)/QALY (quality-adjusted life-year; range 10,000-88,000), with the worst cost-effectiveness when recommended stop rules for non-responding patients were not applied. All studies but three were funded by the manufacturing company, and the median ICER was considerably higher for independent than for sponsored analyses (62,000 euro vs 15,000 euro/QALY). However, two of the three independent CUAs did not use recommended stop rules, as compared with one of eight manufacturer-sponsored analyses. The results were most sensitive to assumptions regarding weight loss sustainability and utility per kilogram lost. Side effects and dropout because of reasons other than lack of efficacy were generally not incorporated.. Published economic evaluations indicate that orlistat, sibutramine and rimonabant are within the range of what is generally regarded as cost-effective. Uncertainty remains about weight loss sustainability, utility gain associated with weight loss and extrapolations from transient weight loss to long-term health benefits. Modeling of head-to-head comparisons and attrition is needed, as are analyses conducted independently of manufacturing companies.

Topics: Anti-Obesity Agents; Appetite Depressants; Body Mass Index; Cost-Benefit Analysis; Cyclobutanes; Europe; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Quality-Adjusted Life Years; Rimonabant; Treatment Outcome; United States

Obesity is a growing public health problem that is already reaching epidemic proportions and is increasingly encompassing young children and adolescents. Despite the increasing prevalence and the health risks associated with obesity, the pharmacotherapeutic options for treating obesity are limited. The endogenous cannabinoid or endocan-nabinoid system (ECS) was discovered in the early 1990s in relation to work on the action of components of marijuana. Central activation of the ECS promotes food ingestion. The endogenous cannabinoids exert their pharmacologic action through interaction with the specific receptors, CB(1) and CB(2). CB(1) receptors are located predominantly in the brain and peripherally in adipose tissue, liver, skeletal muscle and the gastrointestinal tract. In July 2006, European regulatory authorities approved the use of rimonabant, SR141716, a selective CB1 receptor antagonist, in obese patients (BMI > or =30kg/m(2), or >27kg/m(2) with complications). However, in June 2007, despite extensive clinical trial data, the FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded that the safety of rimonabant had not been adequately demonstrated by the manufacturer Sanofi-Aventis; the full application was subsequently withdrawn. This review article provides evidence and outlines some patents for the use of rimonabant and potential safety concerns which still prevent its use in the single largest market for drugs of its kind.

Topics: Cannabinoid Receptor Antagonists; Clinical Trials as Topic; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant

It has been long known that the frequency of overweight and obese people is higher among depressed and bipolar patients than in the general population. The marked alteration of body weight (and appetite) is one of the most frequent of the 9 symptoms of major depressive episode, and these symptoms occur during recurrent episodes of depression with a remarkably high consequence. According to studies with representative adult population samples, in case of obesity (BMI over 30) unipolar or bipolar depression is significantly more frequently (20-45%) observable. Since in case of depressed patients appetite and body weight reduction is observable during the acute phase, the more frequent obesity in case of depressed patients is related (primarily) not only to depressive episodes, but rather to lifestyle factors, to diabetes mellitus also more frequently occurring in depressed patients, to comorbid bulimia, and probably to genetic-biological factors (as well as to pharmacotherapy in case of medicated patients). At the same time, according to certain studies, circadian symptoms of depression give rise to such metabolic processes in the body which eventually lead to obesity and insulin resistance. According to studies in unipolar and bipolar patients, 57-68% of patients is overweight or obese, and the rate of metabolic syndrome was found to be between 25-49% in bipolar patients. The rate of metabolic syndrome is further increased by pharmacotherapy. Low total and HDL cholesterol level increases the risk for depression and suicide and recent studies suggest that omega-3-fatty acids possess antidepressive efficacy. Certain lifestyle factors relevant to healthy metabolism (calorie reduction in food intake, regular exercise) may be protective factors related to depression as well. The depression- and possibly suicide-provoking effect of sibutramine and rimonabant used in the pharmacotherapy of obesity is one of the greatest recent challenges for professionals and patients alike.

Topics: Anti-Obesity Agents; Antidepressive Agents; Appetite Depressants; Appetite Regulation; Bipolar Disorder; Circadian Rhythm; Cyclobutanes; Depression; Depressive Disorder, Major; Dietary Carbohydrates; Energy Intake; Ghrelin; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Obesity; Piperidines; Pituitary-Adrenal System; Pyrazoles; Rimonabant; Seasonal Affective Disorder; Sleep Wake Disorders; Surveys and Questionnaires; Weight Gain; Weight Loss

Recent research in bio-medical science has shown an integral role of endocannabinoid system (ECS) in determining cardio-metabolic risk of human body. The mechanism is mediated through binding of endocannabinoids at the CB1 receptors. The stimulation of CB1 receptor in the brain is believed to control and mediate the effects on appetite. In normal physiology, CB1 receptors activation is responsible for energy homeostasis, govern emotions and behaviors such as anxiety, fear, appetite, food and water intake. CB1 receptors also found in peripheral tissues like liver, pancreas, skeletal muscles and adipose tissues, which play an important role in lipid and glucose metabolism. Over-activation of ECS is associated with various metabolic diseases such as dyslipidemia, insulin resistance, lipogenesis, excessive weight gain and increasing intra-abdominal obesity. All these events lead to increased cardiovascular risk. Use of selective CB1 receptor blocker such as rimonabant has shown to reduced waist circumference, better glycemic control, lower triglyceride levels, raise HDL cholesterol and over all reduction in total body fat. This drug has been recommended for patients with metabolic syndrome.

Topics: Animals; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Endocannabinoids; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Diet, exercise and behavioral therapy are the basics for every treatment of obesity. If lifestyle intervention does not result in a weight loss of 5% within 3 to 6 months, an additional pharmacotherapy can be considered. Treated patients should have a BMI >/=30 kg/m(2) or at least a BMI >/=27 kg/m(2) plus accompanying comorbidities, such as type 2 diabetes, dyslipidemia or hypertension. Current guidelines list orlistat, sibutramine and rimonabant as possible options for the pharmacotherapy of obesity. These compounds result in moderate weight reduction and improvement of cardiovascular risk profile. Especially the improvement of glucose metabolism can be considered as clinically relevant. Different side effects of the various compounds need to be considered before their use. Additional options for the pharmacotherapy of obesity are currently developed, their approval, however, is unlikely to happen within the next couple of years.

Topics: Anti-Obesity Agents; Appetite Depressants; Cyclobutanes; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome

Growing evidence suggests an important role in metabolic control of the endocannabinoid system, which is composed of cannabinoid receptors, endocannabinoids, and related enzymes. In this short review, we describe the latest advances in this research field, including the antiobesity effect of the cannabinoid receptor CB1 antagonist rimonabant and the anorexic effect of N-oleoylethanolamine, an endocannabinoid-related, endogenous substance.. CB1 is expressed not only in various brain regions, including hypothalamus, but also in peripheral organs such as adipose tissue and liver. The endocannabinoid system appears to function as a physiological system regulating food intake, energy balance, and lipid metabolism through both central and peripheral mechanisms. Obesity may be associated with hyperactivity of the endocannabinoid system. Large phase III trials of rimonabant confirmed significant weight loss and waist circumference reduction in overweight and obese patients. The levels of HDL-cholesterol, triglycerides, and HbA1c were also improved. The anorexic effect of N-oleoylethanolamine was suggested to be mediated by peroxisome proliferator-activated receptor-alpha and the G protein-coupled receptor GPR119.. These results highlight the importance of an endocannabinoid tone in metabolic control and therapeutic usefulness of CB1 antagonists. Derivatives of N-oleoylethanolamine may be developed as new antiobesity drugs.

Topics: Anorexia; Cannabinoid Receptor Modulators; Central Nervous System; Endocannabinoids; Ethanolamines; Humans; Obesity; Oleic Acids; Piperidines; Pyrazoles; Rimonabant

The prevalence of obesity in the developed world is increasing. Approximately 23% of adult Canadians (5.5 million people) are obese. Obesity is associated with an increased risk of developing several comorbid diseases, ranging from cardiovascular diseases to cholelithiasis and nonalcoholic fatty liver disease. The etiology of obesity is multifactorial, involving a complex interaction among genetics, hormones and the environment. The available evidence and recommendations for nonpharmacological management of obesity, including dietary therapy, physical activity and behavioural therapy, in addition to pharmacotherapy are discussed. A brief discussion on endoscopic and surgical procedures is undertaken. Several antiobesity treatment options are available and may be indicated in appropriate situations. Selecting obesity therapy may be guided by body mass index measurements, comorbid illnesses and patient preference.

Topics: Anti-Obesity Agents; Bariatric Surgery; Behavior Therapy; Caloric Restriction; Cyclobutanes; Dietary Carbohydrates; Dietary Fats; Exercise; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Weight Loss

The increase of obesity and type 2 diabetes on a global scale has increased the interest in how to counteract this epidemic. Improved lifestyle in general is a fundamental approach, but other remedies such as specific weight reduction or diabetes preventive drugs and surgery have also been tested. One problem to understand is what really happens after weight loss. Ongoing studies will try to address this question, such as the Swedish Obese Subjects (SOS) surgery study, the Look AHEAD (Action for Health in Diabetes) trial in the U.S. (recruiting obese type 2 diabetic patients), and the Comprehensive Rimonabant Evaluation Study of Cardiovascular End Points and Outcomes (CRESCENDO) trial (by use of rimonabant versus placebo). This is very important, since previously, several observational studies in large population-based cohorts have indicated some detrimental effects of weight loss, even after intentional weight loss, with increased morbidity and mortality rates.

Topics: Bariatric Surgery; Cannabinoids; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Life Style; Multicenter Studies as Topic; Obesity; Piperidines; Power, Psychological; Pyrazoles; Rimonabant; Self Concept; Weight Loss

The endogenous cannabinoid system (ECS) is a neuromodulatory system recently recognized to have a role in the regulation of various aspects of eating behavior and energy balance through central and peripheral mechanisms. In the central nervous system, cannabinoid type 1 receptors and their endogenous ligands, the endocannabinoids, are involved in modulating food intake and motivation to consume palatable food. Moreover, the ECS is present in peripheral organs, such as liver, white adipose tissue, muscle, and pancreas, where it seems to be involved in the regulation of lipid and glucose homeostasis. Dysregulation of the ECS has been associated with the development of obesity and its sequelae, such as dyslipidemia and diabetes. Conversely, recent clinical trials have shown that cannabinoid type 1 receptor blockade may ameliorate these metabolic abnormalities. Although further investigation is needed to better define the actual mechanisms of action, pharmacologic approaches targeting the ECS may provide a novel, effective option for the management of obesity, type 2 diabetes and cardiovascular disease.

Topics: Adipose Tissue; Animals; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Eating; Endocannabinoids; Energy Metabolism; Humans; Hypothalamus; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reward; Rimonabant

The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their remission or improvement. In combination with lifestyle measures, currently available pharmacological therapies -- rimonabant, orlistat and sibutramine -- achieve 5-10% weight loss, although a return to baseline is the norm after cessation of medication. All these agents demonstrate approximately 0.5% reduction in HbA1c in diabetic subjects; orlistat also reduces the new incidence of type 2 diabetes. Modest improvement in lipid profiles and reduced calculated cardiovascular risk is observed, but data on improvement of other co-morbidities are sparse. In contrast, surgical procedures that restrict food ingestion and/or curtail the absorptive surface area of the gut consistently achieve substantial weight loss, typically 20-35%, effect resolution of co-morbid conditions and improve quality of life. Although mortality is low, complications and hospitalisation are not uncommon after bariatric surgery. Intriguingly, surgical patients experience a reduction in appetite and report changes in food preference. Accentuation of the normal gastrointestinal hormonal response to food intake and possible changes in vagal afferent signalling are proposed to induce satiety. Increased understanding of body weight homeostasis and appetite regulation has provided an impressive list of potential targets for drug development, with the promise that single or combination therapy may ultimately challenge the supremacy of bariatric surgery.

Topics: Adipose Tissue; Amyloid; Anticonvulsants; Antidepressive Agents; Anxiety; Appetite Regulation; Bariatric Surgery; Body Mass Index; Bupropion; Cholecystokinin; Ciliary Neurotrophic Factor; Clinical Trials as Topic; Cyclobutanes; Depression; Diabetes Mellitus, Type 2; Female; Fluoxetine; Fructose; Ghrelin; Humans; Intra-Abdominal Fat; Islet Amyloid Polypeptide; Isoxazoles; Lactones; Leptin; Metabolic Syndrome; Metformin; Obesity; Obesity, Morbid; Orlistat; Oxyntomodulin; Peptide YY; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Sertraline; Sleep Apnea, Obstructive; Surgical Procedures, Operative; Topiramate; Zonisamide

The endogenous cannabinoid system has been identified as playing a central role in the regulation of energy homeostasis, and its overactivity has been associated with obesity. Rimonabant is a selective endocannabinoid CB(1) receptor antagonist that has been shown to be an effective treatment for obesity and cardiometabolic risk factors. Studies comparing 20 mg/d of rimonabant with placebo show a placebo-subtracted weight loss between 6.3 and 6.9 kg at 1 year. In addition to the health benefits already associated with weight loss, rimonabant has shown additional improvements in lipid and glycemic cardiometabolic biomarkers such as low-density lipoprotein cholesterol, triglycerides, C-reactive protein, glucose, and adiponectin. The use of endocannabinoid antagonists such as rimonabant provides a promising therapeutic approach to the treatment of obesity and its associated cardiometabolic risks.

Topics: Adipose Tissue; Animals; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Cholesterol, HDL; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors

The effects of exogenous and endogenous cannabinoids on the cardiovascular system have been the focus of extensive research. The direct and indirect effects of cannabinoids on heart and blood vessels depend upon experimental conditions, animal species, and, in humans, clinical background. Cannabinoids decrease blood pressure in hypertensive rodents primarily because of decrease cardiac contractility, leading researchers to postulate a role in the treatment of hypertension and cardiac hypertrophy. Rimonabant, the CB(1) receptor blocker in clinical use in many countries, induced a marked and sustained increase in cardiac contractility and blood pressure in hypertensive rats but, on the contrary, contributed to decrease blood pressure in weight-loss clinical trials especially in obese patients with hypertension. In the midst of the obesity pandemic and from the cardiometabolic point of view, the overactivation of the endocannabinoid system present in intra-abdominal obesity appears to be very harmful. Moreover, novel human findings suggest a relationship between CB(1)-mediated overactive endocannabinoid system and nephrovascular damage. Overall, it appears that CB(1) blockade in obese patients behaves as a 'multiplier' of the many beneficial effects of body weight loss induced by a hypocaloric diet and increased physical activity (the 'lifestyle changes' that are so difficult to start and maintain). Thus, the concept - based mostly on experimental results using in vitro or animal models - that CB(1)-mediated endocannabinoid effects are beneficial for the cardiovascular system should be revised at least in obese patients. The results of long-term clinical trials such as the STRADIVARIUS and the CRESCENDO trials will tell whether the improvement in the cardiometabolic risk profile induced by Rimonabant translates into vascular changes, reducing the risk of myocardial infarction, stroke and cardiovascular death in patients with abdominal obesity. Time (and much more work) will tell us much more about cannabinoids and the human heart.

Topics: Blood Pressure; Blood Vessels; Cannabinoid Receptor Modulators; Cannabinoids; Cardiovascular Physiological Phenomena; Cardiovascular System; Clinical Trials as Topic; Endocannabinoids; Heart; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant

Obesity-related hypertension represents a common clinical condition characterised by complex pathophysiological and therapeutic features. From a pathophysiological view point, results of experimental and animal studies have led to the hypothesis that neurogenic mechanisms participate in the development and progression of the disease. The hypothesis is based on the evidence that metabolic (i.e. insulin-resistance) and neural (sympathetic activation) alterations frequently co-exist in the obese hypertensive patient and that they reciprocally potentiate each other. From a therapeutic view point, the 2007 European Society of Hypertension/European Society of Cardiology emphasised the importance in this clinical condition of treatment not only through antihypertensive drugs but also via lifestyle changes and drug-induced interventions that reduce body weight. The four Rimonabant In Obesity (RIO) studies have shown that rimonabant can decrease body weight. A recent meta-analysis, based on the RIO results, showed that rimonabant, particularly in obese hypertensive patients, can also decrease - although modestly (2.8 mmHg for systolic and 2.2 mmHg for diastolic) - blood pressure. These effects, which appear to be triggered by the weight reduction induced by the drug, are clinically relevant because they contribute favourably to lower the elevated cardiovascular risk profile of the obese hypertensive patient.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cannabinoids; Down-Regulation; Humans; Hypertension; Obesity; Piperidines; Pyrazoles; Rimonabant; Sympathetic Nervous System

The endogenous cannabinoid system plays an important modulatory role in feeding behaviour and metabolism, acting at both central and peripheral levels. Chronic administration of cannabinoid CB(1) receptor antagonists has been found to be effective in experimental obesity. However, clinically available cannabinoid receptor antagonists are inverse agonists that can target CB(1) receptors located in both central circuits regulating appetite and motivation and in peripheral organs regulating metabolism and energy expenditure. This profile complicates understanding of cannabinoid CB(1) receptor blockade as a therapeutic strategy in obesity and metabolic disorders. This review aims to explore the relevance of both inverse agonism and peripheral cannabinoid receptor blockade on the beneficial actions of chronic cannabinoid receptor blockade, by comparing the actions of the reference antagonist/inverse agonist rimonabant and the newly designed drug LH-21. LH-21 is a triazol derivative and a neutral cannabinoid receptor antagonist; it has a poor penetration rate into the central nervous system. When given acutely it decreases food intake and enhances the anorectic actions of oleoylethanolamide, a feeding suppressant lipid that acts on peripheral sensory terminals in a similar way as rimonabant. Unlike rimonabant, chronic administration of LH-21 (3 mg/kg) reduces feeding but does not improve hypertriglyceridaemia or hypercholesterolaemia; nor does it reduce liver fat deposits in Zucker rats. These results suggest that the inverse agonism and/or the antagonism of central cannabinoid CB(1) receptors are necessary for the metabolic benefits of cannabinoid CB(1) receptor blockade, but not for the appetite reduction.

Topics: Animals; Anorexia; Anti-Obesity Agents; Biological Availability; Brain; Cannabinoids; Central Nervous System; Drug Synergism; Eating; Endocannabinoids; Energy Metabolism; Feeding Behavior; Obesity; Oleic Acids; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Rimonabant; Triazoles

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.

Topics: Algorithms; Anti-Obesity Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metabolic Syndrome; Metformin; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Treatment Outcome

Blockade of the CB(1) receptor is one of the promising strategies for the treatment of obesity. The first selective CB(1) receptor antagonist, rimonabant, which has already successfully completed phase III clinical trials, led to sustained weight loss and a reduction in waist circumference. Patients treated with rimonabant also demonstrated statistically significant improvement in high-density lipoprotein cholesterol levels, triglyceride levels and insulin resistance, as well as a reduced overall prevalence of metabolic syndrome. Currently, one of the most discussed aspects of endocannabinoid system function is to what extent the endocannabinoid system might affect metabolism independently of its control over body weight and food intake. Specifically, a food-intake- and body-weight-independent role in the regulation of glucose homeostasis and insulin sensitivity could have major impact on the potential of drug candidates targeting the endocannabinoid system for the prevention and treatment of metabolic syndrome. This review summarises the effects of the endocannabinoid system on glucose homeostasis and insulin sensitivity.

Topics: Adipose Tissue, White; Animals; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Endocannabinoids; Energy Metabolism; Glucose; Homeostasis; Humans; Liver; Models, Biological; Muscles; Obesity; Pancreas; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Rodentia

Obesity and cardiometabolic risk, or the metabolic syndrome, continue to be major public health concerns. To date, treatment with lifestyle and pharmacotherapy interventions has resulted in limited efficacy in reversing the upward trend in this present-day health crisis. Research reveals that a modest 5% to 10% weight loss results in substantial improvement in health. While obtaining modest weight loss is often achievable, maintaining lost weight is challenging. Research has recently improved our understanding of several endogenous pathways that influence body weight regulation and disease risk. The endocannabinoid system has been found to regulate appetite and energy expenditure, as well as lipid and glucose metabolism. Interest in blocking stimulation of this pathway to aid weight loss and reduce cardiometabolic risk factor development is an area of interest and research. This article reviews the mechanisms by which the endocannabinoid system is believed to influence body weight regulation and cardiometabolic risk factors, as well as the results of clinical trials investigating the safety and efficacy of a selective cannabinoid-1 receptor antagonist (rimonabant). Clinical trials investigating rimonabant treatment resulted in substantial reductions in body weight and markers for cardiometabolic risk in study participants. However, increases in adverse events were reported in the drug-treated group. Data regarding long-term benefit and adverse events from rimonabant treatment are being collected in several ongoing clinical trials. Rimonabant is currently available in 42 countries, but has not received United States Food and Drug Administration approval. Food and nutrition professionals play a pivotal role in tackling the current obesity crisis; it is essential that they understand the many physiological mechanisms regulating body weight. Emerging research data reveals pathways that influence appetite and energy metabolism, and this knowledge may form the foundation for new clinical treatment options for obese individuals.

Topics: Appetite Regulation; Blood Glucose; Cannabinoid Receptor Modulators; Drug Approval; Endocannabinoids; Energy Metabolism; Humans; Lipid Metabolism; Obesity; Piperidines; Pyrazoles; Rimonabant; United States; United States Food and Drug Administration; Weight Loss

The unabated rise in the prevalence of obesity is a challenge for global health care systems. Efforts to reverse this trend by dietary or behavioral counseling have not been successful, which has stimulated efforts to find a role for pharmacotherapy. Currently only a small number of antiobesity drugs are approved for long-term use and only a few compounds are in clinical development. Despite recent progress in the understanding of the regulation of energy balance, drug discovery has been less productive than expected. In the present review, the clinically available antiobesity agents are discussed. Examples of drug candidates that are currently in development are given and the possible future range of antiobesity agents is illustrated by the targets being addressed in drug discovery. Finally, the efficacy of antiobesity agents and their value in the treatment of obesity are assessed in comparison with other therapeutic approaches, such as surgery and changes in lifestyle.

Topics: Anti-Obesity Agents; Cyclobutanes; Disease Outbreaks; Drug Design; Drugs, Investigational; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant

The prevalence of metabolic syndrome has increased dramatically in recent years, and the cluster of metabolic abnormalities it encompasses results in increased cardiovascular morbidity and mortality. The role of abdominal (visceral) obesity and the underlying molecular and cellular mechanisms central to this association have been the subject of intensive research in recent times. The aim of this review is to correlate data in this area, highlighting the central role of excess visceral fat and its secreted adipokines, and to review existing and emerging therapies.. Data were generated from a search of the PubMed database using the terms 'abdominal obesity', 'metabolic syndrome', 'insulin resistance', 'adipokines', 'interleukin-6 (IL-6)', 'adiponectin', 'tumour necrosis factor-alpha (TNF-alpha)' and 'cardiovascular disease'.. Metabolic syndrome is associated with a pro-inflammatory state, and the role of visceral obesity is thought to be central to this. Visceral obesity leads to alteration of the normal physiological balance of adipokines, insulin resistance, endothelial dysfunction and a pro-atherogenic state. In association with this, the presence of conventional cardiovascular risk factors such as hypertension, dyslipidaemia and smoking results in a significantly elevated cardiovascular and metabolic (cardiometabolic) risk. Better understanding of the molecular mechanisms central to this association has led to the development of potential therapeutic agents.

Topics: Cardiovascular Diseases; Fatty Acids, Nonesterified; Humans; Inflammation; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Tumor Necrosis Factor-alpha

Antiobesity treatment is recommended for selected patients in whom lifestyle modification is unsuccessful. Two antiobesity drugs are currently licensed for long-term use. Orlistat, a gastrointestinal lipase inhibitor, reduces weight by around 3 kg on average and decreases progression to diabetes in high-risk patients; adverse gastrointestinal effects are common. Sibutramine, a monoamine-reuptake inhibitor, results in mean weight losses of 4-5 kg, but is associated with increases in blood pressure and pulse rate. Rimonabant, the first of the endocannabinoid receptor antagonists, reduces weight by 4-5 kg on average and improves waist circumference and concentrations of HDL cholesterol and triglyceride; however, an increased incidence of mood-related disorders has been reported. To date, all antiobesity drug trials have been limited by their high attrition rates and lack of long-term morbidity and mortality data. Other promising antiobesity drugs, including those acting within the central melanocortin pathway, are in development, but are years away from clinical use. In light of the lack of successful weight-loss treatments and the public-health implications of the obesity pandemic, the development of safe and effective drugs should be a priority. However, as new drugs are developed we suggest that the assessment processes should include both surrogate endpoints (ie, weight loss) and clinical outcomes (ie, major obesity-related morbidity and mortality). Only then can patients and their physicians be confident that the putative benefits of such drugs outweigh their risks and costs.

Topics: Anti-Obesity Agents; Blood Pressure; Cholesterol, HDL; Cyclobutanes; Half-Life; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Weight Loss

Recent findings in animals and in humans have shown that cannabinoid type 1 receptor antagonists are suitable to become the most promising validated class of drugs to tackle obesity and related disorders. This mini-review will provide a concise and updated revision of the state of art on this topic.

Topics: Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant

Abdominal obesity is a prevalent, worldwide problem linked to cardiometabolic comorbidities and an increased risk of coronary heart disease. First-line therapy to reduce such risk revolves around diet and exercise; however, such changes are often difficult to implement and unsuccessful. Understanding the underlying pathophysiology of underlying metabolic derangements could provide new targets for pharmacologic therapy. One system that has gained recent attention is the endocannabinoid system. The endocannabinoid system has a significant role in central appetite control and peripheral lipogenesis and is up-regulated in diet-induced obesity. Rimonabant is a selective cannabinoid-1 receptor antagonist and is the first compound of its type to test the hypothesis that down-regulating an overactive endocannabinoid system could have therapeutic benefit not only for weight loss but also for the atherogenic dyslipidemia and insulin resistance that cluster with abdominal obesity in particular. Animal models have been critical for elucidating the role of the endocannabinoid system in obesity and in demonstrating that antagonism with rimonabant can induce loss of visceral fat and improve insulin sensitivity. Early human trials with rimonabant have confirmed significant reductions in weight, as well as favorable changes in atherogenic dyslipidemia, insulin resistance, and markers of inflammation. Interestingly, some of these beneficial metabolic effects are partially weight-loss-independent, confirming the importance of peripheral endocannabinoid system effects in addition to central effects.

Topics: Animals; Humans; Hypothalamo-Hypophyseal System; Intra-Abdominal Fat; Obesity; Piperidines; Pituitary-Adrenal System; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant

The pharmacology, pharmacokinetics, clinical efficacy, safety, drug interactions, and dosage and administration of rimonabant in the treatment of obesity and related metabolic factors are reviewed.. Discovery of the cannabinoid receptors has led to the development of rimonabant, a cannabinoid-1 (CB(1)) antagonist. Selective blockade of this receptor has been shown to lead to decreased appetite and food intake in animal models. Clinical studies have shown that rimonabant 20 mg once daily produces significant decreases in weight and waist circumference in obese human subjects and improves the lipid profile and glucose control. The frequency of metabolic syndrome also decreased significantly with rimonabant 20 mg daily. Limited data are available regarding the pharmacokinetics and pharmacodynamics of rimonabant. Preclinical data have demonstrated a long duration of action. As of yet, no drug-drug, drug-food, or drug-disease interactions have been identified with rimonabant. Adverse reactions occurred rarely, with nausea, dizziness, diarrhea, arthralgia, and back pain being the most common. Psychiatric disorders, including depression and anxiety, were the most common reasons for subjects to withdraw from rimonabant studies. Rimonabant has been shown to be safe for up to two years of treatment. Further research will clarify currently unknown areas, including pharmacokinetics, drug interactions, and the drug's role in standard therapy.. Rimonabant, a selective CB(1) antagonist, is a novel treatment option for obese and overweight individuals. Significant weight loss, decrease in waist circumference, and improvements in lipid profile and glucose control have been shown in clinical trials of rimonabant.

Topics: Anti-Obesity Agents; Cannabinoid Receptor Modulators; Drug Interactions; Female; Humans; Male; Obesity; Piperidines; Pyrazoles; Rimonabant

The advent of the highly selective cannabinoid receptor (CB1) antagonist, rimonabant (SR141716; Acomplia) can revolutionize the ability of the clinicians to manage obesity. Large-scale clinical trials have demonstrated that rimonabant therapy can reduce obesity. Although, the precise mechanisms of action of rimonabant have to be further dissected, it is emerging, from both preclinical and clinical research, that not only is rimonabant an antiobesity drug, but also its pleiotropic functions affect a broad range of diseases, from obesity-related comorbidities to drug dependence and cancer. Here we review recent data from the literature and discuss the full pharmacological potential of this drug.

Topics: Anti-Obesity Agents; Antineoplastic Agents; Body Weight; Humans; Neurodegenerative Diseases; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Smoking Cessation; Substance-Related Disorders

This review considers the use of the first selective blocker of the cannabinoid receptor type 1, rimonabant, to reduce weight and improve cardiovascular disease risk factors in obese patients with metabolic syndrome or multiple cardiovascular disease risk factors. In 4 large trials-Rimonabant in Obesity (RIO)-Lipids, RIO-Europe, RIO-North America, and RIO-Diabetes-after 1 to 2 years of treatment, rimonabant (20 mg/day) led to a significantly greater weight loss and reduction in waist circumference compared with placebo. Treatment with rimonabant was also associated with other favorable changes, including better glycemic control in type 2 diabetes mellitus, improved lipid profile, reduced blood pressure, increased adiponectin levels, fall in high-sensitivity C-reactive protein concentrations, and an overall decrease in the prevalence of the metabolic syndrome. Initial experience with rimonabant shows that it is generally well tolerated with the most common side effect of mild nausea. Rimonabant may be a useful adjunct to lifestyle and behavior modification in the treatment of obese subjects with metabolic syndrome or multiple cardiometabolic risk factors.

Topics: Cardiovascular Diseases; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors

Clinical reports (RIO trials) have shown that chronic administration of a CB-cannabinoid receptor antagonist (rimonabant) provides improvements of disturbed metabolic parameters observed in overweight and obese patients with type 2 diabetes. The production of endocannabinoid and the expression of CB1-cannabinoid receptors are largely distributed in the different organs aside from the brain. It is now clearly established that endocannabinoids act both through orexigenic effects and peripheral metabolic effects in various tissues involved in the control of metabolism and energy expenditure (i.e. adipose tissue, liver, gastrointestinal tract, skeletal muscle and pancreas). This review will consider: i) the disturbances of glucose and lipid metabolisms in obese type 2 diabetics; ii) an overview of the pharmacological properties of rimonabant and iii) the various mechanisms involved in tissues and organs to explain the therapeutic efficacy of rimonabant. A special attention will be paid to its utilization in obese type 2 diabetics. The emerging concept of endocannabinoids acting as metabolic regulators is the more likely explanation of the success of rimonabant treatments in phase III studies.

Topics: Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Energy Metabolism; Glucose; Humans; Lipids; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Treatment of obesity continues to rely upon the classical triad of nutritional advise, increase of physical activity and use of drugs. However, in recent years, there have appeared novelties in both therapeutic targets and new molecules. With regard to therapeutic targets of obesity, success does not consist of losing much weight but attaining a moderate yet maintained weight lose (5-10% of initial weight) at the expense of visceral fat. In other words, instead of weight, what is needed is a waist reduction, mainly to improve or prevent obesity-related metabolic and vascular complications. Regarding drugs, a new molecules is about to appear in the international pharmaceutical market: rimonabant. A selective blocker of the endocannabinoid receptor CB1, it has proven to be effective and safe in treating obesity and its comorbidities. Another known agent, orlistat, has proven to be effective in the prevention of the development of type 2 diabetes in obese patients with or without glucose intolerance.

Topics: Anti-Obesity Agents; Cyclobutanes; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant

Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. It has been evaluated in the RIO ("Rimonabant In Obesity and related disorders") programme including above 6.600 overweight/obese patients with or without comorbidities followed for 1 to 2 years. 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. In patients with type 2 diabetes, rimonabant also diminishes HbA1c levels, an effect confirmed in the recent SERENADE trial. Almost half of the metabolic effects occurs beyond weight loss, suggesting direct peripheral effects of rimonabant. Rimonabant is indicated in Europe as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.

Topics: Anti-Obesity Agents; Bradykinin; Cannabinoids; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dyslipidemias; Follow-Up Studies; Glycated Hemoglobin; Heart; Humans; Insulin Resistance; Metabolic Syndrome; Obesity; Overweight; Piperidines; Placebos; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Triglycerides; Waist-Hip Ratio; Weight Loss

There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Towards this end, antagonists of cannabinoid receptors have been designed through rational drug discovery efforts. Devoid of the abuse concerns that confound and impede the use of cannabinoid receptor agonists for legitimate medical purposes, investigation of the use of cannabinoid receptor antagonists as possible pharmacotherapeutic agents is currently being actively investigated. The compound furthest along this pathway is rimonabant, a selective CB(1) (cannabinoid receptor subtype 1) antagonist, or inverse agonist, approved in the European Union and under regulatory review in the United States for the treatment of obesity. This article summarizes the basic science of the endocannabinoid system and the therapeutic potential of cannabinoid receptor antagonists, with emphasis on the treatment of obesity.

Topics: Animals; Anti-Obesity Agents; Cannabinoid Receptor Modulators; Endocannabinoids; Humans; Models, Biological; Molecular Structure; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Three medications with approval for long-term use in the treatment of obesity are currently available in the United States. Sibutramine (U.S. Food and Drug Administration [FDA] approved in 1997), orlistat (FDA approved in 1999), and rimonabant (available in Europe and given FDA approvable status in 2006 and expected to be marketed in 2007) represent modern approaches to medications used adjunctively for weight management. As demonstrated in large clinical trials of 2 to 4 years' duration, these medications significantly increase weight loss compared with placebo; weight loss with these drugs reaches a nadir between 20 and 28 weeks; weight loss, averaged 8%-10%, with the placebo contributing 4%-6% of that. Weight maintenance is demonstrated as long as adherence to medication continues. All medications have side effects that need to be considered. For sibutramine, there is a rise in blood pressure and heart rate that may require discontinuation of the drug in a small percent of patients. For orlistat, steatorrhea produces the principal gastrointestinal side effects. Rimonabant appears to have a favorable safety and tolerability profile. Nausea and gastrointestinal symptoms are the chief tolerability issue, but they are usually self-limited. In addition there are several drugs and drug combinations in phase 2 or phase 2 trials that will be reported on in the coming years.

Topics: Animals; Anti-Obesity Agents; Clinical Trials, Phase II as Topic; Cyclobutanes; Humans; Lactones; Obesity; Orlistat; Overweight; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome

The endocannabinoid system (ECS) is an endogenous physiological system composed of two cannabinoid receptors and several endogenous ligands. The ECS is intimately involved in appetite regulation and energy homeostasis, which makes it an intriguing target for pharmacological treatment of obesity, diabetes, and the metabolic syndrome. Rimonabant is the first cannabinoid receptor (CB-1) antagonist being studied and utilized to treat obesity (it is approved in Europe but is currently under review in the United States). Large randomized trials with rimonabant have demonstrated efficacy in treatment of overweight and obese individuals with weight loss significantly greater than a reduced calorie diet alone. In addition, multiple other cardiometabolic parameters were improved in the treatment groups including increased levels of high density lipoprotein cholesterol, reduced triglycerides, reduced waist circumference, improved insulin sensitivity, decreased insulin levels, and in diabetic patients improvement in glycosylated hemoglobin percentage. There was an increase in the adverse effects of depression, anxiety, irritability, and nausea in rimonabant-treated groups. This novel medication may become an important therapeutic option in the fight to reduce cardiovascular disease worldwide through its unique action on cardiometabolic risk.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Treatment Outcome

Rimonabant (Acomplia - Sanofi-Aventis) has been licensed in the UK since June 2006 for the treatment of obese and certain overweight adults. Advertisements claim the drug has beneficial effects on "cardiometabolic risk factors", and that "an estimated 50% of the effects. . .on cardiometabolic risk factors are beyond those expected from weight loss alone". Here we review the role of rimonabant in managing patients with obesity.

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Drug Costs; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Treatment Outcome; Weight Loss

Cannabinoid drugs exert their effects primarily through activation of cannabinoid CB1 and CB2 receptors. Both CB1 and CB2 receptors have been implicated in a number of cardiovascular processes, including vasodilation, cardiac protection, modulation of the baroreceptor reflex in the control of systolic blood pressure, and inhibition of endothelial inflammation and the progress of atherosclerosis in a murine model. These effects are mainly mediated through central and peripheral nervous system CB1 receptors, vascular CB1 receptors and immune cell CB2 receptors. Relevant cellular effects include: the inhibition of neurotransmitter release in the nucleus tractus solitarius and in peripheral adrenergic neurons; regulation of NOS activity in vascular beds; inhibition of vascular smooth muscle cell excitability; regulation of endothelial cell migration and proliferation; and effects on immune cell proliferation, activation, and inflammatory functions. We review the pre-clinical evidence for beneficial effects of cannabinoid drugs in a range of vascular and cardiovascular pathologies. We also discuss the clinically relevant potential of cannabinoids.

Topics: Animals; Anti-Obesity Agents; Cannabinoid Receptor Modulators; Cannabinoids; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Risk Factors; Treatment Outcome

Recent studies have provided evidence that the endocannabinoid (EC) system has very significant effects on energy balance and metabolism through the central control of appetite and by affecting peripheral metabolism. Endocannabinoids are endogenous phospholipid derivatives which bind and activate cannabinoid receptors type 1 and type 2 (CB1 and CB2 receptors). The CB1 receptor, a G-protein coupled receptor, is believed to be responsible for the majority of the central effects of endocannaboids on appetite. Chronic positive energy balance and obesity have been associated with an overactivation of the endocannaboid system which has been suggested to contribute to the development of abdominal obesity and to associated metabolic abnormalities which increase the risk of cardiovascular disease and type 2 diabetes. Animal studies had shown that stimulation of the cannabinoid CB1 receptor with endocannaboids such as anandamide could induce first an increase in food intake leading to body weight gain. Furthermore, an exciting development in this field has been the discovery of CB1 receptors in many peripheral tissues, including key organs involved in carbohydrate and lipid metabolism such as the adipose tissue and liver. Thus, blocking CB1 receptors located in the liver and adipose tissue could have an additional impact on the metabolic risk profile beyond what could be explained by the reduction in food intake and the related body weight loss. Preclinical studies have shown that rimonabant, the first CB1-receptor blocker to be available in clinical practice, could not only induce a reduction in food intake, but could also produce body weight loss beyond what could be explained by its effect on food intake. Thus, the evidence from preclinical studies have suggested that CB1 blockade could represent a relevant approach to reduce food intake, to induce body weight loss, and, most importantly, to "fix" the dysmetabolic state of viscerally obese patients at increased cardiometabolic risk.

Topics: Adipocytes; Adiponectin; Animals; Appetite Regulation; Arachidonic Acids; Cannabinoid Receptor Modulators; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Dronabinol; Eating; Endocannabinoids; Energy Metabolism; Humans; Lipid Metabolism; Obesity; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant

Diabetes and cardiovascular disease have emerged as major threats to human health, and the risk of developing these chronic conditions is increased in individuals with abdominal obesity and the metabolic syndrome. Excess visceral abdominal tissue (VAT) accumulation appears to be a key feature of abdominal obesity contributing to the development of the metabolic syndrome. For instance, excess VAT is accompanied by elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol, elevated blood pressure, and/or elevated fasting plasma glucose. In addition, the rather normal or only marginally elevated low-density lipoprotein (LDL) cholesterol concentrations in patients with excess VAT could provide misleading information as viscerally obese patients have an increased plasma concentration of small, dense LDL particles. Prospective studies have suggested that even among patients with LDL cholesterol concentrations within normal limits, an increased concentration of small LDL particles is associated with higher risk of cardiovascular disease. With the treatment of abdominal obesity and excess VAT, an increase in patients' LDL particle size and improvements in other cardiovascular risk factors (eg, insulin levels, glucose tolerance, HDL, C-reactive protein [CRP], and adiponectin levels) can be achieved. Waist circumference can be used in clinical practice as a first approach and as a crude index to identify patients who have excess VAT, particularly when the elevated waistline is accompanied by the clinical features of the metabolic syndrome, among which an elevated fasting triglyceride concentration appears to be predictive of a reduced LDL particle size and of further metabolic abnormalities frequently referred to as the metabolic syndrome. Lifestyle changes, including more physical activity and healthier nutritional habits, are the cornerstone of therapy for high-risk abdominally obese patients with an excess of VAT. In addition, results from the RIO-Lipids study, which was conducted in high-risk obese, dyslipidemic patients, have provided evidence that CB1 receptor blockade with rimonabant can induce significant weight loss, and, more importantly, improve the cardiometabolic risk profile beyond what could be explained by the weight loss effects of the drug.

Topics: Adiponectin; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Humans; Intra-Abdominal Fat; Metabolic Syndrome; Obesity; Piperidines; Prospective Studies; Pyrazoles; Rimonabant; Risk Factors

Interventions that reduce weight and abdominal adiposity have been shown to improve obesity-associated disorders of glucose and lipid metabolism, reduce blood pressure, and promote other beneficial effects on cardiometabolic risk parameters. When long-term adherence to diet/exercise recommendations is suboptimal, management of overweight and obese patients at high cardiometabolic risk includes the use of adjunctive pharmacologic agents to facilitate weight loss and weight loss maintenance. Rimonabant, a cannabinoid-1 (CB1) receptor blocker, has been shown to induce weight loss and improve cardiometabolic parameters, implying that the endocannabinoid system is a promising target for obesity-related health improvement. Herein we summarize the results of the Rimonabant in Obesity (RIO) studies, which have evaluated the effectiveness of CB1 receptor blockade in facilitating weight loss and improving cardiometabolic health in >6,600 patients from the United States and Europe. As compared with placebo, 20 mg/day of rimonabant consistently produced greater reductions in weight and waist circumference, as well as improvements in dyslipidemia and parameters of glucose metabolism. The improvements that were noted for several cardiometabolic parameters with rimonabant were greater than what would be expected from the weight loss alone, suggesting there may be an independent effect of the drug on metabolic function. The results of these studies suggest that CB1 receptor blockade may be a useful treatment for multiple cardiometabolic risk factors in overweight and obese patients.

Topics: Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Evaluation; Female; Humans; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Treatment Outcome; Waist-Hip Ratio

The recent discovery of the endocannabinoid system has led to the development of promising treatments for patients with obesity and associated cardiometabolic risk factors. Basic research has demonstrated that the endocannabinoid system plays an integral role in the regulation of food intake, metabolism, and storage. Research with the endocannabinoid receptor antagonist rimonabant has demonstrated statistically significant improvements in body weight, fasting insulin levels, glucose tolerance, high-density lipoprotein cholesterol levels, serum triglyceride levels, and waist circumference, compared with placebo. Rimonabant has also produced statistically significant improvements in inflammatory markers. Research with rimonabant has demonstrated sustained efficacy for as long as 2 years when used in conjunction with a reduced-calorie diet and moderate physical activity. Rimonabant is the first cannabinoid receptor 1 antagonist to be marketed in Europe and the first to file an New Drug Application in the United States. It may provide a novel therapeutic strategy for the treatment of patients with obesity and associated cardiometabolic risk factors.

Topics: Abdominal Fat; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Controlled Clinical Trials as Topic; Endocannabinoids; Energy Metabolism; Homeostasis; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors

The increasing prevalence of overweight and obesity counteracts the favorable advances of risk factor management achieved for cardiovascular disease (CVD) prevention. Obese and overweight individuals are at increased risk for CVDs and diabetes mellitus, a risk pattern called "cardiometabolic risk." There is a growing interest concerning the role of the endocannabinoid system in energy metabolism and how blockade of cannabinoid receptors (CB(1)) may optimize fat distribution, insulin sensitivity, and blood lipids to improve cardiovascular risk profile.

Topics: Abdominal Fat; Adipokines; Animals; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Endocannabinoids; Humans; Insulin Resistance; Lipids; Obesity; Overweight; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Weight Loss

Modification of lifestyle is the main therapeutical approach in the treatment of obesity, but use to fail on long terms of time. Addition of anti-obesity drugs allows keeping the weight loss during years and improving obesity-related comorbidities.. This review is an actualisation on efficacy, safety and tolerability of the approved drugs on the long-term treatment of obesity (orlistat and sibutramine). New indications and effects of their use far beyond the weight loss are as well commented. Finally, potential benefits of the administration of CB1 antagonist rimonabant on the weight loss and cardiometabolic risk factors are analysed in detail.. A decade of experience on the use of orlistat and sibutramine has demonstrated their higher efficacy on the weight loss when compared to placebo either on adult or teenage population as well as safety and tolerability on long-term administration. Beneficial effects on the lipid profile, glycosilated haemoglobin on diabetic patients, blood pressure and levels of inflammatory cytokines, contribute to decrease the cardiovascular risk on obese patients. Phase III clinical trials using rimonabant show additional benefits to the expected weight loss, mainly reducing visceral fat and cardiometabolic risk factors.. Pharmacological treatment of obesity must be considered as a therapeutical tool that has to be used together with long-term lifestyle changes, contributing to the body weight reduction as well as to the improvement of the cardiometabolic risk related to obesity.

Topics: Anti-Obesity Agents; Cyclobutanes; Humans; Lactones; Life Style; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Safety; Treatment Outcome; Weight Loss

The growing prevalence of obesity is associated with a dramatic increase in a number of related risk factors for cardiovascular disease and diabetes, including high triglyceride and fasting glucose levels, reduced high-density lipoprotein cholesterol, and increased blood pressure. For many patients, lifestyle interventions (eg, exercise and a reduced-calorie diet) are insufficient for overcoming obesity, and pharmacotherapy becomes necessary. Unfortunately, the currently available agents are associated with side effects such as gastrointestinal distress and increased blood pressure. A new class of drugs targeting the cannabinoid receptors is poised to join the obesity-management armamentarium, with one agent-rimonabant-demonstrating efficacy in 4 recent phase III multinational trials. Patients randomized to rimonabant 20 mg/d showed significant reductions in weight and significant improvements in lipid profiles and other measures of cardiometabolic risk factors.

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet; Dyslipidemias; Exercise; Humans; Insulin Resistance; Life Style; Lipids; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Assessment; Risk Factors; Treatment Outcome; Weight Loss

Over the past 15 years, research on the endogenous cannabinoid (CB) system-now usually referred to as the endocannabinoid system (ECS)-has identified the significant effects of the ECS on the regulation of food intake and lipid and glucose metabolism in animals and humans. Endocannabinoids are endogenous lipids capable of binding to endogenous CB1 and CB2 receptors. CB1 receptors are present in the hypothalamic nuclei, which are involved in the control of energy balance and body weight, and in the mesolimbic system, which mediates the motivation to consume palatable food, as well as in adipocytes, the gut, and the liver. In the recent Rimonabant in Obesity (RIO)-Europe study, treatment with the first CB1 receptor antagonist, rimonabant, led to sustained, clinically meaningful weight loss and a reduction in waist circumference. Patients treated with rimonabant also demonstrated statistically significant improvement in high-density lipoprotein cholesterol levels, triglyceride levels, and insulin resistance, as well as a reduced overall prevalence of metabolic syndrome. Results of this and other studies support the role of endocannabinoids in the development and maintenance of obesity. In addition, these findings suggest that CB1 receptor antagonists such as rimonabant may offer a potential new approach to managing obesity and associated cardiometabolic risk factors.

Topics: Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Risk Assessment; Risk Factors

This review summarizes data on currently used antiobesity drugs and new compounds under clinical development. Three antiobesity drugs are currently accepted for long-term use. Sibutramine is a noradrenaline and serotonin reuptake inhibitor which reduces body weight by about 4-5 kg but increases heart rate and arterial blood pressure. Orlistat is a gastrointestinal lipase inhibitor which results in mean weight loss by about 3 kg and reduces the incidence of type 2 diabetes in patients with impaired glucose tolerance; however, adverse gastrointestinal effects have been observed. Rimonabant is an endocannabinoid CB1 receptor antagonist which induces a 4-5 kg mean weight loss and improves glycemic and lipid profiles, but it induces anxiety and depressive disorders. Unfortunately, there are no data on the chronic administration of these drugs. Other drugs can induce weight loss, e.g. some antidepressants, antiseizure agents, and antidiabetic drugs. The moderate efficacy of currently used antiobesity drugs has led to an intense effort to identify new, safe antiobesity drugs with better therapeutic profiles. The new antiobesity drugs under clinical development include: 1) agents that affect neurotransmitters in the central nervous system, including noradrenaline and dopamine reuptake inhibitors (bupropion, radafaxine), selective 5HT2C receptor agonists (lorcaserin), and selective 5HT6 receptor antagonists, 2) agents that modulate the activity of neuropeptides influencing food intake, including leptin analogues, human ciliary neurotrophic factor (Axokine), neuropeptide Y antagonists, and melanine-concentrating hormone antagonists, 3) agents that affect the peripheral satiety signals and brain-gut axis, e.g. selective cholecystokinin receptor A agonists, PYY3-36, agents decreasing ghrelin activity, 4) thermogenic agents, e.g. selective beta3 receptor agonists and selective thyroid hormone receptor beta agonists, and 5) others, e.g. human growth hormone fragment (AOD9604) and gastrointestinal lipase inhibitor (cetilistat).

Topics: Anti-Obesity Agents; Clinical Trials as Topic; Cyclobutanes; Humans; Lactones; Neurotransmitter Agents; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome

Topics: Adult; Aged; Anti-Obesity Agents; Appetite Depressants; Bariatric Surgery; Body Mass Index; Cyclobutanes; Diagnosis, Differential; Enzyme Inhibitors; Humans; Lactones; Male; Middle Aged; Obesity; Obesity, Morbid; Orlistat; Overweight; Piperidines; Prognosis; Pyrazoles; Rimonabant; Time Factors; Weight Loss

The obesity pandemic will likely have a significant impact on the global incidence of cardiovascular disease. Although the mechanisms linking obesity and cardiovascular disease are unclear, recent studies have implicated the adipocyte as a potentially important mediator of vascular complications. The adipocyte is no longer considered a passive storage depot for triglycerides and fatty acids, but rather an active metabolic organ capable of producing several factors, commonly referred to as adipokines, that may have effects on many physiological and pathophysiological processes. With increasing fat mass, several adipose-related factors are upregulated that may affect local and distant inflammatory processes, including atherothrombosis. Other factors, such as adiponectin, are downregulated with increasing fat mass. Although most adipokines are thought to promote vascular disease, several studies over the past few years indicate adiponectin is actually protective against both diabetes and vascular disease. There are now available pharmacologic agents capable of altering the adipocyte transcription profile. This review will focus on the potential impact of adipocyte-derived factors towards vascular disease and emerging therapeutic strategies that may alter these effects.

Topics: Adiponectin; Anti-Obesity Agents; Cardiovascular Diseases; Cyclobutanes; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Hypertension; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Risk Factors

Since the prevalence of obesity continues to increase, there is a demand for effective and safe anti-obesity agents that can produce and maintain weight loss and improve comorbidity. We did a meta-analysis of all published randomised controlled trials to assess the efficacy and safety of the newly approved anti-obesity agent rimonabant.. We searched The Cochrane database and Controlled Trials Register, Medline via Pubmed, Embase via WebSpirs, Web of Science, Scopus, and reference lists up to July, 2007. We collected data from four double-blind, randomised controlled trials (including 4105 participants) that compared 20 mg per day rimonabant with placebo.. Patients given rimonabant had a 4.7 kg (95% CI 4.1-5.3 kg; p<0.0001) greater weight reduction after 1 year than did those given placebo. Rimonabant caused significantly more adverse events than did placebo (OR=1.4; p=0.0007; number needed to harm=25 individuals [95% CI 17-58]), and 1.4 times more serious adverse events (OR=1.4; p=0.03; number needed to harm=59 [27-830]). Patients given rimonabant were 2.5 times more likely to discontinue the treatment because of depressive mood disorders than were those given placebo (OR=2.5; p=0.01; number needed to harm=49 [19-316]). Furthermore, anxiety caused more patients to discontinue treatment in rimonabant groups than in placebo groups (OR=3.0; p=0.03; number needed to harm=166 [47-3716]).. Our findings suggest that 20 mg per day rimonabant increases the risk of psychiatric adverse events--ie, depressed mood disorders and anxiety-despite depressed mood being an exclusion criterion in these trials. Taken together with the recent US Food and Drug Administration finding of increased risk of suicide during treatment with rimonabant, we recommend increased alertness by physicians to these potentially severe psychiatric adverse reactions.

Topics: Anti-Obesity Agents; Anxiety Disorders; Depression; Double-Blind Method; Female; Humans; Male; Multicenter Studies as Topic; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Weight Loss

Although rimonabant has been approved for use in several countries, the Food and Drug Administration has expressed concern about the potential for adverse neurologic and psychiatric effects, considering the widespread distribution of CB1 receptors in the brain. While more research is clearly needed, the clinical evidence shows that CB1-receptor blockade with rimonabant improves multiple cardiovascular and metabolic variables, including body weight and waist circumference, HDL-C, triglycerides, and glucose metabolism. Furthermore, these effects, which are probably mediated by both peripheral and central actions in the ECS, appear to be greater than the improvements that would be expected from weight loss alone. There are multiple ongoing and planned studies with rimonabant as well as several other CB-receptor blockers (e.g., taranabant, CP-945,598). While diet and exercise are the cornerstones of cardiometabolic risk-factor reduction, improved pharmacotherapies are urgently needed. The ECS has provided us with new insights and a promising new avenue for the management of obesity and its associated cardiometabolic risk factors.

Topics: Brain; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Endocannabinoids; Homeostasis; Humans; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Risk Factors

Type-2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a risk of major cardiovascular disease. Several animal and human observations suggest that the endocannabinoid system is over-active in the presence of abdominal obesity and/or diabetes. Both central and peripheral endocannabinoid actions, via the activation of CB1 receptors, promote weight gain and associated metabolic changes. Rimonabant, the first selective CB(1) receptor blocker in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance index and C-reactive protein levels, and to increase high-density lipoprotein (HDL) cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in HbA1c levels was observed in metformin- or sulphonylurea-treated patients with type-2 diabetes and in drug-naïve diabetic patients. Almost half of the metabolic changes, including HbA1c reduction, could not be explained by weight loss, suggesting that there are direct peripheral effects. Rimonabant was generally well-tolerated, and the safety profile was similar in diabetic and non-diabetic patients, with a higher incidence of depressed mood disorders, nausea and dizziness. In conclusion, the potential role of rimonabant in overweight/obese patients with type-2 diabetes and at high risk of cardiovascular disease deserves much consideration.

Topics: Animals; Cannabinoid Receptor Modulators; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Feeding Behavior; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Intra-abdominal fat mass, or central adiposity, and cardiovascular risk are strongly correlated. Adipose tissue is an endocrine organ that secretes hormones and cytokines influencing appetite, energy metabolism, and atherosclerosis. National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend that if dietary and lifestyle interventions fail to produce favorable outcomes in individuals with a body mass index >27 and weight-related comorbidities, as well as those with a body mass index >30, treatment plans may include weight loss medication. The endocannabinoid system has recently emerged as a viable target for the pharmacologic treatment of obesity and cardiometabolic risk factors. This article provides an in-depth review of efficacy results from clinical trials of rimonabant, a selective cannabinoid-1 receptor. (Recently, an FDA Advisory Committee recommended a delay in the approval of rimonabant because of safety issues that need to be addressed in further studies.) Compared with placebo, rimonabant 20 mg significantly decreased body weight and waist circumference measurements. In addition, rimonabant was associated with favorable changes in several other cardiometabolic risk factors, including significant increases in serum levels of high-density lipoprotein cholesterol and adiponectin, as well as reductions in serum levels of triglycerides, small, dense low-density lipoprotein particles, C-reactive protein, insulin resistance, and glycosylated hemoglobin.

Topics: Cardiovascular Diseases; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Treatment Outcome

Rimonabant is the first selective blocker of the cannabinoid-1 receptor in development for the treatment of obesity, diabetes mellitus, and cardiometabolic risk factors. (Recently, an FDA Advisory Committee recommended a delay in the approval of rimonabant because of safety issues that need to be addressed in further studies.) Although it is associated with favorable effects on weight, waist circumference, serum lipids, C-reactive protein, and an improvement in glycemic control in type 2 diabetes, there are concerns about side effects. Generally, rimonabant has been well tolerated, with a primary side effect of nausea. Other side effects seen in trials have been anxiety and depressive symptoms, as well as neurologic events, albeit at low rates. When rimonabant becomes clinically available, physicians should be vigilant regarding the expected side effects and use alternative therapies if needed.

Topics: Cardiovascular Diseases; Drug Tolerance; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Treatment Outcome

--Obesity is an important healthcare issue. --Recent research has led to insights into the role of the endocannabinoid system in the regulation of body weight. --Rimonabant is a CB1-endocannabinoid-receptor antagonist. --Four trials were published recently on the efficacy and safety of rimonabant in the treatment of people with obesity. --When combined with a hypocaloric diet, rimonabant 20 mg/day was more effective than placebo in achieving and maintaining weight loss. In addition, treatment with rimonabant had beneficial effects on insulin resistance, HDL-cholesterol and hypertriglyceridaemia. --There is concern regarding the increased incidence of depression during treatment. --Whether the beneficial effects of rimonabant on weight reduction and cardiovascular risk factors translate into a reduction in cardiovascular morbidity and mortality remains to be established in large phase III trials.

Topics: Cardiovascular Diseases; Depression; Diet, Reducing; Humans; Lipids; Obesity; Obesity, Morbid; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Weight Loss

Diabetes mellitus and obesity have become increasingly prevalent problems worldwide. Unfortunately, with traditionally prescribed glucose-lowering medications most individuals with diagnosed diabetes do not achieve and maintain adequate glycemic control over time; it may be even more challenging to lower blood glucose to an appropriate level without inducing a significant associated weight gain. Exenatide and rimonabant are recently developed agents that have demonstrated benefit in both glucose lowering and reduction of body weight. These medications may well prove to be attractive alternatives or additions to our more established diabetes therapies; however, these drugs have a side-effect profile that may limit their applicability to certain populations.

Topics: Appetite Depressants; Cannabinoid Receptor Antagonists; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Obesity; Peptides; Piperidines; Pyrazoles; Rimonabant; Venoms

Obesity is a chronic metabolic disorder that affects one third of American adults. Modest weight losses of just 5% to 10% of body weight, which are achievable with lifestyle modification and pharmacotherapy, can lead to remarkable improvements in many obesity-associated co-morbidities, including dyslipidemia, hypertension, and type 2 diabetes. In this review, the indications for pharmacotherapy and the goals of treatment are discussed, and current and future pharmacologic approaches to the treatment of obesity are examined. Current pharmacologic therapies for obesity are limited, but recent advances in our understanding of the complex and overlapping endocrine pathways that regulate body weight have led to new opportunities for antiobesity drug development. Important drug targets that are highlighted in this review include adipocyte-derived hormones, hypothalamic neuropeptides, and gastrointestinal hormones.

Topics: Amyloid; Anti-Obesity Agents; Appetite Depressants; Body Weight; Chronic Disease; Comorbidity; Cyclobutanes; Exenatide; Gastrointestinal Hormones; Humans; Islet Amyloid Polypeptide; Lactones; Leptin; Metformin; Obesity; Orlistat; Peptides; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Venoms

The current obesity epidemic is a major public health concern worldwide, in both developed and developing countries, and in adults and children alike. Obesity confers physical stress on multiple biologic processes and is associated with an increased risk of developing cardiovascular disease, type 2 diabetes mellitus, osteoarthritis, and certain forms of cancer, among other serious diseases. Therefore, it is essential that all health care providers take an active role in addressing the issue of obesity with their patients to reduce their cardiometabolic risks. Indeed, there is a 3-fold increase in the odds that a patient will attempt weight loss if it is recommended by a trusted health care professional. A reduction of only 5% to 10% of body weight improves lipid profiles, insulin sensitivity, and endothelial function, and reduces thrombosis and inflammatory markers. There is evidence, however, that humans are highly sensitive to the availability and nature of food in the environment, which presents a formidable obstacle to achieving lasting weight loss. The National Heart, Lung, and Blood Institute of the National Institutes of Health recommends lifestyle modification as the primary intervention. For individuals who do not respond or for those who also have a weight-related illness, a weight loss medication may need to be added to their treatment plan. While there are few medical options currently available, new compounds for the treatment of obesity are under investigation.

Topics: Adipocytes; Adipokines; Cardiovascular Diseases; Humans; Inflammation; Life Style; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Risk Assessment; Risk Factors; United States

Acceptable adverse effects and a clinical relevant weight loss of 3 to 5 kilograms have been found in long-term randomized clinical trials for sibutramine (Reductil) and orlistat (Xenical); these drugs may be prescribed for treatment of obesity for a duration of one and four years, respectively. This also seems to be the case for rimonabant (Acomplia), which is expected to receive approval in 2005 or 2006. However, until data on morbidity and mortality are available from RCTs, there is no absolute indication for prescribing drugs for treatment of obesity.

Topics: Anti-Obesity Agents; Appetite Depressants; Cyclobutanes; Diethylpropion; Enzyme Inhibitors; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Time Factors; Weight Loss

Obesity is strongly associated with conditions such as hypertension, diabetes mellitus and osteoarthritis that have known adverse health outcomes. The rising prevalence of obesity threatens to overburden our health care system. As a result, the need for safe and effective treatment options is urgent. Unfortunately, pharmacologic treatment options have been disappointing either because of poor side effect profiles or limited long-term efficacy. Our goal is to review currently available pharmacologic treatments and the data supporting their use so that practicing physicians may better incorporate them into a comprehensive, long-term treatment strategy for their patients. We focus on orlistat and sibutramine as these are the two medicines approved by the FDA for long-term treatment of obesity. In addition, we review briefly agents approved for short-term use as well as agents such as zonisamide and topiramate which have shown some promise as weight loss agents in specific clinical circumstances. Finally, we highlight one medicine currently in phase III clinical trials, an endocannabinoid receptor antagonist. Given the overwhelming research focus on this disease, it is likely that the coming years will bring more treatment options, raising the chance that our patients will have meaningful and sustained weight loss.

Topics: Anti-Obesity Agents; Appetite Depressants; Cyclobutanes; Fructose; Humans; Isoxazoles; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Selective Serotonin Reuptake Inhibitors; Topiramate; Zonisamide

CBI endocannabinoid system receptors localized in the hypothalamus and the nucleus accumbens are known to regulate hunger. Hyperstimulation of the CBI receptors lead to an increase of food intake, but also to an increase of lipogenesis, decrease of adiponectin and increase of insulin resistance. Rimonabant is the first CBI central and peripheral blocker, tested in international trials (RIO-lipids, RIO-Europe and RIO-North America). Significant results on weight reduction, increased adiponectin and improved metabolic syndrome have been demonstrated. Rimonabant is a new pharmacological therapy and very interesting for tackling obesity and metabolic syndrome.

Topics: Eating; Humans; Insulin Resistance; Lipid Metabolism; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant

The endocannabinoid system modulates synaptic neurotransmission centrally and peripherally and is involved in the brain pathways concerned with addiction, central regulation of body weight and adipose tissue function. The system is overactivated in animal models of obesity and nicotine use. This review discusses the role of rimonabant, a cannabinoid receptor 1 blocker, which has undergone Phase III clinical testing, in the treatment of obesity and tobacco dependence.. Results of Phase III clinical trials have shown that rimonabant has promising efficacy in the treatment of obesity, dyslipidaemia and diabetes associated with obesity, in preventing weight gain following smoking cessation, and possibly in smoking cessation. No critical problems with the tolerance and safety of the compound have appeared in studies to date.. Rimonabant may prove to be a useful aid in the treatment of the most widespread cardiometabolic risk factors.

Topics: Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Smoking Cessation; Tobacco Use Disorder; Treatment Outcome; Weight Gain

Rimonabant is the first selective blocker of the cannabinoid CB1 receptors being developed for the treatment of obesity, tobacco smoking and cardiometabolic risk factors. Following 1 year of treatment, rimonabant 20 mg/day leads to greater weight loss compared with placebo. Therapy with rimonabant is also associated with favourable changes in serum lipids and an improvement in glycaemic control in Type 2 diabetics. At the same dose, rimonabant significantly increases the cigarette smoking quit rates compared with placebo. Rimonabant appears to be generally well tolerated, with primary side effects of mild nausea, diarrhoea, anxiety and depression. As an agent with a novel mechanism of action, rimonabant has the potential to be a useful adjunct to lifestyle modification in the treatment of obesity, metabolic syndrome and cigarette smoking.

Topics: Animals; Disease Management; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Smoking; Smoking Cessation

Currently, the substances orlistat and sibutramine are approved drugs for the pharmacotherapy of obesity. Used in combination with increased exercise and dietary measures, both are capable of significantly reducing weight. In the USA and Europe, official approval for the selective cannabinoid receptor antagonist, rimonabant has been applied for.

Topics: Anti-Obesity Agents; Appetite Depressants; Cannabinoid Receptor Antagonists; Clinical Trials as Topic; Cyclobutanes; Enzyme Inhibitors; Exercise; Humans; Lactones; Lipase; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Time Factors; Weight Loss

Presentations in this symposium addressed effects and modes of action of endocannabinoids in various tissues in relation to metabolic disorders. Endocannabinoids are produced and exert their effect in various brain sites, including the mesolimbic reward circuitry and the hypothalamus. Both of these regions have direct ties to energy metabolism regulation, particularly food intake and energy expenditure. These data clearly suggest that the observed beneficial effects of CB1 (cannabinoid receptor 1) receptor antagonists on obesity may be related to the central endocannabinoid system. On the other hand, data presented on cannabinoid action in the liver and white adipose tissues clearly indicate that CB1-mediated events in affecting metabolic phenotype may occur in peripheral tissues as well. This together with the reported results from human trials on CB1 antagonists showing that the initial anorectic effect of rimonabant is diminished after the first weeks while longer lasting weight loss is achieved do indicate that peripheral action of cannabinoids are very important in body weight regulation. Should this hold true in the long run, antagonizing CB1 receptors with compound not crossing the blood-brain barrier could revolutionize pharmaceutical approaches to obesity by offering a tool that short cuts the central nervous system.

Topics: Adipose Tissue; Animals; Appetite Depressants; Appetite Regulation; Brain; Cannabinoid Receptor Modulators; Drug Tolerance; Energy Metabolism; Homeostasis; Humans; Liver; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The worldwide increase in the prevalence of type 2 diabetes represents a tremendous challenge for our healthcare system, especially if we consider that this phenomenon is largely explained by the epidemic of obesity. However, despite the well-recognized increased morbidity and mortality associated with an elevated body weight, there is now more and more evidence highlighting that abdominal adipose tissue is the fat depot that conveys the greatest risk of metabolic complications. This cluster of metabolic abnormalities has been referred to as the metabolic syndrome and this condition is largely the consequence of abdominal obesity, especially when accompanied by a high accumulation of visceral adipose tissue. This cluster of metabolic complications has also been found to be predictive of a substantially increased risk of coronary heart disease beyond the presence of traditional risk factors. Moreover, a moderate weight loss in initially abdominally obese patients is associated with a selective mobilization of visceral adipose tissue, leading to improvements in the metabolic risk profile predictive of a reduced risk of coronary heart disease and of type 2 diabetes. The recent discovery of the endocannabinoid-CB1 receptor system and of its impact on the regulation of energy metabolism represents a significant advance, which will help physicians target abdominal obesity and its related metabolic complications. In this regard, studies have shown that rimonabant therapy (the first developed CB1 blocker) could be useful for the management of clustering cardiovascular disease risk factors in high-risk abdominally obese patients through its effects not only on energy balance but also on adipose tissue metabolism. For instance, the presence of CB1 receptors in adipose tissue and the recently reported effect of rimonabant on adiponectin production by adipose cells may represent a key factor responsible for the weight loss-independent effect of this CB1 blocker on cardiometabolic risk variables.

Topics: Abdominal Fat; Adiponectin; Animals; Appetite Regulation; Cardiovascular Diseases; Energy Metabolism; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors

Rimonabant is a first selective blocker of the cannabinoid receptor type 1 (CB1) being developed for the treatment of multiple cardiometabolic risk factors, including abdominal obesity and smoking. In four large trials, after one year of treatment, rimonabant 20 mg led to greater weight loss and reduction in waist circumference compared with placebo. Therapy with rimonabant is also associated with favorable changes in serum lipid levels and an improvement in glycemic control in prediabetes patients and in type 2 diabetic patients. At the same dose, rimonabant significantly increased cigarette smoking quit rates as compared with placebo. Rimonabant seems to be well tolerated, with a primary side effect of mild nausea. As an agent with a novel mechanism of action, rimonabant has a potential to be a useful adjunct to lifestyle and behavior modification in treatment of multiple cardiometabolic risk factors, including abdominal obesity and smoking.

Topics: Animals; Atherosclerosis; Blood Glucose; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Cardiovascular System; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Lipid Metabolism; Marijuana Abuse; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Smoking Cessation

Obesity has reached global epidemic proportions because of an increasingly obesogenic environment. This review examines the association between obesity, and in particular visceral fat, as a risk factor for cardiovascular disease and mortality.. The World Health Organization defines obesity based on the body mass index. Recently the waist-to-hip ratio has been shown to be a significantly stronger predictor of cardiovascular events than body mass index. The metabolic syndrome and its evolving definition represent a cluster of metabolic risk factors which help predict cardiovascular disease and mortality. Although insulin resistance plays a central role in the pathophysiology of the metabolic syndrome, there is limited support for therapy with insulin sensitizers, thiazolidinediones, in patients with coronary artery disease. The current anti-obesity drugs, orlistat and sibutramine, have only a modest effect on weight loss. The blockade of the endocannabinoid system with rimonabant, however, may be a promising new strategy.. Obesity is associated with significant increase in cardiovascular risk. Lifestyle modification remains the cornerstone of management although anti-obesity medications may be indicated in high risk individuals with comorbid disease.

Topics: Appetite Depressants; Body Fat Distribution; Body Mass Index; Cardiovascular Diseases; Cyclobutanes; Humans; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Lactones; Life Style; Lipid Metabolism; Metabolic Syndrome; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Thiazolidinediones; Waist-Hip Ratio

This review offers an overview of physiological agents, current therapeutics, as well as medications, which have been extensively used and those agents not currently available or non-classically considered anti-obesity drugs. As obesity - particularly that of central distribution - represents an important triggering factor for insulin resistance, its pharmacological treatment is relevant in the context of metabolic syndrome control. The authors present an extensive review on the criteria for anti-obesity management efficacy, on physiological mechanisms that regulate central and/or peripheral energy homeostasis (nutrients, monoamines, and peptides), on beta-phenethylamine pharmacological derivative agents (fenfluramine, dexfenfluramine, phentermine and sibutramine), tricyclic derivatives (mazindol), phenylpropanolamine derivatives (ephedrin, phenylpropanolamine), phenylpropanolamine oxytrifluorphenyl derivative (fluoxetine), a naftilamine derivative (sertraline) and a lipstatine derivative (orlistat). An analysis of all clinical trials - over ten-week long - is also presented for medications used in the management of obesity, as well as data about future medications, such as a the inverse cannabinoid agonist, rimonabant.

Topics: Amphetamines; Anti-Obesity Agents; Appetite Depressants; Clinical Trials as Topic; Cyclobutanes; Energy Metabolism; Homeostasis; Humans; Lactones; Mazindol; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Weight Loss

The neuropeptide melanin-concentrating hormone (MCH) was originally isolated from the pituitary of salmon, in which it causes skin paling. MCH is also found abundantly in mammalian neurons, and has been detected in the lateral hypothalamus and zona incerta, brain regions that are at the center of feeding behavior. Acute central administration of MCH leads to a rapid and significant increase in food intake, while MCH expression changes in states of altered energy balance, such as fasting and obesity. Furthermore, MCH knockout mice tend toward hypophagia and leanness. In 1999, we and four other groups identified an orphan G-protein-coupled receptor (GPCR) as a specific receptor for MCH (MCH-1 receptor). Although a second MCH receptor (MCH-2 receptor) was isolated in humans, it was found to be non-functional or encode a non-functional pseudogene in non-human species, including rodents. The discovery of these MCH receptors permitted the launch of a broad array of drug screening efforts and three MCH-1 receptor antagonists were identified to reduce food intake and body weight. Interestingly, some antagonists unexpectedly produced evidence that blockade of these receptors has antidepressant and anxiolytic activities. The expressions of the MCH receptors, which have been implicated in regulating emotion, stress and motivation, make MCH an excellent candidate for integrating the various homeostatic stimuli necessary for maintaining the proper conditions of energy metabolism and other physiological functions. Finally, the speed at which MCH receptor studies have been undertaken exemplifies the impact that this deorphanized GPCR will have on setting the stage for more detailed physiological studies.

Topics: Animals; Anti-Obesity Agents; Biphenyl Compounds; Body Weight; Humans; Hypothalamic Hormones; Melanins; Naphthalenes; Obesity; Piperidines; Pituitary Hormones; Pyrimidines; Receptors, Pituitary Hormone

The global obesity epidemic is causing much concern among health professionals due to the major health risks associated with obesity. Excess weight, particularly abdominal obesity, elevates multiple cardiovascular and metabolic risk factors, including Type 2 diabetes, hypertension, dyslipidaemia and cardiovascular disease. Thus obesity management goals should encompass health improvement and cardiometabolic risk reduction as well as weight loss. While lifestyle and diet modification form the basis of all effective strategies for weight reduction, some individuals may need additional intervention. About one in four people with BMI >27 kg/m(2) (those who have weight-related morbidity and who have been unsuccessful losing weight in standard ways) may require adjunctive therapy such as pharmacotherapy, very low energy diets/meal replacements, or bariatric surgery. This review focuses on appropriate use of pharmacotherapy for obesity and cardiometabolic risk. Sibutramine and orlistat are currently available for use in Australia. Rimonabant has been approved for use in the European Union, and is being considered for regulatory approval in the USA and Australia. The efficacy and safety of these three agents are examined. In addition, several novel pharmacotherapy agents in development are discussed.

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Cyclobutanes; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Safety; Treatment Outcome

Topics: Anti-Obesity Agents; Clinical Trials as Topic; Cyclobutanes; Drug Therapy, Combination; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Weight Loss

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.

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Humans; Metabolic Syndrome; Obesity; Overweight; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant

Rimonabant (SR141716, Acomplia) has been described as an antagonist/inverse agonist at the cannabinoid receptor type 1 (CB1). It has been widely used as a tool to evaluate the mechanisms by which cannabinoid agonists produce their pharmacological effects and to elucidate the respective physiological or pathophysiological roles of the CB1 receptor. It has become increasingly clear that rimonabant can exert its own intrinsic actions. These may be viewed as evidence of either the inverse agonist nature of rimonabant or of tonic activity of the endocannabinoid system. To date, data obtained from clinical trials (RIO North America, RIO Europe and RIO Lipid) indicate that rimonabant may have clinical benefits in relation to its anti-obesity properties and as a novel candidate for the treatment of metabolic and cardiovascular disorders associated with overweight and obesity. Other clinical trials, such as the STRATUS study, have also shown that rimonabant may be effective in smoking cessation, and that the drug has a reasonable safety profile. Recently, it has been shown that rimonabant prevents indomethacin-induced intestinal injury by decreasing the levels of pro-inflammatory cytokine tumour necrosis factor alpha (TNFalpha), thus indicating that CB1 receptor antagonists might exhibit potential anti-inflammatory activity in acute and chronic diseases.

Topics: Animals; Cannabinoid Receptor Modulators; Endocannabinoids; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; Smoking Cessation; Substance-Related Disorders

Worldwide, the prevalence of obesity and overweight in industrialized countries and in a substantial number of developing countries is increasing at an alarming rate. Rimonabant is a selective cannabinoid-1 receptor antagonist that has been investigated for its efficacy in reducing body weight and associated risk factors in obese people. Phase III trials are now under way to test the use of rimonabant for long-term weight-loss. Given the prevalence of overweight and obesity, it is important to establish the efficacy and safety of rimonabant.. To assess the effects of rimonabant in overweight and obese people.. MEDLINE, EMBASE, The Cochrane Library, LILACS, databases of ongoing trials and reference lists were used to identify relevant trials. The last search was conducted in June 2006.. Randomised controlled trials comparing rimonabant with placebo or other weight loss interventions in overweight or obese adults.. Two reviewers independently assessed all potentially relevant citations for inclusion and methodological quality. The primary outcome measures were weight loss change, morbidity and adverse effects occurrence.. Four studies evaluating rimonabant 20 mg versus rimonabant 5 mg versus placebo in addition to a hypocaloric diet lasting at least one year were included. Compared with placebo, rimonabant 20 mg produced a 4.9 kg greater reduction in body weight in trials with one-year results. Improvements in waist circumference, high-density lipoprotein cholesterol, triglyceride levels and systolic and diastolic blood pressure were also seen. However, the results with rimonabant 5 mg demonstrated a weight reduction which was only 1.3 kg greater when compared with placebo. No clinically relevant effects on plasma lipids and blood pressure were found. Rimonabant 20 mg caused significant more adverse effects both of general and serious nature, especially of nervous system, psychiatric or gastro-intestinal origin. Attrition rates were approximately 40% at the end of one year.. The use of rimonabant after one year produces modest weight loss of approximately 5%. Even modest amounts of weight loss may be potentially beneficial. The observed results should be interpreted with some caution, though, since the evaluated studies presented some deficiencies in methodological quality. Studies with longer follow-ups after the end of treatment and of more rigorous quality should be done before definitive recommendations can be made regarding the role of this new medication in the management of overweight or obese patients.

Topics: Adult; Anti-Obesity Agents; Diet, Reducing; Humans; Obesity; Overweight; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Weight Loss

Obesity and being overweight are risk factors for kidney diseases. The spectrum ranges from glomerulomegaly with or without focal or segmental glomerulosclerosis, to diabetic nephropathy, to carcinoma of the kidney and nephrolithiasis. The first sign of renal injury is microalbuminuria or frank proteinuria, in particular in the presence of hypertension. The occurrence of microalbuminuria and/or chronic kidney insufficiency (glomerular filtration rate < 60 ml/min/1.73 m(2)) is related to the increasing number of components of the metabolic syndrome; that is, central obesity, elevated fasting blood glucose level, hypertriglycerides, low high-density lipoprotein cholesterol level and hypertension. Obesity-associated renal disease should be prevented or retarded by weight reduction following lifestyle modification (salt restriction, hypocaloric diet, aerobic exercise) or eventually by antiobesity medication or bariatric surgery. Rimonabant, a new antiobesity medication, showed beneficial potential effect in treating clusters of metabolic syndrome, which may ultimately suggest potential benefit in treating obesity-related glomerulopathy.

Topics: Disease Outbreaks; Glomerulonephritis; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rimonabant; United Kingdom

Rimonabant is the first drug to target the endocannabinoid (CB) pathway by inhibiting the actions of anandamide and 2-archidonyl-glycerol on CB1 receptors. This review gives an overview of rimonabant and the CB system and how this system relates to obesity. Rimonabant blocks the central effects of this neurotransmitter pathway involved in obesity and weight control and also blocks the direct effects of CBs on adipocyte and hepatocyte metabolism. Blockade of CB1 receptors leads to a decrease in appetite and also has direct actions in adipose tissue and the liver to improve glucose, fat and cholesterol metabolism so improving insulin resistance, triglycerides and high-density lipoprotein cholesterol (HDL-C) and in some patients, blood pressure. The Rimonabant in Obesity (RIO) trials have shown that rimonabant induces weight loss > 5% in 30-40% of patients and > 10% in 10-20% above both a dietary run-in and long-term hypocaloric management over a 2 year period with a low level of drug-related side effects. Rimonabant therapy is associated with an extra 8-10% increase in HDL-C and a 10-30% reduction in triglycerides and improvements in insulin resistance, glycaemic control in patients with diabetes and also adipokines and cytokines including C-reactive protein over hypocaloric diet therapy. In addition rimonabant abolishes the weight gain associated with smoking cessation and improves the chances of quitting smoking. Thus rimonabant has major effects on both the metabolic syndrome and cardiovascular risk factors thus has the potential to reduce the risks of type 2 diabetes and cardiovascular disease associated with the cardiometabolic phenotype.

Topics: Cannabinoid Receptor Modulators; Cardiovascular Diseases; Endocannabinoids; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Risk Factors; Smoking Cessation

Obesity has become a significant health problem in industrialised and developing countries, and despite all nutritional and behavioural approaches, its prevalence is still increasing. In recent years, the identification and characterisation of central and peripheral mechanisms involved in the regulation of energy balance has made remarkable progress and provided numerous targets for novel anti-obesity agents. However, only few anti-obesity drugs are on the market and not many compounds have entered clinical development. In the present review, the clinically available agents are discussed and their pharmacological profiles are compared. Some of the drugs that are currently in clinical development are mentioned as examples of the possible future range of anti-obesity agents. Selected topics in drug discovery are presented to illustrate novel targets and concepts for the pharmacotherapy of obesity.

Topics: Anti-Obesity Agents; Clinical Trials as Topic; Cyclobutanes; Drug Design; Energy Metabolism; Homeostasis; Humans; Lactones; Life Style; Models, Biological; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Technology, Pharmaceutical

The primary goal of managing patients with metabolic syndrome is to decrease their cardiovascular risk by individualizing treatment strategies according to the patient's specific risk factors. Treatment options for patients with metabolic syndrome include lifestyle modification and drug therapy. Lifestyle modification can be summarized as dietary changes, exercise, and smoking cessation. Drug therapy indicated for cardiometabolic risk reduction includes antihypertensives, insulin sensitizers, and cholesterol-lowering agents. In addition, two drugs-sibutramine and rimonabant-have been evaluated and produced promising outcomes in the overall management of high-risk patients with metabolic syndrome.

Topics: Appetite Depressants; Cardiovascular Diseases; Cyclobutanes; Exercise; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Weight Loss

Topics: Animals; Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Cell Communication; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Signal Transduction

The endogenous cannabinoid system is a novel, remarkably elaborate physiological signaling system, comprising the recently identified endogenous cannabinoid ligands, their corresponding selective receptors, and the machinery of proteins and enzymes that is involved in their biosynthesis, release, transport, and degradation. This system extends widely in both the central nervous system (CNS) and the periphery and exhibits a variety of actions implicated in vital functions (e.g., behavioral, antinociceptive, neuroprotective, immunosuppressive, cardiovascular, and metabolic). Particular interest has been focused on the apparent participation of endocannabinoids in metabolic homeostasis by modulating the activity of CNS circuits that control food intake and energy expenditure, the neuroendocrine response of the stress system, and the metabolic functions of crucial peripheral tissues, such as the adipose tissue, the gastrointestinal tract, the liver, and the skeletal muscles. These effects are predominantly CB(1) receptor mediated and, thus, selective antagonists of this receptor subtype are being vigorously investigated as potential therapeutic agents for the treatment of various metabolic derangements (e.g., obesity, insulin resistance, dyslipidemia, and metabolic syndrome). The first selective CB(1) receptor antagonist, rimonabant, has already successfully completed phase III clinical trials as adjunctive obesity treatment, with significant improvements in several associated metabolic and cardiovascular risk factors that led to the recent approval of its clinical use by the Food and Drug Administration.

Topics: Cannabinoid Receptor Modulators; Central Nervous System Diseases; Clinical Trials as Topic; Endocannabinoids; Humans; Intra-Abdominal Fat; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Signal Transduction

Long-term success in obesity therapy is difficult to obtain, therefore drug therapy appears to be helpful. Until today, end-point studies for obesity drugs beyond the improvement of individual surrogate parameters are still missing. For all available drugs, medical treatment can be recommended only for a limited period of time due to the data of the studies and under consideration of side effects. Although a weight reduction leads to an improvement of cardiovascular risk factors and hence a reduction of cardiovascular morbidity and mortality should be expected, no study could prove it so far. Despite the positive influence on individual surrogate parameters, the use of the present available therapies appears underwhelming. In this overview the approved substances and perspectives of new therapeutic concepts are represented.

Topics: Anti-Obesity Agents; Anticonvulsants; Cyclobutanes; Fructose; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Topiramate

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Clinical Trials as Topic; Endocannabinoids; Humans; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Tobacco Use Disorder

The gastric pacemaker is a new obesity treatment, which pleases by its simplicity and obvious lack of complications on the nutritional level. Its long-term efficacy is however to be confirmed and the criterions of the patients' selection to be defined. The rimonabant is a selective antagonist of the cannabinoid CBI receptor, able to reduce the quantity of the total food intake, and especially the greasy one. The first results on the short term look promising. The multiplication of food pyramids is the consequence of the scientific knowledge development in the nutritional field. On this basis, new pyramids are adapted, depending on the therapeutic objectives (weight loss, cardiovascular risk) and allowing either quantity or quality food. The taking charge of patients in group and according to the therapeutic education criterions makes easy a relation between the medical team and patients and allows these latters a better awareness of their disease and its long term treatment.

Topics: Electric Stimulation Therapy; Humans; Nutritional Physiological Phenomena; Nutritional Requirements; Obesity; Piperidines; Pyrazoles; Rimonabant

Topics: Alcoholism; Animals; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The increase in obesity prevalence is problematic as this condition is associated with health complications such as diabetes and cardiovascular diseases, more particularly when the excess body fat is stored in the deep abdominal region. The mainstay of therapy consists of behavior modification related to obesity such as overeating and physical inactivity. When these lifestyle modifying attempts fail, the use of anti-obesity drugs is warranted. Drug treatment is often indicated but is somewhat limited by the minimal number of well tolerated drugs that have proven to have long-term efficacy in maintaining body weight loss. The currently available drugs, sibutramine and orlistat, appear modestly effective in promoting weight loss. Ongoing studies continue to evaluate other drug treatments that may result in body weight reduction through a number of different mechanisms. Thus, the aim of this review is to present an overview of the current drugs available (particularly sibutramine and orlistat) as well as potential future candidates, and the impact of these agents on obesity and cardiovascular physiology. Furthermore, the therapeutic paradox of sibutramine in preventing obesity will be discussed as well as the beneficial impact of physical exercise on cardiac economy.

Topics: Animals; Anti-Obesity Agents; Appetite Depressants; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Clinical Trials as Topic; Cyclobutanes; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Risk Factors

Marijuana and its major psychotropic component, Delta(9)-tetrahydrocannabinol, stimulate appetite and increase body weight in wasting syndromes, suggesting that the CB(1) cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in controlling energy balance. The endocannabinoid system controls food intake via both central and peripheral mechanisms, and it may also stimulate lipogenesis and fat accumulation. Here we discuss the multifaceted regulation of energy homeostasis by endocannabinoids, together with its applications to the treatment of eating disorders and metabolic syndromes.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Appetite Regulation; Brain; Cannabinoid Receptor Modulators; Endocannabinoids; Energy Metabolism; Humans; Neural Pathways; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Remifentanil (Ultiva), a fentanyl derivative, is an ultra-short acting, nonspecific esterase-metabolised, selective mu-opioid receptor agonist, with a pharmacodynamic profile typical of opioid analgesic agents. Notably, the esterase linkage in remifentanil results in a unique and favourable pharmacokinetic profile for this class of agent. Adjunctive intravenous remifentanil during general anaesthesia is an effective and generally well tolerated opioid analgesic in a broad spectrum of patients, including adults and paediatric patients, undergoing several types of surgical procedures in both the inpatient and outpatient setting. Remifentanil is efficacious in combination with intravenous or volatile hypnotic agents, with these regimens generally being at least as effective as fentanyl- or alfentanil-containing regimens in terms of attenuation of haemodynamic, autonomic and somatic intraoperative responses, and postoperative recovery parameters. The rapid offset of action and short context-sensitive half-time of remifentanil, irrespective of the duration of the infusion, makes the drug a valuable opioid analgesic option for use during balanced general inhalational or total intravenous anaesthesia (TIVA) where rapid, titratable, intense analgesia of variable duration, and a fast and predictable recovery are required.

Topics: Adult; Aged; Anesthesia, General; Anesthetics, Intravenous; Animals; Child; Clinical Trials as Topic; Drug Therapy, Combination; Half-Life; Humans; Obesity; Piperidines; Remifentanil

Topics: Anti-Obesity Agents; Cannabinoids; Humans; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant

Rimonabant hydrochloride, the first drug in a new class of selective cannabinoid type 1 (CB1) receptor antagonists, is showing promise in clinical trials for the treatment of obesity and related metabolic risk factors, in addition to tobacco dependence. Results of phase III clinical trials comparing rimonabant with placebo found that overweight or obese patients, with or without untreated dyslipidemia or type 2 diabetes, lost significant body weight when treated with rimonabant 20 mg for a year. The weight loss was accompanied by a decrease in waist circumference, demonstrating a significant reduction in abdominal obesity, which is an independent marker for cardiovascular disease. Significant improvements were also observed in the lipid profile, with an increase in high-density lipoprotein (HDL) cholesterol and a decrease in triglyceride levels. Improvements in glucose tolerance and insulin levels were also found. Moreover, the number of patients diagnosed with the metabolic syndrome at baseline was significantly reduced. These beneficial effects of rimonabant 20 mg were maintained after 2 years of chronic treatment. Other phase III trials have shown that rimonabant helps people to quit smoking without significant post-cessation weight gain. Rimonabant has a favorable safety profile and is generally well tolerated. Rimonabant is proving to be a very promising approach for managing two major and preventable risk factors for cardiovascular disease. This review summarizes the available evidence on the clinical efficacy and safety of rimonabant as a potential therapy for obesity and smoking cessation.

Topics: Animals; Cardiovascular Diseases; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Smoking Cessation

The endocannabinoid system plays a major role in the regulation of body energy by stimulation of the appetite in the hypothalamus and increase of fat accumulation in adipocytes. The blockade of the cannabinoid system (CB1) by the specific inhibitor (rimonabant) decreases food intake and adiposity in animals and in humans. Moreover rimonabant lowers tobacco addiction. Clinical studies (RIO-LIPIDS and RIO-EUROPE) have recently confirmed that rimonabant combined with a hypocaloric diet over 1 year, promoted significant decrease of body weight, waist circumference and improvement of dyslipidemia. Rimonabant was well tolerated with mild and transient side effects. The future place of rimonabant in the strategy of obesity is still to be clarified.

Topics: Anti-Obesity Agents; Cannabinoid Receptor Modulators; Endocannabinoids; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The safety of obesity drugs has historically been poor. This and the stigmatisation of obesity in society ensured that a higher standard of safety for obesity drugs must be met. The authors review the safety disasters of obesity drugs that were withdrawn. The authors then review the safety of presently available drugs--benzphetamine, phendimetrazine, diethylpropion, phentermine, sibutramine and orlistat. The safety of rimonabant, a drug with a pending new drug application that has an independent effect on metabolic syndrome, is also reviewed. The authors compare the stage of obesity drug development to that of hypertension in the 1950s. As new and safer drugs with more downstream mechanisms are developed that have independent effects on the cardiovascular risks associated with obesity, third party reimbursement for obesity medicine is likely to improve. This may lead to obesity being treated like hypertension and other chronic diseases with long-term medication. With improved technological tools, the authors believe this process will be more rapid for obesity than it was for hypertension.

Topics: Appetite Depressants; Central Nervous System Stimulants; Drug Approval; Humans; Insurance Coverage; Obesity; Piperidines; Pyrazoles; Rimonabant

The endocannabinoid (EC) system consists of 2 types of G-protein-coupled cannabinoid receptors--cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2)--and their natural ligands. The EC system plays a key role in the regulation of food intake and fat accumulation, as well as glucose and lipid metabolism. When overactivated, the EC system triggers dyslipidemia, thrombotic and inflammatory states, and insulin resistance. Blocking CB1 receptors centrally and peripherally in adipose tissue can help normalize an overactivated EC system. CB1 blockade helps regulate food intake and adipose tissue metabolism, contributing to improved insulin sensitivity and other features of the metabolic syndrome. Visceral adipose tissue is most closely associated with the metabolic syndrome, which is a constellation of conditions that place people at high risk for coronary artery disease. Targeting the EC system represents a new approach to treating visceral obesity and reducing cardiovascular risk factors.

Topics: Appetite Regulation; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Endocannabinoids; History, 20th Century; Humans; Intra-Abdominal Fat; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Atherogenic dyslipidemia is one of the major components of the metabolic syndrome, a complex cluster of several risk factors within a single patient that according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III includes at least 3 of the following: large waist circumference, elevated triglyceride levels, low levels of high-density lipoprotein cholesterol (HDL-C), hypertension, and elevated fasting glucose levels, which are directly related to the incidence of coronary heart disease. Atherogenic dyslipidemia clinically presents as elevated serum triglyceride levels, increased levels of small dense low-density lipoprotein (sdLDL) particles, and decreased levels of HDL-C. An important component of atherogenic dyslipidemia is central obesity, which is defined as increased waist circumference and has recently been identified as a chief predictor of the metabolic syndrome in certain patients. Another recent study found that both body mass index and waist circumference were highly predictive of eventual development of the metabolic syndrome. Because atherogenic dyslipidemia usually precedes the clinical manifestation of the metabolic syndrome, strategies to treat it are the focus of pharmacologic intervention. For example, the 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, commonly known as statins, benefit hypercholesterolemic patients who have atherogenic dyslipidemia that is associated with the metabolic syndrome. Pioglitazone, an antidiabetic agent that acts primarily by decreasing insulin resistance, improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels. The investigational agent, rimonabant--a centrally and peripherally acting, selective cannabinoid type-1 receptor blocker--is the first therapy developed for managing several cardiovascular risk factors at one time. Rimonabant has shown promise in attacking atherogenic dyslipidemia from several vantage points by affecting glucose, HDL-C, triglycerides, and waist circumference in patients who are prone to atherogenic dyslipidemia.

Topics: Arteriosclerosis; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Diabetes Mellitus, Type 2; Drugs, Investigational; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin Resistance; Intra-Abdominal Fat; Metabolic Syndrome; Obesity; Pioglitazone; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thiazolidinediones

Cardiovascular disease (CVD) is the leading cause of death of men and women in the United States. The accumulation of visceral adipose tissue, as opposed to subcutaneous fat, increases the risk of developing CVD and metabolic disease. Because visceral adipose tissue uniquely contributes to the pathophysiology of CVD and insulin resistance, waist circumference is now being considered as a more useful marker of potential health risks associated with overweight and obesity than body mass index. Weight loss, particularly a reduction in waist circumference, improves insulin sensitivity, lipid profile, and serum adipocytokines, thereby reducing the risk of developing chronic disease and CVD.

Topics: Anti-Obesity Agents; Coronary Disease; Cyclobutanes; Exercise; Feeding Behavior; Humans; Intra-Abdominal Fat; Lactones; Metabolic Syndrome; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant

Overweight and obesity are recognised as significant risk factors for coronary heart disease (CHD). Weight reduction leads to reduction in associated CHD risk factors. The discovery that endocannabinoid system is involved in regulation of food intake and other reward behaviours has led to development of cannabinoid receptor antagonists. Recent studies with rimonabant, a cannabinoid type 1 receptor (CB(1)) antagonist, demonstrate clinically significant weight loss as well as reduction in metabolic syndromme burden in obese patients.

Topics: Cannabinoid Receptor Antagonists; Humans; Models, Biological; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Rimonabant, an antagonist of central cannabinoid type 1 (CB1) receptors, is being developed by Sanofi-Synthélabo for the potential treatment of obesity and as a potential smoking cessation agent. Phase III trials were initiated for obesity in August 2001 and were ongoing in September 2003. By September 2002, the compound had entered phase III trials for smoking cessation, and these trials were ongoing in September 2003.

Topics: Animals; Anti-Obesity Agents; Antipsychotic Agents; Appetite Depressants; Clinical Trials as Topic; Humans; Obesity; Piperidines; Potassium Channel Blockers; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Smoking Cessation; Structure-Activity Relationship

The current obesity pandemic imposes a major global disease burden. Levels of non-communicable diseases such as type 2 diabetes, cardiovascular disease and some cancers will continue to rise unless an effective approach to treat obesity is found. Sustained weight loss of between 5-10% in the obese, by various means, confers marked health benefits. The currently available pharmacotherapies, orlistat and sibutramine, can induce weight loss of between 5-10% over 2 years or more. In trials, orlistat and sibutramine induced weight loss tends to be only between 2-4 kg greater than that produced by placebo control. However, this additional placebo subtracted weight loss produces marked additional improvements in diabetes and cardiovascular risk factors. Moreover, in the 4 year long XENDOS trial, the modest placebo subtracted weight loss produced by orlistat (2.8 kg) reduced the incidence of diabetes by over a third in those with normal glucose tolerance, and by nearly half in those with impaired glucose tolerance. Despite this, prescription sales of sibutramine in the US have apparently remained static and those of orlistat have fallen, with the drug now entering the global over-the-counter medication market. Recent data on potential anti-obesity drugs currently under going phase III trials, such as Rimonabant and Topiramate, demonstrate these drugs produce greater and more prolonged weight loss. Wider use of pharmacotherapy and enhanced efficacy for the next generation of anti-obesity drugs certainly promise to reduce obesity related illness if not halt the rise in obesity per se.

Topics: Anti-Obesity Agents; Appetite Depressants; Cyclobutanes; Energy Metabolism; Feeding Behavior; Fructose; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Topiramate

Topics: Animals; Energy Intake; Energy Metabolism; Feeding Behavior; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Drug; Rimonabant

Topics: 1-Deoxynojirimycin; Acarbose; Aged; Blood Glucose; Carbamates; Contraindications; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enzyme Inhibitors; Fasting; Follow-Up Studies; Germany; Glucosamine; Glyburide; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Imino Pyranoses; Insulin; Metformin; Middle Aged; Nateglinide; Obesity; Patient Compliance; Phenylalanine; Pioglitazone; Piperidines; Practice Guidelines as Topic; Risk Factors; Rosiglitazone; Sulfonylurea Compounds; Thiazolidinediones; Time Factors

Topics: Alzheimer Disease; Clinical Trials as Topic; Cognition Disorders; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant

Insulin resistance is an early and major feature in the development of non-insulin-dependent diabetes mellitus(NIDDM). It is also associated with hyperlipidemia, hypertension, obesity and cardiovascular disease. It is the clustor of the risk factors for atherosclerosis and recognized as 'insulin-resistance syndrome' (Syndrome X). Central (abdominal) obesity is much more strongly associated with insulin resistance than overall obesity. The increase of both the influx of free fatty acid to liver and the production of TNF-alpha in adipose tissue may play an important role in mechanism of insulin resistance associated with central obesity. Calorie restriction and weight loss improve insulin sensitivity in overweight humans. Exercise training also improves insulin sensitivity via increased oxidative enzymes, glucose transporters (GLUT4) and capillarity in muscle as well as by reducing abdominal fat. The new 'glitazones' (thiazolidinediones) is used clinically to improve insulin sensitivity.

Topics: Fatty Acids, Nonesterified; Humans; Insulin Resistance; Obesity; Piperidines; Syndrome

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines prereceptor metabolism and activation of glucocorticoids within peripheral tissues. Its dysregulation has been implicated in a wide array of metabolic diseases, leading to the development of selective 11β-HSD1 inhibitors. We examined the impact of the reversible competitive 11β-HSD1 inhibitor, AZD4017, on the metabolic profile in an overweight female cohort with idiopathic intracranial hypertension (IIH).. We conducted a UK multicenter phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017. Serum markers of glucose homeostasis, lipid metabolism, renal and hepatic function, inflammation and androgen profiles were determined and examined in relation to changes in fat and lean mass by dual-energy X-ray absorptiometry.. Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased high-density lipoprotein [HDL] and cholesterol/HDL ratio), markers of hepatic function (decreased alkaline phosphatase and gamma-glutamyl transferase), and increased lean muscle mass (1.8%, P < .001). No changes in body mass index, fat mass, and markers of glucose metabolism or inflammation were observed. Patients receiving AZD4017 demonstrated increased levels of circulating androgens, positively correlated with changes in total lean muscle mass.. These beneficial metabolic changes represent a reduction in risk factors associated with raised intracranial pressure and represent further beneficial therapeutic outcomes of 11β-HSD1 inhibition by AZD4017 in this overweight IIH cohort. In particular, beneficial changes in lean muscle mass associated with AZD4017 may reflect new applications for this nature of inhibitor in the management of conditions such as sarcopenia.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adolescent; Adult; Body Composition; Double-Blind Method; Female; Humans; Insulin Resistance; Lipid Metabolism; Lipidomics; Lipids; Middle Aged; Muscles; Niacinamide; Obesity; Organ Size; Overweight; Piperidines; Placebos; Pseudotumor Cerebri; United Kingdom; Young Adult

Second generation antipsychotics are prescribed for an increasing number of psychiatric conditions, despite variable associations with weight gain, dyslipidemia, and impaired glucose tolerance. The mechanism(s) of the apparent causal relationships between these medications and metabolic effects have been inadequately defined and are potentially confounded by genetic risk of mental illness, attendant lifestyle, and concomitant medications. Therefore, we conducted a study in which 24 healthy volunteers were randomized to olanzapine (highly weight-gain liability), iloperidone (less weight-gain liability), or placebo treatment for 28 days under double-blind conditions. We hypothesized that antipsychotics induce weight gain primarily through increased caloric intake, which causes secondary dyslipidemia and insulin resistance. Subjects were phenotyped pre- and post-treatment for body weight, adiposity by dual energy X-ray absorptiometry, energy expenditure by indirect calorimetry, food intake, oral glucose tolerance, plasma lipids, glucose, insulin, and other hormones. We found significantly increased food intake and body weight but no change in energy expenditure in olanzapine-treated subjects, with associated trends towards lipid abnormalities and insulin resistance the extent of which were presumably limited by the duration of treatment. Iloperidone treatment led to modest non-significant and placebo no weightgain, lipid increases and alterations in insulin metabolism. We conclude that second generation antipsychotic drugs, as represented by olanzapine, produce their weight and metabolic effects, predominantly, by increasing food intake which leads to weight gain that in turn induces metabolic consequences, but also through other direct effects on lipid and glucose metabolism independant of food intake and weight gain.

Topics: Adolescent; Adult; Antipsychotic Agents; Blood Glucose; Body Weight; Double-Blind Method; Dyslipidemias; Eating; Energy Metabolism; Female; Glucose Tolerance Test; Healthy Volunteers; Humans; Insulin; Insulin Resistance; Isoxazoles; Lipids; Male; Obesity; Olanzapine; Piperidines; Weight Gain; Young Adult

Impaired β-cell function remains unaddressed in PCOS. The aim of the study was to evaluate whether dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin (ALO) alone or in combination with pioglitazone (PIO) improves β-cell function along with insulin resistance (IR) in metformin (MET) treated obese women with PCOS with persistent IR.. In 12-week randomized study, ALO 25 mg QD (n=15) or ALO 25 mg QD and PIO 30 mg QD (n=15) was added to MET 1000 mg BID in PCOS women (aged 34.4 ± 6.5 years, BMI 39.0 ± 4.9 kg/m. ALO alone and in combination with PIO improved IR along with dynamic IS and meal related β-cell function when added to MET treated PCOS.

Topics: Adult; Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Resistance; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Meals; Metformin; Obesity; Pioglitazone; Piperidines; Polycystic Ovary Syndrome; Prediabetic State; Prevalence; Slovenia; Thiazolidinediones; Uracil

Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile.. Post hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD).. Treatment with rimonabant for 12 weeks reduced both ALT and weight (p < 0.01), and there was a negative correlation between Δ ALT and Δ HOMA-IR (p < 0.001), but not between Δ ALT and Δ weight. There was a significant reduction of weight with orlistat (p < 0.01); however, orlistat, metformin and pioglitazone had no effect on ALT. The free androgen index fell in all groups (p < 0.05). The inflammatory marker hs-CRP was reduced by pioglitazone (p < 0.001) alone and did not correlate with changes in ALT. The inflammatory cytokine profile for IL-1β, IL-6, IL-7, IL-10, IL12, TNF-α, MCP-1 and INF-γ did not differ between groups. None of the interventions had an effect on biological variability of ALT.. Rimonabant through CB1 receptor blockade decreased serum ALT that was independent of weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD.. ISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).

Topics: Alanine Transaminase; Anti-Obesity Agents; Body Mass Index; Cannabinoid Receptor Antagonists; Case-Control Studies; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin Resistance; Lactones; Liver Diseases; Metformin; Obesity; Orlistat; Pioglitazone; Piperidines; Polycystic Ovary Syndrome; Prognosis; Pyrazoles; Receptor, Cannabinoid, CB1; Retrospective Studies; Rimonabant; Thiazolidinediones; Weight Loss

Animal studies suggest that cannabinoid receptor-1 (CB-1) blockade reduces inflammation and neovascularization by decreasing vascular endothelial growth factor (VEGF) levels associated with a reduction in inflammatory markers, thereby potentially reducing cardiovascular risk.. To determine the impact of CB1 antagonism by rimonabant on VEGF and inflammatory markers in obese PCOS women.. Randomized, open-labelled parallel study.. Endocrinology outpatient clinic in a referral centre.. Twenty patients with PCOS (PCOS) and biochemical hyperandrogenaemia with a body mass index of ≥30 kg/m. Post hoc review to detect VEGF and pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 before and after 12 weeks of treatment.. After 12 weeks of rimonabant treatment, there was a significant increase in VEGF (99·2 ± 17·6 vs 116·2 ± 15·8 pg/ml, P < 0·01) and IL-8 (7·4 ± 11·0 vs 18·1 ± 13·2 pg/ml, P < 0·05) but not after metformin (VEGF P = 0·7; IL-8 P = 0·9). There was no significant difference in the pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 following either treatment.. This study suggests that rimonabant CB-I blockade paradoxically raised VEGF and the cytokine IL-8 in obese women with PCOS that may have offset the potential benefit associated with weight loss.

Topics: Biomarkers; Cannabinoid Receptor Antagonists; Cytokines; Female; Humans; Hyperandrogenism; Inflammation; Interleukin-8; Metformin; Obesity; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Vascular Endothelial Growth Factor A; Weight Loss

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

In obese patients, the incidence of postoperative nausea and vomiting (PONV) following sleeve gastrectomy under titration of total intravenous anaesthesia (TIVA) and the relevance of risk factors to indicate prophylaxis is unknown.. The hypothesis was that after automated TIVA, prophylaxis reduces PONV following laparoscopic sleeve gastrectomy. Our objective was to determine the incidence of PONV and evaluate the efficacy of dexamethasone and ondansetron as prophylaxis when automated intravenous anaesthesia is employed.. A randomised, placebo-controlled, single-centre, double-blinded study.. Secondary care centre in New Caledonia from June 2013 to January 2014.. A total of 122 patients were randomised and 117 (92 women) were included in the analysis (58 in the prophylaxis group and 59 in the placebo group). Eligibility criteria included at least two of the known risk factors for PONV: female sex, nonsmoking status, prior history of PONV or motion sickness and expected postoperative opioid analgesia. Exclusion criteria included disorders limiting the use of the bispectral index.. All patients received propofol and remifentanil controlled by the same automated system during induction and maintenance of general anaesthesia. The controller modifies the calculated effect-site concentrations according to bispectral index values. Patients received either intravenous dexamethasone 4 mg after tracheal intubation and ondansetron 4 mg during skin closure, or placebo.. The primary endpoint was the cumulative incidences of 24-h PONV and severe PONV (vomiting or nausea with a score of ≥4 on an 11-point verbal rating scale). Data are presented as percentage (95% confidence interval).. PONV in the first 24 h occurred in 45 (34 to 60)% of patients who received prophylaxis and 54 (41 to 67)% in the placebo group (P = 0.35). The numbers of patients who suffered severe PONV [19 (10 to 32)% in the prophylaxis group vs. 20 (11 to 33)%, P = 1, in the placebo group] and who required rescue antiemetic drugs [55 (41 to 68) vs. 63 (49 to 75)%, P = 0.46] were similar between the groups.. The combination of dexamethasone and ondansetron was not effective in preventing PONV or severe PONV in obese patients undergoing laparoscopic sleeve gastrectomy after TIVA.. Clinicaltrials.gov identifier: NCT01876290.

Topics: Adult; Anesthesia, General; Anesthetics, Intravenous; Dexamethasone; Double-Blind Method; Female; Gastrectomy; Humans; Laparoscopy; Male; Middle Aged; Monitoring, Intraoperative; Obesity; Ondansetron; Piperidines; Postoperative Nausea and Vomiting; Pre-Exposure Prophylaxis; Propofol; Remifentanil

Topics: Body Mass Index; Cannabinoid Receptor Antagonists; Cytokines; Female; Hepatocyte Growth Factor; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Metformin; Non-alcoholic Fatty Liver Disease; Obesity; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant

We used an automated bispectral index (BIS)-guided dual-loop controller to determine propofol and remifentanil requirements during general anaesthesia in obese and lean surgical patients.. Obese patients, BMI>35 kg m(-2), and lean patients (<25 kg m(-2)) having laparoscopic procedures were prospectively evaluated in this multicentre single-blind study. The automated controller targeted BIS between 40 and 60 by adjusting propofol and remifentanil administration. Propofol and remifentanil consumptions were calculated using both total body weight (TBW) and ideal body weight (IBW). Results are expressed as medians (inter-quartile range).. Thirty obese [BMI=43 (40-49) kg m(-2)] and 29 lean [BMI=23 (21-25) kg m(-2)] patients completed the study. BIS was between 40 and 60 during 84 (69-91)% vs 85 (78-92)% of the anaesthetic time, P=0.46. The amount of propofol given during induction [1.2 (1.1-1.6) vs 1.3 (1.0-1.7) mg kg(-1), P=0.47] and maintenance [5.2 (4.1-6) vs 5.3 (4.7-6.4) mg kg(-1) h(-1), P=0.39] calculated using TBW was similar between the two groups. The dual-loop controller delivered half as much remifentanil to the obese patients during induction [1.0 (0.8-1.6) vs 2.2 (1.5-2.7) µg kg(-1), P<0.001] and maintenance [0.12 (0.07-0.16) vs 0.25 (0.17-0.29) µg kg(-1) min(-1), P<0.001] calculated using TBW. But when remifentanil consumption was calculated using IBW, the amounts were similar during induction at 2.2 (1.6-3.5) vs 2.0 (1.6-3.0) µg kg(-1) IBW, P=0.48, and during maintenance at 0.26 (0.16-0.34) vs 0.27 (0.18-0.33 ) µg kg(-1) min(-1), P=0.50.. The amount of propofol-remifentanil administered by the controller is consistent with current knowledge, propofol is best dosed using TBW whereas remifentanil is best dosed using IBW.. NCT00779844.

Topics: Adult; Anesthesia, General; Body Weight; Cohort Studies; Drug Combinations; Electroencephalography; Feasibility Studies; Female; Humans; Male; Middle Aged; Obesity; Piperidines; Propofol; Prospective Studies; Remifentanil; Single-Blind Method

A combination of bioactive food ingredients (capsaicinoids, epigallocatechin gallate, piperin, and l-carnitine, CBFI) may promote satiety and thermogenesis. The study was conducted in order to assess whether there is any effect on satiety, resting energy expenditure (REE), respiratory quotient, glucagon-like peptide-1 (GLP-1), free fatty acids (FFA) and glycerol release, following a standardized mixed meal with or without single consumption of a CBFI.. An 8-week randomized double-blind placebo-controlled trial.. Dietetic and Metabolic Unit, Azienda di Servizi alla Persona, University of Pavia and "Villa delle Querce" Clinical Rehabilitation Institute, Rome, Italy.. Thirty-seven overweight adults (body mass index [BMI]: 25-35).. Nineteen overweight subjects were included in the supplemented group (14 women, 5 men; age 46.4 ± 6.4; BMI: 30.5 ± 3.3) and 18 in the placebo group (13 women, 5 men; age 40.8 ± 11.5; BMI: 30.1 ± 2.6). Satiety was assessed using 100-mm visual analogue scales (VAS) and the area under the curve was calculated.. All measured parameters increased significantly in comparison with baseline in response to meal, both with CBFI and with placebo. However, throughout the study day, the supplemented group experienced a significantly greater increase than the placebo group in their sensation of satiety following acute administration of the supplement.. CBFI may therefore be of great value in the treatment of overweight patients by increasing satiety and stimulating thermogenesis.

Topics: Adult; Alkaloids; Area Under Curve; Basal Metabolism; Benzodioxoles; Capsaicin; Carnitine; Catechin; Dietary Supplements; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Glycerol; Humans; Male; Middle Aged; Obesity; Phytotherapy; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Satiation; Satiety Response

Studies in mice have suggested that endocannabinoid blockade using the cannabinoid receptor type 1 (CB1) blocker rimonabant prevents obesity-induced hepatic steatosis.. To determine effects of rimonabant on liver fat in humans, we measured liver fat content by proton magnetic resonance spectroscopy in 37 subjects who used either a CB1 blocker rimonabant or placebo in a double-blind, randomized manner. This was retrospectively compared with a historical hypocaloric diet weight loss group (n=23).. Weight loss averaged 8.5±1.4 kg in the rimonabant, 1.7±1.0 kg in the placebo and 7.5±0.2 kg in the hypocaloric diet group (P<0.001, rimonabant vs placebo; NS, rimonabant vs hypocaloric diet). Liver fat decreased more in the rimonabant (5.9% (2.5-14.6%) vs 1.8% (0.9-3.5%), before vs after) than in the placebo group (6.8% (2.2-15.7%) vs 4.9% (1.6-7.8%), before vs after, P<0.05). The percentage change in body weight correlated closely with the percentage loss of liver fat (r=0.70, P>0.0001). The decreases in liver fat were comparable between the rimonabant and the young historical hypocaloric diet groups.. We conclude that, unlike in mice, in humans rimonabant decreases liver fat in proportion to weight loss.

Topics: Adult; Aged; Cannabinoid Receptor Antagonists; Double-Blind Method; Fatty Liver; Female; Finland; Humans; Liver; Male; Metabolic Syndrome; Middle Aged; Obesity; Piperidines; Pyrazoles; Retrospective Studies; Rimonabant; Treatment Outcome; Weight Loss

In obesity, a dysregulation of the endocannabinoid system has been shown. The endocannabinoid receptor blockage by rimonabant demonstrated interesting metabolic effects. However, the role of rimonabant in weight loss of patients with binge eating disorder has not been investigated. Thus, our aim was to evaluate the effects of rimonabant on body weight in obese patients with binge eating disorders. This multicenter, randomized, double-blind, placebo-controlled study included 289 obese subjects (age 18-70 years, body mass index 30-45 kg/m(2)) with binge eating disorders. Subjects were randomized (1:1) to receive rimonabant 20 mg/day or placebo for 6 months. In total, 289 participants (age: 43.2±10.5 yrs, 91% of women) were randomized. The completer rate was similar (71%) in both treatment and placebo groups. Participants treated with rimonabant lost 4.7±5.2% of their initial body weight, vs. 0.4±4.5% in the placebo group (difference between both groups: 4.4±0.6 kg, p<0.0001). The rimonabant group showed a greater reduction on the binge eating scale total score (mean±SD  - 40.9±35.2%) vs. placebo ( - 29.9±34.6%, p=0.02). The incidence of treatment emergent adverse events was comparable in both the rimonabant (82.5%) and placebo (76.0%) group. Discontinuations due to treatment emergent adverse events occurred in 13.3% rimonabant-treated vs. 6.2% placebo-treated participants. In conclusion, this is the only randomised, placebo-controlled, double-blind trial having assessed the effect of rimonabant in patients with binge eating disorders. The rimonabant treatment reduced body weight significantly more than placebo in obese subjects with binge eating. Trial registration number (clinicaltrials.gov): NCT00481975.

Topics: Adolescent; Adult; Aged; Binge-Eating Disorder; Cannabinoid Receptor Antagonists; Double-Blind Method; Female; Humans; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

We investigated the association between retinol-binding protein 4 (RBP(4)) and apolipoprotein B (ApoB)-containing lipoproteins. Obese or overweight, hypertriglyceridemic patients underwent the following interventions for 3 months: (1) Diet (n = 20), (2) Diet + fenofibrate (n = 18), (3) Diet + rimonabant (n = 8). Circulating RBP4 decreased during dietary treatment. The percentage change in RBP(4) was positively correlated with the percentage changes in very-low density lipoprotein cholesterol (r = .570, P = .02), low-density lipoprotein cholesterol ([LDL-C]; r = .605, P = .01), ApoB (r = .705, P = .007), and small dense LDL-C ([sdLDL-C]; r = .872, P < .001). The percentage change in RBP4 was the best predictor of the percentage changes in sdLDL-C and ApoB. Rimonabant treatment reduced RBP4, whereas fenofibrate increased RBP4 during the first month of therapy followed by a subsequent decrease. In conclusion, RBP4 may significantly influence the metabolic pathways responsible for changes in ApoB lipoprotein subspecies, thus RBP4 may be associated with cardiovascular disease risk.

Topics: Adult; Apolipoproteins B; Caloric Restriction; Diet, Fat-Restricted; Female; Fenofibrate; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Retinol-Binding Proteins, Plasma; Rimonabant

Endocannabinoid receptor 1 blockade is proposed to improve metabolic complications of obesity via central and peripheral effects.. Our objective was to test whether rimonabant improves insulin regulation of free fatty acid and glucose metabolism after controlling for fat loss.. This was a double-blind, placebo-controlled substudy of the visceral fat reduction assessed by computed tomography scan on rimonabant (VICTORIA) trial.. Sixty-seven abdominally obese, metabolic syndrome volunteers age 35-70 yr participated at academic medical center general clinical research centers.. Intervention included a 12-month lifestyle weight management program plus rimonabant 20 mg/d or placebo.. Body composition and two-step euglycemic, hyperinsulinemic clamp before and after intervention were performed. Insulin sensitivity was assessed as insulin concentration needed to suppress by 50% palmitate concentration [IC50(palmitate)], flux [IC50(palmitate)f], and hepatic glucose output [IC50(HGO)] and as insulin-stimulated glucose disposal (Δ glucose disappearance per Δ insulin concentration--glucose slope).. Body fat decreased by 4.5±2.9% (SD) in the rimonabant and 1.9±4.5% in the placebo group (P<0.005). The primary [improvement in IC50(palmitate) and IC50(palmitate)f] and secondary [improvement in IC50(HGO) and glucose slope] outcomes were not significantly different between the rimonabant and placebo groups. Post hoc analyses revealed that 1) changes in body mass index (BMI) and IC50(palmitate) were correlated (P=0.005) in the rimonabant group; this relationship was not significantly different from placebo when controlling for greater BMI loss (P=0.5); 2) insulin-regulated glucose disposal improved in both groups (P=0.002) and correlated with changes in BMI.. Improvements observed in insulin regulation of free fatty acid and glucose metabolism with rimonabant treatment in humans was not greater than that predicted by weight loss alone.

Topics: Adult; Aged; Behavior Therapy; Body Composition; Cannabinoid Receptor Antagonists; Diet, Reducing; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Humans; Insulin; Intra-Abdominal Fat; Life Style; Male; Metabolic Syndrome; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome; Weight Loss

Rimonabant treatment, examined in Phase 3 trials, showed improvement of cardiovascular risk factors in obese patients.. The objective of this Phase 4 trial is to assess the effectiveness of rimonabant plus lifestyle counselling when used in daily practice, namely in the general practice. The hypothesis was that the effectiveness in Phase 4 would be smaller than the efficacy in Phase 3 due to different patient selection and treatment conditions. At the end of this trial, rimonabant was suspended of all markets due to psychiatric side effects.. This trial randomly assigned 222 patients with enlarged waist circumferences and hyperglycaemia or diabetes mellitus type 2, recruited from Dutch general practices, to double-blinded therapy with either placebo or rimonabant (20 mg/day) for 1 year in addition to lifestyle counselling.. Compared with placebo, the rimonabant group showed significant improvements in body weight, body mass index, high-density lipoprotein (HDL) cholesterol and the main outcome waist circumference after 1 year. The United Kingdom Prospective Diabetes Study risk calculation showed no significant difference. The rimonabant group showed statistically deterioration, compared with the placebo group, in the quality of life in the EuroQol and two domains of the SF-36: role limitations due to physical health problems and bodily pain.. The unique real life data of this Phase 4 trial showed that the effectiveness of rimonabant in daily practice is indeed lower than in controlled circumstances (Phase 3). Rimonabant treatment showed improvement of obesity and the HDL cholesterol, but had no positive effect on the other cardiovascular risk factors and the quality of life.

Topics: Adolescent; Adult; Aged; Anti-Obesity Agents; Cardiovascular Diseases; Counseling; Double-Blind Method; Female; Humans; Male; Middle Aged; Obesity; Outcome Assessment, Health Care; Piperidines; Primary Health Care; Pyrazoles; Quality of Life; Rimonabant; Risk Reduction Behavior; Safety-Based Drug Withdrawals; United Kingdom; Waist Circumference; Young Adult

This study aimed to determine in obese women if endocannabinoid receptor antagonism has effects on fatty acid and triglyceride metabolism and insulin sensitivity which are independent from the metabolic effects of weight loss. Fourteen obese (BMI=33.0±0.5 kg/m(2)) (mean±SEM) Caucasian post-menopausal women, aged 57.8±4.7 years were studied. The women were randomised to 2 groups, one group received the endocannabinoid receptor antagonist rimonabant (20 mg/d) for 12 weeks. A control group achieved the same weight loss by a hypocaloric dietary intervention over 12 weeks. Palmitate production rate (Ra), a measure of lipolysis, and palmitate oxidation rate, and VLDL(1) and VLDL(2) triglyceride (TG) kinetics, were measured using isotopic tracers before and after the intervention. Weight loss was not different in the 2 groups; 2.6±0.5 kg with rimonabant and 3.1±1.0 kg in the control group. Palmitate Ra increased with rimonabant with no change in the control group (p=0.03 between groups). Palmitate oxidation rate increased with rimonabant but decreased in the control group (p=0.005 between groups). VLDL(1) TG secretion rate decreased in the control group and increased in the rimonabant group (p=0.008 between groups). There was no significant effect on insulin sensitivity. This study suggests that endocannabinoid receptor antagonism for 12 weeks in obese women increased lipolysis and fatty acid oxidation. The increase in VLDL(1) TG secretion rate may be due to the increase in lipolysis which exceeded the increase in fatty acid oxidation.

Topics: Adiponectin; Aged; Breath Tests; Cannabinoid Receptor Antagonists; Cholesterol; Diet, Reducing; Energy Intake; Energy Metabolism; Fatty Acids; Female; Humans; Insulin Resistance; Leptin; Lipolysis; Lipoproteins, VLDL; Middle Aged; Obesity; Oxidation-Reduction; Palmitic Acids; Piperidines; Pyrazoles; Rimonabant; Triglycerides; United Kingdom; Weight Loss

We evaluated whether the effect of remifentanil treatment differs between normal weight (NW) patients with real body weight-based remifentanil and mildly obese (Ob) patients with ideal body weight based-remifentanil during short-term anesthetic induction. We enrolled 20 patients aged between 20 and 64 years in each group (NW group: 18.5 kg/m(2) ≤ BMI < 25 kg/m(2); Ob group: BMI ≥ 25 kg/m(2)). Tracheal intubation (TI) was performed after administration of 0.5 μg/kg/min remifentanil for 5 min, including 2 min of antecedent administration, with propofol and rocuronium. Hemodynamic parameters (SBP, DBP, and HR) were measured. Percent changes in hemodynamics resulting from anesthetic induction and TI were calculated, and effect-site concentration (ESC) in each patient was calculated by performing pharmacokinetic simulation. All hemodynamic values in the Ob group after TI were significantly higher than those in the NW group. Percent increases in SBP and HR in the Ob group were significantly higher than the corresponding values in the NW group. ESC of remifentanil at the time of TI in the NW group was higher than that in the Ob group. Remifentanil treatment with anesthetic induction based on the Japanese package insert might have insufficient effects in obese patients.

Topics: Adult; Androstanols; Anesthetics, Intravenous; Female; Humans; Ideal Body Weight; Infusions, Intravenous; Intubation, Intratracheal; Male; Middle Aged; Obesity; Piperidines; Propofol; Remifentanil; Rocuronium

Three double-blind, placebo-controlled, three-parallel-group, multicenter phase 3 trials were conducted to assess the efficacy and safety of CP-945,598 for weight loss and weight-loss maintenance. Two trials were designed to be 2 years in duration (in obese and overweight patients) and one as a 1-year study (in obese and overweight patients with type 2 diabetes). However, the 2-year trials and the CP-945,598 development program were terminated before completion due to changing regulatory perspectives of CB1 receptor-related drugs. In total, 1,253 and 2,536 participants in the two 2-year multinational and North American studies were randomized to 10-mg CP-945,598 (n = 360; 718); 20-mg CP-945,598 (n = 534, 1,084) and placebo (n = 359, 734), respectively; and 975 participants were randomized to 10-mg CP-945,598 (n = 318); 20-mg CP-945,598 (n = 320); and placebo (n = 337) in the 1-year multinational diabetes trial. Baseline demographics were similar between treatment groups within each trial. One year of treatment with CP-945,598 resulted in a dose-related mean percentage reduction from baseline body-weight in all trials. A significant proportion of all participants also achieved 5% and 10% weight loss after 1 year. In participants with mainly well-controlled type 2 diabetes, the combination of lifestyle and CP-945,598 induced substantial improvements in glycemic control. The most frequent adverse events (AEs) for CP-945,598 were: diarrhea, nausea, nasopharyngitis, and headache. Self-reported experiences of anxiety and suicidal thoughts were higher with CP-945,598 than placebo, as were the incidence of depression and depressed mood. However, the reported increases in psychiatric symptoms were not consistently dose dependent.

Topics: Adolescent; Adult; Aged; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drugs, Investigational; Early Termination of Clinical Trials; Female; Humans; Male; Middle Aged; Obesity; Overweight; Patient Dropouts; Piperidines; Purines; Receptor, Cannabinoid, CB1; Secondary Prevention; Weight Loss; Young Adult

Topics: Drug Therapy, Combination; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Metformin; Obesity; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant

Weight loss and hypolipidemic drugs can improve lipid and adipokine levels. We assessed the effects of rimonabant, alone and in combination with fenofibrate or ezetimibe, on adipokine levels in obese/overweight patients with dyslipidemia. Overweight/obese patients (n = 60, body mass index = 27-40 kg/m(2)) with mixed dyslipidemia were recruited. Patients received a hypocaloric diet and were randomized to rimonabant 20 mg/d (group R, n = 20), rimonabant 20 mg/d plus fenofibrate 200 mg/d (group RF, n = 20), or rimonabant 20 mg/d plus ezetimibe 10 mg/d (group RE, n = 20). After 3 months, leptin concentration was significantly reduced in all groups (-38%, P < .005; -40%, P < .005; and -44%, P < .001 in the R, RF, and RE groups, respectively). Total adiponectin remained unaltered. Visfatin concentration decreased significantly only in the RE and RF groups (-18% and -38%, respectively; P < .047). Treatment with rimonabant may improve adipokine levels in overweight/obese patients with dyslipidemia. The addition of fenofibrate or ezetimibe may reinforce this effect.

Topics: Adipokines; Adult; Aged; Azetidines; Body Mass Index; Diet, Reducing; Drug Therapy, Combination; Dyslipidemias; Ezetimibe; Female; Fenofibrate; Humans; Hypolipidemic Agents; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

OBJECTIVE To examine the efficacy and safety of rimonabant, a selective cannabinoid receptor type-1 antagonist, in patients with type 2 diabetes receiving insulin monotherapy. RESEARCH DESIGN AND METHODS Patients (n = 368; A1C > or =7%) were randomized to 20 mg/day rimonabant or placebo in this 48-week, double-blind, placebo-controlled multicenter trial. Change in baseline A1C to week 48 (primary outcome) and changes in body weight, waist circumference, and lipid levels (secondary outcomes) were assessed. RESULTS Rimonabant significantly reduced baseline A1C versus placebo (-0.89 vs. -0.24%; P < 0.0001), and significantly greater improvements were observed in cardiometabolic risk factors. More rimonabant patients achieved >10% reduction in mean total daily insulin dose versus placebo (P = 0.0012), and fewer required rescue medication (P < 0.0001). Hypoglycemia, nausea, dizziness, anxiety, and depression were more frequent with rimonabant. CONCLUSIONS Rimonabant improved glycemic control and cardiometabolic risk factors in patients with type 2 diabetes receiving insulin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Obesity Agents; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Hormone Antagonists; Humans; Insulin; Middle Aged; Obesity; Piperidines; Placebos; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Young Adult

Blockade of the endocannabinoid receptor reduces obesity and improves metabolic abnormalities such as triglycerides, HDL cholesterol, and fasting blood glucose. We assessed whether rimonabant would improve major vascular event-free survival.. This double-blind, placebo-controlled trial was undertaken in 974 hospitals in 42 countries. 18,695 patients with previously manifest or increased risk of vascular disease were randomly assigned to receive either rimonabant 20 mg (n=9381) or matching placebo (n=9314). Randomisation was stratified by centre, implemented with an independent interactive voice response system, and all study personnel and participants were masked to group assignment. The primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke, as determined via central adjudication. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00263042.. At a mean follow-up of 13.8 months (95% CI 13.6-14.0), the trial was prematurely discontinued because of concerns by health regulatory authorities in three countries about suicide in individuals receiving rimonabant. All randomised participants were analysed. At the close of the trial (Nov 6, 2008), the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 364 (3.9%) patients assigned to rimonabant and 375 (4.0%) assigned to placebo (hazard ratio 0.97, 95% CI 0.84-1.12, p=0.68). With rimonabant, gastrointestinal (3038 [33%] vs 2084 [22%]), neuropsychiatric (3028 [32%] vs 1989 [21%]), and serious psychiatric side-effects (232 [2.5%] vs 120 [1.3%]) were significantly increased compared with placebo. Four patients in the rimonabant group and one in the placebo group committed suicide.. The premature termination of this trial has important lessons for drug development. A drug that was being marketed for weight loss, but being tested for improving cardiovascular outcomes, induced a level of serious neuropsychiatric effects that was deemed unacceptable by regulatory authorities, and both the drug and the trial were abruptly terminated.. Sanofi-Aventis.

Topics: Aged; Aged, 80 and over; Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Double-Blind Method; Drug Approval; Female; Gastrointestinal Diseases; Humans; Male; Mental Disorders; Obesity; Piperidines; Pyrazoles; Rimonabant; Suicide

Rimonabant, the first selective cannabinoid type 1 (CB1) 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.. 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<0.0001), as well as low-density lipoprotein (LDL) and HDL particle sizes, apolipoprotein A1 and B, HDL2, HDL3, C-reactive protein, and adiponectin levels (all P<0.05). Rimonabant decreased abdominal subcutaneous adipose tissue (AT) cross-sectional area by 5.1% compared to placebo (P<0.005), with a greater reduction in visceral AT (-10.1% compared to placebo; P<0.0005), thereby reducing the ratio of visceral/subcutaneous AT (P<0.05). Rimonabant significantly reduced liver fat content (liver/spleen attenuation ratio; P<0.005). Systolic (-3.3 mm Hg) and diastolic (-2.4 mm Hg) blood pressure were significantly reduced with rimonabant versus placebo (P<0.0001). The safety profile of rimonabant was consistent with previous studies; gastrointestinal, nervous system, psychiatric, and general adverse events were more common with rimonabant 20 mg.. 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.

Topics: Adiponectin; Adiposity; Adult; Anti-Obesity Agents; Apolipoproteins; Blood Glucose; Blood Pressure; Body Weight; C-Reactive Protein; Cholesterol, HDL; Double-Blind Method; Dyslipidemias; Female; Humans; Insulin; Intra-Abdominal Fat; Lipoproteins, LDL; Liver; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Triglycerides

In obese patients, depth of anaesthesia monitoring could be useful in titrating intravenous anaesthetics. We hypothesized that depth of anaesthesia monitoring would reduce recovery time and use of anaesthetics in obese patients receiving propofol and remifentanil.. We investigated 38 patients with a body mass index >or=30 kg/m(2) scheduled for an abdominal hysterectomy. Patients were randomized to either titration of propofol and remifentanil according to a cerebral state monitor (CSM group) or according to usual clinical criteria (control group). The primary end point was time to eye opening and this was assessed by a blinded observer.. Time to eye opening was 11.8 min in the CSM group vs. 13.4 min in the control group (P=0.58). The average infusion rate for propofol was a median of 516 vs. 617 mg/h (P=0.24) and for remifentanil 2393 vs. 2708 microg/h (P=0.04). During surgery, when the cerebral state index was continuously between 40 and 60, the corresponding optimal propofol infusion rate was 10 mg/kg/h based on ideal body weight.. No significant reduction in time to eye opening could be demonstrated when a CSM was used to titrate propofol and remifentanil in obese patients undergoing a hysterectomy. A significant reduction in remifentanil consumption was found.

Topics: Adult; Aged; Algorithms; Anesthesia; Female; Humans; Hysterectomy; Middle Aged; Obesity; Piperidines; Propofol; Remifentanil

Combinations of insulin and oral antidiabetic drugs (OAD) are often prescribed instead of insulin alone. In this study, the effects of insulin glargine (IG) in combination with repaglinide or acarbose on glycemic parameters were investigated. Obese Type 2 diabetic patients with fasting blood glucose (FBG) levels >or= 7.7 mmol/l [corrected] and hemoglobin glycated (A1C) >or=9% under maximal OAD combination therapy were enrolled. Previous therapies were discontinued, and patients were randomized into 2 groups. The combinations of IG and repaglinide were administered to group 1, and of IG and acarbose to group 2 for 13 weeks. Twenty patients in group 1 and 18 patients in group 2 completed the study. A1C levels were significantly decreased from 10.9+/-1.4% to 7.7+/-1.1% in group 1 and 11.0+/-1.4% to 8.1+/-1.4% in group 2. FBG levels were significantly decreased from 11.9+/-2.7 to 7.1+/-2.3 mmol/l in group 1 and 11.1+/-2.5 to 6.8+/-1.4 mmol/l in group 2. Post-prandial glucose levels were significantly decreased from 15.3+/-3.8 to 10.3+/-3.0 mmol/l in group 1 and 14.0+/-3.1 to 8.9+/-2.2 mmol/l in group 2. Intergroup comparisons indicated no significant differences. More weight gain was detected in group 1, compared to the baseline. Symptomatic hypoglycemia incidence was similar in both groups. Severe hypoglycemic attacks were seen in two patients in group 1. Flatulence incidence was higher in acarbose group. Conclusively, repaglinide and acarbose were equally effective when combined with IG for obese Type 2 diabetic patients controlled inadequately with OAD alone. Furthermore, acarbose seems to have advantages over repaglinide concerning weight gain and severe hypoglycemic attacks.

Topics: Acarbose; Blood Glucose; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Obesity; Piperidines; Weight Gain

Pharmacokinetic studies in obese patients suggest that dosing of rocuronium should be based on ideal body weight (IBW). This may, however, result in a prolonged onset time or compromised conditions for tracheal intubation. In this study, we compared onset time, conditions for tracheal intubation, and duration of action in obese patients when the intubation dose of rocuronium was based on three different weight corrections.. Fifty-one obese patients, with a median (range) body mass index of 44 (34-72) kg/m2, scheduled for laparoscopic gastric banding or gastric bypass under propofol-remifentanil anesthesia were randomized into three groups. The patients received rocuronium (0.6 mg/kg) based on IBW (IBW group, n = 17), IBW plus 20% of excess weight (corrected body weight [CBW]20% group, n = 17), or IBW plus 40% of excess weight (CBW40% group, n = 17). Propofol was administered as a bolus of 200 mg and an infusion at 5 mg x kg(-1) x h(-1) and remifentanil was administered at 1.0 microg x kg(-1) x min(-1), both according to CBW40%. Neuromuscular function was monitored with train-of-four nerve stimulation and acceleromyography. The primary end point was duration of action, defined as time to reappearance of the fourth twitch in train-of-four.. The median (range) duration of action was 32 (18-49), 38 (25-66), and 42 (24-66) min in the IBW, CBW20%, and CBW40% groups, respectively (P = 0.001 for comparison of the IBW and CBW40% group). There were no significant differences in onset time (85 vs 84 vs 80 s) or in intubation conditions 90 s after administration of rocuronium.. In obese patients undergoing gastric banding or gastric bypass, rocuronium dosed according to IBW provided a shorter duration of action without a significantly prolonged onset time or compromised conditions for tracheal intubation.

Topics: Adult; Androstanols; Anesthesia Recovery Period; Anesthetics, Intravenous; Body Mass Index; Body Weight; Female; Gastric Bypass; Humans; Male; Middle Aged; Neuromuscular Nondepolarizing Agents; Obesity; Piperidines; Propofol; Remifentanil; Rocuronium

To compare the effects of ezetimibe plus orlistat or rimonabant on anthropometric and lipid parameters in nondiabetic statin-intolerant overweight/obese patients with dyslipidemia.. Thirty participants received a hypocaloric diet and were randomized to open-label combination of ezetimibe (10 mg/day) with orlistat (120 mg, 3 times a day with meals; ezetimibe/orlistat [EO], n = 15) or rimonabant (20 mg/day; ezetimibe/rimonabant [ER], n = 15). Anthropometric and metabolic variables were assessed at baseline and 3 months posttreatment. Similar reductions in body weight, body mass index, and waist circumference were recorded in both groups (-8.3%, -8.6%, and -5.2% in the EO group and -7.3%, -7.2%, and -7.0% in the ER group, P < .01 vs baseline for all). Low-density lipoprotein cholesterol (LDL-C) levels decreased in both treatment groups, but this reduction tended to be more pronounced in the EO group (28.4% vs 15.3%, respectively; P < .01 vs baseline for both). Triglycerides tended to decrease more in the ER compared with the EO group (-20.4% vs -14.1%, P < .01 vs baseline for both). High-density lipoprotein cholesterol (HDL-C) levels tended to decrease in EO group, but remained unaltered with ER treatment. Apolipoprotein B levels were equally reduced in both treatment groups.. For similar body weight reduction, the combination of ezetimibe with orlistat may be more efficient in LDL-C lowering, whereas the combination of ezetimibe with rimonabant may be more potent in terms of improving HDL-C and triglycerides.

Topics: Anti-Obesity Agents; Anticholesteremic Agents; Azetidines; Body Weight; Drug Therapy, Combination; Dyslipidemias; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lactones; Male; Middle Aged; Obesity; Orlistat; Overweight; Piperidines; Pyrazoles; Rimonabant

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.. 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.. 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%).. 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.

Topics: Adult; Blood Pressure; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Double-Blind Method; Dyslipidemias; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

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.. 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.. 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.. 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).. The primary efficacy parameter was change in percent atheroma volume (PAV); the secondary efficacy parameter was change in normalized total atheroma volume (TAV).. 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 2.2 mm3 (-4.09 to -0.24) vs an increase of 0.88 mm3 (-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 1.95 mm3 (-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 5.8 mg/dL (4.9 to 6.8) (22.4%) vs 1.8 mg/dL (0.9 to 2.7) (6.9%) (P < .001), and median triglyceride levels decreased 24.8 mg/dL (-35.4 to -17.3) (20.5%) vs 8.9 mg/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).. 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.. clinicaltrials.gov Identifier: NCT00124332.

Topics: Aged; Atherosclerosis; Coronary Artery Disease; Coronary Vessels; Diet, Reducing; Disease Progression; Double-Blind Method; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Obesity; Piperidines; Prospective Studies; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Ultrasonography, Interventional

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.. Patients with a body mass index > or =30 or >27 kg/m(2) 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 < 0.001) and 5 mg (-2.9 +/- 6.5 kg; P = 0.002) than placebo (-1.2 +/- 6.8 kg). Rimonabant 20 mg produced significantly greater improvements than placebo in waist circumference, high-density lipoprotein cholesterol, triglycerides, fasting glucose and insulin levels, insulin resistance, and metabolic syndrome prevalence. Rimonabant 20 mg produced clinically meaningful improvements in all Impact of Weight on Quality of Life-Lite questionnaire domain scores at 2 years. Rimonabant was generally well tolerated and rates of adverse events, including depressed mood disorders and disturbances were similar to placebo during year 2. Proportions of patients with clinically significant depression (Hospital Anxiety and Depression Scale score >11) were similar in all treatment groups.. Rimonabant 20 mg over 2 years promoted clinically relevant and durable weight loss and improvements in cardiometabolic risk factors.

Topics: Adult; Anti-Obesity Agents; Blood Glucose; Body Mass Index; Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Cholesterol, HDL; Dose-Response Relationship, Drug; Epidemiologic Methods; Female; Humans; Insulin; Male; Metabolic Syndrome; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome; Triglycerides; Weight Loss

Rimonabant significantly reduces weight and waist circumference and improves dyslipidemias in overweight and obese patients without diabetes mellitus. Numerous other metabolic changes, including reduced prevalence of the metabolic syndrome and associated cardiovascular disease (CVD) risk factors, reduced fasting glucose, and elevated adiponectin, have been demonstrated with the administration of rimonabant. The Rimonabant-in-Obesity (RIO)-Diabetes trial studied the safety and efficacy of rimonabant in overweight and obese patients with type 2 diabetes who were treated with metformin or sulfonylureas. RIO-Diabetes was a 1-year, randomized, double-blind, placebo-controlled, parallel-group study of 1,047 overweight/obese patients with type 2 diabetes in 151 centers in 11 countries. The body mass index of participants ranged from 27 to 40. Glycosylated hemoglobin (HbA1c) at screening ranged from 6.5% to 10.0%. All patients were receiving either metformin or sulfonylurea therapy and were asked to follow a hypocaloric diet (600 kcal/day deficit [1 kcal = 4.2 kJ]) for the duration of the trial. After a 4-week placebo plus diet run-in period, patients were randomized to receive placebo or rimonabant 5 mg or 20 mg once daily. At 1 year, absolute change in weight from baseline in the intention-to-treat, last observation carried forward analysis of the rimonabant 5 mg and 20 mg groups, respectively, was loss of 2.3 kg and 5.3 kg compared with 1.4 kg in the placebo group (P = 0.013 and P <0.001, respectively). Waist circumference was significantly decreased in the rimonabant 5-mg and 20-mg groups by 2.9 cm and 5.2 cm compared with 1.9 cm in the placebo group (P = 0.034 and P <0.001, respectively). HbA1c reductions of 0.1% and 0.6% were significant in the rimonabant 5-mg and 20-mg groups (P = 0.034 and P <0.001, respectively). Some 57% of the improvements in HbA(1c) and high-density lipoprotein cholesterol could not be attributed to observed weight loss. Compared with placebo, rimonabant 20 mg also demonstrated significant improvements in the prevalence of metabolic syndrome and improvement in its constituents, as well as systolic blood pressure and C-reactive protein levels (assay by ICON Laboratories, Farmingdale, NY and Dublin, Ireland). Rimonabant is the first selective cannabinoid1 blocker studied for type 2 diabetes and associated CVD risk factor therapy. Its ability to improve the numerous metabolic pathologies associated with diabetes and CVD risk and concomit

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Lipid Metabolism; Male; Metabolic Syndrome; Middle Aged; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Treatment Outcome

Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. It has been evaluated in the RIO ("Rimonabant In Obesity and related disorders") programme including above 6.600 overweight/obese patients with or without comorbidities followed for 1 to 2 years. 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. In patients with type 2 diabetes, rimonabant also diminishes HbA1c levels, an effect confirmed in the recent SERENADE trial. Almost half of the metabolic effects occurs beyond weight loss, suggesting direct peripheral effects of rimonabant. Rimonabant is indicated in Europe as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.

Topics: Anti-Obesity Agents; Bradykinin; Cannabinoids; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dyslipidemias; Follow-Up Studies; Glycated Hemoglobin; Heart; Humans; Insulin Resistance; Metabolic Syndrome; Obesity; Overweight; Piperidines; Placebos; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Triglycerides; Waist-Hip Ratio; Weight Loss

Rimonabant is a selective blocker of the CB(1) cannabinoid receptor that has been developed for treatment of abdominal obesity, dyslipidemia, and control of diabetes. Four randomized clinical trials have demonstrated that following 1 year of treatment, 20 mg/d of rimonabant is associated with greater weight loss and reduction in waist circumference compared with placebo. Therapy with rimonabant is associated with favorable changes in serum high-density lipoprotein and triglycerides, as well as with an improvement in glycemic control among obese type 2 diabetic patients. Rimonabant appears to be well tolerated, with the most common side effects being nausea, anxiety, and depressive symptoms. Rimonabant is a novel agent that has the potential to be a useful adjunct to lifestyle and behavior modification in treatment of abdominal obesity, dyslipidemia, and dysglycemia.

Topics: Behavior; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Endocannabinoids; Humans; Lipid Metabolism; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Topics: Appetite Depressants; Cannabinoids; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Male; Obesity; Overweight; Patient Dropouts; Piperidines; Placebos; Pyrazoles; Rimonabant; Treatment Outcome; Weight Loss

Rimonabant, a selective cannabinoid-1 receptor blocker, may reduce body weight and improve cardiometabolic risk factors in patients who are overweight or obese.. To compare the efficacy and safety of rimonabant with placebo each in conjunction with diet and exercise for sustained changes in weight and cardiometabolic risk factors over 2 years.. Randomized, double-blind, placebo-controlled trial of 3045 obese (body mass index > or =30) or overweight (body mass index >27 and treated or untreated hypertension or dyslipidemia) adult patients at 64 US and 8 Canadian clinical research centers from August 2001 to April 2004.. After a 4-week single-blind placebo plus diet (600 kcal/d deficit) run-in period, patients were randomized to receive placebo, 5 mg/d of rimonabant, or 20 mg/d of rimonabant for 1 year. Rimonabant-treated patients were rerandomized to receive placebo or continued to receive the same rimonabant dose while the placebo group continued to receive placebo during year 2.. Body weight change over year 1 and prevention of weight regain during year 2. Additional efficacy measures included changes in waist circumference, plasma lipid levels, and other cardiometabolic risk factors.. At year 1, the completion rate was 309 (51%) patients in the placebo group, 620 (51%) patients in the 5 mg of rimonabant group, and 673 (55%) patients in the 20 mg of rimonabant group. Compared with the placebo group, the 20 mg of rimonabant group produced greater mean (SEM) reductions in weight (-6.3 [0.2] kg vs -1.6 [0.2] kg; P<.001), waist circumference (-6.1 [0.2] cm vs -2.5 [0.3] cm; P<.001), and level of triglycerides (percentage change, -5.3 [1.2] vs 7.9 [2.0]; P<.001) and a greater increase in level of high-density lipoprotein cholesterol (percentage change, 12.6 [0.5] vs 5.4 [0.7]; P<.001). Patients who were switched from the 20 mg of rimonabant group to the placebo group during year 2 experienced weight regain while those who continued to receive 20 mg of rimonabant maintained their weight loss and favorable changes in cardiometabolic risk factors. Use of different imputation methods to account for the high rate of dropouts in all 3 groups yielded similar results. Rimonabant was generally well tolerated; the most common drug-related adverse event was nausea (11.2% for the 20 mg of rimonabant group vs 5.8% for the placebo group).. In this multicenter trial, treatment with 20 mg/d of rimonabant plus diet for 2 years promoted modest but sustained reductions in weight and waist circumference and favorable changes in cardiometabolic risk factors. However, the trial was limited by a high drop-out rate and longer-term effects of the drug require further study. Clinical Trials Registration ClinicalTrials.gov Identifier: NCT00029861.

Topics: Adult; Aged; Anti-Obesity Agents; Blood Pressure; Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Cholesterol, HDL; Diet, Reducing; Double-Blind Method; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Weight Loss

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.. 1047 overweight or obese type 2 diabetes patients (body-mass index 27-40 kg/m2) with a haemoglobin A1c (HbA1c) 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.. 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<0.0001 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.. These data indicate that 20 mg/day rimonabant, in combination with diet and exercise, can produce a clinically meaningful reduction in bodyweight and improve HbA1c and a number of cardiovascular and metabolic risk factors in overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas.

Topics: Adolescent; Adult; Aged; Blood Glucose; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Tolerance; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Obesity; Overweight; Patient Satisfaction; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome

Rimonabant, a selective cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factors in obese patients. The Rimonabant in Obesity-Lipids (RIO-Lipids) study examined the effects of rimonabant on metabolic risk factors, including adiponectin levels, in high-risk patients who are overweight or obese and have dyslipidemia.. We randomly assigned 1036 overweight or obese patients (body-mass index [the weight in kilograms divided by the square of the height in meters], 27 to 40) with untreated dyslipidemia (triglyceride levels >1.69 to 7.90 mmol per liter, or a ratio of cholesterol to high-density lipoprotein [HDL] cholesterol of >4.5 among women and >5 among men) to double-blinded therapy with either placebo or rimonabant at a dose of 5 mg or 20 mg daily for 12 months in addition to a hypocaloric diet.. The rates of completion of the study were 62.6 percent, 60.3 percent, and 63.9 percent in the placebo group, the group receiving 5 mg of rimonabant, and the group receiving 20 mg of rimonabant, respectively. The most frequent adverse events resulting in discontinuation of the drug were depression, anxiety, and nausea. As compared with placebo, rimonabant at a dose of 20 mg was associated with a significant (P<0.001) mean weight loss (repeated-measures method, -6.7+/-0.5 kg, and last-observation-carried-forward analyses, -5.4+/-0.4 kg), reduction in waist circumference (repeated-measures method, -5.8+/-0.5 cm, and last-observation-carried-forward analyses, -4.7+/-0.5 cm), increase in HDL cholesterol (repeated-measures method, +10.0+/-1.6 percent, and last-observation-carried-forward analyses, +8.1+/-1.5 percent), and reduction in triglycerides (repeated-measures method, -13.0+/-3.5 percent, and last-observation-carried-forward analyses, -12.4+/-3.2 percent). Rimonabant at a dose of 20 mg also resulted in an increase in plasma adiponectin levels (repeated-measures method, 57.7 percent, and last-observation-carried-forward analyses, 46.2 percent; P<0.001), for a change that was partly independent of weight loss alone.. Selective CB1-receptor blockade with rimonabant significantly reduces body weight and waist circumference and improves the profile of several metabolic risk factors in high-risk patients who are overweight or obese and have an atherogenic dyslipidemia.

Topics: Adiponectin; Adult; Aged; Anti-Obesity Agents; Blood Glucose; Cannabinoid Receptor Antagonists; Cholesterol; Double-Blind Method; Dyslipidemias; Female; Humans; Insulin; Leptin; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Triglycerides; Weight Loss

In obese patients functional residual capacity comes down with a possible hypoxemia in postoperative period. In fact many studies has been begun to determine optimum ventilation regulation and the best position for these patients, but the question has not been solved. As remifentanil can reduce of 50% the inhalatory anaesthetic request and reverse Trendelemburg position is extremely useful for these patients, we hypothesized that use of a continuous remifentanil infusion during balanced anaesthesia with sevoflurane, BIS-titrated, associated to reverse Trendelem-burg position could facilitate emergence from anaesthesia in obese patients undergoing laparascopic cholecystectomy.. We studied 40 patients, ASA II class, with higher than 30 kg/m2 body mass index, undergoing to laparoscopic cholecystectomy. All the patients, in operating room, received standard monitoring and BIS sensor application. All the data were continuously collected. Induction of anaesthesia has been with a refracted bolus in 120 sec of remifentanil 1 mg/kg, followed by propofol 1.5 mg/kg and cisatracurium 0.15 mg/kg. Maintenance of anaesthesia has been by balanced anaesthesia with continuous remifentanil infusion, ventilating patients with sevoflurane in oxygen and air. Patients were randomized into two homogenous groups. Into the control group has been varied sevoflurane inspiratory concentration on the ground of BIS value (from 0.3% to 3%), while into remifentanil group remifentanil infusion has been varied (from 0.25 to 2 mg/kg/min) to maintain medium pressure values which don't stray more than 25% from basal values, on the ground of BIS values. On pre-established times of operation, respiratory mechanics and blood gases were examined.. As it was to expect, sevoflurane concentration variations resulted very high in control group compared to remifentanil group. Awakening time, extubation, orientation and transfer to PACU (postanaesthesia care unit) resulted significantly lower than remifentanil group.. Concluding, remifentanil infusion, BIS-titrated, facilitates awakening times from balanced anaesthesia with Sevoflurane in obese patients, submitted to laparoscopic cholecystectomy.

Topics: Adult; Ambulatory Surgical Procedures; Anesthesia Recovery Period; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Cholecystectomy, Laparoscopic; Electroencephalography; Female; Humans; Infusions, Intravenous; Male; Methyl Ethers; Middle Aged; Obesity; Piperidines; Postoperative Nausea and Vomiting; Remifentanil; Sevoflurane

The aim of the present study was to test whether the serotoninergic system may be involved in the well known reduced growth hormone (GH) response to insulin-induced hypoglycaemia (IIH) in obese patients. Ten obese women and 10 normal-weight control women underwent three IIH tests, at 14-day intervals: the first in basal conditions, the other two after randomized administration of a serotoninergic drug, fenfluramine (FF, 120 mg/day for 7 days) and FF plus ritanserin (RIT, 30 mg/day for the first 2 days and 20 mg/day on the following days). Ritanserin is a new selective 5-HT2 blocker receptor agent. Both controls and obese patients showed similar normal basal GH levels before each test and insulin administration always effectively reduced glucose levels to values lower than 2.2 mmol/l. In the controls, the expected GH increase to IIH (peak value 56 +/- 13.4 mU/l, AUC 234.4 +/- 55 mU/min/ml) was unaffected by FF administration (peak value 43 +/- 11.4; AUC 216.8 +/- 34.8). In response to the first IIH, the obese patients showed a significantly lower GH increase than in the case of the controls (peak value 21.4 +/- 4.6 mU/l, P less than 0.02; AUC 93.2 +/- 18.6, P less than 0.02). However, in comparison with the basal test, FF administration significantly (P less than 0.001) enhanced GH response to insulin hypoglycaemia (peak value 33.4 +/- 4; AUC 150 +/- 14.6), reaching values not significantly different from those of the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Glucose; Female; Fenfluramine; Growth Hormone; Humans; Hypoglycemia; Insulin; Middle Aged; Obesity; Piperidines; Random Allocation; Ritanserin; Serotonin Antagonists; Time Factors

A study was carried out in general practice to compare the effectiveness of femoxetine, a selective serotonin reuptake inhibitor, with the effect of placebo in helper patients more than 20 per cent above their ideal weight to lose weight. Patients were allocated at random to receive either 600 mg femoxetine (36 patients) or placebo (37 patients) daily over a period of 16 weeks. They were also asked to restrict their calorie intake to 1200-1600 kcal. (5.0-6.7 MJ)/day. The results showed that there was no statistically significant greater weight loss in patients treated with femoxetine (median = 8.3 kg) than with placebo (median = 6.2 kg) after 16 weeks. In subgroups of patients with obesity problems for more than 20 years and of patients previously in anorectic treatment, femoxetine tended towards causing a larger weight loss. Side-effects were generally minor in nature, and the incidence and nature of them were almost comparable in the two groups except for gastro-intestinal symptoms, which were reported more often in the femoxetine group. As femoxetine in several randomized group comparative studies in depressive illness has been shown to have an antidepressant efficacy which is comparable with the efficacy amitriptyline and imipramine, femoxetine may be particularly useful in the management of obese patients requiring antidepressant treatment.

Topics: Adolescent; Adult; Aged; Appetite; Body Weight; Clinical Trials as Topic; Diet, Reducing; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Obesity; Piperidines; Random Allocation

The effect of loperamide and diphenoxylate on diarrhoea following jejuno-ileostomy for morbid obesity was investigated in 27 patients by means of a randomized fixed sample size, three-period cross-over trial. Both loperamide and diphenoxylate had significant effect on the diarrhoeas when compared with no treatment, but no significant difference was found between the two drugs. Loperamide is an acceptable alternative in the treatment of diarrhoea following jejuno-ileostomy.

Topics: Adult; Clinical Trials as Topic; Diarrhea; Diphenoxylate; Female; Humans; Ileum; Isonipecotic Acids; Jejunum; Loperamide; Male; Obesity; Piperidines; Postoperative Complications; Random Allocation

Topics: Adult; Appetite Depressants; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Obesity; Piperidines; Pregnancy; Pregnancy Complications

Topics: Adult; Aged; Amides; Aortic Valve Insufficiency; Biometry; Clinical Trials as Topic; Clopamide; Diuretics; Drug Synergism; Edema; Female; Furosemide; Heart Failure; Humans; Hypertension; Liver Cirrhosis; Male; Middle Aged; Mitral Valve Insufficiency; Obesity; Piperidines; Pulmonary Heart Disease

The induction of beige adipocytes in white adipose tissue (WAT), also known as WAT beiging, improves glucose and lipid metabolism. However, the regulation of WAT beiging at the posttranscriptional level remains to be studied. Here, we report that METTL3, the methyltransferase of N6-methyladenosine (m6A) mRNA modification, is induced during WAT beiging in mice. Adipose-specific depletion of the Mettl3 gene undermines WAT beiging and impairs the metabolic capability of mice fed with a high-fat diet. Mechanistically, METTL3-catalyzed m6A installation on thermogenic mRNAs, including Krüppel-like factor 9 (Klf9), prevents their degradation. Activation of the METTL3 complex by its chemical ligand methyl piperidine-3-carboxylate promotes WAT beiging, reduces body weight, and corrects metabolic disorders in diet-induced obese mice. These findings uncover a novel epitranscriptional mechanism in WAT beiging and identify METTL3 as a potential therapeutic target for obesity-associated diseases.. METTL3, the methyltransferase of N6-methyladenosine (m6A) mRNA modification, is induced during WAT beiging. Depletion of Mettl3 undermines WAT beiging and impairs thermogenesis. METTL3-mediated m6A installation promotes the stability of Krüppel-like factor 9 (Klf9). KLF9 rescues impaired beiging elicited by Mettl3 depletion. Pharmaceutical activation of the METTL3 complex by its chemical ligand methyl piperidine-3-carboxylate induces WAT beiging. Methyl piperidine-3-carboxylate corrects obesity-associated disorders. The METTL3-KLF9 pathway may serve as a potential therapeutic target for obesity-associated diseases.

Topics: Adipose Tissue, White; Animals; Kruppel-Like Transcription Factors; Ligands; Methyltransferases; Mice; Obesity; Piperidines; RNA, Messenger

Currently, the weight loss effects of piperine have gained considerable attention; however, the underlying mechanism needs to be comprehensively elucidated. In the present study, we aimed to investigate the relationship between the weight loss effects of piperine and intestinal function. Based on the obtained results, piperine inhibited intestinal fatty acid absorption in both cellular and animal models. The underlying mechanism may be related to the downregulation of fatty acid absorption-related genes, fatty acid-binding protein 2 and cluster of differentiation 36, but not fatty acid transport protein 4. In addition, piperine repaired the tight junction damage induced by obesity by downregulating jejunal tumor necrosis factor-α and reducing lipopolysaccharide-induced damage on intestinal cell proliferation, thus enhancing intestinal barrier function, which is beneficial in reducing chronic inflammation associated with obesity. In conclusion, the anti-obesity effect of piperine is related to the enhancement of intestinal barrier function and inhibition of intestinal fatty acid absorption.

Topics: Alkaloids; Animals; Benzodioxoles; Fatty Acids; Intestinal Absorption; Intestinal Mucosa; Obesity; Piperidines; Polyunsaturated Alkamides

Adipocyte-derived leptin activates multiple oncogenic signaling, leading to breast cancer cell progression and metastasis. Hence, finding effective strategies to inhibit the oncogenic effects of leptin would provide a novel approach for disrupting obesity-associated breast cancer. In the current study, we explored the role of piperine, a major plant alkaloid from

Topics: Alkaloids; Animals; Benzodioxoles; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Diet; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; MicroRNAs; Obesity; Piperidines; Polyunsaturated Alkamides; PPAR alpha

Adiponectin receptors, AdipoR1 and AdipoR2 exert anti-diabetic effects. Although muscle-specific disruption of AdipoR1 has been shown to result in decreased insulin sensitivity and decreased exercise endurance, it remains to be determined whether upregulation of AdipoR1 could reverse them in obese diabetic mice. Here, we show that muscle-specific expression of human AdipoR1 increased expression levels of genes involved in mitochondrial biogenesis and oxidative stress-detoxification to almost the same extents as treadmill exercise, and concomitantly increased insulin sensitivity and exercise endurance in obese diabetic mice. Moreover, we created AdipoR-humanized mice which express human AdipoR1 in muscle of AdipoR1·R2 double-knockout mice. Most importantly, the small-molecule AdipoR agonist AdipoRon could exert its beneficial effects in muscle via human AdipoR, and increased insulin sensitivity and exercise endurance in AdipoR-humanized mice. This study suggests that expression of human AdipoR1 in skeletal muscle could be exercise-mimetics, and that AdipoRon could exert its beneficial effects via human AdipoR1.

Topics: Animals; Drug Evaluation, Preclinical; Exercise Tolerance; Insulin Resistance; Male; Mice; Mice, Knockout; Obesity; Piperidines; Receptors, Adiponectin

The antidiabetic adiponectin receptor agonist AdipoRon has been shown to suppress the tumour growth of human pancreatic cancer cells. Because obesity and diabetes affect pancreatic cancer progression and chemoresistance, we investigated the effect of AdipoRon on orthotopic tumour growth of Panc02 pancreatic cancer cells in DIO (diet-induced obese) prediabetic mice. Administration of AdipoRon into DIO mice fed high-fat diets, in which prediabetic conditions were alleviated to some extent, did not reduce either body weight or tumour growth. However, when the DIO mice were fed low-fat diets, body weight and the blood leptin level gradually decreased, and importantly, AdipoRon became effective in suppressing tumour growth, which was accompanied by increases in necrotic areas and decreases in Ki67-positive cells and tumour microvessels. AdipoRon inhibited cell growth and induced necrotic cell death of Panc02 cells and suppressed angiogenesis of endothelial MSS31 cells. Insulin and IGF-1 only slightly reversed the AdipoRon-induced suppression of Panc02 cell survival but had no effect on the AdipoRon-induced suppression of MSS31 cell angiogenesis. Leptin significantly ameliorated AdipoRon-induced suppression of angiogenesis through inhibition of ERK1/2 activation. These results suggest that obesity-associated factors weaken the anticancer effect of AdipoRon, which indicates the importance of weight loss in combating pancreatic cancer.

Topics: Animals; Cell Line, Tumor; Diet, High-Fat; Disease Models, Animal; Drug Resistance, Neoplasm; Humans; Male; Mice; Obesity; Pancreatic Neoplasms; Piperidines; Receptors, Adiponectin

Piperine, the major pharmacological ingredient of pepper, can delay the procession of "obesity to diabetes". However, the underlying mechanism remains unclear. This study aims to investigate whether piperine protects against β-cell dysfunction by inhibiting macrophage accumulation and M. Pre-diabetic model was induced by feeding 60% high-fat diet (HFD) in C57BL/6C mice, piperine (15 or 30 mg/kg/day) and rosiglitazone (4 mg/kg/day) were given orally for 8 weeks. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), fasting blood glucose (FBG), total cholesterol (TC) and triglyceride (TG) were used to assay the disorder of glycolipid metabolism. Serum levels of cytokines and insulin were measured by Elisa. Hyperglycemic clamp assay was carried out to evaluate β-cell function. RT-PCR, immunofluorescence and western blot were used to detect the expression of biomarkers associated with macrophage polarization and β-cell dedifferentiation.. Piperine markedly ameliorates the dedifferentiation and dysfunction of β-cell by inhibiting the accumulation and M

Topics: Adipose Tissue; Alkaloids; Animals; Benzodioxoles; Cytochrome P-450 Enzyme Inhibitors; Inflammation; Insulin-Secreting Cells; Macrophage Activation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Piperidines; Polyunsaturated Alkamides

Obesity was induced in rats by feeding on a high fat diet (HFD), 60% w/w cholesterol, 20% w/w carbohydrates, and 20% w/w proteins for two months.. Animals were fed on a HFD and treated concurrently with a single daily dose of vehicle or TPPU (2 mg/kg p.o) for two months. Body weights, blood pressure, and biochemical investigations of all animals were registered at 0, 1, and 2 months of the experimental period.. Vehicle-treated rats fed on a HFD had a considerable increase in body weight compared to age-matched control animals fed on a regular diet (regular diet; 311.40 ±9.60 vs. HFD; 446 ± 12.67). The body weight of rats fed on a HFD and concurrently treated with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4yl) urea (TPPU; 2 mg/kg p.o) daily for two months was significantly decreased (p<0.01). A significant (p<0.01) increase in the systolic blood pressure of animals and vascular dysfunction with blunted relaxant response to acetylcholine and sodium nitroprusside was evident in vehicle-treated animals fed on a HFD compared to control rats fed on a regular diet. These HFD-induced disorders were markedly attenuated in animals fed on a HFD and treated concurrently with a single daily dose of TPPU (2 mg/kg p.o). HFD diet-induced deleterious metabolic changes were prevented with concurrent administration of TPPU (2 mg/kg p.o). TPPU treatment decreased the HDF-induced increase in plasma creatinine levels (p<0.001) in rats. The adiponectin levels were decreased (p<0.001) in vehicle-treated rats fed on HFD for two months compared to control rats fed on a normal diet (p<0.001). Adiponectin levels were significantly (p<0.001) increased in rats fed on HFD and treated concurrently with TPPU (2 mg/kg p.o). HFD diet caused a marked increase in plasma leptin levels of animals which were significantly decreased in animals fed on a HFD and treated concurrently with TPPU for two months. Obese animals exhibited increased levels of plasma insulin compared to control animals fed on a regular diet which were significantly suppressed (p<0.001) by TPPU treatment. In the current investigation, TPPU treatment had a favorable impact on the levels of other metabolic parameters such as plasma cholesterol, triglycerides (TGs), low density lipoproteins (LDLs), and high density lipoproteins (HDL). HFD caused a profound increase in the serum liver enzymes, the effect was reversed by treatment of animals with TPPU (2 mg/kg p.o).. The findings of our current study indicate the promising therapeutic potential of TPPU as a new drug candidate to manage obesity-induced cardiovascular and metabolic disorders. Soluble epoxide hydrolase inhibitors such as TPPU could prevent HFD-induced obesity and related cardiovascular and metabolic complications.

Topics: Administration, Oral; Animals; Cardiovascular Diseases; Diet, High-Fat; Enzyme Inhibitors; Epoxide Hydrolases; Female; Male; Metabolic Diseases; Obesity; Phenylurea Compounds; Piperidines; Rats; Rats, Sprague-Dawley

Glucocorticoids (GCs) are highly effective anti-inflammatory and immunosuppressive drugs. However, prolonged GC therapy may cause numerous adverse effects leading to diabetes and obesity, as well as bone disorders such as osteoporosis in adults and growth retardation in children and adolescents. Prevention and care of the GC-induced adverse effects remain challenging. We have previously demonstrated the efficacy of a treatment with a non-peptidic agonist of adiponectin receptors, AdipoRon, to reverse behaviour disorders and fat mass gain induced by long-term GC treatment. In this work, we have established a relevant model of GC-induced growth and metabolic disorders and determined that AdipoRon is a potential therapeutic tool to reverse these metabolic disturbances.. 5-Week-old mice were treated continuously with or without corticosterone (35 mg/L) in drinking water for seven consecutive weeks. Taking advantage of this mouse model displaying various growth and metabolic disorders, we assayed whether AdipoRon (daily intraperitoneal injection of 1 mg/kg/day for the last 20 days) might prevent the GC-induced adverse effects. The control group was treated with vehicle only. Nutritional behaviors and metabolic parameters were followed-up throughout the treatment. Serum insulin and leptin levels were measured by ELISA. Computed tomography and histological analysis of adipose tissue were assessed at the end of the experimental procedure.. We found that GC treatment in young mice resulted in continuously increased body weight gain associated with a food intake increase. Compared to vehicle-, GC-treated mice displayed early major hyperleptinemia (up to 6-fold more) and hyperinsulinemia (up to 20-fold more) maintained throughout the treatment. At the end of the experimental procedure, GC-treated mice displayed bone growth retardation (e.g. femur length 15.1 versus 14.0 mm, P < 0.01), higher abdominal adipose tissue volume (4.1 versus 2.3, P < 0.01) and altered glucose metabolism compared to control mice. Interestingly, AdipoRon prevented GC-induced effects on energy metabolism such as abdominal adiposity, insulinemia and leptinemia. However, AdipoRon failed to counteract bone growth retardation.. We characterized the very early pathological steps induced by long-term GC in young mice in a relevant model, including growth retardation, fat mass gain and glucose homeostasis dysregulation. The adiponectin system stimulation enabled normalization of the adipose tissue and metabolic features of GC-treated mice. Adiponectin receptor agonists such as AdipoRon might constitute a novel way to counteract some GC-induced adverse effects.

Topics: Abdominal Fat; Animals; Bone Development; Carbohydrate Metabolism; Disease Models, Animal; Disease Progression; Glucocorticoids; Glucose; Growth Disorders; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Receptors, Adiponectin

Metabolic inflammation is an essential event in obesity-induced diabetes and insulin resistance. In obesity, an increasing number of macrophages recruited into visceral adipose tissues undergo significant M. Newborn mice were subcutaneously (s.c.) injected with monosodium glutamate (MSG) to establish a diabetes model. After 24 weeks, the MSG obese mice were divided into three groups and treated with piperine (40 mg/kg/day), metformin (150 mg/kg/day) and vehicle for 10 successive weeks, respectively.. The obesity model was successfully established, as the body weight, insulin resistance, fasting blood glucose (FBG) and dyslipidemia were significantly increased. The 10-week administration of piperine to the obese mice not only significantly decreased the elevated FBG (Model: 6.45 ± 0.41 mM; Piperine: 4.72 ± 0.44 mM, p < 0.01), serum TC (Model: 5.66 ± 0.66 mM; Piperine: 3.55 ± 0.30 mM, p < 0.01) and TG (Model: 1.41 ± 0.08 mM; Piperine: 0.94 ± 0.05 mM, p < 0.001), but also enhanced the glucose infusion rate in the hyperglycemic clamp experiment. Meanwhile, piperine improved glucose intolerance and insulin resistance in MSG obese mice. Piperine markedly decreased the total and differential white blood cell (WBC) count, the serum levels of lipopolysaccharide (LPS) and pro-inflammatory cytokines such as galectin-3 (Gal-3) and interleukin-1β (IL-1β). Furthermore, piperine clearly down-regulated the mRNA levels of pro-inflammatory cytokines and the protein levels of M. Piperine served as an immunomodulator for the treatment of obesity-related diabetes through its anti-inflammatory effects, which might be achieved by inhibiting macrophages M

Topics: Adipose Tissue; Alkaloids; Animals; Benzodioxoles; Body Weight; Cytochrome P-450 Enzyme Inhibitors; Cytokines; Female; Flavoring Agents; Glucose Intolerance; Inflammation; Insulin Resistance; Macrophages; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Piperidines; Polyunsaturated Alkamides; Sodium Glutamate

Breast cancer resistance protein (BCRP) is a member of ATP-binding cassette (ABC) transporter proteins whose primary function is to efflux substrates bound to the plasma membrane. Impaired intestinal barrier functions play a major role in chronic low-grade inflammation (CLGI)-associated obesity, but the regulation of BCRP during obesity and its role in maintaining the intestinal barrier function during CLGI-associated obesity are unknown. In the present study, using several approaches, including efflux assays, immunoprecipitation, immunoblotting, immunohistochemistry, paracellular permeability assay, FACS, cytokine assay, and immunofluorescence microscopy, we report that obese individuals have compromised intestinal BCRP functions and that diet-induced obese mice recapitulate these outcomes. We demonstrate that the compromised BCRP functions during obesity are because of loss of Janus kinase 3 (JAK3)-mediated tyrosine phosphorylation of BCRP. Our results indicate that JAK3-mediated phosphorylation of BCRP promotes its interactions with membrane-localized β-catenin essential not only for BCRP expression and surface localization, but also for the maintenance of BCRP-mediated intestinal drug efflux and barrier functions. We observed that reduced intestinal JAK3 expression during human obesity or JAK3 knockout in mouse or siRNA-mediated β-catenin knockdown in human intestinal epithelial cells all result in significant loss of intestinal BCRP expression and compromised colonic drug efflux and barrier functions. Our results uncover a mechanism of BCRP-mediated intestinal drug efflux and barrier functions and establish a role for BCRP in preventing CLGI-associated obesity both in humans and in mice.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 2; beta Catenin; Biological Transport; Colon; Epithelial Cells; HT29 Cells; Humans; Insulin; Intestinal Mucosa; Janus Kinase 3; Mice; Mice, Knockout; Neoplasm Proteins; Obesity; Phosphorylation; Piperidines; Pyrimidines; Pyrroles; Tissue Inhibitor of Metalloproteinase-1

Perivascular adipose tissue (PVAT) regulates vascular function in a paracrine manner and the vasodilatory effect of PVAT on vessels is completely abolished in obesity. In addition, autophagy is required for maintaining biological function of PVAT and has been shown to be inhibited in obesity. The aim of this study was to explore whether alogliptin improves endothelial function by promoting autophagy in PVAT in obese mice.. C57BL/6 mice were maintained on high fat diet with or without alogliptin intervention for 3 months. Vasorelaxation function of thoracic aorta with or without PVAT was determined. Autophagy related protein level of p62 and LC3B, along with phosphorylated mTOR (p-mTOR) were evaluated. In addition, the effects of alogliptin on autophagy were also investigated in cultured adipocytes.. The presence of PVAT significantly impaired endothelium-dependent vasodilation in obese mice and alogliptin intervention corrected this defect. Autophagy in PVAT was decreased in obese mice and alogliptin intervention activated autophagy. Activating autophagy in PVAT improved endothelium-dependent vasodilation while blocking it in PVAT impaired vasodilation function. Further, addition of glucagon-like peptide-1 (GLP-1) but not alogliptin alone activated autophagy. Moreover, GLP-1 and alogliptin co-treatment did not show additive effect on activating autophagy.. These results revealed that promoting autophagy in PVAT improved endothelial function in response to alogliptin intervention. Additionally, the beneficial effect of alogliptin intervention on PVAT was GLP-1 dependent.

Topics: Adipokines; Adipose Tissue; Animals; Aorta, Thoracic; Autophagy; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Endothelium, Vascular; Glucagon-Like Peptide 1; Male; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type III; Obesity; Paracrine Communication; Piperidines; Proto-Oncogene Proteins c-akt; Signal Transduction; Uracil; Vasodilation

Obesity, particularly visceral adiposity, has been linked to mitochondrial dysfunction and increased oxidative stress, which have been suggested as mechanisms of insulin resistance. The mechanism(s) behind this remains incompletely understood. In this study, we hypothesized that mitochondrial complex II dysfunction plays a role in impaired insulin sensitivity in visceral adipose tissue of subjects with obesity. We obtained subcutaneous and visceral adipose tissue biopsies from 43 subjects with obesity (body mass index ≥ 30 kg/m

Topics: Adult; Bariatric Surgery; Cysteine; Electron Transport Complex II; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Intra-Abdominal Fat; Male; Middle Aged; Obesity; Organophosphorus Compounds; Oxidation-Reduction; Piperidines; Protein Processing, Post-Translational; Subcutaneous Fat

Obesity is characterized by chronic low-grade inflammation that contributes to development of cardiometabolic disorders. Cannabinoid receptor 1 (CB1) antagonists attenuate diet-induced obesity (DIO) and related inflammation, although the precise anti-inflammatory mechanisms involved have not been fully explored. In the current study we used a mouse model of DIO intervention to determine the microRNA (miRNA, miR)-mediated anti-obesity and anti-inflammatory effects of the CB1 antagonist, AM251. DIO mice that were fed high-fat diet (HFD) for 12 weeks were treated with AM251 (10 mg/kg) for an additional 4 weeks. HFD + AM251 mice experienced rapid and prolonged weight loss and reduced inflammatory M1 adipose tissue macrophage (ATM) infiltration. To investigate miRNA-mediated regulation of ATMs, F4/80+ cells from stromal vascular fractions (SVF) of epididymal fat were subjected to miR microarray analysis. Several miRs were differentially expressed in AM251-treated mice that were independent of calorie restriction. Prominently, miR-30e-5p was upregulated in ATMs from HFD + AM251 mice while the miR-30e-5p target, DLL4, was downregulated. Consistent with a decrease in DLL4-Notch signaling, fat storage and pro-inflammatory cytokine/chemokine expression was reduced following AM251 treatment. Furthermore, we found that AM251-treated macrophages can suppress DLL4-mediated Th1 polarization in CD4+ T cells. Together these data demonstrate that blocking CB1 receptors leads to upregulation of miR-30e-5p and down regulation of DLL4 in ATMs, which in turn suppress DLL4-Notch signaling-induced polarization of inflammatory Th1 cells and adipocyte energy storage. This combined effect of ATMs and T cells leads to an anti-inflammatory state and attenuation of DIO. These data support therapeutic potential of miR-30 in the treatment of cardiometabolic disorders.

Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue; Animals; Calcium-Binding Proteins; Diet, High-Fat; Inflammation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Obese; MicroRNAs; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Th1 Cells

The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3

Topics: Animals; Blood Glucose; Body Weight; CHO Cells; Cricetulus; Cyclopropanes; Diabetes Mellitus, Experimental; Disease Models, Animal; Dogs; Eating; Glucagon-Like Peptide 1; Humans; Insulin Secretion; Islets of Langerhans; Male; Mice; Obesity; Piperidines; Propionates; Pyridines; Rats; Receptors, G-Protein-Coupled

Obesity is a global public health problem. Orexin and endocannabinoid signaling in the hypothalamus have been shown to regulate feeding and are promising molecular targets for obesity treatment. In this study, we attempted to analyze effects of orexin-A and endocannabinoid signaling modulation in the arcuate nucleus (Arc) on feeding and glucose-responsive (GR) neurons physiology in a diet-induced obesity (DIO) and diet-induced obesity resistant (DR) rat model. Administration of orexin-A or cannabinoid receptor type-1 (CB

Topics: Animals; Arcuate Nucleus of Hypothalamus; Disease Models, Animal; Endocannabinoids; Feeding Behavior; Glucose; Male; Neurons; Obesity; Orexin Receptors; Orexins; Piperidines; Pyrazoles; Rats, Wistar; Receptor, Cannabinoid, CB1; Signal Transduction

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; Histamine Agonists; Histamine H3 Antagonists; Male; Mice; Obesity; Piperidines; Sucrose; Triglycerides

Topics: Administration, Oral; Alkynes; Animals; Biological Availability; Brain; Cyclopropanes; Dogs; Eating; ERG1 Potassium Channel; Humans; Male; Metabolic Diseases; Mice, Inbred C57BL; Microsomes, Liver; Molecular Docking Simulation; Obesity; Piperidines; Rats; Receptors, Ghrelin; Stereoisomerism; Structure-Activity Relationship

Cannabinoid type 1 receptor (CB1R) inhibition tends to be one of the promising strategies for the treatment of obesity and other related metabolic disorders. Although CB1R inhibition may cause adverse psychiatric effects including depression and anxiety, the investigation of the role of peripheral CB1R on weight loss and related metabolic parameters are urgently needed. We first explored the effect of rimonabant, a selective CB1R antagonist/inverse agonist, on some metabolic parameters in high fat-diet (HFD)-induced obesity in mice. Then, real-time PCR and electrophysiology were used to explore the contribution of high voltage-activated Ca2+ channels (HVACCs), especially Cav1.1, on rimonabant's effect in skeletal muscle (SM) in HFD-induced obesity. Five-week HFD feeding caused body weight gain, and decreased glucose/insulin tolerance in mice compared to those in the regular diet group (P<0.05), which was restored by rimonabant treatment compared to the HFD group (P<0.05). Interestingly, HVACCs and Cav1.1 were decreased in soleus muscle cells in the HFD group compared to the control group. Daily treatment with rimonabant for 5 weeks was shown to counter such decrease (P<0.05). Collectively, our findings provided a novel understanding for peripheral CB1R's role in the modulation of body weight and glucose homeostasis and highlight peripheral CB1R as well as Cav1.1 in the SM as potential targets for obesity treatment.

Topics: Animals; Blood Glucose; Body Weight; Calcium Channels; Calcium Channels, L-Type; Cannabinoid Receptor Antagonists; Diet, High-Fat; Glucose Intolerance; Insulin Resistance; Male; Mice, Inbred C57BL; Models, Animal; Muscle, Skeletal; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The influence of obesity on the pharmacokinetic (PK) behavior of remifentanil is incompletely understood. The aim of the current investigation was to develop a new population PK model for remifentanil that would adequately characterize the influence of body weight (among other covariates, e.g., age) on the disposition of remifentanil in the general adult population. We hypothesized that age and various indices of body mass would be important covariates in the new model.. Nine previously published data sets containing 4,455 blood concentration measurements from 229 subjects were merged. A new PK model was built using nonlinear mixed-effects modeling. Satisfactory model performance was assessed graphically and numerically; an internal, boot-strapping validation procedure was performed to determine the CIs of the model.. Body weight, fat-free body mass, and age (but not body mass index) exhibited significant covariate effects on certain three-compartment model parameters. Visual and numerical assessments of model performance were satisfactory. The bootstrap procedure showed satisfactory CIs on all of the model parameters.. A new model estimated from a large, diverse data set provides the PK foundation for remifentanil dosing calculations in adult obese and elderly patients. It is suitable for use in target-controlled infusion systems and pharmacologic simulation.

Topics: Adult; Aged; Aged, 80 and over; Anesthetics, Intravenous; Body Mass Index; Female; Humans; Male; Middle Aged; Models, Biological; Obesity; Piperidines; Remifentanil; Young Adult

PIMSR is among the first neutral antagonists for the CB1R and was demonstrated pharmacologically to bind to the CB1R, yet not alter calcium flux. It was further shown computationally to be able to stabilize both the active and inactive states of CB1R revealing the molecular interactions that mechanistically afford the property of neutral antagonism. PIMSR shows dramatic positive effects in reducing weight, food intake, and adiposity as well as in improving glycemic control and lipid homeostasis in high-fat diet-induced obese mice, but also shows increased ALT and liver weight as markers of liver injury with chronic administration. Further, in a separate study, 3-day administration of PIMSR in C57BL/6J mice, hepatic steatosis from an acute administration of high of ethanol was significantly reduced. Also, it partially prevented alcohol-induced increases in ALT, AST, and LDH. The differences in ALT levels in obese and nonobese mice under different test paradigms are unlikely to be due to neutral antagonism itself since other neutral antagonists (AM6545) do not exhibit liver injury. The brain levels of low micromolar would support significant brain CB1 receptor occupancy (re: Ki=17nM), thus potentially including both CNS and peripheral influences on the observed weight loss. Overall, these studies suggest that marked improvements in aspects of metabolic disease and alcoholic steatosis can be realized with CB1R neutral antagonists and hence warrants the exploration of further members of this class of cannabinoid ligands.

Topics: Alcohol Drinking; Animals; Binge Drinking; Cannabinoid Receptor Antagonists; Diet, High-Fat; Drug Evaluation, Preclinical; Fatty Liver, Alcoholic; Male; Metabolomics; Mice, Inbred C57BL; Obesity; Piperidines; Receptor, Cannabinoid, CB1

Increased activity of the endocannabinoid system has emerged as a pathogenic factor in visceral obesity, which is a risk factor for type 2 diabetes mellitus (T2DM). The endocannabinoid system is composed of at least two Gprotein-coupled receptors (GPCRs), the cannabinoid receptor type 1 (CB1), and the cannabinoid receptor type 2 (CB2). Downregulation of CB1 activity in rodents and humans has proven efficacious to reduce food intake, abdominal adiposity, fasting glucose levels, and cardiometabolic risk factors. Unfortunately, downregulation of CB1 activity by universally active CB1 inverse agonists has been found to elicit psychiatric side effects, which led to the termination of using globally active CB1 inverse agonists to treat diet-induced obesity. Interestingly, preclinical studies have shown that downregulation of CB1 activity by CB1 neutral antagonists or peripherally restricted CB1 inverse agonists provided similar anorectic effects and metabolic benefits without psychiatric side effects seen in globally active CB1 inverse agonists. Furthermore, downregulation of CB1 activity may ease endoplasmic reticulum and mitochondrial stress which are contributors to obesity-induced insulin resistance and type 2 diabetes. This suggests new approaches for cannabinoid-based therapy in the management of obesity and obesity-related metabolic disorders including type 2 diabetes.

Topics: Animals; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Down-Regulation; Drug Inverse Agonism; Eating; Endocannabinoids; Endoplasmic Reticulum Stress; Humans; Inflammation; Insulin Resistance; Mitochondria; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Signal Transduction

The cannabinoid 1 receptor (CB1) is an important regulator of energy metabolism. Reports of in vivo and in vitro studies give conflicting results regarding its role in insulin secretion, possibly due to circulatory factors, such as incretins. We hypothesized that this receptor may be a regulator of the entero-insular axis. We found that despite lower food consumption and lower body weight postprandial GLP-1 plasma concentrations were increased in CB1(-/-) mice compared to CB1(+/+) mice administered a standard diet or high fat/sugar diet. Upon exogenous GLP-1 treatment, CB1(-/-) mice had increased glucose-stimulated insulin secretion. In mouse insulinoma cells, cannabinoids reduced GLP-1R-mediated intracellular cAMP accumulation and subsequent insulin secretion. Importantly, such effects were also evident in human islets, and were prevented by pharmacologic blockade of CB1. Collectively, these findings suggest a novel mechanism in which endocannabinoids are negative modulators of incretin-mediated insulin secretion.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cell Line, Tumor; Cyclic AMP; Endocannabinoids; Genetic Predisposition to Disease; Glucagon-Like Peptide-1 Receptor; Glycerides; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Male; Mice, Inbred C57BL; Mice, Knockout; Obesity; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1

Hepatic glucose production is promoted by forkhead box O1 (FoxO1) under conditions of insulin resistance. The overactivity of cannabinoid receptor type 1 (CB1R) partly causes increased liver fat deposits and metabolic dysfunction in obese rodents by decreasing mitochondrial function. The aim of the present study was to investigate the role of FoxO1 in CB1R-mediated insulin resistance through the dysregulation of mitochondrial function in the livers of mice with high-fat diet (HFD)-induced obesity. For this purpose, male C57BL/6 mice were randomly assigned to groups and either fed a standard diet (STD), a HFD, or a HFD with 1-week treatment of the CB1R inverse agonist, AM251, at 1 or 5 mg/kg. For in vitro experiments, AML12 hepatocytes were incubated with FoxO1 siRNA prior to challenge with arachidonyl-2'-chloroethylamide (ACEA) or a high concentration of free fatty acids (HFFA). Plasma parameters were analyzed using colorimetric methods. Liver histopathology and hepatic status markers were examined. The HFD-fed mice exhibited an increase in CB1R levels in the liver. Moreover, in response to increased hepatic oxidative stress, the HFD-fed mice also displayed hepatic mitochondrial dysfunction, as indicated by the decreased mRNA levels of carnitine palmitoyltransferase-1 (CPT-1), mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF-1) and citrate synthase. On the contrary, these effects in the HFD-fed mice were reversed by treatment with 5 mg/kg AM251. The administration of AM251 suppressed the induction of FoxO1, phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) expression in the livers of the mice fed a HFD by enhancing the phosphorylation of insulin signaling cascades thus, further lowering the high level of the homeostatic model assessment of insulin resistance (HOMA‑IR) index. In our in vitro experiments, transfection with FoxO1 siRNA prevented the HFFA- and ACEA-induced decrease in the gene expression of mitochondrial biogenesis-related factors, and abrogated the HFFA- and ACEA-induced increase in PEPCK and G6Pase expression. Taken together, our findings suggest that the anti-insulin resistance effect of AM251, which leads to an improvement of mitochondrial function in hepatic steatosis, is mediated through FoxO1.

Topics: Animals; Cannabinoid Receptor Agonists; Citrate (si)-Synthase; Diet, High-Fat; DNA-Binding Proteins; Forkhead Box Protein O1; High Mobility Group Proteins; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 1; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid

To observe the effect of alogliptin combined with metformin on pulmonary function in obese patients with type 2 diabetes inadequately controlled by metformin monotherapy (500 mg, bid po, for at least 3 months), and evaluate its efficacy and safety.. After a 2-week screening period, adult patients (aged 36-72 years) entered a 4-week run-in/stabilization period. Then, patients were randomly assigned to either the intervention group (n = 55) or the control group (n = 50) for 26 weeks. The patients in the control group were given metformin (1000 mg, bid po) and the patients in the intervention group were given metformin (500 mg, bid po) combined with alogliptin (25 mg, qd po). All the patients received counseling about diet and exercise from a nutritionist during run-in and treatment periods.The primary endpoints were the between-group differences in the changes in pulmonary function parameters (vital capacity [VC]%, forced vital capacity [FVC]%, forced expiratory volume in 1 second (FEV1)%, peak expiratory force [PEF]%, maximal voluntary ventilation [MVV]%, total lung capacity [TLC%], forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC%], diffusing capacity for carbon monoxide of lung [DLCO]%, and diffusing capacity for carbon monoxide of lung/unit volume [DLCO/VA%]) between pretherapy and posttreatment. The secondary endpoints were changes from baseline to week 26 in glycosylated hemoglobinA1c (HbA1c), FPG, 2hPG, homeostasis model assessment insulin resistance (HOMA-IR), waist circumference (WC), and BMI. The tertiary endpoints were the changes from baseline to week 26 in blood-fat (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides [TG]). The quartus endpoints were the changes from baseline to week 26 in systolic blood pressure (SBP) and diastolic blood pressure (DBP). The 5th endpoints were the changes from baseline to week 26 in oxidative/antioxidative parameters (reactive oxygen species [ROS], malondialdehyde [MDA], superioxide dismutase [SOD], and glutathione peroxidase [GSH-Px]). In addition, safety endpoints were assessed (AEs, clinical laboratory tests, vital signs, and electrocardiographic readings).. Eighty-one patients completed our clinical trial: intervention group (n = 44) and control group (n = 37). At week 26, pulmonary function parameters (VC%, FVC%, FEV1%, PEF%, MVV%, TLC%, FEV1/FVC%, DLCO%, and DLCO/VA%) had increased significantly from pretherapy values in both groups (P < 0.05), and the pulmonary function tests were significantly greater (P < 0.05) in intervention group than in controls posttherapy. Pulmonary function (FVC%, FEV1%, PEF%, TLC%, FEV1/FVC%, DLCO%, and DLCO/VA%) was lower in the group with HbA1c levels ≥8.0 at 26 weeks, but VC%, FEV1%, MVV%, and TLC% were not significantly lower (P > 0.05). Pulmonary function parameters were positively correlated with GSH-Px and SOD and negatively correlated with ROS and MDA. Mean declines in HbA1c, FPG, 2hPG, HOMA-IR, and blood-fat (TC, HDL-C, LDL-C, and TG) were significantly greater (P < 0.05) in intervention group compared with the controls, but mean declines in BMI, WC, and BP (SBP, DBP) did not differ significantly between the 2 groups (P > 0.05). SOD and GSH-Px increased more (P < 0.05) in the intervention group, compared with the controls; ROS and MDA declined more (P < 0.05) in intervention group, as compared with the control group. The most common AEs were gastrointestinal events, headaches, skin-related AEs (mostly pruritic events), and hypoglycemia. The incidences of AEs did not differ significantly (P > 0.05) between the 2 groups except for the headache and skin-related adverse events (the incidence of headache was higher in the intervention group than in controls; P < 0.05). No patient died during the study.. In patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin monotherapy, the addition of alogliptin contributed to clinically significant increases in pulmonary function through regulating glycemia and improving the imbalance of the oxidative-related substances in the serum, without increasing the incidence of hypoglycemia, dyslipidemia, dysarteriotony, and any notable increase in body weight.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Lung; Male; Metformin; Middle Aged; Obesity; Piperidines; Respiratory Function Tests; Uracil

We identify a target for treating obesity and type 2 diabetes, the consumption of calories by an increase in the metabolic rate of resting skeletal muscle. The metabolic rate of skeletal muscle can be increased by shifting myosin heads from the super-relaxed state (SRX), with a low ATPase activity, to a disordered relaxed state (DRX), with a higher ATPase activity. The shift of myosin heads was detected by a change in fluorescent intensity of a probe attached to the myosin regulatory light chain in skinned skeletal fibers, allowing us to perform a high-throughput screen of 2,128 compounds. The screen identified one compound, which destabilized the super-relaxed state, piperine (the main alkaloid component of black pepper). Destabilization of the SRX by piperine was confirmed by single-nucleotide turnover measurements. The effect was only observed in fast twitch skeletal fibers and not in slow twitch fibers or cardiac tissues. Piperine increased ATPase activity of skinned relaxed fibers by 66 ± 15%. The K

Topics: Adenosine Triphosphatases; Alkaloids; Animals; Basal Metabolism; Benzodioxoles; Diabetes Mellitus, Type 2; High-Throughput Screening Assays; Muscle Fibers, Fast-Twitch; Obesity; Piperidines; Polyunsaturated Alkamides; Rabbits; Skeletal Muscle Myosins; Up-Regulation

Remifentanil has a rapid onset and short duration of action, predictable pharmacokinetic/pharmacodynamic profile, and unlike fentanyl, does not accumulate with repeated or prolonged administration. This study evaluated predictors of remifentanil use in surgical patients with renal or hepatic impairment, or obesity in the United States who received remifentanil, fentanyl, or the combination.. Data (2010) from the US Healthcare National Inpatient Database, State Inpatient Database, State Ambulatory Surgery Database, and private hospital and Medicaid databases were used in this analysis. Patients included had presence of hepatic or renal disease, and/or obesity and were >5 and ≤80 years of age.. In 2010, 9,274 patients with renal impairment, 1,896 with hepatic impairment, and 6,278 with obesity were identified. The percentage of surgical patients diagnosed with renal disease, hepatic disease, or obesity who received remifentanil was 41, 28, and 35%, respectively; 29, 17, and 22% received both remifentanil and fentanyl, and 30, 55, and 43% received fentanyl alone, respectively. In patients with renal or hepatic disease the probability of remifentanil use was greater for persons aged >50 years, with Medicare as primary payer, or who were diagnosed with obesity (p < 0.05 all comparisons). In obese patients, the probability of remifentanil use was greater for persons aged >50 years or female (both p < 0.05). For all 3 disease states, the probability of remifentanil use was lower for those receiving epidural anesthesia or with Medicaid as primary payer (p < 0.05 all comparisons).. Remifentanil in combination with fentanyl is used less than fentanyl in surgical patients with hepatic impairment or obesity. This is inconsistent with the fact that the pharmacokinetic/pharmacodynamic features of remifentanil suggest it is the preferred intraoperative opioid in these patients. Predictors of remifentanil use in patients with renal or hepatic impairment, or obesity include older age, obesity, and Medicare as primary payer. Remifentanil in combination with fentanyl was significantly less utilized than fentanyl in persons with Medicaid as primary payer even though there was a disproportionate enrollment of beneficiaries with renal or hepatic disease, or obesity in state Medicaid programs.

Topics: Adult; Aged; Analgesics, Opioid; Anesthetics, Intravenous; Drug Therapy, Combination; Female; Fentanyl; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Obesity; Pain, Postoperative; Piperidines; Predictive Value of Tests; Remifentanil; Retrospective Studies; United States

The rising incidence of obesity and related disorders such as diabetes and heart disease has focused considerable attention on the discovery of new therapeutics. One promising approach has been to increase the number or activity of brown-like adipocytes in white adipose depots, as this has been shown to prevent diet-induced obesity and reduce the incidence and severity of type 2 diabetes. Thus, the conversion of fat-storing cells into metabolically active thermogenic cells has become an appealing therapeutic strategy to combat obesity. Here, we report a screening platform for the identification of small molecules capable of promoting a white-to-brown metabolic conversion in human adipocytes. We identified two inhibitors of Janus kinase (JAK) activity with no precedent in adipose tissue biology that stably confer brown-like metabolic activity to white adipocytes. Importantly, these metabolically converted adipocytes exhibit elevated UCP1 expression and increased mitochondrial activity. We further found that repression of interferon signalling and activation of hedgehog signalling in JAK-inactivated adipocytes contributes to the metabolic conversion observed in these cells. Our findings highlight a previously unknown role for the JAK-STAT pathway in the control of adipocyte function and establish a platform to identify compounds for the treatment of obesity.

Topics: Adipocytes, Brown; Adipocytes, White; Animals; Bone Morphogenetic Protein 7; Cell Differentiation; Cells, Cultured; Gene Expression Profiling; Hedgehog Proteins; Humans; Interferon-gamma; Ion Channels; Janus Kinase 1; Janus Kinase 3; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Proteins; Obesity; Oxazines; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Pyrroles; STAT1 Transcription Factor; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha; Uncoupling Protein 1; Veratrum Alkaloids

To investigate the in vivo metabolic effects of treatment with BPR0912, a novel and potent peripheral cannabinoid receptor 1 (CB1R) antagonist, on both normal mice and diet-induced obese (DIO) mice.. The acute peripheral effects of BPR0912 administration on gastrointestinal transit and energy metabolism in normal mice were investigated. The effects of chronic BPR0912 treatment were compared with those of rimonabant using DIO mice. Alterations to body weight and biochemical and metabolic variables were determined.. Acute treatment with BPR0912 did not alter food intake or energy metabolism, but efficiently reversed CB1R-mediated gastrointestinal delay. Chronic treatment of DIO mice with BPR0912 showed that BPR0912 exerts a food intake-independent mechanism, which contributes to weight loss. Genes involved in β-oxidation and thermogenesis were upregulated in white adipose tissue (WAT) in addition to increased lipolytic activity, whereas Ucp1 expression was induced in brown adipose tissue (BAT) and body temperature was elevated. Expression of the β2-adrenoceptor was specifically elevated in both WAT and BAT in a manner dependent on the BPR0912 dose. Lastly, chronic BPR0912 treatment was more efficacious than rimonabant in reducing hepatic triglycerides in DIO mice.. BPR0912 exhibits significant in vivo efficacy in inducing food intake-independent weight loss in DIO mice, while tending to reduce their hepatic steatosis. The thermogenic effects of BPR0912, as well as its modulation of protein and gene expression patterns in WAT and BAT, may enhance its efficacy as an anti-obesity agent. The results of the present study support the benefits of the use of peripheral CB1R antagonists to combat metabolic disorders.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Eating; Energy Metabolism; Fatty Liver; Ion Channels; Lipolysis; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thermogenesis; Thiophenes; Uncoupling Protein 1; Weight Loss

Over-nutrition in females causes altered fetal growth during pregnancy and permanently programs the metabolism of offspring; however, the temporal and mechanistic origins of these changes, and whether they are reversible, are unknown. We now show that, in obese female mice, cumulus-oocyte complexes exhibit endoplasmic reticulum (ER) stress, high levels of intracellular lipid, spindle abnormalities and reduced PTX3 extracellular matrix protein production. Ovulated oocytes from obese mice contain normal levels of mitochondrial (mt) DNA but have reduced mitochondrial membrane potential and high levels of autophagy compared with oocytes from lean mice. After in vitro fertilization, the oocytes of obese female mice demonstrate reduced developmental potential and form blastocysts with reduced levels of mtDNA. Blastocysts transferred to normal weight surrogates that were then analyzed at E14.5 showed that oocytes from obese mice gave rise to fetuses that were heavier than controls and had reduced liver and kidney mtDNA content per cell, indicating that maternal obesity before conception had altered the transmission of mitochondria to offspring. Treatment of the obese females with the ER stress inhibitor salubrinal or the chaperone inducer BGP-15 before ovulation increased the amount of the mitochondrial replication factors TFAM and DRP1, and mtDNA content in oocytes. Salubrinal and BGP-15 also completely restored oocyte quality, embryo development and the mtDNA content of fetal tissue to levels equivalent to those derived from lean mice. These results demonstrate that obesity before conception imparts a legacy of mitochondrial loss in offspring that is caused by ER stress and is reversible during the final stages of oocyte development and maturation.

Topics: Animals; Cinnamates; DNA, Mitochondrial; Endoplasmic Reticulum Stress; Female; Immunohistochemistry; Male; Membrane Potential, Mitochondrial; Mice; Mitochondria; Obesity; Oocytes; Oximes; Piperidines; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; Thiourea

Modulation of the endocannabinoid system as an anti-obesity therapeutic is well established; however, the direct effects of cannabinoid receptor 1 (CB1) antagonism on renal function and structure in a model of diet-induced obesity (DIO) are unknown. The aim of this study was to characterise the renal effects of the CB1 antagonist AM251 in a model of DIO. Male Sprague-Dawley rats were fed a low- or high-fat diet (HFD: 40% digestible energy from lipids) for 10 weeks to elicit DIO (n=9). In a different cohort, rats were fed a HFD for 15 weeks. After 9 weeks consuming a HFD, rats were injected daily for 6 weeks with 3 mg/kg AM251 (n=9) or saline via i.p. injection (n=9). After 10 weeks consuming a HFD, CB1 and megalin protein expression were significantly increased in the kidneys of obese rats. Antagonism of CB1 with AM251 significantly reduced weight gain, systolic blood pressure, plasma leptin, and reduced albuminuria and plasma creatinine levels in obese rats. Importantly, there was a significant reduction in tubular cross-section diameter in the obese rats treated with AM251. An improvement in albuminuria was likely due to the reduction in tubular size, reduced leptinaemia and maintenance of megalin expression levels. In obese rats, AM251 did not alter diastolic blood pressure, sodium excretion, creatinine clearance or expression of the fibrotic proteins VEGFA, TGFB1 and collagen IV in the kidney. This study demonstrates that treatment with CB1 antagonist AM251 improves renal outcomes in obese rats.

Topics: Albuminuria; Animals; Collagen; Diet, High-Fat; Humans; Kidney Tubules; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

Hepatic steatosis is the accumulation of excess fat in the liver. Recently, hepatic steatosis has become more important because it occurs in the patients with obesity, type 2 diabetes, and hyperlipidemia and is associated with endoplasmic reticulum (ER) stress and insulin resistance. C-C chemokine receptor 2 (CCR2) inhibitor has been reported to improve inflammation and glucose intolerance in diabetes, but its mechanisms remained unknown in hepatic steatosis. We examined whether CCR2 inhibitor improves ER stress-induced hepatic steatosis in type 2 diabetic mice. In this study, db/db and db/m (n = 9) mice were fed CCR2 inhibitor (2 mg/kg/day) for 9 weeks. In diabetic mice, CCR2 inhibitor decreased plasma and hepatic triglycerides levels and improved insulin sensitivity. Moreover, CCR2 inhibitor treatment decreased ER stress markers (e.g., BiP, ATF4, CHOP, and XBP-1) and inflammatory cytokines (e.g., TNFα, IL-6, and MCP-1) while increasing markers of mitochondrial biogenesis (e.g., PGC-1α, Tfam, and COX1) in the liver. We suggest that CCR2 inhibitor may ameliorate hepatic steatosis by reducing ER stress and inflammation in type 2 diabetes mellitus.

Topics: Animals; Benzoxazines; Blotting, Western; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Endoplasmic Reticulum Stress; Fatty Liver; Glucose Tolerance Test; Humans; Immunoenzyme Techniques; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Real-Time Polymerase Chain Reaction; Receptors, CCR2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Signaling by TGF-β/Smad3 plays a key role in renal fibrosis. As obesity is one of the major risk factors of chronic and end-stage renal disease, we studied the role of Smad3 signaling in the pathogenesis of obesity-related renal disease. After switching to a high fat diet, the onset of Smad3 C-terminal phosphorylation, increase in albuminuria, and the early stages of peripheral and renal insulin resistance occurred at 1 day, and 4 and 8 weeks, respectively, in C57BL/6 mice. The loss of synaptopodin, a functional marker of podocytes, and phosphorylation of the Smad3 linker region (T179 and S213) appeared after 4 weeks of the high fat diet. This suggests a temporal pattern of Smad3 signaling activation leading to kidney injury and subsequent insulin resistance in the development of obesity-related renal disease. In vivo, Smad3 knockout attenuated the high fat diet-induced proteinuria, renal fibrosis, overall podocyte injury, and mitochondrial dysfunction in podocytes. In vitro palmitate caused a rapid activation of Smad3 in 30 min, loss of synaptopodin in 2 days, and impaired insulin signaling in 3 days in isolated mouse podocytes. Blockade of either Smad3 phosphorylation by SIS3 (a Smad3 inhibitor) or T179 phosphorylation by flavopiridol (a CDK9 inhibitor) prevented the palmitate-induced loss of synaptopodin and mitochondrial function in podocytes. Thus, Smad3 signaling plays essential roles in obesity-related renal disease and may be a novel therapeutic target.

Topics: Animals; Cells, Cultured; Dietary Fats; Enzyme Inhibitors; Fibrosis; Flavonoids; Gene Knockdown Techniques; Insulin; Insulin Resistance; Isoquinolines; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Mitochondria; Obesity; Palmitic Acid; Phosphorylation; Piperidines; Podocytes; Protective Factors; Protein Kinase Inhibitors; Pyridines; Pyrroles; Signal Transduction; Smad3 Protein

Metabolic syndrome is a major risk factor for the development of diabetes mellitus and cardiovascular diseases. Pharmacological antagonism of the mineralocorticoid receptor (MR), a ligand-activated transcription factor, limits metabolic syndrome in preclinical models, but mechanistic studies are lacking to delineate the role of MR activation in adipose tissue. In this study, we report that MR expression is increased in visceral adipose tissue in a preclinical mouse model of metabolic syndrome and in obese patients. In vivo conditional upregulation of MR in mouse adipocytes led to increased weight and fat mass, insulin resistance, and metabolic syndrome features without affecting blood pressure. We identified prostaglandin D2 synthase as a novel MR target gene in adipocytes and AT56, a specific inhibitor of prostaglandin D2 synthase enzymatic activity, blunted adipogenic aldosterone effects. Moreover, translational studies showed that expression of MR and prostaglandin D2 synthase is strongly correlated in adipose tissues from obese patients.

Topics: 3T3-L1 Cells; Adipocytes, White; Aldosterone; Animals; Cell Line, Tumor; Dibenzocycloheptenes; Enzyme Induction; Humans; Insulin Resistance; Intra-Abdominal Fat; Intramolecular Oxidoreductases; Lipocalins; Male; Metabolic Syndrome; Mice; Mice, Obese; Mice, Transgenic; Mineralocorticoid Receptor Antagonists; Obesity; Piperidines; Receptors, Leptin; Receptors, Mineralocorticoid; RNA, Messenger; Spironolactone; Subcutaneous Fat; Up-Regulation

The CB1 receptor antagonist, rimonabant, causes weight loss but also produces undesirable psychiatric side effects. We investigated using a combination of rimonabant with the opioid receptor antagonists naloxone and norBNI to treat the metabolic sequelae of long-term high fat diet feeding in mice. This combination has previously been shown to have positive effects on both weight loss and mood related behaviour. Diet-induced obese mice were treated chronically with either low dose rimonabant (1 mg/kg) or the combination of rimonabant, naloxone and norBNI (rim nal BNI). After 6 days of treatment, glucose and insulin tolerance tests were performed and body composition analysed using DEXA. Changes in BAT thermogenesis were assessed using implantable radio telemetry probes. Behavioural responses to acute rimonabant or rim nal BNI were examined in the forced swim test and elevated plus maze. Separately, we assessed shifts in Fos immunoreactivity in response to rimonabant or rim nal BNI. Rim nal BNI was significantly better than rimonabant treatment alone at reducing body weight and food intake. In addition, it improved fasting blood glucose and fat mass. Acute low dose rimonabant did not alter behaviour in either the forced swim test or elevated plus maze. Combination rim nal BNI reversed the behavioural effects of high dose (10 mg/kg) rimonabant in obese mice. Rim nal BNI altered Rimonabant-induced Fos in a number of nuclei, with particular shifts in expression in the central and basolateral amygdala, and insular cortex. This study demonstrates that the combination of rimonabant, naloxone and norBNI is effective at producing weight loss over a sustained period of time without altering performance in standardised mouse behaviour tests. Fos expression patterns offer insight into the neuroanatomical substrates subserving these physiological and behavioural changes. These results indicate that CB1-targeted drugs for weight loss may still be feasible.

Topics: Animals; Body Composition; Cannabinoid Receptor Antagonists; Drug Therapy, Combination; Glucose; Insulin; Male; Mice; Mice, Obese; Naloxone; Narcotic Antagonists; Obesity; Piperidines; Pyrazoles; Rimonabant; Thermogenesis; Treatment Outcome

Obesity, a worldwide epidemic, is a major risk factor for the development of metabolic syndrome (MetS) including diabetes and associated health complications. Recent studies indicate that chronic low-grade inflammation (CLGI) plays a key role in metabolic deterioration in the obese population. Previously, we reported that Jak3 was essential for mucosal differentiation and enhanced colonic barrier functions and its loss in mice resulted in basal CLGI and predisposition to DSS induced colitis. Since CLGI is associated with diabetes, obesity, and metabolic syndrome, present studies determined the role of Jak3 in development of such conditions. Our data show that loss of Jak3 resulted in increased body weight, basal systemic CLGI, compromised glycemic homeostasis, hyperinsulinemia, and early symptoms of liver steatosis. Lack of Jak3 also resulted in exaggerated symptoms of metabolic syndrome by western high-fat diet. Mechanistically, Jak3 was essential for reduced expression and activation of Toll-like receptors (TLRs) in murine intestinal mucosa and human intestinal epithelial cells where Jak3 interacted with and activated p85, the regulatory subunit of the PI3K, through tyrosine phosphorylation of adapter protein insulin receptor substrate (IRS1). These interactions resulted in activation of PI3K-Akt axis, which was essential for reduced TLR expression and TLR associated NFκB activation. Collectively, these results demonstrate the essential role of Jak3 in promoting mucosal tolerance through suppressed expression and limiting activation of TLRs thereby preventing intestinal and systemic CLGI and associated obesity and MetS.

Topics: Animals; Body Weight; Caco-2 Cells; Cytokines; Diet, High-Fat; Disease Models, Animal; Genetic Predisposition to Disease; Glucose Tolerance Test; Humans; Immunity, Innate; Inflammation; Insulin; Janus Kinase 3; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Obesity; Organ Size; Piperidines; Pyrimidines; Pyrroles; Risk Factors; Signal Transduction; Toll-Like Receptors

The involvement of the opioid system in energy balance has been known for several decades but many questions remain unanswered. Therefore, this study was designed to investigate the effect of the non-selective opioid receptor antagonist (LY255582) on high fat diet (HFD)-induced obesity.. Twenty-four adult male albino rats were divided into 4 groups: Control, HFD non-treated, HFD+LY255582 treated during the first 4 weeks and Obese-LY255582- treated groups during the following 4 weeks after the induction of obesity. LY255582 (0.31 mg/kg, s.c.) was administrated daily with HFD feeding. Blood samples were collected for measurement of lipid profile, glucose, insulin, and leptin. Body weight, body mass index (BMI), and food intake were also measured.. Consumption of HFD resulted in a significant increase in body weight, body mass index (BMI), glucose, insulin, leptin levels, and induced a state of dyslipideamia. Opioid antagonist LY255582 administration with HFD decreased food intake, body weight and BMI, in addition to the improvement of HFD related metabolic abnormalities (dyslipidemia and insulin resistance) during the dynamic phase of obesity development than in animals with already developed dietary obesity.. The use of opioid antagonist may be a promising approach in treatment of HFD-induced obesity.

Topics: Animals; Anti-Obesity Agents; Biomarkers; Blood Glucose; Body Mass Index; Cyclohexanes; Diet, High-Fat; Disease Models, Animal; Eating; Insulin; Leptin; Lipids; Male; Narcotic Antagonists; Obesity; Piperidines; Rats, Sprague-Dawley; Receptors, Opioid; Time Factors

Cannabinoid CB1 receptors peripherally modulate energy metabolism. Here, we investigated the role of CB1 receptors in the expression of glucose/pyruvate/tricarboxylic acid (TCA) metabolism in rat abdominal muscle. Dihydrolipoamide dehydrogenase (DLD), a flavoprotein component (E3) of α-ketoacid dehydrogenase complexes with diaphorase activity in mitochondria, was specifically analyzed. After assessing the effectiveness of the CB1 receptor antagonist AM251 (3 mg kg(-1), 14 days) on food intake and body weight, we could identified seven key enzymes from either glycolytic pathway or TCA cycle--regulated by both diet and CB1 receptor activity--through comprehensive proteomic approaches involving two-dimensional electrophoresis and MALDI-TOF/LC-ESI trap mass spectrometry. These enzymes were glucose 6-phosphate isomerase (GPI), triosephosphate isomerase (TPI), enolase (Eno3), lactate dehydrogenase (LDHa), glyoxalase-1 (Glo1) and the mitochondrial DLD, whose expressions were modified by AM251 in hypercaloric diet-induced obesity. Specifically, AM251 blocked high-carbohydrate diet (HCD)-induced expression of GPI, TPI, Eno3 and LDHa, suggesting a down-regulation of glucose/pyruvate/lactate pathways under glucose availability. AM251 reversed the HCD-inhibited expression of Glo1 and DLD in the muscle, and the DLD and CB1 receptor expression in the mitochondrial fraction. Interestingly, we identified the presence of CB1 receptors at the membrane of striate muscle mitochondria. DLD over-expression was confirmed in muscle of CB1-/- mice. AM251 increased the pyruvate dehydrogenase and glutathione reductase activity in C2C12 myotubes, and the diaphorase/oxidative activity in the mitochondria fraction. These results indicated an up-regulation of methylglyoxal and TCA cycle activity. Findings suggest that CB1 receptors in muscle modulate glucose/pyruvate/lactate pathways and mitochondrial oxidative activity by targeting DLD.

Topics: Animals; Body Weight; Cell Line; Diet; Dietary Carbohydrates; Dihydrolipoamide Dehydrogenase; Electrophoresis, Gel, Two-Dimensional; Feeding Behavior; Gene Expression Regulation; Glucose; Glutathione Reductase; Male; Mice, Inbred C57BL; Mitochondria; Muscle Fibers, Skeletal; Muscles; Obesity; Oxidation-Reduction; Piperidines; Pyrazoles; Pyruvic Acid; Rats, Wistar; Receptor, Cannabinoid, CB1; Spectrometry, Mass, Electrospray Ionization; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

In type 2 diabetes mellitus (T2DM) patients, the gradual loss of pancreatic β-cell function is a characteristic feature of disease progression that is associated with sustained hyperglycemia. Recently, G protein-coupled receptor 119 (GPR119) has been identified as a promising anti-diabetic therapeutic target. It is predominantly expressed in pancreatic β-cells, directly promotes glucose stimulated insulin secretion and indirectly increases glucagon-like peptide 1 (GLP-1) levels reducing appetite and food intake. Activation of GPR119 leads to insulin release in β-cells by increasing intracellular cAMP. Here, we identified a novel structural class of small-molecule GPR119 agonists, HD0471042, consisting of substituted a 3-isopropyl-1,2,4-oxadiazol-piperidine derivative with promising potential for the treatment of T2DM. The GPR119 agonist, HD0471042 increased intracellular cAMP levels in stably human GPR119 expressing CHO cell lines and HIT-T15 cell lines, hamster β-cell line expressing endogenously GPR119. HD0471042, significantly elevated insulin release in INS-1 cells of rat pancreatic β-cell line. In in vivo experiments, a single dose of HD0471042 improved glucose tolerance. Insulin and GLP-1 level were increased in a dose-dependent manner. Treatment with HD0471042 for 6 weeks in diet induced obesity mice and for 4 weeks in ob/ob and db/db mice improved glycemic control and also reduced weight gain in a dose-dependent manner. These data demonstrate that the novel GPR119 agonist, HD0471042, not only effectively controlled glucose levels, but also had an anti-obesity effect, a feature observed with GLP-1. We therefore suggest that HD0471042 represents a new type of anti-diabetes agent with anti-obesity potential for the effective treatment of type 2 diabetes.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; CHO Cells; Cricetulus; Cyclic AMP; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Obesity; Oxadiazoles; Piperidines; Rats; Receptors, G-Protein-Coupled; Structure-Activity Relationship; Time Factors; Transfection; Weight Gain

Topics: Animals; Diabetes Mellitus, Type 2; Longevity; Obesity; Piperidines; Receptors, Adiponectin

The adipocyte-derived hormone adiponectin promotes fatty acid oxidation and improves insulin sensitivity and thus plays a key role in the regulation of lipid and glucose metabolism and energy homeostasis. Chronic cannabinoid type 1 (CB1) receptor blockade also increases lipid oxidation and improves insulin sensitivity in obese individuals or animals, resulting in reduced cardiometabolic risk. Chronic CB1 blockade reverses the obesity-related decline in serum adiponectin levels, which has been proposed to account for the metabolic effects of CB1 antagonists. Here, we investigated the metabolic actions of the CB1 inverse agonist rimonabant in high-fat diet (HFD)-induced obese adiponectin knockout (Adipo(-/-)) mice and their wild-type littermate controls (Adipo(+/+)). HFD-induced obesity and its hormonal/metabolic consequences were indistinguishable in the two strains. Daily treatment of obese mice with rimonabant for 7 days resulted in significant and comparable reductions in body weight, serum leptin, free fatty acid, cholesterol, and triglyceride levels in the two strains. Rimonabant treatment improved glucose homeostasis and insulin sensitivity to the same extent in Adipo(+/+) and Adipo(-/-) mice, whereas it reversed the HFD-induced hepatic steatosis, fibrosis, and hepatocellular damage only in the former. The adiponectin-dependent, antisteatotic effect of rimonabant was mediated by reduced uptake and increased β-oxidation of fatty acids in the liver. We conclude that reversal of the HFD-induced hepatic steatosis and fibrosis by chronic CB1 blockade, but not the parallel reduction in adiposity and improved glycemic control, is mediated by adiponectin.

Topics: Adiponectin; Adiposity; Animals; Body Weight; Cannabinoid Receptor Antagonists; Diet, High-Fat; Energy Intake; Fatty Liver; Leptin; Lipid Metabolism; Lipids; Liver; Mice; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Cannabinoid antagonists purportedly have greater effects in reducing the intake of highly palatable food compared to less palatable food. However, this assertion is based on free-feeding studies in which the amount of palatable food eaten under baseline conditions is often confounded with other variables, such as unequal access to both food options and differences in qualitative features of the foods.. We attempted to reduce these confounds by using a model of choice that programmed the delivery rates of sucrose and carrot-flavored pellets.. Lever pressing of ten lean (Fa/Fa or Fa/fa) and ten obese (fa/fa) Zucker rats was placed under three conditions in which programmed ratios for food pellets on two levers were 5:1, 1:1, and 1:5. In phase 1, responses on the two levers produced one type of pellet (sucrose or carrot); in phase 2, responses on one lever produced sucrose pellets and on the other lever produced carrot pellets. After responses stabilized under each food ratio, acute doses of rimonabant (0, 3, and 10 mg/kg) were administered before experimental sessions. The number of reinforcers and responses earned per session under each ratio and from each lever was compared.. Rimonabant reduced reinforcers in 1:5 and 5:1 food ratios in phase 1, and across all ratios in phase 2. Rimonabant reduced sucrose and carrot-flavored pellet consumption similarly; rimonabant did not affect bias toward sucrose, but increased sensitivity to amount differences in lean rats. This suggests that relative amount of food, not palatability, may be an important behavioral mechanism in the effects of rimonabant.

Topics: Animals; Behavior, Animal; Choice Behavior; Eating; Feeding Behavior; Food Preferences; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Reinforcement Schedule; Reinforcement, Psychology; Rimonabant

Topics: Abatacept; Adult; Anticoagulants; Antidiarrheals; Antitubercular Agents; Benzazepines; Canagliflozin; Dimethyl Fumarate; Dipeptidyl-Peptidase IV Inhibitors; Drug Approval; Dyspareunia; Humans; Hypoglycemic Agents; Multiple Sclerosis; Obesity; Oligonucleotides; Piperidines; Proanthocyanidins; Tamoxifen; Uracil

There is much recent interest in finding rare genetic variants associated with various diseases. Owing to the scarcity of rare mutations, single-variant analyses often lack power. To enable pooling of information across variants, we use a random effect formulation within a retrospective modeling framework that respects the retrospective data collecting mechanism of case-control studies. More concretely, we model the control allele frequencies of the variants as random effects, and the systematic differences between the case and control frequencies as fixed effects, resulting in a mixed model. The use of Poisson approximation and gamma-distributed random effects results in a generalized negative binomial distribution for the joint distribution of the control and case frequencies. Variants are selected by conducting stepwise likelihood ratio tests. The superiority of the proposed method over two existing variant selection methods is demonstrated in a simulation study. The effects of non-gamma random effects and correlated variants are also found to be not too detrimental in the simulation study. When the proposed procedure is applied to identify rare variants associated with obesity, it identifies one additional variant not picked up by existing methods.

Topics: Aged; Amidohydrolases; Case-Control Studies; Computer Simulation; Female; Gene Frequency; Genetic Variation; Humans; Likelihood Functions; Male; Mathematical Computing; Middle Aged; Models, Genetic; Monoacylglycerol Lipases; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Statistical Distributions

Homeotherms have specific mechanisms to maintain a constant core body temperature despite changes in thermal environment, food supply, and metabolic demand. Brown adipose tissue, the principal thermogenic organ, quickly and efficiently increases heat production by dissipating the mitochondrial proton motive force. It has been suggested that activation of brown fat, via either environmental (i.e. cold exposure) or pharmacologic means, could be used to increase metabolic rate and thus reduce body weight. Here we assess the effects of intermittent cold exposure (4°C for one to eight hours three times a week) on C57BL/6J mice fed a high fat diet. Cold exposure increased metabolic rate approximately two-fold during the challenge and activated brown fat. In response, food intake increased to compensate fully for the increased energy expenditure; thus, the mice showed no reduction in body weight or adiposity. Despite the unchanged adiposity, the cold-treated mice showed transient improvements in glucose homeostasis. Administration of the cannabinoid receptor-1 inverse agonist AM251 caused weight loss and improvements in glucose homeostasis, but showed no further improvements when combined with cold exposure. These data suggest that intermittent cold exposure causes transient, meaningful improvements in glucose homeostasis, but without synergy when combined with AM251. Since energy expenditure is significantly increased during cold exposure, a drug that dissociates food intake from metabolic demand during cold exposure may achieve weight loss and further metabolic improvements.

Topics: Adipose Tissue, Brown; Animals; Biomarkers; Body Composition; Body Weight; Cold Temperature; Deoxyglucose; Dioxoles; Energy Metabolism; Feeding Behavior; Glucose; Homeostasis; Hormones; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles

De novo lipogenesis and hypercaloric diets are thought to contribute to increased fat mass, particularly in abdominal fat depots. CB1 is highly expressed in adipose tissue, and CB1-mediated signalling is associated with stimulation of lipogenesis and diet-induced obesity, though its contribution to increasing fat deposition in adipose tissue is controversial. Lipogenesis is regulated by transcription factors such as liver X receptor (LXR), sterol-response element binding protein (SREBP) and carbohydrate-responsive-element-binding protein (ChREBP). We evaluated the role of CB1 in the gene expression of these factors and their target genes in relation to lipogenesis in the perirenal adipose tissue (PrAT) of rats fed a high-carbohydrate diet (HCHD) or a high-fat diet (HFD). Both obesity models showed an up-regulated gene expression of CB1 and Lxrα in this adipose pad. The Srebf-1 and ChREBP gene expressions were down-regulated in HFD but not in HCHD. The expression of their target genes encoding for lipogenic enzymes showed a decrease in diet-induced obesity and was particularly dramatic in HFD. In HCHD, CB1 blockade by AM251 reduced the Srebf-1 and ChREBP expression and totally abrogated the remnant gene expression of their target lipogenic enzymes. The phosphorylated form of the extracellular signal-regulated kinase (ERK-p), which participates in the CB1-mediated signalling pathway, was markedly present in the PrAT of obese rats. ERK-p was drastically repressed by AM251 indicating that CB1 is actually functional in PrAT of obese animals, though its activation loses the ability to stimulate lipogenesis in PrAT of obese rats. Even so, the remnant expression levels of lipogenic transcription factors found in HCHD-fed rats are still dependent on CB1 activity. Hence, in HCHD-induced obesity, CB1 blockade may help to further potentiate the reduction of lipogenesis in PrAT by means of inducing down-regulation of the ChREBP and Srebf-1 gene expression, and consequently in the expression of lipogenic enzymes.

Topics: Adipose Tissue, White; Animals; Body Weight; Diet, High-Fat; Dietary Carbohydrates; Down-Regulation; Kidney; Lipogenesis; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Signal Transduction; Time Factors; Transcription Factors

Currently, there is no therapy for severe acute pancreatitis (AP) except for supportive care. The lipase inhibitor orlistat, the peroxisome proliferator-activated receptor γ agonist rosiglitazone, and the chemokine receptor 2 antagonists attenuate the severity of AP in rodents if administered before or at the time of induction of pancreatitis. However, it is unknown whether these treatments are effective if administered therapeutically after induction of pancreatitis.. Male C57BL6 mice with diet-induced obesity received 2 injections of mrIL-12 (150 ng per mouse) and mrIL-18 (750 ng per mouse) intraperitoneally at 24-hour intervals. The mice were injected 2, 24, and 48 hours after the second injection of IL-12 + IL-18 with orlistat (2 mg per mouse), rosiglitazone (0.4 mg per mouse), RS102895 (0.3 mg per mouse), or vehicle (20 μL of DMSO and 80 μL of canola oil) and euthanized after 72 hours.. Orlistat decreased intra-abdominal fat necrosis compared with vehicle (P < 0.05). However, none of the drug treatments produced significant decreases in pancreatic edema, acinar necrosis, or intrapancreatic fat necrosis.. Drugs previously shown to improve the severity of AP when given before or at the time of induction of pancreatitis failed to do so when administered therapeutically in the IL-12 + IL-18 model.

Topics: Acute Disease; Animals; Anti-Obesity Agents; Benzoxazines; Interleukin-12; Interleukin-18; Lactones; Male; Mice, Inbred C57BL; Obesity; Orlistat; Pancreatitis; Piperidines; Receptors, CCR2; Rosiglitazone; Severity of Illness Index; Thiazolidinediones; Treatment Failure; Vasodilator Agents

Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2α) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2α), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Progression; Female; Glomerular Mesangium; Hypercholesterolemia; Hypertriglyceridemia; Hypertrophy; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Kidney; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Piperidines; PPAR alpha; Propionates

An increased risk of obesity has become a common public health concern as it is associated with hypertension, diabetes, osteoarthritis, heart diseases, liver steatosis etc. Pharmacological intervention with natural product-based drugs is considered a healthier alternative to treat obesity. This study was aimed to evaluate anti-obesity effects of piperine on high fat diet (HFD) induced obesity in rats. Piperine was isolated from methanolic extract of Piper nigrum by using column chromatography and confirmed by LC-MS analysis. Male SD rats were fed HFD initially for 15weeks to induce obesity. After induction of obesity, piperine was supplemented in different doses (20, 30 and 40mg/kgb.wt) through HFD for 42days to experimental rats. HFD induced changes in body weight, body composition, fat percentage, adiposity index, blood pressure, plasma levels of glucose, insulin resistance, leptin, adiponectin, plasma and tissue lipid profiles, liver antioxidants were explained. The activities of lipase, amylase and lipid metabolic marker enzymes such as HMG-CoA reductase, carnitine palmitoyl transferase (CPT), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), lecithin-cholesterol acyl transferase (LCAT) and lipoprotein lipase (LPL) were assessed in experimental rats. Supplementation of piperine at a dose of 40mg/kgb.wt has significantly (p<0.05) reversed the HFD-induced alterations in experimental rats in a dose dependant manner, the maximum therapeutic effect being noted at a dose of 40mg/kgb.wt. Our study concludes that piperine can be well considered as an effective bioactive molecule to suppress of body weight, improve insulin and leptin sensitivity, ultimately leading to regulate obesity.

Topics: Alkaloids; Animals; Anti-Obesity Agents; Benzodioxoles; Body Weight; Diet, High-Fat; Male; Obesity; Organ Size; Piperidines; Polyunsaturated Alkamides; Rats, Sprague-Dawley

We assessed whether endothelin-1 (ET-1) inhibits NO and contributes to endothelial dysfunction in penile arteries in a model of insulin resistance-associated erectile dysfunction (ED).. Vascular function was assessed in penile arteries, from obese (OZR) and lean (LZR) Zucker rats, mounted in microvascular myographs. Changes in basal and stimulated levels of superoxide (O2 (-) ) were detected by lucigenin-enhanced chemiluminescence and ET receptor expression was determined by immunohistochemistry.. ET-1 stimulated acute O2 (-) production that was blunted by tempol and the NADPH oxidase inhibitor, apocynin, but markedly enhanced in obese animals. ET-1 inhibited the vasorelaxant effects of ACh and of the NO donor S-nitroso-N-acetyl-DL-penicillamine in arteries from both LZR and OZR. Selective ETA (BQ123) or ETB receptor (BQ788) antagonists reduced both basal and ET-1-stimulated superoxide generation and reversed ET-1-induced inhibition of NO-mediated relaxations in OZR, while only BQ-123 antagonized ET-1 actions in LZR. ET-1-induced vasoconstriction was markedly enhanced by NO synthase blockade and reduced by endothelium removal and apocynin. In endothelium-denuded penile arteries, apocynin blunted augmented ET-1-induced contractions in OZR. Both ETA and ETB receptors were expressed in smooth muscle and the endothelial layer and up-regulated in arteries from OZR.. ET-1 stimulates ETA -mediated NADPH oxidase-dependent ROS generation, which inhibits endothelial NO bioavailability and contributes to ET-1-induced contraction in healthy penile arteries. Enhanced vascular expression of ETB receptors contributes to augmented ROS production, endothelial dysfunction and increased vasoconstriction in erectile tissue from insulin-resistant obese rats. Hence, antagonism of ETB receptors might improve the ED associated with insulin-resistant states.

Topics: Animals; Arteries; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Impotence, Vasculogenic; Insulin Resistance; Male; Muscle, Smooth, Vascular; Nitric Oxide; Obesity; Oligopeptides; Penis; Peptides, Cyclic; Piperidines; Rats; Reactive Oxygen Species; Superoxides; Thinness; Vasoconstriction

The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The molecular mechanism by which CB1R blockade reverses dyslipidemia in obesity has not yet been clarified. In this study, we showed that CB1R blockade with the systemic CB1R blocker rimonabant enhanced whole-body energy expenditure and activated brown adipose tissue (BAT), indicated by increased expression of genes involved in BAT thermogenesis and decreased lipid droplet size in BAT. This was accompanied by selectively increased triglyceride (TG) uptake by BAT and lower plasma TG levels. Interestingly, the effects on BAT activation were still present at thermoneutrality and could be recapitulated by using the strictly peripheral CB1R antagonist AM6545, indicating direct peripheral activation of BAT. Indeed, CB1R blockade directly activated T37i brown adipocytes, resulting in enhanced uncoupled respiration, most likely via enhancing cAMP/PKA signaling via the adrenergic receptor pathway. Our data indicate that selective targeting of the peripheral CB1R in BAT has therapeutic potential in attenuating dyslipidemia and obesity.

Topics: 3T3-L1 Cells; Absorptiometry, Photon; Adipose Tissue, Brown; Animals; Base Sequence; DNA Primers; Dyslipidemias; Mice; Mice, Transgenic; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Reverse Transcriptase Polymerase Chain Reaction; Rimonabant

Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Diet, High-Fat; Drug Synergism; Eating; Exenatide; Glucagon; Glucagon-Like Peptide 1; Insulin Resistance; Male; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptides; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Venoms

Treatment of ob/ob (obese) mice with a cannabinoid receptor 1 (Cnr1) antagonist reduces food intake, suggesting a role for endocannabinoid signaling in leptin action. We further evaluated the role of endocannabinoid signaling by analyzing the phenotype of Cnr1 knockout ob/ob mice. Double mutant animals show a more severe growth retardation than ob/ob mice with similar levels of adiposity and reduced IGF-I levels without alterations of growth hormone (GH) levels. The double mutant mice are also significantly more glucose intolerant than ob/ob mice. This is in contrast to treatment of ob/ob mice with a Cnr1 antagonist that had no effect on glucose metabolism, suggesting a possible requirement for endocannabinoid signaling during development for normal glucose homeostasis. Double mutant animals also showed similar leptin sensitivity as ob/ob mice, suggesting that there are developmental changes that compensate for the loss of Cnr1 signaling. These data establish a role for Cnr1 during development and suggest that compensatory changes during development may mitigate the requirement for Cnr1 in mediating the effects of leptin. The data also suggest a developmental role for Cnr1 to promote growth, regulate the GH/IGF-I axis, and improve β-cell function and glucose homeostasis in the setting of leptin deficiency.

Topics: Animals; Cannabinoid Receptor Antagonists; Endocannabinoids; Glucose; Insulin; Insulin-Like Growth Factor I; Leptin; Liver; Mice; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Leptin; Rimonabant; Signal Transduction

The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil elastase (NE) and decreased serum levels of the NE inhibitor α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2(-/-)) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2(-/-) mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis.

Topics: Adiponectin; Adipose Tissue, Brown; alpha 1-Antitrypsin; AMP-Activated Protein Kinase Kinases; Animals; Diet, High-Fat; Energy Metabolism; Fatty Acids; Fatty Liver; Hep G2 Cells; Humans; Inflammation; Insulin Resistance; Ion Channels; Leptin; Leukocyte Elastase; Liver; Metabolome; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Mice, Transgenic; Mitochondrial Proteins; Obesity; Oxidation-Reduction; Phosphorylation; Piperidines; Protein Kinases; Uncoupling Protein 1; Weight Gain

Effects of cannabinoid receptor 1 (CB1R) blockade were observed by comparing 9-day and 6-week SR141716 treatments in monosodium glutamate (MSG)-induced hypometabolic and hypothalamic obesity (HO) in rats for the first time and molecular mechanisms were investigated. Compared with normal rats, the MSG rats display typical symptoms of the metabolic syndrome, i.e., excessive abdominal obesity, hypertriglyceridemia, hyperinsulinemia, insulin resistance, and hepatic steatosis, but with lower food intake. Although both the 9-day and 6-week treatments with the specific CB1R antagonist SR141716 effectively lowered body weight, intraperitoneal adipose tissue mass, serum triglyceride (TG), and insulin level, the effect of chronic treatment is more impressive. Moreover, serum cholesterol, free fatty acids (FFA), fasted and postprandial blood glucose, and insulin insensitivity were more effectively improved by 6-week exposure to SR141716, whereas hypophagia was only effective within the initial 2 weeks. In addition, hepatic steatosis as well as hepatic and adipocyte morphology was improved. Western blot analysis revealed that the markedly increased CB1R expression and decreased insulin receptor (INR) expression in liver and adipose tissues were effectively corrected by SR141716. Consistent with this, deregulated gene expression of lipogenesis and lipolysis as well as glucose metabolic key enzymes were also restored by SR141716. In conclusion, based on present data we found that: (1) alteration of the hypothalamus in MSG rats leads to a lower expression of INR in crucially insulin-targeted tissues and hyperinsulinemia that was reversed by SR141716, (2) the abnormally increased expression of CB1R in liver and adipose tissues plays a vital role in the pathophysiological process of MSG rats, and (3) chronic CB1R blockade leads to a sustained improvement of the metabolic dysfunctions of MSG rats.

Topics: Adipose Tissue; Animals; Animals, Newborn; Cannabinoid Receptor Antagonists; Fatty Liver; Female; Glucose Intolerance; Hyperlipidemias; Insulin Resistance; Liver; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Insulin; Rimonabant; Sodium Glutamate

Abdominal obesity is referred for as a common pathogenic root of multiple risk factors, which include insulin resistance, dyslipidemia, hypertension, and a pro-atherogenic and pro-inflammatory state. Irrespective of its psychiatric side effects, rimonabant through blocking cannabinoid-1 receptor (CB1R) induces an increase in whole body insulin sensitivity. The aim of this work was to study the effect of selected doses of another insulin sensitizer compound BGP-15, and rimonabant on insulin resistance in Zucker obese rats with a promise of inducing insulin sensitization together at lower doses than would have been expected by rimonabant alone. We found that BGP-15 potentiates the insulin sensitizing effect of rimonabant. The combination at doses, which do not induce insulin sensitization by themselves, improved insulin signaling. Furthermore our results suggest that capsaicin-induced signal may play a role in insulin sensitizing effect of both molecules. Our data might indicate that a lower dose of rimonabant in the treatment of insulin resistance and type 2 diabetes is sufficient to administer, thus a lower incidence of the unfavorable psychiatric side effects of rimonabant are to be expected.

Topics: Analysis of Variance; Animals; Blood Glucose; Disease Models, Animal; Drug Synergism; Glucose; Glucose Clamp Technique; Hyperinsulinism; Insulin; Insulin Resistance; Male; Obesity; Oximes; Piperidines; Pyrazoles; Rats; Rats, Zucker; Rimonabant

We have recently synthesized a new series of 4,5-dihydrobenzo-oxa-cycloheptapyrazole derivatives with the aim to discover novel CB1 antagonist agents characterized by anti-obesity activity comparable to that of SR141716A but with reduced adverse effects such as anxiety and depression. Within the novel class, the CB1 antagonist 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta(1,2-c)pyrazole-3-carboxamide (NESS06SM) has been selected as lead compound. We found that NESS06SM is a CB1 neutral antagonist, characterized by poor blood-brain barrier permeability. Moreover, NESS06SM chronic treatment determined both anti-obesity effect and cardiovascular risk factor improvement in C57BL/6N Diet Induced Obesity (DIO) mice fed with fat diet (FD mice). In fact, the mRNA gene expression in Central Nervous System (CNS) and peripheral tissues by real time PCR, showed a significant increase of orexigenic peptides and a decrease of anorexigenic peptides elicited by NESS06SM treatment, compared to control mice fed with the same diet. Moreover, in contrast to SR141716A treatment, the chronic administration of NESS06SM did not change mRNA expression of both monoaminergic transporters and neurotrophins highly related with anxiety and mood disorders. Our results suggest that NESS06SM reduces body weight and it can restore the disrupted expression profile of genes linked to the hunger-satiety circuit without altering monoaminergic transmission probably avoiding SR141716A side effects. Therefore the novel CB1 neutral antagonist could represent a useful candidate agent for the treatment of obesity and its metabolic complications.

Topics: Animals; Anti-Obesity Agents; Benzoxepins; Body Weight; Cannabinoid Receptor Antagonists; Diet, High-Fat; Fatty Acid Synthases; Glucokinase; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Pyruvate Kinase; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; Symporters

Gymnema sylvestre R. BR. (Asclepiadaceae) has been used frequently in traditional Indian folk medicine for the treatment of diabetes. Study was performed in high fat diet (HFD)-induced obesity in murine model. Obesity was induced by oral feeding of HFD for 28 days. The anti obesity effect of water soluble fraction of Gymnema sylvestre extract (120 mg/kg, p.o. for 21 days) in HFD fed rats was evaluated by the measurement of body weight gain, food intake, hemodynamic changes (systolic, diastolic, mean blood pressure and heart rate), serum lipid profiles (triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol), leptin, insulin, glucose, apolipoproteins A1 and B, lactate dehydrogenase (LDH) and antioxidant enzymes such as reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S transferase (GST), superoxide dismutase (SOD) and catalase (CAT) levels in liver tissues. Organs and visceral fat pad weight were measured. Histopathological studies were also carried out. Water soluble fraction of G. sylvestre ethanolic extract and rimonabant significantly reduced serum lipids, leptin, insulin, glucose, apolipoprotein B and LDH levels while it significantly increased the HDL-cholesterol, apolipoprotein A1 and antioxidant enzymes levels in liver tissue as compared to the HFD fed rats. Histopathological studies of tissues showed no pathological changes. The results of this study show that water soluble fraction of G. sylvestre extract possess antiobesity effect.

Topics: Animals; Anti-Obesity Agents; Antioxidants; Diet, High-Fat; Disease Models, Animal; Gymnema sylvestre; Male; Medicine, Ayurvedic; Obesity; Piperidines; Plant Extracts; Pyrazoles; Rats; Rats, Wistar; Rimonabant

Obesity is a primary risk factor for multiple metabolic disorders. Many drugs for the treatment of obesity, which mainly act through CNS as appetite suppressants, have failed during development or been removed from the market due to unacceptable adverse effects. Thus, there are very few efficacious drugs available and remains a great unmet medical need for anti-obesity drugs that increase energy expenditure by acting on peripheral tissues without severe side effects. Here, we report a novel approach involving antisense inhibition of fibroblast growth factor receptor 4 (FGFR4) in peripheral tissues. Treatment of diet-induce obese (DIO) mice with FGFR4 antisense oligonucleotides (ASO) specifically reduced liver FGFR4 expression that not only resulted in decrease in body weight (BW) and adiposity in free-feeding conditions, but also lowered BW and adiposity under caloric restriction. In addition, combination treatment with FGFR4 ASO and rimonabant showed additive reduction in BW and adiposity. FGFR4 ASO treatment increased basal metabolic rate during free-feeding conditions and, more importantly, prevented adaptive decreases of metabolic rate induced by caloric restriction. The treatment increased fatty acid oxidation while decreased lipogenesis in both liver and fat. Mechanistic studies indicated that anti-obesity effect of FGFR4 ASO was mediated at least in part through an induction of plasma FGF15 level resulted from reduction of hepatic FGFR4 expression. The anti-obesity effect was accompanied by improvement in plasma glycemia, whole body insulin sensitivity, plasma lipid levels and liver steatosis. Therefore, FGFR4 could be a potential novel target and antisense reduction of hepatic FGFR4 expression could be an efficacious therapy as an adjunct to diet restriction or to an appetite suppressant for the treatment of obesity and related metabolic disorders.

Topics: Adiposity; Animals; Basal Metabolism; Bile Acids and Salts; Body Weight; Caloric Restriction; Diet; Drug Therapy, Combination; Fatty Acids; Fatty Liver; Feeding Behavior; Fibroblast Growth Factors; Gene Expression Regulation; Hepatocytes; Insulin; Liver; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oligonucleotides, Antisense; Oxidation-Reduction; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Fibroblast Growth Factor, Type 4; Rimonabant

Recent research suggests that cannabinoid receptor CB1 antagonists can affect appetite and body weight gain, although their influence on other parameters related to metabolic syndrome is not well documented. The present study was designed to assess the effects of chronic treatment with the CB1 receptor inverse agonist AM 251 (3 mg/kg for 3 weeks) in obese and lean Zucker rats on parameters related to metabolic syndrome.. Four groups of rats were used: lean Zucker rats, untreated obese Zucker rats, AM 251-treated obese Zucker rats and a pair-fed obese Zucker rat experimental group which received the same amount of food as that consumed by the animals treated with AM251. Food intake, body weight gain, energy expenditure, plasma biochemical parameters, leptin, insulin and hepatic status markers were analysed.. Daily injection of AM 251 in obese Zucker rats produced a marked and sustained decrease in daily food intake and body weight and a considerable increase in energy expenditure in comparison with untreated obese Zucker rats. AM 251 administration to obese rats significantly reduced plasma levels of glucose, leptin, AST, ALT, Gamma GT, total bilirubin and LDL cholesterol whereas HDL cholesterol plasma levels increased. The results also showed a decrease in liver/weight body ratio and total fat content in the liver. The main effects of AM251 (3 mg/kg) found in this study were not observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with AM 251. The results obtained in obese rats can be interpreted as a decrease in leptin and insulin resistance, thereby improving glucose and lipid metabolism, alleviating the steatosis present in the metabolic syndrome and thus favourably modifying plasma levels of hepatic biomarkers.. Our results indicate that the cannabinoid CB1 inverse agonist AM 251 represents a promising therapeutic strategy for the treatment of obesity and metabolic syndrome.

Topics: Animals; Biomarkers; Cannabinoid Receptor Antagonists; Eating; Energy Metabolism; Fatty Liver; Insulin; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Weight Gain

A new series of urea-based, 4-bicyclic heteroaryl-piperidine derivatives as potent SCD1 inhibitors is described. The structure-activity relationships focused on bicyclic heteroarenes and aminothiazole-urea portions are discussed. A trend of dose-dependent decrease in body weight gain in diet-induced obese (DIO) mice is also demonstrated.

Topics: Administration, Oral; Animals; Body Weight; Diet; Enzyme Activation; Enzyme Inhibitors; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Protein Binding; Rats; Stearoyl-CoA Desaturase; Structure-Activity Relationship; Urea

Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.

Topics: Adenylate Kinase; Adiponectin; Adipose Tissue, White; Administration, Oral; Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Evaluation, Preclinical; Dyslipidemias; Enzyme Activation; Glucose Intolerance; Inflammation; Insulin Resistance; Liver; Longevity; Mice; Mitochondria; Muscle Fibers, Skeletal; Muscles; Obesity; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Piperidines; PPAR alpha; Receptors, Adiponectin; Signal Transduction; Small Molecule Libraries; Transcription Factors; Triglycerides

Topics: Adiponectin; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Obesity Agents; Apoptosis; Ceramidases; Diabetes Mellitus, Experimental; Disease Models, Animal; Hypoglycemic Agents; Insulin Resistance; Mice; Molecular Mimicry; Molecular Targeted Therapy; Obesity; Piperidines; Receptors, Adiponectin

Current anti-obesity monotherapies have proven only marginally effective and are often accompanied by adverse side effects. The cannabinoid 1 (CB1) receptor antagonist rimonabant, while effective at producing weight loss, has been discontinued from clinical use owing to increased incidence of depression. This study investigates the interaction between the cannabinoid and melanin-concentrating hormone (MCH) systems in food intake, body weight control, and mood.. Lean male C57BL/6 mice were injected i.p. with rimonabant (0.0, 0.03, 0.3 and 3.0 mg kg(-1)) or the MCH1-R antagonist SNAP-94847 (0.0, 1.0, 5.0 and 10.0 mg kg(-1)) to establish dose response parameters for each drug. Diet-induced obese (DIO) mice were given either vehicle, sub-threshold dose of rimonabant and SNAP-94847 alone or in combination. Impact on behavioral outcomes, food intake, body weight, plasma metabolites and expression of key metabolic proteins in the brown adipose tissue (BAT) and white adipose tissue (WAT) were measured.. The high doses of rimonabant and SNAP-94847 produced a reduction in food intake after 2 and 24 h. Combining sub-threshold doses of rimonabant and SNAP-94847 produced a significantly greater loss of body weight in DIO mice compared with vehicle and monotherapies. In addition, combining sub effective doses of these drugs led to a shift in markers of thermogenesis in BAT and lipid metabolism in WAT consistent with increased energy expenditure and lipolysis. Furthermore, co-administration of rimonabant and SNAP-94847 produced a transient reduction in food intake, and significantly reduced fat mass and adipocyte size. Importantly, SNAP-94847 significantly attenuated the ability of rimonabant to reduced immobility time in the forced swim test.. These results provide proof of principle that combination of rimonabant and a MCH1 receptor antagonist is highly effective in reducing body weight below that achieved by rimonabant and SNAP-94847 monotherapies. In addition, the combination therapy normalizes the rimonabant-induced behavioral changes seen in the forced swim test.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Affect; Animals; Anti-Obesity Agents; Body Weight; Drug Therapy, Combination; Hypothalamic Hormones; Lipolysis; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Physical Conditioning, Animal; Piperidines; Pituitary Hormones; Pyrazoles; Rimonabant; Thermogenesis; Weight Loss

(1) To investigate whether modulation of the cannabinoid type 1 receptor (CB1R) directly regulates the production of adiponectin (ApN) and other adipokines in omental adipose tissue (OAT) of obese subjects, (2) to establish in which cellular fraction of OAT the effects of CB1R blockade take place and (3) to unravel the underlying mechanisms.. OAT was obtained from 30 obese subjects (body mass index: 40.6±1.3 kg m(-2)) undergoing abdominal surgery. Primary cultures of explants or of freshly isolated adipocytes or stromal-vascular cells (SVCs) were used.. In OAT explants, the CB1R blocker Rimonabant upregulated ApN gene expression. mRNA abundance of omentin that exhibits insulin-sensitizing properties was upregulated as well. Conversely, mRNA levels of two pro-inflammatory cytokines, macrophage inflammatory protein (MIP)-1β and interleukin (IL)-7 were downregulated. We next examined where these effects took place within OAT. CB1R expression was similar in both cellular fractions. In isolated mature adipocytes, blockade of CB1R reproduced the increase of ApN mRNA and the decrease of IL-7 mRNA, while inducing a rise of ApN secretion into the medium. In isolated SVC, gene expression of omentin, which is restricted to this fraction, was augmented, while that of MIP-1β was diminished. Finally, we deciphered the mechanisms leading to ApN regulation by the endocannabinoid system (ES). We first established that ApN regulation was actually mediated by the CB1R: ApN gene expression was upregulated by Rimonabant and downregulated by the CB1R agonist arachidonyl-2-chloroethylamide (ACEA). Upregulation of ApN by Rimonabant was unaltered by inhibiting cAMP production. However, downregulation of ApN by ACEA was fully reversed by an inhibitor of p38 mitogen-activated protein kinase (p38MAPK) and ACEA increased p38MAPK phosphorylation.. Blockade of CB1R attenuates the inflammatory state in both cellular fractions of OAT either by increasing ApN and omentin production or by decreasing mRNAs of MIP-1β and IL-7. ApN regulation by the ES partly involves p38MAPK.

Topics: Abdominal Fat; Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Adult; Blotting, Western; Cannabinoid Receptor Antagonists; Cells, Cultured; Chemokine CCL4; Down-Regulation; Female; Gene Expression; Gene Expression Regulation; Humans; Interleukin-1beta; Interleukin-7; Male; Obesity; Omentum; p38 Mitogen-Activated Protein Kinases; Piperidines; Pyrazoles; Real-Time Polymerase Chain Reaction; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-1; Up-Regulation

Diet-induced obesity produces changes in endocannabinoid signaling (ECS), influencing the regulation of energy homeostasis. Recently, we demonstrated that, in high-fat-diet-fed rats, blockade of CB1 receptor by AM251 not only reduced body weight but also increased adult neurogenesis in the hippocampus, suggesting an influence of diet on hippocampal cannabinoid function. To further explore the role of hippocampal ECS in high-fat-diet-induced obesity, we investigated whether the immunohistochemical expression of the enzymes that produce (diacylglycerol lipase alpha and N-acyl phosphatidylethanolamine phospholipase D) and degrade (monoacylglycerol lipase and fatty acid amino hydrolase) endocannabinoids may be altered in the hippocampus of AM251 (3 mg/kg)-treated rats fed three different diets: standard diet (normal chow), high-carbohydrate diet (70% carbohydrate) and high-fat diet (60% fat). Results indicated that AM251 reduced caloric intake and body weight gain, and induced a modulation of the expression of ECS-related proteins in the hippocampus of animals exposed to hypercaloric diets. These effects were differentially restricted to either the 2-arachinodoyl glycerol or anandamide signaling pathways, in a diet-dependent manner. AM251-treated rats fed the high-carbohydrate diet showed a reduction of the diacylglycerol lipase alpha : monoacylglycerol lipase ratio, whereas AM251-treated rats fed the high-fat diet showed a decrease of the N-acyl phosphatidylethanolamine phospholipase D : fatty acid amino hydrolase ratio. These results are consistent with the reduced levels of hippocampal endocannabinoids found after food restriction. Regarding the CB1 expression, AM251 induced specific changes focused in the CA1 stratum pyramidale of high-fat-diet-fed rats. These findings indicated that the cannabinoid antagonist AM251 modulates ECS-related proteins in the rat hippocampus in a diet-specific manner. Overall, these results suggest that the hippocampal ECS participates in the physiological adaptations to different caloric diets.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Diet, High-Fat; Dietary Carbohydrates; Dietary Fats; Endocannabinoids; Hippocampus; Lipoprotein Lipase; Male; Monoacylglycerol Lipases; Obesity; Phospholipase D; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Weight Gain

Obesity is a global problem with often strong neurobiological underpinnings. The cannabinoid 1 receptor (CB1R) was put forward as a promising drug target for antiobesity medication. However, the first marketed CB1R antagonist/inverse agonist rimonabant was discontinued, as its use was occasionally associated with negative affect and suicidality. In artificial cell systems, CB1Rs can become constitutively active in the absence of ligands. Here, we show that such constitutive CB1R activity also regulates GABAergic and glutamatergic neurotransmission in the ventral tegmental area and basolateral amygdala, regions which regulate motivation and emotions. We show that CB1R inverse agonists like rimonabant suppress the constitutive CB1R activity in such regions, and cause anxiety and reduced motivation for reward. The neutral CB1R antagonist NESS0327 does not suppress constitutive activity and lacks these negative effects. Importantly, however, both rimonabant and NESS0327 equally reduce weight gain and food intake. Together, these findings suggest that neutral CB1R antagonists can treat obesity efficiently and more safely than inverse agonists.

Topics: Amygdala; Animals; Anxiety; Dopaminergic Neurons; Eating; GABAergic Neurons; Humans; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Ventral Tegmental Area; Weight Gain

Behavioral-economic studies have shown that differences between lean and obese Zuckers in food consumption depend on the response requirement for food. Since a response requirement inherently increases the delay to reinforcement, differences in sensitivity to delay may also be a relevant mechanism of food consumption in the obese Zucker rat. Furthermore, the endocannabinoid neurotransmitter system has been implicated in impulsivity, but studies that attempt to characterize the effects of cannabinoid drugs (e.g., rimonabant) on impulsive choice may be limited by floor effects. The present study aimed to characterize impulsive-choice patterns for sucrose using an adjusting-delay procedure in genetically lean and obese Zuckers. Ten lean and ten obese Zucker rats chose between one lever that resulted in one pellet after a standard delay (either 1 s or 5 s) and a second lever that resulted in two or three pellets after an adjusting delay. After behavior stabilized under baseline, rimonabant (0-10 mg/kg) was administered prior to some choice sessions in the two-pellet condition. Under baseline, obese Zuckers made more impulsive choices than leans in three of the four standard-delay/pellet conditions. Additionally, in the 2-pellet condition, rimonabant increased impulsive choice in lean rats in the 1-s standard-delay condition; however, rimonabant decreased impulsive choice in obese rats in the 1-s and 5-s standard-delay conditions. These data suggest that genetic factors that influence impulsive choice are stronger in some choice conditions than others, and that the endocannabinoid system may be a relevant neuromechanism.

Topics: Animals; Behavior, Animal; Cannabinoid Receptor Antagonists; Choice Behavior; Conditioning, Operant; Feeding Behavior; Food Preferences; Impulsive Behavior; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Rimonabant; Sucrose

It is well established that inactivation of the central endocannabinoid system (ECS) through antagonism of cannabinoid receptor 1 (CB1R) reduces food intake and improves several pathological features associated with obesity, such as dyslipidemia and liver steatosis. Nevertheless, recent data indicate that inactivation of peripheral CB1R could also be directly involved in the control of lipid metabolism independently of central CB1R. To further investigate this notion, we tested the direct effect of the specific CB1R antagonist, SR141716, on hepatic carbohydrate and lipid metabolism using cultured liver slices. CB1R messenger RNA expression was strongly decreased by SR141716, whereas it was increased by the CB1R agonist, arachidonic acid N-hydroxyethylamide (AEA), indicating the effectiveness of treatments in modulating ECS activity in liver explants both from lean or ob/ob mice. The measurement of O(2) consumption revealed that SR141716 increased carbohydrate or fatty acid utilization, according to the cellular hormonal environment. In line with this, SR141716 stimulated ß-oxidation activity, and the role of CB1R in regulating this pathway was particularly emphasized when ECS was hyperactivated by AEA and in ob/ob tissue. SR141716 also improved carbohydrate and lipid metabolism, blunting the AEA-induced increase in gene expression of proteins related to lipogenesis. In addition, we showed that SR141716 induced cholesterol de novo synthesis and high-density lipoprotein uptake, revealing a relationship between CB1R and cholesterol metabolism.. These data suggest that blocking hepatic CB1R improves both carbohydrate and lipid metabolism and confirm that peripheral CB1R should be considered as a promising target to reduce cardiometabolic risk in obesity.

Topics: AMP-Activated Protein Kinase Kinases; Animals; Carbohydrate Metabolism; Cholesterol; Disease Models, Animal; Dyslipidemias; Fatty Liver; Gene Expression Regulation; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Oxygen Consumption; Piperidines; Protein Kinases; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; Tissue Culture Techniques

Pharmacologic inhibition of the cannabinoid-1 receptor (CB1R) in rodent models leads to weight loss and time-dependent changes in energy balance. This study evaluated the effects of CB1R inhibition on weight loss, energy expenditure (EE), and food intake (FI) in an obese canine model following 4 weeks of treatment. Eighteen maintenance-fed obese beagles were evenly and randomly allocated to a CB1R inverse agonist (AM251) (2 mg/kg), a 70% food-restricted (FR) diet, or a control group (C). Evaluations included body weight and composition (dual-energy x-ray absorptiometry scan), EE (doubly labeled water), and FI. Change in body mass at week 4 was significantly greater (P < .050) in the AM251 (-1476.7 g) and FR groups (-1100.0 g) than in the C group (-228.3 g). Food intake was decreased from week 2 onward in the FR and AM251 groups (P < .05). Absolute and lean mass-adjusted EEs were decreased only in the FR group (P < .01); EE in the AM251 group was greater (P < .05) than that in the FR group. Pharmacologic inhibition of CB1R in a canine model led to sustained effects on FI and EE. Weight loss was greater with AM251 than could be accounted for by food restriction (∼25%), an effect likely mediated by the EE response to CB1R inhibition.

Topics: Absorptiometry, Photon; Animals; Disease Models, Animal; Dogs; Eating; Energy Metabolism; Female; Glucose Tolerance Test; Obesity; Piperidines; Pyrazoles; Random Allocation; Receptor, Cannabinoid, CB1; Weight Loss

Research on free-food intake suggests that cannabinoids are implicated in the regulation of feeding. Few studies, however, have characterized how environmental factors that affect food procurement interact with cannabinoid drugs that reduce food intake. Demand analysis provides a framework to understand how cannabinoid blockers, such as rimonabant, interact with effort in reducing demand for food. The present study examined the effects rimonabant had on demand for sucrose in obese Zucker rats when effort to obtain food varied and characterized the data using the exponential ("essential value") model of demand. Twenty-nine male (15 lean, 14 obese) Zucker rats lever-pressed under eight fixed ratio (FR) schedules of sucrose reinforcement, in which the number of lever-presses to gain access to a single sucrose pellet varied between 1 and 300. After behavior stabilized under each FR schedule, acute doses of rimonabant (1-10mg/kg) were administered prior to some sessions. The number of food reinforcers and responses in each condition was averaged and the exponential and linear demand equations were fit to the data. These demand equations quantify the value of a reinforcer by its sensitivity to price (FR) increases. Under vehicle conditions, obese Zucker rats consumed more sucrose pellets than leans at smaller fixed ratios; however, they were equally sensitive to price increases with both models of demand. Rimonabant dose-dependently reduced reinforcers and responses for lean and obese rats across all FR schedules. Data from the exponential analysis suggest that rimonabant dose-dependently increased elasticity, i.e., reduced the essential value of sucrose, a finding that is consistent with graphical depictions of normalized demand curves.

Topics: Analysis of Variance; Animals; Cannabinoids; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Eating; Feeding Behavior; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Reinforcement Schedule; Rimonabant

We have previously found abrogated ischemia-induced coronary collateral growth in Zucker obese fatty (ZOF) rats compared with Zucker lean (ZLN) rats. Because ZOF rats have structural abnormalities in their mitochondria suggesting dysfunction and also show increased production of O(2), we hypothesized that mitochondrial dysfunction caused by oxidative stress impairs coronary collateral growth in ZOF.. Increased levels of reactive oxygen species were observed in aortic endothelium and smooth muscle cells in ZOF rats compared with ZLN rats. Reactive oxygen species levels were decreased by the mitochondria-targeted antioxidants MitoQuinone (MQ) and MitoTempol (MT) as assessed by MitoSox Red and dihydroethidine staining. Lipid peroxides (a marker of oxidized lipids) were increased in ZOF by ≈47% compared with ZLN rats. The elevation in oxidative stress was accompanied by increased antioxidant enzymes, except glutathione peroxidase-1, and by increased uncoupling protein-2 in ZOF versus ZLN rats. In addition, elevated respiration rates were also observed in the obese compared with lean rats. Administration of MQ significantly normalized the metabolic profiles and reduced lipid peroxides in ZOF rats to the same level observed in lean rats. The protective effect of MQ also suppressed the induction of uncoupling protein-2 in the obese rats. Resolution of mitochondrial oxidative stress by MQ or MT restored coronary collateral growth to the same magnitude observed in ZLN rats in response to repetitive ischemia.. We conclude that mitochondrial oxidative stress and dysfunction play a key role in disrupting coronary collateral growth in obesity and the metabolic syndrome, and elimination of the mitochondrial oxidative stress with MQ or MT rescues collateral growth.

Topics: Animals; Antioxidants; Collateral Circulation; Coronary Vessels; Disease Models, Animal; Lipid Peroxidation; Lipid Peroxides; Male; Metabolic Syndrome; Mitochondria, Heart; Mitochondrial Proteins; Obesity; Organophosphorus Compounds; Oxidative Stress; Piperidines; Rats; Rats, Zucker; Reactive Oxygen Species; Ubiquinone

The endocannabinoids have been recognized as an important system involved in the regulation of energy balance. Rimonabant (SR141716), a selective inverse agonist of cannabinoid receptor 1 (CB1), has been shown to cause weight loss. However, its suppressive impact on food intake is transient, indicating a likely additional effect on energy expenditure. To examine the effects of rimonabant on components of energy balance, we administered rimonabant or its vehicle to diet-induced obese (DIO) C57BL/6 mice once daily for 30 days, by oral gavage. Rimonabant induced a persistent weight reduction and a significant decrease in body fatness across all depots. In addition to transiently reduced food intake, rimonabant-treated mice exhibited decreased apparent energy absorption efficiency (AEAE), reduced metabolizable energy intake (MEI), and increased daily energy expenditure (DEE) on days 4-6 of treatment. However, these effects on the energy budget had disappeared by days 22-24 of treatment. No chronic group differences in resting metabolic rate (RMR) or respiratory quotient (RQ) (P > 0.05) were detected. Rimonabant treatment significantly increased daily physical activity (PA) levels both acutely and chronically. The increase in PA was attributed to elevated activity during the light phase but not during the dark phase. Taken together, these data suggested that rimonabant caused a negative energy balance by acting on both energy intake and expenditure. In the short term, the effect included both reduced intake and elevated PA but the chronic effect was only on increased PA expenditure.

Topics: Adipose Tissue; Administration, Oral; Animals; Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Eating; Energy Intake; Energy Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

The endocannabinoid system is highly implicated in the development of insulin resistance associated with obesity. It has been shown that antagonism of the CB(1) receptor improves insulin sensitivity (S(I)). However, it is unknown whether this improvement is due to the direct effect of CB(1) blockade on peripheral tissues or secondary to decreased fat mass. Here, we examine in the canine dog model the longitudinal changes in S(I) and fat deposition when obesity was induced with a high-fat diet (HFD) and animals were treated with the CB(1) antagonist rimonabant. S(I) was assessed (n = 20) in animals fed a HFD for 6 wk to establish obesity. Thereafter, while HFD was continued for 16 additional weeks, animals were divided into two groups: rimonabant (1.25 mg·kg(-1)·day(-1) RIM; n = 11) and placebo (n = 9). Euglycemic hyperinsulinemic clamps were performed to evaluate changes in insulin resistance and glucose turnover before HFD (week -6) after HFD but before treatment (week 0) and at weeks 2, 6, 12, and 16 of treatment (or placebo) + HFD. Magnetic resonance imaging was performed to determine adiposity- related changes in S(I). Animals developed significant insulin resistance and increased visceral and subcutaneous adiposity after 6 wk of HFD. Treatment with RIM resulted in a modest decrease in total trunk fat with relatively little change in peripheral glucose uptake. However, there was significant improvement in hepatic insulin resistance after only 2 wk of RIM treatment with a concomitant increase in plasma adiponectin levels; both were maintained for the duration of the RIM treatment. CB(1) receptor antagonism appears to have a direct effect on hepatic insulin sensitivity that may be mediated by adiponectin and independent of pronounced reductions in body fat. However, the relatively modest effect on peripheral insulin sensitivity suggests that significant improvements may be secondary to reduced fat mass.

Topics: Abdominal Fat; Adiponectin; Animals; Blood Glucose; Body Composition; Cannabinoid Receptor Antagonists; Dietary Fats; Disease Models, Animal; Dogs; Energy Intake; Fatty Acids, Nonesterified; Glucose Clamp Technique; Insulin; Insulin Resistance; Liver; Male; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

1. The aim of the present study was to determine whether the addition of a subeffective dose of rimonabant (1 mg/kg) to orlistat would be beneficial in the treatment of diet-induced obesity in rats compared with orlistat monotherapy. 2. Male rats were divided into five groups: (i) rats fed a low-fat diet for 4 months; (ii) rats fed a high-fat diet (HFD) for 4 months and treated daily with vehicle (0.2% Tween-80 solution); (iii) orlistat (10 mg/kg per day)-treated HFD-fed rats; (iv) rimonabant (1 mg/kg per day)-treated HFD-fed rats; and (v) HFD-fed rats treated with a combination of orlistat plus rimonabant. Fasting blood glucose, serum insulin, leptin and adiponectin levels were measured. Liver and adiposity indices were calculated and liver and adipose tissues were processed for histological examination. 3. Over the 4 months of the study, vehicle-treated HFD-fed rats exhibited increased cumulative food intake, bodyweight and liver and adiposity indices. Moreover, vehicle-treated HFD-fed rats exhibited a deterioration in liver function and an abnormal lipid profile. Insulin resistance and serum leptin were increased in this group, whereas serum adiponectin levels were decreased. Orlistat monotherapy or combination therapy with orlistat plus rimonabant improved all these parameters. 4. The addition of the low subeffective dose of rimonabant to orlistat therapy ameliorated HFD-induced obesity to a much greater extent than orlistat monotherapy. This combination showed better weight control and metabolic profile compared with orlistat alone. Therefore, the results of the present study encourage reassessment of the use of a low dose of rimonabant to potentiate the effect of orlistat in the clinical management of obesity if proper clinical safety data are available.

Topics: Adiposity; Animals; Anti-Obesity Agents; Body Weight; Diet, High-Fat; Dose-Response Relationship, Drug; Drug Therapy, Combination; Lactones; Male; Obesity; Orlistat; Piperidines; Pyrazoles; Rats; Rats, Wistar; Rimonabant; Weight Gain

Topics: Adolescent; Adult; Advisory Committees; Aged; Anti-Obesity Agents; Bariatric Medicine; Body Mass Index; Child; Congresses as Topic; Cyclobutanes; Diabetes Mellitus, Type 2; Drug Approval; Drug Discovery; Female; History, 20th Century; History, 21st Century; Humans; Male; Middle Aged; Multicenter Studies as Topic; Obesity; Outcome Assessment, Health Care; Piperidines; Practice Guidelines as Topic; Pyrazoles; Randomized Controlled Trials as Topic; Reference Standards; Rimonabant; Safety-Based Drug Withdrawals; United States; United States Food and Drug Administration

Central and peripheral mechanisms modulate food intake and energy balance in mammals and the precise role of the type 1 cannabinoid receptor (CB1) in these processes is still being explored. Using the zebrafish, Danio rerio, we show that rimonabant, a CB1-specific antagonist with an EC(50) of 5.15 × 10(-8) m, decreases embryonic yolk sac reserve use. We reveal a developmental overlap between CART genes and CB1 expression in the hypothalamus and medulla oblongata, two brain structures that play crucial roles in appetite regulation in mammals. We show that morpholino knockdown of CB1 or fasting decreases cocaine- and amphetamine-related transcript (CART)-3 expression. Strikingly, this down-regulation occurs only in regions coexpressing CB1 and CART3, reinforcing the link between CB1, CART, and appetite regulation. We show that rimonabant treatment impairs the fasting-induced down-regulation of CART expression in specific brain regions, whereas vehicle alone-treated embryos do not display this rescue of CART expression. Our data reveal that CB1 lies upstream of CART and signals the appetite through the down-regulation of CART expression. Thus, our results establish the zebrafish as a promising system to study appetite regulation.

Topics: Animals; Appetite Regulation; Brain; Cannabinoid Receptor Agonists; Down-Regulation; Food Deprivation; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Larva; Molecular Sequence Data; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Yolk Sac; Zebrafish

The present work aims to study the effects induced by a chronic treatment with a novel CB1 antagonist (NESS038C6) in C57BL/6N diet-induced obesity (DIO) mice. Mice treated with NESS038C6 and fed with a fat diet (NESS038C6 FD) were compared with the following three reference experimental groups: DIO mice fed with the same fat diet used for NESS038C6 and treated with vehicle or the reference CB1 antagonist/inverse agonist rimonabant, "VH FD" and "SR141716 FD", respectively; DIO mice treated with vehicle and switched to a normal diet (VH ND). NESS038C6 chronic treatment (30 mg/kg/day for 31 days) determined a significant reduction in DIO mice weight relative to that of VH FD. The entity of the effect was comparable to that detected in both SR141716 FD and VH ND groups. Moreover, if compared to VH FD, NESS038C6 FD evidenced: (i) improvement of cardiovascular risk factors; (ii) significant decrease in adipose tissue leptin expression; (iii) increase in mRNA expression of hypothalamic orexigenic peptides and a decrease of anorexigenic peptides; (iv) expression increase of metabolic enzymes and peroxisome proliferator-activated receptor-α in the liver; (v) normalization of monoaminergic transporters and neurotrophic expression in mesolimbic area. However, in contrast to the case of rimonabant, the novel CB1 antagonist improved the disrupted expression profile of genes linked to the hunger-satiety circuit, without altering monoaminergic transmission. In conclusion, the novel CB1 antagonist compound NESS038C6 may represent a useful candidate agent for the treatment of obesity and its metabolic complications, without or with reduced side effects relative to those instead observed with rimonabant.

Topics: Analysis of Variance; Animals; Anti-Obesity Agents; Blood Glucose; Body Mass Index; Body Weight; Brain-Derived Neurotrophic Factor; Cannabinoid Receptor Antagonists; Cholesterol; Dietary Fats; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Gene Expression Regulation; Hypothalamus; Indazoles; Intra-Abdominal Fat; Liver; Male; Mice; Mice, Inbred C57BL; Nerve Growth Factor; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Serotonin Plasma Membrane Transport Proteins; Thiophenes; Transaminases; Triglycerides

G-protein coupled receptor 26 (GPR26) is a brain-specific orphan GPCR with high expression in the brain region that controls satiety. Depletion of GPR26 has been shown to increase fat storage in C. elegans, whereas GPR26 deficiency in the hypothalamus is associated with high genetic susceptibility to the onset of obesity in mice. However, the metabolic function of GPR26 in mammals remains elusive. Herein, we investigated a role of GPR26 in regulating energy homeostasis by generating mice with targeted deletion of the GPR26 gene. We show that GPR26 deficiency causes hyperphagia and hypometabolism, leading to early onset of diet-induced obesity. Accordingly, GPR26 deficiency also caused metabolic complications commonly associated with obesity, including glucose intolerance, hyperinsulinemia, and dyslipidemia. Moreover, consistent with hyperphagia in GPR26 null mice, GPR26 deficiency significantly increased hypothalamic activity of AMPK, a key signaling event that stimulates appetite. In further support of a regulatory role of GPR26 in satiety, GPR26 knockout mice also demonstrate hypersensitivity to treatment of rimonabant, an endocannabinoid receptor-1 antagonist commonly used to treat obesity by suppressing appetite in humans. Together, these findings identified a key role of GPR26 as a central regulator of energy homeostasis though modulation of hypothalamic AMPK activation.

Topics: Adiposity; AMP-Activated Protein Kinases; Animals; Diet; Dyslipidemias; Energy Metabolism; Enzyme Activation; Gene Silencing; Gene Targeting; Glucose Intolerance; Hyperinsulinism; Hyperphagia; Hypothalamus; Mice; Mice, Inbred C57BL; Obesity; Phosphorylation; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Rimonabant; Weight Loss

Weight loss is often difficult to achieve in individuals with type 2 diabetes and anti-obesity drugs are often advocated to support dietary intervention. Despite the extensive use of centrally acting anti-obesity drugs, there is little evidence of how they affect dietary composition. We investigated changes in energy intake and dietary composition of macro- and micronutrients following therapy with the endocannabinoid receptor blocker, rimonabant.. 20 obese patients with type 2 diabetes were studied before and after 6 months dietary intervention with rimonabant. Dietary intervention was supervised by a diabetes dietician. Five-day food diaries were completed at baseline and at 6 months and dietary analysis was performed using computer software (Dietplan 6).. After 6 months, (compared with baseline) there were reductions in weight (107 ± 21Kg versus 112 ± 21, p < 0.001, 4% body weight reduction), and improvements in HbA1c (7.4 ± 1.7 versus 8.0 ± 1.6%, p < 0.05) and HDL cholesterol. Intake of energy (1589 ± 384 versus 2225 ± 1109 kcal, p < 0.01), carbohydrate (199 ± 74 versus 273 ± 194 g, p < 0.05), protein (78 ± 23 versus 98 ± 36 g, p < 0.05), fats (55 ± 18 versus 84 ± 39 g, p < 0.01) and several micronutrients were reduced. However, relative macronutrient composition of the diet was unchanged. Improvement in blood glucose was strongly correlated with a reduction in carbohydrate intake (r = 0.76, p < 0.001).. In obese patients with type 2 diabetes, rimonabant in combination with dietary intervention led to reduced intake of energy and most macronutrients. Despite this, macronutrient composition of the diet was unaltered. These dietary changes (especially carbohydrate restriction) were associated with weight loss and favourable metabolic effects.

Topics: Adult; Aged; Blood Glucose; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Diet; Dietary Carbohydrates; Dietary Fats; Energy Intake; Female; Humans; Male; Micronutrients; Middle Aged; Obesity; Piperidines; Pyrazoles; Regression Analysis; Rimonabant; Weight Loss

Activation of the glucagon-like peptide (GLP)-1 receptor (GLP-1R) and inhibition of dipeptidyl peptidase-4 (DPP-4) are new antidiabetic strategies. The GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they may regulate Na(+) reabsorption. Exendin-4 (EX4) is a naturally occurring antidiabetic polypeptide (from the saliva of the lizard Heloderma suspectum) and GLP-1R agonist; however, part of its nonglucoregulatory effects are through GLP-1R-independent mechanisms. DPP-4 cleaves and inactivates GLP-1; thus the natriuretic effect of DPP-4 inhibition may be mediated by the GLP-1R. We report that parenteral application of EX4 in wild-type mice induced a diuresis and natriuresis associated with increases in glomerular filtration rate, fractional urinary fluid and Na(+) excretion, and renal membrane expression of the Na(+)/H(+) exchanger NHE3 phosphorylated at S552 and S605, established consensus sites for cAMP-dependent PKA. These effects were absent in mice lacking the GLP-1R and independent of adenylyl cyclase 6. In comparison, parenteral application of the DPP-4 inhibitor alogliptin reduced plasma DPP-4 activity by 95% and induced a diuresis and natriuresis independent of the presence of the GLP-1R or changes in phosphorylated NHE3. The inhibitory effect on renal fluid and Na(+) reabsorption of EX4, but not alogliptin, was preserved in diabetic db/db mice and associated with a modest reduction in blood pressure. These results reveal mechanistic differences in how EX4 vs. DPP-4 inhibition induces diuresis and natriuresis under normal states, with preservation of GLP-1R-mediated, but not DPP-4 inhibitor-dependent, natriuretic mechanisms in a mouse model of obese type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Kidney; Mice; Mice, Knockout; Natriuresis; Natriuretic Agents; Obesity; Peptides; Phosphorylation; Piperidines; Receptors, Glucagon; Uracil; Venoms

Obesity, a worldwide health problem, is a metabolic disease currently associated with a cluster and progressive pathologies presenting several features of metabolic syndrome.. The present study was undertaken to investigate the effect of rimonabant, simvastatin and their combination on obesity associated metabolic disorder mediators in adult male rats.. Fifty adult male Wistar rats weighing (120 +/- 10 g) were divided into five groups: Group 1 was kept on standard rodent chow and served as normal diet control. Group 2 was given high fat diet (HFD) for twenty weeks and served as HFD control. Groups 3, 4 and 5 administered HFD for ten weeks and then orally received rimonabant (2 mg/kg/day), simvastatin (10 mg/kg/day), combination of both drugs, respectively for another ten weeks with continuing feeding HFD.. The current results showed that the treatment of HFD rats with either rimonabant or simvastatin significantly reduced body mass index, total cholesterol, triacylglycerides, low density lipoproteins, tumor necrosis factor alpha and monocyte chemoattractant protein-1, while increased adiponectin serum levels. Rimonabant showed to be more effective than simvastatin. Moreover, concomitant administration of rimonabant and simvastatin achieved the highest effect which nearly normalized most of the studied parameters as compared to singular therapy.. Rimonabant is the drug of primary choice as singular therapy for obesity. The adjunct therapy of rimonabant with simvastatin may be a novel and a promising therapeutic approach as it has a beneficial effect on the pathophysiological processes of obesity and its associated metabolic disorders.

Topics: Animals; Chemokine CCL2; Lipids; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Rimonabant; Risk Factors; Simvastatin; Tumor Necrosis Factor-alpha

The synthesis of three series of novel 4-alkyl-5-(5'-chlorothiophen-2'-yl)-pyrazole-3-carbamoyl analogues of rimonabant with affinity for the CB1 cannabinoid receptor subtype is reported. Amongst the novel derivatives, compounds 21j, 22a, 22c, and 22f showed affinity values expressed as Ki ranging from 5.5 to 9.0 nM. Derivative 23e revealed a good CB1 affinity (K(i) = 11.7 nM) and the highest CB1 selectivity of the whole series (K(i)CB2/K(i)CB1 = 384.6). These new compounds appeared to be able to pass the blood brain barrier and to counteract the activity of cannabinoid agonist. According to the results of mice vas deferens assays, as in the case of rimonabant, derivatives 21a, 22a, and 22b showed inverse agonist activity. In contrast, as a preliminary result to be confirmed, compound 23a exhibited neutral antagonist profile. According to the data obtained through an acute animal model, selected compounds 21a, 22a, and 23a evidenced the capability to significantly reduce food intake. At specific conditions, the effect of the novel compounds were higher than that induced by rimonabant. Amongst the novel CB1 antagonist compounds, 23a may represent a useful candidate agent for the treatment of obesity and its metabolic complications, with reduced side effects relative to those instead observed with rimonabant.

Topics: Animals; Appetite Depressants; Blood-Brain Barrier; Body Temperature; Cannabinoid Receptor Antagonists; Drug Evaluation, Preclinical; Eating; Gastrointestinal Transit; Male; Mice; Molecular Structure; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Structure-Activity Relationship; Vas Deferens

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes investigated in efforts to overcome hERG liabilities while having orally active, potent and selective compounds with sufficient brain penetration. A chemometric comparison of ∼2000 diverse MCHR1 and ∼1000 diverse hERG ligands underline the structural similarities. A binding pocket analysis of a MCHR1 model and recent X-ray structures of GPCRs invoked in selectivity issues indicate a way to support future drug design.

Topics: Anti-Obesity Agents; Biphenyl Compounds; Crystallography, X-Ray; Drug Design; Ether-A-Go-Go Potassium Channels; Humans; Models, Molecular; Molecular Structure; Naphthalenes; Obesity; Piperidines; Pyrimidines; Receptors, Somatostatin; Structure-Activity Relationship

Nonalcoholic fatty liver disease (NAFLD), one of chronic liver diseases, seems to be rising as the obesity epidemic continues. In this study, 54 novel (thio)barbituric acid derivatives have been synthesized and evaluated for pharmacological activity. 7h exhibited potent glucose-lowering effects on insulin-resistant HepG2 cells and regulated adiponectin and leptin expression in 3T3-L1 adipocytes. Oral administration of 7h at 25 mg kg(-1) day(-1) for 4 weeks improved the progression of high fat diet-induced NAFLD by reducing the weight of body, liver, and fat, as well as modulating serum levels of fasting glucose, insulin, triglycerides, LDL-c, ALT, adiponectin and hepatic contents of triglycerides, total cholesterol. H&E stainings revealed that 7h blocked fat deposition in liver and the increase of adipocyte number and size in adipose tissues from NAFLD. Furthermore, treatment with 7h alleviated the obese clinical symptoms, recovered serum biomarkers to appropriate ranges, and improved glucose tolerance by OGTT and IGTT in DIO mice.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Alanine Transaminase; Animals; Barbiturates; Body Weight; Cholesterol; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Female; Glucose; Glucose Tolerance Test; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Tissue Distribution; Triglycerides

Early treatment discontinuation will have a negative effect on a drug's benefit-risk profile if discontinuation occurs earlier in time than the positive effects of treatment. This non-persistence of therapy has been associated with an increased risk of adverse health outcomes.. The aim of this study was to explore relationships between patient characteristics and reasons for and time to discontinuation of rimonabant therapy, focusing on psychiatric events, because these were the main safety concerns for rimonabant.. A modified prescription-event monitoring (M-PEM) study was conducted for rimonabant. Descriptive statistics were used to describe the patient population. Rate ratios with 95% confidence intervals (CIs) were calculated to explore associations between patient characteristics and selected categories of reasons for stopping (RfS). Median times to discontinuation were compared using the Mann-Whitney U test.. The cohort comprised 10,011 users of rimonabant, three of which were excluded from this analysis because of missing age or sex. A total of 7204 patients (72.0%) stopped using rimonabant (median observation time 323 days, interquartile range: 279-371 days). In addition, patients with a history of psychiatric illness were more likely to discontinue rimonabant therapy early for all reasons, but most pronounced due to psychiatric events (rate ratio 1.79; 95% CI 1.54, 2.09) than those without a history of psychiatric illness. In contrast, the rates of discontinuation due to lack of effectiveness, any clinical events and psychiatric events in patients with cardiovascular disease, type 2 diabetes mellitus, dyslipidaemia or hypertension tended to be lower (not all being significant) than those without. For patients who discontinued treatment due to lack of effectiveness, the median time to discontinuation was significantly shorter for patients with a history of psychiatric illness, compared with patients without a history of psychiatric illness (86 vs 97 days, p = 0.03). For patients discontinuing treatment due to psychiatric events, the difference in median time to discontinuation was also 11 days (64 vs 75 days, p = 0.38), although not statistically significant. For patients stopping due to any clinical event, median time to discontinuation was comparable for patients with and without a history of psychiatric illness (61 vs 63 days, p = 0.90).. In this study, reasons for and time to discontinuation were associated with patient characteristics such as medical history. Patients discontinued treatment because of psychiatric events early after starting. In general, identification and characterization of early discontinuers, and increasing the understanding of reasons for stopping, may help healthcare professionals to develop targeted interventions to further improve treatment compliance, thereby optimizing treatment benefits and drug safety.

Topics: Adult; Body Mass Index; Cannabinoid Receptor Antagonists; Cohort Studies; Drug Monitoring; Drug Prescriptions; Female; Humans; Male; Mental Disorders; Middle Aged; Obesity; Patient Compliance; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Substance Withdrawal Syndrome; Time Factors

We studied whether cannabinoid receptor (CB1) blockade with rimonabant has an anti-inflammatory effect in obese mice, and whether this effect depends on weight loss and/or diet consumption. High-fat diet (HFD)-induced obese mice were treated orally with rimonabant (HFD-R) or vehicle (HFD-V) for 4 weeks. Paired-feeding was conducted in two additional groups of obese mice to achieve either the same body weight (HFD-BW) or the same HFD intake (HFD DI) as HFD-R. All these groups of mice were maintained on HFD throughout, with mice on normal diet (ND) throughout as lean controls. Rimonabant treatment of obese mice induced marked diet-intake reduction and weight loss during the first week, which was followed by maintenance of low body weight but not diet-intake reduction. Lower HFD intake was required to reach the same degree of weight loss in HFD-BW. HFD-DI had similar weight loss initially, but then started to gain weight, reaching a higher body weight than HFD-R. Despite the same degree of weight loss, HFD-R had less fat mass and lower adipogenic gene expression than HFD-BW. Compared to HFD-V or HFD-DI, HFD-R had reduced inflammation in adipose tissue (AT) and/or liver indicated primarily by lower monocyte chemoattractant protein-1 (MCP-1) levels. However, MCP-1 levels were not significantly different between HFD-R and HFD-BW. In vitro incubation of rimonabant with AT explants did not change MCP-1 levels. Thus, rimonabant induced weight loss in obese mice by diet-intake-dependent and -independent fashions. Rimonabant decreased inflammation in obese mice, possibly through a primary effect on weight reduction.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Chemokine CCL2; Diet; Dietary Fats; Disease Models, Animal; Energy Intake; Inflammation; Liver; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Weight Gain; Weight Loss

This study investigates the molecular mechanisms and the center-periphery cross talk underlying the anti-obesity effect of the cannabinoid receptor 1 (CB(1)) antagonist/inverse agonist rimonabant in diet-induced obese (DIO) mice exposed to a 31 days chronic treatment with the drug. Present data showed a significant and stable weight loss both in animals treated with rimonabant 10mg/kg by oral gavage exposed to a high fat diet (SRFD) and in vehicle treated mice switched to a regular chow (VEND) with respect to vehicle fat diet fed mice (VEFD). Caloric intake was significantly lowered in SRFD and VEND during the first two and four days, respectively, then reaching the VEFD consume throughout the treatment. The drop of body weight was accompanied by leptin mRNA decrease in visceral fat tissue both in VEND and SRFD, as revealed by Real time PCR analysis. No difference in CB(1) mRNA receptor expression in hypothalamus and in visceral fat tissue among groups was observed. Leptin receptors were decreased in the hypothalamus of SRFD but not of VEND mice. Moreover, in SRFD and VEND mice the expression of orexigenic genes Neuropeptide Y and Agouti Related Protein (AGRP) was increased, while anorexigenic ones, Pro-OpioMelanoCortin (POMC) and Cocaine-and-Amphetamine-Regulated Transcript (CART) displayed no alteration in any group. This data contribute to clarify the molecular basis of the anti-obesity properties of rimonabant, underlying the role of the peripheral modulators which affect central circuits involved in the regulation of food intake and energy homeostasis.

Topics: Analysis of Variance; Animals; Body Weight; Diet; Disease Models, Animal; Gene Expression Regulation; Hypothalamus; Leptin; Mice; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; Signal Transduction

Topics: Humans; Hypoglycemic Agents; Metformin; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

In eight studies included in the present Cochrane review the effects of orlistat or sibutramine versus placebo on mortality, cardiovascular mortality and adverse events were investigated in obese people with hypertension. No studies with rimonabant fulfilled the inclusion criteria. The weight loss was larger in the groups treated with orlistat or sibutramine compared with placebo therapy. Orlistat reduced systolic and diastolic blood pressure more than placebo, while blood pressure increased during treatment with sibutramine. The studies were too small and of too short duration to allow an evaluation of the effect on cardiovascular mortality and morbidity.

Topics: Adult; Anti-Obesity Agents; Appetite Depressants; Blood Pressure; Cardiovascular Diseases; Cyclobutanes; Evidence-Based Medicine; Humans; Hypertension; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Time Factors; Treatment Outcome; Weight Loss

Endocannabinoid signalling participates in the control of neurogenesis, especially after brain insults. Obesity may explain alterations in physiology affecting neurogenesis, although it is unclear whether cannabinoid signalling may modulate neural proliferation in obese animals. Here we analyse the impact of obesity by using two approaches, a high-fat diet (HFD, 60% fat) and a standard/low-fat diet (STD, 10% fat), and the response to a subchronic treatment with the cannabinoid receptor type 1 (CB1) inverse agonist AM251 (3 mg/kg) on cell proliferation of two relevant neurogenic regions, namely the subventricular zone in the striatal wall of the lateral ventricle (SVZ) and the subgranular zone of the dentate gyrus (SGZ), and also in the hypothalamus given its role in energy metabolism. We found evidence of an interaction between diet-induced obesity and CB1 signalling in the regulation of cell proliferation. AM251 reduced caloric intake and body weight in obese rats, as well as corrected plasma levels of cholesterol and triglycerides. AM251 is shown, for the first time, to modulate cell proliferation in HFD-obese rats only. We observed an increase in the number of 5-bromo-2-deoxyuridine-labelled (BrdU+) cells in the SGZ, but a decrease in the number of BrdU+ cells in the SVZ and the hypothalamus of AM251-treated HFD rats. These BrdU+ cells expressed the neuron-specific βIII-tubulin. These results suggest that obesity may impact cell proliferation in the brain selectively, and provide support for a role of CB1 signalling regulation of neurogenesis in response to obesity.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Cannabinoid Receptor Modulators; Cell Proliferation; Cholesterol; Dietary Fats; Energy Intake; Female; Insulin; Leptin; Male; Neurogenesis; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Triglycerides

To provide feedback on the initial market authorization of rimonabant, a drug to be used under strict guidelines, we conducted a study with information from the National health insurance reimbursements database for southeastern France. The aims of this study were to: (1) describe the characteristics of subjects who have had one rimonabant prescription reimbursed; (2) study the frequency of prescriptions that did not comply with reimbursement criteria; (3) study the frequency of prescriptions for patients simultaneously treated with antidepressants; and (4) analyse the factors associated with both types of prescription (patient and prescriber characteristics).. Using the database of drug reimbursements maintained by the southeastern France general health insurance fund, we studied the characteristics of outpatients with at least one reimbursement for rimonabant, compared them to the rest of the population, and analysed compliance with the indications, contraindications, and regulations for rimonabant prescription with multivariate logistic regressions.. A total of 10,510 beneficiaries (0.28%) had at least one rimonabant reimbursement. Among them, 55.7% were treated for diabetes. For at least 62.4% of rimonabant beneficiaries, the reimbursement regulations were not respected: this was significantly more frequent among women less than 57 years old, subjects with no chronic diseases, and when the prescriber was not an endocrinologist; 11.4% of rimonabant beneficiaries also received an antidepressant treatment.. Despite the specific status of rimonabant regarding its reimbursement modalities, these results suggest that some prescribers get around reimbursement instructions and that a significant percentage of prescriptions did not respect an important contraindication. Tools to follow up the prescriptions of new drugs with strict guidelines for use should be developed and physicians should be better informed and trained regarding specific prescription regulations.

Topics: Adult; Antidepressive Agents; Body Mass Index; Depressive Disorder; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Prescriptions; Feedback; Female; France; Humans; Insurance, Health, Reimbursement; Logistic Models; Male; Middle Aged; Obesity; Piperidines; Practice Guidelines as Topic; Pyrazoles; Retrospective Studies; Rimonabant

Topics: Adipose Tissue; Body Weight; Cannabinoid Receptor Modulators; Dietary Fats; Eating; Endocannabinoids; Neurogenesis; Neurons; Obesity; Piperidines; Pyrazoles

Retinol-binding protein 4 (RBP4) is an adipocyte-secreted hormone proposed to link obesity with insulin resistance. However, the role of RBP4 in cardiovascular complications is yet to be fully understood. The present study is aimed to decipher the association between RBP4 with pro-inflammatory cytokines and low-density lipoprotein (LDL) cholesterol in diet-induced obese and hyperlipidaemic mice. To understand the correlation, rimonabant, an anti-obesity drug, has been used to relieve the atherosclerotic predisposition.. Adipose and/or aortic tissue expressions of RBP4, pro-inflammatory cytokine genes and circulating LDL levels were measured in high fat (HF)-fed female C57BL/6 and high cholesterol (HC)-fed apolipoprotein E3 (ApoE3) Leiden mice.. Mice fed a HF diet had a significantly increased adipose expression of RBP4, TNF-α and monocyte chemoattractant protein 1 (MCP-1) and down-regulated adiponectin mRNA levels. A significant increase in aortic RBP4 and MCP-1 expression and circulating levels of LDL and C-reactive protein (CRP) was found in the ApoE3 mice fed a HC diet. Interestingly, rimonabant treatment lowered the elevated aortic RBP4, MCP-1 expressions and significantly reduced the serum levels of LDL, CRP, RBP4 and MCP-1.. Our results indicate that RBP4 is positively associated with markers of inflammation in obese and pro-atherogenic conditions and could play a role in a predisposition to atherosclerosis. Furthermore, our results indicate that rimonabant may improve vascular function by modulating RBP4 along with pro-inflammatory cytokines.

Topics: 3T3-L1 Cells; Adipokines; Animals; Apolipoprotein E3; Atherosclerosis; Base Sequence; Cardiovascular Diseases; Cholesterol; DNA Primers; Female; Gene Expression Regulation; Hypercholesterolemia; Inflammation; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Real-Time Polymerase Chain Reaction; Retinol-Binding Proteins, Plasma; Rimonabant

The fruits of Piper retrofractum Vahl. have been used for their anti-flatulent, expectorant, antitussive, antifungal, and appetizing properties in traditional medicine, and they are reported to possess gastroprotective and cholesterol-lowering properties. However, their anti-obesity activity remains unexplored. The present study was conducted to isolate the anti-obesity constituents from P. retrofractum Vahl. and evaluate their effects in high-fat diet (HFD)-induced obese mice. Piperidine alkaloids from P. retrofractum Vahl. (PRPAs), including piperine, pipernonaline, and dehydropipernonaline, were isolated as the anti-obesity constituents through a peroxisome proliferator-activated receptor δ (PPARδ) transactivation assay. The molecular mechanism was investigated in 3T3-L1 adipocytes and L6 myocytes. PRPA treatment activated AMP-activated protein kinase (AMPK) signaling and PPARδ protein and also regulated the expression of lipid metabolism-related proteins. In the animal model, oral PRPA administration (50, 100, or 300mg/kg/day for 8weeks) significantly reduced HFD-induced body weight gain without altering the amount of food intake. Fat pad mass was reduced in the PRPA treatment groups, as evidenced by reduced adipocyte size. In addition, elevated serum levels of total cholesterol, low-density lipoprotein cholesterol, total lipid, leptin, and lipase were suppressed by PRPA treatment. PRPA also protected against the development of nonalcoholic fatty liver by decreasing hepatic triglyceride accumulation. Consistent with the in vitro results, PRPA activated AMPK signaling and altered the expression of lipid metabolism-related proteins in liver and skeletal muscle. Taken together, these findings demonstrate that PRPAs attenuate HFD-induced obesity by activating AMPK and PPARδ, and regulate lipid metabolism, suggesting their potential anti-obesity effects.

Topics: 3T3 Cells; Adiposity; Alkaloids; AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; Chlorocebus aethiops; COS Cells; Diet; Dietary Fats; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Piper; Piperidines; PPAR delta; Rats; Weight Gain

Cannabinoid receptor CB1 is expressed abundantly in the brain and presumably in the peripheral tissues responsible for energy metabolism. It is unclear if the antiobesity effects of rimonabant, a CB1 antagonist, are mediated through the central or the peripheral CB1 receptors. To address this question, we generated transgenic mice with central nervous system (CNS)-specific knockdown (KD) of CB1, by expressing an artificial microRNA (AMIR) under the control of the neuronal Thy1.2 promoter. In the mutant mice, CB1 expression was reduced in the brain and spinal cord, whereas no change was observed in the superior cervical ganglia (SCG), sympathetic trunk, enteric nervous system, and pancreatic ganglia. In contrast to the neuronal tissues, CB1 was undetectable in the brown adipose tissue (BAT) or the liver. Consistent with the selective loss of central CB1, agonist-induced hypothermia was attenuated in the mutant mice, but the agonist-induced delay of gastrointestinal transit (GIT), a primarily peripheral nervous system-mediated effect, was not. Compared to wild-type (WT) littermates, the mutant mice displayed reduced body weight (BW), adiposity, and feeding efficiency, and when fed a high-fat diet (HFD), showed decreased plasma insulin, leptin, cholesterol, and triglyceride levels, and elevated adiponectin levels. Furthermore, the therapeutic effects of rimonabant on food intake (FI), BW, and serum parameters were markedly reduced and correlated with the degree of CB1 KD. Thus, KD of CB1 in the CNS recapitulates the metabolic phenotype of CB1 knockout (KO) mice and diminishes rimonabant's efficacy, indicating that blockade of central CB1 is required for rimonabant's antiobesity actions.

Topics: Adiponectin; Adiposity; Animals; Anti-Obesity Agents; Biomarkers; Body Weight; Central Nervous System; Cholesterol; Diet, High-Fat; Energy Intake; Gastrointestinal Transit; Hypothermia; Insulin; Leptin; Mice; Mice, Knockout; Mice, Transgenic; MicroRNAs; Mutation; Obesity; Peripheral Nervous System; Phenotype; Piperidines; Promoter Regions, Genetic; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Triglycerides

Adipocyte size plays a key role in the development of insulin resistance. We examined longitudinal changes in adipocyte size and distribution in visceral (VIS) and subcutaneous (SQ) fat during obesity-induced insulin resistance and after treatment with CB-1 receptor antagonist, rimonabant (RIM) in canines. We also examined whether adipocyte size and/or distribution is predictive of insulin resistance. Adipocyte morphology was assessed by direct microscopy and analysis of digital images in previously studied animals 6 weeks after high-fat diet (HFD) and 16 weeks of HFD + placebo (PL; n = 8) or HFD + RIM (1.25 mg/kg/day; n = 11). At 6 weeks, mean adipocyte diameter increased in both depots with a bimodal pattern only in VIS. Sixteen weeks of HFD+PL resulted in four normally distributed cell populations in VIS and a bimodal pattern in SQ. Multilevel mixed-effects linear regression with random-effects model of repeated measures showed that size combined with share of adipocytes >75 µm in VIS only was related to hepatic insulin resistance. VIS adipocytes >75 µm were predictive of whole body and hepatic insulin resistance. In contrast, there was no predictive power of SQ adipocytes >75 µm regarding insulin resistance. RIM prevented the formation of large cells, normalizing to pre-fat status in both depots. The appearance of hypertrophic adipocytes in VIS is a critical predictor of insulin resistance, supporting the deleterious effects of increased VIS adiposity in the pathogenesis of insulin resistance.

Topics: Adipocytes; Adiposity; Animals; Cell Size; Diet, High-Fat; Dogs; Insulin Resistance; Intra-Abdominal Fat; Linear Models; Male; Models, Animal; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

To characterize the biological profiles of MJ08, a novel selective CB(1) receptor antagonist.. Radioligand binding assays were performed using rat brain and spleen membrane preparations. CB(1) and CB(2) receptor redistribution and intracellular Ca(2+) ([Ca(2+)](i)) assays were performed with IN CELL Analyzer. Inverse agonism was studied using intracellular cAMP assays, and in guinea-pig ileum and mouse vas deferens smooth muscle preparations. In vivo pharmacologic profile was assessed in diet-induced obesity (DIO) mice.. In radioligand binding assay, MJ08 selectively antagonized CB(1) receptor (IC(50)=99.9 nmol/L). In EGFP-CB(1)_U2OS cells, its IC(50) value against CB(1) receptor activation was 30.23 nmol/L (SR141716A: 32.16 nmol/L). WIN 55,212-2 (1 μmol/L) increased [Ca(2+)](i) in the primary cultured hippocampal neuronal cells and decreased cAMP accumulation in CHO-hCB(1) cells. MJ08 (10 nmol/L-10 μmol/L) blocked both the WIN 55,212-2-induced effects. Furthermore, MJ08 reversed the inhibition of electrically evoked twitches of mouse vas deferens by WIN 55,212-2 (pA(2)=10.29±1.05). MJ08 and SR141716A both showed an inverse agonism activity by markedly promoting the contraction force and frequency of guinea pig ileum muscle. MJ08 significantly increased the cAMP level in CHO-hCB(1) cells with an EC(50) value of 78.6 nmol/L, which was lower than the EC(50) value for SR141716A (159.2 nmol/L). Besides the more potent pharmacological effects of cannabinoid CB(1) receptor antagonism in DIO mice, such as reducing food intake, decreasing body weight, and ameliorating dyslipidemia, MJ08 (10 mg/kg) unexpectedly raised the fasted blood glucose in vivo.. MJ08 is a novel, potent and selective CB(1) receptor antagonist/inverse agonist with potent bioactive responses in vitro and in vivo that may be useful for disclosure the versatile nature of CB(1) receptors.

Topics: Animals; Calcium Signaling; Cell Line; Cell Membrane; Cyclic AMP; Dyslipidemias; Guinea Pigs; Ileum; Male; Mice; Mice, Inbred C57BL; Muscle Contraction; Muscle, Smooth; Neurons; Obesity; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Vas Deferens

Pharmacologic antagonism of cannabinoid 1 receptors (CB1 receptors) in the central nervous system (CNS) suppresses food intake, promotes weight loss, and improves the metabolic profile. Since the CB1 receptor is expressed both in the CNS and in peripheral tissues, therapeutic value may be gained with CB1 receptor inverse agonists acting on receptors in both domains. The present report examines the metabolic and CNS actions of a novel CB1 receptor inverse agonist, compound 64, a 1,5,6-trisubstituted pyrazolopyrimidinone. Compound 64 showed similar or superior binding affinity, in vitro potency, and pharmacokinetic profile compared to rimonabant. Both compounds improved the metabolic profile in diet-induced obese (DIO) rats and obese cynomolgus monkeys. Weight loss tended to be greater in compound 64-treated DIO rats compared to pair-fed counterparts, suggesting that compound 64 may have metabolic effects beyond those elicited by weight loss alone. In the CNS, reversal of agonist-induced hypothermia and hypolocomotion indicated that compound 64 possessed an antagonist activity in vivo. Dosed alone, compound 64 suppressed extinction of conditioned freezing (10 mg/kg) and rapid eye movement (REM) sleep (30 mg/kg), consistent with previous reports for rimonabant, although for REM sleep, compound 64 was greater than threefold less potent than for metabolic effects. Together, these data suggested that (1) impairment of extinction learning and REM sleep suppression are classic, centrally mediated responses to CB1 receptor inverse agonists, and (2) some separation may be achievable between central and peripheral effects with brain-penetrating CB1 receptor inverse agonists while maintaining metabolic efficacy. Furthermore, chronic treatment with compound 64 contributes to evidence that peripheral CB1 receptor blockade may yield beneficial outcomes that exceed those elicited by weight loss alone.

Topics: Animals; Brain; Dose-Response Relationship, Drug; Drug Inverse Agonism; Extinction, Psychological; Macaca fascicularis; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Piperidines; Pyrazoles; Pyrimidinones; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Sleep, REM; Tissue Distribution

Value-based pricing (VBP) is a method of setting prices for products based on perceived benefits to the consumer. When information is symmetric and freely available and agency is perfect, VBP is efficient and desirable. Because of substantial information asymmetries, medical insurance distortions, and the prescribing monopoly of physicians, VBP is rare for prescription drugs, though a number of countries have recently moved in this direction. Because the potential benefits can be sizable, it is high time for a review of actual VBP-based decision-making in practice. Sweden, with its pharmaceutical benefits board (TLV), was an early adopter of VBP decision-making. We illustrate actual decision-making, thus, using the case of Acomplia for the treatment of obesity in Sweden, with and without the presence of co-morbid conditions. This example has a number of features that will be useful in illustrating the strengths and weaknesses of VBP in actual practice, including multiple indications, a need for not just one but two economic simulation models, considerable sub-group analysis, and requirements for additional evidence development. TLV concluded, in 2006, that Acomplia was cost-effective for patients with a body mass index (BMI) exceeding 35 kg/m2 and patients with a BMI exceeding 28 kg/m2 and either dyslipidemia or type 2 diabetes. Because of uncertainty in some of the underlying assumptions, reimbursement was granted only until 31 December 2008, at which time the manufacturer would be required to submit additional documentation of the long-term effects and cost-effectiveness in order to obtain continued reimbursement. Deciding on reimbursement coverage for pharmaceutical products is difficult. Ex ante VBP assessment is a form of risk sharing, which has been used by TLV to speed up reimbursement and dispersion of effective new drugs despite uncertainty in their true cost-effectiveness. Manufacturers are often asked in return to generate additional health economic evidence that will establish cost-effectiveness as part of ex post review. The alternative is to delay the reimbursement approval until satisfactory evidence is available.

Topics: Body Mass Index; Comorbidity; Cost-Benefit Analysis; Decision Making, Organizational; Drug Prescriptions; Dyslipidemias; Economics, Pharmaceutical; Humans; Insurance, Pharmaceutical Services; Obesity; Piperidines; Pyrazoles; Reimbursement Mechanisms; Rimonabant; State Medicine; Sweden

The antiobesity effects of suppressed endocannabinoid signaling may rely, at least in part, on changes in lipid fluxes. As fatty acids exert specific effects depending on their level of saturation, we hypothesized that the dietary fatty acid composition would influence the outcome of treatment with a CB(1)-receptor antagonist (rimonabant).. Mice were treated with rimonabant (10 mg kg(-1) body weight per day) or vehicle while equicalorically fed either a low-fat diet (LF), a high-fat (HF) diet or an HF diet in which 10% of the saturated fatty acids (SFAs) were replaced by poly-unsaturated fatty acids (PUFA) from fish oil (FO). Food intake and body weight were registered daily. Indirect calorimetry was performed and feces were collected. After 3 weeks, mice were killed for blood and tissue collection.. Relative to the LF diet, the HF diet caused anticipated metabolic derangements, which were partly reversed by the HF/FO diet. The HF/FO diet, however, was most obesity-promoting despite inhibiting lipogenesis as indicated by low gene expression levels of lipogenic enzymes. On all three diets, rimonabant treatment improved metabolic derangements and led to significantly lower body weight gain than their respective controls. This latter effect appeared largest in the HF/FO group, but occurred without major changes in nutrient absorption and energy expenditure.. The effects of chronic rimonabant treatment on body weight gain occurred irrespective of diet-induced changes in lipogenic activity, food intake and daily energy expenditure, and were, in fact, most pronounced in HF/FO mice. The effects of dietary PUFA replacement in an HF diet on expansion of adipose tissue might allow the favorable effects of dietary PUFA on dyslipidemia and hepatic steatosis. In light of other disadvantageous effects of weight gain, this might be a risky trade-off.

Topics: Animals; Body Weight; Cannabinoids; Dietary Fats; Energy Metabolism; Fatty Acids; Fish Oils; Gene Expression Regulation, Enzymologic; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The endocannabinoid (EC) system is a major component in the control of energy homeostasis. It mediates a positive energy balance via central and peripheral pathways. Blockade of the cannabinoid type 1 receptor induces weight reduction and improves cardiovascular risk factors in overweight patients. Cannabinoid receptor type 1 (CB1R)-deficient mice are resistant to diet-induced obesity. The mechanisms responsible for these effects remain only partially elucidated. We hypothesized peripheral effects via direct modulation of adipocyte function to be an integral part of EC action on energy metabolism and insulin sensitivity.. SV40 immortalized murine white and brown adipocytes were used for all experiments. We investigated the effect of CB1R blockade by stimulating the cells acutely and chronically with rimonabant, a selective antagonist for the CB1R, or by knocking down the receptor with small interfering RNA (siRNA). Changes in thermogenic mRNA and protein expression as well as mitochondrial biogenesis and function were assessed by real-time RT-PCR, immunoblotting, fluorescent staining techniques, electron microscopy and by measuring oxygen consumption.. Acute and chronic blockade of the CB1R with the selective antagonist rimonabant or by siRNA in murine white adipocytes strongly induced the thermogenic uncoupling protein-1 (UCP-1). UCP-1 expression was increased in a time- and dose-dependent manner both at the RNA and protein level. Furthermore, this effect was paralleled by enhanced peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) expression. In accordance with these findings, AMP-activated protein kinase (AMPK) phosphorylation was also increased after rimonabant treatment. Mitochondria-specific fluorescent staining demonstrated an augmentation in the number of mitochondria. This was confirmed by electron microscopy images. Moreover, rimonabant treatment enhanced the cytochrome c oxidase activity and increased cellular oxygen consumption.. Taken together, our data demonstrate that inhibition of peripheral CB1R action in adipocytes directly promotes transdifferentiation of white adipocytes into a mitochondria-rich, thermogenic brown fat phenotype. Enhanced thermogenesis and insulin sensitivity may represent a peripheral mechanism contributing to weight loss and improved glucose homeostasis in rimonabant-treated patients.

Topics: Adipocytes, White; Adipose Tissue, Brown; Animals; Cannabinoid Receptor Antagonists; Cell Transdifferentiation; Gene Expression; Mice; Obesity; Phenotype; Piperidines; PPAR gamma; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid; Reverse Transcriptase Polymerase Chain Reaction; Rimonabant

A series of amides, amidines and amidoximes have been made from the corresponding nitrile compounds, to provide potent antagonists and inverse agonists for the CB1 receptor with considerably lower lipophiliciy, higher polar surface area and improved plasma/brain ratios compared to the centrally acting rimonabant. Extensive investigations of ADME and in vivo pharmacological properties led to selection of the amide series and specifically the 4-(4-fluorophenyl)piperidin-4-ol derivative D4. A clear improvement in the peripheral profile over rimonabant was seen, although some contribution of central effect on the pronounced weight reduction in obese mice cannot be ruled out.

Topics: Amides; Animals; Anti-Obesity Agents; Blood-Brain Barrier; Body Weight; Drug Inverse Agonism; Mice; Obesity; Piperidines; Protein Binding; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant; Structure-Activity Relationship

The syntheses and SAR investigations of novel CB(1) receptor antagonists based on a 1,2-diaryl piperidine core have been described. Optimization of this core afforded a compound with robust in vivo potency by reducing food intake in a mouse DIO model.

Topics: Animals; Diet; Eating; Mice; Mice, Obese; Obesity; Piperidines; Protein Binding; Receptor, Cannabinoid, CB1; Structure-Activity Relationship

The endocannabinoid system plays a crucial role in the pathophysiology of obesity. However, the clinical use of cannabinoid antagonists has been recently stopped because of its central side-effects. The aim of this study was to compare the effects of a chronic treatment with the CB(1) cannabinoid antagonist rimonabant or the CB(1) inverse agonist taranabant in diet-induced obese female rats to clarify the biological consequences of CB(1) blockade at central and peripheral levels. As expected, chronic treatment with rimonabant and taranabant reduced body weight and fat content. Interestingly, a decrease in the number of CB(1) receptors and its functional activity was observed in all the brain areas investigated after chronic taranabant treatment in both lean and obese rats. In contrast, chronic treatment with rimonabant did not modify the density of CB(1) cannabinoid receptor binding, and decreased its functional activity to a lower degree than taranabant. Six weeks after rimonabant and taranabant withdrawal, CB(1) receptor density and activity recovered to basal levels. These results reveal differential adaptive changes in CB(1) cannabinoid receptors after chronic treatment with rimonabant and taranabant that could be related to the central side-effects reported with the use of these cannabinoid antagonists.

Topics: Amides; Analysis of Variance; Animals; Autoradiography; Benzoxazines; Body Weight; Brain; Cyclohexanols; Diet Fads; Disease Models, Animal; Eating; Female; Guanosine 5'-O-(3-Thiotriphosphate); International Cooperation; Morpholines; Naphthalenes; Obesity; Piperidines; Protein Binding; Pyrazoles; Pyridines; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Sulfur Isotopes; Time Factors; Tomography Scanners, X-Ray Computed; Tritium; Whole Body Imaging

Fatty acid amide hydrolase (FAAH) is the main degrading enzyme of the fatty acid ethanolamides anandamide (AEA) and oleoylethanolamide (OEA), which have opposite effects on food intake and energy balance. AEA, an endogenous ligand of CB(1) cannabinoid receptors, enhances food intake and energy storage, whereas OEA binds to peroxisome proliferator-activated receptors-alpha to reduce food intake and promoting lipolysis. To elucidate the role of FAAH in food intake and energy balance, we have evaluated different metabolic and behavioral responses related to feeding in FAAH-deficient (FAAH(-/-)) mice and their wild-type littermates.. Total daily food intake was similar in both genotypes, but high-fat food consumption was enhanced during the dark hours and decreased during the light hours in FAAH(-/-) mice. The reinforcing and motivational effects of food were also enhanced in FAAH(-/-) mice as revealed by operant behavioral paradigms. These behavioral responses were reversed by the administration of the selective CB(1) cannabinoid antagonist rimonabant. Furthermore, body weight, total amount of adipose tissue, plasma-free fatty acids and triglyceride content in plasma, liver, skeletal muscle and adipose tissue, were increased in FAAH(-/-) mice. Accordingly, leptin levels were increased and adiponectin levels decreased in these mutants, FAAH(-/-) mice also showed enhanced plasma insulin and blood glucose levels revealing an insulin resistance. As expected, both AEA and OEA levels were increased in hypothalamus, small intestine and liver of FAAH(-/-) mice.. These results indicate that the lack of FAAH predominantly promotes energy storage by food intake-independent mechanisms, through the enhancement of AEA levels rather than promoting the anorexic effects of OEA.

Topics: Adiposity; Amidohydrolases; Animals; Arachidonic Acids; Body Weight; Cannabinoid Receptor Modulators; Conditioning, Operant; Darkness; Dietary Fats; Eating; Endocannabinoids; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motivation; Obesity; Oleic Acids; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rimonabant; Triglycerides

To investigate whether drugs targeting peripheral cannabinoid-1 (CB1) receptor ameliorate adiposity comparable to central CB1-receptor antagonist or not.. Receptor binding assay and functional assay in vitro. Pharmacokinetic parameters in mice, brain uptake clearance of compounds in rats and antagonism on the CB1-agonist-induced hypothermia in mice. Diet consumption, body weight changes, hepatic gene expression of sterol-regulatory element-binding protein-1 (SREBP-1) and plasma/tissue concentrations of compounds in HF diet-induced obese (HF-DIO) mice after acute and chronic treatment.. Compound-1, an SR141716A derivative, is a peripheral CB1-receptor-selective antagonist that is 10 times less potent than SR141716A in in vitro evaluations. Although the plasma concentrations of Compound-1 are five times higher than those of SR141716A, its potency is still 10 times lower than that of SR141716A in reducing the consumption of normal or HF diet by mice. Through evaluations of brain uptake and the effect on CB1-agonist-induced hypothermia, it was verified that the blood-brain barrier (BBB) penetration of Compound-1 is much lower than that of SR141716A. In HF-DIO mice, chronic treatment by Compound-1 showed dose-dependent antiobesity activities, while its brain distribution was very low as compared with that of SR141716A. Compound-1's effective doses for antiobesity activity were just over 30 mg kg(-1). However, Compound-1 completely suppressed the elevated hepatic SREBP-1 expression even at 10 mg kg(-1).. These results suggest that (1) central CB1 receptors mediate anorectic response of CB1-receptor antagonists and (2) peripheral modulations, including SREBP-1 expression, are not major mechanisms in the antiobesity effects of CB1-receptor antagonists.

Topics: Adiposity; Animals; Benzoxazines; Brain; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Feeding Behavior; Hypothermia; Male; Mice; Mice, Inbred C57BL; Morpholines; Naphthalenes; Obesity; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Sterol Regulatory Element Binding Protein 1; Tissue Distribution

The beneficial effects of the inactivation of endocannabinoid system (ECS) by administration of antagonists of the cannabinoid receptor (CB) 1 on several pathological features associated with obesity is well demonstrated, but the relative contribution of central versus peripheral mechanisms is unclear. We examined the impact of CB1 antagonism on liver and adipose tissue lipid metabolism in a mouse model of diet-induced obesity.. Mice were fed either with a standard diet or a high-sucrose high-fat (HSHF) diet for 19 weeks and then treated with the CB1-specific antagonist SR141716 (10 mg x kg(-1) x day(-1)) for 6 weeks.. Treatment with SR141716 reduced fat mass, insulin levels, and liver triglycerides primarily increased by HSHF feeding. Serum adiponectin levels were restored after being reduced in HSHF mice. Gene expression of scavenger receptor class B type I and hepatic lipase was induced by CB1 blockade and associated with an increase in HDL-cholesteryl ether uptake. Concomitantly, the expression of CB1, which was strongly increased in the liver and adipose tissue of HSHF mice, was totally normalized by the treatment. Interestingly, in visceral but not subcutaneous fat, genes involved in transport, synthesis, oxidation, and release of fatty acids were upregulated by HSHF feeding, while this effect was counteracted by CB1 antagonism.. A reduction in the CB1-mediated ECS activity in visceral fat is associated with a normalization of adipocyte metabolism, which may be a determining factor in the reversion of liver steatosis induced by treatment with SR141716.

Topics: Adiponectin; Adipose Tissue; Animal Feed; Animals; Apolipoproteins A; Apolipoproteins B; Body Weight; Cannabinoid Receptor Antagonists; Diet; Fatty Liver; Gene Expression Regulation; Liver; Mice; Mice, Obese; Obesity; Organ Size; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Sucrose

Topics: Adult; Anti-Obesity Agents; Female; Humans; Obesity; Piperidines; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pyrazoles; Rimonabant

Cannabinoid CB(1) receptor antagonists exhibit pharmacologic properties favorable for the treatment of metabolic disease. CP-945,598 (1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylamino piperidine-4-carboxylic acid amide hydrochloride) is a recently discovered selective, high affinity, competitive CB(1) receptor antagonist that inhibits both basal and cannabinoid agonist-mediated CB(1) receptor signaling in vitro and in vivo. CP-945,598 exhibits sub-nanomolar potency at human CB(1) receptors in both binding (K(i)=0.7 nM) and functional assays (K(i)=0.2 nM). The compound has low affinity (K(i)=7600 nM) for human CB(2) receptors. In vivo, CP-945,598 reverses four cannabinoid agonist-mediated CNS-driven responses (hypo-locomotion, hypothermia, analgesia, and catalepsy) to a synthetic cannabinoid receptor agonist. CP-945,598 exhibits dose and concentration-dependent anorectic activity in two models of acute food intake in rodents, fast-induced re-feeding and spontaneous, nocturnal feeding. CP-945,598 also acutely stimulates energy expenditure in rats and decreases the respiratory quotient indicating a metabolic switch to increased fat oxidation. CP-945,598 at 10mg/kg promoted a 9%, vehicle adjusted weight loss in a 10 day weight loss study in diet-induced obese mice. Concentration/effect relationships combined with ex vivo brain CB(1) receptor occupancy data were used to evaluate efficacy in behavioral, food intake, and energy expenditure studies. Together, these in vitro, ex vivo, and in vivo data indicate that CP-945,598 is a novel CB(1) receptor competitive antagonist that may further our understanding of the endocannabinoid system.

Topics: Animals; Anti-Obesity Agents; Body Weight; Cell Line; Eating; Humans; Male; Mice; Mice, Inbred C57BL; Obesity; Oxygen Consumption; Piperidines; Purines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1

Brain-derived neurotrophic factor (BDNF) regulates food intake and body weight, but is not useful as a therapeutic because of its short half-life. Chronic activation of its receptor, tyrosine kinase receptor B (TrkB), represents an alternative strategy for lowering body weight. However, because BDNF can raise blood pressure (BP) acutely, it is possible that chronic TrkB activation will produce adverse cardiovascular effects.. We used radiotelemetry to test whether treatment with a TrkB agonist antibody (Ab) causes adverse cardiovascular effects in mice with diet-induced obesity.. High-dose (1 mg/kg) TrkB Ab reduced body weight and significantly increased BP, whereas low-dose (0.3 mg/kg) treatment lowered body weight without adverse cardiovascular effects. Rimonabant, through a different mechanism of action, lowered body weight in this model more than TrkB activation, but showed no adverse effects on heart rate (HR) or BP. These data suggest that elevated BP was a direct effect of high-dose TrkB Ab treatment rather than secondary to substantial weight loss.. Overall, high-dose TrkB Ab lowered body weight and increased BP, whereas low-dose TrkB Ab treatment caused therapeutic weight loss without adverse cardiovascular effects. We conclude that TrkB activation dose-dependently lowers body weight and transiently raises BP in mice with diet-induced obesity.

Topics: Animals; Anti-Obesity Agents; Antibodies, Monoclonal; Blood Pressure; Body Weight; Brain-Derived Neurotrophic Factor; Diet; Dietary Fats; Hypertension; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Receptor, trkB; Rimonabant; Telemetry; Weight Loss

Ligands functioning as antagonists and inverse agonists at the cannabinoid CB(1)-receptor (e.g., AM 251, AM 281, and rimonabant (previously identified as SR141716)) have been demonstrated to have effects on satiety, consumption of, and the motivation to work for, or obtain food. These represent behavioral effects that may also be linked to characteristics such as food palatability or motivation to obtain food. Given the recent removal of rimonabant from clinical trials, a thorough characterization of ingestive behaviors that are associated with other likely candidate drugs is warranted. In the present study, normal weight male Long Evans rats were trained to respond for grain or chocolate-flavored food pellets under progressive-ratio schedules of reinforcement. Rats received acute injections of the CB(1) receptor antagonist AM 251 (0.3-3.0 mg/kg) or vehicle prior to daily testing sessions. Administration of AM 251 produced significant dose-dependent reductions in responding for, deliveries of, and break points (BP) associated with chocolate-flavored but not grain pellets. These data add to the literature demonstrating the ability of CB(1) antagonists to selectively reduce motivation to obtain highly palatable reinforcers.

Topics: Animal Feed; Animals; Appetite Regulation; Appetitive Behavior; Behavior, Animal; Cacao; Cannabinoids; Conditioning, Operant; Diet; Dose-Response Relationship, Drug; Drug Inverse Agonism; Edible Grain; Food Preferences; Male; Motivation; Obesity; Piperidines; Pyrazoles; Random Allocation; Rats; Rats, Long-Evans; Receptor, Cannabinoid, CB1; Reinforcement, Psychology; Taste

Macrophage infiltration into adipose tissue (AT-MP) is thought to induce insulin resistance and diabetes in obesity. Here, we investigated the effect of the antiobesity drug SR141716 (a CB1 antagonist) on macrophage-mediated inhibition of insulin signaling in adipocytes. THP1 macrophages (THP1) were stimulated in vitro with lipopolysaccharide (LPS) and SR141716 or vehicle. The resulting conditioned medium (CM) was analyzed and incubated on human adipocytes. CM from LPS-stimulated THP1 inhibited insulin-induced AKT phosphorylation in adipocytes, in contrast to CM from nonactivated THP1. Moreover, it contained higher concentrations of tumor necrosis factor-α (TNFα) and lower levels of the anti-inflammatory cytokine IL-10. SR141716 reduced TNFα production and increased IL-10 secretion, resulting in a rescue of insulin signaling in adipocytes. To confirm these findings in vivo, AT-MP CM from cafeteria diet-fed or Zucker diabetic fatty (ZDF) rats that had received SR141716 for 3 weeks were isolated, analyzed, and incubated with adipocytes. Cafeteria diet induced macrophage-mediated inhibition of insulin signaling in adipocytes. Interestingly, SR141716 rescued insulin-induced glucose uptake in adipocytes. Finally, AT-MP CM from obese ZDF rats inhibited insulin-stimulated glucose uptake in adipocytes in contrast to AT-MP CM from lean ZDF rats. After treatment with SR141716, AT-MP CM rescued insulin-induced glucose uptake in adipocytes. In summary, our data indicate that CB1 receptor antagonism in macrophages modified their cytokine production and improved the insulin responsiveness of adipocytes that had been incubated with macrophage CM. Thus, SR141716 ameliorated adipose tissue insulin resistance by direct action on AT-MP demonstrating a novel peripheral mode of action of CB1 antagonism.

Topics: Adipocytes; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Cell Line; Culture Media, Conditioned; Diabetes Mellitus, Experimental; Dietary Fats; Female; Humans; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Interleukin-10; Lipopolysaccharides; Macrophages; Male; Mice; Obesity; Phosphorylation; Piperidines; Pyrazoles; Rats; Rats, Wistar; Rats, Zucker; Receptor, Cannabinoid, CB1; Rimonabant; Signal Transduction; Tumor Necrosis Factor-alpha

Tesofensine, a novel triple monoamine reuptake inhibitor, produces a significant weight loss in humans. The present study aimed at characterizing the weight-reducing effects of tesofensine in a rat model of diet-induced obesity. Sibutramine and rimonabant were used as reference comparators. Compared to baseline, long-term treatment with tesofensine (28 days, 1.0 or 2.5mg/kg, p.o.) resulted in a significant, dose-dependent and sustained weight loss of 5.7 and 9.9%, respectively. Sibutramine (7.5mg/kg, p.o.) treatment caused a sustained weight loss of 7.6%, whereas the employed dose of rimonabant (10mg/kg, p.o.) only produced a transient weight reduction. While all compounds exhibited a significant inhibitory effect on food intake which gradually wore off, the hypophagic effect of tesofensine was longer lasting than sibutramine and rimonabant. In contrast to tesofensine, the body weight of pair-fed rats returned to baseline at the end of the study, which may indicate that tesofensine stimulated energy expenditure. The differential efficacy on weight reduction was also reflected in lowered body fat depots, as tesofensine and sibutramine most efficiently reduced abdominal and subcutaneous fat mass which was paralleled by reduced plasma lipid levels. In an oral glucose tolerance test, only tesofensine significantly suppressed the plasma insulin response below the level that could be obtained by paired feeding, indicating that tesofensine further improved glycemic control. In conclusion, the robust weight loss with long-term tesofensine treatment is likely due to a combined synergistic effect of appetite suppression and increased energy expenditure.

Topics: Adipose Tissue; Animals; Appetite; Biogenic Monoamines; Blood Glucose; Bridged Bicyclo Compounds, Heterocyclic; Cyclobutanes; Diet; Eating; Glucose Tolerance Test; Lipids; Male; Neurotransmitter Uptake Inhibitors; Obesity; Piperidines; Pyrazoles; Rats; Rimonabant; Time Factors; Weight Loss

Rimonabant is an anti-obesity agent, at the therapeutic level, and a cannabinoid-1 receptor inverse agonist, at the molecular pharmacology level. The drug is currently off the market after psychiatric disorders were observed in some patients. If the adverse effects are attributed to its inverse agonist character, it makes sense to limit the drug discovery space to neutral antagonists. But do neutral antagonists exist? Here, the influence of the sensitivity of the signal transduction machinery on potential neutral antagonist misclassification is modelled. It is proposed that absolute neutral antagonists do not exist, and it is suggested that decisions about the continuity of the compounds in the drug development process be made in a quantitative inverse agonist scale rather than in a qualitative neutral antagonist and inverse agonist classification.

Topics: Anti-Obesity Agents; Drug Design; Drug Inverse Agonism; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Signal Transduction

Energy homeostasis is regulated by a complex interaction of molecules and pathways, and new antiobesity treatments are likely to require multiple pharmacological targeting of anorexigenic or orexigenic pathways to achieve effective loss of excess body weight and adiposity. Cannabinoids, acting via the cannabinoid-1 (CB1) receptor, and neuropeptide Y (NPY) are important modulators of feeding behaviour, energy metabolism and body composition. We investigated the interaction of CB1 and NPY in the regulation of energy homeostasis, hypothesizing that dual blockade of CB1 and NPY signalling will induce greater weight and/or fat loss than that induced by single blockade of either system alone.. We studied the effects of the CB1 antagonist Rimonabant on food intake, body weight, body composition, energy metabolism and bone physiology in wild-type (WT) and NPY knockout (NPY(-/-)) mice. Rimonabant was administered orally at 10 mg/kg body weight twice per day for 3 weeks. Oral Rimonabant was delivered voluntarily to mice via a novel method enabling studies to be carried out in the absence of gavage-induced stress.. Mice with dual blockade of CB1 and NPY signalling (Rimonabant-treated NPY(-/-) mice) exhibited greater reductions in body weight and adiposity than mice with single blockade of either system alone (Rimonabant-treated WT or vehicle-treated NPY(-/-) mice). These changes occurred without loss of lean tissue mass or bone mass. Furthermore, Rimonabant-treated NPY(-/-) mice showed a lower respiratory exchange ratio than that seen in Rimonabant-treated WT or vehicle-treated NPY(-/-) mice, suggesting that this additive effect of dual blockade of CB1 and NPY involves promotion of lipid oxidation. On the other hand, energy expenditure and physical activity were comparable amongst all treatment groups. Interestingly, Rimonabant similarly and transiently reduced spontaneous and fasting-induced food intake in WT and NPY(-/-) mice in the first hour after administration only, suggesting independent regulation of feeding by CB1 and NPY signalling. In contrast, Rimonabant increased serum corticosterone levels in WT mice, but this effect was not seen in NPY(-/-) mice, indicating that NPY signalling may be required for effects of CB1 on the hypothalamo-pituitary-adrenal axis.. Dual blockade of CB1 and NPY signalling leads to additive reductions in body weight and adiposity without concomitant loss of lean body mass or bone mass. An additive increase in lipid oxidation in dual CB1 and NPY blockade may contribute to the effect on adiposity. These findings open new avenues for more effective treatment of obesity via dual pharmacological manipulations of the CB1 and NPY systems.

Topics: Animals; Body Composition; Eating; Energy Metabolism; Homeostasis; Mice; Neuropeptide Y; Obesity; Oxidation-Reduction; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Neuropeptide Y; Rimonabant

A growing body of evidence supports an important role for the endocannabinoid system as a regulator of appetite, body weight, and systemic metabolism, which is overactive in obesity and type 2 diabetes. While initial attempts to target this system using the cannabinoid receptor inverse agonist rimonabant were successful in producing modest weight loss and improving obesity-related metabolic complications in humans, adverse central nervous system side effects precluded introduction of this drug into clinical practice. However, new data, presented by Tam and colleagues in this issue of the JCI, demonstrate that selective blockade of peripheral cannabinoid receptors may be a novel successful therapeutic approach.

Topics: Animals; Appetite Regulation; Body Weight; Cannabinoid Receptor Modulators; Diabetes Mellitus, Type 2; Endocannabinoids; Humans; Mice; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Obesity and its metabolic consequences are a major public health concern worldwide. Obesity is associated with overactivity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis, and insulin resistance. Cannabinoid-1 receptor (CB1R) antagonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity, but their therapeutic potential is limited by neuropsychiatric side effects. Here we have demonstrated that a CB1R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by CB1R in the brains of mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile. These effects were due to blockade of CB1R in peripheral tissues, including the liver, as verified through the use of CB1R-deficient mice with or without transgenic expression of CB1R in the liver. These results suggest that targeting peripheral CB1R has therapeutic potential for alleviating cardiometabolic risk in obese patients.

Topics: Animals; Insulin Resistance; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Morpholines; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Triglycerides

Obesity is characterised by altered gut microbiota, low-grade inflammation and increased endocannabinoid (eCB) system tone; however, a clear connection between gut microbiota and eCB signalling has yet to be confirmed. Here, we report that gut microbiota modulate the intestinal eCB system tone, which in turn regulates gut permeability and plasma lipopolysaccharide (LPS) levels. The impact of the increased plasma LPS levels and eCB system tone found in obesity on adipose tissue metabolism (e.g. differentiation and lipogenesis) remains unknown. By interfering with the eCB system using CB(1) agonist and antagonist in lean and obese mouse models, we found that the eCB system controls gut permeability and adipogenesis. We also show that LPS acts as a master switch to control adipose tissue metabolism both in vivo and ex vivo by blocking cannabinoid-driven adipogenesis. These data indicate that gut microbiota determine adipose tissue physiology through LPS-eCB system regulatory loops and may have critical functions in adipose tissue plasticity during obesity.

Topics: Adipogenesis; Adipose Tissue; Animals; Arachidonic Acids; Bacterial Translocation; Caco-2 Cells; Cannabinoid Receptor Modulators; Disease Models, Animal; Dronabinol; Endocannabinoids; Glycerides; Humans; Intestinal Mucosa; Intestines; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Myeloid Differentiation Factor 88; Obesity; Permeability; Piperidines; Polyunsaturated Alkamides; Prebiotics; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger

Topics: Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant

To investigate the effect of chronic cannabinoid 1 antagonism on vascular prostanoid production, obese Zucker rats were treated with rimonabant (10 mg/kg per day) during 20 weeks and then vascular and endothelial reactivity were assessed in aortic rings by analyzing response to phenylephrine and acetylcholine. The presence of cyclo-oxygenase-1 and cyclo-oxygenase-2 selective inhibitors (SC-560 and NS-398, respectively) and the enzyme immunoassay revealed lower PGI2 production by aortic rings from obese rats with rimonabant able to restore such response toward levels found in the lean animals. The treatment also reduced TXB2 but did not alter its participation on acetylcholine-induced relaxation as the TP receptor antagonist ICI-192,605 revealed. Those effects were associated with an enhancement of cyclo-oxygenase-2 expression without affecting p38MAPK phosphorylation. Obese rats also exhibited higher nitric oxide plasma concentrations and greater inducible nitric oxide synthase participation on vascular phenylephrine-induced response without changes in inducible nitric oxide synthase protein expression. Although rimonabant reduced such alteration, the values were still higher than those found in lean rats. Finally, rimonabant was also able to reduce tumor necrosis factor-α produced by adipose tissue of obese Zucker rats. These results highlight a crosstalk among cannabinoids and cyclo-oxygenase-derived products in the vasculature of obese animals.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Body Weight; Endothelium, Vascular; Nitric Oxide Synthase Type II; Nitrobenzenes; Obesity; Phenylephrine; Piperidines; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Rimonabant; Sulfonamides; Tumor Necrosis Factor-alpha; Vasodilation; Vasodilator Agents

Topics: Animals; Atherosclerosis; Cannabinoids; Clinical Trials as Topic; Heart Diseases; Humans; Metabolic Diseases; Mice; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, LDL; Rimonabant; Weight Gain

Cannabinoid 1 (CB1) receptor blockade with rimonabant represents a clinical therapeutic strategy for obesity. Recently, the role of the endocannabinoid system has been described in peripheral organs. We sought to determine whether the endocannabinoid system could be involved in human atherosclerosis and whether CB1 receptor blockade could modulate proinflammatory activity in macrophages.. mRNA expression levels of CB1 receptor in coronary atherectomy samples were significantly higher in patients with unstable angina than in those with stable angina (3.62+/-2.96-fold; n=7; P<0.05). Immunoreactive area analysis of the coronary artery showed that CB1 receptor expression was greater in lipid-rich atheromatous plaques than in fibrous plaques, especially in CD68 macrophages (9.5+/-1.2% versus 0.6+/-0.6%; n=5; P<0.01). Levels of blood endocannabinoids were significantly higher in patients with coronary artery disease (n=20) than those without coronary artery disease (n=20) (median [interquartile range]: anandamide, 1.048 pmol/mL [0.687 to 1.387 pmol/mL] versus 0.537 pmol/mL [0.468 to 0.857 pmol/mL], P<0.01; 2-arachidonoyl glycerol, 13.30 pmol/mL [6.65 to 16.21 pmol/mL] versus 7.67 pmol/mL [6.39 to 10.03 pmol/mL], P<0.05). In cultured macrophages, expression of CB1 receptor was significantly increased during monocyte-macrophage differentiation (1.78+/-0.13-fold; n=6; P<0.01). CB1 receptor blockade in macrophages induced a significant increase in cytosolic cAMP (29.9+/-13.0%; n=4; P<0.01), inhibited phosphorylation of c-Jun N-terminal kinase (-19.1+/-12.6%, n=4; P<0.05), and resulted in a significant decrease in the production of proinflammatory mediators (interleukin-1beta, -28.9+/-10.9%; interleukin-6, -24.8+/-7.6%; interleukin-8, -22.7+/-5.2%; tumor necrosis factor-alpha, -13.6+/-4.8%; matrix metalloproteinase-9, -16.4+/-3.8%; n=4 to 8; P<0.01).. Patients with coronary artery disease demonstrated the activation of the endocannabinoid system with elevated levels of blood endocannabinoids and increased expression of CB1 receptor in coronary atheroma. CB1 receptor blockade exhibited antiinflammatory effects on macrophages, which might provide beneficial effects on atherogenesis.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anti-Inflammatory Agents; Atherectomy, Coronary; Cannabinoid Receptor Modulators; Cell Differentiation; Cell Line; Cells, Cultured; Coronary Artery Disease; Cytokines; Endocannabinoids; Humans; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Macrophages; Matrix Metalloproteinase 9; Monocytes; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; RNA, Messenger; Vasculitis

The increase in adiponectin levels in obese patients with untreated dyslipidemia and its mRNA expression in adipose tissue of obese animals are one of the most interesting consequences of rimonabant treatment. Thus, part of rimonabant's metabolic effects could be related to an enhancement of adiponectin secretion and its consequence on the modulation of insulin action, as well as energy homeostasis. The present study investigated the effects of rimonabant in adiponectin knockout mice (Ad(-/-)) exposed to diet-induced obesity conditions. Six-week-old Ad(-/-) male mice and their wild-type littermate controls (Ad(+/+)) were fed a high-fat diet for 7 mo. During the last month, animals were administered daily either with vehicle or rimonabant by mouth (10 mg/kg). High-fat feeding induced weight gain by about 130% in both wild-type and Ad(-/-) mice. Obesity was associated with hyperinsulinemia and insulin resistance. Treatment with rimonabant led to a significant and similar decrease in body weight in both Ad(+/+) and Ad(-/-) mice compared with vehicle-treated animals. In addition, rimonabant significantly improved insulin sensitivity in Ad(+/+) mice compared with Ad(+/+) vehicle-treated mice by decreasing hepatic glucose production and increasing glucose utilization index in both visceral and subcutaneous adipose tissue. In contrast, rimonabant failed to improve insulin sensitivity in Ad(-/-) mice, despite the loss in body weight. Rimonabant's effect on body weight appeared independent of the adiponectin pathway, whereas adiponectin seems required to mediate rimonabant-induced improvement of insulin sensitivity in rodents.

Topics: Adiponectin; Animals; Anti-Obesity Agents; Dietary Fats; Disease Models, Animal; Eating; Glucose; Glucose Tolerance Test; Hyperinsulinism; Insulin; Insulin Resistance; Intra-Abdominal Fat; Lipids; Liver; Male; Mice; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Rimonabant; Subcutaneous Fat; Weight Loss

Cardiovascular mortality remains the first cause of death worldwide. This high mortality rate is directly associated with the increase of cardiovascular risk factors such as: obesity, hypertension, diabetes and hypercholesterolemia. Current tight management and new pharmacological treatment of cardiovascular risk factors decrease the cardiovascular mortality rate in general population. However, insulin resistance, hypo-adiponectinemia and inflammatory factors persist and are linked with atherosclerosis. Additional therapeutic solutions are needed. Rimonabant, a CB1-blocker brings novel perspective to manage several cardiovascular risk factors. Unfortunately, Rimonabant has been withdrawn from the market. Therefore, it has not been possible to assess in long term its efficacy on cardiovascular mortality.

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors

Obesity is a risk factor for increased severity of acute pancreatitis. Adipocytes produce adiponectin, an anti-inflammatory molecule that is paradoxically decreased in the setting of obesity. We have shown that adiponectin concentration inversely mirrors the severity of pancreatitis in obese mice. Cannabinoid receptor CB-1 blockade increases circulating adiponectin concentration. We, therefore, hypothesize that blockade of CB-1 would increase adiponectin and attenuate pancreatitis severity.. Forty lean (C57BL/6J) and 40 obese (Lep(Db)) mice were studied. Half of the mice in each strain received intraperitoneal injection of the CB-1 antagonist rimonabant (10 mg/kg daily for 7 days); the others received vehicle. Pancreatitis was induced by intraperitoneal injection of cerulein (50 microg/g hourly x 6). Pancreatitis severity was determined by histology. Pancreatic chemokine and proinflammatory cytokine concentrations were measured by ELISA.. Rimonabant treatment significantly increased circulating adiponectin concentration in obese mice (p < 0.03 vs. vehicle). After induction of pancreatitis, obese mice treated with rimonabant had significantly decreased histologic pancreatitis (p < 0.001), significantly lower pancreatic tissue levels of monocyte chemoattractant protein-1 (p = 0.03), tumor necrosis factor-alpha (p < 0.001), interleukin-6 (p < 0.001), and myeloperoxidase (p = 0.006) relative to vehicle-treated animals.. In obese mice, cannabinoid receptor CB-1 blockade with rimonabant attenuates the severity of acute pancreatitis by an adiponectin-mediated mechanism.

Topics: Adiponectin; Animals; Chemokine CCL2; Interleukin-6; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pancreatitis; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Severity of Illness Index; Tumor Necrosis Factor-alpha

Topics: Adiponectin; Adiposity; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; C-Reactive Protein; Dyslipidemias; Humans; Insulin; Intra-Abdominal Fat; Lipids; Liver; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors; Treatment Outcome

Topics: Affect; Anti-Obesity Agents; Antidepressive Agents; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Depression; Depressive Disorder; Endocannabinoids; Humans; Ligands; Obesity; Piperidines; Pyrazoles; Research; Rimonabant; Signal Transduction; Tobacco Use Disorder

Overactivity of the endocannabinoid system (ECS) has been linked to abdominal obesity and other risk factors for cardiovascular disease and type 2 diabetes. Conversely, administration of cannabinoid receptor type 1 (CB1) antagonists reduces adiposity in obese animals and humans. This effect is only in part secondary to the anorectic action of CB1 agonists. In order to assess the actions of CB1 antagonism on glucose homeostasis, diet-induced obese (DIO) rats received the CB1 antagonist rimonabant (10 mg/kg, intraperitoneally (IP)) or its vehicle for 4 weeks, or were pair-fed to the rimonabant-treated group for the same length of time. Rimonabant treatment transiently reduced food intake, while inducing body weight loss throughout the study. Rats receiving rimonabant had significantly less body fat and circulating leptin compared to both vehicle and pair-fed groups. Rimonabant, but not pair-feeding, also significantly decreased circulating nonesterified fatty acid (NEFA) and triacylglycerol (TG) levels, and reduced TG content in oxidative skeletal muscle. Although no effects were observed during a glucose tolerance test (GTT), rimonabant restored insulin sensitivity to that of chow-fed, lean controls during an insulin tolerance test (ITT). Conversely, a single dose of rimonabant to DIO rats had no acute effect on insulin sensitivity. These findings suggest that in diet-induced obesity, chronic CB1 antagonism causes weight loss and improves insulin sensitivity by diverting lipids from storage toward utilization. These effects are independent of the anorectic action of the drug.

Topics: Animals; Body Composition; Cannabinoid Receptor Modulators; Eating; Glucose; Glucose Tolerance Test; Insulin; Lipid Metabolism; Lipids; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Long-Evans; Receptor, Cannabinoid, CB1; Rimonabant

A few thienyl substituted pyrazole derivatives were synthesized to aid in the characterization of the cannabinoid receptor antagonist and also to serve as potentially useful antiobesity agent. Structural requirements for selective CB1 receptor antagonistic activity of 5-thienyl pyrazole derivatives included the structural similarity with potent, specific antagonist rimonabant 1. Compound 3 has been identified as a hair growth stimulator and an antiobesity agent in animal models.

Topics: Animals; Benzoxazines; Chemistry, Pharmaceutical; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP; Drug Design; Hair; Inhibitory Concentration 50; Models, Chemical; Morpholines; Naphthalenes; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Previous research has shown that academic physicians conflicted by funding from the pharmaceutical industry have corrupted evidence based medicine and helped enlarge the market for drugs. Physicians made pharmaceutical-friendly statements, engaged in disease mongering, and signed biased review articles ghost-authored by corporate employees. This paper tested the hypothesis that bias affects review articles regarding rimonabant, an anti-obesity drug that blocks the central cannabinoid receptor.. A MEDLINE search was performed for rimonabant review articles, limited to articles authored by USA physicians who served as consultants for the company that manufactures rimonabant. Extracted articles were examined for industry-friendly bias, identified by three methods: analysis with a validated instrument for monitoring bias in continuing medical education (CME); analysis for bias defined as statements that ran contrary to external evidence; and a tally of misrepresentations about the endocannabinoid system. Eight review articles were identified, but only three disclosed authors' financial conflicts of interest, despite easily accessible information to the contrary. The Takhar CME bias instrument demonstrated statistically significant bias in all the review articles. Biased statements that were nearly identical reappeared in the articles, including disease mongering, exaggerating rimonabant's efficacy and safety, lack of criticisms regarding rimonabant clinical trials, and speculations about surrogate markers stated as facts. Distinctive and identical misrepresentations regarding the endocannabinoid system also reappeared in articles by different authors.. The findings are characteristic of bias that arises from financial conflicts of interest, and suggestive of ghostwriting by a common author. Resolutions for this scenario are proposed.

Topics: Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Conflict of Interest; Disclosure; Drug Industry; Endocannabinoids; Humans; MEDLINE; Obesity; Piperidines; Pyrazoles; Research Support as Topic; Review Literature as Topic; Rimonabant; Scientific Misconduct

Siberian hamsters develop hypophagia and increase catabolism of fat reserves in response to short photoperiods resulting in a natural loss of body weight in winter. We previously found that histamine 3 receptor (H3R) mRNA in the posterior hypothalamus is significantly decreased in short photoperiods. We hypothesized that this lower expression of H3R might contribute to the winter hypophagic state, therefore we examined the effects of the H3R agonist imetit and inverse agonists clobenpropit and thioperamide on food intake. We expressed the Siberian hamster H3R receptor in vitro and confirmed that imetit, clobenpropit and thioperamide are bound specifically, thus validating them as tools to investigate the role of H3R in vivo. Intracerebroventricular administration of histamine decreased food intake in hamsters in the fat summer state. Administration of imetit to hamsters in the lean state increased food intake, whereas administration of inverse agonists decreased food intake, though this was associated with decreased locomotor activity. Both H3R inverse agonists prevented the nocturnal rise in body temperature indicating additional effects on energy expenditure. In summary, our results suggest that increased availability of central histamine or the reduction of H3R activity decrease food intake. These effects are similar to those observed in hamsters in short photoperiods.

Topics: Animals; Body Temperature; Cell Line, Transformed; Cricetinae; Disease Models, Animal; Eating; Histamine; Imidazoles; Injections, Intraventricular; Motor Activity; Obesity; Phodopus; Photoperiod; Piperidines; Receptors, Histamine H3; Seasons; Thiourea; Transfection

We investigated whether rimonabant, a type 1 cannabinoid receptor antagonist, reduces visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in dogs maintained on a hypercaloric high-fat diet (HHFD). To determine whether energy expenditure contributed to body weight changes, we also calculated resting metabolic rate. Twenty male dogs received either rimonabant (1.25 mg.kg(-1).day(-1), orally; n = 11) or placebo (n = 9) for 16 wk, concomitant with a HHFD. VAT, SAT, and nonfat tissue were measured by magnetic resonance imaging. Resting metabolic rate was assessed by indirect calorimetry. By week 16 of treatment, rimonabant dogs lost 2.5% of their body weight (P = 0.029), whereas in placebo dogs body weight increased by 6.2% (P < 0.001). Rimonabant reduced food intake (P = 0.027), concomitant with a reduction of SAT by 19.5% (P < 0.001). In contrast with the VAT increase with placebo (P < 0.01), VAT did not change with rimonabant. Nonfat tissue remained unchanged in both groups. Body weight loss was not associated with either resting metabolic rate (r(2) = 0.24; P = 0.154) or food intake (r(2) = 0.24; P = 0.166). In conclusion, rimonabant reduced body weight together with a reduction in abdominal fat, mainly because of SAT loss. Body weight changes were not associated with either resting metabolic rate or food intake. The findings provide evidence of a peripheral effect of rimonabant to reduce adiposity and body weight, possibly through a direct effect on adipose tissue.

Topics: Animals; Body Weight; Dietary Fats; Dogs; Eating; Energy Metabolism; Intra-Abdominal Fat; Magnetic Resonance Imaging; Male; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Subcutaneous Fat, Abdominal

Topics: Anti-Obesity Agents; Dronabinol; Drug Approval; France; History, 21st Century; Humans; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant

Herein, we disclose the discovery and optimization of 2-piperidin-4-yl-acetamide derivatives as MCH-R1 antagonists. Structural investigation of piperidin-4-yl-amide and piperidin-4-yl-ureas identified 2-piperidin-4-yl-acetamide-based MCH-R1 antagonists with outstanding in vivo efficacy but flawed with high affinity towards the hERG potassium channel. While existing hERG SAR information was employed to discover highly potent MCH-R1 antagonists with minimized hERG inhibition, additional hurdles prevented their subsequent clinical exploration.

Topics: Acetamides; Animals; Anti-Obesity Agents; Cell Line; Chemistry, Pharmaceutical; CHO Cells; Cricetinae; Cricetulus; Drug Design; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Inhibitory Concentration 50; Mice; Models, Chemical; Obesity; Piperidines; Receptors, Pituitary Hormone; Time Factors

The discovery and optimization of piperidin-4-yl-urea derivatives as MCH-R1 antagonists is herein described. Previous work around the piperidin-4-yl-amides led to the discovery of potent MCH-R1 antagonists. However, high affinity towards the hERG potassium channel proved to be an issue. Different strategies to increase hERG selectivity were implemented and resulted in the identification of piperidin-4-yl-urea compounds as potent MCH-R1 antagonists with minimized hERG inhibition.

Topics: Animal Feed; Animals; Cell Line; Chemistry, Pharmaceutical; Drug Design; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Feeding Behavior; Humans; Inhibitory Concentration 50; Models, Chemical; Obesity; Piperidines; Protein Binding; Rats; Receptors, Pituitary Hormone; Urea

Ligand-based virtual screening with a 3D pharmacophore led to the discovery of 30 novel, diverse and drug-like ligands of the human cannabinoid receptor 1 (hCB(1)). The pharmacophore was validated with a hit rate of 16%, binding selectivity versus hCB(2), and expected functional profiles. The discovered compounds provide new tools for exploring cannabinoid pharmacology.

Topics: Animals; Cannabinoids; Cannabis; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Humans; Ligands; Mice; Models, Chemical; Molecular Structure; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

Rimonabant (RM) is a cannabinoid CB1 receptor antagonist useful in the treatment of obesity associated cardiovascular risk factors. Since cannabinoids are vasoactive compounds, the aim of this study is to evaluate the effect of chronic treatment with RM on systolic blood pressure (SBP), and endothelial and vascular reactivity. Obese Zucker rats (OZRs) and their lean counterparts were orally treated during 20 weeks with either RM (10 mg/kg/day). Endothelial and vascular function was assessed in aorta and small mesenteric arteries (SMAs) by concentration response curves to acetylcholine (ACh) and phenylephrine (Phe), respectively. Participation of nitric oxide (NO) was evaluated by incubation with the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) and cyclooxygenase (COX)-derived products involvement was analyzed by incubation with indomethacin (INDO). Plasma lipid profile, insulin and adiponectin were also analyzed. Sympathetic activity was evaluated by urinary excretion of noradrenaline. As expected, RM decreased body weight gain and enhanced adiponectin concentration. Insulin resistance and sympathetic activity were also decreased. The increase in SBP observed in OZRs was reduced by treatment with RM. Aortae and SMAs from OZRs exhibited lower contractile response to Phe, being this effect prevented by RM administration. Although ACh-induced response and NO participation remained unaltered with obesity, enhanced COX-derived constrictor products were found in OZRs. RM treatment neither altered endothelium-dependent relaxation nor L-NAME-sensitive component of the response. Nevertheless, it was able to regulate COX-derived vasoactive products participation. Those effects may contribute to explain some of the cardiovascular protective actions elicited by this drug.

Topics: Acetylcholine; Animals; Aorta; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Heart Rate; Indomethacin; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Obesity; Phenylephrine; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Rimonabant; Vasoconstriction; Vasodilation

Topics: Anti-Obesity Agents; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Type 2 diabetes and obesity are characterized by elevated nocturnal circulating free fatty acids, elevated basal insulin secretion, and blunted glucose-stimulated insulin secretion (GSIS). The CB1 receptor antagonist, Rimonabant, has been shown to improve glucose tolerance and insulin sensitivity in vivo but its direct effect on islets has been unclear. Islets from lean littermates and obese Zucker (ZF) and Zucker Diabetic Fatty (ZDF) rats were incubated for 24 h in vitro and exposed to 11 mmol/l glucose and 0.3 mmol/l palmitate (GL) with or without Rimonabant. Insulin secretion was determined at basal (3 mmol/l) or stimulatory (15 mmol/l) glucose concentrations. As expected, basal secretion was significantly elevated in islets from obese or GL-treated lean rats whereas the fold increase in GSIS was diminished. Rimonabant decreased basal hypersecretion in islets from obese rats and GL-treated lean rats without decreasing the fold increase in GSIS. However, it decreased GSIS in islets from lean rats without affecting basal secretion. These findings indicate that Rimonabant has direct effects on islets to reduce insulin secretion when secretion is elevated above normal levels by diet or in obesity. In contrast, it appears to decrease stimulated secretion in islets from lean animals but not in obese or GL-exposed islets.

Topics: Animals; Glucose; Insulin; Insulin Secretion; Islets of Langerhans; Male; Obesity; Palmitates; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Rimonabant; Secretory Rate

We previously showed in female rats that administration of the cannabinoid CB1 receptor antagonist AM251 reduced energy intake by selectively decreasing consumption of a palatable dietary option in comparison to a standard maintenance chow. In the present study we sought to generalize these findings to mice. We presented 6 week old female C57Bl/6J mice with daily 8 h access to a sugar fat whip dietary option along with ad libitum access to moist chow. Mice were injected daily with either vehicle (equal parts polyethylene glycol and saline, 2 ml/kg) or one of three doses of AM251 (1, 3, or 10 mg/kg). Food intake and body weight were measured daily for 21 days. Although 8 h access to sugar fat whip did not induce overconsumption in female mice, AM251 reduced their energy intake and body weight in a dose-dependent manner. The decrease in energy intake occurred for both chow and sugar fat whip. This difference from results in rats suggests that the effect of AM251 on palatable food intake may only be evident in models that induce overconsumption and/or that rats and mice may react differently to CB1 receptor antagonists.

Topics: Analysis of Variance; Animals; Behavior, Animal; Body Weight; Choice Behavior; Diet; Dietary Fats; Dietary Sucrose; Energy Intake; Female; Food Preferences; Mice; Mice, Inbred C57BL; Nutritive Value; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Time Factors

Endocannabinoids (EC) are involved in regulating energy homeostasis, particularly in promoting hyperphagia and the consumption of a palatable diet. We have previously shown that rats given a high-fat (HF) diet display a transient hyperphagia that is normalized by a process partially dependent on leptin. We now propose that the induction of this hyperphagia is mediated, at least partially, by the EC signaling system. Obesity, including diet-induced and age-related, is associated with dysregulation of the EC system, and obese rodent models are hypersensitive to a cannabinoid-1 (CB1) receptor antagonist. This suggests that aged rats will be more responsive to the anorectic effects of a CB1 receptor antagonist. To test this, we examined the responsiveness to CB1 receptor antagonist, AM251, in young and aged rats during two experimental paradigms. First, we administered AM251 simultaneously with the introduction of an HF diet. Second, AM251 treatment began after the establishment of diet-induced obesity. Responses were measured by changes in body weight and composition, calorie intake, serum leptin, and biochemical indicators. The results demonstrated three key findings. 1) CB1 receptor activity contributes to the hyperphagia seen with the introduction of an HF diet. 2) Increased AM251 sensitivity and efficacy is increased with age and HF feeding, with the greatest responsiveness observed in HF-fed, aged rats. 3) AM251 sensitivity is elevated to a greater extent with HF diet than with established obesity. Thus, both age and an HF diet are associated with enhanced anorectic responses to AM251, but the underlying mechanism of these responses remains speculative.

Topics: Age Factors; Animals; Appetite Depressants; Body Composition; Dietary Fats; Energy Intake; Hyperphagia; Ion Channels; Leptin; Male; Mitochondrial Proteins; Obesity; Piperidines; Pyrazoles; Rats; Rats, Inbred F344; Receptor, Cannabinoid, CB1; STAT3 Transcription Factor; Uncoupling Protein 1; Weight Gain

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Comorbidity; Eating; Epilepsies, Partial; Epilepsy, Generalized; Humans; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant

The cannabinoid receptor 1 (CB(1)) and CB(2) cannabinoid receptors, associated with drugs of abuse, may provide a means to treat pain, mood, and addiction disorders affecting widespread segments of society. Whether the orphan G-protein coupled receptor GPR55 is also a cannabinoid receptor remains unclear as a result of conflicting pharmacological studies. GPR55 has been reported to be activated by exogenous and endogenous cannabinoid compounds but surprisingly also by the endogenous non-cannabinoid mediator lysophosphatidylinositol (LPI). We examined the effects of a representative panel of cannabinoid ligands and LPI on GPR55 using a beta-arrestin-green fluorescent protein biosensor as a direct readout of agonist-mediated receptor activation. Our data demonstrate that AM251 and SR141716A (rimonabant), which are cannabinoid antagonists, and the lipid LPI, which is not a cannabinoid receptor ligand, are GPR55 agonists. They possess comparable efficacy in inducing beta-arrestin trafficking and, moreover, activate the G-protein-dependent signaling of protein kinase CbetaII. Conversely, the potent synthetic cannabinoid agonist CP55,940 acts as a GPR55 antagonist/partial agonist. CP55,940 blocks GPR55 internalization, the formation of beta-arrestin GPR55 complexes, and the phosphorylation of ERK1/2; CP55,940 produces only a slight amount of protein kinase CbetaII membrane recruitment but does not stimulate membrane remodeling like LPI, AM251, or rimonabant. Our studies provide a paradigm for measuring the responsiveness of GPR55 to a variety of ligand scaffolds comprising cannabinoid and novel compounds and suggest that at best GPR55 is an atypical cannabinoid responder. The activation of GPR55 by rimonabant may be responsible for some of the off-target effects that led to its removal as a potential obesity therapy.

Topics: Analgesics; Arrestins; beta-Arrestins; Cannabinoid Receptor Agonists; Cannabinoids; Cell Line; Cyclohexanols; Humans; Ligands; Lysophospholipids; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Obesity; Phosphorylation; Piperidines; Protein Kinase C; Protein Kinase C beta; Pyrazoles; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Rimonabant

When compared with other modifiable cardiovascular risk factors, such as hypertension, dyslipidemia and smoking, obesity remains a surprisingly puzzling condition to prevent and treat. The history of the development of anti-obesity drugs has known more defeats than even partial victories. With very few drugs on the market, and bad publicity related to adverse events, obesity remains an almost completely unmet challenge for the pharmaceutical industry. In light of past experience with endocannabinoid-system antagonists, such as rimonabant, we propose that a major paradigm shift in clinical practice might be necessary to justify the use of pharmacotherapy for obesity. Furthermore, we suggest that the criteria currently used by regulatory authorities to evaluate and approve anti-obesity drugs should be rigorously re-examined. Finally, we discuss how pharmacological approaches that aim to counteract overactivity of the endocannabinoid system should be revisited in the future to treat visceral (intra-abdominal) obesity and its metabolic consequences.

Topics: Anti-Obesity Agents; Cannabinoid Receptor Modulators; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

It has been recently reported that blockade of type 1 cannabinoid (CB1) receptors by specific antagonists or genetic manipulation alleviates dyslipidaemia, hyperglycaemia and insulin resistance in animal models of obesity and type 2 diabetes. However, the precise role of adipokines in the insulin-sensitising effects of the CB1 antagonist rimonabant is not clear.. ob/ob mice were treated with different doses of rimonabant and then subjected to an oral glucose tolerance test. The expression of different adipokines in white adipose tissue was analysed by quantitative real-time PCR.. Rimonabant (30 mg/kg) significantly inhibited body weight and fat pad weight gain (P < 0.05) and improved glucose tolerance. Gene expression analysis indicated that tumour necrosis factor-alpha, visfatin and retinol binding protein-4 were downregulated in the adipose tissue of ob/ob mice treated with rimonabant compared with controls, whereas adiponectin was significantly upregulated.. Rimonabant-mediated alteration of adipokines in white adipose tissues may play a role in improving insulin sensitivity in obese animals.

Topics: Adipokines; Adiponectin; Adipose Tissue; Adipose Tissue, White; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Down-Regulation; Female; Gene Expression; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Mice; Mice, Knockout; Models, Animal; Nicotinamide Phosphoribosyltransferase; Obesity; Organ Size; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Retinol-Binding Proteins, Plasma; Reverse Transcriptase Polymerase Chain Reaction; Rimonabant; RNA, Messenger; Tumor Necrosis Factor-alpha

Obesity is associated with increased risk of conditions such as hypertension, dyslipidaemia, diabetes mellitus, and obstructive sleep apnoea. Pharmacotherapy for obesity should be considered in combination with lifestyle changes in obese patients, or overweight patients with other conditions that put them at risk of developing heart disease. Sibutramine and orlistat are the only two anti-obesity medications approved for long-term use. Sibutramine is a serotonergic and adrenergic drug that reduces food intake. Orlistat is a gastrointestinal lipase inhibitor that interferes with fat absorption. However, it commonly causes flatulence and diarrhoea. Rimonabant is the first of a series of endocannabinoid receptor antagonists. It was approved by the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMEA) as an adjunct to diet and exercise in treating obesity in 2006. However, despite the extensive clinical trial data, EMEA announced in 2008 that it has recommended suspension of rimonabant because of its psychiatric side effects. Studies evaluating the long-term safety and efficacy of anti-obesity agents are needed.

Topics: Anti-Obesity Agents; Appetite Depressants; Body Mass Index; Body Weight; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Lactones; Lipase; Meta-Analysis as Topic; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Time Factors

The ability of the endocannabinoid (EC) system to control appetite, food intake and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The EC system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, cannabinoid type 1 receptors (CB1) and ECs are integrated components of the networks controlling appetite and food intake. Interestingly, the EC system has recently been shown to control several metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the skeletal muscles and the endocrine pancreas. The relevance of the system is further strengthened by the notion that visceral obesity seems to be a condition in which an overactivation of the EC system occurs; therefore, drugs interfering with this overactivation by blocking CB1 receptors are considered valuable candidates for the treatment of obesity and related cardiometabolic risk factors.

Topics: Amides; Animals; Cannabinoid Receptor Modulators; Clinical Trials as Topic; Eating; Energy Metabolism; Feeding and Eating Disorders; Humans; Islets of Langerhans; Liver; Muscle, Skeletal; Obesity; Piperidines; Pyrazoles; Pyridines; Receptor, Cannabinoid, CB1; Rimonabant

The endocannabinoid system is a physiological system, which is responsible for the control of glucose and lipid-metabolism, as well as for the regulation of the body weight. The endocannabinoid receptors are distributed both in the central and peripher nervous system. Different studies provide evidence that an hyperactive endocannabinoid system is involved in the development of different cardiovascular risk factors. The pharmacological blockade of these cannabinoid receptors may represent a new approach for cardiometabolic risk management.

Topics: Blood Glucose; Body Weight; Cannabinoid Receptor Modulators; Controlled Clinical Trials as Topic; Diabetes Mellitus, Type 2; Endocannabinoids; Energy Metabolism; Europe; Humans; Insulin Resistance; Lipids; Obesity; Overweight; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Humans; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant

The observed antiobesity effect of rimonabant (1) in a pharmacological rodent model 10 years ago has led to a surge in the search for novel cannabinoid CB1 antagonists as a new therapeutic target for the treatment of obesity. Rimonabant showed clinical efficacy in the treatment of obesity and also improved cardiovascular and metabolic risk factors. Cannabinoid CB1 receptor antagonists have also good prospects in other therapeutic areas, including smoking and alcohol addiction as well as cognitive impairment. Solvay's research achievements in this fast-moving field are reported in relation with the current state of the art. Several medicinal chemistry strategies have been pursued. The application of the concept of conformational constraint led to the discovery of more rigid analogs of the prototypic CB1 receptor antagonist rimonabant. Replacement of the central heterocyclic pyrazole ring in rimonabant yielded imidazoles, triazoles, and thiazoles as selective CB1 receptor antagonists. Dedicated medium-throughput screening efforts delivered one 3,4-diarylpyrazoline hit. Its poor pharmacokinetic properties were successfully optimized which led to the discovery of orally active and highly CB1/CB2 receptor selective analogs in this series. Regioisomeric 1,5-diarylpyrazolines, 1,2-diarylimidazolines, and water-soluble imidazoles have been designed as novel CB1 receptor antagonist structure classes.

Topics: Animals; Anti-Obesity Agents; CHO Cells; Cricetinae; Cricetulus; Humans; Imidazoles; Isomerism; Models, Chemical; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Solubility; Structure-Activity Relationship; Thiazoles; Triazoles; Water

Leptin receptor dysfunction results in overeating and obesity. Leptin regulates hypothalamic signaling that underlies the motivation to hyperphagia, but the interaction between leptin and cannabinoid signaling is poorly understood. We evaluated the role of cannabinoid 1 receptors (CB(1)R) in overeating and the effects of food deprivation on CB(1)R in the brain. One-month-old Zucker rats were divided into unrestricted and restricted (fed 70% of unrestricted rats) diet groups and maintained until adulthood (4 months). Levels of relative binding sites of CB(1)R (CB(1)R binding levels) were assessed using [(3)H] SR141716A in vitro autoradiography. These levels were higher (except cerebellum and hypothalamus) at 4 months than at 1 month of age. One month CB(1)R binding levels for most brain regions did not differ between Ob and Lean (Le) rats (except in frontal and cingulate cortices in Le and in the hypothalamus in Ob). Four month Ob rats had higher CB(1)R binding levels than Le in most brain regions and food restriction was associated with higher CB(1)R levels in all brain regions in Ob, but not in Le rats. CB(1)R binding levels increased between adolescence and young adulthood which we believe was influenced by leptin and food availability. The high levels of CB(1)R in Ob rats suggest that leptin's inhibition of food-intake is in part mediated by downregulation of CB(1)R and that leptin interferes with CB(1)R upregulation under food-deprivation conditions. These results are consistent with prior findings showing increased levels of endogenous cannabinoids in the Ob rats corroborating the regulation of cannabinoid signaling by leptin.

Topics: Age Factors; Animals; Autoradiography; Body Weight; Cannabinoid Receptor Modulators; Eating; Food Deprivation; Hyperphagia; Leptin; Limbic System; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Receptors, Leptin; Rimonabant; Tritium; Up-Regulation

Intra-abdominal fat mass, or central adiposity, and cardiovascular risk are strongly correlated. Adipose tissue is an endocrine organ that secretes hormones and cytokines influencing appetite, energy metabolism, and atherosclerosis. Rimonabant is the first selective blocker of the cannabinoid-1 receptor in development for the treatment of obesity, diabetes mellitus typ 2, and cardiometabolic risk factors. This article provides an review of efficacy of rimonabant the first selective blocker of the cannabinoid-1 receptor.

Topics: Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant

Topics: Animals; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Clinical Trials as Topic; Delusions; Drug Administration Schedule; Humans; Lipogenesis; Mice; Mice, Knockout; Models, Biological; Nerve Endings; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Schizophrenia; Waist-Hip Ratio; Weight Loss

Topics: Anti-Obesity Agents; Atherosclerosis; Coronary Artery Disease; Ethics, Research; Humans; Obesity; Piperidines; Placebos; Pyrazoles; Receptor, Cannabinoid, CB1; Research Design; Rimonabant; Ultrasonography

Topics: Anti-Obesity Agents; Depression; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Safety; Treatment Outcome; Weight Loss

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Humans; Intra-Abdominal Fat; Obesity; Patient Selection; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant; Risk Assessment; Treatment Outcome

Blockade of the CB1 receptor is one of the promising strategies for the treatment of obesity. Although antagonists suppress food intake and reduce body weight, the role of central versus peripheral CB1 activation on weight loss and related metabolic parameters remains to be elucidated. We therefore specifically assessed and compared the respective potential relevance of central nervous system (CNS) versus peripheral CB1 receptors in the regulation of energy homeostasis and lipid and glucose metabolism in diet-induced obese (DIO) rats.. Both lean and DIO rats were used for our experiments. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR, and euglycemic-hyperinsulinemic clamps were used for insulin sensitivity and glucose metabolism studies.. Specific CNS-CB1 blockade decreased body weight and food intake but, independent of those effects, had no beneficial influence on peripheral lipid and glucose metabolism. Peripheral treatment with CB1 antagonist (Rimonabant) also reduced food intake and body weight but, in addition, independently triggered lipid mobilization pathways in white adipose tissue and cellular glucose uptake. Insulin sensitivity and skeletal muscle glucose uptake were enhanced, while hepatic glucose production was decreased during peripheral infusion of the CB1 antagonist. However, these effects depended on the antagonist-elicited reduction of food intake.. Several relevant metabolic processes appear to independently benefit from peripheral blockade of CB1, while CNS-CB1 blockade alone predominantly affects food intake and body weight.

Topics: Acetyl-CoA Carboxylase; Adipose Tissue; Animals; Body Weight; Chromatography, Liquid; Dietary Fats; Eating; Fatty Acid Synthases; Glucose Clamp Technique; Lipid Metabolism; Lipoprotein Lipase; Male; Mass Spectrometry; Obesity; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Reverse Transcriptase Polymerase Chain Reaction; Rimonabant; Triglycerides

Visceral (intra-abdominal) obesity is associated with a cluster of cardiovascular risk factors that together promote macrovascular and microvascular disease. An atherogenic dyslipidemia, characterized by an increase in serum triglyceride-rich lipoproteins, a decrease in plasma levels of high-density lipoprotein cholesterol and increased prevalence of small, dense low-density lipoprotein particles (although low-density lipoprotein cholesterol levels are normal or only modestly elevated), as well as chronic inflammation, play key roles in the pathogenesis of visceral obesity-related complication. These abnormalities may be consequent to a global metabolic effect of insulin resistance. Pharmacological treatments, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, fibric acid derivatives, insulin sensitizers and cannabinoid receptor type 1 blockers, are often required to correct the dyslipidemia of visceral obesity. The basis for a multiple approach to correcting dyslipoproteinemia in visceral obesity and the metabolic syndrome relies on understanding the mechanisms of action of the individual therapeutic components.

Topics: Atherosclerosis; Bradykinin; Cannabinoid Receptor Antagonists; Cannabinoids; Cardiovascular Diseases; Cholesterol, HDL; Clofibric Acid; Dyslipidemias; Female; Humans; Hypolipidemic Agents; Lipoproteins, HDL; Lipoproteins, LDL; Male; Meta-Analysis as Topic; Obesity; Piperidines; Prospective Studies; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Sex Factors

Obesity is reaching epidemic proportions worldwide and it is correlated with various comorbidities, among which the most relevant are diabetes mellitus, arterial hypertension, and cardiovascular diseases. Obesity management is a modern challenge because of the rapid evolution of unfavorable lifestyles and unfortunately there are no effective treatments applicable to the large majority of obese/overweight people. The current medical attitude is to treat the complications of obesity (e.g. dyslipidemia, hypertension, diabetes, and cardiovascular diseases). However, the potential of treating obesity is enormous, bearing in mind that a volitional weight loss of 10 kg is associated with important risk factor improvement: blood pressure -10 mmHg, total cholesterol -10%, LDL cholesterol -15%, triglycerides -30%, fasting glucose -50%, HDL cholesterol +8%. Drug treatment for obesity is an evolving branch of pharmacology, burdened by severe side effects and consequences of the early drugs, withdrawn from the market, and challenged by the lack of long-term data on the effect of medications on obesity-related morbidity and mortality, first of all cardiovascular diseases. In Europe three antiobesity drugs are currently licensed: sibutramine, orlistat, and rimonabant; important trials with clinical endpoints are ongoing for sibutramine and rimonabant. While waiting for their results, it is convenient to evaluate these drugs for their effects on body weight and cardiometabolic risk factors. Sibutramine is a centrally acting serotonin/noradrenaline reuptake inhibitor that mainly increases satiety. At the level of brown adipose tissue, sibutramine can also facilitate energy expenditure by increasing thermogenesis. The long-term studies (five) documented a mean differential weight reduction of 4.45 kg for sibutramine vs placebo. Considering the principal studies, attrition rate was 43%. This drug not only reduces body weight and waist circumference, but it decreases triglycerides and uric acid as well and it increases HDL cholesterol; in diabetics it improves glycated hemoglobin. Sibutramine has conflicting effects on blood pressure: in some studies there was a minimal decrease, in some others a modest increase. In all the studies this drug increased pulse rate. Sibutramine is not recommended in patients with uncontrolled hypertension, or in case of history of cardio- and cerebrovascular disease. Orlistat is a pancreatic lipase inhibitor that reduces fat absorption by parti

Topics: Anti-Obesity Agents; Appetite Depressants; Body Mass Index; Bradykinin; Cannabinoid Receptor Antagonists; Cannabinoids; Cyclobutanes; Diabetes Mellitus, Type 2; Double-Blind Method; Economics, Pharmaceutical; Humans; Lactones; Lipase; Meta-Analysis as Topic; Obesity; Orlistat; Piperidines; Practice Guidelines as Topic; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Risk Factors; Time Factors; Weight Loss

The incidence of obesity is increasing worldwide, and in the USA approximately 100 million adults are overweight or obese. Orlistat and sibutramine are the drugs used at present for weight loss, but they both have a relatively modest effect.. This evaluation is of the Rimonabant in Obesity (RIO) programme of clinical trials, and of the first trial to determine whether rimonabant has any effect on a clinical outcome. The Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant - the Intravascular Ultrasound Study (STRADIVARIUS) determined whether treatment with rimonabant decreased atherosclerosis.. The individual trials of the RIO programme showed that rimonabant 20 mg caused body weight loss, and also caused small decreases in waist circumference, plasma triglycerides and fasting glucose levels, and the incidence of the metabolic syndrome, while increasing levels of HDL cholesterol. Gastrointestinal side effects were the most common reported in the individual trials. However, when the five trials were combined, a small but significant increase in the incidence of depression and anxiety became apparent with rimonabant 20 mg. STRADIVARIUS showed that rimonabant 20 mg had no effect on atherosclerosis that was not progressing in subjects who were mostly also taking antithrombotic agents, statins, beta-blockers and angiotensin inhibitors.. At present, it is doubtful whether the benefits of rimonabant outweigh the risks. Unless rimonabant is shown to have benefits in ongoing clinical outcome studies, there is little rationale to support its use in the treatment of obesity.

Topics: Controlled Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Obesity; Piperidines; Placebos; Pyrazoles; Rimonabant; Treatment Outcome

The Tako-Tsubo syndrome (or transient left ventricular apical balloning) is a new clinical entity, very similar to acute myocardial infarction, but different by its excellent short-term prognosis. It has been reported after a physical or an emotional stress, and it is diagnosed by a coronary angiogram and a left ventriculography. We report here a case of Tako-Tsubo syndrome related to an anaphylactic shock caused by succinylcholine during general anaesthesia of a female patient, wearing an unadjustable gastric band.

Topics: Anaphylaxis; Anesthesia, General; Anesthesia, Intravenous; Diabetes Mellitus, Type 2; Female; Gastroplasty; Heart Arrest; Humans; Intraoperative Complications; Laparoscopy; Middle Aged; Neuromuscular Depolarizing Agents; Obesity; Pelvic Floor; Piperidines; Postoperative Complications; Propofol; Pulmonary Edema; Remifentanil; Succinylcholine; Takotsubo Cardiomyopathy; Ventricular Fibrillation

The visceral (VAT) and subcutaneous (SCAT) adipose tissues play different roles in physiology and obesity. The molecular mechanisms underlying their expansion in obesity and following body weight reduction are poorly defined.. C57Bl/6 mice fed a high fat diet (HFD) for 6 months developed low, medium, or high body weight as compared to normal chow fed mice. Mice from each groups were then treated with the cannabinoid receptor 1 antagonist rimonabant or vehicle for 24 days to normalize their body weight. Transcriptomic data for visceral and subcutaneous adipose tissues from each group of mice were obtained and analyzed to identify: i) genes regulated by HFD irrespective of body weight, ii) genes whose expression correlated with body weight, iii) the biological processes activated in each tissue using gene set enrichment analysis (GSEA), iv) the transcriptional programs affected by rimonabant.. In VAT, "metabolic" genes encoding enzymes for lipid and steroid biosynthesis and glucose catabolism were down-regulated irrespective of body weight whereas "structure" genes controlling cell architecture and tissue remodeling had expression levels correlated with body weight. In SCAT, the identified "metabolic" and "structure" genes were mostly different from those identified in VAT and were regulated irrespective of body weight. GSEA indicated active adipogenesis in both tissues but a more prominent involvement of tissue stroma in VAT than in SCAT. Rimonabant treatment normalized most gene expression but further reduced oxidative phosphorylation gene expression in SCAT but not in VAT.. VAT and SCAT show strikingly different gene expression programs in response to high fat diet and rimonabant treatment. Our results may lead to identification of therapeutic targets acting on specific fat depots to control obesity.

Topics: Abdominal Fat; Adipocytes; Animals; Blood Glucose; Body Weight; Cannabinoid Receptor Antagonists; Dietary Fats; Extracellular Matrix; Gene Expression Regulation; Insulin; Leptin; Lipoproteins, VLDL; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Rimonabant; Subcutaneous Fat; Transcription, Genetic

A wave of terminations of development programmes for cannabinoid receptor 1 blockers for obesity indicates the demise of a drug class that was once anticipated to yield blockbusters. Nevertheless, lessons learned might help salvage something for future such approaches.

Topics: Anti-Obesity Agents; Cannabinoid Receptor Modulators; Dexfenfluramine; Eating; Humans; Life Style; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Risk Assessment; Risk Factors

Overweight and obesity are major factors contributing to the development of type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). In addition to the many physical and metabolic consequences of obesity, there are also mental health consequences, in particular, the risk for depression. Depression can lead to poor self-care, poor treatment compliance, and possible increased morbidity and mortality from such illnesses as type 2 DM and CVD. Lifestyle modification for the treatment of overweight and obesity is rarely successful over the long term, and use of surgery is limited by eligibility criteria; therefore, researchers and clinicians continue to explore pharmacotherapy, with intense efforts being directed toward the development of agents that, optimally, will reduce weight and simultaneously reduce or eliminate modifiable cardiovascular and metabolic risk factors. Among the promising new agents are the CB(1) receptor antagonists. These agents target receptors of the endocannabinoid system, a neuromodulatory system recently found to influence energy balance, eating behavior, and metabolic homeostasis via central and peripheral mechanisms. In animal and clinical studies, antagonism of CB(1) receptors has resulted in meaningful weight loss and improvement of lipid and glycemic profiles. Thus, these agents may provide a rational and effective approach for the management of not only overweight and obesity but also their metabolic and cardiovascular sequelae.

Topics: Amides; Anti-Obesity Agents; Cannabinoid Receptor Modulators; Cyclobutanes; Depression; Endocannabinoids; Humans; Lactones; Life Style; Metabolic Syndrome; Obesity; Orlistat; Piperidines; Pyrazoles; Pyridines; Rimonabant; Risk

In this report, we present the case of a patient with a relapse of schizophrenia following an episode of depression and increased anxiety after antiobesity treatment with rimonabant, a cannabinoid type 1 receptor antagonist.. After 4 weeks of treatment the patient developed psychiatric symptoms, i.e. depressed mood and elevated anxiety. Four months after the discontinuation of rimonabant, the patient presented with psychotic symptoms fulfilling ICD-10 criteria of paranoid schizophrenia. Antipsychotic treatment with quetiapine was initialized. A stable recovery took further 4 weeks in which combined treatment with quetiapine and ziprasidone was given.. The course of the illness suggests that the continuous affective symptoms, which were most likely a side effect of rimonabant, may have triggered the psychosis analogous to the stress-diathesis model of schizophrenia. As a consequence, rimonabant may not be the first choice in obese patients with a history of schizophrenia due to a potentially increased risk of a relapse via an indirect mechanism.

Topics: Adult; Anti-Obesity Agents; Chronic Disease; Female; Humans; Obesity; Piperidines; Pyrazoles; Recurrence; Rimonabant; Schizophrenia, Paranoid

Anandamide and oleoylethanolamide (OEA) are lipid mediators that regulate feeding and lipid metabolism. While anandamide, a cannabinoid CB1 receptor agonist, promotes feeding and lipogenesis, oleoylethanolamide, an endogenous agonist of peroxisome proliferator activated receptor alpha (PPAR-alpha), decreases food intake and activates lipid mobilization and oxidation. The treatment with a cannabinoid CB1 receptor antagonist results in reduction of body weight gain and cholesterol in obese humans and rodents. In the present study, we show the benefits of the treatment of obese Zucker rats with a combination of a cannabinoid CB1 receptor antagonist (Rimonabant) and oleoylethanolamide. This combinational therapy improved the separate effects of Rimonabant and OEA, and resulted in marked decreases on feeding, body weight gain, and plasma cholesterol levels. Additionally, the treatment with both drugs reduced the hepatic steatosis observed in Zucker rats, decreasing liver fat deposits and damage, as revealed by the levels of alanine aminotransferase activity in serum. The combined treatment inhibits the expression of stearoyl coenzyme-A desaturase-1 (SCD-1), a pivotal enzyme in lipid biosynthesis and triglyceride mobilization that is linked to obesity phenotypes. These results support the use of combined therapies with cannabinoid CB1 receptor antagonists and PPAR-alpha agonists for the treatment of obesity associated with dyslipemia.

Topics: Analysis of Variance; Animals; Behavior, Animal; Body Water; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Eating; Endocannabinoids; Gene Expression Regulation, Enzymologic; Lipid Metabolism; Male; Metabolism; Obesity; Oleic Acids; Piperidines; Pyrazoles; Rats; Rats, Wistar; Rats, Zucker; Receptor, Cannabinoid, CB1; Rimonabant; Stearoyl-CoA Desaturase; Time Factors

SR141716 has been shown to significantly inhibit food intake and reduce body weight by antagonizing CB(1) receptors. The gut hormones peptide YY(3-36) (PYY(3-36)) and oxyntomodulin (OXM) inhibit food intake through Y(2) and Glucagon-Like-Peptide (GLP)-1 receptors respectively.. To determine the effects of co-administration of SR141716 with either PYY(3-36) or OXM in mice on food intake.. Mice (n = 14 per group) were fasted for 16 h prior to study days and given two intraperitoneal injections: study 1, vehicle-saline, SR141716-saline, vehicle-PYY3-36 or SR141716-PYY3-36; study 2: vehicle-saline, SR141716-saline, vehicle-OXM or SR141716-OXM. Food was returned and measured following injections.. Co-administration of SR141716-PYY(3-36) or SR141716-OXM showed greater inhibition in food intake when compared with administration of SR141716, PYY(3-36) or OXM alone.. Our data show that SR141716 in combination with PYY(3-36) or OXM reduces food intake additively in mice.

Topics: Animals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Eating; Fasting; Mice; Obesity; Oxyntomodulin; Peptide Fragments; Peptide YY; Piperidines; Pyrazoles; Rimonabant; Treatment Outcome

Topics: Adenoma; Anti-Obesity Agents; Apoptosis; Carcinoma; Cell Transformation, Neoplastic; Colorectal Neoplasms; Dronabinol; Drug Inverse Agonism; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of kappaB kinase, and tumor necrosis factor-alpha, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.

Topics: Adiponectin; Animals; Blood Glucose; HSP72 Heat-Shock Proteins; Humans; Hyperinsulinism; Hyperthermia, Induced; I-kappa B Kinase; Insulin; Insulin Resistance; Liver; MAP Kinase Kinase 4; Mice; Mice, Transgenic; Muscle, Skeletal; Obesity; Oximes; Phosphorylation; Piperidines

To better define the efficacy and safety of rimonabant, the first selective cannabinoid type 1 (CB(1)) receptor antagonist, in a large population of overweight and obese patients using pooled efficacy data from three Phase III nondiabetes Rimonabant in Obesity and Related Metabolic Disorders (RIO) studies, selected efficacy data from the RIO-Diabetes study, and pooled safety data for all four RIO studies.. The RIO studies enrolled patients who were either overweight (BMI >27 kg/m(2)) with at least one comorbidity (i.e., hypertension, dyslipidemia, or, for RIO-Diabetes, type 2 diabetes) or obese. All patients received daily treatment with rimonabant (5 or 20 mg) or placebo for 1 year plus a hypocaloric diet (600 kcal/day deficit) and advice on increased physical activity. RIO-Europe (n = 1,508), RIO-North America (n = 3,045), and RIO-Lipids (n = 1,036) excluded patients with type 2 diabetes; untreated dyslipidemia was an entry requirement for RIO-Lipids. RIO-Diabetes (n = 1,047) required the presence of type 2 diabetes inadequately controlled by sulfonylurea or metformin monotherapy.. The pooled intention-to-treat population comprised 5,580 patients without diabetes (3,165 completed treatment) and 1,047 patients with diabetes (692 completed treatment). Most efficacy measures improved during the 4-week placebo run-in period, except that HDL cholesterol decreased as expected in the early phase of a hypocaloric diet. After 1 year of randomized treatment, changes from baseline with 20 mg rimonabant in the nondiabetic population were as follows: body weight -6.5 kg, waist circumference -6.4 cm, HDL cholesterol +16.4%, triglycerides -6.9%, fasting insulin -0.6 muU/ml, and homeostasis model assessment for insulin resistance (HOMA-IR) -0.2 (all P < 0.001 vs. placebo). In the diabetic population, 20 mg rimonabant reduced A1C levels by 0.6% (P < 0.001 vs. placebo). Regression analysis of change in HDL cholesterol, triglycerides, adiponectin (in RIO-Lipids), and A1C (in RIO-Diabetes) versus body weight at 1 year by ANCOVA suggested that 45-57% of the effect of rimonabant could not be explained by the observed weight loss. At 1 year, adverse events more frequently reported with rimonabant were gastrointestinal, neurological, and psychiatric in nature. Serious adverse events were infrequent and almost equivalent to placebo. Overall discontinuation rates were similar across treatment groups, except discontinuation from adverse events, which occurred more frequently with 20 mg rimonabant versus placebo (most commonly, depressive disorders [1.9 vs. 0.8%], nausea [1.4 vs. 0.1%], mood alterations with depressive symptoms [1.0 vs. 0.6%], and anxiety [1.0 vs. 0.3%]). A thorough review of psychiatric and neurological adverse events was performed.. In overweight/obese patients, 20 mg/day rimonabant produced weight loss and significant improvements in multiple cardiometabolic risk factors such as waist circumference, A1C, HDL cholesterol, and triglycerides. Rimonabant was generally well tolerated, with more frequently reported adverse events being gastrointestinal, neurological, and psychiatric in nature.

Topics: Cannabinoid Receptor Antagonists; Cannabinoids; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Diet, Reducing; Exercise; Heart Diseases; Humans; Metabolic Diseases; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Safety

5-Hydroxytryptamine (5-HT)(2C) receptor agonists hold promise for the treatment of obesity. In this study, we describe the in vitro and in vivo characteristics of lorcaserin [(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3 benzazepine], a selective, high affinity 5-HT(2C) full agonist. Lorcaserin bound to human and rat 5-HT(2C) receptors with high affinity (K(i) = 15 +/- 1 nM, 29 +/- 7 nM, respectively), and it was a full agonist for the human 5-HT(2C) receptor in a functional inositol phosphate accumulation assay, with 18- and 104-fold selectivity over 5-HT(2A) and 5-HT(2B) receptors, respectively. Lorcaserin was also highly selective for human 5-HT(2C) over other human 5-HT receptors (5-HT(1A), 5-HT(3), 5-HT(4C), 5-HT5(5A), 5-HT(6), and 5-HT(7)), in addition to a panel of 67 other G protein-coupled receptors and ion channels. Lorcaserin did not compete for binding of ligands to serotonin, dopamine, and norepinephrine transporters, and it did not alter their function in vitro. Behavioral observations indicated that unlike the 5-HT(2A) agonist (+/-)-1-(2,5-dimethoxy-4-phenyl)-2-aminopropane, lorcaserin did not induce behavioral changes indicative of functional 5-HT(2A) agonist activity. Acutely, lorcaserin reduced food intake in rats, an effect that was reversed by pretreatment with the 5-HT(2C)-selective antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl-carbamoyl]indoline (SB242,084) but not the 5-HT(2A) antagonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (MDL 100,907), demonstrating mediation by the 5-HT(2C) receptor. Chronic daily treatment with lorcaserin to rats maintained on a high fat diet produced dose-dependent reductions in food intake and body weight gain that were maintained during the 4-week study. Upon discontinuation, body weight returned to control levels. These data demonstrate lorcaserin to be a potent, selective, and efficacious agonist of the 5-HT(2C) receptor, with potential for the treatment of obesity.

Topics: Aminopyridines; Animals; Behavior, Animal; Benzazepines; Body Weight; Brain; Cell Line; Dopamine; Eating; Fluorobenzenes; Humans; Indoles; Male; Norepinephrine; Obesity; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Recombinant Proteins; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Transfection

Topics: Anti-Obesity Agents; Depression; Depressive Disorder, Major; Humans; Obesity; Patient Selection; Piperidines; Pyrazoles; Rimonabant; Suicide

Topics: Anti-Obesity Agents; Depression; Depressive Disorder, Major; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant

GIP receptor antagonism with (Pro3)GIP protects against obesity, insulin resistance, glucose intolerance and associated disturbances in mice fed high-fat diet. Furthermore, cannabinoid CB1 receptor antagonism with AM251 reduces appetite and body weight gain in mice. The present study has examined and compared the effects of chronic daily administrations of (Pro3)GIP (25 nmol/kg body weight), AM251 (6 mg/kg body weight) and a combination of both drugs in high-fat fed mice. Daily i.p. injection of (Pro3)GIP, AM251 or combined drug administration over 22 days significantly (P<0.05 to <0.01) decreased body weight compared with saline-treated controls. This was associated with a significant (P<0.05 to <0.01) reduction of food intake in mice treated with AM251. Plasma glucose levels and glucose tolerance were significantly (P<0.05) lowered by 22 days (Pro3)GIP, AM251 or combined drug treatment. These changes were accompanied by a significant (P<0.05) improvement of insulin sensitivity in all treatment groups. In contrast, AM251 lacked effects on glucose tolerance, metabolic response to feeding and insulin sensitivity in high-fat mice when administered acutely. These data indicate that chemical blockade of GIP- or CB1-receptor signaling using (Pro3)GIP or AM251, respectively provides an effective means of countering obesity and related abnormalities induced by consumption of high-fat energy-rich diet. AM251 lacks acute effects on glucose homeostasis and there was no evidence of a synergistic effect of combined treatment with (Pro3)GIP.

Topics: Animals; Appetite; Area Under Curve; Blood Glucose; Body Weight; Dietary Fats; Drug Evaluation, Preclinical; Drug Interactions; Eating; Female; Gastric Inhibitory Polypeptide; Glucose Intolerance; Glucose Tolerance Test; Injections, Intraperitoneal; Insulin; Insulin Resistance; Mice; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1

Rimonabant is a novel drug for treatment of obesity. Four randomised studies have shown a significant effect of 20 mg rimonabant on bodyweight and other cardiovascular risk factors. The weight loss is modest, approximately 5 %, and the patients regain their baseline weight within 9 months after withdrawal. There is no evidence that rimonabant reduces morbidity or mortality, and no comparative studies with orlistat or sibutramine have been performed. Long-term effects of blocking the endocannabinoid system are not known. Side effects are nausea, depressive symptoms, anxiety and dizziness. There are reports on increased suicidality, and rimonabant is contraindicated in depressed patients.

Topics: Animals; Anti-Obesity Agents; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Weight Loss

Topics: Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Antineoplastic Agents; Carcinoma; Cell Survival; Colorectal Neoplasms; Dose-Response Relationship, Drug; Humans; Mice; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors

Diabetes mellitus (DM) is a worldwide epidemic. Its prevalence is rapidly increasing in both developing and developed countries. Coronary heart disease (CHD) is highly prevalent and is the major cause of morbidity and mortality in patients with diabetes. Individuals with prediabetes states, with or without known CHD, should undergo lifestyle modifications aimed at preventing DM. In patients with CHD and DM, routine use of aspirin and an angiotensin-converting enzyme inhibitor, along with strict glycemic, blood pressure, and lipid control, is strongly recommended. Intense insulin therapy may be needed for glycemic control, and high-dose statin therapy may be needed for lipid control. For blood pressure control, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are considered first-line therapy. Noncompliance with medications and/or lifestyle measures and underprescription of evidence-based therapies remain important unsolved problems.

Topics: Antihypertensive Agents; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Diabetes Mellitus; Diabetic Angiopathies; Humans; Hyperglycemia; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Life Style; Myocardial Infarction; Obesity; Pioglitazone; Piperidines; Platelet Aggregation Inhibitors; Prediabetic State; Pyrazoles; Ramipril; Rimonabant; Risk Assessment; Thiazolidinediones; Triglycerides; Weight Loss

The use of oral anti-diabetes medicines should be considered when nutritional control methods and physical exercise programs have failed. These medicines have several types of active mechanisms: to stimulate pancreatic secretion of insulin, to delay the absorption of carbohydrates in the intestines, to sensitize tissues to the action of insulin. Sulfonylureas are the pharmaceutical group most commonly utilized in the treatment of type 2 diabetes mellitus.

Topics: Administration, Oral; Biguanides; Body Mass Index; Contraindications; Diabetes Mellitus; Humans; Hypoglycemic Agents; Motivation; Obesity; Piperidines; Sulfonylurea Compounds; Trisaccharides

A series of 5,6-diaryl-2-amino-pyrazines were prepared and found to have antagonist-like properties at the CB1 receptor. Subsequent SAR studies optimized both receptor potency and drug-like properties including solubility and Cytochrome-P450 inhibition potential. Optimized compounds were demonstrated to be inverse agonists and compared in vivo with rimonabant for their ability to inhibit food intake, to occupy central CB1 receptors and to influence hormonal markers associated with obesity.

Topics: Animals; Blood Glucose; Combinatorial Chemistry Techniques; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Disease Models, Animal; Feeding Behavior; Humans; Microsomes, Liver; Molecular Structure; Obesity; Piperidines; Pyrazines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant; Structure-Activity Relationship

Topics: Anti-Obesity Agents; Drug Interactions; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

A series of pyrrolopyridinones was designed and synthesized as constrained analogs of the pyrazole CB-1 antagonist rimonabant. Certain examples exhibited very potent hCB-1 receptor binding affinity and functional antagonism with Ki and Kb values below 10 nM, and with high selectivity for CB-1 over CB-2 (>100-fold). A representative analog was established to cause significant appetite suppression and reduction in body weight gain in industry-standard rat models used to develop new therapeutics for obesity.

Topics: Animals; Anti-Obesity Agents; Body Weight; Crystallography, X-Ray; Drug Design; Eating; Humans; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Obesity; Piperidines; Pyrazoles; Pyridones; Pyrroles; Rats; Rats, Wistar; Rats, Zucker; Receptor, Cannabinoid, CB1; Rimonabant; Structure-Activity Relationship; Weight Gain

The endocannabinoid system modulates many pathophysiological functions, including the brain pathways involved in the regulation of body weight and adipose tissue function. The selective cannabinoid CB(1) receptor antagonist, rimonabant, has undergone phase III clinical testing as anti-obesity drug. Obesity is considered a mild inflammatory condition and predisposes individuals to an increased risk of developing many diseases. It has been recently suggested that a successful intervention to treat obesity is a therapy combining weight-reducing drugs with anti-inflammatory ones. In this scenario, rimonabant's anti-obesity action is accompanied by favorable changes in markers for insulin resistance, C-reactive protein, adiponectin, tumor necrosis factor alpha (TNFalpha). The results reported by Croci and Zarini in this issue highlight the anti-inflammatory and anti-hyperalgesic effect of rimonabant in obese animals, so suggesting that it could provide a more general and aggressive strategy to protect obese patients from many pathological risks.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Arthritis; Humans; Hyperalgesia; Inflammation; Obesity; Pain Measurement; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Obesity is a risk factor for several inflammation-based diseases including arthritis. We investigated the anti-nociceptive and anti-inflammatory effects of the cannabinoid CB1 receptor antagonist rimonabant in lean and diet-induced obese female rats with arthritis induced by complete Freund's adjuvant (CFA) injected in the right hind-paw.. The effect of oral rimonabant was assessed in rat paws on thermal hyperalgesia, mechanical allodynia, oedema, global arthritis score, nitrite/nitrate levels and ankle widths.. After 7 but not after 14 days, the inflammatory response to CFA was significantly higher in obese than lean rats; however, the nociceptive response (thermal hyperalgesia and mechanical allodynia) was similar. Oral rimonabant (3 or 10 mg kg-1, once a day for 1 week from day 7 after CFA) only reduced the global arthritic score and joint width in obese rats, with no effect on the paw oedema. It also markedly reduced thermal hyperalgesia and mechanical allodynia in both lean and obese rats, with a greater effect in the latter.. Rimonabant appears to be a potent inhibitor of sensorial hypersensitivity associated with CFA-induced arthritis in obese rats, in which the inflammatory reaction is more severe than in lean rats. It may thus have therapeutic potential in obesity-associated inflammatory diseases, particularly in the treatment of the pain associated with arthritis.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Arthritis, Experimental; Body Weight; Edema; Female; Freund's Adjuvant; Hot Temperature; Hyperalgesia; Inflammation; Joints; Nitric Oxide; Obesity; Pain Measurement; Pain Threshold; Piperidines; Pyrazoles; Rats; Reaction Time; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors; Touch

The endocannabinoids, a recently discovered endogenous, lipid derived, signaling system regulating energy metabolism, have effects on central and peripheral energy metabolism predominantly via the cannabinoid receptor type 1 (CB1). CB1 is expressed centrally in the hypothalamus and nucleus accumbens and peripherally in adipocytes and skeletal muscle. This study determined the effect of endocannabinoids on the expression of genes regulating energy metabolism in human skeletal muscle. Primary cultures of myotubes (lean and obese; n=3/group) were treated with the cannabinoid receptor agonist, anandamide (AEA) (0.2 and 5microM) and the CB1 specific antagonist AM251 (0.2 and 5microM) separately and in combination for 24h. The expression of mRNA for AMP-activated protein kinase (AMPK) alpha 1 (alpha1) and alpha 2 (alpha2), pyruvate dehydrogenase kinase 4 (PDK4) and peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) were determined using 'Real Time' RT-PCR. AMPKalpha1 mRNA increased in lean and obese myotubes in response to AM251 (P<0.05). AEA inhibited the effect of AM251 on AMPKalpha1 mRNA levels in myotubes from lean and obese subjects (P<0.05); the dose-response curve was shifted to the left in the obese. In response to AM251, irrespective of the presence of AEA, PDK4 expression was decreased in lean and obese myotubes (P<0.05). Taken together these data suggest that endocannabinoids regulate pathways affecting skeletal muscle oxidation, effects particularly evident in myotubes from obese individuals.

Topics: Adult; AMP-Activated Protein Kinases; Arachidonic Acids; Cells, Cultured; Dose-Response Relationship, Drug; Endocannabinoids; Female; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Heat-Shock Proteins; Humans; Male; Multienzyme Complexes; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Oxidation-Reduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Piperidines; Polyunsaturated Alkamides; Protein Kinases; Protein Serine-Threonine Kinases; Pyrazoles; Receptor, Cannabinoid, CB1; RNA, Messenger; Thinness; Transcription Factors

Topics: Adult; Appetite Depressants; Cannabinoid Receptor Modulators; Female; Fertility; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Topics: Diabetes Mellitus, Type 2; Humans; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant

Topics: Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Exercise; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant

Topics: Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Humans; Obesity; Piperidines; PPAR gamma; Pyrazoles; Rimonabant; Weight Loss

Topics: Depression; Diabetes Mellitus, Type 2; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Endothelin (ET)-1 is a vasoconstrictor and proinflammatory peptide that may inhibit glucose uptake. The objective of the study was to investigate if ET (selective ET(A) and dual ET(A)+ET(B)) receptor blockade improves insulin sensitivity in patients with insulin resistance and coronary artery disease.. Seven patients (aged 58 +/- 2 years) with insulin resistance and coronary artery disease completed three hyperinsulinemic-euglycemic clamp protocols: a control clamp (saline infusion), during ET(A) receptor blockade (BQ123), and during combined ET(A) (BQ123) and ET(B) receptor blockade (BQ788). Splanchnic blood flow (SBF) and renal blood flow (RBF) were determined by infusions of cardiogreen and p-aminohippurate.. Total-body glucose uptake (M) differed between the clamp protocols with the highest value in the BQ123+BQ788 clamp (P < 0.05). The M value corrected by insulin was higher in the BQ123+BQ788 than in the control clamp (P < 0.01) or the BQ123 clamp (P < 0.05). There was no difference between the control clamp and the BQ123 clamp. Mean arterial pressure did not change during the control clamp, whereas it decreased during both the BQ123 (P < 0.01) and BQ123+BQ788 (P < 0.05) clamps. RBF increased and renal vascular resistance decreased in the BQ123+BQ788 clamp (P < 0.05) but not in the BQ123 clamp. There was no change in SBF in either clamp.. Dual ET(A)+ET(B) receptor blockade acutely enhances insulin sensitivity in patients with insulin resistance and coronary artery disease, indicating an important role for endogenous ET-1.

Topics: Antihypertensive Agents; Blood Glucose; Blood Pressure; Coronary Disease; Diabetes Mellitus, Type 2; Endothelin Receptor Antagonists; Glucose Clamp Technique; Glucose Intolerance; Heart Rate; Humans; Insulin; Insulin Resistance; Middle Aged; Obesity; Oligopeptides; Peptides, Cyclic; Piperidines

The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance. To explore the pharmacological utility of CB1R inhibition for the treatment of obesity, we evaluated the efficacy of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364) and determined the relationship between efficacy and brain CB1R occupancy in rodents. MK-0364 was shown to be a highly potent CB1R inverse agonist that inhibited the binding and functional activity of various agonists with a binding K(i) of 0.13 nM for the human CB1R in vitro. MK-0364 dose-dependently inhibited food intake and weight gain, with an acute minimum effective dose of 1 mg/kg in diet-induced obese (DIO) rats. CB1R mechanism-based effect was demonstrated for MK-0364 by its lack of efficacy in CB1R-deficient mice. Chronic treatment of DIO rats with MK-0364 dose-dependently led to significant weight loss with a minimum effective dose of 0.3 mg/kg (p.o.), or a plasma C(max) of 87 nM. Weight loss was accompanied by the loss of fat mass. Partial occupancy (30-40%) of brain CB1R by MK-0364 was sufficient to reduce body weight. The magnitude of weight loss was correlated with brain CB1R occupancy. The partial receptor occupancy requirement for efficacy was also consistent with the reduced food intake of the heterozygous mice carrying one disrupted allele of CB1R gene compared with the wild-type mice. These studies demonstrated that MK-0364 is a highly potent and selective CB1R inverse agonist and that it is orally active in rodent models of obesity.

Topics: Amides; Animals; Anti-Obesity Agents; Binding, Competitive; Body Temperature; Body Weight; CHO Cells; Colforsin; Cricetinae; Cricetulus; Cyclic AMP; Cyclohexanols; Dose-Response Relationship, Drug; Eating; Humans; Indoles; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Structure; Obesity; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Transfection

Topics: Animals; Appetite Depressants; Cannabinoid Receptor Modulators; Cannabinoids; Chronic Disease; Disease Models, Animal; Disease Progression; Endocannabinoids; Fatty Liver; Glycolysis; Hepatitis C, Chronic; Hepatocytes; Humans; Hypertension, Portal; Lipogenesis; Liver; Liver Cirrhosis; Liver Diseases; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

Topics: Chemotherapy, Adjuvant; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Obesity; Piperidines; Pyrazoles; Rimonabant

This study investigated the effects of rimonabant (SR141716), an antagonist of the cannabinoid receptor type 1 (CB1), on obesity-associated hepatic steatosis and related features of metabolic syndrome: inflammation (elevated plasma levels of tumor necrosis factor alpha [TNFalpha]), dyslipidemia, and reduced plasma levels of adiponectin. We report that oral treatment of obese (fa/fa) rats with rimonabant (30 mg/kg) daily for 8 weeks abolished hepatic steatosis. This treatment reduced hepatomegaly, reduced elevation of plasma levels of enzyme markers of hepatic damage (alanine aminotransferase, gamma glutamyltransferase, and alkaline phosphatase) and decreased the high level of local hepatic TNFalpha currently associated with steatohepatitis. In parallel, treatment of obese (fa/fa) rats with rimonabant reduced the high plasma level of the proinflammatory cytokine TNFalpha and increased the reduced plasma level of the anti-inflammatory hormone adiponectin. Finally, rimonabant treatment also improved dyslipidemia by both decreasing plasma levels of triglycerides, free fatty acids, and total cholesterol and increasing the HDLc/LDLc ratio. All the effects of rimonabant found in this study were not or only slightly observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with rimonabant compared to diet. These results demonstrate that rimonabant plays a hepatoprotective role and suggest that this CB1 receptor antagonist potentially has clinical applications in the treatment of obesity-associated liver diseases and related features of metabolic syndrome.

Topics: Animals; Cannabinoid Receptor Antagonists; Fatty Liver; Inflammation; Liver; Male; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; Rimonabant; RNA; Tumor Necrosis Factor-alpha

Oleoyl-estrone (OE) decreases appetite, maintains energy expediture, induces lipolysis (sparing protein), and decreases cholesterolemia and insulin resistance. Rimonabant (SR141716) is a cannabinoid-receptor inhibitor that decreases appetite and mobilizes fat. We studied whether their combination improves their slimming effects. Male overweight rats received daily gavages of 5.3 mg/kg OE, 10 mg/kg rimonabant, or both drugs during 10 days. Body weight and composition, energy balance, adipose tissue weight, and serum hormones and metabolites were measured. OE halved food intake and maintained energy expenditure at the expense of body fat. Rimonabant effects on appetite and energy balance were less marked, resulting in lower lipid mobilization. OE and rimonabant followed the OE pattern, with no additive or synergic effects. Glycemia was maintained, but OE decreased insulin, GLP-1, and cholesterol, whilst rimonabant increased cholecystokinin and cholesterol, and decreased NEFA. Both drugs decreased leptin and triacylglycerols; ghrelin was unchanged. The results hint at different mechanisms of action of both drugs: we can assume that OE effects do not involve the cannabinoid pathway. OE does not seem to act, either, after 10 days, through the secretion of ghrelin or the intestinal appetite-controlling peptides tested.

Topics: Animals; Anti-Obesity Agents; Appetite; Blood Glucose; Cholecystokinin; Cholesterol; Drug Synergism; Drug Therapy, Combination; Eating; Energy Metabolism; Estrone; Fatty Acids, Nonesterified; Ghrelin; Glucagon-Like Peptide 1; Insulin; Leptin; Male; Obesity; Oleic Acids; Overweight; Peptide Hormones; Piperidines; Pyrazoles; Rats; Rats, Wistar; Rimonabant; Triglycerides

Too many adverse effects for a minor effect on weight loss, without reduced rates of complications.

Topics: Anti-Obesity Agents; Clinical Trials as Topic; Diabetes Mellitus; Humans; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Treatment Outcome; Weight Loss

Topics: Advisory Committees; Anti-Obesity Agents; Drug Approval; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; United States

Topics: Benzazepines; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Obesity; Piperidines; Prevalence; Pyrazoles; Quinoxalines; Rimonabant; Risk Factors; Smoking; Smoking Cessation; Tobacco Use Disorder; Varenicline

Regulation of vascular tone and blood flow involves interactions between numerous local and systemic vascular control signals, many of which are altered by Type 2 diabetes (T2D). Vascular responses to endothelin-1 (ET-1) are mediated by endothelin type A (ET(A)) and type B (ET(B)) receptors that have been implicated in cross talk with alpha(1)-adrenoceptors (alpha(1)-AR). ET(A) and ET(B) receptor expression and plasma ET-1 levels are elevated in T2D; however, whether this influences coronary alpha(1)-AR function has not been examined. Therefore, we examined the effect of ET(A) and ET(B) receptor inhibition on coronary vasoconstriction to ET-1 and alpha(1)-AR activation in a mouse model of T2D. Coronary vascular responses were examined in isolated mouse hearts from control and diet-induced T2D C57BL/6J mice. Responses to ET-1 and the selective alpha(1)-AR agonist phenylephrine (PE) were examined alone and in the presence of the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) alone or in combination with selective ET(A) or ET(B) receptor inhibitors BQ-123 and BQ-788, respectively. Vasoconstriction to ET-1 was enhanced, whereas ET(B), but not ET(A), receptor blockade reduced basal coronary tone in T2D hearts. In the presence of l-NAME, ET(A) receptor inhibition attenuated ET-1 vasoconstriction in both groups, whereas ET(B) inhibition abolished this response only in control hearts. In addition, ET(A) inhibition enhanced alpha(1)-AR-mediated vasoconstriction in T2D, but not control, hearts following l-NAME treatment. Therefore, in this model, enhanced coronary ET-1 responsiveness is mediated primarily through smooth muscle ET(B) receptors, whereas the interaction with alpha(1)-ARs is mediated solely through the ET(A) receptor subtype.

Topics: Adrenergic alpha-1 Receptor Agonists; Adrenergic alpha-Agonists; Animals; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Obesity; Oligopeptides; Peptides, Cyclic; Phenylephrine; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Adrenergic, alpha-1; Vasoconstriction

Obesity is a major risk factor for cardiovascular disorders, including peripheral arterial disease. This review outlines the evidence for a 6-step process for the management of obesity, starting with identifying the degree and type of obesity, followed by target setting, life style and behavioural changes, imposed hypocaloric diet and physical activity, pharmacological treatment and consideration of eating disorders and/or bariatric surgery.

Topics: Anti-Obesity Agents; Bariatric Surgery; Body Composition; Body Mass Index; Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Humans; Life Style; Obesity; Peripheral Vascular Diseases; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Tomography, X-Ray Computed

Topics: Adiponectin; Adult; Blood Glucose; Fatty Liver; Female; Humans; Insulin; Lipids; Liver; Mitochondria, Liver; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Severity of Illness Index; Treatment Outcome

Topics: Appetite Depressants; Humans; Mood Disorders; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Obesity is a major risk factor in the development of chronic renal failure. Rimonabant, a cannabinoid CB1 receptor antagonist, improves body weight and metabolic disorders; however, its effect on mortality and chronic renal failure associated with obesity is unknown. Obese Zucker rats received either rimonabant or vehicle for 12 months and were compared to a pair-fed but untreated group of obese rats. Mortality in the obese rats was significantly reduced by rimonabant along with a sustained decrease in body weight, transient reduction in food intake, and an increase in plasma adiponectin. This was associated with significant reduction in plasma total cholesterol, low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, glucose, norepinephrine, plasminogen activator inhibitor 1, and preservation of pancreatic weight and beta-cell mass index. The cannabinoid antagonist attenuated the increase in proteinuria, urinary N-acetylglucosaminidase excretion, plasma creatinine, and urea nitrogen levels while improving creatinine clearance. Renal hypertrophy along with glomerular and tubulointerstitial lesions were reduced by rimonabant. Although the drug did not modify hemodynamics, it normalized the pressor response to angiotensin II. Our study suggests that in a rat model of chronic renal failure due to obesity, rimonabant preserves renal function and increases survival.

Topics: Adiponectin; Animals; Body Weight; Disease Models, Animal; Eating; Kidney; Kidney Failure, Chronic; Lipids; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Rimonabant; Survival Analysis

LY255582 is a pan opioid selective receptor antagonist that has been shown to have high affinity for mu, delta, and kappa receptors in vitro. In order to better understand the in vivo opioid receptor selectivity of LY255582, we developed in vivo receptor occupancy assays in the rat for the opioid mu, kappa and delta receptors using the occupancy tracers naltrexone, GR103545 and naltriben respectively. Individual assays for each target were established and then a "triple tracer" assay was created where all three tracers were injected simultaneously, taking advantage of LC/MS/MS technology to selectively monitor brain tracer levels. This is the first report of a technique to concurrently measure receptor specific occupancy at three opioid receptors in the same animal. The opioid subtype selective antagonists cyprodime, JDTic and naltrindole were used to validate selectivity of the assay. Examination of LY255582 in dose-occupancy experiments demonstrated a relative order of potency of mu>kappa>delta, reproducing the previously reported order determined with in vitro binding.

Topics: Animals; Binding, Competitive; Brain; Chromatography, Liquid; Cyclohexanes; Injections, Intravenous; Male; Mice; Mice, Knockout; Narcotic Antagonists; Obesity; Piperidines; Protein Binding; Rats; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Tandem Mass Spectrometry

Topics: Depression; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Suicide; United States; United States Food and Drug Administration; Weight Loss

The endocannabinoid system controls the regulation of food intake and appetite in the brain and lipogenesis in adipose tissue. Rimonabant belongs to the new drug class of cannabinoid-1 receptor antagonists. It can decrease appetite and food intake and thus stimulate weight loss. Rimonabant is indicated for severe obesity and as an adjunct to lifestyle modifications for obese patients with type 2 diabetes or hyperlipidaemia. Safety concerns limit the clinical applicability of the drug. The drug has not been approved in the US due to its neurological and psychiatric adverse effects. Rimonabant is approved in Europe but is contraindicated in patients with major depression and those taking antidepressants.

Topics: Appetite Regulation; Cardiovascular Diseases; Depression; Diet, Reducing; Energy Intake; Humans; Lipids; Lipogenesis; Obesity; Obesity, Morbid; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Weight Loss

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Depression; Drug Approval; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Risk Factors; Weight Loss

Topics: Appetite Depressants; Drug Evaluation; Drug Industry; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Topics: Animals; Anti-Obesity Agents; Anxiety; Arachidonic Acids; Blood Pressure; Brain; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Controlled Clinical Trials as Topic; Drug Evaluation, Preclinical; Endocannabinoids; Humans; Inflammation; Neurons; Obesity; Osteoporosis; Pain; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Smoking Cessation

Topics: Adolescent; Adult; Appetite Depressants; Body Mass Index; Cardiovascular Diseases; Child; Cyclobutanes; Female; Humans; Life Style; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Risk Factors; Surveys and Questionnaires; Weight Loss

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Dyslipidemias; Glucose Intolerance; Humans; Obesity; Overweight; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Topics: Anti-Obesity Agents; Cardiovascular Diseases; Complementary Therapies; Diabetes Mellitus; Diet; Health Behavior; Humans; Hypoglycemic Agents; Life Style; Metabolic Syndrome; Metformin; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Rosiglitazone; Thiazolidinediones

Topics: Cardiovascular Diseases; Dyslipidemias; Humans; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors

The cannabinoid CB1 receptor inverse agonist rimonabant induces hypophagia and body weight loss. Reduced body weight may potentially be due to decreased food intake or to direct metabolic effects of drug administration on energy expenditure. This study uses a paired-feeding protocol to quantify the contributions of energy intake to rimonabant-induced body weight loss. Diet-induced obese (DIO) rats were dosed with rimonabant (3, 10 mg/kg PO once daily) and matched with pair-fed controls. Food intake and body weight were measured daily. Blood samples and adipose tissue were collected on day 15 for measurement of plasma adiponectin and adiponectin mRNA levels. DIO rats treated with rimonabant and pair-fed controls showed very similar changes in body weight. Although tolerance developed to the anorectic effect of rimonabant, total food intake was significantly decreased over the 14-day study period and fully accounted for the observed reductions in body weight. Adiponectin mRNA and plasma adiponectin were elevated in vehicle-treated chow-fed animals compared to obese controls, and did not differ between rimonabant-treated and pair-fed animals. The similarities between rimonabant-treated and pair-fed animals in body weight loss and the absence of differences in measures of adiponectin activity between drug-treated and pair-fed animals suggest that the outcomes of this experiment were solely mediated by the drug-induced reduction in food intake.

Topics: Adiponectin; Animals; Body Weight; Dietary Fats; Eating; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant

A substituted 4-aminopiperidine was identified as showing activity in an MCH assay from an HTS effort. Subsequent structural modification of the scaffold led to the identification of a number of active MCH antagonists. 3,5-Dimethoxy-N-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)benzamide (5c) was among those with the highest binding affinity to the MCH receptor (K(i)=27nM), when variations were made at benzoyl and naphthylmethyl substitution sites from the initial HTS hit. Further optimization via piperidine ring contraction resulted in enhanced MCH activity in a 3-aminopyrrolidine series, where (R)-3,5-dimethoxy-N-(1-(naphthalen-2-ylmethyl)-pyrrolidin-3-yl)benzamide (10i) was found to be an excellent MCH antagonist (K(i)=7nM).

Topics: Binding, Competitive; Drug Evaluation, Preclinical; Humans; Molecular Structure; Obesity; Piperidines; Pyrrolidines; Receptors, Somatostatin; Stereoisomerism; Structure-Activity Relationship

Topics: Anti-Obesity Agents; Anxiety; Depression; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors

Topics: Anti-Obesity Agents; Humans; Life Style; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk; Weight Loss

Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.

Topics: Animals; Appetite; Body Weight; Diabetes Mellitus; Histamine Agonists; Imidazoles; Insulin; Leptin; Mice; Mice, Knockout; Obesity; Piperidines; Receptors, Histamine H3; Thiourea

(1) The treatment of obesity is based on calorie reduction and moderate physical activity. (2) Rimonabant, a CB1 cannabinoid receptor antagonist, is marketed in Europe for the adjuvant treatment of obesity, in combination with a low-calorie diet and physical exercise. (3) Four double-blind placebo-controlled trials involving about 6500 patients show that, when combined with a low-calorie diet, rimonabant 20 mg/day leads to an average weight loss of 4 or 5 kg more than placebo after one year of treatment. This is similar to the weight loss reported with orlistat (indirect comparison). Effects on the lipid profile are similar to those reported with sibutramine. (4) Rimonabant has not been shown to reduce morbidity or mortality. Patients regain the weight they lost within about 9 months after rimonabant withdrawal. (5) Three placebo-controlled trials have evaluated rimonabant in smoking cessation. The available results (a single conference abstract) are inconclusive. In early 2006 the FDA and the European Medicines Agency refused to approve rimonabant for this use. (6) Adverse effects mentioned in published clinical trials of rimonabant include mental disorders (anxiety, depression), neurological disorders (dizziness) and gastrointestinal disorders (nausea, diarrhoea). No postmarketing safety data are available. The possible long-term adverse effects of rimonabant are unknown. (7) In practice, when drug therapy is considered for weight loss, it seems unwise to prescribe rimonabant: this new drug has only limited symptomatic effects and its adverse effects, especially in the long term, are poorly documented.

Topics: Anti-Obesity Agents; Cholesterol, HDL; Diet, Reducing; Double-Blind Method; Drug Approval; Europe; Exercise; Glycated Hemoglobin; Humans; Lactones; Lipase; Metabolic Syndrome; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Smoking; Treatment Outcome; United States; Weight Loss

Topics: Adolescent; Adult; Age Factors; Aged; Blood Glucose; Body Mass Index; Cardiovascular Diseases; Cholesterol, HDL; Clinical Trials, Phase III as Topic; Contraindications; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Time Factors; Triglycerides; Weight Loss

Topics: Adipocytes; Animals; Anti-Obesity Agents; Cannabinoid Receptor Modulators; Disease Models, Animal; Drug Design; Estrone; Fatty Acids; Humans; Obesity; Oleic Acids; Oxidation-Reduction; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Topics: Adiposity; Anti-Obesity Agents; Cannabinoid Receptor Modulators; Diet Therapy; Humans; Insulin; Insulin Detemir; Insulin, Long-Acting; Leptin; Obesity; Piperidines; Pyrazoles; Rimonabant

The aim of this prospective study was to determine the effect site concentrations of remifentanil maintaining cardiovascular homeostasis in response to surgical stimuli during bispectral index (BIS) guided propofol anesthesia in seriously obese patients.. Twenty-two patients, female/male 15/7, ASA physical status II - III, aged 29-69 years, body mass index (BMI) 54.5+/-12, undergoing major open bariatric surgery, were enrolled to receive a propofol-remifentanil total intravenous anesthesia. All patients were intubated by using a flexible fiberoptic bronchoscopic technique facilitated by a target controlled effect site concentration of remifentanil set at 2.5 ng/mL. After endotracheal intubation, anesthesia was started with a target controlled infusion of propofol initially set at 6 microg/mL, then adjusted to maintain a BIS value between 40 and 50. The mean effect site concentration of remifentanil was recorded at different intervals time during surgery: skin incision-opening of peritoneum (T1), bowel resection (T2), cholecystojejunal anastomosis (T3), ileojejunal anastomosis (T4), closing of peritoneum (T5).. The mean plasma concentrations of propofol required to maintain a BIS value between 40 and 50 were 4+/-0.55, 3.8+/-0.64, 3.8+/- 0.63, 3.8+/-0.65 and 3.8+/-0.63 microg/mL at T1, T2, T3, T4 and T5 interval time, respectively. The mean values of remifentanil target effect site concentration were 5.2+/-1.3, 7.7+/-1.7, 9.1+/-1.8, 9.7+/- 2.2 and 9.9+/-2.5 ng/mL at T1, T2, T3, T4 and T5 interval time.. This study suggests that tolerance to remifentanil infusion is profound and develops very rapidly in morbidly obese patients submitted to open bariatric surgery during BIS guided propofol anesthesia. The administration of opiates during anesthesia based on target-controlled infusion should include corrections for the development of tolerance.

Topics: Adult; Aged; Anesthesia, Intravenous; Anesthetics, Intravenous; Body Mass Index; Electroencephalography; Female; Homeostasis; Humans; Male; Middle Aged; Obesity; Piperidines; Propofol; Prospective Studies; Remifentanil

Topics: Diabetes Mellitus, Type 2; Humans; Obesity; Overweight; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant

Rimonabant is the first of a new class of selective cannabinoid receptor-1 blockers. It reduces the overactivity of the endocannabinoid system, improving lipid and glucose metabolism and regulating food intake and energy balance. In four randomised, double-blind clinical trials in overweight or obese adults with or without type 2 diabetes and/or dyslipidaemia, oral rimonabant 20mg once daily reduced weight and waist circumference to a significantly greater extent than placebo. A significantly greater proportion of rimonabant than placebo recipients achieved the clinically significant weight-loss target of > or =5% or > or =10% of initial weight. Rimonabant was associated with significant improvements in glycaemic control relative to placebo, with approximately equal to 57% of the reduction in glycosylated haemoglobin being independent of the effects of weight loss in one trial. Improvements in other cardiometabolic risk factors (i.e. increases in high-density lipoprotein-cholesterol [HDL-C] and decreases in triglyceride [TG] levels) were significantly greater with rimonabant than with placebo. The improvement in lipid profile also demonstrated a weight-independent effect, with approximately equal to 47-58% of the improvement in HDL-C and TG being beyond that expected through weight loss alone. Rimonabant was generally well tolerated, with most adverse events considered mild to moderate in severity.

Topics: Adult; Animals; Anti-Obesity Agents; Blood Glucose; Clinical Trials as Topic; Diet, Reducing; Drug Approval; Europe; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Topics: Germany; Humans; Insurance, Pharmaceutical Services; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The effects of the cannabinoid-1 receptor (CB(1)) antagonist rimonabant on energy metabolism and fasting-induced hypothalamic-pituitary-adrenal (HPA) axis and neuronal activation were investigated. Lean and obese Zucker rats were treated orally with a daily dose of 10 mg/kg rimonabant for 14 days. A comprehensive energy balance profile based on whole-carcass analyses further demonstrated the potential of CB(1) antagonists for decreasing energy gain through reducing food intake and potentially increasing brown adipose tissue thermogenesis. Rimonabant also reduced plasma glucose, insulin, and homeostasis model assessment of insulin resistance, which further confirms the ability of CB(1) antagonists to improve insulin sensitivity. To test the hypothesis that rimonabant attenuates the effect of fasting on HPA axis activation in the obese Zucker model, rats were either ad libitum-fed or food-deprived for 8 h. Contrary to expectation, rimonabant increased basal circulating corticosterone levels and enhanced the HPA axis response to food deprivation in obese rats. Rimonabant also exacerbated the neuronal activation seen in the arcuate nucleus (ARC) after short-term deprivation. In conclusion, the present study demonstrates that CB(1) blockade does not prevent the hypersensitivity to food deprivation occurring at the level of HPA axis and ARC activation in the obese Zucker rats. This, however, does not prevent CB(1) antagonism from exerting beneficial effects on energy and glucose metabolism.

Topics: Animals; Cannabinoid Receptor Antagonists; Energy Intake; Fasting; Feeding Behavior; Hypothalamo-Hypophyseal System; Male; Neurons; Obesity; Piperidines; Pituitary-Adrenal System; Pyrazoles; Rats; Rats, Zucker; Rimonabant; Thinness; Time Factors

Topics: Adipose Tissue; Antihypertensive Agents; Appetite; Body Weight; C-Reactive Protein; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Cholesterol, HDL; Diabetes Mellitus; Humans; Hypoglycemic Agents; Life Style; Metabolic Syndrome; Obesity; Physician Assistants; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Assessment; Risk Factors; Weight Gain

Topics: Appetite Depressants; Cannabinoid Receptor Antagonists; Drug Approval; Germany; Humans; Insurance, Pharmaceutical Services; Life Style; Metabolic Syndrome; National Health Programs; Obesity; Piperidines; Pyrazoles; Quality of Life; Rimonabant

To investigate the effect of SR141716, a selective CB1 receptor antagonist, on energy expenditure and on glucose uptake in isolated soleus muscle of Lep(ob)/Lep(ob) mice.. Female Lep(ob)/Lep(ob) mice (8-10 weeks old) were treated with SR141716 (10 mg/kg, i.p. once daily) or vehicle for 7 days.. Oxygen consumption, daily food and water intake, body weight and glucose uptake in isolated soleus muscle.. SR141716 (10 mg/kg, i.p. once daily) resulted in a significant reduction of daily food intake (P<0.01) and body weight (P<0.05) 5 days after daily treatment. Body weight continued to be lower for the rest of the treatment period (P<0.05). There was no significant difference in body weight between the pair-fed and vehicle-treated animals. A 7-day treatment with SR141716 (10 mg/kg, i.p. once daily) caused 37% increase in basal oxygen consumption compared to that of vehicle-treated (90 min mean; P<0.01), and a significant 68% increase in glucose uptake in isolated soleus muscle preparations.. It is concluded that SR141716 has a direct effect on energy expenditure suggesting that the antiobesity effect of SR141716 is due to activation of thermogenesis in addition to the initial hypophagia. The increase in soleus muscle glucose uptake with SR141716 treatment may contribute to the improved glycaemia seen in the previous studies.

Topics: Animals; Blood Glucose; Body Weight; Eating; Energy Metabolism; Female; Mice; Mice, Obese; Muscle, Skeletal; Obesity; Oxygen Consumption; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thermogenesis; Tissue Culture Techniques

We report the discovery and optimization of substituted 2-piperazinecarboxamides as potent and selective agonists of the melanocortin subtype-4 receptor. Further in vivo development of lead agonist, MB243, is disclosed.

Topics: Animals; Dogs; Erectile Dysfunction; Haplorhini; Male; Mice; Obesity; Piperazines; Piperidines; Rats; Receptor, Melanocortin, Type 4

We investigated the effects of chronic treatment with the CB1 receptor antagonist rimonabant (10 mg/kg/day p.o. for 10 weeks) in mice with established obesity (5-month high-fat diet). Untreated obese mice showed a weight gain of 46% (45.0 +/- 0.6 g vs. 30.8 +/- 0.5 g) compared with age-matched animals fed a standard diet. Rimonabant treatment, commencing after 5-month high-fat diet, produced a marked and sustained decrease in body weight (34.5 +/- 0.8 g vs. 47.2 +/- 0.5 g in the high-fat vehicle group, p < 0.001). The anti-obesity effect of rimonabant was similar to that obtained by switching obese mice from high-fat diet to standard laboratory diet during 10 weeks (final weight 33.7 +/- 0.6 g) and was associated with only transient (14 days) reduction in energy intake. Serum leptin, insulin and glucose levels were markedly elevated in obese animals. Rimonabant treatment significantly reduced these elevations (leptin -81%, insulin -78%, glucose -67%, p < 0.001 in all cases vs. high-fat vehicle group). In addition, rimonabant treatment modestly but significantly increased serum adiponectin levels (+18%, p < 0.05 vs. high-fat vehicle group). Obese mice demonstrated abnormal serum lipid profiles. Although rimonabant did not modify high-density lipoprotein cholesterol (HDLc) and had modest effects on total cholesterol, it significantly reduced triglycerides and low-density lipoprotein cholesterol (LDLc) and, notably, increased the HDLc/LDLc ratio (12.4 +/- 0.8 vs. 7.9 +/- 0.2 in high-fat vehicle group, p < 0.001). Therefore, in a model of established obesity, chronic rimonabant treatment produces a marked and sustained decrease in body weight (equivalent to that achieved by dietary change) which is associated with favourable modifications in serum biochemical and lipid profiles.

Topics: Adiponectin; Animals; Anti-Obesity Agents; Blood Glucose; Cholesterol; Cholesterol, HDL; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Lipids; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Rimonabant

Topics: Anti-Obesity Agents; Cannabinoids; Cannabis; Humans; Marijuana Abuse; Obesity; Piperidines; Psychopharmacology; Pyrazoles; Rimonabant

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Clinical Trials as Topic; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Topics: Anti-Obesity Agents; Cannabinoid Receptor Antagonists; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant

Topics: Aspirin; Cardiovascular Diseases; Cholesterol, LDL; Clopidogrel; Humans; Hypercholesterolemia; Obesity; Piperidines; Platelet Aggregation Inhibitors; Pyrazoles; Rimonabant; Stroke; Ticlopidine

We investigated the molecular events involved in the long-lasting reduction of adipose mass by the selective CB1 antagonist, SR141716. Its effects were assessed at the transcriptional level both in white (WAT) and brown (BAT) adipose tissues in a diet-induced obesity model in mice. Our data clearly indicated that SR141716 reversed the phenotype of obese adipocytes at both macroscopic and genomic levels. First, oral treatment with SR141716 at 10 mg/kg/d for 40 days induced a robust reduction of obesity, as shown by the 50% decrease in adipose mass together with a major restoration of white adipocyte morphology similar to lean animals. Second, we found that the major alterations in gene expression levels induced by obesity in WAT and BAT were mostly reversed in SR141716-treated obese mice. Importantly, the transcriptional patterns of treated obese mice were similar to those obtained in the CB1 receptor knockout mice fed a high-fat regimen and which are resistant to obesity, supporting a CB1 receptor-mediated process. Functional analysis of these modulations indicated that the reduction of adipose mass by the molecule resulted from an enhanced lipolysis through the induction of enzymes of the beta-oxidation and TCA cycle, increased energy expenditure, mainly through futile cycling (calcium and substrate), and a tight regulation of glucose homeostasis. These changes accompanied a significant cellular remodeling and contributed to a reduction of the obesity-related inflammatory status. In addition to a transient reduction of food consumption, increases of both fatty acid oxidation and energy expenditure induced by the molecule summate leading to a sustained weight loss. Altogether, these data strongly indicate that the endocannabinoid system has a major role in the regulation of energy metabolism.

Topics: Adipocytes; Adiponectin; Animals; Cytoskeleton; Dietary Fats; Energy Intake; Energy Metabolism; Gene Expression Profiling; Glucose; Lipolysis; Male; Mice; Mice, Inbred C57BL; Obesity; Phenotype; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thermogenesis

Topics: Anti-Obesity Agents; Appetite Depressants; Cannabinoids; Cyclobutanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Lactones; Male; Middle Aged; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant

Topics: Cannabinoids; Dexfenfluramine; Drug Approval; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Sleep Initiation and Maintenance Disorders; United States; United States Food and Drug Administration

Topics: Appetite; Appetite Depressants; Clinical Trials as Topic; Diabetes Mellitus; Drug Approval; Drug Industry; Europe; France; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; United States; United States Food and Drug Administration; Weight Loss

Topics: Anti-Obesity Agents; Appetite Depressants; Cannabinoid Receptor Antagonists; Cyclobutanes; Dyslipidemias; Humans; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

Topics: Acetanilides; Angina Pectoris; Benzazepines; Heart Failure; Humans; Obesity; Piperazines; Piperidines; Pyrazoles; Ranolazine; Rimonabant; Tolvaptan

Topics: Animals; Humans; Immunotherapy; Indoles; Obesity; Piperidines; Pyrazoles; Rimonabant; Serotonin Antagonists; Smoking Cessation; Tobacco Use Disorder

Oral administration of the opioid antagonist nalmefene alone (up to 20 mg/kg) failed to show a significant effect on acute food intake in mice. However, combined oral dosing of nalmefene and subthreshold doses of AM251, a cannabinoid CB1 receptor inverse agonist, led to a significant reduction in food intake in both lean and diet-induced obese (DIO) mice. Furthermore, the anorectic effect of a high dose of AM251 was further enhanced when co-administered with nalmefene. The results support a synergistic interaction between opioid and cannabinoid systems in regulating feeding behavior.

Topics: Animals; Appetite Regulation; Body Weight; Brain; Cannabinoid Receptor Modulators; Cannabinoids; Dose-Response Relationship, Drug; Drug Synergism; Homeostasis; Male; Mice; Mice, Inbred C57BL; Naltrexone; Narcotic Antagonists; Obesity; Opioid Peptides; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1

There is growing evidence for an implication of the CB1 receptor subtype of the endocannabinoid system in the regulation of eating and fat deposition. To further define the physiological role of these receptors in the control of energy balance, we characterized the phenotype of CB1 receptor knockout (CB1(-/-)) mice maintained on an obesity-prone regimen or on a standard chow.. CB1(-/-) male mice were compared to wild-type animals (CB1(+/+) male mice) in two feeding paradigms: (1) with a standard laboratory regimen (3.5 kcal/g, 14.5% of energy as fat) and (2) on a free-choice paradigm consisting of offering both the standard laboratory chow and a high-fat diet (HFD) (4.9 kcal/g, 49% of energy as fat).. When maintained on the standard diet, CB1(-/-) mice are lean. At the age of 20 weeks, their body weight and adiposity are, respectively, 24 and 60% lower than that of CB1(+/+) mice. They are slightly hypophagic, but when expressed as percent of body weight, their relative energy intake is similar to that of the wild-type animals. Furthermore, inactivation of CB1 receptors reduces plasma insulin and leptin levels, and enhances the response to intracerebroventricular leptin injection. The free-choice paradigm shows that the preference for a high-fat highly palatable chow is slightly delayed in onset but maintained in CB1(-/-) mice. However, loading CB1(-/-) mice with this obesity-prone diet does not result in development of obesity. Knockout mice do not display hyperphagia or reduction of their relative energy intake in contrast to CB1(+/+) mice, and their feeding efficiency remains low. These data suggest an improved energetic metabolism with the high-fat regimen. Furthermore, the insulin resistance normally occurring in HFD-fed mice is not present in CB1(-/-) mice.. These results provide evidence that the stimulation of CB1 receptors is a key component in the development of diet-induced obesity, and that these receptors and their endogenous ligands are implicated not only in feeding control but also in peripheral metabolic regulations. The lack of effect of SR141716, a selective CB1 receptor antagonist, in CB1(-/-) mice further supports this hypothesis, as this compound was previously shown to display potent anti-obesity properties in diet-induced obese C57BL/6 mice.

Topics: Animals; Body Weight; Diet; Dietary Fats; Eating; Energy Intake; Energy Metabolism; Insulin; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Leptin; Recombinant Proteins; Rimonabant; Thinness

Laboratory research including animal models of human disease suggests that cannabinoids might have therapeutic potential in multiple sclerosis (MS). We have recently seen a 46-year-old woman who developed MS after starting treatment with a cannabinoid receptor antagonist for obesity. The occurrence of MS several months after starting a cannabinoid receptor antagonist suggests that the cannabinoid system might indeed be relevant to disease pathogenesis in MS.

Topics: Appetite Depressants; Cannabinoid Receptor Antagonists; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Multiple Sclerosis; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant

Topics: Appetite; Body Weight; Brain; Humans; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Smoking Cessation; Tobacco Use Disorder; Treatment Outcome

Cannabinoid (CB)(1) receptors are present throughout the nervous system, including several areas implicated in the control of food intake. Central and peripheral administration of CB(1) agonists increase food intake while CB(1) receptor antagonists reduce food intake. However, in some previous studies, tolerance to the anorectic effects of CB(1) antagonists develops within days. To further delineate the role of endogenous cannabinoid signaling in energy intake, we studied the effects of the CB(1) antagonist AM 251 (1.25, 2.5 and 5 mg/kg ip), the anandamide membrane transporter inhibitor VDM 11 (10 mg/kg ip), and the CB(1) agonists anandamide (1 mg/kg ip), and methanandamide (1 mg/kg ip), on food intake. A single administration of the CB(1) antagonist AM 251 significantly reduced food intake for a total of 6 days (P<.05). Reductions in food intake brought about by AM 251 were accompanied by reductions in weight gain for 6 days (P<.05). Contrary to expectations, VDM 11 did not increase food intake in this study. Anandamide was also unable to increase food intake; however, the more stable agonist methanandamide significantly increased food intake 3 h after administration (P<.05). These results support the role of CB(1) receptor antagonists in the treatment of obesity and suggest that the anorectic effect of AM 251 may last longer than previously reported.

Topics: Analysis of Variance; Animals; Arachidonic Acids; Dose-Response Relationship, Drug; Eating; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Inbred Lew; Receptor, Cannabinoid, CB1; Time Factors

Topics: Body Mass Index; Controlled Clinical Trials as Topic; Cultural Characteristics; Humans; Obesity; Piperidines; Placebos; Pyrazoles; Rimonabant; United States

Because the CB1 receptor antagonist SR141716 was previously reported to modulate food intake in rodents, we studied its efficacy in reducing obesity in a diet-induced obesity (DIO) model widely used for research on the human obesity syndrome. During a 5-wk treatment, SR141716 (10 mg. kg(-1). day(-1) orally) induced a transient reduction of food intake (-48% on week 1) and a marked but sustained reduction of body weight (-20%) and adiposity (-50%) of DIO mice. Furthermore, SR141716 corrected the insulin resistance and lowered plasma leptin, insulin, and free fatty acid levels. Most of these effects were present, but less pronounced at 3 mg. kg(-1). day(-1). In addition to its hypophagic action, SR141716 may influence metabolic processes as the body weight loss of SR141716-treated mice was significantly higher during 24-h fasting compared with vehicle-treated animals, and when a 3-day treatment was compared with a pair feeding. SR141716 had no effect in CB1 receptor knockout mice, which confirmed the implication of CB1 receptors in the activity of the compound. These findings suggest that SR141716 has a potential as a novel anti-obesity treatment.

Topics: Animals; Binding Sites; Body Weight; Diet; Dietary Fats; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Time Factors

Topics: Animals; Appetite; Cannabinoids; Feeding Behavior; Mice; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Rimonabant

We determined the effect of a cannabinoid CB1 receptor antagonist (AM-251; N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) on food intake, body weight and adipose tissue mass in Western diet-induced obese (DIO) mice using a chronic, interrupted, oral dosing paradigm. The dosing paradigm was 2 weeks on treatment (treatment 1), 2 weeks off-treatment, followed by 2 weeks on treatment (treatment 2). During treatment 1 and treatment 2, food intake and body weight were reduced after a single dose. At 30 mg/kg/day, anorectic efficacy was maintained through 12 days (treatment 1) and 7 days (treatment 2). Body weight of AM-251-treated mice remained less than vehicle-treated mice throughout treatment 1 and treatment 2. Administration of AM-251 reduced inguinal subcutaneous, retroperitoneal and mesenteric adipose tissue mass. Antiobesity effects of AM-251 were lost during the off-treatment period, and hyperphagia was observed in treated animals. With re-initiation of AM-251 treatment, mice again responded to the effects of the compound. These results support the hypothesis that chronic treatment of obese individuals with cannabinoid CB1 receptor antagonists is a viable pharmacologic approach to sustained weight loss.

Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Dietary Fats; Dose-Response Relationship, Drug; Eating; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Triglycerides

EM-652 is a pure antiestrogen in human breast and uterine cancer cells that also reduces bone loss and plasma lipid levels in the rat. This study aimed to assess the ability of EM-652, alone or with dehydroepiandrosterone (DHEA), to prevent obesity and related metabolic abnormalities induced by an obesity-promoting diet and ovariectomy.. Female rats were fed a high-sucrose, high-fat (HSHF) diet, were left intact or ovariectomized (OVX), and were treated with EM-652, DHEA, or both for 20 days. Variables of energy balance and determinants of lipid metabolism and insulin sensitivity were assessed.. The HSHF diet (vs. chow) and OVX both increased energy intake and gain, as well as energetic efficiency. Both EM-652 and DHEA prevented diet- and OVX-induced energy gain mainly by decreasing fat deposition, without being additive. The modest EM-652-induced increase in liver triglycerides of intact rats was prevented by its combination with DHEA. EM-652, but not DHEA, decreased cholesterolemia. The HSHF diet and OVX reduced insulin sensitivity, an effect that was attenuated by EM-652 and abrogated by DHEA and EM-652+DHEA. Treatment with EM-652, DHEA, or their combination abolished the diet- and OVX-induced increase in adipose lipoprotein lipase activity that accompanied fat gain.. EM-652 is an effective agent to prevent diet- and OVX-induced obesity and its associated cardiovascular risk factors such as insulin resistance. The addition of DHEA prevents hepatic lipid accumulation and further ameliorates insulin sensitivity. The beneficial metabolic effects of such combined steroid therapy may, therefore, eventually prove to be clinically relevant.

Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Cholesterol; Dehydroepiandrosterone; Diet; Dietary Fats; Dietary Sucrose; Eating; Energy Intake; Energy Metabolism; Estrogen Antagonists; Female; Insulin Resistance; Lipoprotein Lipase; Liver; Obesity; Ovariectomy; Piperidines; Rats; Rats, Sprague-Dawley; Triglycerides; Weight Gain

This study investigates the effects of SR141716, a selective CB(1) receptor antagonist that reduces food intake and body weight of rodents, on Acrp30 mRNA expression in adipose tissue. Acrp30, a plasma protein exclusively expressed and secreted by adipose tissue, has been shown to induce free fatty acid oxidation, hyperglycemia and hyperinsulinemia decrease, and body weight reduction. We report that N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716) treatment once daily (10 mg/kg/d, i.p.) from 2 to 14 days reduced body weight and stimulated Acrp30 mRNA expression in adipose tissue of obese Zucker (fa/fa) rats. In parallel, the hyperinsulinemia associated with this animal model was reduced by SR141716 treatment. In cultured mouse adipocytes (3T3 F442A), SR141716 (25 to 100 nM) also induced an overexpression of Acrp30 mRNA and protein. In addition, in adipose tissue of CB(1)-receptor knockout mice, SR141716 had no effect on Acrp30 mRNA expression, demonstrating a CB(1) receptor mediating effect. Furthermore, RT-PCR analysis revealed that rat adipose tissue and 3T3 F442A adipocytes expressed CB(1) receptor mRNA. Relative quantification of this expression revealed an up-regulation (3- to 4-fold) of CB(1) receptor mRNA expression in adipose tissue of obese (fa/fa) rats and in differentiated 3T3 F442A adipocytes compared with lean rats and undifferentiated adipocytes, respectively. Western blot analysis revealed the presence of CB(1) receptors in 3T3 F442A adipocytes, and their expression was up-regulated in differentiated cells. These results show that SR141716 stimulated Acrp30 mRNA expression in adipose tissue by an effect on adipocytes, and reduced hyperinsulinemia in obese (fa/fa) rats. These hormonal regulations may participate in the body weight reduction induced by SR141716 and suggest a role of metabolic regulation in the antiobesity effect of SR141716.

Topics: 3T3 Cells; Adipocytes; Adiponectin; Adipose Tissue; Animals; Body Weight; Cannabinoids; Cells, Cultured; Disease Models, Animal; Gene Expression; Hyperinsulinism; Intercellular Signaling Peptides and Proteins; Male; Mice; Obesity; Piperidines; Protein Biosynthesis; Proteins; Pyrazoles; Rats; Rats, Zucker; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; RNA, Messenger

Topics: Animals; Anti-Obesity Agents; Ciliary Neurotrophic Factor; Cyclobutanes; Drug Evaluation; Drugs, Investigational; Humans; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Recombinant Proteins; Rimonabant; United States; United States Food and Drug Administration

In the present study, we observed evidence of cross-talk between the cannabinoid receptor CB1 and the orexin 1 receptor (OX1R) using a heterologous system. When the two receptors are co-expressed, we observed a major CB1-dependent enhancement of the orexin A potency to activate the mitogen-activated protein kinase pathway; dose-responses curves indicated a 100-fold increase in the potency of orexin-mediated mitogen-activated protein kinase activation. This effect required a functional CB1 receptor as evidenced by the blockade of the orexin response by the specific CB1 antagonist, N-(piperidino-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide (SR141716), but also by pertussis toxin, suggesting that this potentiation is Gi-mediated. In contrast to OX1R, the potency of direct activation of CB1 was not affected by co-expression with OX1R. In addition, electron microscopy experiments revealed that CB1 and OX1R are closely apposed at the plasma membrane level; they are close enough to form hetero-oligomers. Altogether, for the first time our data provide evidence that CB1 is able to potentiate an orexigenic receptor. Considering the antiobesity effect of SR141716, these results open new avenues to understand the mechanism by which the molecule may prevent weight gain through functional interaction between CB1 and other receptors involved in the control of appetite.

Topics: Animals; Carrier Proteins; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Humans; Intracellular Signaling Peptides and Proteins; MAP Kinase Signaling System; Neuropeptides; Obesity; Orexin Receptors; Orexins; Pertussis Toxin; Piperidines; Protein Binding; Pyrazoles; Receptor Cross-Talk; Receptors, Cannabinoid; Receptors, Drug; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Receptors, Neuropeptide Y; Rimonabant; Transfection

Agonists to opioid receptors induce a positive energy balance, whereas antagonists at these receptors reduce food intake and body weight in rodent models of obesity. An analog of 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, LY255582, is a potent non-morphinan antagonist for mu-, kappa-, and delta-receptors (K(i) of 0.4, 2.0, and 5.2 nM, respectively). In the present study, we examined the effects of oral LY255582 treatment on caloric intake, calorie expenditure, and body composition in dietary-induced obese rats. Acute oral treatment of LY255582 produced a dose-dependent decrease in energy intake and respiratory quotient (RQ), which correlated with the occupancy of central opioid receptors. Animals receiving chronic oral treatment with LY255582 for 14 days maintained a negative energy balance that was sustained by increased lipid use. Analysis of body composition revealed a reduction in fat mass accretion, with no change in lean body mass, in animals treated with LY255582. Therefore, chronic treatment with LY255582 reduces adipose tissue mass by reducing energy intake and stimulating lipid use.

Topics: Adipose Tissue; Animals; Body Composition; Cell Respiration; Cyclohexanes; Dose-Response Relationship, Drug; Energy Intake; Energy Metabolism; Feeding Behavior; Lipid Metabolism; Male; Narcotic Antagonists; Obesity; Piperidines; Rats; Rats, Long-Evans; Receptors, Opioid

Histamine is an aminergic neurotransmitter that is localized in the CNS and in peripheral tissues. To date, four histamine receptors have been identified, and the H3 receptor, which was recently cloned, is predominantly expressed in the CNS. The peripheral functions of histamine have been investigated intensively using available molecular and pharmacological tools, and the molecular identification of the H3 receptor opens up new possibilities for investigating the role of histamine in central tissues. To understand the biological function of the histamine presynaptic autoreceptor H3, we inactivated the receptor through homologous recombination. H3(-/-) mice manifest mild obese phenotypes that are characterized by increases in body weight, food intake, and adiposity and by reductions in energy expenditure. Consistent with these observations, homozygous null mice have insulin and leptin resistance, increased levels of plasma leptin and insulin, and decreased levels of histamine in the hypothalamic/thalamic region of their brains coupled with increased histamine turnover. The expression of UCP1 in brown adipose tissue and of UCP3 in brown adipose tissue, white adipose tissue, and skeletal muscle is decreased in H3(-/-) mutants, and the anorexigenic activity of thioperamide is not observed. These results suggest that neuronal histamine is a mediator of body-weight homeostasis and that neuronal histamine functions through H3 receptors in mice.

Topics: Animals; Biomarkers; Body Weight; Brain; Eating; Female; Gene Targeting; Histamine; Histamine Antagonists; Homeostasis; Insulin; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Muscle, Skeletal; Neurons; Obesity; Phenotype; Piperidines; Receptors, Histamine H3

Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake and energy balance. Leptin reduces food intake by upregulating anorexigenic (appetite-reducing) neuropeptides, such as alpha-melanocyte-stimulating hormone, and downregulating orexigenic (appetite-stimulating) factors, primarily neuropeptide Y. Genetic defects in anorexigenic signalling, such as mutations in the melanocortin-4 (ref. 5) or leptin receptors, cause obesity. However, alternative orexigenic pathways maintain food intake in mice deficient in neuropeptide Y. CB1 cannabinoid receptors and the endocannabinoids anandamide and 2-arachidonoyl glycerol are present in the hypothalamus, and marijuana and anandamide stimulate food intake. Here we show that following temporary food restriction, CB1 receptor knockout mice eat less than their wild-type littermates, and the CB1 antagonist SR141716A reduces food intake in wild-type but not knockout mice. Furthermore, defective leptin signalling is associated with elevated hypothalamic, but not cerebellar, levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats. Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus. These findings indicate that endocannabinoids in the hypothalamus may tonically activate CB1 receptors to maintain food intake and form part of the neural circuitry regulated by leptin.

Topics: Animals; Appetite Regulation; Arachidonic Acids; Cannabinoid Receptor Modulators; Cannabinoids; Cerebellum; Eating; Endocannabinoids; Female; Food; Glycerides; Hypothalamus; Leptin; Lipoprotein Lipase; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Phospholipase D; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptors, Cannabinoid; Receptors, Drug; Receptors, Leptin; Rimonabant; Signal Transduction

Topics: Adult; Ambulatory Surgical Procedures; Anesthesia Recovery Period; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Cholecystectomy, Laparoscopic; Humans; Methyl Ethers; Obesity; Piperidines; Postoperative Nausea and Vomiting; Remifentanil; Sevoflurane

The estrogen antagonist EM-652.HCl behaves as a highly potent and pure antiestrogen in human breast and uterine cancer cells. Because of its pure antiestrogenic activity in these cells, and because its prodrug, EM-800, reduces bone loss and decreases serum cholesterol and triglycerides in the rat, EM-652.HCl can be classified as a pure selective estrogen receptor modulator (SERM). This study was conducted to assess the ability of EM-652.HCl to prevent obesity and abnormalities of lipid metabolism induced by ovariectomy in a rat model.. Female rats were left intact or ovariectomized (OVX), and OVX rats were treated with placebo, estradiol (E2), or EM-652.HCl for 20 days. At the end of the treatment period, parameters of energy balance and determinants of lipid metabolism were assessed.. As expected, OVX increased energy intake, which in turn was accompanied by an increased energy, fat and protein gain and higher food efficiency. OVX also increased the triglyceride content of the liver and produced hypercholesterolemia and hyperinsulinemia. The weight of representative white adipose depots was higher in OVX than in intact rats. Lipoprotein lipase activity was higher in white adipose tissues of OVX rats than in those of intact animals, whereas its activity was lower in oxidative tissues (brown adipose and soleus muscle). Replacement therapy with a physiological dose of E2 prevented most of the abnormalities in energy and lipid metabolism brought about by OVX, although its orexigenic effect was only partially corrected. In contrast, treatment of OVX rats with EM-652. HCl completely abolished OVX-induced obesity and its related abnormalities in lipid metabolism and glucose/insulin homeostasis.. These findings demonstrate that EM-652.HCl can be considered as an effective agent to prevent OVX-induced obesity. The present study also shows that EM-652.HCl reduces cardiovascular risk factors associated with obesity such as hyperlipidemia and insulin resistance.

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Energy Metabolism; Estrogen Antagonists; Female; Hyperlipidemias; Insulin Resistance; Lipid Metabolism; Obesity; Ovariectomy; Piperidines; Rats; Rats, Sprague-Dawley; Risk Factors; Selective Estrogen Receptor Modulators

Repaglinide is the first stimulator of insulin secretion from the new meglitinide family. Via specific binding to the ATP-sensitive potassium channel of the beta cell membrane, it stimulates the rapid release of insulin. In preclinical studies, the insulin-stimulating effect of repaglinide has been found to be 10 to 20 times more potent than that of glibenclamide. Repaglinide is rapidly absorbed and has a short action, which makes it particularly well suited for the regulation of prandial blood glucose and meal-related dose adjustment. Since repaglinide is eliminated almost exclusively by non-renal routes, it can be used without danger in patients with moderately reduced renal function. Repaglinide is a suitable agent for first-line monotherapy in patients whose glucose metabolism cannot be optimally controlled by increasing physical activity and appropriate dietary measures. Repaglinide is clearly superior to glibenclamide in reducing postprandial hyperglycemia, and has a lower hypoglycemia risk than all the sulphonylureas. The flexibility of repaglinide makes it possible for good oral meal-related treatment.

Topics: Blood Glucose; Carbamates; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hypoglycemic Agents; Obesity; Piperidines

While insulin is known to promote vascular smooth muscle (VSM) relaxation, it also enhances endothelin-1 (ET-1) secretion and action in conditions such as NIDDM and hypertension. We examined the effect of insulin pretreatment on intracellular free calcium ([Ca2+]i) responses to ET-1 in cultured aortic smooth muscle cells (ASMCs) isolated from Sprague-Dawley (SD) rats and measured ET(A) receptor characteristics and ET-1-evoked tension responses in aorta obtained from insulin-resistant, hyperinsulinemic Zucker-obese (ZO) and control Zucker-lean (ZL) rats. Pretreatment of rat ASMCs with insulin (10 nmol/l for 24 h) failed to affect basal [Ca2+]i levels but led to a significant increase in peak [Ca2+]i response (1.7-fold; P < 0.01) to ET-1. The responses to IRL-1620 (an ET(B) selective agonist), ANG II, and vasopressin remained unaffected. ET-1-evoked peak [Ca2+]i responses were significantly attenuated by the inclusion of the ET(A) antagonist, BQ123, in both groups. The ET(B) antagonist, BQ788, abolished [Ca2+]i responses to IRL-1620 but failed to affect the exaggerated [Ca2+]i responses to ET-1. Saturation binding studies revealed a twofold increase (P < 0.01) in maximal number of binding sites labeled by 125I-labeled ET-1 in insulin-pretreated cells and no significant differences in sites labeled by 125I-labeled IRL-1620 between control and treatment groups. Northern blot analysis revealed an increase in ET(A) mRNA levels after insulin pretreatment for 20 h, an effect that was blocked by genistein, actinomycin D, and cycloheximide. Maximal tension development to ET-1 was significantly greater (P < 0.01), and microsomal binding studies using [3H]BQ-123 revealed a twofold higher number of ET(A) specific binding sites (P < 0.01) in aorta from ZO rats compared with that of ZL rats. These data suggest that insulin exaggerates ET-1-evoked peak [Ca2+]i responses via increased vascular ET(A) receptor expression, which may contribute to enhanced vasoconstriction observed in hyperinsulinemic states.

Topics: Animals; Aorta; Calcium; Cells, Cultured; Drug Synergism; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Gene Expression Regulation; Insulin; Kinetics; Male; Muscle, Smooth, Vascular; Obesity; Oligopeptides; Peptide Fragments; Piperidines; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Rats, Zucker; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Transcription, Genetic; Up-Regulation

Remifentanil is a short-acting opioid whose pharmacokinetics have been characterized in detail. However, the impact of obesity on remifentanil pharmacokinetics has not been specifically examined. The goal of this study was to investigate the influence of body weight on remifentanil pharmacokinetics.. Twelve obese and 12 matched lean subjects undergoing elective surgery received a 1-min remifentanil infusion after induction of anesthesia. Arterial blood samples were collected for determination of remifentanil blood concentrations. Each subject's pharmacokinetic parameters were estimated by fitting a two-compartment model to the concentration versus time curves. Nonlinear mixed-effects population models examining the influence of lean body mass (LBM) and total body weight (TBW) were also constructed. Clinical simulations using the final population model were performed.. The obese patient cohort reached substantially higher remifentanil concentrations. The individual pharmacokinetic parameters of a two-compartment model were not significantly different between the obese versus lean cohorts (unless normalized to TBW). The final population model scaled central clearance and the central and peripheral distribution volumes to LBM. The simulations illustrated that remifentanil pharmacokinetics are not grossly different in obese versus lean subjects and that TBW based dosing in obese patients can result in excessively high remifentanil concentrations.. The essential findings of the study are that remifentanil's pharmacokinetics are not appreciably different in obese versus lean subjects and that remifentanil pharmacokinetic parameters are therefore more closely related to LBM than to TBW. Clinically this means that remifentanil dosing regimens should be based on ideal body weight (or LBM) and not TBW.

Topics: Adolescent; Adult; Analgesics, Opioid; Body Weight; Computer Simulation; Female; Humans; Male; Middle Aged; Obesity; Piperidines; Remifentanil

Hyperinsulinemia and exaggerated insulin response to glucose are among the hallmarks of obesity. However, the role of hyperinsulinemia in the etiology and maintenance of obesity has been controversial. If hyperinsulinemia plays a critical role as proposed, then its reversal may have therapeutic potential. To test this hypothesis, the activity of Ro 23-7637, (4-(2,2-diphenylethenyl)-1-[1-oxo-9-(3-pyridinyl) nonyl]piperidine), which partially normalizes plasma insulin by an action on pancreatic islets from obese rats, was assessed. When islets were cultured for 2 days with 10 microM Ro 23-7637, a significant reduction in the exaggerated glucose-induced insulin secretion was observed. When islets from lean rats were exposed to Ro 23-7637, no reduction in insulin secretion was observed. The effects of oral administration of Ro 23-7637 were assessed in Zucker and diet-induced obese rats in doses ranging from 5 to 90 mg/kg/day. Dose-related reductions were observed in: 1) glucose-induced insulin secretion; 2) basal insulin concentration; 3) daily food intake; and 4) bodyweight gain. In diet-induced obese rats, selective mobilization of fat, maintenance of body protein, and decreased energetic efficiency were also observed. An association between the partial normalization of glucose-induced insulin responses and reductions of basal insulin, reduced rates of body weight gain or body weight loss and decreased food intake was observed in obese rats. Therefore, these studies indicate that Ro 23-7637 is an orally active, efficacious antiobesity agent.

Topics: Animals; Body Composition; Body Weight; Culture Techniques; Diet; Eating; Female; Glucose Tolerance Test; Insulin; Insulin Secretion; Islets of Langerhans; Male; Obesity; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Zucker

LY255582, administered subcutaneously, decreased food intake and body weight gain of fed obese Zucker rats during the entire 30-day period of treatment. No tolerance to these biologic effects of LY255582 could be demonstrated. d-Amphetamine and naltrexone, administered subcutaneously, and d,l-fenfluramine and salbutamol, administered orally, decreased food intake for no more than 6 to 12 days, in contrast to the long-lasting effects of LY255582. Salbutamol suppressed the appetite of obese rats for 3-4 days only. After an additional 12 days of treatment, weight gain decreased significantly accompanied by no appetite suppression. Thus, there is a difference in the duration of action of the opioid antagonist, LY255582, when compared to amphetamine, fenfluramine, naltrexone, and salbutamol, on food intake and body weight gain of obese rats.

Topics: Albuterol; Animals; Appetite Depressants; Cyclohexanes; Dextroamphetamine; Drug Tolerance; Eating; Endorphins; Female; Fenfluramine; Injections, Subcutaneous; Male; Naltrexone; Obesity; Piperidines; Rats; Rats, Zucker; Weight Gain

The effects of the phenylpiperidine opioid antagonist, LY255582, on food consumption, water consumption and body weight gain of the meal-fed obese Zucker rat have been determined. A single subcutaneous dose of LY255582 (0.31 mg/kg) decreased food and water consumption of the meal-fed obese rat. LY255582 was effective as an appetite suppressant at lower doses than ephedrine, amphetamine, fenfluramine, naltrexone and nalmefene. Comparison of the relative in vivo biological activity with in vitro receptor binding assays of LY255582 and its stereoisomers shows that the order of the affinity of the mu and kappa opioid receptors correlates well with biological activity. LY255582 is the most biologically effective and has the highest affinity for both receptors. LY255582 administered chronically to meal-fed obese Zucker rats for 68 days at a subcutaneous dose of 0.31 mg/kg significantly reduced food and water consumption and decreased body weight gain during the entire treatment period. There was no development of tolerance to the biological effects of LY255582.

Topics: Animals; Appetite; Body Weight; Cyclohexanes; Drinking; Eating; Endorphins; Female; Injections, Subcutaneous; Male; Molecular Structure; Obesity; Piperidines; Rats; Rats, Zucker; Receptors, Opioid; Stereoisomerism

Meal-fed Zucker rats were used to determine the acute and chronic s.c. effect of certain trans-3,4-dimethyl-4-phenylpiperidines (opioid antagonists) on food consumption. In acute studies, the active compounds suppressed food intake significantly of lean and obese meal-fed Zucker rats. LY117413 was the most effective over the 4-hr period immediately after the s.c. administration of the drug. Long-term chronic s.c. administration to the meal-fed obese Zucker rat showed that LY88329 and LY117413 significantly reduced food consumption for as long as the drug was administered and resulted in a significant decrease in body weight gain when compared to nontreated control obese rats. There was no evidence for the development of tolerance to these effects of LY88329 and LY117413 in this genetically obese rat model.

Topics: Animals; Appetite Depressants; Eating; Narcotic Antagonists; Obesity; Piperidines; Rats; Rats, Zucker; Weight Gain

In order to study the hypothesized impairment of the serotoninergic system in human obesity, an insulin tolerance test (ITT) was carried out on 12 obese normoprolactinemic women and on 6 normal-weight women before (A) and after (B) the administration of a serotoninergic drug, fenfluramine (60 mg twice a day per os for 7 days). After a washout period, a new ITT (C) followed the administration of fenfluramine at the same dose, associated with a specific S2 blocker receptor agent, ritanserin (30 mg/day for the first 2 days and 20 mg/day for a further 5 days). In obese subjects, the prolactin (PRL) response to ITT A was reduced as compared to the controls: in 6 patients ('nonresponders') the PRL levels did not change, while in the other 6 ('responders') they increased (p less than 0.003) but less than in the controls (p less than 0.02). In normal-weight subjects, the administration of fenfluramine alone or with ritanserin did not modify the PRL response to ITT. In the responders, the serotoninergic drug normalized the PRL response to ITT while significantly improving it in the nonresponders; these effects were not antagonized by ritanserin. In conclusion, our data suggest that the serotoninergic system of obese patients is impaired and that the different secretory pattern observed in the two groups before and after fenfluramine may reflect differing degrees of this impairment.

Topics: Adolescent; Adult; Female; Fenfluramine; Humans; Hypoglycemia; Insulin; Middle Aged; Obesity; Piperidines; Prolactin; Ritanserin; Serotonin; Serotonin Antagonists

Gold thioglucose (GTG)-injected mice and lean mice were treated for 16 days with PM 170. The body weight and body fat were significantly increased by GTG injection and these increases in the GTG-obese group were reduced by PM 170. PM 170 also reduced food intake (16%), total body triacylglycerol (51%) and total body cholesterol (36%). Basal lipolysis of white adipose tissue, as measured by glycerol release, was stimulated by 150%. Compared to GTG-PM 170 mice, body weight gain was 2 times higher in GTG-pair-fed mice. Body fat and total body lipid content remained elevated.

Topics: Adipose Tissue; Animals; Appetite Depressants; Aurothioglucose; Body Weight; DNA; Eating; Female; Gold; Liver; Mice; Obesity; Organ Size; Piperidines

The 3-hydroxyméthyl N-méthyl piperidine 4-chlorophenoxyacetate, hydrochloride, A, a potent anorectic, reduces weight gain of gold thioglucose obese mice through a reduced body fat and a decrease in metabolic efficiency. Compound A has much less effect in the lean mice than in the obese models. In contrast with pair-fed obese or lean mice, the decreased food consumption cannot account for all the reduced weight gain of the obese controls. Basal lipolytic activity in parametrial adipose tissue is greater in obese mice treated with A then in controls. It seems that the stimulating effect of A on lipolysis could contribute to the weight reduction.

Topics: Adipose Tissue; Animals; Appetite; Appetite Depressants; Aurothioglucose; Body Weight; DNA; Fatty Acids, Nonesterified; Female; Gold; Lipolysis; Mice; Obesity; Piperidines

Genetically obese Zucker rats and their lean littermates were trained to discriminate between the stimulus properties of 2.0 mg/kg fenfluramine and its vehicle in a two-lever, food-motivated operant task. Both groups learned the discrimination at the same rate and all rats showed a dose-related decrease in discriminative performance with lower fenfluramine doses. Analysis of the dose-response curves indicated an ED50 for the obese rats of 0.56 mg/kg and for the lean group of 0.42 mg/kg. Time-course experiments indicted that the obese rats maintain errorless discrimination through 90 min post-injection but discriminate significantly less than the lean rats at 960 min post-administration. These results suggest a similar sensitivity to fenfluramine in obese and lean rats with a difference in the time-course of drug action. Pre-treatment with the specific serotonin receptor antagonist pirenperone significantly attenuated fenfluramine discrimination in lean rats without a similar effect in the obese rats. Possible reasons for this observation are offered.

Topics: Animals; Discrimination Learning; Dose-Response Relationship, Drug; Female; Fenfluramine; Obesity; Piperidines; Rats; Rats, Zucker; Serotonin; Serotonin Antagonists; Time Factors

The (4-chlorophenoxyacetate) N-methyl 3-hydroxymethyl piperidine, hydrochloride (PM 170), chemically unrelated to amphetamine, was studied in normal rats for any thermogenic effect. It was given in graded doses. After an acute treatment PM 170 increases energy expenditure by increasing resting oxygen consumption (VO2) and in the doses used, produced dose-related increases in VO2. Energy expenditure of rats treated for 16 days was chronically elevated, while body weight gain and food intake were reduced. It also stimulated mitochondrial oxygen consumption probably by partial uncoupling of respiration from ATP synthesis. The disruption of oxidative phosphorylation could partially explain the effect of this compound on resting metabolic rate.

Topics: Animals; Body Temperature Regulation; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Injections, Intraperitoneal; Male; Mitochondria, Liver; Obesity; Oxygen Consumption; Piperidines; Rats; Rats, Inbred Strains; Time Factors

The 3-hydroxymethyl N-methyl piperidine (4-chlorophenoxy) acetate, hydrochloride, A, has been tested for its effect on feeding behavior. This first non-amphetamine substance, with low toxicity and without psychotropic activity, affects the satiety center by reducing gold thioglucose-induced obesity in mice.

Topics: Animals; Appetite Depressants; Aurothioglucose; Feeding Behavior; Female; Glycolates; Humans; Male; Mice; Obesity; Piperidines; Psychomotor Disorders; Rats; Rats, Inbred Strains

Topics: Adult; Humans; Middle Aged; Obesity; Piperidines; Serotonin; Serotonin Antagonists

Weanling mice were injected with gold thioglucose or bipiperidyl mustard which have been previously shown to cause obesity associated with ventromedial hypothalamic damage. There was an increase in both adipocyte number and size compared to controls. Several models of obesity are compared and a possible role for the hypothalamus in the regulation of fat stores is discussed.

Topics: Adipose Tissue; Animals; Body Weight; Cell Count; Gold Sodium Thiomalate; Hypothalamus; Mice; Mustard Compounds; Obesity; Piperidines

Experiments were performed to determine PRL and GH concentrations in mice rendered obese by chemical means and to compare these concentrations with those of mice obese as a result of genetic mutation. Basal levels of serum PRL and GH were generally lower in gold thioglucose (GTG) and bipiperidyl mustard (BPM)-treated obese mice compared with lean controls. In the pituitary gland, the hormonal changes varied from lower or unchanged levels of PRL and GH shortly after drug injection to very high concentrations of PRL (but not of GH) a year later. However, when the mice were challenged with perphenazine, a drug that causes prompt release of PRL, GTG and BPM-obese mice released 2-5 times as much PRL as did lean controls, suggesting an impairment in the hypothalamic control of PRL secretion in GTG/BPM-obese mice. Basal levels of PRL and GH in genetically obese (ob/ob) mice of both sexes were also lower than those in their lean relatives (?/+). This was true for both serum and pituitary concentrations of the two hormones, the only exception being pituitary GH concentrations in females which were higher than or equal to those of controls. However, unlike GTG and BPM-obese mice, genetically obese mice released very little PRL compared with their lean relatives when stimulated with perphenazine, which suggested an insufficiency of pituitary function in ob/ob mice. The results demonstrate abnormalities in the secretion of PRL and GH in obese mice of both types.

Topics: Animals; Aurothioglucose; Female; Growth Hormone; Hypothalamo-Hypophyseal System; Mice; Mice, Obese; Obesity; Perphenazine; Piperidines; Prolactin; Stimulation, Chemical

Topics: Adrenal Glands; Animals; Electrophoresis; Feeding Behavior; Female; Glucose; Growth Hormone; Mice; Mustard Compounds; Obesity; Organ Size; Ovary; Piperidines; Pituitary Gland; Prolactin; Species Specificity; Spectrophotometry; Uterus

Topics: Appetite Depressants; Blood Pressure; Diuresis; Female; Humans; Obesity; Phenethylamines; Phentermine; Piperidines; Time Factors

Topics: Animals; Autoradiography; Cicatrix; Cytoplasmic Granules; Feeding Behavior; Female; Glucose; Gold; Hypothalamus; Injections, Intraperitoneal; Malates; Mice; Necrosis; Nitrogen Mustard Compounds; Obesity; Piperidines; Time Factors

Topics: Aged; Albuminuria; Amides; Brain; Clopamide; Diuresis; Diuretics; Ergoloid Mesylates; Fundus Oculi; Headache; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Obesity; Piperidines; Sodium; Vertigo

Topics: Biopsy; Body Temperature; Body Weight; Brain Diseases; Calcium; Child; Child, Preschool; Chlorides; Creatine; Dehydration; Diabetes Insipidus; Diagnosis, Differential; Diet; Diuresis; Feeding and Eating Disorders; Female; Humans; Hydrochlorothiazide; Hypothalamus; Infant; Kidney; Male; Mineralocorticoid Receptor Antagonists; Obesity; Osmolar Concentration; Osmosis; Piperidines; Potassium; Sodium; Urography; Vasopressins

Topics: Adrenal Cortex Hormones; Adult; Amides; Body Weight; Clopamide; Coronary Disease; Diabetes Insipidus; Diuretics; Edema; Female; Heart Valve Diseases; Humans; Hypertension; Male; Middle Aged; Obesity; Piperidines; Pulmonary Heart Disease

Topics: Acetates; Adipose Tissue; Animals; Carbon Isotopes; Glucose; Hydroxybutyrates; Mice; Mustard Compounds; Obesity; Piperidines; Starvation

Topics: Amides; Clopamide; Diuretics; Humans; Obesity; Piperidines

Topics: Clopamide; Diuretics; Heart Failure; Humans; Hypertension; Liver Cirrhosis; Obesity; Piperidines

Topics: Humans; Obesity; Piperidines

Topics: Benzhydryl Compounds; Central Nervous System Stimulants; Obesity; Piperidines