piperidines and Cardiovascular-Diseases

Migraine has a great impact on public health. Current acute therapies do not satisfy all migraineurs. The novel serotonin 5-HT. To evaluate the clinical efficacy and safety of lasmiditan in treating acute migraine attacks.. The literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) which assessed the effect and safety of lasmiditan on migraine. The risk of bias was assessed using the Cochrane Collaboration's risk of bias tool. Results were extracted and pooled as risk ratios (RRs) with a fixed or random-effects model.. Based on the four included RCTs, pooled estimates showed that lasmiditan with the 50 mg, 100 mg, and 200 mg doses was superior to placebo at 2 h after the first dose in terms of pain freedom, absence of migraine-associated symptoms, headache relief, no/mild disability, and global impression of change (very much/much better) (RRs ranged from 1.13 to 1.96), except for nausea-free and vomiting-free. Both lasmiditan 100 mg and 200 mg resulted in significantly fewer patients using rescue medication (100 mg: RR = 0.75, 95% CI (0.61, 0.92),. Lasmiditan with the 50 mg, 100 mg, and 200 mg doses are effective and safe in acute migraine treatment. Lasmiditan 200 mg is more effective than lasmiditan 100 mg in pain freedom, while lasmiditan 100 mg is better tolerated in the short-term follow-up. Further larger sample-size RCTs are required to verify the applicability and tolerability in the long term.

Topics: Adult; Benzamides; Cardiovascular Diseases; Confidence Intervals; Disability Evaluation; Female; Humans; Male; Migraine Disorders; Piperidines; Publication Bias; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Risk; Serotonin Receptor Agonists; Treatment Outcome

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; 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Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

The treatment of rheumatoid arthritis has changed dramatically over the last two decades since the development of biological disease-modifying anti-rheumatic drugs (bDMARDs). Moreover, Janus kinase (JAK) inhibitors became available in 2013. JAK inhibitors are low-molecular-weight compounds, which exert anti-rheumatic effects by suppressing the action of JAK, an intracellular tyrosine kinase. Of note, biologics bind to extracellular proteins and block their activity. The availability of JAK inhibitors that are as effective as bDMARDs, despite the completely different route of administration and mode of action, has enabled the treatment of rheumatoid arthritis to enter a new stage. JAK inhibitors are useful in a variety of cases, including patients who inadequately responded to treatment with methotrexate and/or bDMARDs. Oral administration is convenient for patients. Nevertheless, the drugs should be carefully prescribed as they are metabolized in the liver and kidneys. Attention should also be paid to adverse events, such as infections including herpes zoster. It is necessary to understand the characteristics of JAK inhibitors and use these agents judiciously.

Topics: Adamantane; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Benzofurans; Cardiovascular Diseases; Herpes Zoster; Humans; Janus Kinases; Molecular Targeted Therapy; Neutropenia; Niacinamide; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Pyrroles; Sulfonamides; Venous Thromboembolism

Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified.. To assess the effects of metformin monotherapy in adults with T2DM.. We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017).. We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM.. Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument.. We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trial. There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.

Topics: Adult; Carbamates; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Metformin; Myocardial Infarction; Piperidines; Quality of Life; Randomized Controlled Trials as Topic; Stroke; Sulfonylurea Compounds

The term prediabetes is used to describe a population with an elevated risk of developing type 2 diabetes mellitus (T2DM). With projections of an increase in the incidence of T2DM, prevention or delay of the disease and its complications is paramount. It is currently unknown whether pioglitazone is beneficial in the treatment of people with increased risk of developing T2DM.. To assess the effects of pioglitazone for prevention or delay of T2DM and its associated complications in people at risk of developing T2DM.. We searched CENTRAL, MEDLINE, Chinese databases, ICTRP Search Portal and ClinicalTrials.gov. We did not apply any language restrictions. Further, we investigated the reference lists of all included studies and reviews. We tried to contact all study authors. The date of the last search of databases was November 2019 (March 2020 for Chinese databases).. We included randomised controlled trials (RCTs) with a minimum duration of 24 weeks, and participants diagnosed with intermediate hyperglycaemia with no concomitant diseases, comparing pioglitazone as monotherapy or part of dual therapy with other glucose-lowering drugs, behaviour-changing interventions, placebo or no intervention.. Two review authors independently screened abstracts, read full-text articles and records, assessed risk of bias and extracted data. We performed meta-analyses with a random-effects model and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, with 95% confidence intervals (CIs) for effect estimates. We evaluated the certainty of the evidence with the GRADE.. We included 27 studies with a total of 4186 randomised participants. The size of individual studies ranged between 43 and 605 participants and the duration varied between 6 and 36 months. We judged none of the included studies as having low risk of bias across all 'Risk of bias' domains. Most studies identified people at increased risk of T2DM by impaired fasting glucose or impaired glucose tolerance (IGT), or both. Our main outcome measures were all-cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, nonfatal myocardial infarction or stroke (NMI/S), health-related quality of life (QoL) and socioeconomic effects. The following comparisons mostly reported only a fraction of our main outcome set. Three studies compared pioglitazone with metformin. They did not report all-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects. Incidence of T2DM was 9/168 participants in the pioglitazone groups versus 9/163 participants in the metformin groups (RR 0.98, 95% CI 0.40 to 2.38; P = 0.96; 3 studies, 331 participants; low-certainty evidence). No SAEs were reported in two studies (201 participants; low-certainty evidence). One study compared pioglitazone with acarbose. Incidence of T2DM was 1/50 participants in the pioglitazone group versus 2/46 participants in the acarbose group (very low-certainty evidence). No participant experienced a SAE (very low-certainty evidence).One study compared pioglitazone with repaglinide. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 1/48 participants in the repaglinide group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). One study compared pioglitazone with a personalised diet and exercise consultation. All-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects were not reported. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 5/48 participants in the diet and exercise consultation group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence). Six studies compared pioglitazone with placebo. No study reported on QoL or socioeconomic effects. All-cause mortality was 5/577 participants the in the pioglitazone groups versus 2/579 participants in the placebo groups (Peto odds ratio 2.38, 95% CI 0.54 to 10.50; P = 0.25; 4 studies, 1156 participants; very low-certainty evidence). Incidence of T2DM was 80/700 participants in the pioglitazone groups ve. Pioglitazone reduced or delayed the development of T2DM in people at increased risk of T2DM compared with placebo (low-certainty evidence) and compared with no intervention (moderate-certainty evidence). It is unclear whether the effect of pioglitazone is sustained once discontinued. Pioglitazone compared with metformin neither showed advantage nor disadvantage regarding the development of T2DM in people at increased risk (low-certainty evidence). The data and reporting of all-cause mortality, SAEs, micro- and macrovascular complications were generally sparse. None of the included studies reported on QoL or socioeconomic effects.

Topics: Acarbose; Bias; Carbamates; Cardiovascular Diseases; Confidence Intervals; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Pioglitazone; Piperidines; Placebos; Randomized Controlled Trials as Topic; Risk

Tofacitinib is an oral, small-molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We analyzed inflammation, lipid concentrations, and incidence rates of major adverse cardiovascular (CV) events (MACEs) in patients who received tofacitinib in worldwide studies.. We collected data from 1157 patients who participated in 3 8-week induction studies (1 phase-2 study and 2 phase-3 studies; patients received tofacitinib 10 mg twice daily or placebo), a 52-week phase-3 maintenance study of responders (patients received tofacitinib 5 or 10 mg twice daily or placebo), and an ongoing long-term extension study of patients who did and did not respond to induction or maintenance therapy (patients received tofacitinib 5 or 10 mg twice daily). Lipid concentrations were assessed from induction baseline to week 61 (week 52 of maintenance therapy). We calculated MACE incidence rates (patients with ≥1 event per 100 patient-years of exposure) and Reynolds risk score (RRS; a composite score used to determine CV risk) for patients given tofacitinib vs placebo.. The mean RRS was <5% at baseline and week 8 of treatment with tofacitinib. At week 8, there were greater increases from baseline in total cholesterol, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol in patients given tofacitinib compared with placebo. There were correlations between reduced levels of high-sensitivity C-reactive protein and increased serum concentrations of lipid in patients given tofacitinib or placebo (P < .001). Lipid concentrations were increased in patients given tofacitinib vs patients given placebo through week 61. Overall, ratios of low-density lipoprotein cholesterol to HDL-c and total cholesterol to HDL-c did not change significantly over the 61-week period. Four MACEs were reported; the incidence rate was 0.24 (95% CI, 0.07-0.62) and 3 of these patients had 4 or more CV risk factors.. In an analysis of data from 5 trials of patients with UC who received tofacitinib, we found reversible increases in lipids with treatment and inverse correlations with reduced levels of high-sensitivity C-reactive protein. We did not find clinically meaningful changes in lipid ratios or RRS. MACEs were infrequent and not dose-related. Clinicaltrials.gov: A3921063 (NCT00787202); OCTAVE Induction 1 (NCT01465763); OCTAVE Induction 2 (NCT01458951); OCTAVE Sustain (NCT01458574); OCTAVE Open (NCT01470612).

Topics: Adult; Aged; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Colitis, Ulcerative; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Risk Factors

Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral antidiabetic drugs that safely reduce the blood glucose level over the long term. In Japan, DPP-4 inhibitors have become the oral antidiabetic drugs most frequently prescribed for patients with type 2 diabetes. However, the results of several cardiovascular outcomes studies have suggested that some DPP-4 inhibitors may increase the risk of hospitalization for heart failure. In patients with diabetes, heart failure is the most frequent cardiovascular condition, and it has a negative impact on the quality of life as well as being a potentially fatal complication. Therefore, it is important to determine whether an increased risk of heart failure is associated with certain DPP-4 inhibitors or is a class effect of these drugs. This review explores the mechanism by which DPP-4 inhibitors may increase the risk of heart failure and possible differences among these drugs. The available research suggests that DPP-4 inhibitors cause sympathetic activation as a class effect and this may increase the risk of heart failure. Unlike other DPP-4 inhibitors, sitagliptin and alogliptin are mainly excreted in the urine and suppress renal sodium-hydrogen exchanger 3 activity. These two drugs did not increase the risk of hospitalization for heart failure in large-scale cardiovascular outcomes studies.

Topics: Adult; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Japan; Male; Middle Aged; Piperidines; Quality of Life; Sitagliptin Phosphate; Uracil

Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare and fatal disease with features of premature aging and cardiovascular diseases (atherosclerosis, myocardial infarction, and stroke). Several landmark studies in 2018-2019 have revealed novel mechanisms underlying cardiovascular pathologies in HGPS, and implicate future potential therapies for HGPS, and possibly physiological aging.

Topics: Cardiovascular Diseases; Humans; Piperidines; Progeria; Pyridines

The risk of cardiovascular disease (CVD) is higher in patients with psoriatic arthritis (PsA) compared to the general population. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Because tofacitinib increases circulating lipid levels in some patients, we evaluated CVD risk factors and major adverse cardiovascular events (MACE) in patients with active PsA receiving tofacitinib 5 or 10 mg twice daily plus conventional synthetic disease-modifying antirheumatic drugs.. Data were pooled from 2 phase III studies (Efficacy and Safety of Tofacitinib in Psoriatic Arthritis [OPAL Broaden] and Tofacitinib in Patients with Psoriatic Arthritis With Inadequate Response to TNF Inhibitors [OPAL Beyond]) and 1 ongoing long-term extension (Open-Label Extension Study of Tofacitinib in Psoriatic Arthritis [OPAL Balance], data cutoff January 2017; database not locked). Outcomes included fasting lipid levels, blood pressure, hypertension-related adverse events (AEs; including hypertension, high blood pressure, and increased blood pressure), and MACE.. Overall, 783 tofacitinib-treated patients were included. Percentage increases from baseline in low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) levels ranged from 9% to 14% for tofacitinib 5 mg and 10 mg at 3 and 6 months; no meaningful changes in LDL-c:HDL-c or total cholesterol:HDL-c ratios were observed. Blood pressure remained stable for 24 months. Fifty-eight patients (7.4%) had hypertension-related AEs; none were fatal (incidence rate [IR] per 100 patient-years 4.81 [95% confidence interval (95% CI) 3.65-6.22]). Five patients (0.6%) had MACE (IR 0.24 [95% CI 0.05-0.70]); 2 were fatal.. Serum lipid level increases at month 3 following tofacitinib treatment in PsA were consistent with observations in rheumatoid arthritis and psoriasis. The IR of hypertension-related AEs and MACE was low; long-term follow-up is ongoing.

Topics: Arthritis, Psoriatic; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Humans; Incidence; Lipids; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Treatment Outcome

Mantle cell lymphoma (MCL) is a heterogeneous and uncommon non-Hodgkin lymphoma that affects predominantly older patients and often is associated with an aggressive clinical course. MCL relies upon B-cell receptor signaling through Bruton tyrosine kinase (BTK); therefore, the development of the BTK inhibitors ibrutinib and acalabrutinib represents a therapeutic breakthrough. In this review, we provide a summary of the efficacy and safety data from the landmark trials of single-agent ibrutinib and acalabrutinib that led to US Food and Drug Administration approval of these agents for patients with relapsed or refractory MCL. Toxicities of interest observed with ibrutinib include bleeding, atrial fibrillation, and increased risk for infection. The selectivity of acalabrutinib for BTK is greater than that of ibrutinib, which mitigates the risk for certain off-target toxicities, including atrial fibrillation; however, these toxicities, along with frequent headaches, still occur. Ongoing clinical trials are investigating both alternate BTK inhibitors and BTK inhibitors in combination with chemo-immunotherapy or other targeted agents in an effort to enhance the depth and duration of response. Trials to evaluate the use of these agents in the frontline setting are emerging and are likely to build upon the success of BTK inhibitors in patients with MCL.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antigens, CD20; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cardiovascular Diseases; Clinical Trials as Topic; Forecasting; Gastrointestinal Neoplasms; Hemorrhage; Humans; Immunologic Factors; Lymphocytosis; Lymphoma, Mantle-Cell; Molecular Targeted Therapy; Neoplasm Proteins; Opportunistic Infections; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Salvage Therapy

Rheumatic diseases are autoimmune, inflammatory diseases often associated with cardiovascular (CV) disease, a major cause of mortality in these patients. In recent years, treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), either as monotherapy or in combination with other drugs, have become the standard of treatment. In this systematic literature review, we evaluated the effect of treatment with biologic or tofacitinib on the CV risk and outcomes in these patients.. A systematic search was performed in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for articles reporting on CV risk and events in patients with rheumatic disease treated with a biologic agent or tofacitinib. Articles identified were subjected to two levels of screening. Articles that passed the first level based on title and abstract were assessed on full-text evaluation. The quality of randomized clinical trials was assessed by Jadad scoring system and the quality of the other studies and abstracts was assessed using the Downs and Black instrument. The data extracted included study design, baseline patient characteristics, and measurements of CV risk and events.. Of the 5722 articles identified in the initial search, screening yielded 105 unique publications from 90 unique studies (33 clinical trials, 39 prospective cohort studies, and an additional 18 retrospective studies) that reported CV risk outcomes. A risk of bias analysis for each type of report indicated that they were of good or excellent quality. Importantly, despite some limitations in data reported, there were no indications of significant increase in adverse CV events or risk in response to treatment with the agents evaluated.. Treatment with biologic or tofacitinib appears to be well-tolerated with respect to CV outcomes in these patients.

Topics: Animals; Antirheumatic Agents; Biological Products; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Piperidines; Prospective Studies; Pyrimidines; Pyrroles; Retrospective Studies; Rheumatic Diseases; Risk Factors

Alvimopan is used in abdominal surgery to reduce postoperative ileus in patients undergoing small bowel resections with primary anastomosis. The role and efficacy of alvimopan in patients undergoing radical cystectomy with urinary diversion is not well understood.. To assess the effects of alvimopan in the context of enhanced recovery pathways compared to enhanced recovery pathways alone for perioperative bowel dysfunction in patients undergoing radical cystectomy.. The terms alvimopan and cystectomy were used to search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We also reviewed abstracts from the past four years (2013 to 2016) of the American Urologic Association, Society of Urologic Oncology, and American Society of Clinical Oncology Genitourinary Cancers.. We searched for randomized controlled trials that compared alvimopan to placebo.. This study was based on a published protocol. We performed a comprehensive search of multiple databases including CENTRAL in the Cochrane Library, MEDLINE, Embase, LILACS, Web of Science, Scopus and Biosis, which we last updated on 6 February 2017. We also searched abstract proceedings for major relevant meetings (2013 to 2016), databases of the grey literature, trial registries, citations of relevant reviews and contacted clinical experts and the drug manufacturer.Two independent reviewers screened the literature in two stages (title and abstract, full-text) using Covidence software. Two independent reviewers assessed the risk of bias on a 'per outcome' basis using the Cochrane 'Risk of bias; tool and rated the quality of evidence according to GRADE. Results of the single eligible trial were reported in a 'Summary of findings' table based on an intention-to-treat analysis.. Based on a single trial and moderate-quality evidence, alvimopan reduced the time to reach a composite endpoint of tolerance of solid food and documented bowel movements (hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.41 to 2.23). This represents 165 more patients (109 more to 207 more) per 1000 meeting this endpoint within 10 days of surgery. Based on moderate-quality evidence, alvimopan reduced the time to hospital discharge (HR 1.67, 95% CI 1.38 to 2.01). This represents 138 more patients (82 more to 198 more) per 1000 being discharged within 10 days of surgery. Also based on moderate-quality evidence, alvimopan was associated with a reduced risk of major adverse events (risk ratio (RR) 0.28, 95% CI 0.18 to 0.44) representing 355 fewer patients (404 fewer to 276 fewer) with major adverse events per 1000. We downgraded this outcome for indirectness as it included adverse events that we did not consider major.In terms of secondary outcomes, alvimopan did not appear to alter the rate of readmission (RR 0.89, 95% CI 0.59 to 1.33), change the rate of any cardiovascular event (RR 0.54, 95% CI 0.27 to 1.05) or alter the mean narcotic pain medication use (mean difference 0, 95% CI 14.08 fewer to 14.08 more morphine equivalents). The quality of evidence was moderate for all three outcomes. Based on high-quality evidence, alvimopan reduced the rate of nasogastric tube replacement (RR 0.31, 95% CI 0.16 to 0.59). We did not find evidence for the drug's impact on rates of parenteral nutrition. All outcomes were short term and limited to a 30-day time horizon.Based on the existence of only one trial, we were unable to perform any subgroup or sensitivity analyses.. In patients undergoing radical cystectomy and urinary diversion, the use of alvimopan administered as part of an enhanced recovery pathway for a limited duration (up to 15 doses for up to seven days) probably reduces the time to tolerance of solid food, time to hospital discharge and rates of major adverse events. Readmission rates, rates of cardiovascular events and narcotic pain requirements are probably similar. The need for reinsertion of nasogastric tubes is reduced. We found no evidence for the impact on rates of parenteral nutrition within 30 postoperative days.

Topics: Cardiovascular Diseases; Cystectomy; Defecation; Eating; Gastrointestinal Agents; Humans; Ileus; Patient Discharge; Patient Readmission; Piperidines; Postoperative Complications; Randomized Controlled Trials as Topic; Recovery of Function; Time Factors; Urinary Diversion

Migraine is among the most disabling disorders worldwide, with a significant therapeutic need. Triptans are drugs of choice in the acute attack treatment, but they are contraindicated in patients with vascular conditions due to their potential vasoconstrictive properties. Further limitations include side effects, inconsistency in therapeutic action and possible non-response. Lasmiditan, a highly selective 5-HT1F receptor agonist, is a novel acute anti-migraine substance devoid of vasoconstriction. Areas covered: This article reviews the clinical efficacy and safety of oral and intravenous lasmiditan as a possible acute migraine treatment. We analyze all currently available results in Phase I to III studies. Expert opinion: Lasmiditan is a promising acute migraine therapy, in particular for patients at cardiovascular risk. Phase II and the first Phase III clinical trials show a significant better headache response in comparison to placebo. The efficacy of lasmiditan proves that vasoconstriction is not essential for acute migraine therapy and thereby points, in addition to a well-established trigeminal contribution, to central neuronal mechanisms in migraine pathophysiology. Lasmiditan penetrates the blood-brain barrier and CNS associated adverse events are common, but mostly in mild to moderate severity. The results of long-term Phase III studies will determine if these adverse events represent a limitation in clinical practice.

Topics: Benzamides; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Risk Factors; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Regulatory requirements mandate that new drugs for treatment of patients with type 2 diabetes mellitus (T2DM), such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, are evaluated to show that they do not increase cardiovascular (CV) risk.. A systematic review was undertaken to evaluate the association between DPP-4 inhibitor and GLP-1 receptor agonist use and major adverse cardiac events (MACE). The National Institutes of Health Medline database was searched for pooled analyses, meta-analyses, and randomized controlled trials (RCTs) of DPP-4 inhibitors and GLP-1 receptor agonists that included CV endpoints.. Thirty-six articles met the inclusion criteria encompassing 11 pooled analyses, 17 meta-analyses, and eight RCTs (including secondary analyses). Over the short term (up to 4 years), patients with T2DM exposed to a DPP-4 inhibitor or GLP-1 receptor agonist were not at increased risk for MACE (or its component endpoints) compared with those who received comparator agents. Two meta-analyses showed a significant reduction in the incidence of MACE associated with DPP-4 inhibitor therapy as a drug class, but this beneficial effect was not observed in other meta-analyses that included large RCT CV outcome studies. In four RCTs that evaluated alogliptin, saxagliptin, sitagliptin, or lixisenatide, there was no overall increased risk for MACE relative to placebo in T2DM patients at high risk for CV events or with established CV disease, although there was an increased rate of hospitalization for heart failure associated with saxagliptin. A fifth RCT showed that liraglutide reduced MACE risk by 13% versus placebo.. Overall, incretin therapy does not appear to increase risk for MACE in the short term.

Topics: Adamantane; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Meta-Analysis as Topic; Peptides; Piperidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Uracil

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; 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The incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, are important new classes of therapy for type 2 diabetes mellitus (T2DM). These agents prolong the action of the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), by inhibiting their breakdown. The incretin hormones improve glycemic control in T2DM by increasing insulin secretion and suppressing glucagon levels. The cardiovascular (CV) effects of the incretin-based therapies have been of substantial interest since 2008, when the US Food and Drug Administration began to require that all new therapies for diabetes undergo rigorous assessment of CV safety through large-scale CV outcome trials. This article reviews the most recent CV outcome trials of the DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) as evidence that the incretin-based therapies have acceptable CV safety profiles for patients with T2DM. The studies differ with regard to patient population, trial duration, and heart failure outcomes but show similar findings for CV death, nonfatal myocardial infarction, and stroke, as well as hospitalization for unstable angina.

Topics: Adamantane; Cardiovascular Diseases; Cardiovascular System; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Piperidines; Sitagliptin Phosphate; Uracil

Cardiovascular disease (CVD) is the greatest burden of type 2 diabetes mellitus (T2DM) in terms of morbility, mortality and costs for individuals and societies. Therefore, its prevention is a major goal in diabetes care. Optimal treatment of hyperglycemia is certainly instrumental to CVD prevention. Optimal treatment means both establishing the most appropriate glycemic target for the given individual and selecting the medication(s) with the most favourable benefit/safety ratio. CVD safety, if not a clear CVD benefit, is certainly required for all antidiabetic agents. Dipeptidyl-peptidase-4 (DPP-4) inhibitors are among the classes of antidiabetic agents most recently made available for diabetes care. A major question to be addressed is the effect of these compounds on CVD. Expectations were high for their mechanism of action, which targets also post-prandial glucose and minimize hypoglycemia risk, thereby providing a sort of global glucose control, and for some potentially beneficial extra-glycemic effects. This article reviews the existing literature on this issue.. Data published so far document that DPP-4 inhibitors have a wide spectrum of glycemic and extra-glycemic effects potentially reducing the risk of CVD as well as favourable effects on intermediate or surrogate CVD endpoints. These data heralded a better CVD outcome. Accordingly, pooling CVD safety data from phase 3 and 4 studies conducted with DPP-4 inhibitors suggested that their use might translate into a better CVD outcome. Data from three CVD outcome RCTs with alogliptin, saxagliptin and sitagliptin documented no harm but did not show any benefit on major CVD events. A modest but significant increased risk of hospitalization for heart failure was observed with saxagliptin and with alogliptin (only in subjects with no history of heart failure before randomization) but not with sitagliptin. A study currently in progress with linagliptin will provide further insights in the issue of CVD safety and benefit.. It should be considered that most alternative oral antidiabetic agents generally do not possess a better CVD risk profile than DPP-4 inhibitors and that some of them, indeed, should be used with caution because of potentially adverse effects on heart and vasculature. Overall, the selection of antidiabetic agent(s) with the most favourable CVD profile is mandatory but still challenging in diabetes care.

Topics: Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endpoint Determination; Humans; Hypoglycemic Agents; Linagliptin; Meta-Analysis as Topic; Observational Studies as Topic; Piperidines; Randomized Controlled Trials as Topic; Risk Factors; Sitagliptin Phosphate; Uracil

Cardiovascular (CV) disease is the leading cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). However, improving glycaemic control alone has not decreased CV events. Therapies that improve glycaemic control, CV disease risk factors and CV function are more likely to be successful. Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent breakdown of incretin hormones glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic peptide and improve glycaemic control in patients with T2DM. DPP-4 acts on other substrates, many associated with cardioprotection. Thus, inhibition of DPP-4 may lead to elevations in these potentially beneficial substrates. Data from animal studies and small observational studies in humans suggest that DPP-4 inhibitors may potentially reduce CV risk. However, recently completed CV outcome trials in patients with T2DM and CV disease or at high risk of adverse CV events have shown that the DPP-4 inhibitors saxagliptin and alogliptin neither increased nor decreased major adverse CV events.

Topics: Adamantane; Animals; Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Incretins; Piperidines; Protective Factors; Risk Assessment; Risk Factors; Treatment Outcome; Uracil

Vandetanib has recently demonstrated clinically meaningful benefits in patients with unresectable, locally advanced or metastatic medullary thyroid cancer (MTC). Given the potential for long-term vandetanib therapy in this setting, in addition to treatment for disease-related symptoms, effective management of related adverse events (AEs) is vital to ensure patient compliance and maximize clinical benefit with vandetanib therapy.. This expert meeting-based review aims to summarize published data on AEs associated with vandetanib therapy and to provide clinicians with specific practical guidance on education, monitoring, and management of toxicities induced in patients treated with vandetanib in advanced and metastatic MTC. The content of this review is based on the expert discussions from a multidisciplinary meeting held in October 2012.. Characteristics, frequency, and risk data are outlined for a number of dermatological, cardiovascular, gastrointestinal, and general AEs related to vandetanib treatment. Preventive strategies, practical treatment suggestions, and points for clinical consideration are provided.. Good patient and team communication is necessary for the prevention, early detection, and management of AEs of vandetanib. Physicians, nurses, and other healthcare providers play a critical role in providing AE management and patient support to optimize outcomes with vandetanib in MTC.

Topics: Carcinoma, Neuroendocrine; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Eruptions; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Diseases; Humans; Male; Neoplasm Invasiveness; Neoplasm Staging; Patient Selection; Piperidines; Prognosis; Quinazolines; Risk Assessment; Thyroid Neoplasms; Treatment Outcome

The authors conducted a review of randomized controlled trials to identify advantages in clinically relevant outcomes in patients undergoing cardiac surgery with remifentanil.. Meta-analysis.. Hospitals.. A total of 1,473 patients from 16 randomized trials.. None.. PubMed, BioMedCentral, and conference proceedings were searched (updated May 2010) for randomized trials that compared remifentanil with fentanyl or sufentanil in cardiac anesthesia. Four independent reviewers performed data extraction, with divergences resolved by consensus. Overall analysis showed that the use of remifentanil was associated with a significant reduction in postoperative mechanical ventilation (WMD = -139 min [-244, -32], p for effect = 0.01, p for heterogeneity < 0.001, I(2) = 89%); length of hospital stay (WMD = -1.08 days [-1.60, -0.57], p for effect < 0.0001, p for heterogeneity = 0.004, I(2) = 71%); and cardiac troponin-I release (WMD = -2.08 ng/mL [-3.93, -0.24], p for effect = 0.03, p for heterogeneity < 0.02, I(2) = 74%). No difference was noted in mortality (3/344 [0.87%] in the remifentanil group vs [1.06%] the control group, OR 0.76 [0.17-3.38], p for effect = 0.72, p for heterogeneity = 0.35, I(2) = 5%).. Remifentanil reduces cardiac troponin release, time of mechanical ventilation, and length of hospital stay in patients undergoing cardiac surgery.

Topics: Cardiac Surgical Procedures; Cardiovascular Diseases; Humans; Length of Stay; Piperidines; Randomized Controlled Trials as Topic; Remifentanil; Respiration, Artificial

Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic β-cells (SUR1). However, these drugs also bind to receptor isoforms on cardiac myocytes (SUR2A) and vascular smooth muscle (SUR2B). Binding to SUR2A/SUR2B may inhibit ischaemic preconditioning, an endogenous protective mechanism enabling cardiac tissue to survive periods of ischaemia. This study was designed to identify insulin secretagogues that selectively bind to SUR1 when given at therapeutic doses.. Using accepted systematic review methods, three electronic databases were searched from inception to 13 June 2011. Original studies measuring the half-maximal inhibitory concentration (IC(50)) for an insulin secretagogue on K(ATP) channels using standard electrophysiological techniques were included. Steady-state concentrations (C(SS)) were estimated from the usual oral dose and clearance values for each drug.. Data were extracted from 27 studies meeting all inclusion criteria. IC(50) values for SUR1 were below those for SUR2A/SUR2B for all insulin secretagogues and addition of C(SS) values identified three distinct patterns. The C(SS) for gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values for SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic receptors. The C(SS) for glimepiride and glyburide (glibenclamide) was above IC(50) values for all three isoforms, suggesting these drugs are non-selective. Tolbutamide and repaglinide may have partial pancreatic receptor selectivity because IC(50) values for SUR1 and SUR2A/SUR2B overlapped somewhat, with the C(SS) in the midst of these values.. Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.

Topics: Animals; ATP-Binding Cassette Transporters; Carbamates; Cardiovascular Diseases; Cricetinae; Cyclohexanes; Diabetes Mellitus, Type 2; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Ischemic Preconditioning, Myocardial; Isoindoles; Mice; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nateglinide; Phenylalanine; Piperidines; Potassium Channels, Inwardly Rectifying; Rats; Receptors, Drug; Risk Factors; Sulfonylurea Compounds; Sulfonylurea Receptors; Tolbutamide

Currently available second-generation H1-antihistamines include a wide group of drugs with a better therapeutic index (or risk-benefit ratio) than the classic antihistamines, although their properties and safety profiles may differ. Bilastine is a newly registered H1-antihistamine for the oral treatment of allergic rhinitis and urticaria, with established antihistaminic and antiallergic properties. Clinical studies in allergic rhinitis and chronic urticaria show that once-daily treatment with bilastine 20 mg is effective in managing symptoms and improving patient's quality of life, with at least comparable efficacy to other nonsedative H1-antihistamines. As far as studies in healthy volunteers, clinical assays and clinical experience can establish, bilastine's safety profile is satisfactory, since it lacks anticholinergic effects, does not impair psychomotor performance or actual driving, and appears to be entirely free from cardiovascular effects.

Topics: Automobile Driving; Benzimidazoles; Cardiovascular Diseases; Clinical Trials as Topic; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis, Allergic, Seasonal; Urticaria

Opioids play an important role in every aspect of modern anesthetic practice. Remifentanil is an ultra-short-acting opioid featuring a unique pharmacokinetic profile allowing clinical versatility and improved control of its action. In this review, we assess the pharmacology of remifentanil, its clinical uses as well as safety issues on its action on the major organ systems and in particular clinical settings.. A synthesis of evidence from a MEDLINE search for articles from 1993 to 2009 for available up-to-date information on remifentanil and its current applications and safety profile.. A synopsis of the unique pharmacokinetic properties of remifentanil and its action on major organ systems will provide insight on the safe and effective use of the drug in a variety of clinical settings.. Remifentanil is a valuable opioid in the armamentarium of the clinician, providing great clinical flexibility and safety but vigilance is required to avoid pitfalls.

Topics: Analgesics, Opioid; Animals; Cardiovascular Diseases; Humans; Pain; Piperidines; Remifentanil; Respiration Disorders

Currently used immunosuppressants exacerbate cardiovascular risk. However, attempts to limit the use of these agents increase the risk of allograft rejection. Immunosuppressants targeting signal 2 and signal 3 lymphocyte activation pathways are under clinical development. Clinical data from trials of the Janus family protein tyrosine kinase-3 inhibitor tasocitinib and the costimulation blocker belatacept are presented. Additional pipeline agents are described. Results from two phase III clinical trials of belatacept revealed efficacy that is not inferior to that provided by cyclosporine (CsA). In the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial enrolling recipients of standard criteria living or deceased donor organs, the risk of rejection was higher among patients treated with a more intensive treatment regimen. Increased risk of posttransplant lymphoproliferative disorder, particularly among Epstein-Barr virus-patients, was a notable adverse event. Data from a phase II trial of tasocitinib suggested good prophylaxis of rejection. Safety signals included increased risk of infection and potential myelosuppression, leading to anemia, neutropenia, and leukopenia. Both belatacept and tasocitinib were associated with a low cardiovascular risk profile and improved renal function compared with CsA. New immunosuppressive regimens should maintain the effectiveness provided by current agents while preserving renal function and cardiovascular health. Surveillance for new adverse events must be an integral part of the long-term management strategy.

Topics: Abatacept; Cardiovascular Diseases; Clinical Trials as Topic; Graft Rejection; Humans; Immunoconjugates; Immunosuppression Therapy; Immunosuppressive Agents; Janus Kinase 3; Kidney Transplantation; Piperidines; Pyrimidines; Pyrroles

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

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

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

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

Several cardiometabolic factors present in obese and insulin-resistant individuals represent a continuum of increasing risk for the development of type 2 diabetes and cardiovascular disease. The importance of abdominal obesity as an independent risk factor is underscored by its association with adverse endocrine function. Recent evidence from animal and human studies has shown a role for the endocannabinoid system in maintaining energy balance and glucose and lipoprotein metabolism, with overactivity linked to aberrant glycemic and lipoprotein control, and a link to adiposity. Modulation of this system through endocannabinoid-receptor blockade has resulted in an improvement in a number of important risk factors in clinical trials, including visceral and subcutaneous abdominal adipose tissue, glucose tolerance, dyslipidemia and measures of inflammation. These findings may have significant implications for the management of patients at risk of developing cardiovascular and metabolic disease; however, the occurrence of psychiatric adverse events with rimonabant may preclude further development of centrally active endocannabinoid receptor antagonists for the treatment of cardiometabolic disorders. Future research is needed to explore the role of selective peripheral CB(1) receptor antagonists in the treatment of patients at high cardiometabolic risk.

Topics: Animals; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Clinical Trials as Topic; Endocannabinoids; Humans; Mental Disorders; Obesity, Abdominal; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors

Lapaquistat was the only squalene synthase inhibitor in Phase III clinical trials in Europe and the United States, but was recently discontinued from clinical development. Unlike statins, the inhibition of de novo cholesterol biosynthesis by lapaquistat does not deplete mevalonate, a precursor of isoprenoids. Isoprenoids are critical in cell growth and metabolism.. The present review will focus on the chemistry, pharmacology, and lipid-lowering effects of novel squalene synthase inhibitors.. A search of Pubmed, IPA, and GoogleScholar for studies (animal and human) and review articles published in English between 1990 and April 2008, using the search terms "squalene synthase inhibitors" or "lapaquistat". All clinical trials identified were then cross-referenced for their citations. All literature identified was then complied for this analysis.. Lapaquistat mainly targets LDL-C, but may have some effect on HDL-C and TG. Preliminary reports on Phase II and Phase III associated lapaquistat 100 mg with elevated hepatic enzymes. Hepatotoxicity, possible drug-drug interaction with statins, and the investigation of a statin/coenzyme Q10 combination are among the few challenges that impeded lapaquistat's clinical development.

Topics: Animals; Cardiovascular Diseases; Clinical Trials as Topic; Drug Design; Enzyme Inhibitors; Farnesyl-Diphosphate Farnesyltransferase; Humans; Hyperlipidemias; Hypolipidemic Agents; Oxazepines; Piperidines

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

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 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

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

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

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

Cigarette smoking and exposure to secondhand smoke cause coronary heart disease. Cessation dramatically reduces the incidence of primary and secondary cardiac events. The review presents up-to-date information regarding nicotine dependence, recent findings related to its treatment, and recommendations for addressing smoking cessation for the primary and secondary prevention of coronary heart disease.. Bans on smoking in public places are associated with significant reductions in the incidence of acute myocardial infarction. Counseling and pharmacotherapy (nicotine replacement therapy, bupropion) are proven, effective treatments for nicotine dependence. Clinical trials of two new pharmacotherapies, varenicline and rimonabant, have recently been reported. Varenicline is a safe and efficacious medication for smoking cessation, and has been approved in the US, Canada and Europe. Rimonabant has shown mixed results for smoking cessation and is undergoing further evaluation.. All patients should be screened for tobacco use. Clinicians can effectively treat nicotine dependence in the general population using counseling and first-line pharmacotherapies (nicotine replacement therapy, bupropion, varenicline). These same treatments, with some modification, are appropriate for smokers with coronary heart disease; however, brief interventions without follow-up are not effective in this population. For smokers with coronary heart disease, the best time to intervene may be during hospitalization.

Topics: Benzazepines; Bupropion; Cardiovascular Diseases; Clinical Trials as Topic; Dopamine Uptake Inhibitors; Humans; Nicotinic Agonists; Piperidines; Pyrazoles; Quinoxalines; Rimonabant; Smoking; Smoking Cessation; Smoking Prevention; Varenicline

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

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

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

Risk factors for the development of cardiovascular disease, in particular myocardial infarction, are smoking, high body weight, sedentary lifestyle, unfavorable diet, high blood pressure, elevated fasting glucose or diabetes, and dyslipidemia (Tables 1 and 2). If the risk for cardiovascular mortality of 5% (using the SCORE Score) or for nonfatal cardiovascular events of 20% (PROCAM Score) within the next 10 years is exceeded or overt atherosclerosis or type 2 diabetes mellitus is present, the use of (poly)pharmacotherapy is indicated and lifestyle intervention (diet, physical activity) alone is not sufficient at that point (Figure 1). A new therapeutic option, able to modify a number of cardiovascular risk factors at a time, is the blockade of the so-called endocannabinoid system (Figure 2). For rimonabant not only a reduction of body weight and waist circumference was shown in clinical trials, its use was also accompanied by an increase of HDL cholesterol, a decrease in triglycerides, and a reduction in HbA1c and fasting blood glucose (Table 4). Together with preliminary data on the efficacy in smoking cessation, rimonabant has a therapeutic impact on four out of eight relevant risk factors in order to prevent myocardial infarction as promoted by the American College of Cardiology/American Heart Association. Currently, a large clinical study program is ongoing to further investigate the role of rimonabant in managing cardiovascular risk (Table 3). Published clinical trial results have revealed, that rimonabant is generally well tolerated (most frequent side effect: nausea) and the data are promising with regard to the potential future role of rimonabant in managing cardiovascular risk.

Topics: Cannabinoids; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Piperidines; Prevalence; Pyrazoles; Rimonabant; Treatment Outcome

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

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

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

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

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

Endocannabinoid system, the complex of specific cannabinoid receptors (CB1 and CB2 subtypes) and their endogenous agonistic ligands (endocannabinoids) plays, besides others, an important role in the central and peripheral regulation of food intake, fat accumulation, and lipid and glucose metabolism. Alterations of these functions are associated with endocannabinoid system hyperactivity. The cannabinoid receptor CB1 antagonist rimonabant normalizes the over activated endocannabinoid system which contributes to the regulation of energy homeostasis, and improves lipid and glucose metabolism--decreases body weight, waist circumference, intra-abdominal obesity and triglycerides, increases HDL-C, improves insulin sensitivity according to HOMA index. Results of the international multicentric clinical trials confirm that rimonabant is well tolerated and show antiatherogenic effects (increased adiponectin, decreased marker of inflammation CRP and improvement of LDL profile) as well as decreased percentage of subjects with NCEP/ATPIII (National Cholesterol Education Program Adult Treatment Panel III) defined metabolic syndrome. Thus, the CB1 cannabinoid receptor antagonist rimonabant is suggested to be a prospective drug decreasing cardiometabolic risk factors.

Topics: Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Cardiovascular Diseases; Endocannabinoids; Humans; Lipid Metabolism; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Risk Factors

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

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

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

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

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 basic CNS neuropharmacology of naratriptan is reviewed here. Naratriptan is a second-generation triptan antimigraine drug, developed at a time when CNS activity was thought not to be relevant to its therapeutic effect in migraine. It was, however, developed to be a more lipid-soluble, more readily absorbed and less readily metabolized variant on preexisting triptans and these variations conferred on it a higher CNS profile. Naratriptan is a 5-HT(1B/1D) receptor agonist with a highly selective action on migraine pain and nausea, without significant effect on other pain or even other trigeminal pain. Probable sites of therapeutic action of naratriptan include any or all of: the cranial vasculature; the peripheral terminations of trigeminovascular sensory nerves; the first-order synapses of the trigeminovascular sensory system; the descending pain control system; and the nuclei of the thalamus. Naratriptan may prevent painful dilatation of intracranial vessels or reverse such painful dilatation. Naratriptan can prevent the release of sensory peptides and inhibit painful neurogenic vasodilatation of intracranial blood vessels. At the first order synapse of the trigeminal sensory system, naratriptan can selectively suppress neurotransmission from sensory fibers from dural and vascular tissue, while sparing transmission from other trigeminal fibers, probably through inhibition of neuropeptide transmitter release. In the periaqueductal gray matter and in the nucleus raphe magnus, naratriptan selectively activates inhibitory neurons which project to the trigeminal nucleus and spinal cord and which exert inhibitory influences on trigeminovascular sensory input. Naratriptan has also a therapeutic effect on the nausea of migraine, possibly exerting its action at the level of the nucleus tractus solitarius via the same mechanisms by which it inhibits trigeminovascular nociceptive input. The incidence of naratriptan-induced adverse effects in the CNS is low and it is not an analgesic for pain other than that of vascular headache. In patients receiving selective serotonin uptake inhibitors (SSRIs) naratriptan may cause serotonin syndrome-like behavioral side effects. The mechanism of action involved in the production of behavioral and other CNS side effects of naratriptan is unknown.

Topics: Analgesia; Animals; Cardiovascular Diseases; Humans; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines

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

The metabolic syndrome is a constellation of risk factors that contribute to the onset of type 2 diabetes mellitus and cardiovascular disease (CVD). CVD has been identified by the National Cholesterol Education Program (NCEP) as the primary clinical outcome of the metabolic syndrome. Although no algorithm is currently available for estimating the absolute risk of CVD for patients with the metabolic syndrome, screening for cardiovascular (CV) risk in these patients involves testing for lipoprotein abnormalities (namely, an analysis of specific low-density lipoprotein particle numbers) and an assessment of various surrogate markers for subclinical coronary artery disease. Such screening can be used to help predict the development of CVD and thereby allow for effective interventions to help prevent coronary events. Strategies for reducing CV risk in patients with the metabolic syndrome are multifactorial. In addition to placing an emphasis on therapeutic lifestyle changes that increase levels of physical activity, dietary modification, and weight reduction, several pharmacologic therapies are available. One novel approach for managing CV risk in patients with the metabolic syndrome involves the inhibition of the endocannabinoid system, including the use of rimonabant. A review of CV risk factors in patients with the metabolic syndrome is beneficial for clinicians to apply in the care of their patients, along with a discussion about strategies for identifying at-risk patients and managing CVD risk for these patients.

Topics: Cardiovascular Diseases; Exercise; Feeding Behavior; Humans; Metabolic Syndrome; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Assessment; Risk Factors

Cholinesterase (ChE) inhibitors, which prevent the hydrolysis of acetylcholine, have been approved for the symptomatic treatment of Alzheimer's disease (AD) for over a decade. However, the first ChE inhibitors were associated with a high incidence of side-effects and general tolerability concerns, including hepatotoxicity. Side-effects associated with increased cholinergic activity, particularly in the gastrointestinal (GI) system, can prevent patients from achieving effective doses of drug. In addition, the advanced age and frail nature of patients with AD mean that poor tolerability is a serious concern. The potential for drug-drug interactions is also an important consideration, due to the high prevalence of comorbid disease in these patients. Data both from clinical trials and studies in routine clinical practice have shown that donepezil is associated with a low incidence of GI adverse events (AEs) that is comparable with placebo. Donepezil is a potent, selective inhibitor of acetylcholinesterase, and selective inhibition of central as opposed to peripheral ChEs might be expected to reduce the incidence of AEs, thus this may explain the lower incidence of cholinergic AEs observed following treatment with donepezil, compared with nonselective ChE inhibitors. There are no differences in cardiovascular AEs, including bradycardia, between placebo and donepezil groups in the clinical trials published to date, even in a very sick vascular dementia population with high rates of comorbidity and concomitant medication use. Data from single- and multiple-dose studies of donepezil in patients with hepatic impairment and with moderately to severely impaired renal function indicate that donepezil is safe and well tolerated in these groups. Furthermore, both in vitro and clinical studies have shown that donepezil is not associated with drug-drug interactions. The incidence of weight loss is very similar between donepezil- and placebo-treated patients. Although insomnia and other sleep disorders have been reported following administration of donepezil, lengthening the time period before increasing the dose of donepezil from 5 to 10 mg day(-1) or switching to morning dosing can reduce these events to the levels of placebo-treated patients. Over 770 million days of patient use and an extensive publication database demonstrate that donepezil has a good tolerability and safety profile.

Topics: Alzheimer Disease; Cardiovascular Diseases; Cholinesterase Inhibitors; Donepezil; Drug Interactions; Humans; Indans; Piperidines; Sleep Wake Disorders; Weight Loss

Triptans, beginning with sumatriptan, have revolutionized the treatment of migraine. New triptans in several formulations will soon become available in the United States. Although the similarities of these 5-hydroxytryptamine (5-HT) 1B/1D receptor agonists outweigh their differences, important differences in pharmacokinetics and clinical responses do exist. Subcutaneous sumatriptan has the most rapid onset of action and greatest efficacy but the most adverse effects. Intranasal sumatriptan also has rapid onset of action, but at 2 hours its efficacy is comparable to that of oral zolmitriptan. Of the oral triptans, rizatriptan seems to have the greatest early efficacy. Both rizatriptan and zolmitriptan are now available as rapidly dissolving wafers. Almotriptan, the newest of the triptans, has a response rate similar to that of oral sumatriptan and may produce fewer adverse effects. Naratriptan and frovatriptan, with their slow onset, high tolerability, and long half-lives, may have a role in aborting prolonged migraine attacks and in headache prevention. Eletriptan at higher doses (80 mg) has a response rate approaching that of rizatriptan but may be limited by potential side effects. The many triptans available offer the opportunity to individualize migraine treatment, depending on the patient's attack characteristics, tolerance, and preferences.

Topics: Carbazoles; Cardiovascular Diseases; Humans; Indoles; Migraine Disorders; Oxazolidinones; Patient Satisfaction; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

The pharmacologic profile of a cyproheptadine-related compound, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]piperidine hydrochloride (AH-1058), was assessed in various in vivo and in vitro models. In guinea pig cardiomyocytes, AH-1058 effectively suppressed L-type Ca2+ channel currents without affecting other ion channel or ion exchange currents. In rat cerebral cortical membranes AH-1058 appears to bind preferentially to L-type Ca2+ channels at phenylalkylamine- and benzothiazepine-binding sites. In canine isolated, blood-perfused heart preparations, AH-1058 exerted negative inotropic, dromotropic, and chronotropic and weak coronary vasodilator effects. In halothane-anesthetized dogs, AH-1058 suppressed ventricular contractility and decreased blood pressure and cardiac output. Total peripheral vascular resistance was hardly affected by the drug, suggesting that in vivo AH-1058 can selectively suppress cardiac, as compared to peripheral vascular, function. In conscious dogs, by intravenous administration AH-1058 reduced systolic blood pressure and maximal upstroke velocity of the left ventricular pressure, while it increased heart rate in a dose-dependent manner. The drug did not affect diastolic blood pressure, which is quite different from cardiovascular properties of well-known Ca2+ channel blockers, verapamil and diltiazem. This unique cardiovascular profile of AH-1058 is expected to be useful in the treatment of certain pathological processes such as the obstructive hypertrophic cardiomyopathy, vasovagal syncope, dissecting aortic aneurysm, and ventricular arrhythmias, in which selective inhibition of the ventricular Ca2+ channels is essential for drug therapy.

Topics: Animals; Anti-Arrhythmia Agents; Blood Pressure; Bridged Bicyclo Compounds; Calcium Channel Blockers; Calcium Channels, L-Type; Cardiovascular Diseases; Heart Rate; Hemodynamics; Myocardial Contraction; Piperidines

Topics: Animals; Cardiovascular Diseases; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; GTP-Binding Proteins; Humans; Oligopeptides; Peptides, Cyclic; Piperidines; Receptors, Endothelin; Signal Transduction

Endothelin (ET) -1 is a potent vasoconstrictor and promitogenic peptide produced by the vascular endothelium. The ET system is activated in atherosclerosis and in most cardiovascular conditions associated with increased vascular tone and remodelling. There are two ET-receptor (ET-R) subtypes: the ETA-Rs mediate smooth muscle vasoconstriction and proliferation, and the more complex ETB-Rs have antagonistic actions - they serve a dual role of clearance and vasodilation in the endothelium, while in smooth muscle cells they also provoke vasoconstriction. Selective ETA-R and nonselective ETA/B-R antagonists are entering the clinical development phase. These agents have shown their effectiveness in the therapy of various models of heart failure, pulmonary hypertension, systemic hypertension and ischemia-reperfusion and in the prevention of restenosis. In patients with congestive heart failure, short term ET-antagonist (ET-R) therapy provides hemodynamic and symptomatic improvement. Because of the dual role of the ETB-R, nonselective antagonists may provide greater or fewer benefits than selective ETA-R antagonists: a lack of direct comparison of the two categories of agents, however, does not allow this distinction at present. In the evaluation of this new class of therapeutic agents, particular attention should be paid to potency and receptor selectivity of a compound, the alterations in ETA-R and ETB-R activity brought on by pathological conditions, the proportions of ETA versus ETB-R of the target system, and finally, the net importance of the possible protective role of the endothelial ETB versus the deleterious effects of the smooth muscle ETB-R.

Topics: Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Drug Evaluation; Endothelin Receptor Antagonists; Humans; Oligopeptides; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Treatment Outcome; Vasoconstriction

The complementary roles of platelets and thrombin in the pathophysiology of acute coronary syndromes suggests that for treatment to be effective, both mediators must be targeted. Although great strides have been made in the development of antiplatelet therapies, attempts to inhibit thrombin have been less successful. Unfractionated heparin is limited by a number of pharmacologic shortcomings as well as an inability to meaningfully suppress thrombin generation. The low molecular weight heparins have yielded encouraging results in large-scale clinical trials, but it remains unclear whether their benefit stems from a superior pharmacologic profile to unfractionated heparin or is determined by an enhanced ability to suppress thrombin generation (by virtue of a direct anti-Xa effect). Regardless, investigators have become increasingly interested in factor Xa as a potential target for antithrombotic therapy. A number of naturally occurring Xa antagonists have been identified. Work with recombinant forms of these proteins confirms that factor Xa inhibition can suppress thrombin generation in a variety of animal thrombosis models. Accordingly, a number of synthetic direct and indirect Xa antagonists are under development for the prevention and treatment of thrombotic disorders. The following review summarizes the evolution of factor Xa antagonists.

Topics: Animals; Antithrombin III; Arthropod Proteins; Cardiovascular Diseases; Factor X; Factor Xa Inhibitors; Fibrinolytic Agents; Helminth Proteins; Heparin, Low-Molecular-Weight; Humans; Intercellular Signaling Peptides and Proteins; Invertebrate Hormones; Leeches; Naphthalenes; Oligosaccharides; Peptides; Piperidines; Propionates

Platelets play a major role in thrombus formation, as well as in the pathogenesis of atherothrombosis. Inhibition of platelet function is now emphasised more than ever for prevention and treatment of almost all vascular diseases, since thrombosis is established as the key pathogenic event causing acute ischaemic coronary and cerebrovascular syndromes. Although acetylsalicylic acid (aspirin) has been shown to reduce the incidence of myocardial infarction and stroke, its effect is weak and more effective antithrombotic agents are required to manage patients at high-risk for recurrent vascular events. Platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa) blockade represents a significant advance in interventional cardiology and treatment of acute ischaemic syndromes. The past several years have seen the introduction of many platelet GPIIb/IIIa blockers into the clinical arena targeting the unique platelet GPIIb/IIIa receptor for the adhesive proteins, fibrinogen and von Willebrand Factor. Platelet GPIIb/IIIa blockers administered intravenously have proven efficacious in mitigating arterial thrombosis in acute coronary syndromes (unstable angina and non-ST-elevation myocardial infarction) and percutaneous coronary interventions (PCI) such as balloon dilatation and stent implantation. Currently, orally-active platelet GPIIb/IIIa blockers are being developed to provide additional benefits for primary and secondary prevention of thrombosis as chronic treatment, especially in high-risk patients. Lotrafiban (SmithKline Beecham) is a member of the latest generation of orally-active platelet GPIIb/IIIa blockers undergoing Phase III clinical trials to test the relative effectiveness versus other oral platelet inhibitors for ischaemic conditions including unstable angina, restenosis after PCI and stroke. Lotrafiban is converted from an esterified prodrug by plasma and liver esterases to a peptidomimetic of the arginine-glycine-aspartic acid amino acid sequence. This sequence itself mimics the binding site of fibrinogen and von Willebrand Factor to the platelet GPIIb/IIIa receptor. Preliminary results of the clinical trial APLAUD (antiplatelet useful dose) show that lotrafiban is clinically safe and well-tolerated in patients with recent myocardial infarction, unstable angina, transient ischaemic attack (TIA), or stroke when added to aspirin therapy. With lotrafiban, a worldwide large-scale Phase III clinical trial BRAVO (blockage of the GPIIb/IIIa receptor to avoid vas

Topics: Animals; Benzodiazepines; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex

Topics: Breast Neoplasms; Cardiovascular Diseases; Clinical Trials as Topic; Estrogen Antagonists; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Menopause; Osteoporosis; Phytoestrogens; Piperidines; Plant Preparations; Raloxifene Hydrochloride; Receptors, Estrogen; Survivors

Menopause, regardless of age at onset, is associated with a marked increase in coronary artery disease (CAD) risk. A large body of observational clinical studies repeatedly demonstrated favorable associations between postmenopausal hormone replacement therapy (HRT) and cardiovascular morbidity, mortality, and risk factors. Estrogens may act in a gender-specific way on vascular endothelial cells and other components of the vessel wall, enhancing the synthesis and release of nitric oxide (NO) and other vasodilators, and by inhibiting the synthesis and release of vasoconstricting agents, thus favoring vasodilation. Menopause-related changes in metabolic cardiovascular risk factors are identifiable, as are HRT-related changes in these factors. The metabolic effects include changes in lipoprotein (a), coagulation and fibrinolysis as well as homocysteine metabolism. The various actions of estrogen alone and combined with progestogen on the vascular system are reviewed. Furthermore, the outcome of the recently published Heart and estrogen/progestin replacement study (HERS) data are put in perspective. In addition, we outline the present data on the effects of raloxifene, a new second generation selective estrogen receptor modulator (SERM), which has been shown to favorably alter several markers of cardiovascular risk in postmenopausal women.

Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Endothelium, Vascular; Estrogen Antagonists; Estrogens; Female; Hemostasis; Homocysteine; Hormone Replacement Therapy; Humans; Lipoprotein(a); Muscle, Smooth, Vascular; Piperidines; Progestins; Raloxifene Hydrochloride; Risk Factors

A new class of compounds known as selective estrogen receptor modulators (SERMs) may possess the optimal combination of characteristics desirable in a drug designed for use in postmenopausal women. Among this class of compounds, raloxifene is the most studied and is currently available for clinical use in some countries for the prevention of osteoporosis in post-menopausal women. Raloxifene is a non-steroidal benzotiophene derivative shown to prevent bone loss at axial and appendicular sites and reduce serum cholesterol, like estrogen, in oophorectomized rats and in postmenopausal women. In animal models, unlike estrogen, raloxifene does not stimulate breast or uterine tissues. These appealing attributes make raloxifene a potential treatment for osteoporosis and other menopause related risks in middle aged and elderly women. Multicenter studies have been performed in early postmenopausal women, randomly assigned to receive raloxifene 30, 60, or 150 mg/day or placebo. All subjects received a calcium supplement. Bone mineral density, which was measured twice a year over 24 months by dual X-ray absorptiometry, decreased significantly at all skeletal sites with placebo, and significantly increased with raloxifene at the spine, hip, and total body at the three doses. At 24 months, the mean increase with raloxifene 60 mg compared with placebo was 2.4% at the lumbar spine and at the total hip, and 2% at the total body. Markers of bone formation (serum osteocalcin and bone specific alkaline phosphatase) and of resorption (urinary CrossLaps) decreased significantly to the premenopausal range within 3-6 months of treatment with raloxifene. In addition, total serum and low-density lipoprotein cholesterol decreased significantly in all raloxifene therapy groups in a dose-related fashion. Serum HDL-cholesterol and triglycerides were not significantly changed by therapy. The most commonly observed side-effect was hot flushes, with patients taking raloxifene reporting a slightly higher rate of flushes (25%) than those on placebo (18%). This adverse event usually occurred within the first few months of therapy, was generally mild, and did not result in excess study dropout (raloxifene 1.5%, placebo 2.1%). Preliminary 2-year data indicated that raloxifene is not associated with an increased risk of breast cancer. In summary, the clinical efficacy and safety of raloxifene is very promising and this compound will offer a particularly attractive choice for postmenopausal wom

Topics: Cardiovascular Diseases; Estrogen Antagonists; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic

Multiple health benefits have been postulated for the long-term use of hormone therapy in postmenopausal women, most notably for prevention of osteoporotic fractures and coronary heart disease, as well as several risks, including cancer of the breast and uterus and venous thromboembolism. Cardiovascular disease is the most common cause of death among postmenopausal women. If real, the reduction in risk of coronary heart disease by hormone use suggested by observational studies would likely outweigh the risks. The decision to initiate and maintain hormone therapy is complicated by uncertainties about estrogen's true benefits and risks. Raloxifene, a selective estrogen receptor modulator (SERM), appears to have many of the benefits of estrogen without the cancer risks. It is not known if SERMs can provide significant cardiovascular protection. This article reviews the relation of use of postmenopausal hormones and raloxifene to women's health and addresses the need for large randomized trials to quantify the effect of both postmenopausal estrogen and raloxifene on cardiovascular health.

Topics: Cardiovascular Diseases; Estrogen Replacement Therapy; Estrogens; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic

Selective estrogen receptor modulators represent an alternative approach to the use of estrogen replacement therapy or hormone replacement therapy for decreasing postmenopausal bone loss, as well as for reducing the incidence of serious cardiovascular disease in this population. Of particular interest is raloxifene, a benzothiophene compound, which binds with high affinity to the estrogen receptor and produces effects similar to estrogen on the skeleton and cardiovascular system but behaves as a complete estrogen antagonist in the uterus and the breast. The pharmacologic profile of raloxifene, a discussion of a possible mechanism of action, and the potential role of this drug in women's postmenopausal health are the subjects of this review.

Topics: Aged; Cardiovascular Diseases; Estrogen Antagonists; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Raloxifene Hydrochloride; Receptors, Estrogen; Women's Health

The calcium channel blocking agents have multiple hemodynamic effects that make them potentially valuable in treating many cardiovascular disorders. They are potent dilators of coronary and peripheral arteries and in isolated tissue preparations exert potent negative inotropic, chronotropic, and dromotropic effects. In intact animals the peripheral arterial vasodilatation induces reflex-mediated adrenergic activity, which opposes the direct negative inotropic, chronotropic, dromotropic, and hypotensive effects. The individual calcium channel blockers have different relative potencies on various cardiovascular functions. The net hemodynamic and electrophysiologic effect of each agent, therefore, results from a complex interplay of direct and reflex phenomena. The clinical efficacy of these agents in classic angina pectoris relates to their ability to decrease afterload, myocardial contractility, and heart rate and increase coronary blood flow. The agents have been used to prevent coronary spasm in Prinzmetal's variant angina. The negative inotropic effects of verapamil are valuable in improving the symptoms and hemodynamic disturbances of hypertrophic cardiomyopathy. The role of these agents in treating arterial hypertension, unstable angina pectoris, acute myocardial infarction, and ischemia during cardiopulmonary bypass needs to be determined.

Topics: Benzazepines; Calcium Channel Blockers; Cardiovascular Diseases; Coronary Circulation; Diltiazem; Hemodynamics; Humans; Myocardial Contraction; Nifedipine; Nitrogen; Perhexiline; Piperidines; Pyridines; Regional Blood Flow; Vasodilation; Verapamil

Increases in lipid levels and cancers with tofacitinib prompted a trial of major adverse cardiovascular events (MACE) and cancers in patients with rheumatoid arthritis receiving tofacitinib as compared with a tumor necrosis factor (TNF) inhibitor.. We conducted a randomized, open-label, noninferiority, postauthorization, safety end-point trial involving patients with active rheumatoid arthritis despite methotrexate treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor. Patients were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 mg or 10 mg twice daily or a TNF inhibitor. The coprimary end points were adjudicated MACE and cancers, excluding nonmelanoma skin cancer. The noninferiority of tofacitinib would be shown if the upper boundary of the two-sided 95% confidence interval for the hazard ratio was less than 1.8 for the combined tofacitinib doses as compared with a TNF inhibitor.. A total of 1455 patients received tofacitinib at a dose of 5 mg twice daily, 1456 received tofacitinib at a dose of 10 mg twice daily, and 1451 received a TNF inhibitor. During a median follow-up of 4.0 years, the incidences of MACE and cancer were higher with the combined tofacitinib doses (3.4% [98 patients] and 4.2% [122 patients], respectively) than with a TNF inhibitor (2.5% [37 patients] and 2.9% [42 patients]). The hazard ratios were 1.33 (95% confidence interval [CI], 0.91 to 1.94) for MACE and 1.48 (95% CI, 1.04 to 2.09) for cancers; the noninferiority of tofacitinib was not shown. The incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (nonserious and serious), and adjudicated nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor. Efficacy was similar in all three groups, with improvements from month 2 that were sustained through trial completion.. In this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk-enriched population, risks of MACE and cancers were higher with tofacitinib and did not meet noninferiority criteria. Several adverse events were more common with tofacitinib. (Funded by Pfizer; ORAL Surveillance ClinicalTrials.gov number, NCT02092467.).

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Cardiovascular Diseases; Female; Heart Disease Risk Factors; Humans; Incidence; Janus Kinase Inhibitors; Male; Middle Aged; Neoplasms; Piperidines; Pyrimidines

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1-not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki-intolerant CLL population can result in durable well-tolerated responses.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Cardiovascular Diseases; Class I Phosphatidylinositol 3-Kinases; Drug Eruptions; Drug Resistance, Neoplasm; Female; Gastrointestinal Diseases; Heterocyclic Compounds, 4 or More Rings; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Proteins; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors

In addition to the increased risk for cardiovascular (CV) disease and CV events associated with migraine, patients with migraine can also present with a number of CV risk factors (CVRFs). Existing treatment options can be limited due to contraindications, increased burden associated with monitoring, or patient avoidance of side effects. Safe and effective migraine treatment options are needed for patients with migraine and a history of CV or cerebrovascular disease or with increased risk for CV events. This analysis was designed to evaluate the safety and efficacy of oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor agonist, in acute treatment of migraine attacks in patients with CVRFs.. SAMURAI and SPARTAN were similarly designed, Phase 3, randomized, double-blind, placebo-controlled trials in adults treating a single migraine attack with lasmiditan 50, 100, or 200 mg. Both studies included patients with CVRFs, and SPARTAN allowed patients with coronary artery disease, clinically significant arrhythmia, or uncontrolled hypertension. Efficacy and safety of lasmiditan in subgroups of patients with differing levels of CVRFs are reported. For efficacy analyses, logistic regression was used to assess treatment-by-subgroup interactions. For safety analyses, Cochran-Mantel-Haenszel test of general association evaluated treatment comparisons; Mantel-Haenszel odds ratio assessed significant treatment effects.. In this pooled analysis, a total of 4439 patients received ≥1 dose of study drug. A total of 3500 patients (78.8%) had ≥1 CVRF, and 1833 patients (41.3%) had ≥2 CVRFs at baseline. Both trials met the primary endpoints of headache pain freedom and most bothersome symptom freedom at 2 h. The presence of CVRFs did not affect efficacy results. There was a low frequency of likely CV treatment-emergent adverse events (TEAEs) overall (lasmiditan, 30 [0.9%]; placebo, 5 [0.4%]). There was no statistical difference in the frequency of likely CV TEAEs in either the absence or presence of any CVRFs. The only likely CV TEAE seen across patients with ≥1, ≥ 2, ≥ 3, or ≥ 4 CVRFs was palpitations.. When analyzed by the presence of CVRFs, there was no statistical difference in lasmiditan efficacy or the frequency of likely CV TEAEs. Despite the analysis being limited by a single-migraine-attack design, the lack of differences in efficacy and safety with increasing numbers of CVRFs indicates that lasmiditan might be considered in the treatment algorithm for patients with CVRFs. Future studies are needed to assess long-term efficacy and safety.. ClinicalTrials.gov NCT02439320 (SAMURAI), registered 18 March 2015 and ClinicalTrials.gov NCT02605174 (SPARTAN), registered 11 November 2015.

Topics: Adult; Benzamides; Cardiovascular Diseases; Double-Blind Method; Female; Headache; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists; Treatment Outcome

Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Cardiovascular Diseases; Female; Follow-Up Studies; Hematologic Diseases; Humans; Infections; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Remission Induction; Risk; Salvage Therapy; Treatment Outcome

Final data are presented for the ORAL Sequel long-term extension (LTE) study evaluating the safety and efficacy of tofacitinib 5 mg and 10 mg twice daily (BID) for up to 9.5 years in patients with rheumatoid arthritis (RA).. Eligible patients had previously completed a phase 1, 2, or 3 qualifying index study of tofacitinib and received open-label tofacitinib 5 mg or 10 mg BID. Stable background therapy, including csDMARDs, was continued; adjustments to tofacitinib or background therapy were permitted at investigators' discretion. Assignment to dose groups (5 mg or 10 mg BID) was based on patients' average total daily dose. The primary objective was to determine the long-term safety and tolerability of tofacitinib 5 mg and 10 mg BID; the key secondary objective was to evaluate the long-term persistence of efficacy.. Between February 5, 2007, and November 30, 2016, 4481 patients were enrolled. Total tofacitinib exposure was 16,291 patient-years. Safety data are reported up to month 114 for all tofacitinib; efficacy data are reported up to month 96 for tofacitinib 5 mg BID and month 72 for 10 mg BID (with low patient numbers limiting interpretation beyond these time points). Overall, 52% of patients discontinued (24% due to adverse events [AEs] and 4% due to insufficient clinical response); the safety profile remained consistent with that observed in prior phase 1, 2, 3, or LTE studies. The incidence rate (IR; number of patients with events per 100 patient-years) for AEs leading to discontinuation was 6.8. For all-cause AEs of special interest, IRs were 3.4 for herpes zoster, 2.4 for serious infections, 0.8 for malignancies excluding non-melanoma skin cancer, 0.4 for major adverse cardiovascular events, and 0.3 for all-cause mortality. Clinically meaningful improvements in the signs and symptoms of RA and physical functioning, which were observed in the index studies, were maintained.. Tofacitinib 5 mg and 10 mg BID demonstrated a consistent safety profile (as monotherapy or combination therapy) and sustained efficacy in this open-label LTE study of patients with RA. Safety data are reported up to 9.5 years, and efficacy data up to 8 years, based on adequate patient numbers to support conclusions.. NCT00413699 , funded by Pfizer Inc (date of trial registration: December 20, 2006).

Topics: Administration, Oral; Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Herpes Zoster; Humans; Male; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Time Factors; Treatment Outcome

Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.

Topics: Adult; Benzamides; Cardiovascular Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Migraine Disorders; Piperidines; Pyridines; Risk Factors; Serotonin Receptor Agonists; Time Factors; Young Adult

Patients with psoriasis have an increased risk of myocardial infarction, and psoriasis is now recognized as an independent risk factor for coronary heart disease and cardiovascular mortality. To understand the effects of psoriasis medications on systemic inflammation associated with cardiovascular risks, we studied blood proteins related to inflammation and cardiovascular disease archived from a phase 3 clinical trial of tofacitinib and etanercept in adults with moderate-to-severe psoriasis. A total of 157 blood proteins were quantified by a proximity extension assay from 266 patients at baseline and week 4. Protein changes in the blood after 1 month of treatment were compared between tofacitinib (10 mg two times a day) and etanercept (50 mg biweekly), and by response status at week 12. Tofacitinib and etanercept commonly reduced IL-6, CCL20, and CXCL10, but IL-17A was significantly reduced only in responders of either treatment. Compared with etanercept, tofacitinib showed a wider spectrum of cardiovascular blood protein reduction, but the protein reduction effects of tofacitinib were strictly confined to treatment responders. Tumor necrosis factor receptor 1, E-selectin, hK11, tumor necrosis factor-related activation-induced cytokine, CHI3L1, IL-16, and matrix metalloproteinase-12 were cardiovascular proteins significantly reduced only in tofacitinib responders. Our data suggest that a short-term systemic psoriasis treatment can cause reductions in circulating inflammatory and other proteins associated with cardiovascular risks.

Topics: Adult; Aged; Cardiovascular Diseases; Cytokines; Etanercept; Female; Humans; Inflammation; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Proteomics; Psoriasis; Pyrimidines; Pyrroles; Risk Factors; Treatment Outcome; Young Adult

Head fixation can induce hemodynamic instability. Remifentanil is commonly used with propofol for total intravenous anesthesia (TIVA) during neurosurgery. This study investigated the 90% effective concentration (EC. Fifty patients undergoing neurosurgery requiring head fixation were enrolled. This study was performed using the biased coin up-and-down design sequential method (BCD). After tracheal intubation, the effect-site target concentration (Ce) of remifentanil was adjusted to achieve hemodynamic stability and reset to the level preoperatively assigned to each patient, according to the BCD method, approximately 10 min before head fixation. Baseline hemodynamic values were recorded before head fixation. An ineffective response was defined as a case with a > 20% increase in hemodynamic values from baseline. Otherwise, the response was determined to be effective. The EC. Adjustment of the Ce of remifentanil to approximately 6.5 ng/mL before head fixation could prevent noxious cardiovascular responses in 90% of neurosurgical ASA I-II patients aged 20 to 65 years old during propofol target-controlled infusion titrated to maintain BIS between 40 and 50.. ClinicalTrials.gov Identifier NCT01489137 , retrospectively registered 5 December 2011.

Topics: Adult; Aged; Anesthesia, Intravenous; Anesthetics, Intravenous; Cardiovascular Diseases; Consciousness Monitors; Electroencephalography; Female; Humans; Male; Middle Aged; Neurosurgical Procedures; Patient Positioning; Piperidines; Propofol; Remifentanil

To investigate relationships between glycated haemoglobin (HbA1c) and reported hypoglycaemia and risk of major adverse cardiovascular events (MACE).. The EXAMINE trial randomized 5380 patients with type 2 diabetes (T2DM) and a recent acute coronary syndrome (ACS) event, in 49 countries, to double-blind treatment with alogliptin or placebo in addition to standard of care. We used Cox proportional hazards models to analyse relationships among MACE, HbA1c levels and hypoglycaemic events.. Patients randomized to alogliptin achieved lower HbA1c levels than the placebo group in all baseline HbA1c categories without differences in hypoglycaemia rates. No systematic change was found in MACE rates according to baseline HbA1c (P. There were no relationships between baseline HbA1c levels or HbA1c levels after 1 month of treatment and the risk of MACE. Alogliptin improved glycaemic control without increasing hypoglycaemia. Reported events of hypoglycaemia and serious hypoglycaemia were associated with MACE. These data underscore the safety of alogliptin in improving glycaemic control in T2DM post-ACS. Further study of hypoglycaemia as an independent risk factor for MACE in patients with T2DM and coronary disease is needed.

Topics: Acute Coronary Syndrome; Cardiovascular Diseases; Cohort Studies; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Male; Middle Aged; Piperidines; Risk Factors; Secondary Prevention; Severity of Illness Index; Uracil

To investigate adiponectin levels and cardiovascular (CV) outcomes in patients with diabetes and recent acute coronary syndrome (ACS).. We analysed baseline adiponectin concentration and CV outcomes in 5213 patients with type 2 diabetes enrolled in the EXAMINE trial of alogliptin vs placebo 15 to 90 days (median 45 days) after ACS. Event rates at 18 months are reported.. The median (interquartile range) baseline adiponectin concentration was 5.2 (3.5-7.9) μg/mL. Patients with the highest baseline adiponectin concentration (quartile [Q]4) were at significantly higher risk of death from a CV event (8.4% vs 1.7%; P < .0001), hospitalization for heart failure (HF; 7.5% vs 1.7%; P < .0001), and all-cause mortality (10.8% vs 2.4%; P < .0001) compared with those in Q1. After adjusting for age, sex, index event, HF, estimated glomerular filtration rate and hypertension, adiponectin concentration in Q4 remained associated with an increased risk of death from CV causes (hazard ratio [HR] 2.43, 95% confidence interval [CI] 1.52, 3.88), all-cause mortality (HR 2.45, 95% CI 1.65, 3.64), and HF (HR 2.44, 95% CI 1.47, 4.05), without change after stratification by body mass index. There was no significant difference in the rate of myocardial infarction or stroke.. In this contemporary population of patients with diabetes and ACS, adiponectin concentration was independently associated with increased risk of death from CV causes, all-cause mortality, and hospitalization for HF. The relationship between adiponectin and CV outcomes is complex and deserves further study.

Topics: Acute Coronary Syndrome; Adiponectin; Aged; Biomarkers; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Mortality; Piperidines; Proportional Hazards Models; Risk; Secondary Prevention; Uracil

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; 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We evaluated the risk of cardiovascular (CV) death in all Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study participants and in those who experienced an on-study, major nonfatal CV event.. The study randomly assigned 5,380 patients with type 2 diabetes to alogliptin or placebo within 15 to 90 days of an acute coronary syndrome (ACS). Deaths and nonfatal CV events (myocardial infarction [MI], stroke, hospitalized heart failure [HHF], and hospitalization for unstable angina [UA]) were adjudicated. Patients were monitored until censoring or death, regardless of a prior postrandomized nonfatal CV event. Time-updated multivariable Cox models were used to estimate the risk of death in the absence of or after each nonfatal event.. Rates of CV death were 4.1% for alogliptin and 4.9% for placebo (hazard ratio [HR] 0.85; 95% CI 0.66, 1.10). A total of 736 patients (13.7%) experienced a first nonfatal CV event (5.9% MI, 1.1% stroke, 3.0% HHF, and 3.8% UA). Compared with patients not experiencing a nonfatal event, the adjusted HR (95% CI) for death was 3.12 after MI (2.13, 4.58; P < 0.0001) 4.96 after HHF (3.29, 7.47; P < 0.0001), 3.08 after stroke (1.29, 7.37; P = 0.011), and 1.66 after UA (0.81, 3.37; P = 0.164). Mortality rates after a nonfatal event were comparable for alogliptin and placebo.. In patients with type 2 diabetes and a recent ACS, the risk of CV death was higher after a postrandomization, nonfatal CV event, particularly heart failure, compared with those who did not experience a CV event. The risk of CV death was similar between alogliptin and placebo.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Hospitalization; Humans; Hypoglycemic Agents; Male; Middle Aged; Multivariate Analysis; Piperidines; Proportional Hazards Models; Risk; Uracil

To evaluate the efficacy and safety of atorvastatin versus placebo in modifying lipids in patients with rheumatoid arthritis (RA) receiving the oral Janus kinase inhibitor, tofacitinib.. A randomised, placebo controlled, multicentre phase 2 study, open-label for tofacitinib and blinded for atorvastatin. Patients received tofacitinib 10 mg twice daily for 12 weeks; at week 6, patients were randomly assigned 1:1 to receive oral atorvastatin 10 mg once daily or placebo for 6 weeks. Main outcome measures were lipid moieties, American College of Rheumatology (ACR) response rates, disease activity score in 28 joint counts and safety.. 111 patients meeting ACR 1987 RA criteria with active disease were enrolled. Tofacitinib-induced elevation of mean total, low-density lipoprotein (LDL) and high-density lipoprotein-cholesterol, triglycerides and apolipoprotein A-1 concentrations were sustained in placebo recipients to week 12; atorvastatin added at week 6 significantly reduced tofacitinib-associated increases in total and LDL-cholesterol, triglycerides and apolipoprotein B to below week 0 levels. Co-administration of atorvastatin resulted in a significant reduction of LDL-cholesterol versus placebo (primary endpoint; p<0.0001); from week 6 to week 12 the least squares mean reduction was 35.3% with atorvastatin, versus 5.8% increase with placebo. ACR responses were observed with tofacitinib; numerically greater rates were seen with atorvastatin versus placebo. Adverse events were consistent with phase 3 studies.. Tofacitinib-associated elevated total and LDL-cholesterol and triglycerides were rapidly and significantly reduced by atorvastatin. Further investigation is required to explore the significance of reductions in RA disease activity in patients receiving tofacitinib and atorvastatin. (Pfizer protocol A3921109).

Topics: Administration, Oral; Adult; Arthritis, Rheumatoid; Atorvastatin; Cardiovascular Diseases; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Middle Aged; Piperidines; Placebos; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Treatment Outcome

Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS).. To assess the efficacy of alvimopan to accelerate GI recovery after RC.. We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics.. Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo.. The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed.. Patients were randomized to alvimopan (n=143) or placebo (n=137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p<0.0001), shorter mean LOS (7.4 vs 10.1 d; p=0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p<0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p=0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy.. Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo.. This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety.. ClinicalTrials.gov identifier NCT00708201.

Topics: Aged; Analgesics, Opioid; Cardiovascular Diseases; Cystectomy; Defecation; Double-Blind Method; Eating; Female; Gastrointestinal Agents; Gastrointestinal Tract; Humans; Ileus; Length of Stay; Male; Middle Aged; Piperidines; Postoperative Care; Prospective Studies; Recovery of Function; Time Factors

To evaluate the long-term durability of the efficacy of alogliptin compared with glipizide in combination with metformin in people with type 2 diabetes inadequately controlled on stable-dose metformin.. This multicentre, double-blind, active-controlled study randomized 2639 patients aged 18-80 years to 104 weeks of treatment with metformin in addition to alogliptin 12.5 mg once daily (n = 880), alogliptin 25 mg once daily (n = 885) or glipizide 5 mg once daily, titrated to a maximum of 20 mg (n = 874). The primary endpoint was least square mean change from baseline in HbA1c level at 104 weeks.. The mean patient age was 55.4 years, the mean diabetes duration was 5.5 years and the mean baseline HbA1c was 7.6%. HbA1c reductions at week 104 were -0.68%, -0.72% and -0.59% for alogliptin 12.5 and 25 mg and glipizide, respectively [both doses met the criteria for non-inferiority to glipizide (p<0.001); alogliptin 25 mg met superiority criteria (p=0.010)]. Fasting plasma glucose concentration decreased by 0.05 and 0.18 mmol/l for alogliptin 12.5 and 25 mg, respectively, and increased by 0.30 mmol/l for glipizide (p < 0.001 for both comparisons with glipizide). Mean weight changes were -0.68, -0.89 and 0.95 kg for alogliptin 12.5 and 25 mg and glipizide, respectively (p < 0.001 for both comparisons with glipizide). Hypoglycaemia occurred in 23.2% of patients in the glipizide group vs. 2.5 and 1.4% of patients in the alogliptin 12.5 and 25 mg groups, respectively. Pancreatitis occurred in one patient in the alogliptin 25 mg group and three in the glipizide group.. Alogliptin efficacy was sustained over 2 years in patients with inadequate glycaemic control on metformin alone.

Topics: Adult; Aged; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pancreatitis; Piperidines; Treatment Outcome; Uracil

As there have been concerns that some classes or agents for the treatment of type 2 diabetes may increase CV risk, we evaluated the cardiovascular profile of the dipeptidyl peptidase-4 inhibitor alogliptin.. We evaluated the incidence of CV events in patients treated with alogliptin, placebo or comparator antihyperglycaemic drugs in the clinical trial database for alogliptin using the composite major adverse cardiovascular event (MACE) endpoints of CV death, non-fatal myocardial infarction and non-fatal stroke.. The pooled analysis included 4168 patients exposed to alogliptin 12.5 and 25 mg daily for 2023 patient-years compared to 691 patients treated with placebo for 263 patient-years and 1169 patients treated with other antidiabetic agents (metformin, sulfonylureas and thiazolidinediones) for 703 patient-years. CV events were adjudicated by an expert endpoint committee blinded to treatment allocation. The incidence rates of the combined MACE were not significantly different between patients treated with alogliptin and comparator therapies (hazard ratio=0.635, 95% confidence interval, 0.0, 1.41). Additionally, other types of serious CV events were not significantly different between patients treated with alogliptin and comparator therapies.. These analyses have not shown a signal of increased CV risk with alogliptin in patients with type 2 diabetes. Future results from the adequately powered EXAMINE trial will definitively assess the CV safety profile of aloglipin in patients with type 2 diabetes mellitus.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Humans; Incidence; Male; Middle Aged; Piperidines; Proportional Hazards Models; Severity of Illness Index; Uracil

The experimental aim of this study was to determine whether ET-1-mediated vasoconstrictor tone is elevated in adult humans with impaired fasting blood glucose concentrations, independent of other cardiovascular risk factors.. Forearm blood flow (FBF: plethysmography) responses to intra-arterial infusion of selective ETA receptor blockade (BQ-123: 100 nmol/min for 60 min) and non-selective ETA/B blockade (BQ-123 + BQ-788: 50 nmol/min for 60 min) were determined in 28 middle-aged, sedentary adults (17 M/11 F): 14 with normal fasting blood glucose (age: 57 ± 2 yr; 6 F/8 M; BMI: 29.2 ± 0.9 kg/m(2); glucose: 4.9 ± 0.1 mmol/L) and 14 impaired fasting blood glucose (58 ± 1 yr; 5 F/9 M; 29.6 ± 1.1 kg/m(2); 5.8 ± 0.1 mmol/L) concentrations.. Selective ETA receptor blockade elicited a significantly greater (∼20%) increase in FBF in the impaired fasting glucose adults compared with the normoglycemia controls. ETA/B blockade resulted in a further 2-fold increase (P < 0.05) in FBF above that elicited by ETA receptor antagonism in the impaired fasting glucose but not normal fasting glucose adults. There was a positive correlation between fasting blood glucose levels and the peak vascular responses to ETA (r = 0.44; P < 0.05) and ETA/B (r = 0.62; P < 0.05) blockade. No other anthropometric, hemodynamic or metabolic variable was correlated with the blood flow responses to ET-1 receptor blockade.. ET-1-mediated vasoconstrictor tone is elevated in adults with impaired fasting blood glucose concentrations, independent of other cardiometabolic risk factors. Enhanced ET-1 system activity may underlie endothelial vasomotor dysfunction and increased cardiovascular risk in adults with impaired fasting blood glucose concentrations.

Topics: Antihypertensive Agents; Blood Glucose; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Fasting; Female; Glucose Intolerance; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Plethysmography; Risk Factors; Sedentary Behavior; Vasoconstriction

To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome.. We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.. A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo.. Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.).

Topics: Aged; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Myocardial Infarction; Piperidines; Uracil

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

Comprehensive safety evaluation of new drugs for diabetes mellitus is needed in the area of cardiovascular (CV) outcomes, particularly in populations with high CV risk. Alogliptin, a dipeptidyl peptidase 4 inhibitor, is under development for the treatment of type 2 diabetes mellitus alone or in combination with other antidiabetic therapies. Long-term CV safety of alogliptin is being established in a randomized, placebo-controlled clinical study in patients with acute coronary syndrome (ACS) using an analytical approach that has both an interim and final assessment. The primary CV end point for this trial is a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. Approximately 5,400 men and women with type 2 diabetes and ACS (acute myocardial infarction or unstable angina) are being recruited and will be followed up for up to 4.5 years postrandomization. The statistical plan for the trial uses a design that evaluates the hazard ratio (HR) of alogliptin to placebo first based on the primary CV composite end point after accrual of 80 to 150 primary CV events and again when there are 550 to 650 primary CV events. In the first series of analyses, the upper bound of a group-sequential 1-sided repeated CI for the HR must be ≤1.8 for registration in the United States. At end of study, the upper bound of a subsequent group-sequential 1-sided repeated CI for the HR must be ≤1.3. For both group sequential analyses, the repeated CIs are calculated to insure simultaneous coverage probabilities of 97.5% for the true HR. Study progress: More than 2,000 ACS patients were randomized as of June 2011. EXAMINE will define the CV safety profile of this dipeptidyl peptidase 4 inhibitor in patients at high risk for CV events.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Male; Middle Aged; Piperidines; Prospective Studies; Treatment Outcome; Uracil

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 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, 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

Aim our study is to compare the effects of repaglinide vs glimepiride administration on cardiovascular risk factors after meal test. Thus, after 2 weeks washout period, a 3-month randomised, cross-over parallel group trial of repaglinide (1 mg x 2/day) vs glimepiride (2 mg/day) in 14 patients with type 2 diabetes "naive" on diet treatment was made. Both treatments significantly declined plasma glucose, total-cholesterol, LDL-cholesterol, triglycerides, PAI-1, PAP levels and increased HDL-cholesterol. Lowering in plasma PAI-1 and PAP levels was significantly greater in repaglinide group. Furthermore, repaglinide administration resulted in a significant decrease in fasting plasma free fatty acids, fibrinogen, thrombin-antithrombin complex and reaction product of malondialdehyde with thiobarbituric acid (TBARS) levels, in absence of significant difference in fasting plasma insulin levels. Decrease in plasma TBARS levels correlated with the decrease in Plasminogen Activator Inhibitor-1 (r = 0.72; P < 0.003) and free fatty acids concentrations (r = 0.62; P < 0.01). Analysis of the insulin and glucose concentrations throughout the meal test revealed that AUC for glucose (758 +/- 19 vs 780 +/- 28 mg/Lxmin; P = 0.02) was significantly lower after repaglinide than glimepiride administration despite similar AUC for insulin (2327 +/- 269 vs 2148 +/- 292 mU/Lxmin; P = 0.105). At time 120' of meal test, repaglinide vs glimepiride administration was associated with a significant decline in plasma triglycerides, free fatty acids, fibrinogen, Plasminogen Activator Inhibitor-1, plasmin-alpha(2)-antiplasmin complex, thrombin-antithrombin complex, TBARS levels and increase in plasma HDL-cholesterol levels. In repaglinide group a negative correlation between insulin secretion during 1st phase of meal-test and plasma TBARS levels (r = -0.55; P < 0.03) at time 120' was found. Such correlation was lost after adjusting for changes in postprandial hyperglycaemia (r = -0.48; P < 0.09). In conclusion, our results support the hypothesis that repaglinide is more efficient than glimepiride on controlling for postprandial glucose excursion and may have beneficial effect on reducing cardiovascular risk factors.

Topics: Aged; Aged, 80 and over; Area Under Curve; Blood Glucose; Carbamates; Cardiovascular Diseases; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Diabetic; Eating; Female; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Middle Aged; Piperidines; Sulfonylurea Compounds; Thiobarbituric Acid Reactive Substances

This multicenter open-label clinical trial was designed to investigate the safety and efficacy of donepezil, a selective acetylcholinesterase inhibitor, in the treatment of Alzheimer's disease (AD) in routine clinical practice in Germany. A total of 237 patients with mild-to-moderate AD were treated with donepezil for 24 weeks, 186 completed the study according to the protocol. In the completer group, mean MMSE score for efficacy showed an improvement from baseline of +1.6 points at week 12 (95% CI +1.1 to +2.1) and of +1.1 points at week 24 (95% CI +0.5 to +1.7). In more than 80% of the patients, global tolerability was rated to be very good or good. There were only insignificant effects on ECG parameters. This study confirms the results obtained in previous double-blind trials, which showed that donepezil is effective and well tolerated in patients with mild-to-moderately severe AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cardiovascular Diseases; Cholinesterase Inhibitors; Donepezil; Electrocardiography; Female; Germany; Hemodynamics; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Treatment Outcome

[corrected] To study the analgesia, hemodynamic stability and inflammatory response in patients undergoing carotid endarterectomy under different types of general anesthesia.. A comparison of 80 patients randomized to 4 groups: group 1, maintenance with sevoflurane at a minimum alveolar concentration (MAC) of 1; group 2, sevoflurane at MAC 1.5; group 3, remifentanil; group 4, propofol. Variables studied were hemodynamic alterations during and after surgery, level of postoperative analgesia, differential white cell counts, levels of interleukin-6 (IL-6), and clinical signs and symptoms of systemic inflammatory response syndrome in the first 24 hours after surgery.. The incidences of episodes of intraoperative hypertension were 60% in group 1, 65% in group 2, 50% in group 3, and 60% in group 4. The incidences of episodes of intraoperative hypotension were 85% in group 1, 80% in group 2, 80% in group 3, and 75% in group 4. Patients in groups 3 and 4 had higher incidences of systemic inflammatory response syndrome (p<0.05) in the first 24 hours after surgery and higher levels of IL-6 (p<0.05). Postoperative analgesia was similar in all 4 groups.. Increased levels of IL-6 in peripheral blood and of systemic inflammatory response syndrome were found in the early postoperative period in groups that did not receive halogenated gases. Hemodynamic stability and analgesia were similar in all groups, however.

Topics: Aged; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Cardiovascular Diseases; Endarterectomy, Carotid; Hemodynamics; Humans; Incidence; Inflammation; Interleukin-6; Intraoperative Complications; Male; Methyl Ethers; Middle Aged; Pain, Postoperative; Piperidines; Propofol; Prospective Studies; Remifentanil; Sevoflurane

To compare glycaemic control and cardiovascular risk profile in patients with type 2 diabetes following 12 months' treatment with either repaglinide or metformin.. This was an open uncontrolled randomised study in n=112 patients with inadequately controlled type 2 diabetes not previously treated with oral hypoglycaemic agents. Patients beginning treatment with either repaglinide or metformin entered an 8-week titration period (to optimise dosage: repaglinide, 2-4 mg/day; metformin, 1500-2500 mg/day) followed by a 12-month treatment period. Glycaemic control and cardiovascular risk factors were determined at baseline and at the end of the treatment period.. Mean (S.D.) final drug doses were 3 (+/-1) mg/day in the repaglinide group and 2000 (+/-500) mg/day in the metformin group. Significant improvements in glycaemic control [glycated haemoglobin, fasting and 2-h postprandial plasma glucose (PPG)] were demonstrated in both treatment groups. The decrease in PPG was significantly greater in the repaglinide group (P<0.05). During the treatment period, fasting plasma insulin (FPI) decreased significantly in both groups, more so with metformin (P<0.05). Two-hour postprandial plasma insulin (PPI) levels decreased only in the metformin group (P<0.05). Significant improvements between baseline and final visit were demonstrated in one or both groups in the following cardiovascular risk factors: total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, plasminogen activator inhibitor, lipoprotein(a) and homocysteine. No changes were observed in high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I, apolipoprotein B, fibrinogen, body mass index (BMI) or blood pressure.. The use of repaglinide or metformin in drug therapy-nai;ve patients with type 2 diabetes over a 12-month period is associated with improvements in both glycaemic control and cardiovascular risk profile. The latter cannot necessarily be attributed to the pharmacotherapy per se, but provides reassurance in the context of initiating oral hypoglycaemic drug therapy with these agents.

Topics: Blood Glucose; Carbamates; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Lipoproteins; Male; Metformin; Middle Aged; Piperidines; Prospective Studies; Risk Factors; Triglycerides

Long-term postmenopausal estrogen replacement therapy lowers the risk of osteoporotic fractures and coronary artery disease but increases the risk of endometrial cancer and probably breast cancer. Raloxifene, a nonsteroidal estrogen receptor ligand, seems to have a tissue-specific antiestrogenic action on endometrium and breast and the desired estrogenic action on bone and lipid metabolism. The purpose of this study was to investigate the effects of 24-month treatment with orally administered raloxifene in two doses (60 mg and 150 mg daily) and conjugated equine estrogens in a standard oral dose (0.625 mg daily) on serum lipoprotein(a) [Lp(a)], an independent risk factor for coronary artery disease, in healthy postmenopausal women who had undergone hysterectomy.. A randomized, double-blind, placebo-controlled study was performed with 56 women.. In the placebo group serum Lp(a) levels did not change throughout the study. After 6 months, serum Lp(a) was significantly reduced versus baseline in the raloxifene 150 (-17%; p = 0.003) and conjugated equine estrogens (-26%; p = 0.003) groups, but this reduction was significantly different from placebo only in the conjugated equine estrogens group. At 12 and 24 months, serum Lp(a) levels were significantly lowered versus baseline in all active treatment groups. However, these reductions were significantly different from placebo only in the raloxifene 150 and conjugated equine estrogens groups. After 24 months, serum Lp(a) was reduced versus baseline with 30% (p = 0.001) in the raloxifene 150 group and 35% (p = 0.001) in the conjugated equine estrogens group.. Long term raloxifene treatment significantly lowers serum Lp(a) levels in postmenopausal women and thus might reduce the risk of coronary artery disease.

Topics: Administration, Oral; Analysis of Variance; Cardiovascular Diseases; Double-Blind Method; Drug Administration Schedule; Estrogen Antagonists; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Follow-Up Studies; Humans; Hysterectomy; Lipoprotein(a); Middle Aged; Piperidines; Postmenopause; Raloxifene Hydrochloride; Treatment Outcome

Extubation and the immediate postoperative period are critical periods with strong sympatho-adrenergic stimulation. The aim of the present study was to investigate this period after balanced anaesthesia with remifentanil and alfentanil in cardiac risk patients.. 52 patients with coronary artery disease or with risk factors for coronary heart disease scheduled for elective extraperitoneal and extrathoracic operation were included in this study. Anaesthesia was induced by intravenous administration of etomidate, vecuronium and remifentanil (n = 27, 1 microgram/kg) or alfentanil (n = 25, 25 micrograms/kg). Anaesthesia was maintained with an Isoflurane/N2O/O2 mixture and by continuous intravenous infusion of remifentanil (0.25 microgram/kg/min) or alfentanil (45 micrograms/kg/h). During the first 60 minutes after extubation haemodynamic parameters were monitored and catecholamines were determined at defined time intervals. Parameters of recovery, the requirement of analgesics and cardiac medications were compared in both groups. Myocardial ischaemia was assessed by two-channel Holter electrocardiography.. The beginning of spontaneous respiration and time of extubation were similar in both groups. The time interval until opening eyes and the time between the beginning of spontaneous respiration and extubation was shorter in the patients treated with remifentanil. In this group patients suffered earlier from pain and had a higher pain score. Although the plasma catecholamines were comparable in both groups, in the patients treated with remifentanil changes in haemodynamic parameters were more pronounced. The incidence of shivering and the requirements of analgesics and cardiac medications were higher in these patients. The incidence of ST-segment changes indicating myocardial ischaemia was similar.. After balanced anaesthesia with remifentanil a more pronounced sympatho-adrenergic stimulation occurs because of the more rapid clearance of the analgesic effect in the recovery period compared to alfentanil requiring more analgesics and medications for the control of the haemodynamic parameters. Because of these specific pharmacological effects the use of remifentanil in cardiac risk patients has to be critically discussed.

Topics: Aged; Alfentanil; Anesthesia, Intravenous; Anesthetics, Intravenous; Cardiovascular Diseases; Catecholamines; Electrocardiography; Electrocardiography, Ambulatory; Female; Hemodynamics; Humans; Male; Piperidines; Postoperative Complications; Remifentanil; Risk Factors; Sympathetic Nervous System

Raloxifene is a selective estrogen receptor modulator that has estrogen-agonistic effects on bone and estrogen-antagonistic effects on breast and uterus.. To identify the effects of raloxifene on markers of cardiovascular risk in postmenopausal women, and to compare them with those induced by hormone replacement therapy (HRT).. Double-blind, randomized, parallel trial.. Eight sites in the United States.. 390 healthy postmenopausal women recruited by advertisement.. Participants were randomized to receive 1 of 4 treatments: raloxifene, 60 mg/d; raloxifene, 120 mg/d; HRT (conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d); or placebo.. Change and percent change from baseline of lipid levels and coagulation parameters after 3 months and 6 months of treatment.. At the last visit completed, compared with placebo, both dosages of raloxifene significantly lowered low-density lipoprotein cholesterol (LDL-C) by 12% (P < .001), similar to the 14% reduction with HRT (P < .001). Both dosages of raloxifene significantly lowered lipoprotein(a) by 7% to 8% (P < .001), less than the 19% decrease with HRT (P<.001). Raloxifene increased high-density lipoprotein-2 cholesterol (HDL2-C) by 15% to 17% (P < .05), less than the 33% increase with HRT (P < .001). Raloxifene did not significantly change high-density lipoprotein cholesterol (HDL-C), triglycerides, or plasminogen activator inhibitor-1 (PAI-1); whereas HRT increased HDL-C by 11% and triglycerides by 20%, and decreased PAI-1 by 29% (for all, P < .001). Raloxifene significantly lowered fibrinogen by 12% to 14% (P < .001), unlike HRT, which had no effect. Neither treatment changed fibrinopeptide A or prothrombin fragment 1 and 2.. Raloxifene favorably alters biochemical markers of cardiovascular risk by decreasing LDL-C, fibrinogen, and lipoprotein(a), and by increasing HDL2-C without raising triglycerides. In contrast to HRT, raloxifene had no effect on HDL-C and PAI-1, and a lesser effect on HDL2-C and lipoprotein(a). Further clinical trials are necessary to determine whether these favorable biochemical effects are associated with protection against cardiovascular disease.

Topics: Aged; Analysis of Variance; Blood Coagulation Factors; Cardiovascular Diseases; Double-Blind Method; Estrogen Antagonists; Estrogen Replacement Therapy; Estrogens; Estrogens, Conjugated (USP); Female; Humans; Lipoproteins; Medroxyprogesterone Acetate; Middle Aged; Piperidines; Postmenopause; Progesterone Congeners; Prospective Studies; Raloxifene Hydrochloride; Risk Factors

Platelet aggregation in response to 5-hydroxytryptamine (5-HT) was investigated in 110 patients with cardiovascular diseases and in 40 age-matched control subjects. It was found that 40% of those patients had a biphasic irreversible platelet aggregation in response to 5-HT, whereas 92.5% of the control subjects responded with a weak reversible aggregation. A double-blind, placebo-controlled study, including 41 patients, showed that a subacute treatment with ketanserin significantly abolished platelet aggregation in patients hyperreactive to 5-HT. In an additional open study, including 10 patients with peripheral arterial obstructive disease, chronic treatment with ketanserin for a period of 3 months significantly suppressed the primary platelet aggregation to 5-HT at 2 X 10(-5) M and at 2 X 10(-6) M and significantly lowered the plasma beta-thromboglobulin levels.

Topics: Adult; Aged; beta-Thromboglobulin; Blood Platelets; Cardiovascular Diseases; Double-Blind Method; Humans; Ketanserin; Middle Aged; Piperidines; Platelet Aggregation; Serotonin; Serotonin Antagonists

Platelet aggregation in response to 5-hydroxytryptamine was investigated in 40 normal subjects, in 45 patients with acute myocardial infarction, and in 65 patients with peripheral arterial obstructive disease. It was found that of the 110 patients with cardiovascular disease, 40% had a biphasic irreversible platelet aggregation, whereas this phenomenon occurred in only 7.5% of the normal population. A double-blind placebo-controlled study further showed that a subacute treatment with ketanserin, a selective 5-HT2-receptor antagonist both on platelets and on vascular tissue, efficiently abolished the irreversible platelet aggregation in patients hyperreactive to 5-hydroxytryptamine. In an additional open study, including 10 patients with peripheral arterial obstructive disease, a chronic treatment with ketanserin 40 mg t.i.d. for a period of 3 months significantly suppressed the primary platelet aggregation to 5-HT at 2 X 10(-5) M and at 2 X 10(-6) M and significantly lowered the plasma beta thromboglobulin levels. Since 5-HT is a potent mediator of vasospasm, treatment with ketanserin might be of therapeutic value in atherosclerotic diseases, where platelet activation is thought to be involved.

Topics: Aged; Arterial Occlusive Diseases; beta-Thromboglobulin; Cardiovascular Diseases; Double-Blind Method; Female; Humans; Ketanserin; Male; Middle Aged; Myocardial Infarction; Piperidines; Placebos; Platelet Aggregation; Serotonin

Piperine (PIP) was evaluated as a natural coformer in the preparation of multicomponent organic materials for enhancing solubility and dissolution rate of the poorly water-soluble drugs: curcumin (CUR), lovastatin (LOV), and irbesartan (IBS). A screening based on liquid assisted grinding technique was performed using 1:1 drug-PIP molar ratio mixtures, followed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) analyses. Three eutectic mixtures (EMs) composed of CUR-PIP, LOV-PIP, and IBS-PIP were obtained. Therefore, binary phase and Tamman's diagrams were constructed for each system to obtain the exact eutectic composition, which was 0.41:0.59, 0.29:0.71, and 0.31:0.69 for CUR-PIP, LOV-PIP, and IBS-PIP, respectively. Further, bulk materials of each system were prepared to characterize them through DSC, PXRD fully, Fourier transform infrared spectroscopy (FT-IR), and solution-state nuclear magnetic resonance (NMR) spectroscopy. In addition, the contact angle, solubility, and dissolution rate of each system were evaluated. The preserved characteristic in the PXRD patterns and FT-IR spectra of the bulk material of each system confirmed the formation of EM mixture without molecular interaction in solid-state. The formation of EM resulted in improved aqueous solubility and dissolution rate associated with the increased wettability observed by the decrease in contact angle. In addition, solution NMR analyses of CUR-PIP, LOV-PIP, and IBS-PIP suggested no significant intermolecular interactions in solution between the components of the EM. Hence, this study concludes that PIP could be an effective coformer to improve the solubility and dissolution rate of CUR, LOV, and IBS.

Topics: Alkaloids; Benzodioxoles; Cardiovascular Diseases; Curcumin; Irbesartan; Lovastatin; Piperidines; Polyunsaturated Alkamides; Powders; Spectroscopy, Fourier Transform Infrared

cGMP-dependent protein kinase (PKG) represents a compelling drug target for treatment of cardiovascular diseases. PKG1 is the major effector of beneficial cGMP signaling which is involved in smooth muscle relaxation and vascular tone, inhibition of platelet aggregation and signaling that leads to cardioprotection. In this study, a novel piperidine series of activators previously identified from an ultrahigh-throughput screen were validated to directly bind partially activated PKG1α and subsequently enhance its kinase activity in a concentration-dependent manner. Compounds from initial optimization efforts showed an ability to activate PKG1α independent of the endogenous activator, cGMP. We demonstrate these small molecule activators mimic the effect of cGMP on the kinetic parameters of PKG1α by positively modulating the K

Topics: Adenosine Triphosphate; Allosteric Regulation; Allosteric Site; Cardiovascular Diseases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Humans; Piperidines; Small Molecule Libraries

Ibrutinib reduces mortality in chronic lymphocytic leukemia (CLL). It increases the risk of atrial fibrillation (AF) and bleeding and there are concerns about heart failure (HF) and central nervous system ischemic events. The magnitude of these risks remains poorly quantified.. Using linked administrative databases, we conducted a population-based cohort study of Ontario patients who were treated for CLL diagnosed between 2007 and 2019. We matched ibrutinib-treated patients with controls treated with chemotherapy but unexposed to ibrutinib on prior AF, age ≥ 66 years, anticoagulant exposure, and propensity for receiving ibrutinib. Study outcomes were AF-related health care contact, hospital-diagnosed bleeding, new diagnoses of HF, and hospitalizations for stroke and acute myocardial infarction (AMI). The cumulative incidence function was used to estimate absolute risks. We used cause-specific regression to study the association of ibrutinib with bleeding rates, while adjusting for anticoagulation as a time-varying covariate.. We matched 778 pairs of ibrutinib-treated and unexposed patients with CLL (N = 1,556). The 3-year incidence of AF-related health care contact was 22.7% (95% CI, 19.0 to 26.6) in ibrutinib-treated patients and 11.7% (95% CI, 9.0 to 14.8) in controls. The 3-year risk of hospital-diagnosed bleeding was 8.8% (95% CI, 6.5 to 11.7) in ibrutinib-treated patients and 3.1% (95% CI, 1.9 to 4.6) in controls. Ibrutinib-treated patients were more likely to start anticoagulation after the index date. After adjusting for anticoagulation as a time-varying covariate, ibrutinib remained positively associated with bleeding (HR, 2.58; 95% CI, 1.76 to 3.78). The 3-year risk of HF was 7.7% (95% CI, 5.4 to 10.6%) in ibrutinib-treated patients and 3.6% (95% CI, 2.2 to 5.4) in controls. There was no significant difference in the risk of ischemic stroke or AMI.. Ibrutinib is associated with higher risk of AF, bleeding, and HF, but not AMI or stroke.

Topics: Adenine; Aged; Aged, 80 and over; Canada; Cardiovascular Diseases; Case-Control Studies; Cohort Studies; Female; Follow-Up Studies; Heart Disease Risk Factors; Hospitalization; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Prognosis; Risk Factors; Survival Rate

Patients with ulcerative colitis (UC) are at elevated risk of cardiovascular disease vs the general population, despite a lower prevalence of traditional risk factors, including hyperlipidemia. Mechanistic studies in patients with rheumatoid arthritis and psoriasis suggest that tofacitinib restores serum lipids to preinflammation levels by reversing inflammation-induced cholesterol metabolism changes. We reviewed data on lipid levels and cardiovascular events, alongside recommendations for managing lipid levels during tofacitinib treatment in patients with UC, based on up-to-date expert guidelines.. Data were identified from a phase 3/open-label, long-term extension (OLE) tofacitinib UC clinical program (cutoff May 27, 2019). Literature was identified from PubMed (search terms "lipid," "cholesterol," "lipoprotein," "cardiovascular," "inflammation," "atherosclerosis," "tofacitinib," "rheumatoid arthritis," "psoriasis," "inflammatory bowel disease," "ulcerative colitis," "hyperlipidemia," and "guidelines") and author knowledge. Data were available from 4 phase 3 clinical trials of 1124 patients with moderately to severely active UC who received ≥1 dose of tofacitinib 5 or 10 mg twice daily in induction (two identical trials), maintenance, and OLE studies (treatment duration ≤6.8 years; 2576.4 patient-years of drug exposure).. In the OLE study, tofacitinib treatment was not associated with major changes from baseline in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, total cholesterol/high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol, with lipid levels and ratios generally remaining stable over time. The major adverse cardiovascular events incidence rate was 0.26/100 patient-years (95% confidence interval, 0.11-0.54).. Lipid levels and ratios remained generally unchanged from baseline in the OLE study after tofacitinib treatment, and major adverse cardiovascular events were infrequent. Long-term studies are ongoing.. NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Topics: Arthritis, Rheumatoid; Cardiovascular Diseases; Cholesterol; Clinical Trials, Phase III as Topic; Colitis, Ulcerative; Heart Disease Risk Factors; Humans; Inflammation; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Risk Factors; Treatment Outcome

Topics: Cardiovascular Diseases; Colitis, Ulcerative; Heart Disease Risk Factors; Humans; Lipids; Piperidines; Pyrimidines; Risk Factors

Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.. This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross-sectional FDA's Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques.. In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49-69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14-2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12-2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12-2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46-60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%-36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%-20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01-2.42); p = 0.045).. In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Cardiovascular Diseases; Colonic Neoplasms; Cross-Sectional Studies; Female; Heart Failure; Humans; Hypertension; Imidazoles; Lung Neoplasms; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Registries; Regression Analysis; Skin Neoplasms; Sulfonamides; Vemurafenib; Venous Thromboembolism; Young Adult

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

To assess the association of metformin monotherapy with the risk of all-cause deaths and cardiovascular deaths and events in type 2 diabetes patients in real clinical practice.. This retrospective, observational study comprised patients with type 2 diabetes initially treated with metformin or nonmetformin monotherapy over 2011-2016. Data were extracted from the National Healthcare Big Data database in Fuzhou, China. Propensity score matching (PSM) was performed, matching each patient on metformin to one on nonmetformin in terms of a set of covariates. The primary endpoint was all-cause death, and secondary endpoints were cardiovascular death, heart failure, and heart failure hospitalization. Covariate-adjusted associations of metformin use with all the endpoints were assessed by Cox proportional hazards models.. Among 24,099 patients, 5491 were initially treated with metformin and 18,608 with nonmetformin. PSM yielded 5482 patients in each cohort. During a median follow-up of 2.02 years, we observed 110 and 211 deaths in the metformin and nonmetformin groups, respectively. Metformin was significantly associated with reduced risk of all-cause death (adjusted hazard ratio (aHR) 0.52, 95% confidence interval (CI) 0.39-0.69), cardiovascular death (aHR 0.63, 95% CI 0.43-0.91), and heart failure (aHR 0.61, 95% CI 0.52-0.73), whereas the reduced risk in heart failure hospitalization was not statistically significant (aHR 0.70, 95% CI 0.47-1.02).. In this analysis of electronic health record data from a large database in China, metformin as first-line monotherapy greatly reduced the risk of all-cause death, cardiovascular death, and heart failure in diabetes patients as compared with nonmetformin medications.

Topics: Aged; Benzamides; Carbamates; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycoside Hydrolase Inhibitors; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Mortality; Nateglinide; Piperidines; Proportional Hazards Models; Retrospective Studies; Sulfonylurea Compounds; Thiazolidinediones

Ibrutinib is the first clinically approved inhibitor of Bruton's tyrosine kinase, an enzyme that is essential for survival and proliferation of B‑cells by activating the B‑cell receptor signalling pathway. Ibrutinib has been shown to be highly effective in B‑cell malignancies in clinical trials and is recommended in current international guidelines as a first and/or second line treatment of chronic lymphocytic leukemia. The drug has a favorable tolerability and safety profile but the occurrence of specific side effects (e.g. atrial fibrillation, bleeding and hypertension) may complicate or be of concern for doctors and patients considering the use of this treatment. In many cases, however, it is not necessary to withhold this effective therapy. In contrast, ibrutinib treatment can be initiated or continued, if certain recommendations are followed. The possibilities of prevention, diagnosis and management of specific clinical situations are discussed in detail and recommendations are derived, which should facilitate ibrutinib use.

Topics: Adenine; Atrial Fibrillation; Cardiovascular Diseases; Humans; Piperidines; Pyrazoles; Pyrimidines; Risk Factors

Topics: Anti-Inflammatory Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; Cardiovascular Diseases; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines

Ibrutinib has revolutionized treatment for several B-cell malignancies. However, a recent clinical trial where ibrutinib was used in a front-line setting showed increased mortality during treatment compared with conventional chemotherapy. Cardiovascular toxicities were suspected as the culprit but not directly assessed in the study.. The purpose of this study was to identify and characterize cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib.. This study utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) and information component (IC) to determine whether CV-ADR and CV-ADR deaths were associated with ibrutinib. IC compares observed and expected values to find associations between drugs and adverse drug reactions using disproportionate Bayesian-reporting; IC. This study identified 303 ibrutinib-associated cardiovascular deaths. Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVAs) (ROR: 23.1; 95% confidence interval: 21.6 to 24.7; p < 0.0001; IC. Severe and occasionally fatal cardiac events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs. (Evaluation of Reporting of Cardio-vascular Adverse Events With Antineoplastic and Immunomodulating Agents [EROCA]; NCT03530215).

Topics: Adenine; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Cardiovascular Diseases; Databases, Factual; Female; Humans; Male; Mortality; Pharmacovigilance; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies

Topics: Adenine; Cardiovascular Diseases; Humans; Piperidines; Pyrazoles; Pyrimidines

Several insulin secretagogues are widely used to treat diabetes; however, few outcome-based comparative studies have clarified which one of these should be used when indicated. We investigated mortality and cardiovascular event risk associated with optimal forms of insulin secretagogues.. In this cohort study using real-world data from the diabetes database of Taiwan's National Health Insurance program, patients with diabetes were enrolled if their initial treatment was glimepiride, gliclazide, glipizide, glyburide, or repaglinide from 1999 to 2013. Each group was propensity score-matched to the glimepiride group before comparison. Primary outcomes were all-cause mortality and the combined cardiovascular event risk of acute myocardial infarction and ischemic stroke. Hazard ratios were calculated by Cox proportional hazard regression models.. There were 66,790, 97,426, 38,806, 92,970, and 11,468 participants in the glimepiride, gliclazide, glipizide, glyburide, and repaglinide groups, respectively. The median follow-up time was 8 years. Glimepiride was associated with the best clinical outcome, showing the lowest mortality and lowest cardiovascular event risk of the five insulin secretagogues. Using patients on glimepiride as the reference group, the adjusted hazard ratios of all-cause mortality and cardiovascular event risk were 1.52 (p < 0.001) and 1.22 (p = 0.005) for gliclazide, 1.42 (p < 0.001) and 1.19 (p = 0.073) for glipizide, 1.43 (p < 0.001) and 1.32 (p < 0.001) for glyburide, and 1.88 (p < 0.001) and 1.69 (p = 0.001) for repaglinide.. For patients with diabetes taking an insulin secretagogue, glimepiride was associated with the best clinical outcome, showing the lowest mortality and cardiovascular event risk.

Topics: Aged; Carbamates; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Follow-Up Studies; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Mortality; Piperidines; Secretagogues; Sulfonylurea Compounds; Taiwan

Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). This study was undertaken to evaluate the risk of major adverse cardiovascular events (MACE) in patients with RA receiving tofacitinib.. Data were pooled from patients with moderately to severely active RA receiving ≥1 tofacitinib dose in 6 phase III and 2 long-term extension studies over 7 years. MACE (myocardial infarction, stroke, cardiovascular death) were independently adjudicated. Cox regression models were used to evaluate associations between baseline variables and time to first MACE. Following 24 weeks of tofacitinib, changes in variables and time to future MACE were evaluated after adjusment for age, baseline values, and time-varying tofacitinib dose. Hazard ratios and 95% confidence intervals were calculated.. Fifty-two MACE occurred in 4,076 patients over 12,873 patient-years of exposure (incidence rate 0.4 patients with events per 100 patient-years). In univariable analyses of baseline variables, traditional cardiovascular risk factors and glucocorticoid and statin use were associated with MACE risk; disease activity and inflammation measures were not. In subsequent multivariable analyses, baseline age, hypertension, and the total cholesterol to high-density lipoprotein (HDL) cholesterol ratio remained significantly associated with risk of MACE. After 24 weeks of treatment, an increase in HDL cholesterol and a decrease in the total to HDL cholesterol were associated with decreased MACE risk; changes in total cholesterol, low-density lipoprotein (LDL) cholesterol, and disease activity measures were not. Increased erythrocyte sedimentation rates trended with increased future MACE risk.. In this post hoc analysis, after 24 weeks of tofacitinib treatment, increased HDL cholesterol, but not increased LDL cholesterol or total cholesterol, appeared to be associated with lower future MACE risk. Further data are needed to test the cardiovascular safety of tofacitinib.

Topics: Aged; Arthritis, Rheumatoid; Blood Sedimentation; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials, Phase III as Topic; Female; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Piperidines; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Risk Factors; Stroke; Treatment Outcome

The current study addressed the hypothesis that the local decrease in endothelin-1 (ET-1) bioavailability during sustained flow increases contributes to endothelium-dependent, flow-mediated dilatation (FMD) of conduit arteries and is altered in presence of cardiovascular risk factors.. In nine young healthy individuals, the decrease in local ET-1 plasma levels and radial artery FMD in response to hand skin heating (from 34 to 44 °C) was not affected by endothelin type A (ETA) receptor blockade, achieved using the brachial infusion of BQ-123 (100 nmol/min per l of forearm), as compared with physiological saline (0.9% NaCl) infusion. In contrast, endothelin type B (ETB) receptor blockade with BQ-788 (10 nmol/min per l) suppressed the decrease in plasma ET-1 during heating and reduced FMD, without altering nitric oxide release. The coinfusion of BQ-123 did not affect the inhibitory effect of ETB receptor blockade on the decrease in ET-1 plasma levels during heating but prevented the reduction in FMD. Basal radial artery parameters, systemic hemodynamics, and endothelium-independent dilatation to glyceryl trinitrate were not modified by ETA and/or ETB blockade. In a general population of 40 participants without treatment or major cardiovascular diseases, including the nine healthy individuals, the reduction in endothelin-1 level during heating was correlated with FMD (r = -0.55, P < 0.001) and decreased with increased age (r = 0.49, P = 0.001), mean arterial blood pressure (r = 0.48, P = 0.002), and total cholesterol level (r = 0.37, P = 0.024).. The uptake of endothelin-1 by ETB receptors contributes to conduit artery FMD, preventing its vasoconstrictor action mediated by ETA receptors. The alteration of this mechanism by cardiovascular risk factors may contribute to endothelial dysfunction.

Topics: Adult; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Female; Hemodynamics; Humans; Male; Nitric Oxide; Oligopeptides; Peptides, Cyclic; Piperidines; Risk Factors; Vasodilation; Young Adult

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Female; France; Gastrointestinal Diseases; Hematologic Diseases; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Salvage Therapy; Treatment Outcome

Topics: Adamantane; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Heart Failure; Humans; Hypoglycemic Agents; Piperidines; Risk Factors; Sitagliptin Phosphate; Uracil

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The implications of treatment with tofacitinib on cardiovascular (CV) risk in RA are unknown. Therefore, CV adverse events (AEs), and blood pressure and lipid level changes, in tofacitinib-treated patients with RA were evaluated.. Data were pooled from six Phase (P)3 studies (24 months) and two open-label long-term extension (LTE) studies (60 months) of tofacitinib in patients with RA and inadequate response to DMARDs. Tofacitinib was administered alone or with non-biologic DMARDs. CV events, including major adverse CV events (MACE: CV death and non-fatal CV events) and congestive heart failure (CHF), were assessed by a blinded adjudication committee.. Overall, 4271 patients from P3 studies and 4827 enrolled from P2/P3 studies into LTE studies were evaluated, representing 3942 and 8699 patient-years of exposure to tofacitinib, respectively. Blood pressure remained stable over time across studies. The number of investigator-reported hypertension-related AEs in tofacitinib-treated patients was low in P3 studies (Months 0-3: 2.8%; Months 3-6: 1.4%; >6 months: 2.8%). Across studies, lipid level increases were generally observed within 1-3 months of treatment and stabilized thereafter. Patients with events (incidence rate [IR]/100 patient-years) for MACE and CHF, respectively, were: 23 (0.58) and 9 (0.23) in P3 studies, and 32 (0.37) and 8 (0.09) in LTE studies; IRs were comparable with placebo (P3) and did not increase over time (LTE).. Tofacitinib was associated with a low incidence of CV events in a large Phase 3 program, including LTE studies. Further long-term studies are underway.

Topics: Arthritis, Rheumatoid; Blood Pressure; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials, Phase III as Topic; Heart Failure; Humans; Hyperlipidemias; Hypertension; Incidence; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Triglycerides

Psoriasis is a systemic inflammatory condition that is associated with a higher risk of cardiovascular (CV) disease. Tofacitinib is being investigated as a treatment for psoriasis.. We sought to evaluate the effects of tofacitinib on CV risk factors and major adverse CV events (MACEs) in patients with plaque psoriasis.. Changes in select CV risk factors and the incidence rate (IR) of MACEs were evaluated in patients who were treated with tofacitinib.. Tofacitinib treatment was associated with small, dose-dependent increases in total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, while the total/HDL cholesterol ratio was unchanged. There were no changes in blood pressure and glycated hemoglobin levels; C-reactive protein levels decreased. The IRs of a MACE were low and similar for both tofacitinib doses. Among 3623 subjects treated with tofacitinib, the total patient-years of exposure was 5204, with a median follow-up of 527 days, and the IR of MACEs was 0.37 (95% confidence interval, 0.22-0.57) patients with events per 100 patient-years.. There was relatively short follow-up time for patients who had MACEs.. While treatment with tofacitinib is associated with a small increase in cholesterol levels, the total/HDL cholesterol ratio does not change, there are no unfavorable changes in several CV risk factors, and the incidence of MACEs is low.

Topics: Adult; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Comorbidity; Dyslipidemias; Female; Glycated Hemoglobin; Humans; Male; Metabolic Syndrome; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Risk Factors; Treatment Outcome; Triglycerides

The introduction of tumor necrosis factor (TNF)-α inhibitors dramatically improved the management of psoriasis. Some newer or investigational biologics with different mechanisms of action have demonstrated noninferiority or superiority to etanercept, the first self-injectable anti-TNF-α agent to become available in the United States. Nonetheless, TNF-α inhibitors are likely to remain a mainstay of therapy for many years.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Psoriatic; Cardiovascular Diseases; Certolizumab Pegol; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Dermatologic Agents; Etanercept; Humans; Infliximab; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome; Tumor Necrosis Factor-alpha; Ustekinumab

Topics: Adamantane; Benzhydryl Compounds; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucosides; Humans; Hypoglycemic Agents; Liraglutide; Peptides; Piperidines; Risk; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Uracil

Metformin is the first-line treatment for most patients with type 2 diabetes but many patients need additional treatment with insulin secretagogues (IS) to achieve glycemic control. We aimed to compare mortality and cardiovascular risk among users of metformin in combination with pharmacologically different ISs.. Using nationwide administrative Danish registries, we followed all individuals without prior stroke or myocardial infarction who initiated metformin and an IS from 1997 through 2009. Rate ratios (RR) of all-cause mortality, cardiovascular death, and a composite of myocardial infarction, stroke, or cardiovascular death were compared between user groups using time-dependent multivariable Poisson regression models. The most common combination, glimepiride+metformin, was used as reference.. A total of 56,827 patients were included, 56% male, the mean age was 61 ± 12.5 years, and median duration of prior monotherapy was 2.2 (inter quartile range 0.5-4.5) years. Crude incidence rates of mortality for combinations of ISs with metformin were; 15.4 (repaglinide), 28.1 (glipizide), 23.7 (glibenclamide), 21.1 (gliclazide), 20.7 (glimepiride), 27.7 (tolbutamide) deaths per 1000 person years. In adjusted analysis, the associated mortality risk was similar for users of gliclazide+metformin (RR=1.01 [0.88-1.15]), repaglinide+metformin (RR=0.81 [0.62-1.05]), glibenclamide+metformin (RR=0.98 [0.87-1.10]), and tolbutamide+metformin (RR=1.04 [0.85-1.28]). Users of glipizide+metformin was associated with increased all-cause mortality (RR=1.16 [1.02-1.32], p=0.02), cardiovascular death (RR=1.21 [1.01-1.46], p=0.04), and the combined endpoint (RR=1.20 [1.06-1.36, p=0.005).. Most ISs in combination with metformin were associated with similar mortality and cardiovascular risk. Whether glipizide is associated with increased risk compared with other ISs when used in combinations with metformin warrants further study.

Topics: Aged; Carbamates; Cardiovascular Diseases; Denmark; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Morbidity; Myocardial Infarction; Piperidines; Registries; Retrospective Studies; Risk Factors; Stroke; Sulfonylurea Compounds; Tolbutamide

To evaluate the association between insulin secretagogues and adverse cardiovascular sequelae in type 2 diabetes patients hospitalized for ischemic heart disease (IHD).. Administrative health records from Alberta, Canada between 1998 and 2010 were used to identify 2,254 gliclazide, 3,289 glyburide and 740 repaglinide users prior to an IHD-related hospitalization. Multivariable Cox regression models were used to compare the 30-day risk of a composite outcome of all-cause mortality or new onset of atrial fibrillation, stroke, heart failure or myocardial infarction according to insulin secretagogue use.. Mean (SD) age was 76.1 (6.9) years, and 60.7% were men. The composite outcome occurred in 322 (30.2%) gliclazide users, 455 (28.1%) glyburide users and 81 (23.4%) repaglinide users within 30 days of IHD hospitalization. There were no differences in risk for glyburide use (adjusted hazard ratio [aHR] 0.91; 95% confidence interval [CI] 0.78-1.05) or repaglinide use (aHR 0.80; 95% CI 0.63-1.03) compared to gliclazide. Similar results were observed in analyses for each element of the composite outcome.. In older patients with type 2 diabetes hospitalized for IHD, prior use of gliclazide, glyburide, or repaglinide appears to be associated with a similar risk of adverse cardiovascular sequelae.

Topics: Aged; Aged, 80 and over; Alberta; Blue Cross Blue Shield Insurance Plans; Carbamates; Cardiovascular Diseases; Cohort Studies; Databases, Factual; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Female; Gliclazide; Glyburide; Hospitalization; Humans; Hypoglycemic Agents; Male; Myocardial Ischemia; Piperidines; Proportional Hazards Models; Retrospective Studies; Risk; Universal Health Insurance

Topics: Adamantane; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Male; Myocardial Infarction; Piperidines; Uracil

In 2008, the US FDA required all new glucose-lowering therapies to show cardiovascular safety, and this applies to the dipeptidyl peptidase-4 inhibitors ('gliptins').. The cardiovascular safety trials of saxagliptin and alogliptin have recently been published and are the subject of this evaluation.. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus - Thrombolysis in Myocardial Infarction 53 trial and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care were both multicentre, randomised, double-blind, placebo-controlled, Phase IV clinical trials. These trials showed that saxagliptin and alogliptin did not increase the primary end point, which was a composite of cardiovascular outcomes that did not include hospitalisations for heart failure. However, saxagliptin significantly increased hospitalisation for heart failure, which was a component of the secondary end point. The effect of alogliptin on hospitalisations for heart failure has not been reported. Neither agent improved cardiovascular outcomes. As there is no published evidence of improved outcomes with gliptins, it is unclear to us why these agents are so widely available for use. We suggest that the use of gliptins be restricted to Phase IV clinical trials until such time as cardiovascular safety and benefits/superiority are clearly established.

Topics: Adamantane; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Male; Myocardial Infarction; Piperidines; Uracil

Topics: Adamantane; Blood Glucose; Cardiovascular Diseases; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Piperidines; Uracil

Topics: Adamantane; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Male; Myocardial Infarction; Piperidines; Uracil

Methoxphenidine is a novel dissociative designer drug of the diarylethylamine class which shares structural features with phencyclidine (PCP), and is not at present subject to restrictive regulations. There is very limited information about the acute toxicity profile of methoxphenidine and the only sources are anonymous internet sites and a 1989 patent of the Searle Company. We report a case of analytically confirmed oral methoxphenidine toxicity.. A 53-year-old man was found on the street in a somnolent and confusional state. Observed signs and symptoms such as tachycardia (112 bpm), hypertension (220/125 mmHg), echolalia, confusion, agitation, opisthotonus, nystagmus and amnesia were consistent with phencyclidine-induced adverse effects. Temperature (99.1°F (37.3°C)) and peripheral oxygen saturation while breathing room air (99%) were normal. Laboratory analysis revealed an increase of creatine kinase (max 865 U/L), alanine aminotransferase (72 U/L) and gamma-glutamyl transpeptidase (123 U/L). Methoxphenidine was identified by a liquid chromatography tandem mass spectrometry toxicological screening method using turbulent flow online extraction in plasma and urine samples collected on admission. The clinical course was favourable and signs and symptoms resolved with symptomatic treatment.. Based on this case report and users' web reports, and compatible with the chemical structure, methoxphenidine produces effects similar to those of the arylcyclohexylamines, as PCP.

Topics: Biomarkers; Biotransformation; Cardiovascular Diseases; Cardiovascular System; Chromatography, Liquid; Confusion; Humans; Illicit Drugs; Male; Middle Aged; Nervous System; Neurotoxicity Syndromes; Piperidines; Psychotropic Drugs; Substance-Related Disorders; Tandem Mass Spectrometry; Treatment Outcome

Topics: Adamantane; Cardiovascular Diseases; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Piperidines; Randomized Controlled Trials as Topic; Treatment Failure; Uracil

Topics: Adamantane; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Male; Myocardial Infarction; Piperidines; Uracil

Topics: Adamantane; Angina, Unstable; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Male; Myocardial Infarction; Piperidines; Uracil

Topics: Adamantane; Blood Glucose; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptides; Drug Approval; Humans; Hypoglycemic Agents; Piperidines; Uracil

Topics: Adamantane; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Drug Approval; Humans; Hypoglycemic Agents; Piperidines; Treatment Outcome; Uracil

We investigated both the effects of the endothelin type B (ETB) receptor antagonist, BQ-788, on amitriptyline-induced cardiotoxicity and the role of ETB receptors on amitriptyline-induced cardiovascular depression.. Male Wistar rats were anaesthetized with urethane/chloralose. Mean arterial pressure (MAP), heart rate (HR) and QRS duration were recorded. Toxicity was induced by amitriptyline infusion (0.94 mg/kg per min) until the 50% inhibition of MAP. In the first protocol, 5% dextrose or BQ-788 bolus was administered to control or experimental group animals, respectively. In the second protocol, after incubation with BQ-788 or 5% dextrose, amitriptyline was infused.. Amitriptyline caused a significant decrease in MAP, prolonged QRS duration and decreased HR for both the groups. BQ-788 administration improved MAP (5, 10 and 15 min), shortened the prolonged QRS (5 and 10 minutes) and increased HR (5, 10 and 15 min) compared with dextrose group. While all the amitriptyline-infused rats survived in BQ-788 group, all the amitriptyline-infused rats died within 20 min in dextrose group. In the second protocol, BQ-788 incubation did not cause any statistically significant change in amitriptyline-induced cardiovascular depression.. BQ-788 may have beneficial effects in amitriptyline-induced cardiovascular changes via a physiologic antagonism. ETB receptor antagonists may be the promising antidotes for the cardiovascular toxicity with hypotension and bradycardia.

Topics: Amitriptyline; Animals; Antidotes; Arterial Pressure; Cardiovascular Diseases; Endothelin B Receptor Antagonists; Heart Rate; Male; Oligopeptides; Piperidines; Rats; Rats, Wistar

Donepezil is a commonly used drug in older people that due to its procholinergic effects can provoke bradycardia and neurocardiogenic syncope. Donepezil is metabolized by the cytochrome P450 isozyme 3A4 (CYP3A4). Clarithromycin is a potent inhibitor of CYP3A4, and patients taking both of these drugs may be at increased risk of cardiac adverse events.. The aim of this study was to evaluate the association between recent use of clarithromycin and adverse cardiovascular events in elderly patients receiving donepezil.. A population-based, nested case-control study using provincial healthcare databases was conducted. The base cohort was made up of persons 66 years of age or older who were prescribed donepezil and also were prescribed clarithromycin, erythromycin, azithromycin, cefuroxime, moxifloxacin or levofloxacin. Cases were those members of the base cohort hospitalized for bradycardia, syncope or complete atrioventricular block. For each case patient, five controls were matched according to age, sex and residence (community or long-term care).. Between July 2002 and March 2010, 17,712 patients continuously receiving donepezil were prescribed one of the antibacterials. In 1400 person-years of follow-up, 59 cases were identified. As compared with azithromycin, there was no statistically significant association between use of clarithromycin in donepezil users and subsequent adverse cardiovascular events (odds ratio 0.67; 95% CI 0.28, 1.63). There was no significant risk associated with exposure to either cefuroxime or respiratory quinolones.. The use of clarithromycin in elderly donepezil users did not significantly increase the risk of adverse cardiovascular outcomes. However, our study cannot rule out a possible small increase in risk. Although antibacterials can be beneficial, care should be taken in selecting antibacterials for use in older people receiving donepezil.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Atrioventricular Block; Bradycardia; Cardiovascular Diseases; Case-Control Studies; Cholinesterase Inhibitors; Clarithromycin; Cohort Studies; Cytochrome P-450 CYP3A Inhibitors; Donepezil; Drug Interactions; Drug Prescriptions; Enzyme Inhibitors; Female; Humans; Indans; Macrolides; Male; Ontario; Piperidines; Syncope

We examined the impact of FDA's 2008 guidelines for addressing cardiovascular risks of new therapies for type 2 diabetes on clinical trials. We focused on the new class of incretin-modulating drugs, exenatide, sitagliptin, saxagliptin and liraglutide, which were approved in 2005-2010. We contrasted these findings with those from 2 different groups: 1. diabetes drugs approved in the same timeframe but with a non-incretin mechanism of action (colesevelam HCl and bromocriptine mesylate) and 2. diabetes drugs with NDAs delayed and not yet approved within the same time frame (vildagliptin, alogliptin, insulin inhalation powder, and exenatide long acting release). The new guidelines have had an important impact on clinical development. Review time has increased over 2-fold. The increase is seen even if a drug with the same mechanism of action has been already approved. Whereas exenatide (approved in 2005) required 10 months of regulatory review, the approval of liraglutide in 2010 required more than twice as long (21 months). In contrast, the marketing authorization of liraglutide in the EU required 14 months. Additionally, the manufacturer of vildagliptin announced in June 2008, 30 months after the NDA was filed, that a re-submission to meet FDA's demands was not planned. The drug however received marketing authorization in the EU in 2007. The number of randomized patients and patient-years in NDAs increased more than 2.5 and 4 fold, respectively since the guidelines. The significant cost increases and negative publicity because of rare adverse reactions will adversely affect future clinical research in type 2 diabetes and not address its burgeoning health care impact.

Topics: Adamantane; Allylamine; Cardiovascular Diseases; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Investigational New Drug Application; Liraglutide; Nitriles; Peptides; Piperidines; Practice Guidelines as Topic; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Time Factors; Triazoles; United States; United States Food and Drug Administration; Uracil; Venoms; Vildagliptin

Topics: Alzheimer Disease; Cardiovascular Diseases; Cholinesterase Inhibitors; Donepezil; Galantamine; Humans; Indans; Multivariate Analysis; Phenylcarbamates; Piperidines; Retrospective Studies; Rivastigmine

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

Topics: Anticholesteremic Agents; Cardiovascular Diseases; Farnesyl-Diphosphate Farnesyltransferase; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Oxazepines; Piperidines

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

Endothelin-1 is elevated in women with polycystic ovary syndrome (PCOS), and may play a role in the endothelial dysfunction associated with PCOS. Endothelin-1 binds two receptor subtypes, endothelin A (ET-A) and endothelin B (ET-B). We hypothesized that ET-A mediates vasoconstriction in the cutaneous microvasculature in women with and without PCOS. We further hypothesized that while the ET-B receptors mediate vasodilatation in both groups of women, this response would be blunted in women with PCOS. During local skin warming, we used laser Doppler flowmetry combined with intradermal microdialysis to measure skin blood flow (SkBF) during graded ET-A (BQ-123) and ET-B (BQ-788) antagonist infusions in women with (n = 6) and without (n = 8) PCOS. In both groups, SkBF increased during local heating. The percentage of maximal SkBF-[BQ123] sigmoidal dose-response curve indicated a vasodilatory response as the concentration of the antagonist increased (Hill slope 4.96 ± 4.77, 4.74 ± 5.01; logED(50) 2.53 ± 0.09, 2.49 ± 0.09 nm, for PCOS and Control, respectively). In contrast, the % max SkBF-[BQ788] curve indicated a vasoconstrictive response (Hill slope -4.69 ± 3.85, -4.03 ± 3.85; logED(50), 2.56 ± 0.09, 2.41 ± 0.12 nm, in PCOS and Control). Moreover, the SkBF-[BQ788] curve shifted to the right in women with PCOS, suggesting attenuated ET-B receptor mediated vasodilatation during local skin warming compared to Controls. Thus, the endothelium located ET-B receptors function similarly in women with and without PCOS, although with blunted responsiveness in women with PCOS. Our studies suggest that the lower ET-B receptor responsiveness associated with PCOS may reflect lower endothelial-mediated vasodilatation independent of generally lower vascular reactivity.

Topics: Adult; Cardiovascular Diseases; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelium, Vascular; Female; Humans; Microcirculation; Microvessels; Oligopeptides; Peptides, Cyclic; Piperidines; Polycystic Ovary Syndrome; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow; Skin; Vasoconstriction; Vasodilation; Young Adult

Adenosine-induced transient flow arrest has been used to facilitate clip ligation of intracranial aneurysms. However, the starting dose that is most likely to produce an adequate duration of profound hypotension remains unclear. We reviewed our experience to determine the dose-response relationship and apparent perioperative safety profile of adenosine in intracranial aneurysm patients.. This case series describes 24 aneurysm clip ligation procedures performed under an anesthetic consisting of remifentanil, low-dose volatile anesthetic, and propofol in which adenosine was used. The report focuses on the doses administered; duration of systolic blood pressure <60 mm Hg (SBP(<60 mm Hg)); and any cardiovascular, neurologic, or pulmonary complications observed in the perioperative period.. A median dose of 0.34 mg/kg ideal body weight (range: 0.29-0.44 mg/kg) resulted in a SBP(<60 mm Hg) for a median of 57 seconds (range: 26-105 seconds). There was a linear relationship between the log-transformed dose of adenosine and the duration of a SBP(<60 mm Hg) (R(2) = 0.38). Two patients developed transient, hemodynamically stable atrial fibrillation, 2 had postoperative troponin levels >0.03 ng/mL without any evidence of cardiac dysfunction, and 3 had postoperative neurologic changes.. For intracranial aneurysms in which temporary occlusion is impractical or difficult, adenosine is capable of providing brief periods of profound systemic hypotension with low perioperative morbidity. On the basis of these data, a dose of 0.3 to 0.4 mg/kg ideal body weight may be the recommended starting dose to achieve approximately 45 seconds of profound systemic hypotension during a remifentanil/low-dose volatile anesthetic with propofol induced burst suppression.

Topics: Adenosine; Adult; Aged; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Atrial Fibrillation; Cardiovascular Diseases; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Female; Humans; Intracranial Aneurysm; Ligation; Male; Middle Aged; Nervous System Diseases; Neurosurgical Procedures; Piperidines; Postoperative Complications; Propofol; Remifentanil; Vasodilator Agents

The acetylcholinesterase inhibitor donepezil hydrochloride improves cognitive function in patients with Alzheimer's disease and vascular dementia. Given acetylcholine's important actions on the heart, we undertook a retrospective cohort investigation to assess whether donepezil usage affects cardiovascular mortality. In patients treated with donepezil, hazard ratios for total and cardiovascular mortality were 0.68 (P = 0.045, 95% confidence interval 0.46-0.99) and 0.54 (P = 0.042, 95% confidence interval 0.30-0.98), respectively. The apparent survival benefit in donepezil-treated patients should not be overinterpreted. Prospective clinical trials are warranted.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cardiovascular Diseases; Cholinesterase Inhibitors; Cohort Studies; Dementia, Vascular; Donepezil; Female; Follow-Up Studies; Humans; Indans; Male; Nootropic Agents; Piperidines; Proportional Hazards Models; Retrospective Studies

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

Donepezil, a reversible acetylcholinesterase inhibitor, improves cognitive function of Alzheimer's disease. Stimulation of cholinergic system was reported to improve long-term survival of rats with chronic heart failure and to attenuate inflammatory response in mice with lipopolysaccharide-induced sepsis. We sought to determine whether the pharmacological stimulation of cholinergic system by donepezil reduces atherogenesis in apolipoprotein (Apo) E-knockout (KO) mice.. Male ApoE-KO mice (10-week-old) were fed a high-fat diet and received infusion of angiotensin (Ang) II (490 ng/kg/day). Donepezil or physostigmine was administered for 4 weeks. Oral administration of donepezil (5 mg/kg/day) or infusion of physostigmine (2 mg/kg/day) significantly attenuated atherogenesis (Oil Red O-positive area) without significant changes in heart rate, blood pressure and total cholesterol levels. Administration of donepezil suppressed expression of monocyte chemoattractant protein-1 and tumor necrosis factor-α, NADPH oxidase activity and production of reactive oxygen species in the aorta.. The present study revealed novel anti-oxidative and anti-atherosclerotic effects of pharmacological stimulation of cholinergic system by donepezil. Donepezil may be used as a novel therapeutics for the atherosclerotic cardiovascular diseases.

Topics: Alzheimer Disease; Animals; Apolipoproteins E; Atherosclerosis; Cardiovascular Diseases; Cholinesterase Inhibitors; Cytokines; Donepezil; Indans; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Knockout; Oxidative Stress; Piperidines; Sepsis

Topics: Anti-Obesity Agents; Cardiovascular Agents; Cardiovascular Diseases; Depressive Disorder; Drug Approval; Europe; Humans; Multicenter Studies as Topic; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Suicide; Treatment Failure

Topics: Anti-Obesity Agents; Cardiovascular Agents; Cardiovascular Diseases; Cytochrome P-450 CYP2D6; Depressive Disorder; Europe; Humans; Multicenter Studies as Topic; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Research Design; Rimonabant; Suicide; Treatment Failure

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

Air pollutant levels positively correlate with increases in both acute and chronic cardiovascular disease. The pollutant diesel exhaust (DE) increases endothelin (ET) levels, suggesting that this peptide may contribute to DE-induced cardiovascular disease. We hypothesized that acute exposure to DE also enhances ET-1-mediated coronary artery constrictor sensitivity. Constrictor responses to KCl, U-46619, and ET-1 were recorded by videomicroscopy in pressurized intraseptal coronary arteries from rats exposed for 5 h to DE (300 microg/m(3)) or filtered air (Air). ET-1 constriction was augmented in arteries from DE-exposed rats. Nitric oxide synthase (NOS) inhibition [N(omega)-nitro-L-arginine (L-NNA), 100 microM] and endothelium inactivation augmented ET-1 responses in arteries from Air but not DE rats so that after either treatment responses were not different between groups. DE exposure did not affect KCl and U-46619 constrictor responses, while NOS inhibition augmented KCl constriction equally in both groups. Thus basal NOS activity does not appear to be affected by DE exposure. The endothelin type B (ET(B)) receptor antagonist BQ-788 (10 microM) inhibited ET-1 constriction in DE but not Air arteries, and constriction in the presence of the antagonist was not different between groups. Cytokine levels were not different in plasma from DE and AIR rats, suggesting that acute exposure to DE does not cause an immediate inflammatory response. In summary, a 5-h DE exposure selectively increases constrictor sensitivity to ET-1. This augmentation is endothelium-, NOS-, and ET(B) receptor dependent. These data suggest that DE exposure diminishes ET(B) receptor activation of endothelial NOS and augments ET(B)-dependent vasoconstriction. This augmented coronary vasoreactivity to ET-1 after DE, coupled with previous reports that DE induces production of ET-1, suggests that ET-1 may contribute to the increased incidence of cardiac events during acute increases in air pollution levels.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Air Pollutants; Animals; Cardiovascular Diseases; Coronary Vessels; Cytokines; Dose-Response Relationship, Drug; Endothelin-1; Enzyme Inhibitors; Inflammation Mediators; Inhalation Exposure; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oligopeptides; Particulate Matter; Piperidines; Potassium Chloride; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Time Factors; Vasoconstriction; Vasoconstrictor Agents; Vehicle Emissions

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

Despite meaningful progress in the identification of risk factors and the development of highly effective prevention tools, the residual risk of cardiovascular events remains high (about 60-70% in the major outcome trials dealing with statins). Awareness of this problem can properly orient the search for new effective and efficient preventive strategies.

Topics: Atherosclerosis; Blood Pressure; Body Weight; Cannabinoid Receptor Antagonists; Cannabinoids; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Follow-Up Studies; Humans; Hypolipidemic Agents; Kaplan-Meier Estimate; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Risk Factors; Smoking Cessation; Thiazolidines; Time Factors

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

Topics: Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Overweight; Piperidines; Pyrazoles; Rimonabant

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

The contribution of endothelin-1 (ET-1) to vascular hyper-reactivity associated with chronic ethanol intake, a major risk factor in several cardiovascular diseases, remains to be investigated.. The biphasic haemodynamic responses to ET-1 (0.01-0.1 nmol kg(-1), i.v.) or to the selective ETB agonist, IRL1620 (0.001-1.0 nmol kg(-1), i.v.), with or without ETA or ETB antagonists (BQ123 (c(DTrp-Dasp-Pro-Dval-Leu)) at 1 and 2.5 mg kg(-1) and BQ788 (N-cis-2,6-dimethyl-piperidinocarbonyl-L-gamma-methylleucyl1-D-1methoxycarbonyltryptophanyl-D-norleucine) at 0.25 mg kg(-1), respectively) were tested in anaesthetized rats, after 2 weeks' chronic ethanol treatment. Hepatic parameters and ET receptor protein levels were also determined.. The initial hypotensive responses to ET-1 or IRL1620 were unaffected by chronic ethanol intake, whereas the subsequent pressor effects induced by ET-1, but not by IRL1620, were potentiated. BQ123 at 2.5 but not 1 mg kg(-1) reduced the pressor responses to ET-1 in ethanol-treated rats. Conversely, BQ788 (0.25 mg kg(-1)) potentiated ET-1-induced increases in mean arterial blood pressure in control as well as in ethanol-treated rats. Interestingly, in the latter group, increases in heart rate, induced by ET-1 at a dose of 0.025 mg kg(-1) were enhanced following ETB receptor blockade. Finally, we observed higher levels of ETA receptor in the heart and mesenteric artery and a reduction of ETB receptor protein levels in the aorta and kidney from rats chronically treated with ethanol.. Increased vascular reactivity to ET-1 and altered protein levels of ETA and ETB receptors could play a role in the pathogenesis of cardiovascular complications associated with chronic ethanol consumption.

Topics: Acetylcholine; Alcohol Drinking; Animals; Aorta; Blood Pressure; Cardiovascular Diseases; Endothelin-1; Endothelins; Ethanol; Heart Rate; Kidney; Liver; Male; Mesenteric Arteries; Myocardium; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Phenylephrine; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Self Administration; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

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

Cardiovascular disorders are the most frequently reported adverse effects of drugs used to treat Alzheimer's disease. They are potentially fatal.

Topics: Alzheimer Disease; Cardiovascular Diseases; Cholinesterase Inhibitors; France; Galantamine; Humans; Indans; Memantine; Phenylcarbamates; Piperidines

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

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

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: 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

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: 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

Blocking the endocannabinoid system is an option that substantially reduces cardiovascular risk beyond reducing body weight. Endocannabinoids and their receptors are expressed in the central nervous system as well as in the peripheral organs and regulate the central circuits for food uptake and peripheral metabolic circuits. Within the context of food uptake the cannabinoid receptors 1 (CB (1)-receptor) is of crucial importance. Its stimulation with Delta (9)-tetrahydrocannabiol (Delta (9)-THC) or its blockade with rimonabant are clinically relevant therapeutic means to maintain body weight. Rimonabant is the first of a new class of drugs, that interferes with the endocannabinoid system by blocking the CB (1)-Receptor. In recent clinical studies a substantial reduction of body weight and waist circumference was associated with an improvement of the cardiovascular risk profile, which was marked by increased HDL-cholesterol, serum triglycerides and improved insulin sensivity.

Topics: Cannabinoid Receptor Modulators; Cardiovascular Diseases; Clinical Trials as Topic; Endocannabinoids; Humans; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Risk Factors; Treatment Outcome; Weight Loss

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

Cerebrovascular disease (CVD) and ischemic brain injury secondary to cardiovascular disease are common causes of dementia and cognitive decline in the elderly. CVD also contributes to cognitive loss in Alzheimer disease (AD).. Progress in understanding vascular cognitive impairment (VCI) and vascular dementia (VaD) has resulted in promising symptomatic and preventive treatments. Cholinergic deficits in VaD due to ischemia of basal forebrain nuclei and cholinergic pathways can be treated with cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil and galantamine in patients with VaD, as well as in patients with AD plus CVD, have demonstrated improvement in cognition, behavior, and activities of daily living. The N-methyl-D-aspartate receptor antagonist memantine stabilized progression of VaD compared with placebo. Primary and secondary stroke prevention, in particular with control of hypertension and hyperlipidemia, can decrease VaD incidence.. From a public health viewpoint, recognition of VCI before the development of dementia and correction of vascular burden on the brain may lead to a global decrease of incident dementia.

Topics: Carbamates; Cardiovascular Diseases; Cerebrovascular Disorders; Cholinesterase Inhibitors; Cognition Disorders; Controlled Clinical Trials as Topic; Dementia, Vascular; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Risk Factors; Rivastigmine; Stroke; Terminology as Topic

The aim of this study was to assess the cardiovascular effects of a selective phosphodiesterase 5 inhibitor ER-118585, 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinecarbonitrile monohydrochloride. The present results indicated that 1) ER-118585 significantly inhibited the human ether-a-go-go related gene (HERG) tail current at 10 nM and above with an IC(50) value of 40.7 nM in human embryonic kidney 293 cells transfected with HERG cDNA; 2) ER-118585 at 100 and 1000 nM significantly increased the action potential duration (APD) at 50% and 90% repolarization in isolated papillary muscles of guinea pig; and 3) intravenous infusion of ER-118585 at 10 microg/kg/min significantly prolonged the QT interval by 10.5+/-1.6% from 281+/-2 ms to 311+/-6 ms in six anesthetized dogs subjected to atrial pacing. In consideration of both the plasma concentration of ER-118585 (984+/-78 nM, n=3) and its protein binding fraction (99.0+/-0.1%, n=5), the free plasma concentration was estimated at 9.8+/-0.8 nM, which is consistent with the minimum concentration of HERG current inhibition. In conclusion, these evaluation methods demonstrated that ER-118585 could prolong the QT interval via APD prolongation, attributable to the inhibition of the HERG potassium current.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Action Potentials; Animals; Cardiac Pacing, Artificial; Cardiovascular Diseases; Cell Line; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Electrocardiography; Electrophysiology; Guinea Pigs; Humans; Infusions, Intravenous; Kidney; Long QT Syndrome; Male; Papillary Muscles; Patch-Clamp Techniques; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Phthalazines; Piperidines; Potassium Channels, Voltage-Gated; Protein Binding; Pyridines; Spiro Compounds; Transfection; Ventricular Function; Ventricular Premature Complexes

Cannabinoids, including the endogenous ligand anandamide, elicit pronounced hypotension and bradycardia through the activation of CB1 cannabinoid receptors. A second endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), has been proposed to be the natural ligand of CB1 receptors. In the present study, we examined the effects of 2-AG on mean arterial pressure and heart rate in anesthetized mice and assessed the role of CB1 receptors through the use of selective cannabinoid receptor antagonists and CB1 receptor knockout (CB1(-/-)) mice. In control ICR mice, intravenous injections of 2-AG or its isomer 1-AG elicit dose-dependent hypotension and moderate tachycardia that are unaffected by the CB1 receptor antagonist SR141716A. The same dose of SR141716A (6 nmol/g IV) completely blocks the hypotensive effect and attenuates the bradycardic effect of anandamide. 2-AG elicits a similar hypotensive effect, resistant to blockade by either SR141716A or the CB2 antagonist SR144528, in both CB1(-/-) mice and their homozygous (CB1(+/+)) control littermates. In ICR mice, arachidonic acid (AA, 15 nmol/g IV) elicits hypotension and tachycardia, and indomethacin (14 nmol/g IV) inhibits the hypotensive effect of both AA and 2-AG. Synthetic 2-AG incubated with mouse blood is rapidly (<2 minutes) and completely degraded with the parallel appearance of AA, whereas anandamide is stable under the same conditions. A metabolically stable ether analogue of 2-AG causes prolonged hypotension and bradycardia in ICR mice, and both effects are completely blocked by SR141716A, whereas the same dose of 2-AG-ether does not influence blood pressure and heart rate in CB1(-/-) mice. These findings are interpreted to indicate that exogenous 2-AG is rapidly degraded in mouse blood, probably by a lipase, which masks its ability to interact with CB1 receptors. Although the observed cardiovascular effects of 2-AG probably are produced by an arachidonate metabolite through a noncannabinoid mechanism, the CB1 receptor-mediated cardiovascular effects of a stable analogue of 2-AG leaves open the possibility that endogenous 2-AG may elicit cardiovascular effects through CB1 receptors.

Topics: Anesthesia; Animals; Arachidonic Acids; Blood Pressure; Camphanes; Cardiovascular Agents; Cardiovascular Diseases; Dose-Response Relationship, Drug; Endocannabinoids; Female; Glycerides; Heart Rate; Hypotension; Indomethacin; Ligands; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Tachycardia

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

Topics: Angiotensin-Converting Enzyme Inhibitors; Aspirin; Cardiovascular Diseases; Humans; Multicenter Studies as Topic; Myocardial Ischemia; Oximes; Piperidines; Platelet Aggregation Inhibitors; Ramipril; Randomized Controlled Trials as Topic

Topics: Aged; Cardiovascular Diseases; Estrogen Antagonists; Female; Humans; Middle Aged; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Raloxifene Hydrochloride; Tamoxifen

Topics: Cardiovascular Diseases; Estrogen Antagonists; Estrogen Replacement Therapy; Estrogens; Humans; Piperidines; Raloxifene Hydrochloride; Risk Factors; Tamoxifen

In a 38-year-old male patient suffering from a severe postzosteric trigeminal neuralgia, intravenous application of 10 mg biperiden lactate led to a long-lasting paradoxical reaction characterized by considerable bradycardia, dysarthria, and dysphagia. The heart rate was back to normal within 12 hours upon administration of orciprenaline under cardiac monitoring in an intensive care unit. Bradycardia induced by biperiden is attributed to the speed of injection and to a dose-related dual effect of atropine-like drugs on muscarine receptors.

Topics: Adult; Biperiden; Cardiovascular Diseases; Heart Rate; Humans; Male; Neuralgia; Piperidines

Topics: Cardiovascular Diseases; Drug Therapy, Combination; Humans; Hypertension; Ketanserin; Piperidines; Serotonin

We compared side effects with flecainide trough levels and ECG intervals among 43 patients who received flecainide for up to 34 months. Flecainide plasma levels were higher when associated with cardiovascular side effects (mean 1063 ng/ml; range 296 to 2050 ng/ml) than when no side effects occurred (mean 609 ng/ml; range 89 to 1508 ng/ml; P less than 0.001). The PR interval (P less than 0.001), QRS interval (P less than 0.001), and the rate-corrected QT interval (P less than 0.001) were greater at the time of cardiovascular side effects, but the rate-corrected JT interval was not. The therapeutic-toxic window for flecainide plasma level was 381 ng/ml (at least 50% probability of efficacy) to 710 ng/ml (less than 10% probability of cardiovascular side effects). The risk of cardiovascular side effects increases at higher plasma levels of flecainide and is associated with greater increases in the PR and QRS intervals from baseline than are routinely observed during flecainide dosing.

Topics: Aged; Arrhythmias, Cardiac; Cardiovascular Diseases; Dose-Response Relationship, Drug; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Piperidines

The oral form of pirmenol has not been administered to man. Pirmenol was given by mouth to eight patients with chronic, stable premature ventricular beats (PVBs) to determine effective dose and kinetics. The patients were evaluated with a dose-ranging protocol following by a double-blind, crossover, placebo-controlled study of doses that were effective during dose ranging. Oral doses of 150 to 250 mg induced at least 90% suppression of PVBs 18 of the 19 times they were administered during both protocols. During the double blind experiment, a single oral dose of pirmenol suppressed 95 +/- 8% PVBs/hr (mean +/- SD) for 3 consecutive hr, while placebo suppressed 4 +/- 42% PVBs/hr (P less than 0.01). a 90% or greater reduction in PVBs persisted for a median of 6 hr (range 1 to 8 hr). The range of plasma pirmenol concentrations associated with an at last 90% reduction in PVBs was 0.7 to 2.0 micrograms/ml. Median half-life (t1/2) was 9.3 hr (range 6.0 to 12.4) with 86.6 +/- 2.4% protein binding and 82.6 +/- 23.6% bioavailability. At peak drug level there was lengthening of the QTc interval (0.036 sec, P less than 0.05), but no change in heart rate, blood pressure, PR interval or QRS duration, or symptoms. In this single-dose study, pirmenol effectively reduced PVBs, has a relatively long t1/2, and was minimally toxic.

Topics: Administration, Oral; Blood Pressure; Cardiovascular Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Heart Rate; Humans; Kinetics; Male; Middle Aged; Piperidines; Time Factors

Topics: Anesthetics, Local; Anilides; Cardiovascular Diseases; Humans; Neuritis; Pain; Piperidines; Spondylitis; Surgical Procedures, Operative; Xylenes

Topics: Adult; Aged; Anxiety Disorders; Biliary Tract Diseases; Cardiovascular Diseases; Depression; Dysautonomia, Familial; Female; Gastrointestinal Diseases; Humans; Hypertension; Lung Diseases; Male; Middle Aged; Neoplasms; Piperidines; Tranquilizing Agents