Pharmacokinetics and safety of erenumab in pediatric patients with migraine: A phase I, randomized, open-label, multiple-dose study.

Erenumab, a fully human monoclonal antibody targeting the calcitonin gene-related peptide receptor, is efficacious and safe for prevention of attacks of migraine in adults. This phase I, randomized, open-label, multiple-dose study evaluated the safety, tolerability, and pharmacokinetics (PK) of erenumab in children and adolescents with migraine. The initial treatment phase lasted 12 weeks, followed by an optional 40-week extension phase for adolescents.

Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1-pyrazol-1-yl)methyl)phosphonate (BMS-820132).

Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators.

Risk of hypertension in erenumab-treated patients with migraine: Analyses of clinical trial and postmarketing data.

Objective: To assess the risk of hypertension in patients with migraine who received erenumab in clinical trials and in the postmarketing setting.

Background: Erenumab is a monoclonal antibody for migraine prevention that targets the calcitonin gene-related peptide (CGRP) receptor. Hypertension is a theoretical risk for inhibitors of the CGRP pathway.

Estimation of Long-Term Efficacy of Denosumab Treatment in Postmenopausal Women With Osteoporosis: A FRAX- and Virtual Twin-Based Post Hoc Analysis From the FREEDOM and FREEDOM Extension Trials.

The 3-year placebo-controlled FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial established the antifracture efficacy of denosumab in postmenopausal women with osteoporosis. The 7-year open-label extension demonstrated that denosumab treatment for up to 10 years was associated with low rates of adverse events and low fracture incidence. The extension lacked a long-term control group, thus limiting the ability to fully evaluate long-term efficacy.

Favorable skeletal benefit/risk of long-term denosumab therapy: A virtual-twin analysis of fractures prevented relative to skeletal safety events observed.

Antiresorptive therapies reduce fracture risk; however, long-term bone turnover inhibition may raise concerns about rare, but serious, skeletal adverse events-atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). Denosumab, a fully human monoclonal antibody against RANKL, has demonstrated sustained low vertebral and nonvertebral fracture rates with low skeletal adverse event rates in the 3-year FREEDOM trial and its 7-year Extension (in which all subjects received open-label denosumab). In this analysis, we aimed to estimate fractures prevented relative to skeletal adverse events observed with 10 years of denosumab therapy.

Denosumab Versus Risedronate in Glucocorticoid-Induced Osteoporosis: Final Results of a Twenty-Four-Month Randomized, Double-Blind, Double-Dummy Trial.

Objective: Clinical trial results have shown that, in glucocorticoid-treated patients, treatment with denosumab 60 mg subcutaneously once every 6 months (Q6M) increased spine and hip bone mineral density (BMD) at month 12 significantly more than treatment with risedronate 5 mg orally once daily (QD). The present analysis was performed to compare efficacy and characterize safety through month 24.

Methods: This phase III study enrolled men and women ≥18 years old who had received ≥7.

Glucocorticoid Exposure and Fracture Risk in a Cohort of US Patients With Selected Conditions.

The purpose of this work was to evaluate systemic glucocorticoid exposure and fracture among patients with newly-diagnosed inflammatory and immune-modulated conditions. Using administrative data, inception cohorts of rheumatoid arthritis (RA), asthma/chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), multiple sclerosis (MS), lupus, and sarcoidosis patients age 18 to 64 years with benefits coverage ≥12 months before diagnosis (January 1, 2005 to December 31, 2012) were followed to clinical fracture, cancer diagnosis, or December 31, 2012. Glucocorticoid users were new to therapy.

Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy, non-inferiority study.

Background: Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis and is associated with an estimated annual fracture rate of 5%. We aimed to assess the efficacy and safety of denosumab compared with risedronate in glucocorticoid-induced osteoporosis.

Methods: We did a 24-month, double-blind, active-controlled, double-dummy, non-inferiority study at 79 centres in Europe, Latin America, Asia, and North America.

Effect of denosumab on fasting glucose in women with diabetes or prediabetes from the FREEDOM trial.

Background: RANKL is a key regulator of bone resorption that may also modulate glucose metabolism. Denosumab (DMAb) is a fully human monoclonal antibody that binds RANKL and was associated with fracture risk reduction in the FREEDOM trial. We hypothesized that DMAb treatment decreased fasting serum glucose (FSG) relative to placebo in women with diabetes or prediabetes enrolled in FREEDOM trial.

Occurrence of Serious Infection in Patients with Rheumatoid Arthritis Treated with Biologics and Denosumab Observed in a Clinical Setting.

Objective: Previous studies combining biologic disease-modifying antirheumatic drugs (bDMARD) to treat rheumatoid arthritis (RA) have shown an increased risk of infection. However, the risk of infection with concurrent use of denosumab, a biologic agent for the treatment of osteoporosis, and a bDMARD remains unclear. Here, we evaluated the incidence of serious and opportunistic infections in patients treated concurrently with denosumab and a bDMARD and patients treated with a bDMARD alone.

10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension.

Background: Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis.

Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years.

Pharmacokinetic drug-drug interaction study of ranolazine and metformin in subjects with type 2 diabetes mellitus.

Ranolazine and metformin may be frequently co-administered in subjects with chronic angina and co-morbid type 2 diabetes mellitus (T2DM). The potential for a drug-drug interaction was explored in two phase 1 clinical studies in subjects with T2DM to evaluate the pharmacokinetics and safety of metformin 1000 mg BID when administered with ranolazine 1000 mg BID (Study 1, N = 28) or ranolazine 500 mg BID (Study 2, N = 25) as compared to metformin alone. Co-administration of ranolazine 1000 mg BID with metformin 1000 mg BID resulted in 1.

Extent and determinants of thermogenic responses to 24 hours of fasting, energy balance, and five different overfeeding diets in humans.

Context: Individual variation in the ability to convert excess calories to heat and the effects of dietary macronutrient composition are unclear.

Objective: Stability and determinants of the energy expenditure (EE) response to overconsumption were assessed.

Design, Setting, And Participants: Twenty subjects (75% male) with normal glucose regulation were evaluated during 24 hours each of energy balance, fasting, and 5 different diets with 200% energy requirements in a clinical research unit.

Reanalysis of the obesity-related attenuation in the left dorsolateral prefrontal cortex response to a satiating meal using gyral regions-of-interest.

Objective: The left dorsolateral prefrontal cortex (LDLPFC), which includes the inferior (IFG), middle (MFG), and superior (SFG) frontal gyri, has been implicated in satiation. Using a voxel-based approach, we previously identified an LDLPFC region (as reported as peak voxel) in which a reduced neuronal response to a meal was associated with obesity. In this study, we sought to determine which gyri in the LDLPFC best distinguished the neuronal responses to a meal using a different statistical approach.

Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals.

Background: Thyroid hormones (TH) may influence glucose metabolism. Hyperthyroid subjects have higher insulin secretion rates when compared with euthyroid individuals.

Objective: To evaluate the association between TH concentrations and insulin secretion in euthyroid, healthy Pima Indian adults (n=55, 29+/-7 years, females/males 36/19) with normal glucose tolerance (NGT) admitted to a Clinical Research Unit.

The 24-h carbohydrate oxidation rate in a human respiratory chamber predicts ad libitum food intake.

Background: The 24-h respiratory quotient (24-h RQ) and 24-h carbohydrate balance (24-h CHO-Bal) are predictors of weight change. Whether these relations are mediated by the effects of substrate oxidation and balance on food intake is not known.

Objective: We tested whether substrate oxidation and balance predict future ad libitum food intake.

Less activation in the left dorsolateral prefrontal cortex in the reanalysis of the response to a meal in obese than in lean women and its association with successful weight loss.

Background: We previously found that obese men have less activation in the left dorsolateral prefrontal cortex (LDLPFC) in response to a meal than do lean men, which indicates an association between this altered neuronal response and the pathophysiology of obesity.

Objectives: The objectives of the study were to extend this finding in obese women and to investigate activity in this region in women with a history of severe obesity who have successfully lost weight (ie, formerly obese women, sometimes called postobese women).

Design: We reanalyzed previously collected data to compare postmeal (after receiving a liquid meal) with premeal (after a 36-h fast) regional cerebral blood flow, a marker of neuronal activity, by using (15)O-water positron emission tomography in 10 lean [26 +/- 6% body fat (BF)], 9 obese (39 +/- 3%BF) and 8 formerly obese (28 +/- 4%BF) right-handed women.

Glucose response to an oral glucose tolerance test predicts weight change in non-diabetic subjects.

Objective: Glucose exerts a dual action in the regulation of energy balance, consisting of inhibition of energy intake and stimulation of energy expenditure. Whether blood glucose affects long-term regulation of body weight in humans remains to be established. We sought to test the hypothesis that the post-challenge glucose response is a predictor of weight change.

Postprandial glucagon-like peptide-1 (GLP-1) response is positively associated with changes in neuronal activity of brain areas implicated in satiety and food intake regulation in humans.

Postprandial glucagon-like peptide-1 (GLP-1) secretion can act as a meal termination signal in animals and humans. We tested the hypothesis that the postprandial changes in plasma GLP-1 concentrations are associated with changes in the human brain activity in response to satiety by performing a post-hoc analysis of a cross-sectional study of neuroanatomical correlates of hunger and satiation using (15)O-water positron-emission tomography (PET). Forty-two subjects (22M/20F, age 31+/-8 years) spanning a wide range of adiposity (body fat: 7-44%) were included in this analysis.

Plasma concentrations of free triiodothyronine predict weight change in euthyroid persons.

Background: Factors that influence energy metabolism and substrate oxidation, such as thyroid hormones (THs), may be important regulators of body weight.

Objective: We investigated associations of THs cross-sectionally with obesity, energy expenditure, and substrate oxidation and prospectively with weight change.

Design: Euthyroid, nondiabetic, healthy, adult Pima Indians (n = 89; 47 M, 42 F) were studied.

Inhibitory effect of obesity on gonadotropin, estradiol, and inhibin B levels in fertile women.

Objective: To examine whether obesity and insulin resistance have an independent effect on the gonadotropin, estradiol, and inhibin B serum levels and follicle count in the early follicular phase of fertile women with a wide range of BMI and without signs of hyperandrogenism.

Research Methods And Procedures: Twenty-two overweight and obese (BMI > or =25.0 kg/m(2)) women and 10 normal-weight (BMI <25.

Relationships between plasma leptin concentrations and human brain structure: a voxel-based morphometric study.

We have previously demonstrated that obese people have reduced grey matter (GM) in several brain areas, including regions implicated in the regulation of taste (i.e., inferior frontal operculum and postcentral gyrus), reward (i.

Less activation of the left dorsolateral prefrontal cortex in response to a meal: a feature of obesity.

Background: In an exploratory positron emission tomography study of postprandial regional cerebral blood flow, which is a marker of neuronal activity, obese men differed from lean men in several brain regions, including the prefrontal cortex. The subjects received a meal proportional to their body size; therefore, the meal volume was different for each person.

Objective: We investigated whether differences in the brain responses of obese and lean men to a meal represent satiety or feelings of gastric distension.