Pharmacokinetics and Pharmacodynamics of the BACE1 Inhibitor Verubecestat (MK-8931) in Healthy Japanese Adults: A Randomized, Placebo-Controlled Study.

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ) peptides and is considered a potential treatment target for Alzheimer's disease (AD). To support Japan's participation in the global clinical development program, we characterized the safety, pharmacokinetics (PKs), and pharmacodynamics of the BACE1 inhibitor verubecestat (MK-8931) in 24 healthy Japanese adults in a two-part, single-center, randomized, placebo-controlled phase I trial (protocol MK-8931-007) and compared the results with historical data from non-Japanese subjects. Both single (20, 100, and 450 mg) and multiple (80 and 150 mg once daily for 14 days) doses of verubecestat were well tolerated.

Treatments for Hypertension in Type 2 Diabetes-Non-pharmacological and Pharmacological Measurements.

Obesity, hypertension, obesity-related hypertension such as hypertension with diabetes are growing health problems. Obesity, hypertension and diabetes are important, independent risk factors for the onset and development of cardiovascular diseases. Hypertension in obesity is characterized by stimulation of the renin-angiotensin-aldosterone system (RAAS), elevated sympathetic activity, insulin resistance and selective leptin resistance.

The effects of dietary weight loss on indices of norepinephrine turnover: modulatory influence of hyperinsulinemia.

Objectives: This study was conducted to examine (1) the effects of dietary weight loss on indices of norepinephrine (NE) turnover and (2) whether baseline hyperinsulinemia modulates sympathetic neural adaptations.

Methods: Obese individuals aged 56 ± 1 year, BMI 32.5 ± 0.

Different mechanisms in weight loss-induced blood pressure reduction between a calorie-restricted diet and exercise.

The present study compared the effectiveness of a mild calorie-restricted diet (D) alone, exercise (EX) alone and a combination of D+EX on weight loss-induced blood pressure (BP) reduction over 24 weeks. We focussed especially on the relationship between sympathetic nervous activity, as indicated from measures of plasma norepinephrine (NE), and insulin resistance (homeostasis model of insulin resistance, HOMA-IR). The three groups each comprised 30 obese, hypertensive men.

Relationships of adrenoceptor polymorphisms with obesity.

Obesity, hypertension, and type 2 diabetes are rapidly growing public health problems. Heightened sympathetic nerve activity is a well-established observation in obesity, hypertension, and type 2 diabetes. Human obesity, hypertension, and diabetes have strong genetic as well as environmental determinants.

Effects of weight loss on renal function in overweight Japanese men.

Obesity is known as an independent risk factor for renal injury. Sympathetic nerve activation may have an important role of the pathogenesis of obesity, and hypertension may underpin the development of cardiovascular events. In the present study, we evaluated the effects of weight loss (WL) on renal function, especially focusing on sympathetic nervous activity.

The effects of weight loss versus weight loss maintenance on sympathetic nervous system activity and metabolic syndrome components.

Context: Sympathetic nervous system (SNS) overactivity participates in both the pathogenesis and adverse clinical complications of metabolic syndrome (MetS) obesity.

Objective: We conducted a prospective lifestyle intervention trial to compare the effects of active weight loss and extended weight loss maintenance on SNS function and MetS components.

Methods: Untreated subjects (14 males, four females; mean age, 53 ± 1 yr; body mass index, 30.

Exercise augments weight loss induced improvement in renal function in obese metabolic syndrome individuals.

Objective: Metabolic syndrome (MetS) obesity is an independent risk factor for chronic kidney disease. This study was conducted to examine the effects of lifestyle interventions on renal parameters and putative metabolic, neuroadrenergic and hemodynamic mediators of renal injury.

Methods: Untreated men and women (mean age 55 ± 1 years; BMI 32.

Roles of beta2- and beta3-adrenoceptor polymorphisms in hypertension and metabolic syndrome.

Hypertension, diabetes mellitus (especially type 2 diabetes mellitus), metabolic syndrome and obesity are rapidly growing public health problems. Sympathetic nerve activation is observed in obesity, hypertension and diabetes mellitus, which have strong genetic as well as environmental determinants. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis.

The role of sympathetic nervous activity in renal injury and end-stage renal disease.

Sympathetic nervous system hyperactivity is observed in patients with renal injury, renovascular hypertension, chronic kidney disease (CKD) and end-stage renal disease (ESRD). Elevated sympathetic activity is of prognostic relevance in that plasma norepinephrine concentrations predict survival and the incidence of cardiovascular events in patients with ESRD, as well as future renal injury in normotensive healthy subjects with renal function in the normal range. Renal injury, CKD and ESRD are often associated with obesity, and its common sequelae hypertension and diabetes.

Cardiovascular and renal complications of type 2 diabetes in obesity: role of sympathetic nerve activity and insulin resistance.

Overweight and obesity is a growing "world-wide epidemic problem". Because as many as, two-thirds of the adult population and a growing number of children are overweight. The prevalence of diabetes, especially type 2 diabetes and hypertension have significantly increased with the prevalence of obesity.

Sympathetic neural adaptation to hypocaloric diet with or without exercise training in obese metabolic syndrome subjects.

Objective: Sympathetic nervous system (SNS) overactivity contributes to the pathogenesis and target organ complications of obesity. This study was conducted to examine the effects of lifestyle interventions (weight loss alone or together with exercise) on SNS function.

Research Design And Methods: Untreated men and women (mean age 55 +/- 1 year; BMI 32.

Weight loss may reverse blunted sympathetic neural responsiveness to glucose ingestion in obese subjects with metabolic syndrome.

Objective: The purpose of this study was to examine the effects of weight loss on sympathetic nervous system responsiveness to glucose ingestion in obese subjects with metabolic syndrome, in whom such responses are reportedly blunted.

Research Design And Methods: Thirty four subjects, 19 insulin resistant and 15 insulin sensitive and aged 55 +/- 1 years (mean +/- SE) with BMI 31.6 +/- 0.

Blunted sympathetic neural response to oral glucose in obese subjects with the insulin-resistant metabolic syndrome.

Background: Glucose ingestion stimulates sympathetic nervous system (SNS) activity in lean subjects, whereas blunted responses have been reported in the obese.

Objective: The objective was to investigate the impact of insulin resistance on the SNS response to oral glucose.

Design: Nineteen insulin-resistant (IR) and 12 insulin-sensitive (IS) obese subjects with the metabolic syndrome and matched for age, sex, and blood pressure participated.

Leptin-receptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic nerve activation in a Caucasian male population.

Leptin plays a key role in the regulation of body weight through the sympathetic nervous system; however, the contributions of leptin-receptor polymorphisms to obesity and sympathetic nerve activity have not been fully clarified. In the present study, we examined the relationships between leptin-receptor polymorphisms, plasma leptin and whole-body norepinephrine (NE) spillover as an index of sympathetic nerve activity in a Caucasian male cohort. In 129 young healthy normotensive men with a wide range of body mass index (BMI) (19.

High plasma norepinephrine levels associated with beta2-adrenoceptor polymorphisms predict future renal damage in nonobese normotensive individuals.

Renal injury is common in obesity and hypertension. In the present study, we examined relationships between renal function alterations, plasma norepinephrine (NE), and beta2-adrenoceptor polymorphisms in a longitudinal design over 5 years. In 219 nonobese, normotensive men with entry-normal renal function, we measured serum blood urea nitrogen (BUN), creatinine, creatinine clearance, plasma NE, homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), total body fat mass, and blood pressure (BP) annually for 5 years.

Gender differences in sympathetic nervous activity: influence of body mass and blood pressure.

Background: Obesity and high blood pressure (BP) commonly coexist in patients, and both conditions are associated with elevated sympathetic nervous activity. We tested whether the sympathetic nervous system was differently affected in men and women by the body mass index (BMI), BP, leptin and weight loss.

Methods: We measured muscle sympathetic nerve activity (MSNA, microneurography), BP and plasma leptin concentrations in 167 age-matched normotensive and hypertensive men and women divided into three subgroups: lean, BMI < 25 kg/m; overweight, BMI > or = 25 and < 30 kg/m; and obese, BMI > or = 30 kg/m.

beta2- and beta3-Adrenoceptor polymorphisms relate to subsequent weight gain and blood pressure elevation in obese normotensive individuals.

High blood pressure (BP) is a major determinant of cardiovascular events in obesity. The beta2- and beta3-adrenoceptor polymorphisms are associated with obesity and hypertension. In the present study, we examine the relationships of beta2- and beta3-adrenoceptor polymorphisms with further weight gain-induced BP elevation in obese subjects.

Beta2-adrenoceptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic activation.

Background: Obesity is a growing public health problem. It has been reported that beta2-adrenoceptor polymorphisms are associated with obesity. This study examines the associations of beta2-adrenoceptor polymorphism with relationships between plasma norepinephrine (NE) and leptin to evaluate further the mechanisms of obesity.

Rebound weight gain as associated with high plasma norepinephrine levels that are mediated through polymorphisms in the beta2-adrenoceptor.

Background: A successful weight loss program is essential treatment for obesity-related diseases, but it is well known that the majority of individuals do not succeed in weight loss maintenance. The present study evaluates hormonal mechanisms and the relationship of beta2-adrenoceptor polymorphisms involved in individuals who regain weight after initially successful weight loss.

Methods: Overweight Japanese men (n = 154) were enrolled in a 24-month weight loss program.