Pharmacokinetics and pharmacodynamics of intravenous dexmedetomidine in healthy Korean subjects.

WHAT IS KNOWN AND OBJECTIVE: Dexmedetomidine is a selective alpha2-adrenoreceptor agonist used for sedation in critically ill patients. The current study aimed to evaluate the pharmacokinetics (PKs), pharmacodynamics and tolerability of intravenous dexmedetomidine in healthy Korean subjects. METHODS: A randomized, double-blind, placebo-controlled study with three parallel dosage groups was conducted. Twenty-four subjects were randomly assigned to placebo or one of three dexmedetomidine dosing regimens, 3 µg/kg/h for 10 min followed by 0.17 µg/kg/h for 50 min (low dose), 6 µg/kg/h for 10 min followed by 0.34 µg/kg/h for 50 min (middle dose) and 3.7 µg/kg/h for 35 min followed by 0.7 µg/kg/h for 25 min (high dose). Serial blood samples for PK analysis were taken up to 12 h. PK parameters were determined using non-compartmental methods (WinNonlin(®)), and a population PK model was developed using nonmem(®). The sedative effect of dexmedetomidine was assessed by Ramsay sedation score and visual analogue scales/sedation. Adverse events, clinical laboratory tests, electrocardiograms, physical examinations and vital signs were monitored for tolerability assessment. RESULTS: Six subjects were assigned to each of the three active treatment group or placebo group. The AUC(last) of the low-, middle- and high-dose group were 1096.8 ± 119.9 (mean ± SD) ng*h/L, 2643.0 ± 353.2 ng*h/L and 5600.6 ± 411.0 ng*h/L, respectively. PK of dexmedetomidine was best described using a two-compartment model. The typical value of the population model can be calculated using the following equations: central volume of distribution (L) = 19.9 (age/27)(0.954), peripheral volume of distribution (L) = 59.4, clearance (L/h) = 33.7 (albumin level/4.3)(1.42) and inter-compartment clearance (L/h) = 67.7. Sedative effects were significantly increased by dexmedetomidine compared to placebo. The blood pressure and heart rate were decreased, but oxygen saturation was maintained stable. WHAT IS NEW AND CONCLUSION: Dexmedetomidine shows linear PK characteristics and dose-dependent sedative effects. A two-compartment population PK model was developed for healthy Korean subjects. The PK parameter estimates are similar in Koreans and Caucasians.

Steady-state pharmacokinetics of micafungin and voriconazole after separate and concomitant dosing in healthy adults.

We assessed the pharmacokinetics and interactions of steady-state micafungin (Mycamine) or placebo with steady-state voriconazole in 35 volunteers. The 90% confidence intervals around the least-squares mean ratios for micafungin pharmacokinetic parameters and placebo-corrected voriconazole pharmacokinetic parameters were within the 80%-to-125% limits, indicating an absence of drug interaction.

Sex differences in bone mass acquisition during growth: the Fels Longitudinal Study.

Risk of osteoporosis in later life may be determined during adolescence and young adulthood. The present study used longitudinal data to examine the accumulation of bone mineral content (BMC) and bone mineral density (BMD) in Caucasian subjects ages 6-36 yr. Growth in BMC and BMD (measured by dual X-ray absorptiometry; Lunar, Madison, WI) of 94 males and 92 females was monitored for a mean period of 4.29 yr. The main findings were that there were no sex differences in BMC or BMD during the prepubertal stage; however, females had significantly higher BMD of the pelvis and BMC and BMD of the spine during puberty, and postpubertal males generally had significantly higher BMC and BMD than their female counterparts. In addition, the longitudinal rate of bone accumulation in both sexes increased rapidly during childhood and adolescence and was nearly complete at the end of puberty. Finally, peak BMC and BMD was achieved between the ages of 20 and 25 and occurred earlier in females than in males. The rates of growth and timing of peak bone mass as reported here define the crucial period during which intervention protocols should be developed for maximizing skeletal mass to prevent the development of osteoporosis.

Childhood body composition in relation to body mass index.

OBJECTIVE: The aim is to describe body composition in relation to body mass index (BMI; body weight/stature(2)) to provide health care professionals insight into the meaning, significance, and limitations of BMI as an index of adiposity during childhood. METHODS: Data from 387 healthy, white children 8 to 18 years of age from the Fels Longitudinal Study were analyzed. Measurements were scheduled annually and each child was examined 1 to 11 times, totaling 1748 observations. Total body fat (TBF) and fat-free mass (FFM) were determined from hydrodensitometry. Stature and weight were measured using standard methods and BMI and the components of BMI, TBF/stature(2), and FFM/stature(2) were calculated. Analyses included correlations between BMI and body composition variables; age-related patterns of BMI, TBF/stature(2), and FFM/stature(2); and annual changes in BMI, TBF/stature(2), and FFM/stature(2). RESULTS: Generally, correlations between BMI and body composition variables were strong and significantly different from zero. Means for BMI throughout childhood were similar for boys and girls, although significantly larger values were observed for girls at ages 12 to 13 years. Age-related patterns of TBF/stature(2) and FFM/stature(2) differed between sexes. In each sex, annual increases in BMI were driven primarily by increases in FFM/stature(2) until late adolescence, with increases in TBF/stature(2) contributing to a larger proportion of the BMI increases in girls than in boys. CONCLUSIONS: Unlike adults, annual increases in BMI during childhood are generally attributed to the lean rather than to the fat component of BMI. Because the properties of BMI vary during childhood, health care professionals must consider factors such as age and sex when interpreting BMI.

Lifetime overweight status in relation to serial changes in body composition and risk factors for cardiovascular disease: The Fels Longitudinal Study.

OBJECTIVE: The aims were to determine if 1) individuals who became and maintained overweight during their entire lifetime differ from those who were never-overweight in terms of annual changes in adiposity and concurrent changes in cardiovascular disease (CVD) risk factors; 2) the changes and their relationships to each other varied between these groups or by sex within the groups; and 3) alcohol usage, smoking habits, and level of physical activity differed between groups. RESEARCH METHODS AND PROCEDURES: Data from 16,315 examinations of 414 individuals were utilized to assess lifetime overweight (body mass index [BMI] > 25 kg/m2) status. A regressive analytic approach was used to determine the average annual changes for each individual over an adult serial interval ranging from 4 to 20 years. RESULTS: Men and women who have become and maintained overweight have higher blood pressure and a poorer lipid/lipoprotein risk profile than those who have never been overweight. There is an accelerated deterioration in the atherogenic profile of overweight men and women as indicated by annual changes in CVD risk factors about double that of their never-overweight counterparts. In women, increased risk is derived from increasing systolic and diastolic blood pressure, whereas in men the increased risk comes not only from increasing diastolic blood pressure but also cholesterol, triglycerides, and low-density lipoprotein cholesterol levels and, to a lesser extent, decreasing high-density lipoprotein cholesterol. DISCUSSION: The reduced physical activity observed in the overweight adults may be related to their accumulation of adipose tissue at a rate about double their never-overweight counterparts, and this may be driving the higher rate of increase of CVD risk factors in the overweight groups.

Childhood weight, stature, and body mass index among never overweight, early-onset overweight, and late-onset overweight groups.

OBJECTIVE: To determine the effects of timing of onset of overweight (OW) on childhood anthropometric adiposity levels using long-term serial data from the Fels Longitudinal Study. CLASSIFICATION: OW was defined as body mass index (BMI; kg/m(2)) >25, and the age at first measurement of BMI >25 was the age of onset of OW. Early onset of OW (early-OW) and late onset of OW (late-OW) were defined as having onset of OW before and after 25 years of age, respectively, whereas never OW (never-OW) was defined as never having a BMI >25. SUBJECTS: Subjects consisted of 67 males and 47 females in early-OW groups, 62 males and 48 females in late-OW groups, and 80 males and 114 females in never-OW groups. RESULTS: Levels of weight and BMI in early-OW males and females were significantly greater than those in never-OW and late-OW males and females beginning at the time of adiposity rebound, which generally occurs between 4 and 8 years of age. Median BMI and weight patterns between never-OW and late-OW males were similar throughout childhood. However, significant differences in median levels of BMI for never-OW and late-OW females began at 11 years of age, although onset of OW was not until >25 years of age in the latter group. CONCLUSIONS: For both males and females, adiposity rebound is likely an effective time in a child's development to detect and initiate prevention for childhood and early adulthood onset of OW. Although later-onset OW needs additional study, puberty seems to be a critical phase in the development of later adult onset of OW in females.

Serum leptin concentration, body composition, and gonadal hormones during puberty.

BACKGROUND: Recent evidence has suggested that leptin concentration is associated with gonadal hormone levels, and that changes in leptin concentration may trigger the onset of reproductive function in children. However, the concurrent changes in body composition during puberty make the independent associations between leptin and gonadal hormone concentrations in children difficult to resolve. METHODS: To investigate the nature of associations between leptin levels and pubertal maturation, serum concentrations of leptin, estradiol, and testosterone and body composition measures were examined in a sample of 152 healthy pre-pubertal, pubertal, and post-pubertal children. RESULTS: Leptin concentration was nearly three-fold higher in post-pubertal girls than in pre-pubertal girls, but was relatively similar in pre- and post-pubertal boys. Significant sex differences in leptin concentration existed in prepubertal, pubertal and post-pubertal children, and these remained significant after controlling for adiposity. After adjusting for total body fat, fat-free mass and age, testosterone concentration was negatively associated with leptin levels in pubertal boys, while estradiol concentration was positively associated with leptin level in pubertal girls. CONCLUSIONS: Girls have higher serum leptin concentration before, during, and after puberty than boys, even after accounting for the development of greater female adiposity. Although other factors may be involved, sexual dimorphism in leptin concentrations during puberty appears to be partly due to a stimulatory effect of estradiol on leptin concentration in females and a suppressive effect of testosterone on leptin concentration in males.

Total-body and regional bone mineral content and areal bone mineral density in children aged 8-18 y: the Fels Longitudinal Study.

BACKGROUND: Techniques for cross-calibration of bone mineral content (BMC) and bone mineral density (BMD) between manufacturers of dual-energy X-ray absorptiometry (DXA) instruments are currently inadequate for total body measurements. Therefore, manufacturer-specific data for BMC and BMD in children are needed. OBJECTIVE: We provided age- and sex-specific means and SDs for total-body and regional BMC and areal BMD in 8-18-y-old white children. DESIGN: BMC and BMD of the head, arms, legs, pelvis, spine, and total body were determined by DXA. Data include 465 annual measurements from 148 healthy children with body weights between 30 and 100 kg and statures <190 cm. RESULTS: There were significant sex differences in BMC at ages 15-18 y for the total body and legs, at ages 12 and 15-18 y for arms and pelvis, at ages 11-13 and 16-18 y for the spine, and at ages 10-11 y for the head. There were significant sex differences in BMD at ages 16-18 y for total body, arms, and legs; at ages 12-13 and 16-18 y for the pelvis; at ages 12-14 and 18 y for the spine; and at ages 13-18 y for the head. CONCLUSIONS: Data presented in this investigation can be used to compare the BMC and BMD of 8-18-y-old white children (with statures <190 cm and body weights between 30 and 100 kg) using DXA.

Serial changes in body composition throughout adulthood and their relationships to changes in lipid and lipoprotein levels. The Fels Longitudinal Study.

Few studies have examined the relationships between measures of body composition and lipid and lipoprotein levels in long-term serial data from individuals unselected for cardiovascular disease- or obesity-related variables, and none have considered such extensive serial data as used in the current study. The aim was to examine in such individuals the associations between annual changes in lipid and lipoprotein levels and concurrent changes in total body fat, fat-free mass, percent body fat, and body mass index. Serial data from 1304 examinations of 423 adult white participants in the Fels Longitudinal Study were analyzed sex-specifically in 2 age groups, 18 through 44 years and 45 to 65 years. A regressive analytic approach utilized the long-term (4 to 20 years) serial data of individuals. Annual changes in adiposity, independent of levels of lean tissue changes, before and after age 45 for men and women were significantly correlated with corresponding annual changes in cholesterol and low density lipoprotein cholesterol. In men before age 45, changes in triglycerides and high density lipoprotein cholesterol were also significantly associated with changes in adiposity, with the relationship remaining after age 45 in high density lipoprotein cholesterol. Increases in adiposity in individuals are associated with changes in lipid and lipoprotein levels in the direction of increased risk for cardiovascular disease. Adult levels of total cholesterol and low density lipoprotein cholesterol across age and sex and high density lipoprotein cholesterol in men are responsive to changes in adiposity, independent of initial adiposity or lipid and lipoprotein levels.

Adult changes in body composition are associated with changes in cholesterol levels: the Fels longitudinal study.

Serial data from 507 adult participants in the Fels Longitudinal Study were used to study relationships between average annual changes in serum cholesterol levels and annual changes in total body fat, fat-free mass, percent body fat or body mass index in men and women aged 18-45 years or 45-65 years. Average annual changes in adiposity before and after 45 years of age for men and women show statistically significant, strong, positive relationships with corresponding changes in cholesterol levels.