Arlette C. Perry

Effects of Sibutramine Treatment in Obese Adolescents: A Randomized Trial

Context Few trials have evaluated drugs for obesity in adolescents. Contribution This 12-month randomized, double-blind trial evaluated behavioral therapy plus either sibutramine or placebo in 498 very obese adolescents who were 12 to 16 years of age. Sibutramine reduced mean body mass index (between-group difference, 2.9 kg/m2) and mean weight (between-group difference, 8.4 kg) more than placebo. Sibutramine also improved some lipid and glycemic measures and was associated with tachycardia. Cautions Only 76% and 62% of the sibutramine and placebo recipients, respectively, completed the trial. Implications Sibutramine plus behavioral therapy for 1 year can reduce weight and improve metabolic risk factors in some very obese adolescents. The Editors Adolescent obesity is a major public health problem, with 15.5% of U.S. adolescents 12 to 19 years of age defined as overweight (>95th percentile for age- and sex-specific measures for body mass index [BMI]) (1, 2). Overweight often leads to serious health consequences during childhood, such as hypertension, depression, and social exclusion (3). Recently, the incidence of type 2 diabetes, typically an adult disease, has dramatically increased in the pediatric population (46). Cardiovascular risk factors, such as dyslipidemia, insulin sensitivity, and hypertension, are also more prevalent in adolescents with a BMI greater than the 95th percentile than in those with a BMI less than the 85th percentile (7). Management of adult obesity relies on a range of options, including diet, physical activity, behavior modification, pharmacotherapy, and surgery (8, 9). The serotonin and norepinephrine reuptake inhibitor sibutramine facilitates weight loss and weight maintenance in obese adults with commensurate improvements in metabolic variables for up to 2 years of treatment (1012). Prevention is the optimal approach; however, effective treatment in children with a BMI greater than the 95th percentile is needed. Comprehensive behavioral methods have shown weight loss benefit in younger children (13). In most studies, adolescents typically remain overweight after therapy (14). In an earlier single-center, 6-month controlled trial, sibutramine and a comprehensive behavioral program induced statistically significantly more weight loss in obese adolescents than the behavioral program alone (15). Overall, sibutramine is well tolerated; however, increases in mean blood pressure and pulse rate have been reported in some adults (10, 16) and adolescents (15). Our large multicenter study examined the longer-term effects on weight loss by adding sibutramine to behavior therapy in obese adolescents. Methods Design Overview The protocol-designated objective of our 12-month, double-blind study was to evaluate the efficacy and safety of sibutramine in addition to behavior therapy in obese adolescents. At baseline, we randomly assigned participants (3:1 randomization ratio) to sibutramine or placebo (Figure 1). The randomization schedule was stratified by center and baseline BMI (37 kg/m2 or >37 kg/m2) and was computer-generated in blocks of 4 by the sponsor. Each site was responsible for assigning sequential treatments within each stratum. The sponsor kept allocation codes sealed and secure until the database was locked before analysis. Participants, their parents, and study personnel were blinded to treatment. All participants received a behavior therapy program that included lifestyle modification instructions to improve nutrition and increase physical activity. We conducted the study from July 2000 to February 2002 at 33 U.S. weight loss clinics. Individual sites were responsible for recruitment, and we selected eligible participants from the sites clinical database or from responses to advertisements of the study. We obtained approval from individual institutional review boards. Figure 1. Study flow diagram. P P P Participants We included adolescents 12 to 16 years of age with a BMI (calculated as weight [kg] divided by height [m2]) that was at least 2 units more than the U.S. weighted mean of the 95th percentile based on age and sex (17) and was not more than 44 kg/m2. Contraindications included cardiovascular disease (including arrhythmias), type 1 or 2 diabetes mellitus, major psychiatric disorders, pregnancy, use of a weight loss medication or participation in structured weight loss programs for more than 2 weeks, medication use promoting weight gain or contraindicated with sibutramine (16), or cigarette smoking. We excluded candidates with systolic blood pressure greater than 130 mm Hg, diastolic blood pressure greater than 85 mm Hg, or pulse rate greater than 95 beats/min. We included candidates with stable hypertension who were receiving therapy. Participants completed behavioral assessments conducted by a staff psychologist or psychiatrist. We obtained written, informed consent from the parent and assent from the adolescent. Interventions Behavioral Protocol Participants received instruction in a center-specific behavior therapy program. Individual centers implemented flexible lifestyle modification approaches that were specific to the participants needs. This included self-monitoring of eating habits and physical activity, stress management, stimulus control, problem solving, contingency management, cognitive restructuring, and social support. Counseling at each visit promoted increased physical activity and reduced sedentary behavior. Nutritional counseling encouraged development of healthy eating habits and promoted dietary consumption based on a 500-kcal/d deficit. Medication Protocol At baseline, we randomly assigned participants (3:1 randomization ratio) to receive 10 mg of sibutramine or placebo daily. At month 6, doses of all participants who had not lost more than 10% of their initial BMI were uptitrated (blinded) to 15 mg of sibutramine or placebo. Abbott (previously Knoll Pharmaceuticals) manufactured and provided all capsules. Placebo and sibutramine capsules appeared identical and were dispensed similarly. We discontinued therapy for or closely monitored the participants with systolic blood pressure, diastolic blood pressure, or pulse rate that increased at a single visit to more than 150 mm Hg or by more than 20 mm Hg, to 95 mm Hg or by more than 15 mm Hg, or to 110 beats/min or by more than 20 beats/min, respectively, until acceptable values returned. We used a protocol-driven algorithm for repeating visits or withdrawing participants whose values did not return to specified limits. In the case of intolerance, participants were to be withdrawn from the study. Measurements and Follow-up Procedures The primary efficacy measure was absolute change from baseline in BMI. Secondary outcomes included percentage change in BMI, proportion of patients achieving reductions in BMI of 5% or more or 10% or more, absolute and percentage changes in body weight and lipid and glycemic variables, and absolute change in waist circumference. Participants had weekly visits for the first 2 weeks, visits every 2 weeks until week 12, and monthly visits thereafter. At each visit, we recorded weight to the nearest 0.1 kg, with the participant in light clothing and without shoes, and height to the nearest 0.5 cm. We measured waist circumference monthly. We evaluated medication adherence by capsule count. We assessed growth by using a pediatric growth chart (18) and performed full physical examinations at screening and at months 3, 6, and 12 (or at discontinuation). We assessed sexual maturation by self-reported changes in Tanner staging (19). We determined fasting lipid and glycemic variables at major assessments (Clinical Reference Laboratory, Lenexa, Kansas). We performed electrocardiography before treatment and at month 12 or at discontinuation. We obtained blood pressure (manually) and pulse rate (by palpation of the radial or brachial artery) at all visits. We withheld study medication until blood samples were obtained for laboratory assessments at months 3, 6, and 12. The investigator recorded all adverse events, both observed and volunteered, on the appropriate case report form, as well as in the participants clinic, office, or hospital chart. For each event, the investigator provided information on severity, start and stop dates, relationship to study drug, actions taken, and outcome. The investigator also recorded adverse events resulting from concomitant illnesses, reactions to concomitant medications, or progression of disease states. Statistical Analysis The planned sample size was approximately 400 participants with a 3:1 randomization ratio of sibutramine to placebo. On the basis of previous 12-month adult trials, we determined that 300 participants in the sibutramine group would be adequate to assess safety and exposure, allowing an overall dropout rate of approximately 50% and a probability that approximately 50% of participants receiving 10 mg of sibutramine would lose 10% or more of initial BMI at 6 months. The inflated sample size ensured enough participants with echocardiograms, ambulatory blood pressure monitoring, and dual-energy x-ray absorptiometry measurements (minimum of 120, 80, and 100 participants, respectively, at baseline) since these assessments would be performed in subsets. Although the protocol did not document a formal sample size calculation for efficacy, approximately 132 adolescents (99 in the sibutramine group and 33 in the placebo group) would allow a between-group difference in BMI of 2 kg/m2, with 90% power (2-sided level of 0.05) to be statistically significant, assuming a common SD of 3 kg/m2. We documented the prespecified statistical analysis methods while all study and sponsor personnel, including the statistician, were blinded to treatment. The primary efficacy variable was the absolute change from baseline in BMI. Secondary efficacy variables determined from baseline included percentage change in BMI, proportions of participants achieving 5%

Physical and psychological changes with vigorous exercise in sedentary primigravidae

PURPOSE The present study examined the effects of exercise on physical and psychological variables in sedentary primigravidae (PRA). METHODS A total of nine women randomly assigned to an exercise (E) (mean age = 31.3 +/- 3.1 yr) and six subjects randomly assigned to a control (C) group (mean age = 27.8 +/- 3.1 yr) fulfilled all requirements for the study. Exercise included a variety of exercise activities performed to a target heart rate of 150-156 beats x min(-1), three times per week for 15 wk. RESULTS Results showed no significant differences between E and C groups in physical characteristics initially. A repeated measures ANOVA showed a significant group effect (P < 0.05) and a significant group by time interaction (P = 0.001) with the E group showing a significantly longer amount of time on the PWC150 test than the C group. There was no significant group, time, or group by time interaction for lactate accumulation. This occurred, despite the fact that the E group spent 56% longer on the PWC150 test and the C group spent 30% less time on the same test at the conclusion of the study. Finally, the E group in comparison to the C group showed more favorable improvements in several items related to health and well-being on the Body Cathexis Scale. There were no significant differences between E and C groups in any pregnancy outcome measures. All babies were delivered healthy at term. CONCLUSIONS These data suggest that a vigorous exercise program can lead to significant improvements in aerobic fitness at similar lactate concentrations compared to a control group and can be well tolerated by low risk sedentary PRA without any deleterious effects occurring to herself or unborn child.

Aerobic circuit exercise training: Effect on adolescents with well-controlled insulin-dependent diabetes mellitus

OBJECTIVES To test the safety and effects of exercise conditioning on cardiorespiratory fitness, body composition, muscle strength, glucose regulation, and lipid/cholesterol levels. SUBJECTS Ten male adolescents with insulin-dependent diabetes mellitus (IDDM) and 10 adolescent nondiabetic (ND) subjects. DESIGN Pretest, posttest intervention trial with control group. SETTING University-based human performance laboratory. INTERVENTION Mixed endurance and calisthenic/strength activities performed at a rapid pace three times weekly for 12 weeks. RESULTS Only one subject with IDDM experienced hypoglycemia after a single exercise session. Both subject groups improved their cardiorespiratory endurance (p < .05). Lean body mass of IDDM subjects increased by 3.5% (p < .05). Subjects with and without IDDM lowered their percent body fat (p < .05 and .001, respectively). Strength improvement of IDDM subjects ranged from 13.7% (p < .001) to 44.4% (p < .01), depending upon the maneuver. Fasting blood plasma glucose for all subjects was unchanged by training, but glycosylated hemoglobin A1c of IDDM subjects was reduced by .96 percentage point (p < .05). Reductions of HbA1c benefitted subjects exhibiting poor preconditioning glycemic control. Low-density lipoprotein cholesterol was decreased in subjects with IDDM (p < .05), but not total cholesterol or triglycerides. CONCLUSION Adolescents with IDDM undergoing aerobic circuit training improve their cardiorespiratory endurance, muscle strength, lipid profile, and glucose regulation. Aerobic circuit training is safe for properly trained and monitored adolescent diabetics.

The effects of albuterol and isokinetic exercise on the quadriceps muscle group.

Subjects performed 9 wk of isokinetic knee extensions twice weekly. Albuterol (N = 13) or placebo (N = 9) was administered for 6 wk; groups received 16 mg.d-1 of either treatment. Training consisted of three sets of 10 repetitions at 45 degrees.s-1. Data were collected at weeks 0, 6, and 9. Concentric and eccentric variables examined included: peak torque (CPT, EPT), total work (CTW, ETW), average power (CAP, EAP), time to peak torque (CTTPT, ETTPT), peak torque to body weight ratio (CPT/BW), and work to body weight ratio (CW/BW, EW/BW). Other variables included: thigh circumference (CIRC), thigh cross-sectional area (CSA), forced vital capacity (FVC), and forced expiratory volume (FEV1), MANOVA and the Dunn-Bonferroni post-hoc found differences within groups for CPT, CTW, CAP, CPR/BW, EPT, ETTPT, and CSA. Interactions were noted for CW/BW, ETW, EAP, EPT/BW, and ETW/BW; with persons administered albuterol yielding superior values. CW/BW, ETW, and EAP showed interactions at post-testing, while EPT/BW and EW/BW interacted at both midtesting and post-testing. Results indicate therapeutic doses of albuterol administered with resistance exercise may augment strength gains.

Dose-response effect of walking exercise on weight loss. How much is enough?

OBJECTIVE: Exercise is the cornerstone of behavioral weight loss programs. The total volume of exercise needed to both promote weight loss and elicit health benefits has not been sufficiently investigated. The aim of this study was to examine the effects of two different volumes of walking ‘metabolic fitness’ exercise prescriptions, in combination with a low-fat, ad libitum diet (LFAL) on weight loss and additional modifiable health-related variables (HRV) in an ethnically diverse sample of overweight premenopausal women.DESIGN: Clinical 12 week weight loss intervention study with a 5.0–5.8 MJ diet daily with (a) participants walking 30 min, 5 days per week (DEX1), (b) participants walking 60 min, five times per week (DEX2) or (c) a diet only control group (DO).SUBJECTS: A mixed racial sample (predominantly Hispanic) of 56 subjects (mean BMI=34.26±6.61, mean age= 39.45±7.34) completed the 12 week program.MEASUREMENTS: Various body weight, body composition and fat distribution variables, dietary intake and additional HRV such as blood lipids, blood pressure and an estimate of cardiorespiratory fitness at baseline and after 3 months.RESULTS: All groups showed similar and significant (P<0.001) declines in body weight, percentage body fat, BMI, WHR, fat mass, fat-free mass and diastolic blood pressure following the program. In addition, total cholesterol, triacylglycerol and the TC:HDL ratio displayed a significant time effect (P<0.05). Significant interactions (P<0.05) were found for waist circumference, sagittal diameter, estimated VO2max and LDL-C, with both exercise groups showing similar and significantly greater (P<0.05) improvements than DO. Significant interactions (P<0.05) were also observed for several dietary variables.CONCLUSION: Our study showed no dose–response effect of walking exercise on weight loss over diet alone. Both lower and higher volume metabolic fitness prescriptions resulted in similar and significant beneficial changes in several HRV. This data suggests that 30 min of walking on most days of the week may be as beneficial as 60 min (in combination with diet) in promoting numerous additional healthful outcomes over diet alone following a 12 week weight loss program.

Effects of acute inhalation of the bronchodilator, albuterol, on power output

This study was designed to examine the effects of acute inhalation of the bronchodilator, albuterol (Proventil, Schering Corp.), on high intensity power output. Fifteen healthy nonasthmatic subjects (eight male, seven female, 18-33 yr) performed four supramaximal 15-s rides on a bicycle ergometer. Rides were arranged in pairs with a 10-min rest interval. Each pair of rides was preceded by a 5-min warm-up. Sessions were separated by a minimum of 48 h. The study design was fully randomized and double blind. Ten minutes prior to each pair of rides subjects inhaled two metered doses (180 micrograms) of albuterol (A) or a placebo (P). Individual ANOVAs revealed a significant difference between the A and P treatment for peak power (A = 886.6 W, P = 858.3 W) and fatigue (A = 27.2%, P = 24.4%). Mean changes in FEF25-75% (A = 0.712, P = 0.040 l.s-1), FEV1.0 (A = 0.188, P = 0.007 l), and PEF (A = 0.573, P = -0.155 l.s-1) were also statistically significant; however, these changes did not correlate to the anaerobic performance changes. No significant differences were found between treatments for heart rate increases resulting from the power test (A = 56.73 bpm, P = 53.20 bpm). These results indicate an ergogenic effect of the bronchodilator on short-term power output independent of impact on respiratory smooth muscle, with no effect on cardiac response.

Peak power, ground reaction forces, and velocity during the squat exercise performed at different loads.

Zink, A.J., A.C. Perry, B.L. Robertson, K.E. Roach, and J.F. Signorile. Peak power, ground reaction forces, and velocity during the squat exercise performed at different loads. J. Strength Cond. Res. 20(3):658-664. 2006.-This study examined the changes in peak power, ground reaction force and velocity with different loads during the performance of the parallel squat movement. Twelve experienced male lifters (26.83 ± 4.67 years of age) performed the standard parallel squat, using loads equal to 20, 30, 40, 50, 60, 70, 80, and 90% of 1 repetition maximum (1RM). Each subject performed all parallel squats with as much explosiveness as possible using his own technique. Peak power (PP), peak ground reaction force (PGRF), peak barbell velocity (PV), force at the time of PP (FPP), and velocity at the time of PP (VPP) were determined from force, velocity, and power curves calculated using barbell velocity and ground reaction force data. No significant differences were detected among loads for PP; however, the greatest PP values were associated with loads of 40 and 50% of 1RM. Higher loads produced greater PGRF and FPP values than lower loads (p < 0.05) in all cases except between loads equal to 60-50, 50-40, and 40-30% of 1RM for PGRF, and between loads equal to 70-60 and 60-50% of 1RM for FPP. Higher loads produced lower PV and VPP values than lower loads (p < 0.05) in all cases except between the 20-30, 70-80, and 80-90% of 1RM conditions. These results may be helpful in determining loads when prescribing need-specific training protocols targeting different areas of the load-velocity continuum

Correlation Analyses and Regression Modeling between Isokinetic Testing and On-Court Performance in Competitive Adolescent Tennis Players

Tennis requires skill, physical attributes, and strategy. Ball velocity and placement are two of the most important components in winning the faster-paced modern game. Although isokinetic testing has been used to evaluate physical characteristics and injury potential in tennis players, few studies have compared isokinetics and on-court performance. Such a comparison would help establish links between speed-specific properties of functioning muscles and stroke production and could affect overall training strategy. This study compared isokinetic peak torque (PT), average power (AP), and total work (TW) during specific testing patterns correlated with ball velocity or stroke accuracy during the service, forehand, and backhand and developed predictive equations for each stroke using these variables. Thirty-five players, aged 13–18 years with at least 4 years playing experience, were evaluated using internal and external shoulder rotation, leg extension, and diagonal throwing motions. Ball velocity was measured using a radar gun. Accuracy was evaluated on the basis of shot position and depth. Significant correlations were found between ball velocity and a number of isokinetic variables, while no significant correlations were observed with shot accuracy. Significant isokinetic variables for each stroke were entered into regression models. One isokinetic speed sufficiently predicted ball velocity for each stroke, since no increase in predictive capacity was observed with the addition of other isokinetic parameters. We conclude that isokinetics at testing speeds between 1.57 and 4.71 rad·s-1 can effectively predict ball velocity, but not accuracy, and that our results may be helpful in planning strategies for training and rehabilitation.

Comparative Effect of Power Training and High-Speed Yoga on Motor Function in Older Patients With Parkinson Disease.

OBJECTIVES To compare the effects of power training (PWT) and a high-speed yoga program on physical performances in older patients with Parkinson disease (PD), and to test the hypothesis that both training interventions would attenuate PD symptoms and improve physical performance. DESIGN Randomized controlled trial. SETTING A laboratory of neuromuscular research and active aging. PARTICIPANTS Patients with PD (N=41; mean age ± SD, 72.2 ± 6.5y). INTERVENTIONS Two high-speed exercise interventions (specifically designed yoga program and PWT) were given for 12 weeks (twice a week), and 1 nonexercise control group. MAIN OUTCOME MEASURES Unified Parkinson Disease Rating Scale motor score (UPDRSMS), Berg Balance Scale (BBS), Mini-Balance Evaluation Systems Test (Mini-BESTest), Timed Up and Go, functional reach, single leg stance (SLS), postural sway test, 10-m usual and maximal walking speed tests, 1 repetition maximum (RM), and peak power (PPW) for leg press. RESULTS For the posttests, both training groups showed significant improvements (P<.05) in all physical measurements except functional reach on the more affected side, SLS, and postural sway compared with the pretests, and significantly better scores for UPDRSMS, BBS, Mini-BESTest, Timed Up and Go, functional reach on the less affected side, 10-m usual and maximal walking speed tests, 1RM, and PPW than controls, with no differences detected between the yoga program and PWT. CONCLUSIONS Both the specially designed yoga program and PWT programs can significantly improve physical performance in older persons with PD.

Insulin resistance but not visceral adipose tissue is associated with plasminogen activator inhibitor type 1 levels in overweight and obese premenopausal African-American women.

OBJECTIVE: To compare plasma plasminogen activator inhibitor type 1 (PAI-1) levels and to examine the association of PAI-1 with visceral adiposity and other components of the metabolic syndrome in overweight and obese premenopausal African-American (AA) and Caucasian (CC) women.DESIGN: Cross-sectional study.SUBJECTS: 33 CC and 23 AA healthy, overweight and obese, premenopausal women (age 19–53 y, body mass index 28.1–48.9 kg/m2).MEASUREMENTS: Body mass index, sagittal diameter, waist circumference, percentage body fat, visceral and subcutaneous adipose tissue (by anthropometry, magnetic resonance imaging (MRI), and bioelectric impedance techniques), PAI-1, leptin, lipids, glucose, insulin, and insulin resistance (by HOMA IR).RESULTS: AA women had lower triglyceride levels and less visceral adipose tissue (VAT) volume than CC despite similar BMI. PAI-1 levels were not significantly different in the two groups. Insulin resistance was associated with PAI-1 in both groups but only in CC women were VAT, triglyceride, HDL cholesterol and blood pressure related to plasma PAI-1 levels. Multiple regression analysis showed that VAT in CC and insulin resistance in AA were independent predictors of PAI-1.CONCLUSION: VAT is significantly associated with circulating PAI-1 levels in overweight and obese CC but not AA premenopausal women.