Effects of Sibutramine on Resting Metabolic Rate and Weight Loss in Overweight Women

Transcription

1 Effects of Sibutramine on Resting Metabolic Rate and Weight Loss in Overweight Women Helen M. Seagle, Dan H. Bessesen, James 0. Hill Abstract SEAGLE, HELEN M., DAN H. BESSESEN, JAMES 0. HILL. Effects of sibutramine on resting metabolic rate and weight loss in overweight women. Obes Res. 1998; 6: Sibutramine, a monoamine re-uptake inhibitor, has recently been approved by the Food and Drug Administration as a weight loss agent. Sibutramine lowers bodyweight in rodents by reducing energy intake and increasing energy expenditure. Sibutramine facilitates weight loss in human subjects, but it is not clear whether it acts on energy intake, energy expenditure, or both. The present study was a randomized clinical trial designed to assess the effects of sibutramine (at 10 or 30 mg/day) on body weight and resting metabolic rate (RMR). Forty-four overweight women were randomized to 1) placebo (n=15); 2) sibutramine at 10 mg/day (n=15) or, 3) sibutramine at 30 mg/day (n=14). All subjects were instructed to consume a 1200 kcayday diet for 8 weeks while receiving drug or placebo. RMR was assessed by indirect calorimetry at baseline, at 3 hours after the first dose of drug (or placebo), and at the end of the 8-week weight-loss period. Sibutramine reduced body weightrelative to placebo, but there was no difference between weight loss on the two sibutramine doses. No significant differences in RMR between sibutramine and placebo were seen, either 3-hour post dose or after the 8-week weight-loss period. After the weight loss period, all groups were taken off medication and kept weight stable for another 4 weeks. RMR was measured again and was not different among groups. That there was no change in RMR when sibutramine was stopped further suggests that the drug does not directly affect RMR. In summary, Submitted for publication July 3, Accepted for publication December 21, From the Departments of Pediatrics and Medicine, Center for Human Nutrition, University of Colorado Health Sciences Center, Denver, CO. Reprint requests to Dr. James 0. Hill, Center for Human Nutrition, Box C225, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, CO Copyright NAASO. while sibutramine was shown to be an effective weightloss agent over 8 weeks, we found no evidence that it increased RMR. Key words: pharmacotherapy, sibutramine, metabolic rate, weight loss, obesity Introduction Sibutramine hydrochloride is a monoamine re-uptake inhibitor that blocks neuronal uptake of norepinephrine, serotonin and, to a less extent, dopamine (5). While initially developed as an antidepressant, sibutramine was found to decrease appetite and produce weight loss in rodents (5,13). In an 8-week double-blind, placebo-controlled clinical trial, sibutramine showed a dose-dependent effect on weight loss (18). Bray et al. (3) showed that this dose-dependent reduction in body weight persisted over a 24-week treatment period. The mechanism by which sibutramine causes weight loss in human subjects could be because of its anorectic effect (leading to decreased energy intake), to a stimulatory effect on energy expenditure, or a combination of the two. Sympathomimetic drugs (e.g., ephedrine, ephedrine/ methylxanthine mixtures, fenfluramine) have been shown to produce weight loss (16,l) and increase metabolic rate (2,9,15,17). Sibutramine has been reported to increase energy expenditure in rodents via selective sympathetic activation of brown adipose tissue (6,7). It is, therefore, possible that sibutramine may have both an anorectic and stimulatory effect in humans. The purpose of this study was to determine the effect of sibutramine on metabolic rate and weight loss in moderately obese women. Methods Subject Selection Forty-nine premenopausal women, between the ages of I845 years, and with a body mass index of between 2840 kg/m2 were recruited for this study from the Denver metropolitan area by newspaper advertisements and flyers. Smokers and subjects with cardiovascular disorders, high OBESITY RESEARCH Vol. 6 No. 2 Mar

2 Table 1. Baseline characteristics Characteristics Placebo Sibutramine 10 mg 30 mg Age (years) Bodyweight (kg) BMI (kg/m2) Body fat (%) Fat mass (kg) Fat-free mass (kg) Adjusted" RMR (kcavday) Unadjusted RMR (kcavday) Waist Circumference (cm) Hip Circumference (cm) Waist-to-hip ratio n= t f f f f f f f f f n= f f f k f f f f f f f n= f f f f f f f f f f f Values are mean f standard error of the mean. aadjusted for fat mass and fat-free mass. blood pressure, diabetes, thyroid dysfunction, or any other disorder known to interfere with intermediary metabolism were excluded from the study. All subjects were determined to be in good health by medical history, physical examination, and laboratory screening tests. All subjects had been stable at their current weight (2 2.3 kg) for at least 6 months. The Colorado Multiple Institutional Review Board approved this study and all subjects gave informed consent. Forty-nine subjects were randomized to one of three treatments; 16 to placebo, 17 to 10 mg sibutramine, and 16 to 30 mg sibutramine. Of the 49 randomized subjects, five failed to complete the study. Forty-four subjects (15 placebo, 15 sibutramine 10 mg, 14 sibutramine 30 mg) completed both the double-blind and weight stabilization periods. Of the five subjects who failed to complete the study, two relocated to another city and two had conflicts with the study scheduling. No subject withdrew because of adverse events. Table 1 presents the baseline characteristics of the 44 subjects completing the study. Subjects in the three groups had similar body weight and body composition at the beginning of the study. There were no statistically significant differences among treatment groups with respect to demographic variables, obesity history, and prior, concomitant or post-treatment medications. Overall, subject compliance to the double-blind study medication was excellent and was comparable among treatment groups. Overall Study Design After screening, baseline measurements of body composition and resting metabolic rate were performed. Eligible subjects were randomized into one of the following 3 treatment conditions for 8 weeks of therapy: 1) placebo, 2) sibutramine at 10 mg per day, and 3) sibutramine at 30 mg per day. These two doses were chosen to represent the range of potential doses that might be used by weight loss patients and each dose was compared to the placebo treatment. During the 8-week treatment period all subjects were instructed to follow a 1200 kcal per day diet. After 8 weeks of doubleblind therapy, treatment was withdrawn. Using diet alone, subjects were maintained at their week 8 body weights for an additional 4 weeks. RMR was assessed before and 3 hours after the administration of the first dose of drug/ placebo. Sibutramine is rapidly absorbed and peak plasma concentrations of the drug metabolites occur at 3 hours postingestion (14). During the treatment phase, subjects were instructed to take the study medication (1 tablet q.d.) with approximately 4 ounces of water at about the same time each morning. RMR and body composition were measured at the end of the 8-week treatment and 4-week post-treatment periods. The study design is illustrated in Figure 1. Weight Loss Period During the treatment period, all subjects were instructed to consume a 1200 kcal per day diet. The diet plan was an exchange-type diet with approximately 50% of the calories from carbohydrate, 30% from fat, and 20% from protein. All subjects received individual instruction on following the diet plan. Subjects were encouraged to become more physically active but were not given any specific ac OBESITY RESEARCH Vol. 6 No. 2 Mar. 1998

3 Baseline Phase Wught Loss Phase: : Maintenance PhrM ; 1200 kcal diet + drudplacebo j Web Figure 1: Study design showing intended weight change goals. tivity goals. Subjects came to the laboratory for 5 visits during the treatment period (weeks 1, 2, 4, 6, 8). Bodyweight, blood pressure, and pulse were measured at these visits. Body weight was measured to the nearest 100 gm on an electronic Detecto scale with the subject wearing light clothing but no shoes. Each subject was queried about adverse events and about the use of other medications. The subject met with the dietitian at each of these visits to review dietary compliance and any issues related to following the prescribed diet plan. At the week 8 visit, body composition and RMR were also measured. Weight Stabilization Period Following the end of the 8-week treatment program, subjects were taken off treatment and were maintained at their week 8 visit body weight (? 1.4 kg) for 4 weeks. The calorie level of the diet plan was variable; it was modified for each subject based on the 8-week RMR adjusted for usual activity. The weight stabilization diet plan was based on the same exchange-type diet plan (same macronutrient distribution) used during the weight loss period. Subjects came to the laboratory weekly during the 4-week stabilization period. Body weight, blood pressure, and pulse rates were measured at the weekly visits. Each subject was queried about adverse events and about the use of other medications. The subject met with the dietitian at each of these visits and the prescribed diet plan was altered if weight stability was not achieved. At the week 12 visit, body composition and RMR were also measured. Dependent Variables The following dependent variables were measured at baseline, at the end of the weight loss treatment, and at the end of the weight stabilization period. Body Composition. Body composition was determined from measurements of body density estimated by underwater weighing (10). Body weight in air was measured to the nearest 0.25 pound using a balance Detecto platform scale. Body weight in water was measured to the nearest 25 g using a Chatillon (Kew Gardens, NY) spring scale. Residual I lung volume was determined (simultaneously with underwater weighing) using a closed-circuit nitrogen dilution technique (20). Nitrogen concentration during re-breathing was measured using a Med-Science 505-D Nitralyzer (St. Louis, MO). Seven to ten trials were run and the average taken. Percent body fat was estimated from body density using the equation of Brozek, et al. (4). Reproducibility tests in our laboratory showed an average difference of 2-3% between tests of the same subjects. Waist circumference was measured at the smallest part of the waist. Hip circumference was measured at the largest circumference of the hips. Measurements were made to the nearest 0.5 cm. These measurements were made at baseline, week 8, and at week 12. Resting Metabolic Rate (RMR). RMR was measured by ventilated hood, indirect calorimetry using a SensorMedics 2900 oxygen uptake system (Yorba Unda, CA). Subjects reported to the laboratory in the morning after an overnight fast. Oxygen consumption and carbon dioxide production were measured continuously over 20 minutes after the subject had been lying quietly for 45 minutes. Energy expenditure was calculated from these values using standard equations (19). In our laboratory, intra-subject variability for RMR is 45%. Blood Pressure. Pulse rate and blood pressures were measured at all visits. Pulse rate was measured by palpation of the radial pulse for 30 seconds after 5 minutes in the supine position. Blood pressure was taken after the pulse rate. The systolic and diastolic measurements were determined by the first and fifth Korotkoff s sounds. The same arm and an appropriately sized cuff were used throughout the study. Subjective Food Consumption Ratings. At 4 visits (Baseline, Weeks 4, 8, and 12), subjects completed 10 cm visual analogue scales (VAS) to evaluate variables related to food intake over the preceding week. The scales included evening hunger, evening satiety, overall appetite, ease of following diet, sweet foods craving, savory foods craving, complex carbohydrate foods craving and carbohydrate snacking. Data Analysis There were three treatment groups with parameter assessments (body weight, body composition, RMR) at different time points. We used a repeated measured analysis of variance to determine differences due to treatment group and time as well as any group * time interaction. For changes in RMR, fat-free mass and fat mass were included as covariates in the repeated measures analysis. Data is presented as mean? standard error of the mean. Results Body weight Figure 2 shows the change in bodyweight from baseline during treatment and stabilization. Sibutramine-treated sub- OBESITY RESEARCH Vol. 6 No. 2 Mar

4 J n + - C + a S L P S S f l S Weight 1.0~s Phase Maintenance Phase - 10 mg Sibutramine Figure 2: Mean changes in weight in the 3 treatment groups during the study. jects lost significantly more weight during the 8-week treatment phase than subjects receiving placebo (p<o.ool). There was no difference in mean weight loss between the 2 sibutramine groups. Subjects receiving sibutramine lost about 8% of initial body weight (-7.5 kg) in 8 weeks compared with about 3% in subjects receiving placebo (-3 kg). Figure 3 shows the proportion of subjects in each group achieving either a 5 or 10% loss of initial body weight. This was greater in subjects receiving sibutramine than in subjects receiving placebo. None of the subjects in the placebo group achieved a 10% weight loss. During the weight maintenance phase (week 8 to week 12), all groups remained weight stable. The average change in weight was 0.0 * 0.32 kg for the placebo group whereas the sibutramine-treated groups gained an average of 0.85 k 0.23 kg. There was no difference in weight change during the weight maintenance phase between the 10 mg vs. 30 mg sibutramine groups. Body Composition Table 2 shows the changes from baseline in body fat and fat-free mass (FFM) at weeks 8 and 12. The decrease in fat mass was significant for all groups at week 8 and week 12. This decrease in fat mass was significantly greater for the sibutramine-treated groups versus placebo at both time points. However, there was no difference in fat mass change between the 2 sibutramine groups. Fat mass did not change in any of the groups between week 8 and week 12. When considered as a proportion of total weight loss, subjects receiving sibutramine lost 6670% of total weight from fat mass. This is similar to changes in body composition seen in many studies using energy restriction to produce weight loss (8,12). Although there was a high proportion of fat loss in the placebo group (approximately 90%), the amount of total weight lost was minimal. With such a small weight change, the ability to accurately quantify changes in body fat mass using the underwater weighing technique is limited. FFM did not change between baseline and week 8 for the placebo group but decreased significantly in the sibutra- mine-treated As shown in Table 2, this decrease in FFM was not different between the 2 sibutramine-treated groups but was different from the placebo group (~~0.05). Between week 8 and week 12, FFM increased a small but statistically significant amount in the sibutramine-treated groups ( kg FFM, p<o.oool : mean change for combined sibutramine groups). FFM did not change in the placebo group during this weight maintenance period. Both sibutramine conditions resulted in a significant reduction (p<0.05) in body mass index (BMI) as compared to the placebo condition (Table 2). A significant reduction (~~0.05) in waist circumference was only seen between the 10 mg sibutramine and placebo conditions at week 12. However, a trend for a greater reduction in waist circumference between placebo and both sibutramine conditions was also seen at week 8 (Table 2). Resting Metabolic Rate (RMR) We assessed RMR before and 3 hours after the initial treatment dose (either sibutramine or placebo). The changes in RMR from baseline to 3 hours after drug (or placebo) administration were not significant in any group (0.72,0.48, 0.96 kcakg FFM/day, respectively for placebo, 10 mg sibutramine, and 30 mg sibutramine). Changes in RMR over Time As shown in Table 2, RMR (unadjusted) decreased from baseline to week 8, as would be expected from the change in weight and body composition, in both sibutramine groups ( kcal, p<o.oool) but not in the placebo group (-65 k 55 kcal, p=o.2471). There was no difference in the change in unadjusted RMR among all groups during this weight loss period. Unadjusted RMR did mg Sibutramine >5% Weight Logs >lo% Weight Loss Figure 3: Proportion of subjects achieving 25% and 2 10% weight loss. 118 OBESITY RESEARCH Vol. 6 No. 2 Mar. 1998

5 Table 2. Changes in characteristics from baseline Week 8 Week 12 Sibutramine Sibutramine Placebo 10 mg 30 mg Placebo 10 mg 30 mg Bodyweight (kg) f 0.7** Fat mass (kg) * Fat-free mass (kg) -0.3 f * BMI (kg/m2) -1.2 f f 0.3* Adjusted RMR (kcayday) -33 f f 53 Unadjusted RMR (kcayday) -65 f f 55 Waist circumference (cm) -2.4 f f 1.0 Hip circumference (cm) -2.0 f * Waist-to-hip ratio f f ** -5.2 f 0.6* -2.4 f 0.5* * -87 f f f * f f f f f f k f f 1.0* -4.7 f f 0.4* f 1.1* -4.7 f f f 0.5* -5.0 f f f 0.2* f f f 0.7* f Values are mean k standard error of the mean. Adjusted for fat mass and fat-free mass. *pc0.05 versus placebo. **p<o.ool versus placebo. not change in any of the groups during the weight maintenance period. Figure 4 shows RMR (adjusted for fat mass and fat-free mass) at baseline, at the end of treatment, and at the end of the weight stabilization period. The sibutramine-treated groups experienced a significant decrease in adjusted RMR from baseline to week 8 (-96 -c 39 kcal, p<0.05: mean change for combined sibutramine groups). However, this decrease in adjusted RMR from baseline to week 8 was not different among all the groups. During the weight maintenance period, adjusted RMR remained unchanged for all groups t W mo Basellne Week 8 Week 12 Figure 4: Mean metabolic rates (adjusted for fat-free mass and fat mass) during the study. Adverse Events Overall, sibutramine was well tolerated. There were no discontinuations because of adverse events. Most adverse events were reported as either mild or moderate. Some of the most frequently reported adverse events that appeared to be associated with sibutramine were anorexia, nausea, CNS stimulation, dizziness, dry mouth, insomnia, and rhinitis. The occurrence of these events is consistent with the adverse event profile noted in previous sibutramine trials. One serious adverse event was reported during the study which occurred in a patient who was randomized to placebo and was treated in the Emergency Room for a possible peptic ulcer. No deaths occurred during the study. No unusual effects were noted for laboratory parameters, vital signs, or heart rate parameters as measured by electrocardiograms. No significant treatment differences were noted for prolactin levels. Blood Pressure No clinically significant treatment effects were observed for either supine systolic or diastolic blood pressure. However, mean dose-related increases in pulse rate were observed for sibutramine relative to placebo. However, using one-way ANOVA, the changes in pulse rate were not statistically significant between treatment groups at any time point. OBESITY RESEARCH Vol. 6 No. 2 Mar

6 Subjective Ratings of HungedSatiety No significant treatment effects were noted for the VAS measuring evening hunger, evening satiety, sweet food craving, savory food craving, carbohydrate craving, or carbohydrate snacking. However, the 30 mg sibutramine dose produced a significant decrease in overall appetite at week 8 as compared to the other two groups (p=0.009). Discussion Sibutramine was effective in producing weight loss. Subjects treated with sibutramine lost, on average, approximately twice as much weight as subjects receiving the placebo treatment. No significant difference in weight loss was detected for the 10 mg vs. the 30 mg sibutramine treatment groups. Achieving a 5-10% weight loss is thought to be effective in reducing risk of chronic disease (1 1). On average, significantly more subjects receiving sibutramine lost at least 5% of initial body weight as compared to subjects receiving placebo. Subjects receiving sibutramine lost approximately 7% of initial body weight in only 8 weeks as compared with less than 3% in the placebo group. Changes in body composition were different between groups for the weight loss and weight maintenance periods. The loss of FFM in the placebo group was much smaller than is usually seen with dietary restriction. Because weight loss was small in this group, errors in assessment of body composition will be magnified when expressed as percent of total weight loss. The proportionate change in composition of weight loss for the sibutramine-treated group is similar to that produced in other weight loss studies using energy restriction alone (8,12). There was no acute effect of sibutramine on RMR as measured 3 hours after an initial dose, nor was there evidence that either doses of sibutramine increased RMR relative to placebo during either the weight loss or weight maintenance phases of the study. Unadjusted RMR decreased more in the sibutramine-treated groups than in the placebo group during the 8-week weight-loss period. However, when comparing adjusted RMR, a decrease was seen for all groups at week 8 and this was not significantly different between groups. Adjusting RMR for fat mass and FFM is necessary as both are important determinants of RMR and are greatly affected by weight loss. Finally, the change in adjusted RMR was not different from the placebo group after sibutramine withdrawal during the weight maintenance period. It is difficult to assess the impact of a weight loss agent on energy expenditure. Potential increases in energy expenditure can be partially masked by decreases in energy expenditure because of loss of body mass. In order to examine the effect of sibutramine on resting metabolic rate, we studied subjects both during active weight loss and weight maintenance. Energy expenditure is expected to decline with weight loss so we first explored whether sibutramine would produce lesser decrease in RMR when compared to placebo. This did not occur. Next, we hypothesized that if sibutramine increased RMR, we should see a decline in RMR during a period of weight maintenance following drug withdrawal. RMR did not change during weight maintenance in any group. Thus, we feel confident that within the confines of this experimental design, sibutramine did not significantly increase RMR. These data, obtained in human subjects, differ from data obtained in rodents. In rodents, sibutramine produces substantial increases in energy expenditure (6,7). There are several possible explanations of this discrepancy. First, the study was powered to detect an increase in energy expenditure of approximately 8%. It is possible that sibutramine produced smaller increases in RMR. Over time, such small increases could have contributed to the greater weight loss seen with sibutramine. Second, we measured only RMR in the present study. It is possible that sibutramine produced increases in other components of energy expenditure such as the thermic effect of food and physical activity. Sibutramine could, for example, increase voluntary physical activity, thereby increasing energy expenditure from physical activity. Many sibutramine-treated subjects in the present study reported having more energy. The sibutraminetreated subjects may have become generally more active and reduced the amount of time spent in sedentary activities. This possibility remains to be tested. A third reason for different results in human subjects could be related to the amount of brown adipose tissue (BAT) in rodents vs. humans. The increased energy expenditure in rodents may arise largely via thermogenesis in BAT. Although controversial, it appears that adult humans may not have large amounts of BAT and thus would not be expected to show this form of thermogenesis. Alternatively, a drug such as sibutramine may act to increase BAT and such an increase may require some period of drug administration. The 8-week period used in this study may not be long enough to elicit changes in BAT. It is important to note that although all subjects received the same dietary instruction, actual energy intake was not quantified. It is possible that the sibutramine-treated subjects experienced a decrease in appetite that decreased their actual energy intake to below 1200 kcdday. Additionally, the placebo group may have had difficulty adhering to the 1200 kcal/day diet plan, thus consuming more than 1200 kcauday. Such a discrepancy in energy intake could explain some of the difference in weight loss between groups. However, the subjective food consumption ratings were only significantly different for the 30 mg sibutramine vs. placebo group for overall appetite. None of the other consumption ratings or change in ratings (including easeof-following diet) were significantly different between groups at screening, week 4, week 8, or at week 12. The consumption ratings were administered while the subject 120 OBESITY RESEARCH Vol. 6 No. 2 Mar. 1998

7 was fasted during an office visit and, therefore, it is possible that we did not capture true changes in appetite that may have occurred during the course of a subject s typical day. In summary, sibutramine has demonstrated efficacy as a weight-loss agent in a number of controlled clinical trials (3,18), including this one. Although longer-term studies are needed, sibutramine may be a particularly useful agent for achieving a weight loss of 5-10% of initial body weight. Results of the present study suggest the efficacy of either 10 or 30 mg sibutramine is not caused by an increase in RMR, but future studies should examine effects of sibutramine on other components of daily energy expenditure. Acknowledgment This study was supported by a grant from Knoll Pharmaceuticals. References 1. Astrup A, Lundsgaard C, Madsen J, Christensen NJ. Enhanced thermogenic responsiveness during chronic ephedrine treatment in man. Am J Cfin Invest. 1985;42: Astrup A, Madsen J, Holst JJ, Christensen NJ. The effect of chronic ephedrine treatment on substrate utilization, the sympathoadrenal activity, and energy expenditure during glucose-induced thermogenesis in man. Metabolism. 1986;35: Bray GA, Ryan DH, Gordon D, Heidingsfelder S, Cerise F, Wilson K. A double-blind randomized placebo-controlled trial of sibutramine. Obes Res. 1996;4: Brozek JF, Grande JT, Anderson, Keys A. Densitometric analysis of body composition: revision of some quantitative assumptions. Ann NY Acad Sci. 1963:llO: Buckett WP, Thomas PL, Luscombe GP. The pharmacology of sibutramine hydrochloride (BTS 54524), a new antidepressant which induces rapid noradrenergic downregulation. Pro Neuropsychopharmacof Biol Psychiatry. 1988;12: Connoley IP, Frost I, Heal DJ, Stock MJ. Role of b- adrenoceptors in mediating the thermogenic effects of sibutramine. Br J Pharmacof. 1996;117: 170P. 7. Connoley IP, Heal DJ, Stock MJ. A study in rats of the effects of sibutramine on food intake and thermogenesis. Br J Pharmacof. 1995;114:388P. 8. Donnelly JE, Jakicic J, Gunderson S. Diet and body composition effect of very low calorie diets and exercise. Sports Med. 1991;12(4): Dulloo AG, Miller DS. The thermogenic properties of ephedrinehethylxanthine mixtures 11: human studies. Int J Obes. 1986;10: Goldman RF, Buskirk ER. Body volume measurement by underwater weighing: description of a method. In: Brozek, J., ed. Techniques for measuring body composition. Washington, DC: National Academy of Sciences, 1961; I. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes. 1992;16: Hill JO, Drougas H, Peters JC. Physical activity and moderate obesity. In: Bouchard C, Shephard R, Stephens T, eds. Physical Activity, Fitness & Health. Toronto: Human Kinetics Publishers: King DJ, Devaney N. Clinical pharmacology of sibutramine hydrochloride (BTS 54524), a new antidepressant, in healthy volunteers. Br J Cfin Pharmac. 1988;26: Knoll Pharmaceuticals, Inc. Unpublished data on file. 15. Levitsky DA, Troiano R. Metabolic consequences of Fenfluramine for the control of body weight. Am J Cfin Nutr. 1992; 55: S. 16. Malchow-Moller A, Larsen S, Hey H, Stokholm KH, Juhl E, Quaade F. Ephedrine as an anorectic: the story of the Elsinore pill. Int J Obes. 1981;5: Morgan JB, York DA, Wasilewska A, Portman J. A study of the thermic responses to a meal and to a sympathomimetic drug (ephedrine) in relation to energy balance in man. Br J Nutr. 1982;47: Weintraub M, Rubio A, Byrne L, Scheinbaum ML. Sibutramine in weight control: A dose-ranging, efficacy study. Cfin Pharmacof Ther. 1991;50: Weir JB. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol. 1946;109: Wilmore JH. A simplified method for determination of residual lung volumes. J Appl Physiof. 1969;27: OBESITY RESEARCH Vol. 6 No. 2 Mar