Ignite Creation Date:
2024-05-06 @ 2:26 AM
Last Modification Date:
2024-10-26 @ 11:18 AM
Study NCT ID:
NCT02048215
Status:
COMPLETED
Last Update Posted:
2014-01-29
First Post:
2014-01-22
Brief Title:
Effect on Energy Metabolism at Cellular Level of Diet Plus Treatment With Ephedrine and Caffeine in Obesity
Sponsor:
Istituto Auxologico Italiano
Organization:
Istituto Auxologico Italiano
Study Overview
Official Title:
Evaluation of Diet and Treatment With a Combination of Ephedrine and Caffeine on Thermogenesis Cardiac Function and on Uncoupling Proteins Expression in Adipose and Muscle Tissue of Morbid Obese Patients Undergoing Bariatric Surgery
Status:
COMPLETED
Status Verified Date:
2014-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Brief Summary This trial was part of a sub-project targeted to diet thermogenesis and obesity of a larger multicentre study named Interaction between nutritional social-behavioral and metabolic factors for prevention of cardiovascular disease development of nutritional strategies on general population
Ephedrine and caffeine EC combination has been widely used in human obesity treatment It is known that this drug increases the metabolic rate in both animals and humans Ephedrine is an agonist of both α and β-adrenoceptors moreover it induces norepinephrine release from sympathetic neurons Caffeine increases both norepinephrine and dopamine release and stimulates the neuronal activity in several brain regions We hypothesize that EC treatment might exert a specific effect on lipolysis and thermogenesis by stimulation of beta-3 adrenoreceptors on adipose tissue and by stimulating uncoupling of oxidative phosphorylation ie energy being dissipated as heat rather than being converted to adenosine triphosphate ATP
Our study is a double-blind placebo-controlled 4-week trial to investigate the effect of hypocaloric diet alone or coupled to EC treatment of morbidly obese women on thermogenesis expression of UCP 3 in muscle tissue and of beta-3 adrenoreceptors in adipose tissue Subjects are randomly assigned to EC 20020 mg or to placebo administered three times a day orally together with a energy-deficit diet 70 of resting energy expenditure starting one month before undergoing bariatric surgery Primary study endpoints are weight change analysed by intention to treat changes in resting energy expenditure UCP3 long and short isoform messenger ribonucleic acid mRNA levels in rectus abdominis and immunostaining for beta-3 adrenoreceptors in subcutaneous and omental adipose tissue Also plasma epinephrine norepinephrine triglycerides free fatty acids glycerol TSH free thyroxine fT4 free triiodothyronine fT3 fasting glucose insulin and homeostasis model assessment HOMA index are measured at baseline and at the end of treatments
Ephedrine and caffeine EC combination has been widely used in human obesity treatment It is known that this drug increases the metabolic rate in both animals and humans Ephedrine is an agonist of both α and β-adrenoceptors moreover it induces norepinephrine release from sympathetic neurons Caffeine increases both norepinephrine and dopamine release and stimulates the neuronal activity in several brain regions We hypothesize that EC treatment might exert a specific effect on lipolysis and thermogenesis by stimulation of beta-3 adrenoreceptors on adipose tissue and by stimulating uncoupling of oxidative phosphorylation ie energy being dissipated as heat rather than being converted to adenosine triphosphate ATP
Our study is a double-blind placebo-controlled 4-week trial to investigate the effect of hypocaloric diet alone or coupled to EC treatment of morbidly obese women on thermogenesis expression of UCP 3 in muscle tissue and of beta-3 adrenoreceptors in adipose tissue Subjects are randomly assigned to EC 20020 mg or to placebo administered three times a day orally together with a energy-deficit diet 70 of resting energy expenditure starting one month before undergoing bariatric surgery Primary study endpoints are weight change analysed by intention to treat changes in resting energy expenditure UCP3 long and short isoform messenger ribonucleic acid mRNA levels in rectus abdominis and immunostaining for beta-3 adrenoreceptors in subcutaneous and omental adipose tissue Also plasma epinephrine norepinephrine triglycerides free fatty acids glycerol TSH free thyroxine fT4 free triiodothyronine fT3 fasting glucose insulin and homeostasis model assessment HOMA index are measured at baseline and at the end of treatments
Detailed Description:
This trial was part of a sub-project of a multicentre study named Interaction between nutritional social-behavioral and metabolic factors for prevention of cardiovascular disease development of nutritional strategies on general population approved by the Italian Ministry of Health The sub-project was specifically addressed to diet thermogenesis and obesity
1 Ephedrine and caffeine EC combination has been widely used in human obesity treatment and is still present in many herbal preparations sold widespread in many countries for weight loss It is well known that this drug increases the metabolic rate in both animals and humans Ephedrine is an agonist of both α and β-adrenoceptors moreover it induces norepinephrine release from sympathetic neurons and thus is a sympatho-mimetic drug with a mixed profile Caffeine increases both norepinephrine and dopamine release and stimulates the neuronal activity in several brain regions In addition caffeine antagonizes the inhibitory effects of adenosine on sympathetic nervous system SNS This modulation of SNS activity may be a possible explanation for the thermic effect of EC In fact epinephrine activates the uncoupling protein 1 UCP1 a member of mitochondrial carriers localized on the inner mitochondrial membrane in brown adipocytes The physiological role of UCP1 is to uncouple oxidative phosphorylation therefore most of the energy is dissipated as heat rather than being converted to ATP UCP1 is unique to brown adipocyte mitochondria although brown-like multilocular adipocytes expressing UCP1 interspersed within human WAT have been observed Actually UCP1 mRNA has been detected in all adipose tissues in adult humans and it has been estimated that 1 in 100-200 adipocytes in human intraperitoneal adipose tissue expresses UCP1 It has been shown that the cold-induced occurrence of brown-like adipocytes and UCP1 requires the presence of the β3-adrenoceptor in previously white adipose tissue and the presence of the β3-adrenoceptor is required for full stimulation of energy expenditure and oxygen consumption in white adipose tissue
In addition to UCP1 expressed exclusively in brown adipose tissue BAT another member of the mitochondrial anion carrier protein family ie uncoupling protein 3 UCP3 could play a physiological role in energy homeostasis It is expressed almost exclusively in skeletal muscle and exhibits two transcriptional isoforms a long form UCP3L and a short form UCP3S A brief caloric restriction resulted in 2- to 3-fold increase in UCP3 mRNA levels in lean and obese humans
2 Because only a few small studies have been done in humans to investigate the thermogenic effects of EC as compared to diet only in the present study we examined the UCP3 expression in skeletal muscle and the beta-3 adrenoceptor expression in adipose tissue of pre-menopausal morbidly obese females treated with either placebo or EC for 30 days who subsequently underwent bariatric surgery
3 Study subjects are adult females with morbid obesity ie body mass index 40 kgm2 selected from the waiting list for bariatric surgery at Department of Surgery Molinette Hospital Turin Italy During the treatment period all patients are fed a hypocaloric diet total energy content of 70 of energy expenditure as measured by indirect calorimetry and containing 20 proteins 55 carbohydrates 25 fat half of which was monounsaturated and 35 gday fibres Patients are randomised to 30-day treatment with either EC 20020mg tid or placebo They are hospitalised during the whole treatment period at the metabolic unit of San Giuseppe Hospital-Istituto Auxologico Italiano at Piancavallo VB Italy The EC administration starts with an initial dose of 10010 mg tid for the first week and then proceeds with the full dose of 20020 mg tid Resting energy expenditure is measured by indirect calorimetry at baseline and at the end of the study The study pills active compound and placebo were prepared by the Hospitals Pharmacy
4 In order to evaluate drug safety and effect on cardiac function the blood pressure is measured three times a day both electrocardiography and echocardiography are being recorded at baseline and every week After diet and drug period the patients are transferred to the Department of Surgery Molinette Hospital Turin for the bariatric surgery The drug treatment EC and placebo is stopped the day before surgical intervention Small biopsies of rectus abdominis and of subcutaneous and omental adipose tissues are taken during surgery immediately frozen in liquid nitrogen and stored at -80C for subsequent analysis
5 UCP3S and UCP3L mRNA levels are measured by quantitative polymerase chain reaction at the Department of Pharmacology University of Milan Presence of beta-3 adrenoceptor in adipose tissue is evaluated by immunohistochemistry by the avidin-biotin peroxidase technique using monoclonal anti-human beta 3-adrenoceptor antibody at the Department of Human Anatomy University of Ancona
1 Ephedrine and caffeine EC combination has been widely used in human obesity treatment and is still present in many herbal preparations sold widespread in many countries for weight loss It is well known that this drug increases the metabolic rate in both animals and humans Ephedrine is an agonist of both α and β-adrenoceptors moreover it induces norepinephrine release from sympathetic neurons and thus is a sympatho-mimetic drug with a mixed profile Caffeine increases both norepinephrine and dopamine release and stimulates the neuronal activity in several brain regions In addition caffeine antagonizes the inhibitory effects of adenosine on sympathetic nervous system SNS This modulation of SNS activity may be a possible explanation for the thermic effect of EC In fact epinephrine activates the uncoupling protein 1 UCP1 a member of mitochondrial carriers localized on the inner mitochondrial membrane in brown adipocytes The physiological role of UCP1 is to uncouple oxidative phosphorylation therefore most of the energy is dissipated as heat rather than being converted to ATP UCP1 is unique to brown adipocyte mitochondria although brown-like multilocular adipocytes expressing UCP1 interspersed within human WAT have been observed Actually UCP1 mRNA has been detected in all adipose tissues in adult humans and it has been estimated that 1 in 100-200 adipocytes in human intraperitoneal adipose tissue expresses UCP1 It has been shown that the cold-induced occurrence of brown-like adipocytes and UCP1 requires the presence of the β3-adrenoceptor in previously white adipose tissue and the presence of the β3-adrenoceptor is required for full stimulation of energy expenditure and oxygen consumption in white adipose tissue
In addition to UCP1 expressed exclusively in brown adipose tissue BAT another member of the mitochondrial anion carrier protein family ie uncoupling protein 3 UCP3 could play a physiological role in energy homeostasis It is expressed almost exclusively in skeletal muscle and exhibits two transcriptional isoforms a long form UCP3L and a short form UCP3S A brief caloric restriction resulted in 2- to 3-fold increase in UCP3 mRNA levels in lean and obese humans
2 Because only a few small studies have been done in humans to investigate the thermogenic effects of EC as compared to diet only in the present study we examined the UCP3 expression in skeletal muscle and the beta-3 adrenoceptor expression in adipose tissue of pre-menopausal morbidly obese females treated with either placebo or EC for 30 days who subsequently underwent bariatric surgery
3 Study subjects are adult females with morbid obesity ie body mass index 40 kgm2 selected from the waiting list for bariatric surgery at Department of Surgery Molinette Hospital Turin Italy During the treatment period all patients are fed a hypocaloric diet total energy content of 70 of energy expenditure as measured by indirect calorimetry and containing 20 proteins 55 carbohydrates 25 fat half of which was monounsaturated and 35 gday fibres Patients are randomised to 30-day treatment with either EC 20020mg tid or placebo They are hospitalised during the whole treatment period at the metabolic unit of San Giuseppe Hospital-Istituto Auxologico Italiano at Piancavallo VB Italy The EC administration starts with an initial dose of 10010 mg tid for the first week and then proceeds with the full dose of 20020 mg tid Resting energy expenditure is measured by indirect calorimetry at baseline and at the end of the study The study pills active compound and placebo were prepared by the Hospitals Pharmacy
4 In order to evaluate drug safety and effect on cardiac function the blood pressure is measured three times a day both electrocardiography and echocardiography are being recorded at baseline and every week After diet and drug period the patients are transferred to the Department of Surgery Molinette Hospital Turin for the bariatric surgery The drug treatment EC and placebo is stopped the day before surgical intervention Small biopsies of rectus abdominis and of subcutaneous and omental adipose tissues are taken during surgery immediately frozen in liquid nitrogen and stored at -80C for subsequent analysis
5 UCP3S and UCP3L mRNA levels are measured by quantitative polymerase chain reaction at the Department of Pharmacology University of Milan Presence of beta-3 adrenoceptor in adipose tissue is evaluated by immunohistochemistry by the avidin-biotin peroxidase technique using monoclonal anti-human beta 3-adrenoceptor antibody at the Department of Human Anatomy University of Ancona
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None