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Effect on Energy Metabolism at Cellular Level of Diet Plus Treatment With Ephedrine and Caffeine in Obesity

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ClinicalTrials.gov Identifier: NCT02048215
Recruitment Status : Completed
First Posted : January 29, 2014
Last Update Posted : January 29, 2014
Sponsor:
Collaborators:
University of Milan
Università Politecnica delle Marche
Information provided by (Responsible Party):
Istituto Auxologico Italiano

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, i.e. 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 (200/20 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.


Condition or disease Intervention/treatment Phase
Obesity Drug: Caffeine Drug: Placebo Drug: Ephedrine Other: Hypocaloric diet Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
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.
Study Start Date : February 2000
Actual Primary Completion Date : January 2001
Actual Study Completion Date : November 2007


Arm Intervention/treatment
Active Comparator: Ephedrine + Caffeine + diet
Ephedrine 20 mg + Caffeine 200 mg capsule t.i.d. for one month plus hypocaloric diet
Drug: Caffeine
Patients are randomised to 30-day treatment with either EC (200/20mg t.i.d.) or placebo. The EC administration starts with an initial dose of 100/10 mg t.i.d. for the first week and then proceeds with the full dose of 200/20 mg t.i.d. Patients are hospitalised during the whole treatment period, at the metabolic unit of San Giuseppe Hospital-Istituto Auxologico Italiano at Piancavallo (VB, 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 g/day fibres.
Other Name: Randomization number 2, 4, 5, 6, 8, 11

Drug: Ephedrine
Patients are randomised to 30-day treatment with either EC (200/20mg t.i.d.) or placebo. The EC administration starts with an initial dose of 100/10 mg t.i.d. for the first week and then proceeds with the full dose of 200/20 mg t.i.d. Patients are hospitalised during the whole treatment period, at the metabolic unit of San Giuseppe Hospital-Istituto Auxologico Italiano at Piancavallo (VB, 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 g/day fibres.
Other Name: Randomization number 2, 4, 5, 6, 8, 11

Other: Hypocaloric diet
Patients are randomised to 30-day treatment with either EC (200/20mg t.i.d.) or placebo. The EC administration starts with an initial dose of 100/10 mg t.i.d. for the first week and then proceeds with the full dose of 200/20 mg t.i.d. Patients are hospitalised during the whole treatment period, at the metabolic unit of San Giuseppe Hospital-Istituto Auxologico Italiano at Piancavallo (VB, 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 g/day fibres.
Other Name: Low-calorie diet 70% of measured energy expenditure

Placebo Comparator: Placebo + diet
Similarly-looking placebo capsule t.i.d. for one month plus hypocaloric diet
Drug: Placebo
Patients are randomised to 30-day treatment with either EC (200/20mg t.i.d.) or placebo. The EC administration starts with an initial dose of 100/10 mg t.i.d. for the first week and then proceeds with the full dose of 200/20 mg t.i.d. Patients are hospitalised during the whole treatment period, at the metabolic unit of San Giuseppe Hospital-Istituto Auxologico Italiano at Piancavallo (VB, 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 g/day fibres.
Other Name: Randomization number 1, 3, 7, 9, 10, 12, 13

Other: Hypocaloric diet
Patients are randomised to 30-day treatment with either EC (200/20mg t.i.d.) or placebo. The EC administration starts with an initial dose of 100/10 mg t.i.d. for the first week and then proceeds with the full dose of 200/20 mg t.i.d. Patients are hospitalised during the whole treatment period, at the metabolic unit of San Giuseppe Hospital-Istituto Auxologico Italiano at Piancavallo (VB, 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 g/day fibres.
Other Name: Low-calorie diet 70% of measured energy expenditure




Primary Outcome Measures :
  1. Change in resting energy expenditure [ Time Frame: Baseline and 1 month ]
    Resting energy expenditure is measured by indirect calorimetry


Secondary Outcome Measures :
  1. Blood pressure monitoring [ Time Frame: Baseline and daily for 30 days (t.i.d.) ]
  2. Electrocardiograpic monitoring [ Time Frame: Baseline and at week 2,3,4 ]
  3. Cardiac ultrasound monitoring [ Time Frame: Baseline and at week 2,3,4 ]
    Cardiac ultrasound measurement for assessing possible detrimental changes

  4. Changes in fasting glucose [ Time Frame: Baseline and at one month ]
    Patients are assessed by oral glucose tolerance test at baseline and following one month of treatment, with assessment of glucose, insulin, free-fatty acids and glycerol

  5. Changes in fasting insulin [ Time Frame: baseline and one month ]
    Patients are assessed by oral glucose tolerance test at baseline and following one month of treatment, with assessment of glucose, insulin, free-fatty acids and glycerol

  6. Changes in fasting free fatty acids [ Time Frame: baseline ans one month ]
    Patients are assessed by oral glucose tolerance test at baseline and following one month of treatment, with assessment of glucose, insulin, free-fatty acids and glycerol

  7. Changes in fasting glycerol [ Time Frame: baseine and one month ]
    Patients are assessed by oral glucose tolerance test at baseline and following one month of treatment, with assessment of glucose, insulin, free-fatty acids and glycerol

  8. Changes in thyroid function (TSH, T3, T4) [ Time Frame: Baseline and 1 month ]
  9. Changes in plasma noradrenalin [ Time Frame: Baseline and 1 month ]
  10. Changes in body weight [ Time Frame: baseline and 1 month ]
  11. Beta-3 adrenoceptor expression in human adipose tissue [ Time Frame: one month ]
    Beta-3 adrenoceptor expression is measured in subcutaneous and omental tissue sampled during bariatric surgery following one month of pharmacological intervention

  12. UCP-3 expression in human muscle tissue [ Time Frame: One month ]
    UCP-3 expression is measured in rectus abdominis muscle tissue sampled during bariatric surgery following one month of pharmacological intervention



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • pre-menopausal females
  • body mass index ≥ 40 kg/m2
  • with stable weight in the three month before the study
  • scheduled for bariatric surgery
  • in whom weight loss was clinically advisable before surgery to reduce surgical risk
  • non-smokers or smoking less than 5 cigarettes per day

Exclusion Criteria:

  • pregnancy
  • ischaemic heart disease
  • cardiac failure
  • high blood pressure requiring drug treatment
  • tachyarrhythmia
  • sick sinus syndrome
  • atrioventricular block
  • two-bundle ventricular block
  • cerebrovascular diseases
  • occlusive peripheral artery disease
  • renal failure
  • current treatment with drugs that might affect metabolic rate (e.g. β-adrenergic blockers, thyroid hormones).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02048215


Locations
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Italy
Istituto Auxologico Italiano -Ospedale San Giuseppe
Verbania, VB, Italy, 28824
Sponsors and Collaborators
Istituto Auxologico Italiano
University of Milan
Università Politecnica delle Marche
Investigators
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Principal Investigator: Maria L Petroni, MD Istituto Auxologico Italiano
Publications of Results:
Other Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Istituto Auxologico Italiano
ClinicalTrials.gov Identifier: NCT02048215    
Other Study ID Numbers: THERMODIET
First Posted: January 29, 2014    Key Record Dates
Last Update Posted: January 29, 2014
Last Verified: January 2014
Keywords provided by Istituto Auxologico Italiano:
thermogenesis
low-calorie diet
uncoupling-protein 3
beta-3 adrenoceptors
thermogenic drugs
Additional relevant MeSH terms:
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Obesity
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Ephedrine
Caffeine
Central Nervous System Stimulants
Physiological Effects of Drugs
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Vasoconstrictor Agents
Adrenergic Agents