BNP Pharmacodynamics and Effects on Metabolism in Lean and Obese Subjects

Obesity Clinical Trial

Official title:

BNP Pharmacodynamics and Effects on Metabolism in Lean and Obese Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01977859
• Other study ID #: TRIMDFH 472930
• Status: Completed
• Phase: Phase 1
• First received: October 31, 2013
• Last updated: February 13, 2018
• Start date: November 2013
• Est. completion date: February 28, 2017

Study information

• Verified date: February 2018
• Source: Translational Research Institute for Metabolism and Diabetes, Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to collect data to help researchers better understand the various causes of obesity, which may lead to the development of new obesity treatment options.

Description:

Obesity is major metabolic health concern and the potential beneficial effects of natriuretic peptides, specifically B-type natriuretic peptide (BNP) on adipocyte biology, energy expenditure and body weight could be of great significance. This study will provide insight into the mechanisms of dysregulation of the natriuretic peptides system in obesity and will contribute to delineate the roles and the clinical importance of BNP in the treatment of obesity.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4
• Est. completion date: February 28, 2017
• Est. primary completion date: February 15, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Age 18-65 years, inclusive

• Men and women

• Able to provide written, informed consent

• Weight stable (± 3 kg) during the 3 months prior to enrollment

• BMI = 25 kg/m2 for lean subjects or = 30 kg/m2 for obese subjects

Exclusion Criteria:

• 1) Diagnosed with any of the following co-morbidities: a) coronary artery disease, angina or heart failure, b) diabetes, c) bleeding disorders, d) infections, e) hepatitis and/or cirrhosis, f) severe asthma or Chronic obstructive pulmonary disease (COPD), g) renal insufficiency, h) bariatric surgery, i) inflammatory bowel disease or malabsorption, j) cancer within the last 3 years (except non-melanoma skin cancer or treated cervical carcinoma in situ), k) psychiatric or eating disorders, l) untreated or inadequately controlled thyroid or other endocrine disorders, m) active rheumatoid arthritis or other inflammatory rheumatic disorder

• Pregnant or nursing women

• Presence of clinically significant abnormalities on electrocardiogram;

• Smoking

• Known hypersensitivity to nesiritide or any of its excipients

• Poor intravenous access

• Use of medications: a) nitrates, b) beta-blockers, c) digoxin, d) anti-diabetic agents, e) oral, injected or chronic topical steroids (inhaled steroids for mild asthma are acceptable), f) chronic use of aspirin or other non-steroidal anti-inflammatory drugs, including COX-2 inhibitors, g) other drugs known to affect immune or metabolic function and h) orlistat, phentermine or other weight loss or anorectic agents.

• Your blood pressure at your screening visit is less than or equal to 100/60 or greater than or equal to 160/100.

Related Conditions & MeSH terms

• Cardiovascular Disease
• Cardiovascular Diseases
• Diabetes
• Hypertension
• Obesity

Intervention

Drug:
• Nesiritide

• Saline

Locations

Country	Name	City	State
United States	Translational Research Institute for Metabolism and Diabetes	Orlando	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Translational Research Institute for Metabolism and Diabetes, Florida	Sanford-Burnham Medical Research Institute

Country where clinical trial is conducted

United States, 

References & Publications (18)

Aneja A, El-Atat F, McFarlane SI, Sowers JR. Hypertension and obesity. Recent Prog Horm Res. 2004;59:169-205. Review. — View Citation

Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessì-Fulgheri P, Zhang C, Takahashi N, Sarzani R, Collins S. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest. 2012 Mar;122(3):1022-36. doi: 10.1172/JCI59701. Epub 2012 Feb 6. Erratum in: J Clin Invest. 2012 Apr 2;122(4):1584. — View Citation

Freda PU, Shen W, Reyes-Vidal CM, Geer EB, Arias-Mendoza F, Gallagher D, Heymsfield SB. Skeletal muscle mass in acromegaly assessed by magnetic resonance imaging and dual-photon x-ray absorptiometry. J Clin Endocrinol Metab. 2009 Aug;94(8):2880-6. doi: 10.1210/jc.2009-0026. Epub 2009 Jun 2. — View Citation

Goodfriend TL, Kelley DE, Goodpaster BH, Winters SJ. Visceral obesity and insulin resistance are associated with plasma aldosterone levels in women. Obes Res. 1999 Jul;7(4):355-62. — View Citation

Holmes SJ, Espiner EA, Richards AM, Yandle TG, Frampton C. Renal, endocrine, and hemodynamic effects of human brain natriuretic peptide in normal man. J Clin Endocrinol Metab. 1993 Jan;76(1):91-6. — View Citation

Khan AM, Cheng S, Magnusson M, Larson MG, Newton-Cheh C, McCabe EL, Coviello AD, Florez JC, Fox CS, Levy D, Robins SJ, Arora P, Bhasin S, Lam CS, Vasan RS, Melander O, Wang TJ. Cardiac natriuretic peptides, obesity, and insulin resistance: evidence from two community-based studies. J Clin Endocrinol Metab. 2011 Oct;96(10):3242-9. doi: 10.1210/jc.2011-1182. Epub 2011 Aug 17. — View Citation

Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004 Aug 31;110(9):1042-6. Epub 2004 Aug 16. — View Citation

Mancia G, Bousquet P, Elghozi JL, Esler M, Grassi G, Julius S, Reid J, Van Zwieten PA. The sympathetic nervous system and the metabolic syndrome. J Hypertens. 2007 May;25(5):909-20. Review. — View Citation

Miyashita K, Itoh H, Tsujimoto H, Tamura N, Fukunaga Y, Sone M, Yamahara K, Taura D, Inuzuka M, Sonoyama T, Nakao K. Natriuretic peptides/cGMP/cGMP-dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity. Diabetes. 2009 Dec;58(12):2880-92. doi: 10.2337/db09-0393. Epub 2009 Aug 18. — View Citation

Pacini G, Bergman RN. MINMOD: a computer program to calculate insulin sensitivity and pancreatic responsivity from the frequently sampled intravenous glucose tolerance test. Comput Methods Programs Biomed. 1986 Oct;23(2):113-22. — View Citation

Pivovarova O, Gögebakan Ö, Klöting N, Sparwasser A, Weickert MO, Haddad I, Nikiforova VJ, Bergmann A, Kruse M, Seltmann AC, Blüher M, Pfeiffer AF, Rudovich N. Insulin up-regulates natriuretic peptide clearance receptor expression in the subcutaneous fat depot in obese subjects: a missing link between CVD risk and obesity? J Clin Endocrinol Metab. 2012 May;97(5):E731-9. doi: 10.1210/jc.2011-2839. Epub 2012 Mar 14. — View Citation

Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH; American Heart Association; Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006 Feb 14;113(6):898-918. Epub 2005 Dec 27. Review. — View Citation

Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev. 2006 Feb;27(1):47-72. Epub 2005 Nov 16. Review. — View Citation

Sarzani R, Dessì-Fulgheri P, Paci VM, Espinosa E, Rappelli A. Expression of natriuretic peptide receptors in human adipose and other tissues. J Endocrinol Invest. 1996 Oct;19(9):581-5. — View Citation

Stein CJ, Colditz GA. The epidemic of obesity. J Clin Endocrinol Metab. 2004 Jun;89(6):2522-5. Review. — View Citation

Tsukamoto O, Fujita M, Kato M, Yamazaki S, Asano Y, Ogai A, Okazaki H, Asai M, Nagamachi Y, Maeda N, Shintani Y, Minamino T, Asakura M, Kishimoto I, Funahashi T, Tomoike H, Kitakaze M. Natriuretic peptides enhance the production of adiponectin in human adipocytes and in patients with chronic heart failure. J Am Coll Cardiol. 2009 Jun 2;53(22):2070-7. doi: 10.1016/j.jacc.2009.02.038. — View Citation

Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Wilson PW, Vasan RS. Impact of obesity on plasma natriuretic peptide levels. Circulation. 2004 Feb 10;109(5):594-600. — View Citation

Welch S, Gebhart SS, Bergman RN, Phillips LS. Minimal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects. J Clin Endocrinol Metab. 1990 Dec;71(6):1508-18. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Difference in level of B-type Natriuretic Peptide (BNP)	Blood samples will be obtained at baseline, during the infusion and after the termination of the infusion for measurement of levels of recombinant human BNP (rhBNP) and N-terminal pro-brain natriuretic peptide (NTpro-BNP).	Days -2, 7, 14
Secondary	Differences in the expression of NPRC	Natriuretic peptides Type-A and Type-C (NPRA,NPRC) expression will be measured by RT-PCR in subcutaneous abdominal adipose tissue samples obtained by percutaneous biopsy prior to infusion of rhBNP and related to the Metabolic Clearance Rate (MCR) for BNP	Day 7
Secondary	Determine whether short term infusion of rhBNP increases metabolic rate and/or fat oxidation	Energy expenditure and substrate oxidation rates will be measured for 30 min at baseline, prior to the infusion of BNP, then continuously during the rhBNP infusion in a 3200 Liters Flex Room Calorimeter respiratory chambers.	Day 7
Secondary	determine whether short term infusion of rhBNP alters gene expression in subcutaneous adipose tissue and skeletal muscle in a pattern consistent with activation of thermogenic pathways	Adipose tissue will be obtained from subcutaneous abdominal sites and skeletal muscle from the vastus lateralis by percutaneous biopsy prior to and after the infusion of rhBNP. The expression of Uncoupling Protein 1 (UCP1), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 a (PGC-1a), cytochrome c and PR domain containing 16 (PRDM16) (a significant factor in brown adipogenesis) will be measured by Reverse transcription polymerase chain reaction (RT-PCR).	Day 7
Secondary	Difference in responses of lean and obese subjects	Blood pressure and heart rate will be monitored at 10 minute intervals with an automated blood pressure cuff to measure physiological response and to monitor hemodynamic status and safety. Fractional sodium excretion, cGMP and creatinine, and total urine output in response to the rhBNP infusion will be compared in lean and obese subjects. Blood samples will be obtained at baseline, during the infusion and after termination of the infusion for measurement of cyclic Guanosine 3´,5´-Cyclic Monophosphate (cGMP), Plasma Renin Activity (PRA), Aldosterone (ALD), Renin (REN), NE, glucose, insulin, Non-essential fatty acid (NEFA), glycerol, adiponectin, C-Reactive Protein (CRP), Tumor Necrosis Factor- a (TNF-a) and other cytokines/chemokines.	Days -2, 7, 14

External Links

•   Translational Research Institute for Metabolism and Diabetes