Effect of Sulforaphane in Broccoli Sprouts on Nrf2 Activation

Cystic Fibrosis Clinical Trial

Official title:

Evaluation of the Effect of Sulforaphane in Broccoli Sprouts on Nrf2 Activation, Measures of Oxidative Stress, and Neutrophil Migration to Mucosal Surfaces in Healthy and CF Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01315665
• Other study ID #: UHCMC-CFRC-2011-01
• Status: Completed
• Phase: N/A
• Start date: April 2011
• Est. completion date: February 2013

Study information

• Verified date: January 2019
• Source: University Hospitals Cleveland Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study to investigate the effect of sulforaphane from macerated broccoli sprouts in humans and to evaluate less invasive methods of assessing potential anti-inflammatory drugs in CF.

Description:

The hypothesis to be tested is that sulforaphane consumed from macerated broccoli sprouts will activate Nrf2, reduce oxidative metabolites and reduce neutrophils in the oral mucosa after 5 days of therapy in healthy volunteers and CF subjects.

The study requires 6 brief outpatient visits over 8 days. Study procedures include medical history, height, weight, vital signs, blood and urine collection, nasal curettage, saline mouthwash, and ingestion of broccoli sprouts (100 gm of 3 to 5 day old raw broccoli sprouts once daily for 5 consecutive days).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: February 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 49 Years

Eligibility

Inclusion Criteria:

• Healthy volunteers and patients with cystic fibrosis = 18 < 50 years of age

• Healthy volunteers must be in general good health as determined by a medical history

• CF subjects must have a documented diagnosis of CF (positive sweat chloride = 60 mEq/liter, by pilocarpine iontophoresis) and/or a genotype with two identifiable mutations consistent with CF accompanied by one or more clinical features with the CF) phenotype

• CF subjects must have a baseline FEV1 percent predicted > 50% (in the last year, obtained from medical record)

• CF subjects must be clinically stable: free of any acute illness for > 14 days CF subjects must not have been prescribed any new systemic antibiotics for the 14 days prior to enrollment

• Ability to provide written informed consent

• Ability to adhere to the protocol

Exclusion Criteria:

• Use of NSAIDS (e.g., ibuprofen) or corticosteroids including inhaled steroids for the 4 weeks prior to enrollment

• Active gingival disease (active tooth or gum disease)

• History of nephrolithiasis or cholelithiasis

• Allergy to broccoli

• Any chronic condition that compromises the participant as determined by medical history

• Pregnancy

• Inability to tolerate the study procedures

• CF subjects: Infected with B. cepacia

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Dietary Supplement:
• Broccoli sprouts
Subjects (both healthy volunteers and subjects with cystic fibrosis) will consume 100 gm of raw broccoli sprouts once daily for 5 consecutive days.

Locations

Country	Name	City	State
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
University Hospitals Cleveland Medical Center	Cystic Fibrosis Foundation

Country where clinical trial is conducted

United States, 

References & Publications (19)

Ahmad R, Raina D, Meyer C, Kharbanda S, Kufe D. Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179. J Biol Chem. 2006 Nov 24;281(47):35764-9. Epub 2006 Sep 24. — View Citation

Chen J, Kinter M, Shank S, Cotton C, Kelley TJ, Ziady AG. Dysfunction of Nrf-2 in CF epithelia leads to excess intracellular H2O2 and inflammatory cytokine production. PLoS One. 2008;3(10):e3367. doi: 10.1371/journal.pone.0003367. Epub 2008 Oct 10. — View Citation

Chmiel JF, Berger M, Konstan MW. The role of inflammation in the pathophysiology of CF lung disease. Clin Rev Allergy Immunol. 2002 Aug;23(1):5-27. Review. — View Citation

Chmiel JF, Konstan MW. Inflammation and anti-inflammatory therapies for cystic fibrosis. Clin Chest Med. 2007 Jun;28(2):331-46. Review. — View Citation

Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, Sporn MB, Talalay P. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4584-9. Epub 2005 Mar 14. — View Citation

Escotte S, Tabary O, Dusser D, Majer-Teboul C, Puchelle E, Jacquot J. Fluticasone reduces IL-6 and IL-8 production of cystic fibrosis bronchial epithelial cells via IKK-beta kinase pathway. Eur Respir J. 2003 Apr;21(4):574-81. — View Citation

Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, Bujan J, Finder J, Lester M, Quittell L, Rosenblatt R, Vender RL, Hazle L, Sabadosa K, Marshall B; Cystic Fibrosis Foundation, Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007 Nov 15;176(10):957-69. Epub 2007 Aug 29. — View Citation

Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med. 1995 Mar 30;332(13):848-54. — View Citation

Konstan MW, Krenicky JE, Finney MR, Kirchner HL, Hilliard KA, Hilliard JB, Davis PB, Hoppel CL. Effect of ibuprofen on neutrophil migration in vivo in cystic fibrosis and healthy subjects. J Pharmacol Exp Ther. 2003 Sep;306(3):1086-91. Epub 2003 Jun 13. — View Citation

Konstan MW, Schluchter MD, Xue W, Davis PB. Clinical use of Ibuprofen is associated with slower FEV1 decline in children with cystic fibrosis. Am J Respir Crit Care Med. 2007 Dec 1;176(11):1084-9. Epub 2007 Sep 13. — View Citation

Konstan MW. Ibuprofen therapy for cystic fibrosis lung disease: revisited. Curr Opin Pulm Med. 2008 Nov;14(6):567-73. doi: 10.1097/MCP.0b013e32831311e8. Review. — View Citation

Lands LC, Stanojevic S. Oral non-steroidal anti-inflammatory drug therapy for cystic fibrosis. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD001505. Review. Update in: Cochrane Database Syst Rev. 2013;6:CD001505. — View Citation

Li J, Johnson XD, Iazvovskaia S, Tan A, Lin A, Hershenson MB. Signaling intermediates required for NF-kappa B activation and IL-8 expression in CF bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2003 Feb;284(2):L307-15. Epub 2002 Sep 27. — View Citation

Liby K, Hock T, Yore MM, Suh N, Place AE, Risingsong R, Williams CR, Royce DB, Honda T, Honda Y, Gribble GW, Hill-Kapturczak N, Agarwal A, Sporn MB. The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res. 2005 Jun 1;65(11):4789-98. — View Citation

Nichols DP, Ziady AG, Shank SL, Eastman JF, Davis PB. The triterpenoid CDDO limits inflammation in preclinical models of cystic fibrosis lung disease. Am J Physiol Lung Cell Mol Physiol. 2009 Nov;297(5):L828-36. doi: 10.1152/ajplung.00171.2009. Epub 2009 Aug 21. — View Citation

Oermann CM, Sockrider MM, Konstan MW. The use of anti-inflammatory medications in cystic fibrosis: trends and physician attitudes. Chest. 1999 Apr;115(4):1053-8. — View Citation

Shishodia S, Sethi G, Konopleva M, Andreeff M, Aggarwal BB. A synthetic triterpenoid, CDDO-Me, inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells. Clin Cancer Res. 2006 Mar 15;12(6):1828-38. — View Citation

Verhaeghe C, Remouchamps C, Hennuy B, Vanderplasschen A, Chariot A, Tabruyn SP, Oury C, Bours V. Role of IKK and ERK pathways in intrinsic inflammation of cystic fibrosis airways. Biochem Pharmacol. 2007 Jun 15;73(12):1982-94. Epub 2007 Mar 24. — View Citation

Yates MS, Tauchi M, Katsuoka F, Flanders KC, Liby KT, Honda T, Gribble GW, Johnson DA, Johnson JA, Burton NC, Guilarte TR, Yamamoto M, Sporn MB, Kensler TW. Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Mol Cancer Ther. 2007 Jan;6(1):154-62. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Nrf2 Activation in Nasal Epithelial Cells	Number of subjects with activated Nrf-2 in the cytoplasm of nasal epithelial cells after 5 days of study treatment (consuming broccoli sprouts)	Baseline and of end of 5 day treatment period
Secondary	Measures of Lipid Peroxidation in Nasal Epithelial Cells	Products of lipid peroxidation will be determined by western blot analysis on nasal epithelial cells obtained by curettage after 5 days of study treatment (consuming broccoli sprouts)	End of 5 day treatment period
Secondary	Measures of Glutathione From Blood Lymphocytes	Change in lymphocyte glutathione measurements after 5 days of study treatment (consuming broccoli sprouts).	Baseline and end of 5 day treatment period
Secondary	Measures of Oxidative Stress in Urine	Change in urine bromotyrosine (measured by mass spectrometry) will be measured after 5 days of study treatment (consuming broccoli sprouts).	Baseline and end of 5 day treatment period
Secondary	Measure of Neutrophil Migration Into the Gingival Crevices	Change in gingival neutrophils measured after 5 days of study treatment (consuming broccoli sprouts). Patients will perform mouthwashes with normal saline. Neutrophil counts will be performed on fresh samples. Acridine orange will be added to the saline rinses and neutrophils will be counted under the microscope.	Baseline and end of 5 day treatment period