Effects of Trehalose and Polyphenols in Vasculopathic Patients

NCT04061070 | Completed

• 1 other identifier: PAD2307/2019 and 454/2020
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 2

Brief Summary

Peripheral arterial disease (PAD) is an important manifestation of systemic atherosclerosis and is characterized by obstruction of the arteries of the lower extremities. PAD is usually associated with vascular complications that occur not only in peripheral circulation but also in cerebral and coronary trees (PubMed ID: 9892517). Endothelial dysfunction, reduced glucose oxidation, accumulation of toxic metabolites, alteration in nitric oxide (NO) generation and oxidative stress seem to play a role among the factors that contribute to reducing blood flow in PAD patients (PubMed ID: 17298965). Hypertension is a risk factor for vascular disorders, including PAD. In fact, it has been shown that 55% of PAD patients are hypertensive. (PubMed ID: 15579058) PAD and hypertension patients have a risk of cardiovascular and cerebrovascular mortality increased two to three times compared to healthy subjects. The alteration of platelet function is implicated in the development and progression of atherosclerosis, as well as in the pathogenesis of acute cardiac ischemic events. Platelet activation is increased in patients with PAD and hypertension compared to healthy controls, suggesting a pro-thrombotic state. Polyphenols are a class of natural, synthetic and semisynthetic substances with beneficial effects on human health. In particular, the polyphenols exert their beneficial effect through 1) the inhibition of NADPH oxidase (Nox2), which is crucial for the formation of reactive oxygen species (ROS); 2) an antiplatelet effects 3) the activation of autophagy. Trehalose is a natural disaccharide that performs multiple functions such as a protective action against oxidative stress, temperature changes, accumulation of protein aggregates and dehydration. Furthermore, recent evidence has shown that trehalose could prevent inflammatory responses induced by endotoxic shock both in vivo and in vitro. Therefore the purpose of this work will be to determine in PAD and hypertension patients the effect of the intake of trehalose and a polyphenol mix on oxidative stress biomarkers, autophagic activity and endothelial dysfunction.

Conditions

Oxidative Stress; Cardiovascular Diseases

Outcome Measures

Primary Outcomes (2)

• Change o oxidative stress biomarkers in PAD patients after mix supplementation of trehalose and polyphenols

  Oxidative stress biomarkers such as Nox2 activity (pg/ml) production will be measured. Differences of these markers among patients taking or not the supplementation will be described.

  12 months

• Change o oxidative stress biomarkers in hypertensive patients after mix supplementation

  To verify whether there is a reduction in the Nox2 activity in hypertensive patients after supplementation with the trehalose and polyphenols mix.

  12 months

Secondary Outcomes (6)

• Change of autophagy in PAD and hypertensive patients patients after mix supplementation of trehalose and polyphenols

  12 months

• Change of endothelial function in PAD and hypertensive patients after mix supplementation of trehalose and polyphenols

  12 months

• Change of systolic and diastolic pressure in PAD and hypertensive patients after mix supplementation of trehalose and polyphenols

  12 months

• Analysis of maximal walking distance (MWD) in PAD patients after mix supplementation of trehalose and polyphenols

  12 months

• Analysis of maximal walking time (MWT) in PAD

  12 months

Study Arms (2)

No Intervention with the mix threalose plus polyphenols

SHAM COMPARATOR

The patients allocated in this arm will not treated with a mix of threalose plus polyphenols

Other: No Supplementation with mix of threalose plus polyphenols

Intervention with the mix threalose plus polyhenols

ACTIVE COMPARATOR

The patients allocated in this arm will treated with a mix of threalose plus polyphenols

Other: Supplementation with mix of threalose plus polyphenols

Interventions

Supplementation with mix of threalose plus polyphenols OTHER

The patients will be treated with a mix of trehalose plus polyphenols for 60 days

Intervention with the mix threalose plus polyhenols

No Supplementation with mix of threalose plus polyphenols OTHER

The patients will not be treated with a mix trehalose plus polyphenols for 60 days

No Intervention with the mix threalose plus polyphenols

Eligibility Criteria

• Age: 60 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• claudication (defined as pain in the legs during walking which disappears within 10 minutes of standing);
• ankle/brachial index (ABI), evaluated as an ankle/arm systolic blood pressure ratio using Doppler ultrasound on the worst resting leg;
• stable condition without sudden changes in ABI (\> 20%) in the last month before enrollment
• Office systolic BP (SBP) values ≥140 mmHg and/or diastolic BP (DBP) values ≥90 mmHg (average of 3 repeated measurements made by the same doctor with an oscillometric automatic sphygmomanometer). Treatment with antihypertensive drugs, namely ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), thiazide/thiazide-like diuretics, loop diuretics, mineralocorticoid receptor antagonists (MRA), beta-blockers and alpha-blockers, were considered hypertensives.

You may not qualify if:

• liver failure;
• severe kidney disorders (serum creatinine \[mt\] 2.8 mg / dL);
• acute cerebrovascular disease;
• acute myocardial infarction;
• smokers;
• patients under treatment with antioxidants for at least 30 days before enrollment
• Patients with diabetes mellitus or known history of ischemic heart disease, peripheral artery disease, and chronic renal failure were excluded.

Sponsors & Collaborators

• University of Roma La Sapienza: lead
• Peruzzi Mariangela: collaborator

Study Sites (2)

Umberto I Policlinico di Roma, Sapienza Università di Roma

Roma, Italia, 00155, Italy

Location

Umberto I Policlinico di Roma, Sapienza Università di Roma

Rome, 00155, Italy

Location

Related Publications (16)

• Criqui MH, Denenberg JO. The generalized nature of atherosclerosis: how peripheral arterial disease may predict adverse events from coronary artery disease. Vasc Med. 1998;3(3):241-5. doi: 10.1177/1358836X9800300311.

  PMID: 9892517 RESULT

• Loffredo L, Marcoccia A, Pignatelli P, Andreozzi P, Borgia MC, Cangemi R, Chiarotti F, Violi F. Oxidative-stress-mediated arterial dysfunction in patients with peripheral arterial disease. Eur Heart J. 2007 Mar;28(5):608-12. doi: 10.1093/eurheartj/ehl533. Epub 2007 Feb 13.

  PMID: 17298965 RESULT

• Dormandy J, Mahir M, Ascady G, Balsano F, De Leeuw P, Blombery P, Bousser MG, Clement D, Coffman J, Deutshinoff A, et al. Fate of the patient with chronic leg ischaemia. A review article. J Cardiovasc Surg (Torino). 1989 Jan-Feb;30(1):50-7.

  PMID: 2647761 RESULT

• Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004 Apr;6(4):463-77. doi: 10.1016/s1534-5807(04)00099-1.

  PMID: 15068787 RESULT

• Li F, Lang F, Zhang H, Xu L, Wang Y, Hao E. Role of TFEB Mediated Autophagy, Oxidative Stress, Inflammation, and Cell Death in Endotoxin Induced Myocardial Toxicity of Young and Aged Mice. Oxid Med Cell Longev. 2016;2016:5380319. doi: 10.1155/2016/5380319. Epub 2016 Apr 21.

  PMID: 27200146 RESULT

• Mizushima N. Autophagy: process and function. Genes Dev. 2007 Nov 15;21(22):2861-73. doi: 10.1101/gad.1599207.

  PMID: 18006683 RESULT

• Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008 Jan 11;132(1):27-42. doi: 10.1016/j.cell.2007.12.018.

  PMID: 18191218 RESULT

• Elbein AD, Pan YT, Pastuszak I, Carroll D. New insights on trehalose: a multifunctional molecule. Glycobiology. 2003 Apr;13(4):17R-27R. doi: 10.1093/glycob/cwg047. Epub 2003 Jan 22.

  PMID: 12626396 RESULT

• Minutoli L, Altavilla D, Bitto A, Polito F, Bellocco E, Lagana G, Giuliani D, Fiumara T, Magazu S, Ruggeri P, Guarini S, Squadrito F. The disaccharide trehalose inhibits proinflammatory phenotype activation in macrophages and prevents mortality in experimental septic shock. Shock. 2007 Jan;27(1):91-6. doi: 10.1097/01.shk.0000235092.76292.bc.

  PMID: 17172986 RESULT

• Minutoli L, Altavilla D, Bitto A, Polito F, Bellocco E, Lagana G, Fiumara T, Magazu S, Migliardo F, Venuti FS, Squadrito F. Retracted: Trehalose: a biophysics approach to modulate the inflammatory response during endotoxic shock. Eur J Pharmacol. 2008 Jul 28;589(1-3):272-80. doi: 10.1016/j.ejphar.2008.04.005. Epub 2008 Apr 12.

  PMID: 18555988 RESULT

• Schaeffer V, Lavenir I, Ozcelik S, Tolnay M, Winkler DT, Goedert M. Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain. 2012 Jul;135(Pt 7):2169-77. doi: 10.1093/brain/aws143. Epub 2012 Jun 10.

  PMID: 22689910 RESULT

• Arai C, Arai N, Mizote A, Kohno K, Iwaki K, Hanaya T, Arai S, Ushio S, Fukuda S. Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance. Nutr Res. 2010 Dec;30(12):840-8. doi: 10.1016/j.nutres.2010.10.009.

  PMID: 21147367 RESULT

• Sciarretta S, Yee D, Nagarajan N, Bianchi F, Saito T, Valenti V, Tong M, Del Re DP, Vecchione C, Schirone L, Forte M, Rubattu S, Shirakabe A, Boppana VS, Volpe M, Frati G, Zhai P, Sadoshima J. Trehalose-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction. J Am Coll Cardiol. 2018 May 8;71(18):1999-2010. doi: 10.1016/j.jacc.2018.02.066.

  PMID: 29724354 RESULT

• Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem. 2007 Feb 23;282(8):5641-52. doi: 10.1074/jbc.M609532200. Epub 2006 Dec 20.

  PMID: 17182613 RESULT

• Clement DL, De Buyzere ML, Duprez DA. Hypertension in peripheral arterial disease. Curr Pharm Des. 2004;10(29):3615-20. doi: 10.2174/1381612043382819.

  PMID: 15579058 RESULT

• Martinelli O, Peruzzi M, Bartimoccia S, D'Amico A, Marchitti S, Rubattu S, Chiariello GA, D'Ambrosio L, Schiavon S, Miraldi F, Saade W, D'Abramo M, Pingitore A, Loffredo L, Nocella C, Forte M, Pignatelli P. Natural Activators of Autophagy Increase Maximal Walking Distance and Reduce Oxidative Stress in Patients with Peripheral Artery Disease: A Pilot Study. Antioxidants (Basel). 2022 Sep 18;11(9):1836. doi: 10.3390/antiox11091836.

  PMID: 36139910 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases

Interventions

Dietary Supplements; Polyphenols

Intervention Hierarchy (Ancestors)

Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 24, 2019
• First Posted: August 19, 2019
• Study Start: December 12, 2019
• Primary Completion: September 30, 2020
• Study Completion: April 30, 2021
• Last Updated: June 18, 2023

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (2)