Pilot Study of Losartan and N-acetylcysteine as Inhibitors of Muscle Oxidative Stress in Elderly

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Lantheus Medical Imaging
Information provided by (Responsible Party):
The University of Texas, Galveston
ClinicalTrials.gov Identifier:
NCT01384591
First received: June 23, 2011
Last updated: January 31, 2014
Last verified: January 2014
  Purpose

The general hypothesis is that elderly have diminished nutritive flow to skeletal muscle and impaired capacity for building of muscles. In aging populations, this decreased ability to build muscles may represent a tipping point in the progression towards chronic physical frailty and disability. The goal is to examine whether novel pharmacologic therapies can improve nutritive blood flow to the muscles and muscle building in the elderly.

The purpose of this study is 1) to determine if losartan administration will enhance the building of muscles via proteins and suppress muscle breakdown 2) to determine if N-acetylcysteine (NAC) will enhance blood flow to muscles and the building of muscles via proteins.

The investigators will study community dwelling, healthy older men and women (60-85 years). Subjects will be randomized to one of three groups:

Experimental Group 1: Placebo losartan and placebo N-acetylcysteine (NAC). Experimental Group 2: losartan (25mg/dose) and placebo N-acetylcysteine (NAC). Experimental Group 3: N-acetylcysteine (NAC) (50 mg/kg/dose) and placebo

Subjects will admit the night before and get their first dose of NAC/ losartan/ placebo with dinner. Subjects will be fasted after 10 pm. The next morning at 6 am blood samples will be taken and leg blood flow (LBF) will be measured. Subjects will receive their second dose of NAC/ losartan/ placebo. As from 6 am every hour blood will be drawn until 1 pm. At 8am, the second biopsy is taken and LFB and CEU will be measured. At 11am they get their third dose of NAC/ losartan/ placebo together with leucine (oral) and again a muscle biopsy is taken and LBF is measured. Leucine is anabolic to skeletal muscle of elderly and so the investigators will use it to stimulate muscle building.


Condition Intervention Phase
Aging
Drug: N-acetylcysteine
Drug: Losartan
Other: PLacebo losartan and placebo NAC
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Pilot Study of Losartan and N-acetylcysteine as Inhibitors of Muscle Oxidative Stress in Elderly

Resource links provided by NLM:


Further study details as provided by The University of Texas, Galveston:

Primary Outcome Measures:
  • Lean body mass [ Time Frame: Patients will be in the clinical research center for 24 hours. They admit at 3pm, stay overnight and will be discharged at 3pm the next day. Lean body mass will be measured once, the first day of their 24hr stay at 6pm. ] [ Designated as safety issue: No ]
    Lean body mass will be determined by DEXA (GE Lunar iDXA). The same operator will perform all analyses. Whole-body scan will be divided in subregions: Truncal area, android, gynoid, right and left arm, and right and left leg.

  • Fatigue [ Time Frame: Patients will be in the clinical research center for 24 hours. They admit at 3pm, stay overnight and will be discharged at 3pm the next day. Fatigue will be measured 3 times: the night before, at 9am the next morning and at 1pm. ] [ Designated as safety issue: No ]
    Muscle strength will be measured using a Biodex 4 dynamometer, as described above under "Muscle function testing".

  • Fractional synthetic rate (FSR) [ Time Frame: Patients will be in the clinical research center for 24 hours. They admit at 3pm, stay overnight and will be discharged at 3pm the next day. FSR will be measured 4 times: at 8am, 11 am, noon and 1pm ] [ Designated as safety issue: No ]
    Fractional synthetic rate (FSR) of muscle protein synthesis will be measured in the basal and absorptive period during the stable isotope infusion protocol. We will measure changes in basal and absorptive muscle protein synthesis.


Secondary Outcome Measures:
  • Blood Flow and Muscle Perfusion [ Time Frame: Leg blood flow will be measured 7 times: the night before at 6pm, 6,7,8am and 11,am, noon and 1pm. Perfusion will be measured 3 times: the night before, at 8am and 1pm. ] [ Designated as safety issue: No ]
    Mean Arterial Blood Flow Velocity in the femoral artery will be measured using a Doppler ultrasound system (HDI-5000; Philips Medical Systems, Bothell, WA). Microvascular Blood Flow Velocity in the vastus lateralis muscle will be measured with Contrast-Enhanced Ultrasound using an intravenously infused suspension of octafluoropropane gas-filled albumin microbubbles (Definity®, Lantheus Medical).

  • Signaling pathways involved in muscle protein synthesis and degradation [ Time Frame: Biopsies will be taken 4 times at the second day at 8am, 11 am, noon and 1 pm. ] [ Designated as safety issue: No ]
    Protein expression and IGF-1, total abundance and phoshorylation of AMPK-α, Akt, mTOR, S6K1, FoxO1, FoxO3, FoxO4, GSK-3β, eIF-2β, eIF-4, 4E-BP1and Smad 2/3 will be measured. Nuclear activation of NF-κB will be determined. Serum and muscle inflammatory biomarkers (TNF-a, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, GM-CSF, IFN-γ, and TGF-β) will be assessed by immunoassays. Hormone immunoassays will include serum CRP, IGF-I, IGFBP-3, insulin, hGH, C-peptide, and urinary cortisol. Serum levels of losartan, angiotensin, renin, and aldosterone will be measured.

  • Muscle morphology and satellite cell activation. [ Time Frame: Patients will be in the clinical research center for 24 hours. They admit at 3pm, stay overnight and will be discharged at 3pm the next day. Biopsies will be taken 4 times at the second day at 8am, 11 am, noon and 1 pm. ] [ Designated as safety issue: No ]
    Muscle morphology will be determined using immunohistochemical techniques. Muscle fiber cross sectional area (CSA), proportion, and assessment of intramuscular oxidative enzyme content, glycolytic enzyme content, and lipid content will be determined using standard methods. Satellite cell content will be determined using anti-CD56 antibody directed against the neural cell adhesion molecule (NCAM)identical to the Leu 19 antigen) [Clone MOC-1, (DakoCytomation, Carpinteria, CA) and Pax7.


Estimated Enrollment: 24
Study Start Date: July 2011
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: losartan and placebo NAC
Intervention: losartan (25mg/dose) (and placebo N-acetylcysteine (NAC))
Drug: Losartan
25mg/dose. They get this the night before with dinner, at 6am when fasted and at 11am with a meal.
Other Name: Cozaar
Placebo Comparator: Placebo losartan and placebo NAC
Placebo losartan and placebo N-acetylcysteine (NAC)
Other: PLacebo losartan and placebo NAC
Placebo losartan and placebo NAC is administered 3 times.
Experimental: NAC and placebo Losartan
N-acetylcysteine (NAC) (50 mg/kg/dose) and placebo
Drug: N-acetylcysteine
50 mg/kg/dose. They get this the night before with dinner, at 6am when fasted and at 11am with a meal.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   60 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Age between 60-85 years.
  2. Ability to sign informed consent.
  3. Ability to sign consent form.
  4. Ability to pass a mini-mental status exam (score >23 on the 30-item Mini Mental State Examination, MMSE).
  5. Free-living, prior to admission.

Exclusion Criteria:

  1. Subjects with cardiac abnormalities considered exclusionary by the study physicians (e.g., unstable angina or a cardiology-confirmed ECG that demonstrates cardiac abnormalities such as > 0.2 mV horizontal or downsloping ST segment depression, frequent arrhythmia's (> 10 PVC/min), or valvular disease).
  2. Subjects with uncontrolled metabolic disease, including liver or renal disease.
  3. Subjects with vascular disease characterized by a combination of risk factors of peripheral atherosclerosis. (e.g., uncontrolled hypertension, obesity, uncontrolled diabetes, hypercholesterolemia > 250 mg/dl, claudication or evidence of venous or arterial insufficiency upon palpitation of femoral, popliteal, and pedal arteries.
  4. Any history of hypo- or hyper-coagulation disorders. (e.g., Coumadin use or history of DVT or PE).
  5. Subjects with chronically elevated systolic pressure >170 or a diastolic blood pressure > 100. Subjects may be included if they are taking medication and have a blood pressure below these criteria.
  6. Subjects with cancer or recently (6 months) treated cancer other than basal cell carcinoma.
  7. Any subject currently on a weight-loss diet or a body mass index > 33 kg/m2.
  8. Inability to abstain from smoking for duration of study.
  9. A history of > 20 pack per year smoking.
  10. Subjects with atrial fibrillation, history of syncope, angina, or congestive heart failure.
  11. Any subject that is HIV-seropositive or has active hepatitis.
  12. Recent anabolic or corticosteroids use (within 3 months).
  13. Subjects with low hemoglobin or hematocrit (i.e., lower than accepted lab values).
  14. Agitation/aggression disorder.
  15. Dementia.
  16. History of stroke with motor disability.
  17. A recent history (<12 months) of GI bleed.
  18. Alcohol (more than 3 drinks per day) or drug abuse.
  19. Polycystic ovary syndrome (PCOS) and/or hyperthecosis.
  20. Non-classical adrenal hyperplasia.
  21. Cushing's syndrome.
  22. Pregnancy.
  23. Hyperprolactinoma, hypothyroidism.
  24. Lactose intolerance.
  25. Subjects with coronary heart or mitral valvular rheumatic heart disease.
  26. Subjects with impaired renal function and/or renal artery stenosis.
  27. Subjects with pulmonary hypertension.
  28. Subjects on any medications known to vasodilate the peripheral arteries.
  29. Subjects taking NSAIDs
  30. Physical dependence or frailty (impairment of activities of daily living, ADLs).
  31. History of falls (>2/year).
  32. Depression (>5 of the 15 items on the Geriatric Depression Scale (GDS).
  33. Subjects suffering malnutrition or with a BMI < 20 kg/m2 with low albumin or transferrin.
  34. Asthma
  35. Any other condition or event considered exclusionary by the PI and covering faculty physician.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01384591

Locations
United States, Texas
University of Texas Medical Branch
Galveston, Texas, United States, 77555
Sponsors and Collaborators
The University of Texas, Galveston
Lantheus Medical Imaging
Investigators
Principal Investigator: Melinda Sheffield-Moore, PhD UTMB
Study Director: Astrid M Horstman, PhD UTMB
  More Information

No publications provided

Responsible Party: The University of Texas, Galveston
ClinicalTrials.gov Identifier: NCT01384591     History of Changes
Other Study ID Numbers: 11-091
Study First Received: June 23, 2011
Last Updated: January 31, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by The University of Texas, Galveston:
oxidative stress
blood flow
antioxidant
muscle
elderly

Additional relevant MeSH terms:
Acetylcysteine
Losartan
N-monoacetylcystine
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Anti-Arrhythmia Agents
Anti-Infective Agents
Antidotes
Antihypertensive Agents
Antioxidants
Antiviral Agents
Cardiovascular Agents
Expectorants
Free Radical Scavengers
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Respiratory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014