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

NCT01384591 | Completed Phase 1 Results DMC

• 1 other identifier: 11-091
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

The general hypothesis is that elderly have diminished nutritive flow to skeletal muscle and impaired capacity for building muscle. In aging populations, this decreased ability to build muscle 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 blood flow and 2) to determine if N-acetylcysteine (NAC) will enhance blood flow. 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 to the clinic on day 1 of the study. Baseline testing consisting of leg blood flow (LBF), contrast enhanced ultrasound, handgrip testing and fatigue questionnaires. After testing is completed the subjects will recieve their first dose of NAC/ losartan/ placebo with dinner. Subjects will be fasted after 10 pm. On day 2, leg blood flow (LBF) will be measured approximately 12 hours post dose 1. Subjects will receive their second dose of NAC/ losartan/ placebo. Leg blood flow will be measured 1 hour and 2 hours post dose 2 of study interventions. The subjects will eat a meal and receive their third dose of the study intervention. Leg blood flow will be repeated at 1 hour and 2 hours post dose 3. Appoximately 30 minutes after dose 3 of the study intervention, handgrip testing will be performed and fatigue questionnaires completed.

Conditions

Aging

Keywords

oxidative stress; blood flow; antioxidant; muscle; elderly

Outcome Measures

Primary Outcomes (7)

• Leg Blood Flow as Measured by Doppler Ultrasound

  Femoral Doppler Blood Flow was evaluated via Doppler ultrasound. For the two-dimensional (2-D) and Doppler ultrasound measurements, an ultrasound system (HDI-5000; Philips Medical Systems, Bothell, WA) with a linear array transducer (L7-4) was used with a transmit frequency of 12MHz. 2-D imaging of the common femoral artery will be performed in the long axis. Images will be triggered to the R wave of the cardiac cycle, and the femoral artery diameter will be measured using online video calipers. A pulsed-wave Doppler sample blood volume will be placed at the same location in the center of the artery, and the mean blood velocity will be measured using online angle correction and analysis software. Femoral artery mean blood flow will be calculated from 2-D and Doppler ultrasound data using the equation: Q = vπ ∙ (d/2)2, where Q is femoral blood flow, v is mean femoral artery blood flow velocity, and d is femoral artery diameter.

  Baseline

• Leg Blood Flow as Measured by Doppler Ultrasound

  Femoral Doppler Blood Flow was evaluated via Doppler ultrasound. For the two-dimensional (2-D) and Doppler ultrasound measurements, an ultrasound system (HDI-5000; Philips Medical Systems, Bothell, WA) with a linear array transducer (L7-4) was used with a transmit frequency of 12MHz. 2-D imaging of the common femoral artery will be performed in the long axis. Images will be triggered to the R wave of the cardiac cycle, and the femoral artery diameter will be measured using online video calipers. A pulsed-wave Doppler sample blood volume will be placed at the same location in the center of the artery, and the mean blood velocity will be measured using online angle correction and analysis software. Femoral artery mean blood flow will be calculated from 2-D and Doppler ultrasound data using the equation: Q = vπ ∙ (d/2)2, where Q is femoral blood flow, v is mean femoral artery blood flow velocity, and d is femoral artery diameter.

  12 hours post dose one of the intervention

• Leg Blood Flow as Measured by Doppler Ultrasound

  Femoral Doppler Blood Flow was evaluated via Doppler ultrasound. For the two-dimensional (2-D) and Doppler ultrasound measurements, an ultrasound system (HDI-5000; Philips Medical Systems, Bothell, WA) with a linear array transducer (L7-4) was used with a transmit frequency of 12MHz. 2-D imaging of the common femoral artery will be performed in the long axis. Images will be triggered to the R wave of the cardiac cycle, and the femoral artery diameter will be measured using online video calipers. A pulsed-wave Doppler sample blood volume will be placed at the same location in the center of the artery, and the mean blood velocity will be measured using online angle correction and analysis software. Femoral artery mean blood flow will be calculated from 2-D and Doppler ultrasound data using the equation: Q = vπ ∙ (d/2)2, where Q is femoral blood flow, v is mean femoral artery blood flow velocity, and d is femoral artery diameter.

  1 hour post dose two of the intervention, average of 13 hours post dose 1 of the intervention

• Leg Blood Flow as Measured by Doppler Ultrasound

  Femoral Doppler Blood Flow was evaluated via Doppler ultrasound. For the two-dimensional (2-D) and Doppler ultrasound measurements, an ultrasound system (HDI-5000; Philips Medical Systems, Bothell, WA) with a linear array transducer (L7-4) was used with a transmit frequency of 12MHz. 2-D imaging of the common femoral artery will be performed in the long axis. Images will be triggered to the R wave of the cardiac cycle, and the femoral artery diameter will be measured using online video calipers. A pulsed-wave Doppler sample blood volume will be placed at the same location in the center of the artery, and the mean blood velocity will be measured using online angle correction and analysis software. Femoral artery mean blood flow will be calculated from 2-D and Doppler ultrasound data using the equation: Q = vπ ∙ (d/2)2, where Q is femoral blood flow, v is mean femoral artery blood flow velocity, and d is femoral artery diameter.

  2 hours post dose two of the intervention, average of 14 hours post dose one of the intervention

• Leg Blood Flow as Measured by Doppler Ultrasound

  Femoral Doppler Blood Flow was evaluated via Doppler ultrasound. For the two-dimensional (2-D) and Doppler ultrasound measurements, an ultrasound system (HDI-5000; Philips Medical Systems, Bothell, WA) with a linear array transducer (L7-4) was used with a transmit frequency of 12MHz. 2-D imaging of the common femoral artery will be performed in the long axis. Images will be triggered to the R wave of the cardiac cycle, and the femoral artery diameter will be measured using online video calipers. A pulsed-wave Doppler sample blood volume will be placed at the same location in the center of the artery, and the mean blood velocity will be measured using online angle correction and analysis software. Femoral artery mean blood flow will be calculated from 2-D and Doppler ultrasound data using the equation: Q = vπ ∙ (d/2)2, where Q is femoral blood flow, v is mean femoral artery blood flow velocity, and d is femoral artery diameter.

  Post dose three of the intervention and a meal, average of 17 hours post dose one of the intervention

• Leg Blood Flow as Measured by Doppler Ultrasound

  Femoral Doppler Blood Flow was evaluated via Doppler ultrasound. For the two-dimensional (2-D) and Doppler ultrasound measurements, an ultrasound system (HDI-5000; Philips Medical Systems, Bothell, WA) with a linear array transducer (L7-4) was used with a transmit frequency of 12MHz. 2-D imaging of the common femoral artery will be performed in the long axis. Images will be triggered to the R wave of the cardiac cycle, and the femoral artery diameter will be measured using online video calipers. A pulsed-wave Doppler sample blood volume will be placed at the same location in the center of the artery, and the mean blood velocity will be measured using online angle correction and analysis software. Femoral artery mean blood flow will be calculated from 2-D and Doppler ultrasound data using the equation: Q = vπ ∙ (d/2)2, where Q is femoral blood flow, v is mean femoral artery blood flow velocity, and d is femoral artery diameter.

  1 hour post dose three of the intervention and a meal, average of 18 hours post dose one of the intervention

• Leg Blood Flow as Measured by Doppler Ultrasound

  Femoral Doppler Blood Flow was evaluated via Doppler ultrasound. For the two-dimensional (2-D) and Doppler ultrasound measurements, an ultrasound system (HDI-5000; Philips Medical Systems, Bothell, WA) with a linear array transducer (L7-4) was used with a transmit frequency of 12MHz. 2-D imaging of the common femoral artery will be performed in the long axis. Images will be triggered to the R wave of the cardiac cycle, and the femoral artery diameter will be measured using online video calipers. A pulsed-wave Doppler sample blood volume will be placed at the same location in the center of the artery, and the mean blood velocity will be measured using online angle correction and analysis software. Femoral artery mean blood flow will be calculated from 2-D and Doppler ultrasound data using the equation: Q = vπ ∙ (d/2)2, where Q is femoral blood flow, v is mean femoral artery blood flow velocity, and d is femoral artery diameter.

  2 hours post dose three of the intervention and a meal, average of 19 hours post dose one of the intervention

Secondary Outcomes (34)

• Handgrip Strength of Dominant Hand as Measured by Handgrip Dynamometry at 50% Perceived Effort at Baseline

  baseline

• Handgrip Strength of Non-dominant Hand as Measured by Handgrip Dynamometry at 50% Perceived Effort at Baseline

  baseline

• Handgrip Strength of Dominant Hand as Measured by Handgrip Dynamometry at 100% Effort at Baseline

  baseline

• Handgrip Strength of Non-dominant Hand as Measured by Handgrip Dynamometry at 100% Effort at Baseline

  baseline

• Handgrip Fatigue of Dominant Hand as Measured by Handgrip Dynamometry at Baseline

  baseline

Study Arms (3)

Losartan and placebo N-acetylcysteine

EXPERIMENTAL

losartan (25mg/dose) and placebo N-acetylcysteine (NAC) 3 total doses: 1 dose on day 1, 2 doses on day 2.

Drug: Losartan; Drug: Placebo N-acetylcysteine

Placebo losartan and placebo N-acetylcysteine

PLACEBO COMPARATOR

Placebo losartan and placebo N-acetylcysteine (NAC) 3 total doses: 1 dose on day 1, 2 doses on day 2.

Drug: Placebo losartan; Drug: Placebo N-acetylcysteine

N-acetylcysteine and placebo losartan

EXPERIMENTAL

N-acetylcysteine (NAC) (50 mg/kg/dose) and placebo losartan 3 total doses: 1 dose on day 1, 2 doses on day 2.

Drug: N-acetylcysteine; Drug: Placebo losartan

Interventions

N-acetylcysteine DRUG

50 mg/kg/dose. 3 total doses: 1 dose on day 1, 2 doses on day 2.

Also known as: NAC

N-acetylcysteine and placebo losartan

Losartan DRUG

25mg/dose. 3 total doses: 1 dose on day 1, 2 doses on day 2.

Also known as: Cozaar

Losartan and placebo N-acetylcysteine

Placebo losartan DRUG

Placebo losartan 3 total doses: 1 dose on day 1, 2 doses on day 2.

Also known as: Placebo

N-acetylcysteine and placebo losartan; Placebo losartan and placebo N-acetylcysteine

Placebo N-acetylcysteine DRUG

Placebo N-acetylcysteine 3 total doses: 1 dose on day 1, 2 doses on day 2.

Also known as: Placebo

Losartan and placebo N-acetylcysteine; Placebo losartan and placebo N-acetylcysteine

Eligibility Criteria

• Age: 60 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Subjects with uncontrolled metabolic disease, including liver or renal disease.
• 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.
• Any history of hypo- or hyper-coagulation disorders. (e.g., Coumadin use or history of DVT or PE).
• 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.
• Subjects with cancer or recently (6 months) treated cancer other than basal cell carcinoma.
• Any subject currently on a weight-loss diet or a body mass index \> 33 kg/m2.
• Inability to abstain from smoking for duration of study.
• A history of \> 20 pack per year smoking.
• Subjects with atrial fibrillation, history of syncope, angina, or congestive heart failure.
• Any subject that is HIV-seropositive or has active hepatitis.
• Recent anabolic or corticosteroids use (within 3 months).
• Subjects with low hemoglobin or hematocrit (i.e., lower than accepted lab values).
• Agitation/aggression disorder.
• Dementia.
• History of stroke with motor disability.

Sponsors & Collaborators

• The University of Texas Medical Branch, Galveston: lead
• Lantheus Medical Imaging: collaborator

Study Sites (1)

University of Texas Medical Branch

Galveston, Texas, 77555, United States

Location

MeSH Terms

Interventions

Acetylcysteine; Losartan

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles

Results Point of Contact

• Title: Melinda Sheffield-Moore
• Organization: University of Texas Medical Branch

melmoore@utmb.edu

409-772-8126

Study Officials

• Melinda Sheffield-Moore, PhD

  UTMB

  PRINCIPAL INVESTIGATOR

• Astrid M Horstman, PhD

  UTMB

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 23, 2011
• First Posted: June 29, 2011
• Study Start: July 1, 2011
• Primary Completion: May 1, 2015
• Study Completion: May 1, 2015
• Last Updated: May 8, 2018
• Results First Posted: May 8, 2018

Record last verified: 2018-04

Locations

US (1)