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Autonomic Nervous System Drugs

Discussion in 'Active Clinical Studies' started by Cort, Jun 15, 2009.

  1. Cort

    Cort Phoenix Rising Founder

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    Raleigh, NC
    NIH URL

    This study is currently recruiting participants.
    Verified by Vanderbilt University, April 2009
    First Received: December 17, 2007 Last Updated: April 8, 2009 History of Changes
    Sponsored by: Vanderbilt University
    Information provided by: Vanderbilt University
    ClinicalTrials.gov Identifier: NCT00580619
    Purpose
    The investigators propose to test the hypothesis that the sympathetic nervous system contributes to the cardiovascular and inflammatory abnormalities present in the chronic fatigue syndrome (CFS) and, in particular in the subset of patients characterized by postural tachycardia syndrome (POTS). CFS and POTS are seen mostly in otherwise normal young women, and are the cause of significant disability. A substantial proportion of patients referred for evaluation of POTS met diagnostic criteria for CFS and, conversely, a subset of patients referred for treatment for CFS have POTS. The investigators hypothesize that sympathetic activation underlies the pathophysiology of patients in whom CFS and POTS overlap (CFS-P).


    Condition Intervention
    Chronic Fatigue Syndrome
    Orthostatic Intolerance
    Postural Tachycardia Syndrome
    Other: Autonomic Function Tests
    Other: Saline infusions
    Drug: L-NMMA trimethaphan
    Drug: methyldopa

    Study Type: Interventional
    Study Design: Open Label, Placebo Control, Parallel Assignment, Efficacy Study
    Official Title: Autonomic Nervous System and Chronic Fatigue Syndrome

    Resource links provided by NLM:

    Genetics Home Reference related topics: Brugada syndrome short QT syndrome
    MedlinePlus related topics: Chronic Fatigue Syndrome Marijuana Mitral Valve Prolapse Mobility Aids
    Drug Information available for: Trimethaphan camsylate omega-N-Methylarginine Methyldopa Methyldopa ethyl ester hydrochloride Methyldopate Trimethaphan
    U.S. FDA Resources

    Further study details as provided by Vanderbilt University:

    Primary Outcome Measures:
    Heart rate [ Time Frame: Duration of the intervention ] [ Designated as safety issue: No ]

    Secondary Outcome Measures:
    Blood Pressure [ Time Frame: Duration of the intervention ] [ Designated as safety issue: No ]

    Estimated Enrollment: 80
    Study Start Date: April 2007
    Estimated Study Completion Date: December 2012
    Estimated Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
    Arms Assigned Interventions
    1: Experimental
    To evaluate if the various indices of sympathetic activity differ between patients with chronic fatigue syndrome and postural tachycardia syndrome (CFS-P), and CFS without POTS.
    Other: Autonomic Function Tests
    The autonomic function tests include asking the subject to breathe deeply for two minutes and breathing as fast and as hard as they can for 30 seconds, maintaining a handgrip for 3 minutes, breathing against pressure for 15 seconds and placing one hand in ice water for 1 minute. All these tests are meant to stimulate the autonomic nervous system to produce changes in blood pressure and heart rate of short duration that reflect how well the involuntary nervous system is working.
    2: Experimental
    To test the null hypothesis that there is no difference between two saline therapies (pulse saline vs. sham saline) in improving both the fatigue score and postural tachycardia syndrome.
    Other: Saline infusions
    The effects of continuous IV infusion or pulse IV administration of saline in increasing total blood volume and fatigue score will be evaluated
    3: Experimental
    Response to nitric oxide inhibition in the presence and absence of an intact autonomic nervous system will be evaluated.
    Drug: L-NMMA trimethaphan
    Trimethaphan IV infusion for approximately 60 minutes at a dose of 4-6 mg/min L-NMMA IV infusion for approximately 45 minutes at 125, 250, and 500 mg/kg/min for 15 minutes each
    4: Active Comparator
    The effects of chronic autonomic withdrawal on improving symptoms of chronic fatigue and postural tachycardia syndrome will be evaluated
    Drug: methyldopa
    Aldomet oral twice a day for 12 weeks

    Detailed Description:
    In Specific Aim 1, the investigators will use state-of-the-art measurements of sympathetic activity (response to trimethaphan, direct nerve sympathetic traffic recordings with microneurography, plasma norepinephrine, and intraneuronal metabolites), inflammatory mediators (C-reactive protein, IL-6), and oxidative stress (isoprostanes) in patients with CFS-P. It is important that appropriate control groups be included, and we will also study patients with CFS without orthostatic tachycardia, patients with POTS without CFS, and normal controls.

    The investigators have documented abnormalities in volume regulation in POTS patients. Hypovolemia can contribute to sympathetic activation and, vice versa, sympathetic activation can contribute to hypovolemia. Interrupting this vicious circle with acute saline infusion is the most effective treatment to improve symptoms in POTS patients. Not surprisingly, many POTS patients followed by the investigators, and CFS patients followed by Dr. David Bell, are using saline pulse therapy as a way to alleviate symptoms. However, the efficacy and safety of this approach has not been proven. The investigators propose to validate this treatment in Specific Aim 2. This group studies show that nitric oxide is arguably the most important metabolic factor involved in cardiovascular regulation. Abnormalities in nitric oxide have been proposed to contribute to CFS and POTS, but proving this has been challenging in part due to its interaction with the sympathetic nervous system. In Specific Aim 3, the investigators propose to investigate the importance of nitric oxide in CFS-P patients using an experimental approach developed in our laboratory to eliminate nitric oxide/autonomic interactions.

    Finally, in Specific Aim 4, they propose a proof-of-concept study to test the hypothesis that sympathetic activation contributes to many of the abnormalities found in CFS patients. If our hypothesis is correct, inhibition of sympathetic tone will result in improvement of the abnormalities described in volume, inflammation, and oxidative stress. More importantly, it will result in symptomatic improvement in these patients. The investigators believe, therefore, that the studies proposed in this application will improve the understanding of the pathophysiology of CFS, and provide a rationale approach to the treatment of this disabling condition.

    Eligibility

    Ages Eligible for Study: 18 Years to 65 Years
    Genders Eligible for Study: Both
    Accepts Healthy Volunteers: Yes
    Criteria
    Inclusion Criteria:

    Meet CDC diagnostic criteria of CFS (Fukuda et al., 1994)
    Meet diagnostic criteria of POTS (Raj et al., 2005)
    Age between 18-65 years
    Male and female are eligible (although the majority of patients with CFS-P are female)
    Exclusion Criteria:

    Presence of medical conditions that can explain postural tachycardia syndrome (e.g., dehydration, medications)
    Presence of medical or psychiatric conditions known to cause fatigue (Fukuda et al., 1994). Inability to give, or withdrawal of, informed consent
    Inability to acquire or maintain adequate long-term intravenous access (peripheral indwelling catheter, PIC)
    Pregnancy
    Other factors which in the investigator's opinion would prevent the subject from completing the protocol
    Patients who are bedridden or chair-ridden
    Contacts and Locations
    Please refer to this study by its ClinicalTrials.gov identifier: NCT00580619

    Locations
    United States, Tennessee
    Vanderbilt University Medical Center Recruiting
    Nashville, Tennessee, United States, 37232
    Contact: Ginnie Farley, RA adcresearch@vanderbilt.edu
    Principal Investigator: Italo Biaggioni, M.D.
    Sub-Investigator: Alfredo Gamboa, M.D.
    Sub-Investigator: Luis Okamoto, M.D.
    Sub-Investigator: Andre Diedrich, M.D., Ph.D
    Sub-Investigator: Satish Raj, M.D.
    Sub-Investigator: Bonnie Black, R.N.
    Sub-Investigator: David Robertson, M.D.
    Sub-Investigator: Ginnie Farley, RA

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