The Effects of a Glutathione Precursor (FT061452),on Serum and Intracellular Glutathione Levels
Condition: Oxidative Stress
Study type: Interventional
Phase: Phase 1

Summary: 
      Glutathione is a powerful protective substance found within every cell in the body. It has
      been shown that glutathione levels go down as a person gets older, which makes a person more
      likely to get heart disease, high blood sugar problems and different kind of cancers.
      N-Acetyl Cysteine is used as a dietary supplement. It has been reported to increase
      glutathione levels in the body. The diet supplement called ProImmune is also changed by the
      body into glutathione. Therefore, the purpose of this study is to find out the effect of
      ProImmune in healthy people. This study will also help to prove whether or not the ProImmune
      is able to improve the blood levels of glutathione in healthy people.
    

Detailed description: 
      Glutathione (gamma-glutamyl-cysteine-glycine; GSH) is a powerful antioxidant found within
      every cell. GSH is predominantly known to protect the cells from damage caused by free
      radicals. The concentration of glutathione declines with age, stress, and in some age-related
      diseases. When glutathione becomes deficient, a series of events are initiated termed
      "oxidative stress" and the associated cell signaling leads to impaired immune function and
      similar abnormalities in numerous cell systems.

      Oral glutathione is ineffective in replenishing glutathione levels and reversing the abnormal
      signaling pathways associated with oxidative stress. Intravenous glutathione has been shown
      to be effective but is short-lived. N-Acetyl Cysteine, a glutathione precursor, has had
      limited efficacy in clinical settings and suffers from an adverse effect profile.Null
      Hypothesis (primary): The administration of FT061452 will not increase serum and
      intracellular glutathione levels in comparison to N-Acetyl Cysteine (NAC), and placebo.

      Null Hypothesis (secondary): The administration of FT061452 will not improve vascular
      function in comparison to N-Acetyl Cysteine (NAC), and placebo.

      The Specific Aims of this pilot study are to:

        -  Compare the change in serum and intracellular glutathione levels following the
           administration of a novel oral glutathione precursor, FT061452, (modified glutathione
           with selenium added, and cystine replacing cysteine, in doses equivalent to NAC)
           compared to low dose or usual dose of NAC, and placebo.

        -  Compare the change in select clinical parameters (vascular function) following the
           administration of a novel oral glutathione precursor, FT061452, (modified glutathione
           with selenium added, and cystine replacing cysteine) compared to N-Acetyl Cysteine
           (NAC), and placebo.

        -  As a pilot study a third goal is to generate effect sizes for appropriately powering
           future clinical trials.

      Background:

      Increased rates of adverse health outcomes for racial and ethnic minorities have been linked
      to a confluence of socio-cultural, environmental, immunological, and genetic based factors,
      frequently acting in concert. Ultimately, the majority of these factors lead to adverse
      physiologic and cellular changes. However, it is the chronic activation of these
      neurohormonal systems through the above stresses that lead to maladaptive health consequences
      such as accelerated apoptosis, atherogenesis, altered immune function, and other
      dysregulations of cellular function. Ultimately, stress related cellular activities
      contribute to many of the observed premature chronic diseases in humans, many of which are
      found in disproportionately high rates in minority communities. Glutathione is the major
      regulator of the cellular oxidative state that buffers many of these stress related pathways.
      When glutathione becomes deficient there occurs an increase in reactive oxidative species
      (ROS) that collectively can be termed "oxidative stress". Clinically, oral glutathione (GSH)
      has been ineffective in replenishing glutathione levels and reversing the associated abnormal
      cellular signaling. GSH as a whole molecule cannot be taken up by cells in mammals but is
      largely metabolized in the gastrointestinal tract into constituent amino acids, including the
      highly oxidizable L-cysteine, which cannot be re-united extracellularly into glutathione as
      its re-assimilation requires two cytosolic, ATP-dependent enzymes. Thus, the processes that
      achieve glutathione synthesis require special conditions that are only present within the
      cell. Oral glutathione preparations are limited by their ability to provide adequate
      substrate to stimulate intracellular glutathione synthesis due to L-cysteine being highly
      oxidizable. Intravenous glutathione administration is expensive, short-lived, and
      impractical, as the transiently higher plasma concentrations are largely independent of
      intracellular glutathione activity, where much of the oxidative balance is performed.
      N-Acetyl Cysteine (NAC), a glutathione precursor, has had limited efficacy in clinical
      settings and suffers from an adverse side-effect profile. However, preliminary findings of a
      novel glutathione precursor with vitamin implications (FT061452) indicate it can affect the
      metabolism of glutathione via 2 mechanisms: 1) increasing the availability of intracellular
      cysteine by using the more stable cystine as the physiologic and more stable cysteine carrier
      which can traverse the cell membrane and create a more optimal Cys/CySS redox state, and 2)
      adding selenium, an important co-factor for glutathione reductase. Thus, FT061452 appears to
      provide a greater cellular delivery of substrate to attenuate oxidative stress, in comparison
      to traditional glutathione precursors, which despite showing promise,have not demonstrated
      consistent clinical efficacy.

      Preliminary studies ; Preliminary studies to investigate GSH and several GSH analogs might
      protect spermine-induced apoptosis in aortic vascular smooth muscle cells (VSMC) have been
      promising. Given that spermine (a uremic toxin) increases intracellular ROS and promotes
      apoptosis in some cultured cells, we first examined the generation of ROS along with
      intracellular levels of reduced GSH and the ratio of reduced GSH and oxidized glutathione
      (GSH/GSSG) in VSMC in response to spermine treatment and its attenuation by concomitant
      administration of similar strengths of GSH, NAC and FT061452. While concomitant exposure of
      these cells to NAC, GSH, or FT061452 attenuated spermine-induced decrease in GSH levels, only
      the addition of the novel glutathione precursor, FT061452, to spermine treated cells
      increased intracellular GSH levels above control values.

      Study Design & Method:

      This is a prospective randomized controlled pilot study, which will include twenty-four (24)
      healthy individuals between ages of 30-65 years old. The study will occur over the course of
      two days. On Day 1, potential subjects will be screened to determine eligibility by mini
      history and physical exam, complete blood count (CBC) and complete metabolic panel (CMP). On
      Day 2, eligible subjects will report to Participant and Clinical Interactions Resource Center
      (formerly known as the CRC) after fasting overnight. The first 12 subjects (low dose) will be
      randomized into three groups, 1) those given a single dose of placebo, 2) those given 600 mg
      (low dose) of N-Acetyl Cysteine (NAC) or 3) those given 3000 mg of study drug (FT061452).
      Serum and intracellular glutathione levels, biomarkers, and non-invasive measures of vascular
      function were assessed at baseline, 2, 4 and 6 hours. During their stay in CRC, subjects in
      every group will be fed the same meal. The second 12 subjects (usual dose) will be randomized
      into three groups, 1) those given a single dose of placebo, 2) those given 1200 mg (usual
      dose) of N-Acetyl Cysteine (NAC) or 3) those given 6000 mg of study drug (FT061452). Serum
      and intracellular glutathione levels, biomarkers, and non-invasive measures of vascular
      function will be assessed at baseline, 2, 4 and 6 hours. During their stay in CRC, subjects
      in every group will be fed the same meal.

      At baseline, 2, 4 and 6 hours, a blood sample (15 cc per draw) will be obtained for serum and
      intracellular glutathione levels, stored serum for biomarkers, and non-invasive measures of
      vascular function will be assessed at baseline and 6 hours, as follows: 1) Pulse wave
      velocity and Augmentation Index (via SphygmoCor): (central artery pressure and central aortic
      pulse pressure) and 2) Peripheral vascular endothelial function (via EndoPat): (% flow
      mediated dilation).

      This study has potential benefits to others. The knowledge gained will provide realistic and
      practical information that guides the implementation of a non-pharmacological intervention to
      reduce the progression of age related morbidities. Because CDU's community is largely
      minority, the community of color will be included in this recruitment. The IRB exercises
      oversight of all protocols involving human subjects, monitors for adverse events, and
      performs audits of all approved protocols.
    

Intervention name(s): Placebo low dose; N Acetyl cysteine, 600mg (low dose); Proimmune 200 (FT061452) 3000mg low dose; Placebo (high dose); N Acetyl cysteine, 1200mg (high dose); FT061452, 6000mg high dose
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): This is a prospective randomized controlled pilot study, which will include twenty-four (24) healthy individuals.The first 12 subjects (low dose) will be randomized into three sub groups. The first group will be given a single dose of placebo.; The sub-group of four subjects (low dose) will be given a single dose of 600 mg of N-Acetyl Cysteine (NAC).; The sub-group of four subjects (low dose) will be given a single dose of Proimmune 200 (FT061452) 3000mg low dose'; The second sub set of 12 subjects (high dose) will be randomized into three sub groups. The first group will be given a single dose of placebo.; N Acetyl cysteine (high dose) N-Acetyl Cysteine(NAC)1200mg (high dose) given as a single dose.; Proimmune 200(FT061452) high dose group given 6000 mg as a single dose.
Other intervention name(s): Cellulose; NAC; Proimmune-200 (FT061452); Cellulose; NAC; Proimmune-200 (Glutathione precursor)
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Glutathione; Antioxidant; Free radical; Oxidative stress; N-Acetyl Cysteine; Glutathione precursor