Sodium Pyruvate Therapy in COPD Patients
Condition: Chronic Obstructive Pulmonary Disease (COPD)
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 2

Summary: 
      In animal models, sodium pyruvate has been shown to be an effective anti-inflammatory agent,
      and in human studies sodium pyruvate has been shown to be a bronchodilating agent. Subjects
      with COPD are known to have inflammation in the lung, and often have bronchoconstriction. As
      such, these subjects typically are on multiple therapies, including steroid therapy. This
      trial will study the effect of inhaled sodium pyruvate on inflammation and lung function in
      COPD subjects over a six week period.
    

Detailed description: 
      Chronic obstructive pulmonary disease (COPD) is a disease, which involves the conducting
      airways of the respiratory tract and affects 5-10% of individuals in the United States. The
      morbidity and mortality associated with this disease are increasing both in the United States
      and worldwide (1). The mechanisms involved in the pathogenesis of COPD are complex but it can
      be classified as an inflammatory disease of the airways characterized by an increase in
      inflammatory cells (neutrophils, macrophages, and lymphocytes) both in the bronchial mucosa
      and in bronchoalvaeolar lavage fluid (2). Some of the many therapeutic approaches to managing
      this disease include various inhaled compounds, such as, bronchodilators (i.e. beta agonists)
      and both inhaled and systemic steroid treatment. The current therapies are not without
      adverse side effects. The purpose of this study is to test the safety and therapeutic value
      of an endogenous compound, sodium pyruvate, with anti-inflammatory properties (anti-oxidant)
      in patients with COPD.

      Reactive oxygen species (ROS), such as superoxide anion, free hydroxyl radical, and hydrogen
      peroxide, have been shown to be toxic to various mammalian tissue (3), including lung (4--6),
      and have been implicated in many human diseases (7). Anti- oxidant therapy has been shown to
      be effective in several animal models of inflammatory lung diseases (8-10). Sodium pyruvate
      is a part of the body's natural endogenous anti-oxidant defense system. It is secreted by
      cells, readily enters cells, and can react with peroxide to "detoxify it (11-13). Since
      hydrogen peroxide is also a precursor to other ROS, inhibition of it has broad anti-oxidant
      effects. Sodium pyruvate has been shown to have protective anti-oxidant activity both in
      vitro (11, 14-17) and in vivo (18, 19).

      Clinically, sodium pyruvate has been given to patients for a variety of disorders ranging
      from Friedreich's ataxia (20) to open heart operations (21). It has been administered via
      several routes including intravenous (20-23), topical administration for hyperkeratotic
      disorders (24), and in dietary supplementation (25-29). Animal model studies in rats and
      rabbits were conducted to assess potential adverse effects. Rats were used to assess the
      impact of sodium pyruvate administered directly to the lungs by intratracheal injection (Rat
      Study). Rabbits were used to assess the impact of sodium pyruvate administered as an inhaled
      mist using a nebulizer (Pyruvate Inhalation Study in Rabbits). There were no adverse effects
      noted in the parameters, which were monitored for acute lung injury (histology,
      bronchoalveolar lavage fluid content, and arterial blood gas analysis). In addition, it was
      shown that the intratrachcheal administration of sodium pyruvate was beneficial in
      diminishing the development of acute lung injury in rats induced by bleomycin. The generation
      of toxic oxygen radicals is believed to be a major mechanism of bleomycin lung toxicity.

      There are two major groups of COPD medications: 1) Bronchodilator agents that inhibit the
      bronchoconstriction characteristic of some patients with COPD; and 2) anti-inflammatory
      agents which inhibit the inflammatory components responsible for the airway narrowing and
      increased mucus production, also characteristic features of patients with COPD. The known
      anti-oxidant properties of sodium pyruvate make it an attractive compound for possible
      therapeutic efficacy, which should have in vivo anti-inflammatory effects. In addition to its
      possible anti-inflammatory properties, we previously observed (Phase I study of this
      compound, see Phase I report) acute therapeutic efficacy in patients with mild bronchial
      asthma. The observed improvement in FEV1 at 30 minutes to 2 hours post inhalation of sodium
      pyruvate suggests a bronchodilator effect in these patients. The mechanism of action is
      unclear at this time but it may be a result of the ability of inhaled sodium pyruvate to
      modulate reactive oxygen and nitrogen species such as H2O2 and nitric oxide (NO). These
      species have both been shown to be elevated in expired breath of patients with COPD and
      asthma and thus implicated in the pathogenesis (30-39). Nitric oxide has been shown to play
      an important role in maintaining normal physiologic homeostasis in the normal and injured
      lung (40-42). It has been shown to reverse acetylcholine and histamine induced
      bronchoconstriction and to maintain normal vascular integrity (40-42). It is possible that
      inhaled sodium pyruvate alters airway levels of both oxygen and nitrogen reactive species
      resulting in a beneficial effect.

      Since sodium pyruvate is endogenous, has been used previously in patients, had no adverse
      affects in our animal model studies, and had no adverse effects in our acute Phase I Clinical
      Trial in patients with mild bronchial asthma, we feel that we will be able to use it safely
      in this long term multiple use study in patients with COPD. For safety considerations only
      the lowest concentration of sodium pyruvate (0.5mM) studied previously in our single dose
      Safety Trial will be studied in this 3-times/day double blind placebo controlled 6 week
      study. The total daily dose per subject will be similar to the 1.5mM concentration (3 doses
      of 0.5mM). In addition, it is approximately 3 times less than the total daily dose given to
      subjects who received the 5.0mM concentration in our Single Dose Phase I Safety Trial. The
      proposed study is designed to address both the long term multiple dose safety aspects of
      inhaled sodium pyruvate as well as both the acute and long-term efficacy of the compound. The
      acute study is designed to evaluate the possible bronchodilator effects and the long term
      multiple use study is designed to evaluate the anti-inflammatory properties of sodium
      pyruvate.
    

Intervention name(s): sodium pyruvate in 0.9% sodium chloride solution
Intervention type(s): Drug
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Sodium Pyruvate; COPD; Chronic Obstructive Pulmonary Disease