Chronic Obstructive Pulmonary Disease (COPD) Clinical Trial
Official title:
Long-Term Use of Inhaled Sodium Pyruvate for the Treatment of Chronic Obstructive Pulmonary Disease
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.
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.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment
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