Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Reexamination Certificate
2002-07-25
2004-02-10
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
C514S557000, C514S826000
Reexamination Certificate
active
06689810
ABSTRACT:
FIELD OF THE INVENTION
The present invention pertains to a method for treating a pulmonary disease state in mammals by altering indigenous in vivo levels of nitric oxide in mammalian cells.
DESCRIPTION OF THE PRIOR ART
The disclosures referred to herein to illustrate the background of the invention and to provide additional detail with respect to its practice are incorporated herein by reference and, for convenience, are referenced in the following text and respectively grouped in the appended bibliography.
Nitric oxide (NO), an oxidation product of nitrogen, is produced normally by many cell types, including endothelial cells and macrophages. Nitric oxide has functions ranging from neurotransmission to vasodilatation. Nitric oxide also produces clinically useful bronchodilation (1) and is also used by the body to kill bacteria, fungal infections, viral infections, and tumors. Nitric oxide can kill these cell types because bacterial, viral, and tumor cells have no defenses against nitric oxide. Normal mammalian cells can cope with normal levels of nitric oxide by using enzyme systems to use or deactivate elevated cellular levels of nitric oxide (28-32). Nitric oxide is the main mediator of the tumoricidal action of activated macrophages (29-32). While over 30,000 papers have been written to date on nitric oxide, the role of nitric oxide in tumor biology is not completely understood. Nitric oxide appears to have both tumor promoting and inhibiting effects (31). Recent publications have implicated the reactive oxygen species made from nitric oxide during the inflammatory process as being the tumor promoting agents, not nitric oxide itself (28).
Nitric oxide has been used successfully in patients with persistent fetal circulation, persistent pulmonary hypertension in newborn (11), pulmonary hypertension secondary to cardiac dysfunction or surgery, and with adult respiratory distress syndrome (ARDS) (1,2). Nitric oxide can become a toxic oxidant when it reacts with excess oxygen radicals to produce nitrogen dioxide (NO
2
) (1-3) and peroxynitrite (ONOO). Oxygen radicals, such as superoxide (O
2
) and hydrogen peroxide, destroy nitric oxide and produce the toxic NO
2
and peroxynitrite (1-3). Peroxynitrite ion and peroxynitrous acid, formed from the interaction of nitric oxide and superoxide anions, are strong oxidant species that work against nitric oxide by inducing single-strand breaks in DNA and enhancing tumor formation and growth (28) rather than death. Superoxide and hydrogen peroxide also cause vascular constriction (1). H
2
O
2
is the oxygen radical that appears to have the major effect on airway tone and causes contraction in both bovine and guinea pig airways.(14,15). H
2
O
2
markedly potentiates the cytotoxic effects of eosinophil derived enzymes such as 5,8,11,14,17-eicosapentaenoic acid (16). Excess superoxide anions and hydrogen peroxide, produced during the inflammatory phase of an injury, will destroy healthy tissue surrounding the site and will mitigate the positive bronchodilation effect of nitric oxide (26). Oxygen radicals can also initiate lipid peroxidation employing arachidonic acid as an substrate producing prostaglandins and leukotrienes. H
2
O
2
can induce arachidonic acid metabolism in alveolar macrophages (17,26). Oxygen radicals also produce 8-isoprostanes which are potent renal and pulmonary artery vasoconstrictors, bronchoconstrictors, and induce airflow obstructions (26, 27). Because oxygen radicals contribute to the instability of nitric oxide, the addition of superoxide dismutase (SOD) or catalase (15) or Vitamin E (28) protect nitric oxide to produce its desired bronchodilation (2). Hydrogen peroxide is elevated in patients with chronic obstructive pulmonary disease (COPD), asthma, and ARDS (26). A study in 28 patients showed a significant correlation between oxygen radical generation in white blood cell count (WBC) and the degree of bronchial hyperreactivity in vivo in nonallergic patient's (18). The authors suggested that direct suppression of oxygen radical production by corticosteriods might be involved.
Nitrogen dioxide is a major air pollutant and a deep lung irritant. Nitrogen dioxide is formed in combustion processes, either directly or through secondary oxidation of nitric oxide (8). Nitrogen dioxide causes pulmonary inflammation, lower levels of lung antioxidants (10), deterioration of respiratory defense mechanisms, and increases susceptibility to respiratory pathogens (8). Nitrogen dioxide can also increase the incidence and severity of respiratory infections, can reduce lung function, and can aggravate the symptoms of asthmatics or subjects with COPD (8). Nitric oxide can also combine with superoxide anions to form peroxynitrite, which can generate the highly reactive hydroxyl anion (OH). According to epidemiological studies, the population group most susceptible to these adverse effects is small children, either with and without asthma (8). This group develops respiratory illnesses, shortness of breath, persistent wheeze, chronic cough, chronic phlegm, and bronchitis (4-8). Even though asthmatic children have increased amounts of exhaled nitric oxide over non-asthmatic children, there is persuasive evidence that higher levels of nitric oxide are decreased by the overproduction of oxygen radicals during the inflammatory process (1-8). This becomes a problematic situation for which the only solution is denied by the circumstance inherent in the problem. The underlying chronic inflammatory process in asthma, which induces nitric oxide synthesis, also produces excess oxygen radicals, which will destroy nitric oxide (6). The inhalation of a pulmonary irritant has been shown to enhance nitric oxide production by alveolar macrophages in rats, which also produces an increased level of oxygen radical that can react directly with nitric oxide to produce NO
2
(1-3, 6).
Sodium pyruvate is an antioxidant that reacts directly with oxygen radicals to neutralize them. In macrophages, and other cell lines, sodium pyruvate regulates the production and level of inflammatory mediators including oxygen radical production and also increases the synthesis of nitric oxide (9). It can specifically lower the overproduction of superoxide anions. Sodium pyruvate also increases cellular levels of glutathione, a major cellular antioxidant (12). It was recently discovered that glutathione is reduced dramatically in antigen-induced asthmatic patients (13) and inhaled glutathione does not readily enter cells. Pyruvate does enter all cells via a transport system and can also cross the blood brain barrier. Excess sodium pyruvate beyond that needed to neutralize oxygen radicals will enter the bronchial and lung cells. All cells have a transport system that allow cells to concentrate pyruvate at higher concentrations than serum levels. In the cell, pyruvate raises the pH level, increases levels of ATP, decreasing levels of ADP and cAMP, and increases levels of GTP, while decreasing levels of cGMP. Nitric oxide acts in the opposite mode by increasing levels of cGMP and ADP, and requires an acid pH range in which to work (19).
U.S. Pat. No. 6,063,407 (Zapol et al.) discloses methods of treating, inhibiting or preventing vascular thrombosis or arterial restenosis in a mammal. The methods include causing the mammal to inhale a therapeutically effective concentration of gaseous nitric oxide. Also disclosed are methods that include the administration of the following types of agents in conjunction with inhaled nitric oxide: compounds that potentiate the beneficial effects of inhaled nitric oxide, and antithrombotic agents that complement or supplement the beneficial effects of inhaled nitric oxide.
U.S. Pat. No. 6,020,308 (Dewhirst et al.) discloses the use of an inhibitor of NO activity, such as a nitric oxide scavenger or an NO synthase inhibitor, as an adjunct to treatment of inappropriate tissue vascularization disorders
U.S. Pat. No. 5,891,459 (Cooke et al.) discloses the maintenance or improvement of vascular function and structure by long term administration
Cellular Sciences Inc.
Muccino Richard R.
Weddington Kevin E.
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