Title:  Method for treating bronchial constriction and bronchospasm

United States Patent:  6,623,723

Issued:  September 23, 2003

Inventors:  Katz; Stanley E. (Milltown, NJ)

Assignee:  Cellular Sciences Inc. (Flemington, NJ)

Appl. No.:  933981

Filed:  August 21, 2001

Abstract

The present invention is directed to a method for treating bronchial constriction in mammals. The method comprises contacting mammalian lung with a compound selected from the group consisting of pyruvate and pyruvate precursors. The compound is present in a therapeutically effective amount to produce bronchial dilation. The present invention is also directed to a method for treating airway disease in mammals. The method comprises contacting mammalian lung with a compound selected from the group consisting of pyruvate and pyruvate precursors. The compound is present in an amount from about 0.0001 millimoles to about 0.005 millimoles. The present invention is further directed to a method for treating airway disease in mammals. The method comprises contacting the mammalian lung with a compound selected from the group consisting of pyruvate and pyruvate precursors. The compound is present in a therapeutically effective amount to prevent bronchial spasm. The present invention is still further directed to a method for treating airway disease in mammals. The method comprises contacting the mammalian lung with a compound selected from the group consisting of pyruvate and pyruvate precursors. The compound is present in a therapeutically effective amount to prevent bronchial constriction.

SUMMARY OF THE INVENTION

The present invention pertains to a method for treating an airway condition in mammals which may be characterized by one or more of the following most common symptoms: chronic cough, increased mucus, frequent clearing of the throat, wheezing, chest tightness, coughing, gasping for breath, shortness of breath and other conditions related to bronchial constriction and bronchial spasm. The method for treating such airway condition in mammals comprises contacting the lungs with a compound selected from the group consisting of pyruvate and a pyruvate precursor; wherein the compound is present in an amount capable of producing bronchial dilation. The invention further comprises a method for treating airway condition in mammals which comprises contacting the mammalian lung with a compound selected from the group consisting of pyruvate and pyruvate precursor; wherein the compound is present in a therapeutically effective amount to prevent bronchial spasm.

DETAILED DESCRIPTION OF THE INVENTION

Conditions having the symptoms of chronic cough, increased mucus, frequent clearing of the throat, wheezing, chest tightness, coughing, gasping for breath, shortness of breath and other conditions related to bronchial constriction and bronchial spasm are often caused by over reaction to a stimuli. Such a stimuli can be classed as a trigger or an inducer and vary from person to person. The triggers irritate the airways and result in bronchial constriction and bronchial spasm. Common triggers include but are not limited to: cold air, dust, strong fumes, exercise, inhaled irritants, emotional upsets and smoke. Inducers may also cause bronchial constriction. Typical inducers include allergens and respiratory viral infections. Allergens include but are not limited to: pollen, animal secretions, molds and house dust mites. Exposure to inducers not only results in bronchial constriction, but can also lead to inflammation and serious lung disorders.

During bronchial constriction, the muscles in the bronchial tubes constrict, causing difficulty in breathing. Airflow through these passages becomes difficult resulting in labored breathing. This is often followed by increased mucous secretions, which further plug the airways. Bronchial constriction and increased mucus may result in cough and wheezing. With less and less air available through the lungs, oxygen in the blood decreases.

It has been found that low doses of pyruvate act as a bronchial dilator in mammals with bronchial constriction; whereas high doses of pyruvate do not act as a bronchial dilator. It is believed that when low concentration levels of pyruvate are applied to lung tissue, pyruvate acts outside of the lung cells. Without being held to a specific theory of operation, it is believed that the extra cellular pyruvate acts as a reactive oxygen species antagonist reducing the active oxygen species present in the lung. It is believed these reactive oxygen species are either directly or indirectly responsible for bronchial constriction and bronchial spasm. When the active oxygen agents are removed, the lungs return to normal. In reducing the active oxygen species present in the lung, pyruvate is consumed. When low levels of pyruvate were employed to treat lungs, there would be little or no residual pyruvate available to enter lung cells. When high levels of pyruvate are employed to treat lungs, the reactive oxygen species are inactivated but the presence of excess pyruvate in the airway results in maintaining bronchial constriction. Bronchial spasm is a series of short duration bronchial constrictions alternating with periods of bronchial relaxation.

In a preferred embodiment, the therapeutic compositions containing the bronchial dilator are administered locally to the bronchi. In another preferred embodiment, the therapeutic compositions are administered systemically. In yet another preferred embodiment, the therapeutic compositions are administered systemically and locally concomitantly.

In a preferred embodiment, the therapeutic compositions are administered by inhalation. The therapeutic compositions may be first nebulized by any suitable means. The means of delivering the medicine to the lungs may be for example by nebulizer or metered dose inhalers (MDI's). Such MDI's may use propellants such as gases or they may be dry powder inhalers or mini-nebulizers. The therapeutic compositions may be in liquid or solid form with liquid droplets or particle size being small enough to facilitate access to the bronchi by inhalation.

In another preferred embodiment, a sterile solution of bronchial dilator is nebulized and inhaled by the patient. A therapeutically effective amount of bronchial dilator is inhaled. This may be accomplished in a single inhalation or by repeated inhalations over a period of time of about 1 to 30 minutes. Preferably, inhalation will be complete in less than 20 minutes. Most preferably inhalation will be complete in less than 15 minutes.

The preferred bronchial dilator is at least one compound selected from the group consisting of a pyruvate precursor and pyruvate. A precursor is a substance from which another substance is formed and in this text also includes salts. The preferred bronchial dilator will prevent bronchial spasm.

Preferably the pyruvate is selected from the group consisting of pyruvic acid, lithium pyruvate, sodium pyruvate, potassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate, manganese pyruvate, and the like and mixtures thereof. Sodium pyruvate is most preferred.

Another preferred bronchial dilator is selected from the group pyruvate precursors consisting of pyruvyl-glycine, pyruvyl-cystine, pyruvyl-alanine, pyruvyl-leucine, pyruvyl-valine, pyruvyl-isoleucine, pyruvyl-phenylalanine and pyruvamide.

Compositions for treating airway disease in mammals comprise: a bronchial dilator; and a carrier composition. The carrier composition is selected from the group consisting of tablets, capsules, powders, liquids, isotonic liquids, isotonic media, powders, microparticulates and the like.

The bronchial dilator is administered in a therapeutically effective amount to reduce the undesired bronchial constriction. In the typical case, the bronchial dilator is administered from about 0.0001 to about 0.005 millimoles per dose, preferably about 0.0005 to about 0.005 millimole per dose more preferably about 0.0005 to about 0.004 millimoles per dose, still more preferably about 0.0005 to about 0.0035 millimoles per dose and most preferably about 0.0005 to about 0.003. A millimole of pyruvate is the equivalent weight of one millimole of pyruvate anion or approximately 109 mg. A 5 ml solution of 0.5 millimolar concentration pyruvate will contain 0.0025 millimoles of pyruvate.

Bronchial spasm is treated by administering the bronchial dilator in a therapeutically effective amount to reduce the undesired bronchial constriction. In the typical case, the bronchial dilator is administered from about 0.0001 to about 0.005 millimoles per dose, preferably about 0.0005 to about 0.005 millimole per dose more preferably about 0.0005 to about 0.004 millimoles per dose, still more preferably about 0.0005 to about 0.0035 millimoles per dose and most preferably about 0.0005 to about 0.003. A millimole of pyruvate is the equivalent weight of one millimole of pyruvate anion or approximately 109 mg. A 5 ml solution of 0.5 millimolar concentration pyruvate will contain 0.0025 millimoles of pyruvate.

Typical airway diseases causing bronchial spasm, bronchial constriction or both treatable by the present compositions and method include but are not limited to acute bronchitis, asthma, emphysema, chronic obstructive emphysema, chronic obstructive pulmonary disease, centrilobular emphysema, panacinar emphysema, chronic obstructive bronchitis, reactive airway disease, cystic fibrosis, bronchiectasis, acquired bronchiectasis, interstitial lung disease, kartaagener's syndrome, atelectasis, acute atelectasis, chronic atelectasis, pneumonia, legionnaires disease, psittacosis, fibrogenic dust disease, diseases due to organic dust, diseases due to irritant gases and chemicals, hypersensitivity diseases of the lung, idiopathic infiltrative diseases of the lungs, chronic obstructive pulmonary disease and the like.

The bronchial dilator of the present invention may be administered prior to, after and/or with other therapeutic agents. Typical therapeutic agents are antibacterials, antivirals, antifungals, antihistamines, bronchial dilators, leukotriene receptor antagonists, proteins, enzymes, hormones, nonsteroidal anti-inflammatories, cytokines, steroids, and the like.

It is understood that the method of administration and the condition being treated will greatly affect the dose required to achieve the desired therapeutic effect. A mild asthmatic would be expected to respond to a lower dose than a severe asthmatic.

Claim 1 of 25 Claims

I claim:

1. A method for treating bronchial constriction in mammals comprising contacting mammalian lung with a compound selected from the group consisting of pyruvate and pyruvate precursors; wherein the compound is present in a therapeutically effective amount to produce bronchial dilation.

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