Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-27
2001-09-04
Henley, Jr., Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S289000, C514S653000
Reexamination Certificate
active
06284765
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is a composition for and method of alleviating nasal congestion or lung ailments, and for providing energy to persons in emergency situations. More specifically, the present invention is a therapy comprising the opiate antagonist (+)naloxone in combination with an adrenergic agonist/bronchodilator.
2. Description of the Prior Art
Naloxone is a narcotic antagonist that prevents or reverses the effects of opiates. The compound and methods for its synthesis are described in U.S. Pat. No. 3,254,088 and its use as a narcotic antagonist is described in U.S. Pat. No. 4,267,182. Like many compounds, naloxone is a racemic mixture of stereoisomers, termed (+)naloxone and (−)naloxone. The racemic mixture (+/−), and in particular the (+)enantiomer, have been shown to potentiate inotropic responses to catecholamines such as epinephrine. Caffrey et al., 31 Circulatory Shock 317-332 (1990).
Catecholamines, including epinephrine (adrenaline), norepinephrine (noradrenaline), dobutamine, and isoproterenol, act as adrenergic agonists in exerting inotropic influences on cardiac muscle and on the constriction or relaxation of blood vessels and the relaxation of bronchial muscle in mammals. The major inotropic influences of these agonists is to increase the contractility of cardiac muscle, and stimulate heart rate. Adrenergic agonists also increase the level of blood glucose and improve air flow in the lungs and nasal passageway. These adrenergic agonists are powerful inotropic agents and are potentially useful interventions for treatment of asthmatic attacks, nasal congestion, or to improve energy in persons who are facing emergency situations such as in combat or emergency rescue personnel.
Adrenergic agents are also widely employed locally in the nasal passages to constrict blood vessels and relieve swelling and congestion. Adrenergic agents are also widely used in the lungs and airways to dilate the airways and ease passage of air. There are two major problems in regard to there uses. First, the adrenergic agents can escape from the point of local application in the nose or airways into the general circulation with the potential to contribute to the heart problems cited below. Second, when these agents are used frequently during chronic, reoccurring or protracted episodes of illness, they loose effectiveness. The return or intensification of symptoms often necessitates more frequent application of the medication or an increase in the dose. This leads to a further loss of efficacy and a much greater probability of a significant spread of the agent from the local site into the general circulation. The systemic distribution of the adrenergic agents into the general circulation is associated with a significant cardiovascular risk. This risk significantly limits the use of these agents, especially in patients with any degree of coronary heart disease, cardiac instability, arrhythmia, hypertension, cerebral vascular disease, or any other peripheral vascular disease (e.g. athrosclerosis, Reynauds disease, intermittent claudication, and arterial spasm).
There are important disadvantages to the use of adrenergic agonists to stimulate cardiac, cardiovascular, and cardiopulmonary functions in humans. Potentially lethal cardiac arrhythmias and cardiac necrosis can result due to an imbalance between nutritional supply and energy demand when adrenergic agonists are used in patients. As stated above, this concern is particularly important for those patients with any form of cardiovascular disease. Specifically, adrenergic agonists produce disproportionate increases in cardiac energy requirements relative to increases in function, especially at higher doses, and deplete energy reserves of post-ischemic, failing cardiac muscle. The depletion of the energy reserves is characterized by a decrease in levels of ATP and the free energy of ATP hydrolysis, used to transfer free energy between energy-producing and energy consuming systems within virtually all living organisms.
The harmful effects of using adrenergic agonists may serve to worsen cardiac trauma. In order to avoid the deleterious effects of the agonists, lower concentrations must be used. However, these low dose levels are often ineffective in stimulating the heart or as a bronchodilator. Thus, there is a need for a method of increasing the sensitivity of adrenergic agonists in humans.
When used in conjunction with naloxone, catecholamines can be used in lower doses, thus decreasing the negative effects of adrenergic agonists. This potentiating effect has been shown to occur with the racemic mixture (both the (−)naloxone and (+)naloxone enantiomers). Gu et al., 40 Circulatory Shock, 206-211 (1993). However, another problem arises in using naloxone in that the racemic mixture, and in particular the (−)naloxone enantiomer, acts as an opiate antagonist and thus heightens the pain sensations of the person being treated, and would in fact be contraindicated for those with injuries, those in pain, and/or when opiates such as morphine are being administered simultaneously.
The (+)naloxone enantiomer does not act as an opiate antagonist. Yet, (+)naloxone is an active potentiator of adrenergic agonists. Given this effect, it would be highly desirable to develop a therapy that takes advantage of the benefits of agonists while eliminating the detrimental side effects. In particular, the use of such adrenergic agonists and bronchodilators as epinephrine is highly desirable in treating asthmatic attack, nasal congestion due to cold, allergies, and other diseases involving airway compromise. What is needed is an improved method of treating breathing passageway compromise in humans.
SUMMARY OF THE INVENTION
It is therefore one object of the present invention to provide an improved nasal decongestant.
It is another object of the present invention to provide an improved treatment for asthmatic attacks.
It is yet another object of the present invention to provide a drug therapy wherein the benefits of improved air flow in a human are achieved while avoiding excessive blood vessel constriction.
It is yet another object of the present invention to avoid the use of racemic mixtures of naloxone that may be contraindicated due to pain in the human or where opiates are being concurrently administered.
It is yet another object of the present invention to provide a method of increasing the heart rate, stroke volume, cardiac output blood glucose, blood lipids and blood pressure for a user in an emergency, stressful situation. This would provide strength, endurance, energy, and help prevent fatigue.
It is yet another object of the present invention to support the circulation and improve blood pressure when blood pressure is reduced due to blood loss, trauma, infection, toxins, stress, fear, pain, or allergic reaction.
It is yet another object of the present invention to enhance local vasoconstriction and serve as an adjuvant administered with other pharmaceuticals in order to contain those other pharmaceuticals in a high therapeutically effective concentration at their site of administration. This object of the present invention would also serve to restrict the spread of those other pharmaceuticals to the rest of the body where they might produce undesirable or toxic consequences.
These and other objects are achieved by a composition formulated for dose-wise delivery to a breathing passageway of a human, the composition comprising a carrier solution containing (+)naloxone and a pharmacologically effective amount of at least one adrenergic agonist or bronchodilator (hereinafter “adrenergic agonist” or “agonist”), the (+)naloxone and agonist forming a mixture in the carrier. As an example of an effective amount, the dose of the composition is typically metered to deliver between about 0.01 and 5 &mgr;g/mL of the adrenergic agonist and between about 0.1 and 6 &mgr;g/mL of (+)naloxone. At least one adrenergic agonist is selected from the
Bracewell & Patterson LLP
Henley, Jr. Raymond
The University of North Texas Health Science Center at Fort Wort
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