MX2008003935A - Combination s-nitrosothiol-based pharmaceutical products for restoring normal breathing rhythm - Google Patents

Abstract

The present invention is directed to a method of treating a lack of normal breathing control including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions. In an aspect, the invention is directed to treating disordered control of breathing by administering an composition comprising a combination of two or more compounds, at least one of which treats lack of normal breathing. In one aspect, a compound is an S-nitrosylating agent.

Description

PHARMACEUTICAL PRODUCTS OF COMBINATION BASED ON S-NITROSOTIOL TO RESTORE THE RATE OF NORMAL BREATHING BACKGROUND OF THE INVENTION The normal control of breathing is a complex process that involves the interpretation and response of the body to chemical stimuli such as levels of carbon dioxide, pH and oxygen in the blood, tissues and in the brain. The control of breathing is also affected by the waking state (ie, whether the patient is awake or asleep). Within the brain marrow there is a respiratory control center that interprets the various signals that affect breathing and issues commands to the muscles that perform the breathing work. The key muscle groups are located in the abdomen, diaphragm, pharynx and thorax. Sensors located centrally and peripherally then provide input to the brain's central breathing control areas that allow the response to change oxygen requirements. The normal respiratory rhythm is maintained mainly by the body's rapid response to changes in carbon dioxide (CO2) levels. Increased levels of (C02) send the signal to the body to increase the speed and depth of breathing resulting in higher oxygen levels and subsequent levels of (C02) inferiors Conversely, low levels of (CO2) can result in periods of apnea (without breathing) because there is no stimulation to breathe. This is what happens when a person hyperventilates. In addition to the function of the brain, the control of respiration is the result of the feedback of both peripheral and central chemoreceptors, although the exact contribution of each is unknown. There is a wide variety of diseases that have loss of normal breathing rhythm as a primary or secondary feature of the disease. Examples of a primary loss of control of the breathing rhythm are: apnea (central, mixed and obstructive where breathing stops repeatedly for 10 to 60 seconds) and congenital central hypoventilation syndrome. Secondary loss of breathing rhythm may be due to chronic cardiopulmonary diseases (eg, heart failure, chronic bronchitis, emphysema, and imminent respiratory impairment), excessive weight (eg, hypoventilation syndrome due to obesity), certain drugs (e.g. , anesthetics, sedatives, anxiolytics, hypnotics, alcohol, narcotic analgesics) and / or factors that affect the neurological system (eg, stroke, tumor, trauma, radiation damage, ALS). In chronic obstructive pulmonary diseases where the body is exposed to chronically low levels of oxygen, the body adapts to the lower pH through a bicarbonate retention mediated by the kidney which has the effect of partially neutralizing the Respiratory stimulation of CO2 / pH. In this way, the patient must have a less sensitive oxygen-based system. In particular, the loss of normal breathing rhythm during sleep is a common condition. Sleep apnea is characterized by frequent periods of null or partial breathing. Key factors that contribute to these apneas include: decrease in sensitivity of the C02 receptor, decrease in sensitivity of the hypoxic ventilation response (eg, decreased response to low oxygen levels) and loss of "waking state". Taken together, the normal breathing rhythm is altered resulting in hypoxia (and the associated oxidative stress) and finally severe cardiovascular consequences (high blood pressure, stroke, heart attack). Snoring has some characteristics in combination with sleep apnea. The muscles of the upper airways lose their tone resulting in sounds associated with snoring but also an inefficient air flow which can result in hypoxia. The definitive treatment for many respiratory control disorders is either mechanical ventilation or devices for positive airway pressure (for example, device for continuous positive airway pressure (CPAP device), device for double-level positive pressure in the airways (BiPAP device). Some pharmacological agents have been proposed as interventions to control respiration in breathing disorders related to the dream. De Backer provided a review and described Progestin, Almitrin and Acetazolide (De Backer WA, 1995 Eur. Respir J. 8: 1372-1383) Hudgel and Thanakitcharu also provided a pharmacological treatment review of sleep disturbed breathing and described medroxyprogesterone, thyroid replacement, acetazolamide, theophylline, tricyclic antidepressants, serotonin and clonidine reuptake inhibitors in addition to other agents (Hudgel DW and Thanakitcharu S. 1998 Am J Respir Crit Care Med 158: 691-699). In 2005, Qureshi and Lee-Chiong provided a review of various medical options to treat obstructive sleep apnea, including a wide variety of pharmacological treatments. A few of the agents included benzodiazepines, narcotics, acetazolamide, antidepressants and agents that affect serotonin either as agonists, reuptake inhibitors or antagonists (Qureshi A and Lee-Chiong, JR, TL Sem. Resp Crit Care Med 2005; 26: In particular, De Backer noted that low doses of the carbonic anhydrase inhibitor acetazolamide seemed to exert a beneficial effect unrelated to its traditional action of reducing pH as a mechanism of respiratory stimulation. In patients with central apnea, it was found that low doses of acetazolamide reduce episodes of apnea from 25.5 before treatment to 6.8 after one month of treatment (73%). Smaller reductions (approximately 25%) were observed in patients who had mainly obstructive sleep apnea.

More recently, Carley and Radulovacki described the use of a serotonin agonist / antagonist combination to increase motor tone in the portion of the throat that collapses in obstructive sleep apnea (Carley and Radulovacki, 1999, Am. J. Respir. Care Med. 1 60: 1824-1829). This concept is currently in commercial development through a company formed by Organon and Cypress Bioscience and a separate group, BTG, foot (see, for example, the Patent Application Publications of E.U.A. Nos. 20060039866, 20060039867, 20060122127). Gaston and Gozal proposed a fundamentally different method by demonstrating that the S-nitrosothiol signaling pathway can be used to exercise control over respiration by increasing minute ventilation (International Patent Application Publication No. WO 03/015605, the entirety of which it is incorporated herein by reference). For the first time, they demonstrated that the centrally mediated hypoxic ventilation response system is under the control of certain S-nitrosothiol compounds. Gastón and Gozal demonstrate a group of compounds that can induce the typical response of the body to low oxygen levels that trigger, among other reactions, increases in the speed and depth of breathing. A mammal's ability to breathe, and to modify breathing according to the amount of oxygen available and body demands, is essential for survival. There are a variety of conditions that are characterized by the loss of respiratory rate due to either a primary or secondary cause. Estimates for individuals affected by several of the most frequent conditions in the United States include, sleep apnea: 15-20 million; hypoventilation syndrome due to obesity: 5-10 million; Chronic heart disease: 5 million; chronic obstructive pulmonary disease (COPD) / chronic bronchitis: 10 million; Drug-induced hypoventilation: 2-5 million; and dehabituation of mechanical ventilation: 0.5 million. The control of breathing is a complex process. It involves a respiratory impulse, and also the diameter of the tubes through which the air flow occurs. For example, assume that an animal is breathing through a straw. If the straw is dry and the walls are stiff, air will flow evenly during inspiration (negative pressure) and exhalation (positive pressure). However, if the straw gets wet, during inhalation, the walls collapse and the animal can not inhale air. This example of "wet straw" is partially descriptive of what happens in patients afflicted with sleep apnea. When a patient with sleep apnea goes to sleep, the respiratory impulse decreases and muscle tone in the airway decreases and the airway collapses during inspiration, causing an obstruction to normal breathing. The current treatment for sleep apnea is mainly the use of devices for positive airway pressure (PAP). Compliance with these devices is usually very poor. Pharmaceutical products that can be used either alone or as an adjuvant for devices for positive airway pressure thus reducing the pressure required to maintain airway opening, would be an important advance to improve compliance with these PAP devices or provide an alternative means of treatment. Accordingly, a combination pharmaceutical product that could restore all or part of the body's normal breathing control system in response to changes in C02 and / or oxygen would be of benefit in decreasing the incidence and severity of alterations in breath control . Currently, there is an unmet need for said product that can be administered to a patient with minimal side effects. The present invention raises and fulfills this need.

BRIEF DESCRIPTION OF THE INVENTION The invention includes a therapeutic composition for stabilizing the respiration rate, comprising a first composition comprising a first S-nitrosothiol compound and a second composition comprising a second compound that is not an S-nitrosothiol compound, wherein the Second compound has the activity of stabilizing the breathing rhythm. In one aspect, the second compound is selected from the group consisting of a carbonic anhydrase inhibitor, a serotonin agonist, a serotonin antagonist, an NADPH oxidase inhibitor, a leukotriene antagonist, a COX-2 inhibitor and theophylline. In one embodiment, a carbonic anhydrase inhibitor is selected from the group consisting of acetazolamide and topiramate. In another embodiment, the second compound is a tetracyclic antidepressant selected from the group consisting of mirtazipine and setiptilin. In another embodiment, a serotonin agonist is selected from the group consisting of mirtazapene, buspirone and a serotonin reuptake inhibitor. In one embodiment, a serotonin antagonist is ondansetron. In another embodiment, the invention includes an NADPH oxidase inhibitor selected from the group consisting of apocynin, 4-hydroxy-3'-methoxyacetophenone, N-vanillylnonamnide, and staurosporine. The invention includes a method for stabilizing the respiration rate of a mammal, which comprises administering to a mammal the therapeutic composition comprising a first composition comprising a first compound of S-nitrosothiol and a second composition comprising a second compound not is a compound of S-nitrosothiol, where the second compound has the activity of stabilizing the rhythm of respiration. The invention includes a therapeutic composition further comprising a third compound, wherein the third compound is an S-nitrosothiol compound. The invention further includes a therapeutic composition further comprising a third compound, wherein the third compound is not an S-nitrosothiol compound. The invention includes a pharmaceutical composition comprising the composition as set forth herein and a pharmaceutically acceptable carrier. The invention includes a method for stabilizing the respiration rate of a mammal, which comprises administering to a mammal a therapeutic composition as described herein. The invention further includes a method for stabilizing the respiration rate of a mammal, said method comprising administering to a mammal the therapeutic composition of claim 1, said method further comprising treating said mammal with an auxiliary ventilation device. In one embodiment, the auxiliary ventilation device is selected from the group consisting of a CPAP device and a BiPAP device. In a method of the invention, the route of administration is selected from the group consisting of parenteral, oral and buccal. In one embodiment, a parenteral route of administration is selected from the group consisting of transdermal, intravenous, intramuscular, and intradermal. In another embodiment, a composition is administered at least through two administration routes. The invention includes a method for increasing minute ventilation (VE) to the level of respiratory control centers of the brainstem in the nucleus of the solitary tract of an individual, comprising the step of administering to an individual a therapeutic composition comprising a first composition comprising a first compound of S-nitrosothiol; and a second composition comprising a second compound that is not an S-nitrosothiol compound, wherein the second compound has the activity of increasing minute ventilation (VE) at the level of the respiratory control centers of the brainstem at the nucleus of the lonely tract.

BRIEF DESCRIPTION OF THE DRAWINGS For the purpose of illustrating the invention, certain embodiments of the invention are represented in the drawings. However, the invention is not limited to the precise arrangements and mediations of the embodiments illustrated in the drawings. Figure 1 illustrates the complex and interconnected nature of mammalian respiration control; and Figures 2A-2C illustrate the factors that affect the control of respiration. Figure 2A illustrates the factors that affect the control of normal breathing. Normally, the respiratory drive can operate through a scale of conditions, and the levels of carbon dioxide and oxygen are the main drivers and act in an interrelated manner. Figure 2B illustrates factors that affect the control of deranged respiration. A wide range of factors act in a Individual or in combination to decrease the respiratory impulse resulting in stoppages in breathing or inefficient breathing. The eventual result is hypoxia that leads to cardiovascular, neurological and / or metabolic consequences. Figure 2C illustrates factors that will be considered for effective pharmacotherapy control of deranged breathing. The drugs are useful to help restore the respiratory drive through defined pathways or by improving airflow in the upper airways. The eventual result, in one embodiment of the invention, is to decrease deranged respiration (eg, apnea, hypopnea, hyperventilation), hypoxia and the associated consequences.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method of combination, or "of multiple drugs", for the treatment of sleep apnea by combining the control of the hypoxic ventilation response, by means of the administration of S-nitrosothiols, with other drugs that they provide a complementary activity. The invention provides that a composition comprising a combination of two or more compounds can provide improved effectiveness in the treatment of respiratory control disorders by acting on two or more physiological pathways, wherein one of the pathways is affected by the treatment with S-nitrosothiol for restoration of the respiratory rhythm. In other aspect of the invention, a composition comprising a combination of two or more compounds can provide improved effectiveness in the treatment of breathing control disorders by acting on the same physiological pathway. Poor or inefficient respiratory drive results in hypoventilation, which then results in hypoxia. A primary initial clinical manifestation of hypoxia is drowsiness or excessive sleepiness during the day. Therefore, drugs that cause a decreased respiratory drive and the resulting hypoxia are sometimes limited in their usefulness due to fear of life-threatening respiratory depression and / or excessive sleepiness during the day that negatively impacts the quality of life. lifetime. Another result of hypoxia derived from respiratory impulse deficiency is oxidative stress, which has been linked to longer-term cardiovascular and / or metabolic outcomes. Combination products that combine a compound to restore respiratory rate with an agent that helps reduce oxidative stress can provide an important dual mode of action to alleviate the short and long-term consequences of hypoxia. As set forth herein, combination compositions comprising an S-nitrosothiol compound to counteract the respiratory depressant effect of drugs that decrease the respiratory drive may provide a benefit to patients by helping to maintain normal oxygen levels in the patient. blood and tissues. TO As a non-limiting example, narcotic analgesics (eg, morphine, fentanyl, oxycodone, buprenorphine) are administered to cancer patients to relieve pain. The dose is often limited by a fear of respiratory depression. In addition, even a partial respiratory depression derived from these drugs causes hypoxia and a resulting excessive sleepiness during the day that can be debilitating and can severely decrease the quality of life. General anesthetics can exert a similar depressive effect on respiration and delay the transfer of a patient from the operating room to a surgical recovery area. A combination composition comprising an S-nitrosothiol compound is therefore useful for counteracting the persistent effects of the anesthetic, and for restoring the proper respiratory drive to allow the patient to breathe on their own. By way of another non-limiting example, excessive weight can decrease the respiratory drive which results in hypoventilation and hypoxia. This condition is called hypoventilation syndrome due to obesity. Excess weight is also a risk factor in breathing disorders related to sleep. Therefore, a combination composition comprising an S-nitrosothiol compound is useful to counteract the respiratory depressant effects of obesity. The combination compositions of the invention are also useful for increasing muscle tone of the upper airways, improve the ventilation / perfusion association and increase the production of erythropoietin, among other things, as set forth in detail here.

Definitions As used herein, each of the following terms has the meaning associated with it in this section. The articles "a", "an" are used herein to refer to one or more than one (ie, at least one) of the grammatical object of the article. By way of example, "an element" means an element or more than one element. The term "approximately" will be understood by those skilled in the art and will vary to some extent in the context in which it is used. As used herein, the term "apnea" means the absence of normal breathing resulting in intermittent stops of respiration. "Antisense" refers particularly to the nucleic acid sequence of the non-coding strand of a double-stranded DNA molecule encoding a polypeptide, or to a sequence that is substantially homologous to the non-coding strand. As defined herein, an antisense sequence is complementary to the sequence of a double-stranded DNA molecule encoding a polypeptide. It is not necessary that the antisense sequence be complementary only to the coding portion of the coding strand of the DNA molecule. Sequence antisense may be complementary to specified regulatory sequences in the coding strand of a DNA molecule encoding a polypeptide, regulatory sequences which control the expression of the coding sequences. "Cheyne-Stokes respiration" refers to a specific breathing pattern characterized by a crescendo breathing pattern that results in apneas and / or hypopneas. A hallmark of this condition is that breathing gets out of phase with oxygen levels in the blood. As used herein, "endogenous" refers to any material from or produced within an organism, cell, tissue or system. As used herein, the term "exogenous" refers to any material introduced from or produced outside of an organism, cell, tissue or system. The term "expression" as used herein, is defined as the transcription and / or translation of a particular nucleotide sequence driven by its promoter. The term "expression vector" as used herein, refers to a vector that contains a sequence of nucleic acids that encode at least part of a gene product capable of being transcribed. In some cases, the RNA molecules are then translated into a protein, polypeptide, or peptide. In other cases, these sequences are not translated, for example, in the production of antisense molecules, siRNA, ribozymes, and the like. Expression vectors can contain a variety of control sequences, which refer to nucleic acid sequences necessary for the transcription and possibly translation of a coding sequence operably linked in a particular host organism. In addition to the control sequences that regulate transcription and translation, the vectors and expression vectors may contain nucleic acid sequences that also perform other functions. "Hypopnea" is similar in many aspects to apnea; however, breathing does not stop completely, but stops partially (ie, less than 100% normal breathing, but more than 0% normal breathing). Hypopnea is also referred to herein as "partial apnea" and can be subdivided into the obstructive, central or mixed types. An "isolated nucleic acid" refers to a segment or fragment of nucleic acid which has been separated from flanking sequences in a natural state, i.e., a fragment of DNA that has been removed from the sequences that are normally adjacent to the nucleic acid. fragment, that is, the sequences adjacent to the fragment in a genome in which it occurs naturally. The term also applies to nucleic acids that have been substantially purified from other components that naturally accompany the nucleic acid, i.e., RNA or DNA or proteins, which naturally accompany it in the cell. Therefore, the term includes, for example, a recombinant DNA that is incorporated in a vector, in a plasmid or virus of autonomous replication, or in the genomic DNA of a prokaryote or eukaryote, or that exists as a separate molecule (ie, as a cDNA or a genomic or cDNA fragment produced by PCR or digestion of restriction enzymes) independently of other sequences. It also includes a recombinant DNA that is part of a hybrid gene that encodes an additional polypeptide sequence. As used herein, the term "modular" is intended to refer to any change in biological state, i.e., increase, decrease, and the like. As used herein, the term "promoter / regulatory sequence" means a nucleic acid sequence that is required for expression of a gene product operably linked to the promoter / regulatory sequence. In some cases, this sequence may be the core promoter sequence and in other cases, this sequence may also include an enhancer sequence and other regulatory elements that are required for the expression of the gene product. The promoter / regulatory sequence, for example, may be one which expresses the gene product in a tissue-specific manner. As used herein, a "therapeutically effective amount" is the amount of a therapeutic composition sufficient to provide a beneficial effect to a mammal to which the composition is administered.

"S-nitrosothiol pathway", as the term is used herein, refers to the signaling pathway and the signaling mechanisms that occur as information regarding oxygen levels in blood is transmitted to the brain through S-nitrosothiol signaling.

Compositions of the invention and uses thereof The present invention includes compositions and methods for treating deranged control of respiration. In one embodiment, the invention provides methods and compositions for treating sleep apnea. During sleep, breathing changes with the stage or depth of sleep. Some individuals stop breathing for short intervals. When those episodes of apnea become more frequent and last longer, they can cause the body's oxygen level to decrease, which can disturb sleep. The patient may not be fully awake, but rises from the deep sleep rest stages, and therefore feels tired the next day. There are two main types of sleep apnea that can occur together. The most common is obstructive sleep apnea, during which breathing is blocked by a temporary obstruction of the main airway, usually in the back of the throat. This often occurs because the muscles of the tongue and throat relax, causing the main airway to close. The muscles of the chest and diaphragm continue to make breathing efforts, but the Obstruction prevents any airflow. After a short interval that lasts from seconds to minutes, the oxygen level drops, causing the breathing efforts to become more vigorous, which eventually opens the obstruction and allows the air flow to be restored. This often occurs with a loud snorting and sudden spasmodic movement of the body, causing the patient to wake up from a deep sleep. After a few breaths, the oxygen level is normalized, the patient goes back to sleep, the muscles of the main airway relax and the obstruction occurs again. This cycle is repeated again and again during certain stages of sleep. Most people with obstructive sleep apnea are hoarse, suggesting that their main airway is already partially obstructed during sleep, but not all people who snore have obstructive sleep apnea. A less common form of sleep apnea is central sleep apnea, so called because the central control of breathing is abnormal. This control center resides in the brain, and its function can be altered by a variety of factors. There is no obstruction for the air flow. The patient with sleep apnea stops breathing because the brain suddenly stops sending signals to the muscles of the chest and diaphragm to continue breathing. These patients do not restore breathing with a snorting and sudden spasmodic movement of the body, but simply start and stop breathing at various intervals. Although the mechanism is different from obstructive sleep apnea, the dream of all forms is altered by periodic decreases in oxygen, and patients suffer from the same symptoms during the day. Some patients may suffer from a combination of the two causes of apnea, a condition called mixed sleep apnea, also called "complex sleep apnea." Sleep apnea should be assumed in individuals who are distinguished by excessive sleepiness during the day and other symptoms described above, especially if they are known to snore and have restless sleep. Commonly, these patients have experienced severe snoring for many years, more often men, and note that drowsiness during the day has become a progressive problem for many months. Less commonly, they may have the discomfort of bedwetting or impotence. Sleep problems are often aggravated by alcohol or sedative medications. They are also more easily perceived by the patient's family and friends, especially the bed partner. It should be understood that the compounds and methods of the present invention are applicable to any other respiratory control that is associated with an S-nitrosothiol signaling pathway. That is, the present invention provides that a composition comprising a combination of two or more compounds can provide improved effectiveness in the treatment of disorders of breath control by acting on two or more physiological pathways, wherein one of the pathways is seen. affected by treatment with S-nitrosothiol to restore the respiratory rhythm.

In another aspect of the invention, a composition comprising a combination of two or more compounds can provide improved effectiveness in the treatment of breathing control disorders by acting on the same physiological pathway. In one aspect of the invention, a composition for treating sleep apnea is used. According to the present invention, the second compound used together with an S-nitrosothiol compound, can be selected by a specific property or activity, as described in detail herein. In one aspect of the invention, the third, fourth compound, or additional compound may also be a compound other than S-nitrosothiol, selected by a specific property or activity, as described in detail herein. The following are non-limiting examples of said compounds, but they should not be interpreted in any way as the only compounds of that type useful in the present invention. The person skilled in the art, when having the basis of the present description, will understand how to identify a second (or third, fourth, fifth, etc.) compound useful in combination with an S-nitrosothiol compound according to the present invention.

TABLE 1 Examples of useful compounds in combination with an S-nitrosothiol compound according to the present invention to. A compound with the activity of stabilizing the rhythm of respiration i. Carbonic anhydrase inhibitor (eg, acetazolamide, topiramate) i. Respiratory stimulation (eg, caffeine, theophylline, doxapram) iii. Narcotic antagonists (for example, naloxone) iv. Hormones (eg, medroxyprogesterone) b. A compound with the activity of increasing the opening of the upper airway through activity on serotonin, dopamine, norepinephrine or GABA i. Serotonin agents (eg, 5HT1A buspirone agonist, serotonin reuptake inhibitors, 5HT3 receptor antagonists such as ondansetron) ii. Dopamine and / or norepinephrine agents (eg, ropinerol, milnacipran) iii. Tetracyclic antidepressants (for example, mirtazipine, setiptilin) c. A compound with the activity of promoting the waking state i. Modafinil, r-modafinil, amphetamine d. A compound with the activity of decreasing seizures i. Zonisamide e. A compound with the activity of increasing the opening of the upper airway by decreasing inflammation i. Antihistamines (eg, cetirizine, azelastine, desloratidine, fexofenadine) ii. Leukotriene antagonists (eg, montelukast) iii. 5-lipoxygenase inhibitors (eg, zileuton) iv. Steroids (for example, fluticasone) v. COX-2 inhibitors f. A compound with the activity of decreasing the respiratory drive as a side effect to its main therapeutic effect i. Opioid analgesics (eg, morphine, meperidine, fentanyl, oxycodone, buprenorphine) ii. Sedative hypnotics (eg, lorazepam, zolpidem, zaleplon) iii. General anesthetics (for example, halothane, enflurane, thiopental) iv. Ethyl alcohol g. A compound with the activity of improving lung function in diseases such as asthma and / or chronic obstructive pulmonary disease i. Steroids (for example, budesonide, fluticasone, combinations of salmeterol / fluticasone) ii. Bronchodilators (eg, salbutamol, salmeterol) iii. Anticholinergic (for example, tiotropium, ipatropium) h. A device used to help breathing through mechanical ventilation or positive airway pressure i. Mechanical fans ii. CPAP iii. BiPAP Combination drugs in the pharmaceutical industry are reasonably common, and the preparation and use of such drugs will be understood by the person skilled in the art. For example, Advair® is a combination of a steroid compound and a bronchodilator compound, and is used for the treatment of asthma. Combinations comprising two or more compounds according to the present invention include, but are not limited to compounds of S-nitrosothiol + acetazolamide (and other inhibitors of carbonic anhydrase including topiramate), S-nitrosothiol compounds + serotonin agonist agents ( for example, 5HT1 A agonist buspirone, serotonin reuptake inhibitors), S-nitrosothiol compounds + agents serotonin antagonists (e.g., 5HT3 receptor antagonists, such as ondansetron), S-nitrosothiol compounds + tetracyclic antidepressants (e.g., mirtazipine, setiptilin), S-nitrosothiol + modafinil compounds, S-nitrosothiol + r- compounds modafinil, S-nitrosothiol compounds + compounds that effect the neuronal uptake of norepinephrine and / or dopamine (for example, ropinerol, milnacipran), S-nitrosothiol + zonisamide compounds, S-nitrosothiol compounds + agents that stimulate brain activity and / or which are opioid antagonists (eg, doxapram, naloxone, caffeine), S-nitrosothiol compounds + narcotic analgesics that cause respiratory depression (eg, morphine, meperidine, fentanyl, oxycodone, buprenorphine), S-nitrosothiol compounds + General anesthetics that cause respiratory depression (halothane, enflurane, thiopental), S-nitrosothiol compounds + theophylline S-nitrosothiol compounds + steroid and / or bronchodilator agents commonly used to treat asthma or chronic obstructive pulmonary disease (eg, budesonide, fluticasone, salbutamol, formoterol, combinations of salmeterol / fluticasone, tiotropium, patropio), S-nitrosothiols + antihistamines (eg, cetirizine, azelastine, desloratidine, fexofenadine), S-nitrosothiol + sedative / hypnotic compounds (eg, lorazepam, zolpidem, zaleplon), and compounds of S-nitrosothiol in combination with breathing devices for positive pressure in the airways (including CPAP and BiPAP). Other useful compounds in combination with the S-nitrosothiol compounds, as set forth herein, are described in the Application Publication. of Patent of E.U.A. No. 20060039866, which is incorporated herein by reference in its entirety. In one embodiment of the invention, a combination of two or more compounds, wherein at least one compound acts through the path of S-nitrosothiol provides an additive or synergistic effect to restore the rhythm of normal respiration. In another embodiment of the invention, a combination of two or more compounds, wherein at least one compound acts through the path of S-nitrosothiol, provides an effect to counteract the respiratory depressant effect of another drug that may or may not be administered at the same time. It has been described that S-nitrosothiol compounds, or "SNOs," have various clinical benefits. These include, but are not limited to, increased respiratory drive, increased muscle tone in the upper airway, improved oxygen exchange in the lungs ("ventilation perfusion association"), and increased production of erythropoietin (EPO), a natural hormone that increases the production of red blood cells. Increased EPO production may be especially useful in patients who have breathing problems (with accompanying hypoxia) and anemia. These conditions result in a "double negative effect" of low oxygen levels and a low oxygen-carrying cell count (eg, prematurity apnea, patients with kidney dialysis).

In one aspect of the invention, a compound of the invention is useful in the manner in which the compound is administered. That is, the chemical structure and formula of the compound that is administered to the patient is the compound that is active according to a method of the invention. In another aspect, a compound of the invention is active in a form other than that structure or formula that is administered to a patient. In this aspect of the invention, a compound must first be altered, added, disintegrated, metabolized or otherwise modified from the manner in which the compound is administered to the patient. By way of non-limiting example, N-acetylcysteine (NAC) is such a compound. NAC is administered to a patient as a prodrug, which is metabolized by the body in S-nitrosothiol-N-acetylcysteine (SNOAC). SNOAC, the metabolized compound, is subsequently active to order, for example, the breathing of a patient. See, for example, International Patent Application Publication No. WO 03/015605, the entirety of which is incorporated herein by reference. In another aspect of the invention, the S-nitrosothiol compound is an analogue, derivative or modification of a known S-nitrosothiol compound. By way of several non-limiting examples, an S-nitrosothiol compound encompassed by the present invention includes an N-acetylcysteine analog, an N-acetylcysteine derivative, a N-acetylcysteine modification, and an N-acetylcysteine metabolite. The person skilled in the art will understand, when he has the basis of the description set forth herein, that analogs and derivatives of S-nitrosothiol compounds can be prepared and used according to the invention described herein. The person skilled in the art will understand how to identify which portion or portions of an S-nitrosothiol compound to modify, and further, how to make such modifications, in accordance with the present invention. In addition, based on the detailed description set forth herein, one skilled in the art will know how to analyze said compounds to identify analogs or derivatives having the activity of a compound of the invention, particularly, the ability to control respiration in accordance with the present invention, when used in combination with one or more additional compounds. By way of a non-limiting example, a combination according to the invention comprises acetazolamide combined with N-acetylcysteine. In one embodiment, a combination according to the invention comprises a low dose of acetazolamide (e.g., 250 mg / day or less) combined with N-acetylcysteine. Without intending to be limited to any particular theory, a combination of acetazolamide and N-acetylcysteine can work in a complementary or synergistic way to restore the normal respiratory rate. Acetazolamide may work to restore the body's sensitivity to C02 and N-acetylcysteine may work to restore the sensitivity of the breathing centers to low oxygen levels. Acetazolamide has been used for many years as a light diuretic (that is, to increase urine output or help treat the disease of the heights). It is also believed that acetazolamide works through the trajectory of the respiratory drive based on carbon dioxide. It is proposed that it works by reducing the pH of the blood, but this may not be the only way it affects the respiratory drive. Decreases in respiratory drive can be caused by poor function of the carbon dioxide component, the oxygen component, or both components together. In fact, these components are interrelated and the fact of causing an effect on one can affect the other and the respiratory impulse in general. Therefore, in one embodiment of the invention, in cases such as sleep apnea where the CO2 and O2 pulse is decreased, a combination composition is used to provide a treatment and / or clinical benefit of the patient. That is, in one embodiment, the invention provides a method for treating sleep apnea. Previously, traditional thinking was that the doses of acetazolamide needed for the treatment are too toxic for long-term use in a large number of patients. However, lower doses of acetazolamide may be sufficient to produce the desired effects on the respiratory drive, particularly in combination with one or more other components according to the present invention. Other compounds that may be more effective at lower doses, due to the predominance of side effects when used at higher doses, include, but are not limited to, theophylline.

A combination composition according to the invention is useful for treating any condition characterized by lack of control of normal breathing. By way of a non-limiting example, such conditions include, sleep apnea (central, mixed and obstructive including, but not limited to, coexisting conditions of cardiac deficiency, kidney disease and stroke), sleep-disturbed breathing (especially with snoring and awakening) , chronic bronchitis, COPD, asthma, allergy and neurological diseases (eg, stroke, amyotrophic lateral sclerosis (ALS).) Other conditions that may be treated with the methods and compositions of the present invention include, but are not limited to, snoring, syndrome of hypoventilation due to obesity, prematurity apnea, respiratory depression due to drugs (for example, narcotic analgesics, sedatives, alcohol, sleeping pills, anesthetics), central congenital hypoventilation syndrome, hypoventilation due to stroke, trauma, surgery and / or radiation , and air conditioning at high altitude. The invention is also useful in assisting in the treatment of any condition that can be treated using a positive airway pressure (PAP) device, as described herein. By way of a non-limiting example, the present invention can also be used to treat and / or alleviate symptoms, or to facilitate, the air conditioning at high altitude. Genetic diversity plays a role in how people respond to low levels of oxygen. Some respond rapidly increasing the speed and depth of breathing (the response of hypoxic ventilation) while some others are slower. There are some cases where the ability to adapt quickly is important. For example, soldiers quickly introduced into a battle situation at a high altitude (for example, 3,648 meters in Afghanistan) need to operate at peak performance. A response to slow hypoxia will result in excessive fatigue and poor work performance. For soldiers this can be a threat to life. For the mentioned extreme altitude, the case is well defined. There may also be application at lower altitudes such as the transition from New York to Denver (1, 520 meters) or the jet lag of a prolonged flight (cabin pressure of 1, 824 meters). Reuptake inhibitor compounds or serotonin agonists (eg, mirtazapine) have been shown in animals to help restore upper airway tone to prevent collapse. In one aspect of the invention, a combination composition of SNO / serotonin agonist is used, through which the SNO is used to improve the respiratory drive, and the serotonin agonist improves the tone of the upper airway to help to air flow and help prevent clogging. In another embodiment, the invention includes a combination of a SNO with an agent intended to reduce oxidative stress. When the body stops breathing and oxygen levels fall, there is a series of reactions that lead to oxidative stress that is directly thought to cause the cardiovascular complications associated with sleep apnea and other conditions. Cardiovascular complications are the main cause of death. In one aspect of the invention, a combination composition comprises N-acetylcysteine, which is used to reduce oxidative stress through a metabolic pathway unrelated to SNO production. That is, the invention also includes methods and combination compositions in which N-acetylcysteine or another compound containing SNO reduces oxidative stress in combination with another drug, either a second SNO, or a compound that is not SNO as per example, without limit, acetazolamide, where the second compound acts to increase the respiratory impulse. Other combinations useful in the methods and compositions of the invention will be understood by the person skilled in the art, when it has the basis of the description set forth in the present specification. In another aspect, the invention includes a combination composition comprising a SNO compound and a compound that treats and / or prevents oxidative stress in a mammal. In one embodiment, the invention includes a method of treating a patient who lacks normal breathing by administering a compound of the invention. The frequent events of hypoxia / reoxygenation, which replicate the patterns of oxygenation in sleep apnea, induce NADPH oxidase and proinflammatory gene expression in a modality.

Selected brain regions, which in another modality include active neurons in the waking state. In one modality, it is determined that the lack of functional NADPH oxidase and pharmacological inhibition of NADPH oxidase confers resistance to neurobehavioral changes induced by intermittent, redox and proinflammatory hypoxia, thus emphasizing a potential objective to prevent oxidative morbidity in people with obstructive sleep (OSA). The Patent Application Publication of E.U.A. No. 20060154856 (which is incorporated herein by reference in its entirety) identifies NADPH oxidase as a major source of intermittent hypoxia-induced injury in the brain. In another modality, the activation of NADPH oxidase in people with OSA contributes to the cardiovascular morbidity associated with this disease. Therefore, the trajectory of NADPH oxidase is a valuable pharmacotherapeutic objective for neurobehavioral and cardiovascular morbidity of the predominant disorder, sleep apnea. According to one aspect of the present invention, the invention provides a method for treating a cardiovascular morbidity, a neurobehavioral morbidity or a combination thereof, resulting from sleep apnea-hypopnea syndrome in a subject, comprising administering to said subject a therapeutically effective amount of a combination comprising an inhibitor of NADPH oxidase, and at least one other compound. In one embodiment, the at least one other compound is an inhibitor of the signaling path of S- nitrosothiol. Inhibitors of NADPH oxidase include, but are not limited to apocynin, or 4-hydroxy-3'-methoxyacetophenone, N-vanillylnonamide, and staurosporine. In another embodiment, the invention includes a combination of an SNO with an agent intended to reduce inflammation. Examples include a leukotriene receptor antagonist (or 5-lipoxygenase inhibitor), antihistamine, or anti-inflammatory agent (e.g., COX-2 inhibitor or steroids). In one aspect, the invention includes a method for using said combination composition to treat a patient lacking normal breathing. Patients with sleep disturbed breathing have a turbulent airflow that causes inflammation and reduces their ability to obtain air efficiently. As discussed in this, SNO compounds increase the respiratory impulse and can increase the diameter of the upper airway passages. Therefore, according to the invention, a combination composition comprising an SNO plus an anti-inflammatory compound is useful to provide a complementary therapeutic benefit (Goldbart et al., Am. J. Respir. Crit. Care. Med. 2005; 1 72: 364-370). By way of a non-limiting example, therapy with leukotriene antagonists, utilizing compositions and methods of the present invention, will decrease the inflammation resulting from a turbulent airflow, ordering the respiration of a patient suffering from lack of normal respiration. . This is it owes to the fact that the altered air flow causes inflammation which additionally restricts the flow of air, because the inflammation decreases the size of the passages of airways. According to the present invention, the products of combination compositions that include an anti-inflammatory agent are useful to provide an additional benefit for both adult and pediatric patients with various forms of sleep disturbed breathing. In one aspect of the invention, a combination product of a SNO prodrug (e.g., N-acetylcysteine) or an SNO in combination with a leukotriene antagonist (or a 5-lipoxygenase oxidase inhibitor) are useful for treating the control disturbed breathing, and at the same time, minimize inflammation associated with such breathing disorders. In another aspect of the invention, the invention includes a combination composition comprising three or more compounds for the treatment of a disease or disorder that involves a lack of control of normal respiration. The invention also includes methods for treating a mammal, wherein the method utilizes a combination composition comprising three or more compounds for the treatment of a disease or disorder that involves a lack of control of normal respiration. A composition according to the invention may comprise one or more SNO compounds. In another embodiment, a composition according to the invention can comprise three or more compounds that are not of SNO. The Useful compounds in a combination composition of the invention are described in detail herein. In another aspect of the invention, a method of treating a patient lacking normal respiration, comprises administering a compound of the invention, as described herein, and further treating the patient using a device for treatment of a shortness of breath normal. As described in detail herein, said devices include, but are not limited to, CPAP and BiPAP devices.

Pharmaceutical Compositions The invention also encompasses the use of pharmaceutical compositions of a suitable protein or peptide and / or isolated nucleic acid to practice the methods of the invention. The compositions and combinations of compounds set forth herein may be used alone or in combination with additional compounds to produce additive, complementary or synergistic effects in the treatment of deranged breathing, and in the treatment of sleep-related breathing disorders. In one embodiment, the pharmaceutical compositions useful for practicing the invention can be administered to deliver a dose of between 1 ng / kg / day and 100 mg / kg / day. In another embodiment, the pharmaceutical compositions useful for practicing the invention can be administered to deliver a dose of between 1 ng / kg / day and 500 mg / kg / day.

Pharmaceutically acceptable carriers, which are useful, include, but are not limited to, glycerol, water, saline, ethanol, and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey). The pharmaceutical compositions can be prepared, packaged or sold in the form of a suspension or sterile injectable aqueous or oily solution. This suspension or solution may be formulated according to the known art, and may further comprise the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations can be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example. Other diluents and acceptable solvents include, but are not limited to Ringer's solution, isotonic sodium chloride solution, and fixed oils such as mono or synthetic diglycerides. Pharmaceutical compositions that are useful in the methods of the invention may be administered, prepared, packaged and / or sold in formulations suitable for the oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, ophthalmic or other administration route. route of administration. Other formulations contemplated include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient and immunological base formulations. The compositions of the invention can be administered through numerous routes, including but not limited to oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal or ophthalmic routes of administration. The route or routes of administration will be readily apparent to the person skilled in the art and will depend on any number of factors including the type and severity of the disease being treated, the type and age of the veterinary or human patient being treated, and the like. Pharmaceutical compositions that are useful in the methods of the invention can be administered systemically in oral solid formulations, ophthalmic formulations, suppository, aerosol, topical or other similar formulations. In addition to the compound such as heparin sulfate, or a biological equivalent thereof, said pharmaceutical compositions may contain pharmaceutically acceptable carriers and other ingredients known to improve and facilitate the administration of drugs. Other possible formulations, such as nanoparticles, liposomes, resealed erythrocytes, and immune-based systems can also be used to administer the compounds according to the methods of the invention. Compounds which are identified using any of the methods described herein, and combinations of said compounds, are can formulate and administer to a mammal for treatment of disturbed control of respiration. Said pharmaceutical composition may consist of the active ingredient alone, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least one active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combinations of these. The active ingredient may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is known in the art. An obstacle to the topical administration of pharmaceutical products is the layer of the stratum corneum of the epidermis. The stratum corneum is a highly resistant layer consisting of protein, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes living and keratinized cells. One of the factors that limit the rate of penetration (flow) of a compound through the stratum corneum is the amount of the active substance that can be loaded or applied to the surface of the skin. The greater the amount of active substance applied per unit area of the skin, the greater the concentration gradient between the surface of the skin and the lower layers of the skin, and in turn, the greater the diffusion force of the skin. the active substance through the skin. Therefore, it is more likely that a formulation containing a higher concentration of the active substance results in the penetration of the active substance through the skin, and more of it, and at a more consistent rate, than a formulation having a lower concentration, all other elements remaining the same. The formulations of the pharmaceutical compositions described herein can be prepared by any method known or developed hereinafter in the pharmacology art. In general, said methods of preparation include the step of placing the active ingredient in association with a carrier or one or more other auxiliary ingredients, and then, if necessary or advisable, setting up or packaging the product into a desired unit of individual dose. or multiple. Although the descriptions of the pharmaceutical compositions provided herein are primarily directed to pharmaceutical compositions that are suitable for the ethical administration to humans, the person skilled in the art will understand that said compositions are generally suitable for administration to animals of all kinds. It is understood the modification of pharmaceutical compositions suitable for administration to humans in order to make the compositions suitable for administration to various animals and the skilled veterinary pharmacologist can design and perform said modification if perhaps with a merely ordinary experimentation. Subjects for whom administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to humans and other primates, mammals that include commercially relevant mammals such as cattle, pigs, horses, sheep, cats and dogs. Pharmaceutical compositions that are useful in the methods of the invention can be prepared, packaged or sold in formulations suitable for the oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, ophthalmic, intrathecal or other route of administration. administration. Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient and immunologically based formulations. A pharmaceutical composition of the invention can be prepared, packaged, or sold in bulk, as an individual unit dose, or as a plurality of individual unit doses. As used herein, a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that is administered to a subject or a convenient fraction of said dosage such as, for example, one-half or one-third of said dosage. The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending on the identity, size and condition of the subject being treated and further depends on the route through which the drug is administered. composition. As an example, the The composition may comprise between 0.1% and 100% (w / w) of active ingredient. Controlled or sustained release formulations of a pharmaceutical composition of the invention can be made using conventional technology. Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or suspensions. Topically administrable formulations may comprise, for example, from about 1% to about 10% (w / w) of active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. Penetration enhancers can be used. These materials increase the speed of penetration of drugs through the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, and the like. Other enhancers include oleic acid, oleyl alcohol, ethoxy glycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone. An acceptable carrier for topical delivery of some of the compositions of the invention may contain liposomes. The The composition of the liposomes and their use are known in the art (see for example Constanza, U.S. Patent No. 6,323,219). The source of active compound that will be formulated will generally depend on the particular form of the compound. The small organic molecules and the peptidyl or oligo fragments can be chemically synthesized and provided in pure form suitable for pharmaceutical use. The products of natural extracts can be purified according to known techniques. Recombinant sources of compounds are also available to those skilled in the art. In alternative embodiments, the topically active pharmaceutical composition may optionally be combined with other ingredients such as adjuvants, antioxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifying agents, viscosifiers, pH regulating agents., conservatives, and the like. In another embodiment, a permeation or penetration enhancer is included in the composition and is effective to improve percutaneous penetration of the active ingredient to and through the stratum corneum with respect to a composition lacking a permeation enhancer. Various permeation enhancers, including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone, are known to those skilled in the art. In another aspect, the composition may further comprise a hydrotropic agent, which functions to increase the disorder in the structure of the stratum corneum, and in this way allows increased transport through the stratum corneum. Various hydrotropic agents such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate are known in the art. The topically active pharmaceutical composition must be applied in an effective amount to affect desired changes. As used herein, "effective amount" will mean an amount sufficient to cover the skin surface region where a change is desired. An active compound should be present in the amount of about 0.0001% to about 15% by weight of the volume of the composition. Preferably, it should be present in an amount of about 0.0005% to about 5% of the composition; preferably, it should be present in an amount from about 0.001% to about 1% of the composition. Said compounds can be derived synthetically or naturally. Liquid derivatives and natural extracts made directly from biological sources can be employed in the compositions of this invention in a concentration (w / v) of from about 1 to about 99%. The fractions of natural extracts and protease inhibitors may have a different preferred scale, from about 0.01% to about 20% and preferably from about 1% to about 10% of the composition. Of course, mixtures of Active agents of this invention can be combined and used together in the same formulation, or in serial applications of different formulations. The composition of the invention may comprise a preservative of about 0.005% to 2.0% by total weight of the composition. The preservative is used to prevent deterioration in the case of an aqueous gel due to the repeated use of the patient when exposed to contaminants in the environment, for example by exposure to air or to the patient's skin, including contact with the fingers used for applying a composition of the invention such as a therapeutic cream or gel. Examples of preservatives useful in accordance with the invention include, but are not limited to, those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and combinations thereof. A particularly preferred preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid. The composition preferably includes an antioxidant and a chelating agent that inhibits degradation of the compound for use in the invention in the aqueous gel formulation. Preferred antioxidants for some compounds are BHT, BHA, alpha-tocopherol and ascorbic acid in the preferred range of about 0.01% to 0.3% and preferably BHT in the range of 0.03% to 0.1% by weight per total weight of the composition. Preferably, the chelating agent is present in an amount of 0.01% to 0.5% by weight per total weight of the composition. Chelating agents particularly preferred include edetate salts (e.g., sodium edetate) and citric acid on the weight scale of from about 0.01% to 0.20% and preferably in the range from 0.02% to 0.10% by weight per total weight of the composition . The chelating agent is useful for chelating metal ions in the composition which can be detrimental to the shelf life of the formulation. Although BHT and disodium edetate are respectively particularly preferred antioxidant and chelating agents for some compounds, as is known to those skilled in the art, other suitable antioxidants and chelating agents and equivalents can be substituted. Controlled release preparations can also be used and methods for the use of such preparations are known to those skilled in the art. In some cases, the dosage forms that will be used may be provided as slow or controlled release of one or more active ingredients therein using, for example, hydropropylmethylcellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention. In this way, the present invention contemplates forms of individual unit dosages suitable for oral administration, such as tablets, capsules, gelatin capsules, and tablets, which are adapted for controlled release. Most controlled release pharmaceutical products have a common goal of improving drug therapy over that obtained through their non-controlled counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance used to cure or control the condition in a minimum amount of time. The advantages of controlled release formulations include extended drug activity, reduced dosing frequency, and increased compliance of the patient. In addition, controlled release formulations can be used to affect the onset time of action or other characteristics, such as drug level in blood, and thus can affect the occurrence of side effects. Most controlled release formulations are designed to initially release an amount of drug that rapidly produces the desired therapeutic effect, and gradually and continuously release other amounts of drug to maintain that level of therapeutic effect for a prolonged period. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug that is metabolized and excreted from the body.

The controlled release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlled release component" in the context of the present invention is defined herein as a compound or compounds, including but not limited to polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof. which facilitates the controlled release of the active ingredient. Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water, and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis oil, olive, sesame or coconut, fractionated vegetable oils, and mineral oils such as liquid paraffin. The liquid suspensions may further comprise one or more additional ingredients including, but not limited to suspending agents, dispersing or wetting agents, emulsifying agents, emollients, preservatives, pH regulators, salts, flavors, coloring agents, and sweetening agents. The oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, tragacanth gum, acacia gum, and cellulose derivatives such as carboxymethylcellulose, methylcellulose, sodium hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to natural phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long-chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (for example, polyoxyethylene-stearate, heptadecaethylene-oxyethanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin and acacia. Known conservatives include, but are not limited to methyl, ethyl, or n-propyl-para-hydroxybenzoates, ascorbic acid and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose and saccharin. Known thickeners for oily suspensions include, for example, beeswax, hard paraffin and cetyl alcohol. Liquid solutions of the active ingredient in aqueous or oily solvents can be prepared in substantially the same manner as liquid suspensions, the main difference being that the active ingredient dissolves, rather than being suspended in the solvent. The liquid solutions of the pharmaceutical composition of the invention may comprise each of the described components with respect to the liquid suspensions, it being understood that the suspending agents will not necessarily assist in the dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. The solvents oily ones include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis oil, olive, sesame or coconut, fractionated vegetable oils, and mineral oils such as liquid paraffin. Powdered or granulated formulations of a pharmaceutical preparation of the invention can be prepared using known methods. Said formulations can be administered directly to a subject, they can be used, for example to form tablets, to fill capsules or to prepare an aqueous or oily suspension or solution by the addition thereto of an aqueous or oily vehicle. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent and a preservative. Additional excipients such as fillers and sweetening, flavoring, or coloring agents may also be included in these formulations. A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of an oil-in-water emulsion or a water-in-oil emulsion. The oil phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination thereof. Said compositions may further comprise one or more emulsifying agents such as natural gums, such as, for example, acacia gum or tragacanth gum, natural phosphatides such as soy phosphatide or lecithin, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents. As used herein, an "oily" liquid is one which comprises a liquid molecule containing carbon and having a less polar character than water. A formulation of a pharmaceutical composition of the invention suitable for oral administration can be prepared, packaged or sold in the form of a discrete solid dose unit including, but not limited to, a tablet, a hard or soft capsule, a tablet, a trocisco, or a lozenge each containing a predetermined amount of the active ingredient. Other formulations suitable for oral administration include, but are not limited to, a powder or granule formulation, an aqueous or oily suspension, an aqueous or oily solution, a paste, a gel, a toothpaste, a mouthwash, a coating, a oral rinse, or an emulsion. The terms mouthwash and mouthwash are used interchangeably herein. A pharmaceutical composition of the invention can be prepared, packaged, or sold in a formulation suitable for oral or buccal administration. Said formulation may comprise, but is not limited to, a gel, a liquid, a suspension, a paste, toothpaste, a mouthwash or mouthwash, and a coating. For example, a mouthwash of the invention can comprise a compound of the invention at about 1.4%, chlorhexidine gluconate (0.12%), ethanol (1.1%), sodium saccharin (0.1%), FD Blue &C No. 1 (0.001%), peppermint oil (0.5%), glycerin (10.0%), Tween 60 (0.3%), and water up to 100%. In another embodiment, a toothpaste of the invention may comprise a compound of the invention at about 5.5%, sorbitol, 70% in water (25.0%), sodium saccharin (0.1 5%), sodium lauryl sulfate (1.75%). ), carbopol 934.6% dispersion in (15%), spearmint oil (1.0%), sodium hydroxide, 50% in water (0.76%), dibasic calcium phosphate dihydrate (45%), and water up to 1 00%. The examples of formulations described herein are not exhaustive and it is understood that the invention includes further modifications of these and other formulations not described herein., but which are known to those skilled in the art. A tablet comprising the active ingredient, for example, can be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granulated preparation, optionally mixing with one or more of a binder, a lubricant, an excipient, an agent active surface, and a dispersing agent. Molded tablets can be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least liquid sufficient to wet the mixture. The Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate. Known surface active agents include, but are not limited to sodium laurisulfate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium acid phosphate, and sodium phosphate. Known granulation and disintegration agents include, but are not limited to, corn starch and alginic acid. Known binding agents include, but are not limited to, gelatin, acacia, pregelatinized cob starch, polyvinylpyrrolidone and hydroxypropylmethylcellulose. Known lubricants include, but are not limited to, magnesium stearate, stearic acid, silica and talc. The tablets may not be coated or may be coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate can be used to coat the tablets. In addition, by way of example, the tablets can be coated using the methods described in the patents of E.U.A. Nos. 4,256, 108; 4,160,452; and 4,265,874 to form osmotically controlled release tablets. The tablets may comprise additionally a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination thereof in order to provide a pharmaceutically elegant and palatable preparation. Hard capsules comprising the active ingredient can be made using a physiologically degradable composition, such as gelatin. Said hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. Soft gelatin capsules comprising the active ingredient can be made using a physiologically degradable composition, such as gelatin. Said soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil. Liquid formulations of a pharmaceutical composition of the invention that are suitable for oral administration can be prepared, packaged or sold either in liquid form or in the form of a dry product intended for reconstitution with water or other suitable vehicle before use. A pharmaceutical composition of the invention can be prepared, packaged or sold in a formulation suitable for rectal administration. Said composition may be in the form of, for example, a suppository, a retention enema preparation, and a solution for rectal or colonic irrigation.

Suppository formulations can be made by combining the active ingredient with a pharmaceutically acceptable non-irritating excipient that is solid at ordinary room temperature (i.e., about 20 ° C) and that is liquid at the rectal temperature of the subject (i.e. approximately 37 ° C in a healthy human). Suitable pharmaceutically acceptable excipients include, but are not limited to cocoa butter, polyethylene glycols and various glycerides. The suppository formulations may additionally comprise various additional ingredients including, but not limited to antioxidants and preservatives. Preparations of retention enemas or solutions for rectal or colonic irrigation can be made by combining the active ingredient with a pharmaceutically acceptable liquid carrier. As is known in the art, the enema preparations can be administered using, and can be packaged within, a delivery device adapted for the subject's rectal anatomy. The enema preparations may further comprise various additional ingredients including, but not limited to antioxidants and preservatives. Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods for depositing or binding a chemical composition on a surface, methods for incorporating a chemical composition into the structure of a material during the synthesis of the material (ie, such as with a physiologically degradable material), and methods for absorbing a solution or aqueous or oily suspension in an absorbent material, with or without subsequent drying. As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical disruption of a tissue from a subject and administration of the pharmaceutical composition through tissue breakdown. Parenteral administration, therefore, includes but is not limited to administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a non-surgical wound that penetrates tissue, and the like. In particular, it is contemplated that parenteral administration includes but is not limited to subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialysis infusion techniques. Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Said formulations can be prepared, packaged or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations can be prepared, packaged, or sold in unit dosage form, such as in ampoules or in multiple dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable formulations of sustained release or biodegradable. Said formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry form (ie, powder or granule) for reconstitution with a suitable vehicle (eg, sterile, pyrogen-free water) prior to parenteral administration of the reconstituted composition. . The pharmaceutical compositions can be prepared, packaged, or sold in the form of a suspension or sterile injectable aqueous or oily solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations can be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example. Other diluents and acceptable solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as mono or diglycerides synthetics. Other parenterally administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system. The compositions for sustained release or implant may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a slightly soluble polymer, or a slightly soluble salt. A pharmaceutical composition of the invention can be prepared, packaged or sold in a formulation suitable for buccal administration. Such formulations, for example, may be in the form of tablets or lozenges made using conventional methods, and for example, may contain 0.1 to 20% (w / w) of active ingredient, the remainder comprising an orally soluble or degradable composition and optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder or an aerosolized or atomized solution or suspension comprising the active ingredient. Said powdered, aerosolized or aerosolized formulations, when dispersed, preferably have an average particle size or drop in scale from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein. . As used herein, "additional ingredients" include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulation and disintegration agents; binding agents; agents lubricants; sweetening agents; flavoring agents; coloring agents; conservatives; physiologically degradable compositions such as gelatin; vehicles and aqueous solvents; oily solvents and vehicles; suspension agents; dispersing or wetting agents; emulsifying agents; emollients; pH regulators; you go out; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilization agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other "additional ingredients" that can be included in the pharmaceutical compositions of the invention are known in the art and are described, for example in Genaro, ed. (1985, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA), which is incorporated herein by reference. Typically, dosages of the compound of the invention that can be administered to an animal, preferably a human, will vary depending on any number of factors, including without limitation the type of animal and type of disease state being treated, the age of the animal and the route of administration. The compound can be administered to an animal as frequently as several times a day, or it can be administered less frequently, such as once a day, once a week, once every two weeks, once a month. , or even less frequently, such as once every several months or once a year or less. The frequency of the dose will be readily apparent to those skilled in the art and will depend on any number of factors, such as for example without limit, the type and severity of the disease being treated, the type and age of the animal, etc.

EXAMPLES The invention is now described with reference to the following examples. These examples are provided for purposes of illustration only, and the invention is not limited to these examples, but rather encompasses all variations that are apparent as a result of the teachings provided herein.

EXAMPLE 1 Methods for analyzing combination compositions An established method for evaluating the effects of drugs that act in the control of respiration is to create closed systems where the key factors that affect breathing can be closely controlled and monitored. For example, control systems are established for oxygen concentration, carbon dioxide concentration and atmospheric pressure. For animal-based evaluations, systems are available that allow the evaluation of the entire body or only the nose of multiple measurements of respiratory function. They are also established animal models (eg, guinea pig, dog, rodent) of breathing in combination with allergy, inflammation, COPD and use of narcotic analgesics. As a non-limiting example, Lovelace Respiratory Research Institute (Albuquerque, NM) has extensive experience in establishing such models as part of the evaluation for new drugs and environmental exposure purposes. Similar systems have been established for human testing. Hildebrandt et al. (Blood 2002; 99: 1552-1555) described a protocol that was used for evaluation of N-acetylcysteine under varying conditions of oxygen and carbon dioxide concentrations. In addition, the United States military (Naval Aerospace Medical Research Command, Pensacola FL, US Army Research Institute of Environmental Medicine, Natick, MA) has developed methods that include exposure / monitoring systems for both the entire body and only the face (Sausen et al., Aviat Space Environ Med 2003; 74: 1 190-7). Finally, hospitalized patients who are connected to mechanical ventilation devices represent an opportunity to closely assess the effects of drugs on respiration. Oxygen and carbon dioxide levels can be controlled in an environment where breathing parameters are measured on a minute-by-minute basis. In addition to the animal and human-based systems described above, there is an emerging field where certain markers are used biochemicals to indicate chronic oxidative stress that results from hypoxia. An example is the use of various isoprostanes to indicate oxidative stress. (Cracowski JL and Durand T. Fundam Clin Pharmacol 2006; 20: 417-27). The descriptions of each patent, patent application and publication cited herein are incorporated by reference in their entirety. Although this invention has been described with reference to specific embodiments, it is clear that other embodiments and variations of this invention may be contemplated by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such modalities and equivalent variations.

Claims (2)

1. NOVELTY OF THE INVENTION CLAIMS 1 .- A therapeutic composition to stabilize the rhythm of respiration, said therapeutic composition comprises: a. a first composition comprising a first compound of S-nitrosothiol; and b. a second composition comprising a second compound that is not an S-nitrosothiol compound, wherein said second compound has the activity of stabilizing the respiration rate.
2. 2. The use of a therapeutic composition of claim 1 for the preparation of a medicament useful for stabilizing the respiration rate of a mammal. 3. - The therapeutic composition according to claim 1, further characterized in that said second compound is a compound that has the ability to stabilize the rhythm of respiration. 4. - The therapeutic composition according to claim 3, further characterized in that said second compound is selected from the group consisting of a carbonic anhydrase inhibitor, a respiratory stimulant, a narcotic antagonist, and a hormone. 5. - The therapeutic composition according to claim 1, further characterized in that said second compound is a compound that has the activity of increasing the opening of the upper airway. 6. - The therapeutic composition according to claim 5, further characterized in that said second compound is selected from the group consisting of a serotonin agonist, a serotonin antagonist, a tetracyclic antidepressant, an agent which acts on the dopamine, and an agent which acts on norepinephrine. 7. - The therapeutic composition according to claim 1, further characterized in that said second compound is compound that has the activity of promoting the waking state. 8. - The therapeutic composition according to claim 1, further characterized in that said second compound is a compound which has the activity of decreasing seizures. 9. - The therapeutic composition according to claim 1, further characterized in that said second compound is a compound which has the activity of increasing the opening of the upper airway by decreasing inflammation. 10. - The therapeutic composition according to claim 9, further characterized in that said second compound is selected from the group consisting of an antihistamine, a leukotriene antagonist, a 5-lipoxygenase inhibitor, a steroid, and a COX- inhibitor. 2. eleven . The therapeutic composition according to claim 1, further characterized in that said second compound is a compound which has the activity of decreasing the respiratory impulse. 12. - The therapeutic composition according to claim 1, further characterized in that said second compound is selected from the group consisting of an opioid analgesic, a hypnotic sedative, and a general anesthetic. 13. - The therapeutic composition according to claim 1, further characterized in that said second compound is a compound which has the activity of improving lung function. 14. - The therapeutic composition according to claim 13, further characterized in that said second compound is selected from the group consisting of a steroid, a bronchodilator and an anticholinergic. 5. The therapeutic composition according to claim 1, further characterized in that it additionally comprises a third compound, wherein said third compound is an S-nitrosothiol compound. 16. The therapeutic composition according to claim 1, further characterized in that it additionally comprises a third compound, wherein said third compound is not an S-nitrosothiol compound. 7. The use of the therapeutic composition of one of claims 8 or 9, for the preparation of a medicament useful for stabilizing the respiration rate of a mammal. 18. - The use of the therapeutic composition of claim 1, for the preparation of a medicine useful for stabilizing the respiration rate of a mammal, wherein said medicament is formulated to be administrable in combination with the use of an auxiliary ventilation device. 19. - The use as claimed in claim 18, wherein said auxiliary ventilation device is selected from the group consisting of a mechanical ventilator, a CPAP device and a BiPAP device. 20. - A pharmaceutical composition comprising the therapeutic composition of claim 1 and a pharmaceutically acceptable carrier. twenty-one . - The use of the therapeutic composition of claim 13, for the manufacture of a medicament useful for stabilizing the respiration rate of a mammal. 22. The use as claimed in claim 21, wherein said medicament is formulated to be administrable parenterally, orally and buccally. 23. - The use as claimed in claim 22, wherein the parenteral route is selected from the group consisting of transdermal, intravenous, intramuscular and intradermal. 24. - The use as claimed in claim 22, wherein said medicament is formulated to be administrable at least through two administration routes. 25. - The use of a therapeutic composition comprising: a. a first composition comprising a first compound of S-nitrosothiol; and b. a second composition comprising a second compound that is not an S-nitrosothiol compound, wherein said second compound has the activity of increasing minute ventilation (VE) at the level of the respiratory control centers of the brainstem in the nucleus of the tract solitary, for the elaboration of a useful medicine to increase minute ventilation (VE) at the level of the respiratory control centers of the brainstem in the nucleus of the solitary tract of an individual.