MXPA00003909A - Methods and materials for treating and preventing inflammation ofmucosal tissue - Google Patents

Abstract

The invention involves methods and materials for treating and preventing non-invasive fungus-induced mucositis. Specifically, the invention involves administrating an antifungal agent such that it contacts mucus in an amount, at a frequency, and for a duration effective to prevent, reduce, or eliminate non-invasive fungus-induced rhinosinusitis. This invention also provides methods and materials for diagnosing non-invasive fungus-induced rhinosinusitis and culturing non-invasive fungus from a mammalian mucus sample as well as specific antifungal formulations and medical devices for treating and preventing non-invasive fungus-induced rhinosinusitis. In addition, the invention provides methods and materials for treating and preventing other non-invasive fungus-induced mucositis conditions such as chronic otitismedia, chronic colitis, and Crohn's disease. Further, the invention involves methods and materials for treating and preventing chronic asthma symptoms.

Description

USE OF ANTIGUNAL AGENTS FOR THE TOPICAL TREATMENT OF MUCOSITIS INDUCED BY FUNGI BACKGROUND 1. Technical Field This invention relates to methods and materials involved in the treatment and prevention of non-aggressive fungal-induced inflammation of mucosal tissue as well as asthma symptoms. 2. Background information. Mucositis, the inflammation of mucous tissue, is a serious medical problem that affects millions of people around the world. For example, conservative estimates indicate that between 20 and 40 million Americans suffer from chronic rhinosinusitis, an inflammation of the nasal cavity and / or paranasal cavities. For the most part, the cause of chronic rhinosinusitis is unknown. However, in a small percentage of patients, it seems that the non-aggressive fungal organisms that live inside the mucus are included. Patients who have this condition, now known as allergic fungal sinusitis (AFS), were first described at the beginning of the 1980's (Miller JW, et al., Prod. Scot. Thor. Soc. 36: 710 (1981) and Katzenstein ALA et al., J. Allergy Clin. Immunol. 72 89-93 (1983)). Specifically, approximately three to eight percent of cases of chronic rhinosinusitis require surgery due to nasal obstruction caused by the formation of polyps that have been classified as AFS. Briefly, the AFS is diagnosed by the presence of thickened mucus in the nasal-paranasal cavities. Typically, the mucus contains agglomerations or leaves of eosinophilic necrotic cells, Charcot-Leyden crystals, and non-aggressive fungal reticulate tissue. In addition, patients with AFS typically have a history of paranasal polyposis and may have undergone multiple surgeries. Inflammation can affect all nasal-paranasal cavities, but it can also be asymmetric involving only one side. Computerized topography (CT) scans of patients with AFS have a characteristic appearance and often reveal bone erosion in adjacent structures. In fact, the destruction of the bones adjacent to the areas of the nasal and nasal cavities has been reported, ranging from 19 to 80 percent. Although it seems that fungal organisms are the causative agent of AFS, successful treatment is still absent. Currently, AFS patients as well as most chronic rhinosinusitis patients receive surgical treatment with or without steroid therapy. Surgery can clean the nasal-paranasal cavities when they are blocked by polyps and steroid therapy helps control the inflammatory responses that appear to be responsible for the destruction of tissue and bone. Unfortunately, patients treated with surgery alone almost always experience recurrent symptoms of rhinosinusitis and additional polyp growth. In addition, prolonged use of steroids is associated with significant side effects and the withdrawal of steroid therapy also leads to recurrent episodes of rhinosinusitis. For these reasons, people suffering from chronic rhinosinusitis conditions typically experience repeated cycles of intense inflammation, surgery, and steroid therapy followed by recurrent intense inflammation. Accordingly, no surgery or steroid therapy is particularly effective or desirable as a long-term treatment for chronic rhinosinusitis conditions.

SUMMARY The present invention relates generally to methods and materials for treating and preventing mucositis induced by non-aggressive fungi. The term "mucositis" as used herein means an inflammation, as opposed to an infection, of a mucus membrane. This invention is based on the discovery that the condition known as AFS can be successfully treated by using an antifungal agent in an amount, at a frequency, and for an effective duration to reduce the inflammation caused by the presence of fungal organisms within the nasal mucus. -paranasal. further, this invention is based on the discovery that using an antifungal agent in an amount, at a frequency, and for an effective duration to maintain a reduced level of fungal organisms within nasal-paranasal mucus can prevent the symptoms of AFS. Specifically, the invention involves administering an antifungal agent to a mammal such that the antifungal agent contacts the mucus of the mammal and reduces the presence of fungal organisms in the mucus. In addition to being the only known method for successfully treating and avoiding AFS, the use of an antifungal agent is particularly advantageous for a patient when compared to other medical approaches currently available for AFS such as surgical treatments and steroid therapies. Such medical approaches can have side effects, can be expensive, and can be associated with patient discomfort. This invention is also based on the discovery that most, if not all, conditions of chronic rhinosinusitis have a fungal etiology and that most, if not all, cases of chronic rhinosinusitis can be treated by using a antifungal agent in an amount, at a frequency, and for an effective duration to reduce the presence of fungal organisms within the nasal-paranasal mucus. In addition, using an antifungal agent in an amount, at a frequency, and for an effective duration to maintain a reduced level of fungal organisms within the nasal-paranasal mucus can avoid the symptoms of chronic rhinosinusitis. This finding is contrary to the current view of chronic 5-rhinosinusitis and has far-reaching implications within medicine. For example, numerous medical research articles report that approximately three to eight percent of cases of chronic rhinosinusitis requiring surgery are AFS, a condition of rhinosinusitis that has a non-aggressive fungal etiology. In fact, fewer than 150 AFS cases have been reported in the literature in the previous 15 years. It is observed that the lack of appreciation for the non-aggressive fungal etiology of chronic rhinosinusitis conditions may have occurred because the individuals affected often discover that they have bacterial infections (ie, aggressive bacteria). Presumably, tissue damage caused by inflammation induced by non-agressive fungi results in a high occurrence of bacterial infections in those damaged areas. Therefore, Overlying bacterial infections in affected individuals may have disguised the cause of the reinforcement of the fungal organisms within the mucus. For the purpose of this invention, the term "non-aggressive fungal-induced rhinosinusitis" includes the AFS as well as well as some other condition of nasal-paranasal mucositis that has a non-aggressive fungal etiology. The treatment and prevention of rhinosinusitis induced by non-aggressive fungi, whether diagnosed as AFS or some other rhinosinusitis condition that has a non-aggressive fungal etiology, using an antifungal agent obviates the need for surgical treatments and steroid therapies that cause significant pain and suffering to the patient. In addition, the use of antifungal agents to treat and prevent rhinosinusitis induced by non-aggressive fungi currently addresses the treatment against the etiological agent (i.e. fungi), unlike surgical treatments, steroid therapies, and antibacterial treatments. The term "chronic" as used herein, refers to afflictions present for at least three months. It should be understood that afflictions that are treated as described herein and become asymptomatic may be classified as chronic. Therefore, chronic afflictions can be symptomatic or asymptomatic. This invention is also based on another discovery, equally significant, that the symptoms of chronic asthma can be treated and successfully avoided by using an antifungal agent in an amount, at a frequency, and for an effective duration to reduce the presence of fungal organisms within mucus from the respiratory tract. It is also apparent from the present findings that antifungal agents can be administered directly into the pulmonary airways for the treatment of chronic asthma. Again, these findings are contrary to current opinion about chronic asthma and have far-reaching clinical implications. Taken together, these breakthroughs can potentially allow large populations to experience happier, healthier and more productive daily lives. Specifically, the invention provides methods and materials for treating and preventing a wide variety of mucoinflammatory diseases by using an antifungal agent. The use of an antifungal agent is a safe and highly effective treatment approach involving mucoadministering an antifungal agent in an amount, at a frequency, and for an effective duration to reduce, prevent or eliminate mucositis induced by non-aggressive fungi. The term "mucoadministration" as used herein, refers to some type of administration that places an agent administered in contact with the mucus. This invention also provides specific antifungal formulations that can be applied to the various parts of a mammal that contain mucus. In addition, the invention provides medical devices that can be used to apply antifungal formulations. These devices are particularly advantageous because they can be used by an individual or administer an effective dose of a specific antifungal formulation to the appropriate body area. In addition, the invention provides improved methods and materials for collecting and culturing fungal organisms from mucus samples. These culture techniques can be used to monitor the number of fungal species within the mucus during a particular antifungal treatment regimen. further, these methods and materials for mushroom harvesting and cultivation are useful to identify the genotype and phenotype of specific fungal organisms that cause mucositis induced by non-aggressive fungi. The identification and characterization of non-aggressive fungal organisms based on a mucus from a particular individual can help cynics to determine appropriate treatment and prophylactic approaches. For example, this information can help determine the specific antifungal agent, amount, mode of administration, and number of applications to be used as well as possible combinatorial therapies that may include other drugs and methods such as steroids, antibacterial agents and surgery. In general, the invention features a method for treating a mammal (e.g., human) that has rhinosinusitis induced by non-aggressive fungi. This method involves mucoadministering directly at least a portion of the nasal-paranasal anatomy of the mammal a formulation in an amount, at a frequency, and for an effective duration to reduce or eliminate the rinosinusitis induced by non-aggressive fungi. This formulation contains an antifungal agent or a plurality of antifungal agents and can be in a solid, liquid, or aerosol form (e.g., crystalline substance, gel, paste, ointment, balm, cream, solution, suspension, partial liquid, aerosol ,, nebula, vapor, atomized vapor, aerosol and tincture). In addition, the formulation may be in a form suitable for self-mucoadministration by a human. In addition, the formulation may contain a pharmaceutically acceptable aqueous vehicle (eg, saline and water).

For example, a liquid form of the formulation may contain about 0.00001 percent to about 20 percent of an antifungal agent as determined by the weight of the antifungal agent per volume of the aqueous vehicle. In addition, the formulation may contain about 0.01 ng to about 1000 mg of an antifungal agent (e.g., amphotericin B) per liter in some embodiments of the invention, or about 1 ng to about 500 mg of an antifungal agent per liter in other embodiments of the invention, or about 100 mg of an antifungal agent per liter in still other embodiments of the invention. In addition, an effective amount of these aqueous formulations can be from about 0.01 mL to about 1 L of nasal spray formulation in some embodiments of the invention, or about 5 mL to about 100 mL of nasal spray formulation in other embodiments of the invention . Alternatively, an effective amount of a formulation can be from about 0.01 ng to about 1000 mg of an antifungal agent per kg of body weight of the mammal in some embodiments of the invention or about 1 ng to 500 mg of an antifungal people per kg of weight body of the mammal in other embodiments of the invention. The effective amount of a formulation can change or remain the same for an effective duration. The effective frequency of direct mucoadministration can be from about four times a day to about one each week in some embodiments of the invention, from about twice a day to about one a week in other embodiments of the invention, or approximately twice a week. per day in still other embodiments of this invention. In addition, the effective frequency of direct mucoadministration may be greater than one a day, or greater than one a week. The effective duration may be greater than about 7, 14, 30, 60 or 90 days. The mammal may be atopic or non-atopic and may be immunocompetent or immunocompromised. In addition, rhinosinusitis induced by non-aggressive fungi can be characterized by the formation of polyps or change of polypoids. Rhinosinusitis induced by non-aggressive fungi can also be a chronic condition. The mucoadministration can be an irrigation of at least a portion of the nasal-paranasal anatomy with a liquid form of the formulation. Alternatively, the mucoadministration may involve the application of an aerosol form of the formulation to at least a portion of the nasal-paranasal anatomy. An antifungal agent can be found in solid, liquid, or aerosol form. In addition, an antifungal agent can be a polyene macrolide, tetrane macrolide, pentaenic macrolide, fluorinated pyrimidine, imidazole, azole, triazole, halogenated phenolic ether, thiocarbamate, allylamine, sterol inhibitor, and an agent that interpolates cell wall components fungal Such antifungal agents include amphotericin B, fluctosin, acetoconazole, miconazole, itraconazole, fluconazole, griseofulvin, clotrimazole, econazole, terconazole, butoconazole, oxiconazole, sulconazole, saperconazole, voriconazole, cyclopirox, olamine, haloprogin, tolnaftate, naftifine, terbinafine hydrochloride, morpholines , nystatin, natamycin, butenafine, undecylenic acid, Whitefield ointment, propionic acid, and caprylic acid. In addition to containing an antifungal agent, the formulation may contain, without limitation, a pharmaceutically acceptable aqueous carrier, pharmaceutically acceptable solid carrier, mucolytic agent, antibacterial agent, anti-inflammatory agent, immunosuppressant, dilator, vasoconstrictor, decongestant, leukotriene inhibitor. , anti-cholinergic, anti-histamine, therapeutic compound, and combinations thereof. The method may involve the administration of a second formulation containing, without limitation, an antifungal agent, antibacterial agent, steroid, mucolytic agent, anti-inflammatory agent, immunosuppressant, dilator, vasoconstrictor, decongestant, leukotriene inhibitor, anti-cholinergic, anti-histamine, therapeutic compound, and combinations of same. Also, the method may involve an additional step after direct mucoadministration. This additional step can be a prophylactic mucoadministration of a prophylactic formulation to the mammal in an amount, at a frequency, and for an effective duration to prevent rhinosinusitis induced by non-aggressive fungi. This prophylactic formulation also contains an antifungal agent and can be in a solid, liquid, or aerosol form (eg, powder, crystalline substance, gel, paste, ointment, balm, cream, solution, suspension, partial liquid, aerosol, nebula, vapor, atomized vapor, aerosol, tincture, pill, capsule, tablet and gel capsule). In addition, prophylactic mucoadministration can be a direct or indirect mucoadministration. For example, prophylactic mucoadministration can be an irrigation of at least a portion of the nasal-paranasal anatomy with a liquid form of the prophylactic formulation, an application of an aerosol form of the prophylactic formulation towards at least a portion of the nasal anatomy -paranasal, or an oral administration of the prophylactic formulation of the mammal in the form of a solid or liquid. It will be understood that each of the additional features of the invention described above can be applied to the following embodiments and additional aspects of the invention. For example, methods for prophylactically treating a mammal at risk of developing non-aggressive fungal-induced rhinosinusitis, and methods of treating asthma, can use a formulation in which the antifungal agent is about 0.00001 percent up to about 20 percent in weight or volume of a formulation, and so on. In another embodiment, the invention features a method of prophylactically treating a mammal at risk of developing rhinosinusitis induced by non-agressive fungi. This method involves mucoadministering to the mammal a formulation in a quantity, at a frequency, and for an effective duration to avoid the rinosinusitis induced by non-aggressive fungi. This formulation contains an antifungal agent. Another embodiment of the invention features a method for treating a mammal that has rhinosinusitis induced by non-aggressive fungi. This method involves the steps of identifying (e.g., diagnosing) the mammal, and directly supplying a formulation to at least a portion of the nasal-paranasal anatomy of the mammal in an amount, at a frequency, and for an effective duration to reduce or eliminate rhinosinusitis induced by non-aggressive fungi. This formulation contains an antifungal agent. Another embodiment of the invention presents a method for prophylactically treating a mammal at risk of developing rhinosinusitis induced by non-aggressive fungi. This method involves the steps of identifying the mammal (eg, diagnosing), and muco-administering a formulation to at least a portion of the nasal-paranasal anatomy of the mammal in an amount, at a frequency, and for an effective duration to reduce or eliminate rhinosinusitis induced by non-aggressive fungi. This formulation contains an antifungal agent. In another aspect, the invention features a method for treating a mammal having asthma. This method involves mucoadministering directly to at least a portion of the respiratory tract (eg, nasal-paranasal airways and pulmonary airways). of the mammal a formulation in an amount, at a frequency, and for an effective duration to reduce or eliminate the symptoms of asthma. This formulation contains an antifungal agent. Direct mucoadministration may be the irrigation of the nasal-paranasal anatomy of the mammal with a liquid form of the formulation. Alternatively, the direct mucoadministration can be the inhalation of the formulation through the mouth or nose of the mammal. In addition, the method may involve an additional step after direct mucoadministration. This additional step can be the prophylactic mucoadministration of a prophylactic formulation to the mammal in an amount, at a frequency, and for an effective duration to avoid the symptoms of asthma. This formulation contains an antifungal agent. Another embodiment of the invention features a method for treating a mammal who has asthma. This method involves the steps of identifying (eg, diagnosing) the mammal, and directly providing a formulation to at least a portion of the respiratory tract (eg, nasal-paranasal airways and pulmonary airways) of the mammal in an amount , at a frequency, and for an effective duration to reduce or eliminate asthma symptoms. This formulation contains an antifungal agent. Another embodiment of the invention presents a method for prophylactically treating a mammal at risk of developing asthma. This method involves the steps of identifying the mammal (eg, diagnosis), and muco-administering a formulation to at least a portion of the respiratory tract (eg, nasal-paranasal airways and pulmonary airways) of the mammal in an amount, at a frequency, and for an effective duration to avoid asthma symptoms. This formulation contains an antifungal agent. In another aspect, the invention features a method of treating a mammal having intestinal mucositis induced by non-aggressive fungi (e.g., chronic colitis and Crohn's disease). This method involves mucoadministering to the mammal a formulation in an amount, at a frequency, and for an effective duration to reduce or eliminate the symptoms of intestinal mucositis induced by non-aggressive fungi. This formulation contains a and muco-administered directly a formulation to at least a portion of the nasal-paranasal anatomy of the mammal in an amount, at a frequency, and for an effective duration to reduce or eliminate rinosinusitis induced by non-aggressive fungi. This formulation contains an antifungal agent and can be in the form of a regulated release capsule (eg, pH or time regulated release capsule). Mucoadministration may be the oral application of the formulation within the mammalian digestive tract. Alternatively, the mucoadministration within the mammalian digestive tract by means of an enema. In another embodiment, the invention features a method of prophylactically treating a mammal at risk of developing intestinal mucositis induced by non-aggressive fungi (e.g., chronic colitis and Crohn's disease). This method involves mucoadministering to the mammal a formulation in a quantity, at a frequency, and for an effective duration to avoid the symptoms of intestinal mucositis induced by non-aggressive fungi. This formulation contains an antifungal agent. In another aspect, the invention features a method for treating a mammal that has otitis media induced by non-aggressive fungi. This method involves mucoadministering to the mammal a formulation in a quantity, at a frequency, and for an effective duration to reduce or eliminate the otitis media induced by non-aggressive fungi. This formulation contains an antifungal agent. The mucoadministration may be the application of the formulation within the middle ear of the mammal. For example, a liquid form of the formulation can be used to irrigate the middle ear if the tympanic membrane rises or is not intact. Alternatively, a formulation can be injected into the middle ear or a myringotomy can be used to bypass the tympanic membrane. In addition, a formulation can be mucoadministered to the middle ear through the nose and the eustachian tube. In another modality, the invention presents a method for prophylactically treating a mammal at risk of developing otitis media induced by non-aggressive fungi. This method involves the mucoadministration to the mammal of a formulation in an amount, at a frequency, and for an effective duration to prevent otitis media induced by non-aggressive fungi. This formulation contains an antifungal agent. In another aspect, the invention features an article of manufacture containing packaging material (eg, boxes, wrappers, jars, and other containers) and a formulation contained within the packaging material. This formulation contains an antifungal agent. The packaging material contains a label or insert packet which indicates that the formulation can mucoadministered directly to at least a portion of the nasal-paranasal anatomy of a mammal having rhinosinusitis induced by non-aggressive fungi in an amount, at a frequency, and during an effective duration for reducing or eliminating rhinosinusitis induced by non-aggressive fungi In another embodiment, the invention features an article of manufacture containing packaging material and a formulation contained within the packaging material. This formulation contains an antifungal agent and the packaging material contains a label or insert packet which indicates that the formulation can be mucoadministered to at least a portion of the nasal-paranasal anatomy of a mammal at risk of developing non-aggressive fungal-induced rhinosinusitis in a quantity, at a frequency, and for an effective duration to avoid rhinosinusitis induced by non-aggressive fungi. Another embodiment of the invention features an article of manufacture containing packaging material and a formulation contained within the packaging material. This formulation contains an antifungal agent. The packaging material contains a label or insert packet which indicates that the formulation can be directly metered to at least a portion of the respiratory tract of a mammal having asthma in an amount, at a frequency, and for an effective duration to reduce or eliminate the symptoms of asthma. Another embodiment of the invention features an article of manufacture containing packaging material and a formulation contained within the packaging material. This formulation contains an antifungal agent and the packaging material contains a label or insert packet which indicates that the formulation can be mucoadministered to at least a portion of the respiratory tract of a mammal at risk of developing asthma in an amount, at a frequency, and for an effective duration to avoid asthma symptoms. Another embodiment of the invention features an article of manufacture containing packaging material and a formulation contained within the packaging material. This formulation contains an antifungal agent. The packaging material contains a label or insert packet which indicates that the formulation can be mucoadministered to a mammal having intestinal mucositis induced by non-aggressive fungi in an amount, at a frequency, and for an effective duration to reduce or eliminate the symptoms of intestinal mucositis induced by non-aggressive fungi. Another embodiment of the invention features an article of manufacture containing packaging material and a formulation contained within the packaging material. This formulation contains an antifungal agent. The packaging material contains a label or insert packet which indicates that the formulation can be mucoadministered to a mammal having otitis media induced by non-aggressive fungi in an amount, at a frequency, and for an effective duration to reduce or eliminate the symptoms of otitis. media induced by non-aggressive fungi. Another embodiment of the invention features an article of manufacture containing packaging material and a formulation contained within the packaging material. This formulation contains an antifungal agent and the packaging material contains a label or insert packet which indicates that the formulation can be mucoadministered to a mammal at risk of developing otitis media induced by non-aggressive fungi in an amount, at a frequency, and for an effective duration to avoid the symptoms of otitis media induced by non-aggressive fungi. In another aspect, the invention features the use of an antifungal agent for the manufacture of a medicament for the treatment or prevention of rhinosinusitis induced by non-aggressive fungi. In another embodiment, the invention features the use of an antifungal agent for the manufacture of a medicament for the treatment or prevention of asthma symptoms. Another embodiment of the invention features the use of an antifungal agent for the manufacture of a medicament for the treatment or prevention of intestinal mucositis induced by non-aggressive fungi. Another embodiment of the invention features the use of an antifungal agent for the manufacture of a medicament for the treatment or prevention of otitis media induced by non-aggressive fungi. In another aspect, the invention features an anti-fungal formulation containing an antifungal agent, a flavoring, and water. The water constitutes at least about 50 percent of the formulation. For example, the water may constitute at least about 55, 60, 70, 75, 80, 85, 90, 95 or 99 percent of the formulation. In another embodiment, the invention features an antifungal formulation containing itraconazole and water. Itraconazole is dissolved in the formulation in a concentration greater than about 30, 40, 50, 60, 70, 80, 90, 1 00, 1 1 0, 1 20, 1 30, 140, 1 50, 160, 1 70, or 1 80 μg per mL. In addition, the water constitutes at least about 50 percent of the formulation. For example, the water may constitute at least about 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99 percent of the formulation. The formulation may also contain polyethylene glycol (e.g., PEG-200, PEG-400, PEG-800, etc.). The formulation may also contain flavoring (eg, peppermint oil, cherry flavoring, syrup, and the like).

In another embodiment, the invention features an antifungal formulation containing itraconazole and water. Itraconazole is suspended in the formulation at a concentration greater than about 25 μg per mL. For example, itraconazole can be suspended in the formulation at a concentration greater than about 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 150, 160, 170 or 180 μg per mL. In addition, the water constitutes at least about 50 percent of the formulation. For example, the water may constitute at least about 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99 percent of the formulation. The formulation may also contain polyethylene glycol (e.g., PEG-200, PEG-400, PEG-800, etc.). The formulation may also contain flavoring (eg, peppermint oil, cherry flavoring, syrup, and the like). In another embodiment, the invention features an antifungal formulation containing an antifungal agent, a flavoring, and water. The water constitutes at least about 50 percent of the formulation. For example, the water may constitute at least about 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99 percent of the formulation. In addition, the antifungal agent may be amphotericin B, acetoconazole, saperconazole, voriconazole, fluctosin, miconazole, fluconazole, griseofulvin, clotrimazole, econazole, terconazole, butoconazole, oxiconazole, sulconazole, cyclopirox olamine, haloprogin, tolnaftate, naftifine, terbinafine hydrochloride, morfoiins, nystatin, natamycin, butenafine, undecylenic acid, Whitefield ointment, propionic acid and caprylic acid. In another aspect, the invention features a method for making an antifungal formulation. The formulation contains itraconazole and water. Itraconazole is dissolved in the formulation in a concentration greater than about 25 μg per mL. For example, itraconazole can be dissolved in the formulation in a concentration greater than about 30, 40, 50, 60, 70, 80, 90, 100, 110, 20, 130, 140, 150, 160, 1 70, or 1 80 μg per m L .. The water constitutes at least about 50 percent of the formulation. For example, the water may constitute at least about 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99 percent of the formulation. The method includes the addition of water to a base solution containing the traconazole. In another aspect, the invention features a method for cultivating fungi derived from the mucus of a mammal. The method includes (1) contacting the mucus with a mucolytic agent to reduce the viscosity of the mucus, (2) separating the fungi from the mucus of reduced viscosity, (3) contacting the separated fungi with a fungal growth medium to form a mushroom culture, and (4) incubating the mushroom culture in such a way that the separated fungi grow. In another aspect, the invention features a method for obtaining a fungal antigen. The method includes (1) contacting the mucus of a mammal with a mucolytic agent to reduce the viscosity of the mucus, (2) separating the fungi from the mucus of reduced viscosity, (3) contacting the separated fungi with a growth medium of fungi to form a fungal culture, (4) incubate the fungal culture in such a way that the fungi grow apart, and (5) isolate the antigen from the cultured fungi. In another aspect, the invention features a method for producing a specific fungal antibody. The method includes (1) contacting the mucus of a mammal with a mucolytic agent to reduce the viscosity of the mucus, (2) separating the fungi from the mucus of reduced viscosity, (3) contacting the separated fungi with a growth medium of fungi to form a fungal culture, (4) incubate the fungal culture in such a way that the fungi grow apart, (5) isolate the fungal antigen from the cultured fungi, and (6) immunize an animal with the antifungal agent to produce the antibody. In another aspect, the invention presents a nasal mucus collection apparatus. The apparatus contains a collection container, a collection tube, and a connection portion. The collection container is adequate to retain mucus. The collection tube extends from the collection container and defines a distal end and a passage such that the mucus can traverse the passage from the distal end of the collection tube to the collection container. The collection tube is generally flexible over at least a portion of the length of the tube such that the collection tube can be selectively manipulated in a configuration desired by a professional during a collection procedure. The collection tube is also generally malleable in such a way that the collection tube generally retains the desired configuration until the professional manipulates the collection tube to form a different configuration. The connection portion extends from the collection container and defines a second passage communicating with the interior of the holding container. The connection portion is adapted to receive a vacuum source. In addition, the apparatus may also contain a valve that adjusts the opening of the second passage. The collection container can be extractable from the collection tube and the connection portion. In another aspect, the invention features a pharmaceutical composition containing an antifungal agent. In another aspect, the invention features a pharmaceutical composition containing an antifungal agent and a mucolytic agent. Another embodiment presents a pharmaceutical composition containing an antifungal agent and a steroid. Another embodiment has a pharmaceutical composition containing an antifungal agent and a decongestant. Another embodiment has a pharmaceutical composition containing an antifungal agent and an antibiotic. Another embodiment presents a pharmaceutical composition containing an antifungal agent and an anti-inflammatory agent. Another embodiment has a pharmaceutical composition containing an antifungal agent and an anti-histamine. Another embodiment presents a pharmaceutical composition containing an antifungal agent and an anti-cholinergic. Another embodiment has a pharmaceutical composition containing an antifungal agent and a leukotriene inhibitor. In another aspect, the invention features a composition for treating an immune response to fungi in a mammal, characterized by an agent configured for direct mucoadministration to the mucus of the mammal and having antifungal means to eliminate or reduce fungi below a level. threshold where fungi cease to activate eosinophilic migration to the affected area. In another aspect, the invention features a pharmaceutical composition for treating a related fungal condition in nasal anatomy-nasal cavity, pulmonary anatomy, ear anatomy, or intestinal anatomy of a mammalian patient, said composition comprising an effective dose. of an anti-fungal as described herein. In another aspect, the invention features a pharmaceutical composition for treating a related fungal condition in the nasal anatomy-nasal cavity, lung anatomy, ear anatomy, or intestinal anatomy of a mammalian patient, said composition comprising an effective dose of an anti-inflammatory agent. fungal and at least one other agent or inhibitor as described herein. In another aspect, the invention features a pharmaceutical composition for treating a related fungal condition in nasal anatomy-nasal cavity, pulmonary anatomy, anatomy of the ear, or intestinal anatomy of a mammalian patient, said composition comprising an effective dose of an anti-fungal suitable for long-term use within the nasal-nasal cavity anatomy. In another aspect, the invention presents a medicament for treating sinusitis, asthma, otitis media, or colitis of a patient, comprising a mucolytic agent; and an anti-fungal compound as described herein. In another aspect, the invention features an irrigation medicament for treating a nasal area, lung area, ear area, or inflamed intestinal area of a patient, originating the nasal area, lung area, ear area or inflamed intestinal area by the presence of fungi, the medicament comprising effective doses of an antifungal compound and a steroid as described herein. In another aspect, the invention features an irrigation medicament for treating a nasal area, lung area, ear area, or inflamed intestinal area of a patient, originating the nasal area, lung area, ear area or inflamed intestinal area by the presence of fungi, the medicament comprising effective doses of an antifungal compound and a mucolytic agent. In another aspect, the invention features an irrigation medicament for treating a nasal area, lung area, ear area, or inflamed intestinal area of a patient, originating the nasal area, lung area, ear area or inflamed intestinal area by the presence of fungi, the medicament comprising effective doses of a steroid and a mucolytic agent as described herein. In another aspect, the invention features an irrigation medicament for treating a nasal area, lung area, ear area, or inflamed intestinal area of a patient, originating the nasal area, lung area, ear area or inflamed intestinal area by the presence of fungi, the medicament comprising effective doses of an antifungal compound, a steroid and a mucolytic agent as described herein. In another aspect, the invention features an irrigation medicament for treating a nasal area, lung area, ear area, or inflamed intestinal area of a patient, originating the nasal area, lung area, ear area or inflamed intestinal area by the presence of fungi, the medicament comprising an effective dose of at least one medicine selected from the group consisting of an antifungal compound, a spheroid, a mucolytic agent, and some combination thereof as described herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary experience in the subject matter to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, this specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

DESCRIPTION OF THE DICHES Figure 1 is a CT scan of a patient with bilateral chronic rhinosinusitis. Figure 2 is a CT scan of the patient of Figure 1, four months later, after treatment with antifungal irrigations. Figure 3 is a diagram representing a device for collecting mucus. Figure 4 is a diagram representing a device for collecting mucus.

DETAILED DESCRIPTION The invention involves methods and materials to treat and prevent mucositis induced by non-aggressive fungi. Specifically, the invention involves the mucoadministration of an antifungal agent in an amount, at a frequency, and for an effective duration to prevent, reduce or eliminate rhinosinusitis induced by non-aggressive fungi. This invention also provides methods and materials for diagnosing chronic non-aggressive fungal-induced rhinosinusitis and cultivating non-aggressive fungi derived from a mammalian mucus sample as well as specific antifungal formulations and medical devices for treating and preventing non-aggressive fungal-induced rhinosinusitis. . In addition, the invention provides methods and materials for treating and preventing other non-aggressive fungal-induced mucositis conditions such as chronic otitis media, chronic colitis, and Crohn's disease. In addition, the invention includes methods and materials for treating and avoiding the symptoms of chronic asthma. Although not limited to any particular mode of action, the present invention involves the treatment and prevention of non-aggressive fungal-induced inflammation of mucosal tissue by using an antifungal agent based on the following proposed mechanism of disease progression derived from the discoveries reported in the present. In general, most, if not all, individuals have fungal organisms living in their mucus. Normally, most individuals tolerate these non-aggressive organisms and live normal lives free of disease. For unknown reasons, some individuals do not tolerate these fungal organisms and begin to increase an immune response against them. As the immune response progresses, eosinophilic cells accumulate within the local tissue. This accumulation of eosinophilic cells can contribute to the formation of obstructive tissue masses (for example, polyps and polypoid structures) as well as the transmigration of eosinophilic cells activated from the tissue (inside the body) to the mucus (outside the body). These masses of obstructive tissue appear to prevent normal cavity clearance and therefore can facilitate additional fungal growth. Once the eosinophil cells are inside the mucus, they can release the content of their granules presumably after the activation of the surface Fc receptors. Granules of eosinophilic cells contain many toxic molecules such as the cationic eosinophilic protein (ECP), eosinophil peroxidase (EPO), and a major basic protein (MBP). When released, these toxic molecules can damage both the targeted foreign microorganisms (for example, fungi) as well as their own tissues. The degree of damage caused by eosinophil cell accumulation and eosinophil cell degranulation varies significantly from mild inflammatory pain and discomfort to major structural abnormalities such as destruction of tissue and bone and the formation of polyps, polypoid structures, and other tumors. Once the tissues themselves are damaged, the individual may have an improved susceptibility to bacterial infections as well. Accordingly, the characteristic inflammatory responses, resultant injuries, and resultant bacterial infections within the majority, if not all, of chronic rhinosinusitis patients are currently activated by non-aggressive fungal organisms. It is observed that fungal organisms can be observed inside tissue under conditions of extreme mucositis of tissue and bone destruction because the barrea (ie, the epithelium) between the inside and outside of the body has been destroyed or damaged. In these situations, the mere observed presence of a small number of fungal organisms within a localized area of damaged tissue does not discourage the fact that the affliction is mucositis induced by non-aggressive fungi and not an infection. The discovery that most, if not all, cases of chronic rhinosinusitis originate from non-aggressive fungal organisms suggests that other chronic inflammatory conditions such as chronic otitis media, chronic colitis, Crohn's disease are most likely caused by fungal organisms. Non-aggressive living inside the mucus. In addition, the finding that non-aggressive fungal-induced rhinosinusitis can be treated and successfully prevented with antifungal agents when mucoadministrated in an amount, at a frequency, and for an effective duration suggests that these other non-aggressive fungal-induced mucositis conditions can treated and also avoided with antifungal agents when used appropriately as described herein. In addition, the discovery that chronic asthma symptoms can be treated and prevented with antifungal agents when they are directly administered to the respiratory tract by means of nasal-paranasal irrigation suggests that antifungal agents can be effective when they are directly administered to the respiratory tract by mucoadministration. inhalation through the nose or mouth. Accordingly, the methods and materials described herein have the potential to treat millions of people suffering from chronic rhinosinusitis, chronic otitis media, chronic colitis, Crohn's disease, and any other non-aggressive fungal-induced mucositis condition as well as chronic asthma As described above, a mucositis induced by non-aggressive fungi is an inflammation, not an infection. In general, inflammations are fundamentally and clinically different from infections. An infection is defined as the growth of an organism within the tissue. In addition, an infection is characterized as an aggressive disease comprising an infectious organism entering the tissue of a host and then activating a host immune response and / or causing damage. Therefore, the role of an infectious organism is typically that of an aggressive pathogen. In addition, an infected individual may be immunocompetent or immunocompromised. When the infected individual is immunocompromised, the infection is often called an "opportunistic" infection. In addition, infections can be acute or chronic depending on multiple factors such as the competence of the immune system of the infected individual, the nature of the aggressive pathogen, and the availability of medical treatments. In contrast, an inflammation is characterized as a localized protective response that serves to destroy, dilute, and / or remove a harmful agent or insult. In addition, inflammatory responses will typically result in red discoloration, swelling, warming and pain. In the case of mucositis induced by non-aggressive fungi, the localized protective response is against a non-aggressive fungal organism that lives outside the tissue (for example, inside the mucus). Typically, some individuals suffering from non-aggressive fungal-induced mucositis are atopic and / or immunocompetent. In addition, the role of the harmful agent (i.e., fungi) is that of a non-aggressive allergen. Therefore, mucositis induced by non-aggresive fungi is an allergic reaction increased by the immune system of the individual against a fungal organism living outside the tissue of an individual. As described herein, the invention provides methods and materials that reduce the presence of fungal organisms within the mucus at a level and for a period of time such that the characteristic inflammatory responses and resultant damages associated with mucositis are stopped., treat or avoid. For purposes of clarity, reducing the presence of fungal organisms within the mucus to treat or prevent mucositis is similar to removing an allergen (e.g., pollen) from the presence of an individual suffering from an allergic reaction (e.g. hay fever). Again, the allergic reaction against, for example, pollen is not an infection but an inflammation. In addition, the simplicity of this invention underscores the far-reaching clinical implications that follow these discoveries. For example, once clinicians understand that most, if not all, chronic rhinosinusitis are caused by non-aggressive fungal organisms and that this inflammatory disease can be treated and prevented by reducing the level of non-fungal organisms within the body. Nasal-paranasal mucus using the methods and materials described herein, then millions of people will be able to have healthier, happier and more productive lives.

Identification of non-aggressive fungal-induced mucositis A mucositis induced by non-aggressive fungi is defined as an inflammation of any mucous tissue induced by a non-aggressive fungal organism. Examples of mucosal tissue include, without limitation, the mucous membrane of the mouth, intestine, nasal passages, paranasal cavities, airways of the lung, trachea, middle ear, eustachian tube, vagina and urethra. In general, an inflammation of a mucosal tissue can be determined using any of the methods commonly known to a skilled artisan. For example, an individual can be identified by having an inflammation of a mucosal tissue after examination of a tissue biopsy as well as by visual examination, endoscopic analysis, and image analysis techniques (e.g., X-rays, CT scans, and magnetic resonance imaging (MRI) scans because the various inflamed mucosal anatomies tend to exhibit observable abnormal features. Multiple diagnostic methods can be used to determine if a particular mucositis is mucositis induced by non-aggressive fungi. In general, such diagnostic methods include, without limitation, reviewing the prior medical conditions and treatments of the affected individual, interviewing and evaluating the affected individual, and collecting and analyzing biological samples from the affected individual. The review of the medical history of an affected individual can be useful to determine if a particular mucositis is a mucositis induced by non-aggressive fungi because such inflammations are typically recurrent and chronic. Therefore, the signs of a previous episode of mucositis induced by non-aggressive fungi would suggest that an instantaneous mucositis is also a mucositis induced by non-aggressive fungi. Other useful information within an individual's medical history could include, without limitation, allergies, surgeries, and other diseases such as cystic fibrosis and ciliary immobility syndromes.

The interview and evaluation of an affected individual can also help to identify mucositis induced by non-aggressive fungi. For example, individuals suffering from symptoms of chronic mucositis such as airway obstructions, loss of smell, hearing loss, asthmatic breathing, dyspnea, coughing attack, headache, and facial pressure may have mucositis-induced mucositis. non-aggressive fungi. In addition, mucositis induced by non-aggressive fungi can be ruled out in individuals who exhibit the symptoms of an infection such as fever, fungal dissemination, fungemia, increased polymorphonuclear leukocytes, and acute attack. It is observed that recurrent bacterial infections can indicate a fundamental condition of mucositis induced by non-aggressive fungi because chronic inflammation can lead to the destruction of the epithelium and therefore increase the susceptibility of the individual to bacterial infection. In addition, multiple diagnostic tests can be performed to help identify mucositis induced by non-aggressive fungi. For example, a common allergy examination using a panel of fungal and non-fungal antigens can be used to determine if an individual is atopic because some cases of non-aggressive fungal-induced mucositis involve atopic individuals. In addition, tests based on immunology for the presence of anti-fungal antigen antibodies, tests for abnormal lung function with or without methacholine, audiograms, and tympanograms can be used to identify mucositis induced by non-aggressive fungi. The collection and analysis of biological samples from an affected individual can help to identify mucositis induced by non-aggressive fungi. In general, biological samples such as mucus, stool, urine, sputum, and blood can be collected and analyzed for signs that indicate the intervention of a non-aggressive fungal organism. Such signs may include, without limitation, the presence of an antigenic marker for mucositis induced by non-aggressive fungi.; the presence of eosinophil cells, eosinophilic cell products (eg, MBP and ECP), antibodies, fungal antigens, or fungal organisms within a sample of mucus, deposition, urine or sputum; and the absence of fungal organisms within a blood sample. For example, the identification of allergic mucus (ie, mucus that contains evidence of the presence of eosinophilic cells) may indicate mucositis induced by non-aggresive fungi. Such evidence of presence of eosinophilic cells includes, without limitation, the presence of intact eosinophilic cells, necrotic eosinophils, and eosinophilic products. They are well known in the art and many methods can be used to detect the presence of these various signs and markers within a biological sample. For example, the presence of eosinophilic cells within the allergic mucus can be determined using a haematoxylin / eosin stain followed by a microscopic examination. In addition, a tissue biopsy can be collected and analyzed for the lack of aggressive fungi. As noted above, fungal organisms can be observed within the tissue under conditions of extreme mucositis of tissue and bone destruction when a tissue biopsy is examined simply because the barrier (i.e., the epithelium) between the inside and the outside of the tissue. Body has been destroyed or damaged. In these situations, the mere presence of a small amount of fungal organisms within a localized area of damaged tissue does not necessarily mean that the affliction is not a mucositis induced by non-aggressive fungi. In addition, immunology-based assays can be used to detect the presence of various signs of mucositis induced by non-aggressive fungi within a biological sample. Many immunology-based assays are well known in the art including, without limitation, immunoabsorbent assays based on immunology (ELISA) and radioallergosorbent assays (RAST). Methods of using RAST are described, for example, in McRury J et al., (Clin Exp Immunol 65: 631-638 (1986)), Mabry RL and Manning S (Otolaryngol, Head Neck Surg. : 721-723 (1995)), and Lynch NR er al., (Int Arch Allergy Immunol 1 14: 59-67 (1997)). Immunology-based assays can utilize polyclonal antibodies, monoclonal antibodies, or fragments thereof that have specificity for an antigen that can be used as a diagnostic marker for mucositis induced by non-aggressive fungi. For example, monoclonal antibodies that have specificity for fungal organisms that are known to cause non-aggressive fungal-induced mucositis can be produced and used for biological examination samples. Such antibodies can be produced using the methods described elsewhere (Zeidan et al., Experimental Approaches in Biochemistry and Molecular Biology, William C. Brown Publisher (1 996) and Seaver, Commercial Production of Monoclonal Antibodies: A Guide for Scale-Up , Marcel Dekker I nc., New York, NY (1 987)). Briefly, a mouse can be immunized with a sample of a fungal organism isolate. A few weeks later the spleen lymphocytes of the immunized mouse can be recovered and fused with the myeloma cells to produce hybridoma cells. Hybridoma cells exhibit specificity for the immunizing fungal isolate can then be isolated and preparations of monoclonal antibody can be produced. Because the specific methods and materials used to identify mucositis induced by non-aggressive fungi may vary depending on the specific location of the mucositis, a more detailed description is given below for various exemplary mucosal tissues. 1. Nasal-paranasal cavities. The external osseous structure of the nose consists of two oblong nasal bones. A nasal bone is arranged on each side of a midline, with the two bones forming an arched cross section. The nasal septum divides the nasal cavity in half. The lateral nasal wall has three turbinates that increase the mucosal surface area of the nasal cavity or vestibule. The nasal vestibule is limited by the nasal septum and the lateral wall. This large surface area of the turbinates and nasal septum promotes extensive contact with the inspired air, thus facilitating humidification, removal of particles, and regulation of the temperature of the inspired air. The paranasales cavities are spaces that contain air joining the nasal cavity by means of openings or ostias. Although they are arranged in pairs, the paranasal cavities are commonly asymmetric in shape and location, and include the maxillary, frontal, ethmoidal and sphenoid cavities. Suggested functions of the paranasal cavities include lightening the bones of the skull, providing mucus for the nasal cavity, and acting as resonating chambers for the production of sound. The maxillary cavities are the longest paranasal cavities. Each maxillary cavity is located in the maxilla and opens inside the middle meatus. The frontal cavities are located in the frontal bone and are superior and medial to the orbit of the eye. The frontal cavities are also empty in the intermediate meatus. The ethmoidal cavities are numerous and irregularly formed air spaces within the intermediate and superior meatos. The sphenoid cavity is located in the sphenoid bone and is posterior to both the eye and the upper portion of the nasal cavity. The sphenoid cavity drains into the superior meatus. The mucosal tissue (mucosal membrane) coats both the nasal cavity and the paranasal cavities, and generally comprises an epithelial layer, connective tissue, and mucus glands. A layer of mucus normally covers the mucous membrane. The mucus that is secreted from the mucous membrane serves to entrap the particles and to prevent dehydration of the nasal and paranasal tissues that are otherwise exposed to air. The mucus is normally transported by the cilium to the nasopharynx and then swallowed. Individuals suffering from rhinosinusitis can be identified by using methods commonly known in the art. Symptoms of rhinosinusitis include, without limitation, nasal airway obstruction, loss of smell, facial pain, headache, post nasal discharge, and runny nose. When examining, the presence of thick mucus or visual identification of nasal or paranasal obstruction with mucus or polyps frequently indicates a condition of rhinosinusitis. Nasal polyps are natural consequences of the nasal-paranasal mucous membrane that are typically soft, gelatinous, semitransparent, round or pear-shaped, and pale. In general, nasal polyps are located in the lateral wall of the nose, usually in the middle meatus or along the intermediate and superior turbinates. Most nasal polyps come from the ethmoid cavities but some polyps originate in the maxillary sphenoid cavities. The mass of a nasal polyp is composed mainly of edematous fluid with scarce fibrous cells and few mucous glands. The surface epithelium of the nasal and paranasal polyps usually reveals squamous metaplasia. Eosinophilic cells are usually present in polyps in moderate to large numbers, and it is not known that nasal polyp fluid contains higher than normal concentrations of IgA, IgE, IgG and IgM antibodies as well as abnormally high concentrations of I L -5, a cytokine that contributes to eosinophilic activation and survival. As demonstrated herein, the presence of nasal polyps is not a risk factor for rhinosinusitis, but rather a final stage of chronic inflammation. The following methods and materials can be used to identify individuals suffering from non-aggressive fungal-induced rhinosinusitis. As described above, the condition known as AFS is a condition of rhinosinusitis induced by non-aggressive fungi. Accordingly, any method known in the art that is used to identify AFS can be used to identify rinosinusitis induced by non-aggressive fungi (Cody DT et al., Laryngoscope 1 04: 1074-1079 (1 994) and Kupferberg SB et al. , Otolaryngol, Head Neck Surg 1 17: 35-41 (1 997)). For example, rhinosinusitis induced by non-aggressive fungi can be identified by the presence of thickened mucus that contains agglomerations or leaves of necrotic eosinophils, Charcot-Leyden crystals, and non-aggressive fungal reticulate tissue. In addition, image analyzes such as MRI and CT scans can be used to identify non-aggressive fungal-induced rhinosinusitis because such conditions typically exhibit a characteristic appearance, often leading to bone erosion in adjacent structures (Quarishi et al., Otolaryngol. Surg. 1 1 7: 29-34 (1 997); Manning ei al., Laryngoscope 107: 1 70-176 (1 997); Kinsella eí al., Head & Neck 1 8: 21-1-21 (1996); Allbery I went to. , RadioGraphics 15: 131-1-1327 (1995); Roth MR, Ear, Nose & Throat J. 73: 928-930 (1994); and Bartynski went to., Otolaryngol. Head Neck Surg. 1 03: 32-39 (1,990)). In addition, individuals with non-aggressive fungal-induced rhinosinusitis may have a history of nasal-paranasal polyposis and may have undergone multiple surgeries. The results using currently available diagnostic methodology indicate that approximately three to eight percent of cases of chronic rhinosinusitis requiring surgery are AFS cases. In general, these current AFS diagnostic methods involve criteria such as the presence of a characteristic appearance on a CT scan, the presence of allergic mucus, and the presence of fungal organisms within the mucus samples as confirmed by the histology or fungal growth in culture. The present invention demonstrates that percentages greater than 90 percent of all cases of chronic rhinosinusitis have a fungal etiology based on a better understanding of chronic rhinosinusitis, improved diagnostic procedures, and the impressive success rate of the antifungal treatment approaches described. at the moment.

In addition, the present invention demonstrates that the ability to develop fungal organisms from a mucus sample is not a useful criterion for diagnosing a non-aggressive fungal-induced rhinosinusitis condition, such as AFS, because most, if not is that all human beings have fungal organisms within their nasal-paranasal mucus (See Example 1). However, it is observed that the collection, analysis, and / or culture of fungal organisms derived from a nasal-paranasal mucus sample can provide useful diagnostic information. Such information may include, without limitation, information about the level of fungal organisms and the number of different fungal species present within a particular mucus sample. The lack of appreciation for the non-aggressive fungal etiology of chronic rhinosinusitis conditions seems to have occurred for several reasons. First, confidence in inadequate techniques of mucus collection and fungal culture seems to lead to misinterpretation of negative fungal growth results. As observed in the present, these negative results were mostly false-negative results because the fungal organisms can grow from samples of nasal-paranasal mucus collected mostly, if not in all cases, from Humans. Consequently, the ability to develop fungal organisms from a nasal-paranasal mucus sample is negligible as a diagnostic criterion for non-aggressive fungal-induced pnosinusitis conditions that include AFS. Second, clinics, during surgery, routinely cleanse with water or remove mucus from the nasal-paranasal cavities before removing and examining a polyp for the presence of allergic mucus. Therefore, the failure to detect allergic mucus is most likely the result of a failure to collect the appropriate medium in which to examine. This in turn can lead to the widely recognized and medically accepted theory that polyposis is the cause of some inflammatory conditions in nasal-paranasal anatomies. As described above, polyposis can be considered a result of the final stage of chronic inflammation. Third, chronic inflammatory conditions, as described herein, can lead to recurrent bacterial infections that may have camouflaged an underlying non-aggressive fungal-induced rhinosinusitis condition. In addition, any temporary relief observed after antibacterial treatment may have complicated the diagnosis of a condition that has a non-aggressive fungal etiology. I ndependently, the present invention teaches that special care must be taken in order to preserve that the mucus for analysis and that the presence of allergic mucus can be used to identify rhinosinusitis induced by non-aggressive fungi. In addition, recurrent bacterial infections within the nasal-paranasal anatomy may indicate non-aggressive fungal-induced rhinosinusitis. Any individual who has had a previous episode of rhinosinusitis is at risk of developing rhinosinusitis induced by non-aggressive fungi. In addition, older individuals as well as individuals who have cystic fibrosis, asthma, and a family history of nasal problems or allergies may be at risk of developing non-aggressive fungal-induced rhinosinusitis. In addition, individuals who are exposed to significant levels of allergens (eg, fungal spores, pollen and chemicals) may be at risk of developing rhinosinusitis induced by non-aggressive fungi. 2. Middle ear. The ear can be divided into three parts: the outer ear, the middle ear and the inner ear. The middle ear is a cavity that connects to the nasopharynx through the eustachian tube. further, the middle ear is separated from the opening of the outer ear by the tympanic membrane and contains a chain of three small bones that connect the tympanic membrane to the inner ear. The mucous tissue coats most of the middle ear space. Individuals suffering from inflammation of the mucous tissue of the middle ear (otitis media) can be identified based on a medical history of middle ear afflictions, visual examination, tissue biopsy, and symptoms such as hearing loss, otorrhea, and effusion of the ear. middle ear. In general, an otitis media condition induced by non-aggressive fungi can be identified by (1) collecting and analyzing fluid or mucus samples from the middle ear for the presence of fungal organisms or eosinophilic cells, (2) tissue biopsy analysis for organisms non-aggressive fungal infections; (3) an audiogram consistent with conductive ear loss; and (4) a flat tympanogram. Unlike nasal-paranasal mucus, the identification of the presence of fungal organisms in samples collected from the middle ear may indicate an inflammatory condition induced by non-aggressive fungi because the middle ear is usually quite sterile. Any individual who has had a previous episode of otitis media is at risk of developing otitis media induced by non-aggressive fungi. In addition, young individuals (for example, babies and toddlers) as well as individuals who have a family history of ear problems or allergies may be at risk of developing otitis media induced by non-aggressive fungi. 3. Intestines Mucous tissue lines both the small and large intestines. Individuals suffering from inflammation in the intestines (e.g., ulcerative colitis and Crohn's disease) can be identified using methods and materials commonly known in the art. For example, tissue biopsy analysis as well as endoscopic analysis can be used to identify conditions of intestinal mucositis, such as intestinal polyposis. In addition, symptoms such as diarrhea, abdominal cramps, gas and nausea may indicate inflammation of the intestines. In general, a condition of intestinal mucositis induced by non-aggressive fungi can be identified by the presence of fungal organisms, eosinophilic cells or eosinophilic cell products within the deposition samples. In addition, tissue biopsies that reveal the presence of non-aggressive fungal organisms may indicate a condition of intestinal mucositis induced by non-aggressive fungi. Any individual who has had a previous episode of an inflammatory bowel condition is at risk of developing intestinal mucositis induced by non-aggressive fungi. In addition, elderly individuals as well as individuals who have a family history of digestive problems, intestinal polyposis or allergies may be at risk of developing intestinal mucositis induced by non-aggressive fungi.

Fungal Organisms Any fungal organism that lives in the mucus of a mammal can be a non-aggressive fungal organism that is capable of inducing mucositis, since it is the mere presence of the organism in a mucus of the intolerant individual that causes inflammation. For example, all fungal organisms previously identified in mucus samples from AFS patients can be non-aggressive fungal organisms capable of inducing mucositis induced by non-agressive fungi including, without limitation, Absidia, Aspergillus flavus, Aspergillus fumigatus, Aspergillus glaucus, Aspergillus nidulans, Aspergillus versicolor, Alternaria, Basidiobolus, Bipolaris, Candida albicans, Candida lypolytica, Candida parapsilosis, Cladosporium, Conidiobolus, Cunninahamella, Curvularia, Dreschlera, Exserohilum, Fusarium, Malbranchia, Paecilomvces, Penicillium, Pseudallescheria, Rhizopus, Schizophylum and Sporothrix. In addition, fungal organisms that have not yet been identified in mucus samples from patients diagnosed as positive for ASF may be non-aggressive fungal organisms capable of causing mucositis induced by non-aggressive fungi including, without limitation, Acremonium, Arachniotus citrinus, Aurobasidioum, Beauveria , Chaetomium, Chryosporium, Epicoccum, Exophilia jeanselmei, Geotrichum, Oidiodendron, Phoma, Pithomyces, Rhinocladiella, Rhodoturula, Sagrahamala, Scolebasidium, Scopulariopsis, Ustilago, Trichoderma and Zygomycete. A list of additional fungal organisms that may be non-aggressive fungal organisms capable of inducing mucositis induced by non-aggressive fungi can be found in most taxonomic mycology textbooks.

Collection of Mucus Samples In general, mucus can be collected from the surface of any mucosal tissue by using a collection solution to wash the mucus-containing cavity. Appropriate mucus collection techniques should maximize the recovery of a mucus-containing collection solution by allowing sufficient penetration of the appropriate anatomical cavities and by minimizing the absorption of the collection solution by the individual. The vasoconstrictive agents can be used to maximize the collection of mucus and the mucolytic agents can be used to dissolve the obstructive mucus, in such a way that the penetration of the collection solution is increased. Thus, before collecting a sample of mucus, an individual can be treated with a vasoconstrictor agent and / or a mucolytic agent in such a manner that sufficient mucolytic action and / or vasoconstriction is induced in the appropriate region. Suitable vasoconstrictive agents may include, without limitation, phenylephrine hydrochloride (NEO-SYNEPHRI NE®; Sanofi Pharmaceuticals), cocaine and epinephrine. A mucolytic agent is any agent that liquefies mucus, so that it can be recovered from the patient. Suitable mucolytic agents may include, without limitation, N-acetyl-L-cysteine (MUCOSIL ™, Dey Laboratories) and recombinant human DNase (PULMOZYME®, Genentech, Inc.). Any vasoconstrictor agent or mucolytic agent administered should be allowed to take effect by waiting for a sufficient period of time after administration such as approximately two to five minutes. The following methods and materials can be used to collect a sample of nasal-paranasal mucus. First, an individual prepares to receive a collection solution in at least one nostril or nasal-paranasal cavity, by ordering the individual to inhale and lower the chin, or in some other way squeeze fluid access out of the mouth and through of the esophagus. In an individual standing or sitting vertically, these maneuvers tend to minimize the loss or ingestion of the collection solution. Other possible maneuvers are also provided for this objective to be achieved. Second, an injection and collection system is configured. In general, the configuration is such that a collection solution can be administered to the individual's nostril and then efficiently collected in a container. The injection system can be, without limitation, a syringe with a curved blunt needle or a set of tubes. The container can be any type of container that stores the liquid. In addition, the container can be, without limitation, a storage container that is suitable for use as a conveyor or apparatus that can be sealed, such that the collected sample can be handled or shipped. These containers may also contain an agent such as a preservative or antibacterial agent depending on the intended use of the mucus sample. Third, a collection solution is administered in the individual's nostril and collected. Before administration, the individual can be instructed to expel the collection solution after feeling the fluid in his or her nasal-paranasal anatomy. Alternatively, the individual can be instructed to expel the collection solution simultaneously with the administration. During administration, the collection solution can be forcibly injected into at least one nostril or next to the nasal-paranasal anatomy. The volume of the collection solution may vary according to the individual and state of the mucositis. For example, fluid volumes may be, without limitation, between about 0.1 mL to about 1 00 mL or more, and specifically between 0.1 mL and about 25 mL. The collection solution can be, without limitation, a saline solution, water and any other suitable solution, suitable to contact the mucosal tissue. In addition, the collection solution may contain other agents that may be useful for the collection of mucus such as a mucolytic agent. One goal of a collection solution is to dislodge and remove mucus within cavities that contain mucus. In addition to a collection solution that acts as a natural washing agent, the penetration effect of a mucolytic agent into a collection solution can help liquefy thick obstructive mucus. In addition, the combination of the force of administration with simultaneous, direct pressurized expulsion by an individual can help to dislodge and collect mucus. Typically, a collection solution can be administered for a period of less than about 5 seconds per side. In addition, a collection solution can be administered for a period of less than about 3 seconds. Alternatively, the time period of the administration of the collection solution may be extended beyond 5 seconds depending on specific factors such as the degree of inflammation., the presence of obstructions, and the size of the individual. In addition, an administration greater than 5 seconds may be used when very small volumes or streams of the collection solution are desired. Other collection procedures can also be used to collect mucus samples, particularly if an individual is unable to comply with or move forward with a fluid collection procedure. Such additional procedures are well known in the art and include, without limitation, surgical removal of mucus, a swab or mechanical mucus removal procedure, and pressure and vacuum systems that extract mucus. In addition, these other methods of collection as well as the methods and materials described herein may be modified or adapted to obtain biological fluids from other areas of the body such as the middle ear and intestines. After a sample of mucus is collected, the sample can be analyzed for the presence of markers that indicate the involvement of mucositis induced by non-aggressive fungi. For example, a sample of mucus can be examined for the presence of allergic mucus. In addition, fungal organisms can be cultured and analyzed from a mucus sample using the techniques described herein as well as those techniques known in the art. Figures 3 and 4 depict an exemplary device 1 0 for aspirating and collecting mucus and other liquids. Device 1 0 includes a top member 1 2, a collection container 14 and a collection tube 16. The top member 12, in turn, broadly includes a central portion 22, a threaded portion 24, a connecting portion 26 and a receiving member of the tube 28. The central portion 22 can generally define the opening 29 therein. The valve 30 is operatively positioned within the opening 29. The threaded portion 24 can extend downwardly from the central portion 22. The connecting portion 26 extends radially from the central portion 22, is generally circular in cross-section in its embodiment, and defines the interior surface 32. The interior surface 32 communicates the exterior of the device 10 with an interior portion thereof. The receiving member 28 extends generally radially from the central portion 22. The receiving member of the tube 28 is generally positioned opposite the connecting portion 26 in this embodiment. The receiving member of the tube 28 defines an interior surface 34. As with the interior surface 32, the interior surface 34 communicates the exterior of the device 10 to the interior thereof. In this embodiment, the container 14 is threadedly received on the threaded portion. The container 14, however, can be secured to the central portion 22 by other known means. Although a lower conical shape is depicted, the container 14 may assume a variety of configurations and may be within the scope of this invention. The collection tube 16 extends from and is placed inside the interior surface 34. A section of the tube 16 can be placed inside the container 14 to facilitate the placement of the collected material. The collection tube 16 defines a passage 36 through which the collected mucus passes. In one embodiment, the tube 16 comprises a flexible memory means to facilitate adaptation to different patient anatomies. That is, the tube 16 remains in accordance with a desired and flexible configuration, for example, as represented by the dummy lines in Figure 3. In addition, the means for facilitating the passage of the mucus through the collection tube and device 10. they may include a device or tube liner having similar characteristics designed to minimize mucus adhesion thereto. In one embodiment, the 1 0 device is designed for a single use. The 1 0 device can be made from a number of materials, however, synthetic resins such as polyethylene can be used. The connecting portion 26 connects the device 1 0 to a vacuum hose 38. In this way, the connecting portion 26 may have an outer configuration such that a tight fit to the vacuum hose 38 results. The valve 30 adjusts the amount of vacuum communicated through step 36. By adjusting the valve 30, a quantity of vacuum increasing or decreasing gradually can be applied thereto. In this example, the valve 30 includes a generally elongated groove that is configured with a sliding member. The sliding member can be adjusted by the user so that all, none or a portion of the elongated slot is exposed, thus adjusting the vacuum communicated to step 36. A variety of other adjustment means to regulate the vacuum, however, is they are within the scope of this invention. Another example includes a valve type "IV" that utilizes a roller valve to tightly tighten a length or collection tube. In contrast to other devices, the tube-receiving member 28 and the collection tube 16 generally extend perpendicularly from a longitudinal axis of the container 14. This allows users to better position the collection tube 16 when the mucus is recovered and other liquids It is recognized that other collection containers are possible within the scope of this invention, which fit comfortably into a patient's facial anatomy, and which can easily be held in place by either the patient or a care provider. Of the health. Such modalities may depend on vacuum, severity and other collection mechanisms as long as they provide easy access for fluids that are injected into the patient while simultaneously allowing drainage or removal of fluids and mucus from the patient. In this embodiment step 36 is between about 1 mm and 10 mm in diameter, and between about 5 cm and 50 cm in total length. The exemplary container 14 is generally between approximately 2.54 cm to 7.62 cm in diameter and 7.62 cm to 1 5.24 cm in height, although various other sizes may be useful. The device 10 is advantageously used to obtain mucus or fluid samples from the patient's lung, paranasal or nasal anatomy. In obtaining mucus or fluid samples, the device 10 is connected to a vacuum source and the valve 30 is adjusted as desired. The tube 1 6 is configured to a desired position. The tube 16 is then inserted into a portion of the patient's anatomy from which the mucus or fluid is to be obtained. The valve 30 is further adjusted as needed to obtain the sample, still ensuring patient safety. The fluid or mucus obtained is collected in a container 14. Once the collection is complete, the container 14 can be separated from the upper member 1 2 for storage or shipping of the sample of fluid or mucus obtained.

Cultivation of Fungal Organisms of a Mucus Sample A sample of mucus can be prepared for the culture of the fungal organism by treating the sample with a mucolytic agent such as N-acetyl-L-cysteine or dithiothreitol (DTT) to improve or facilitate the additional liquefaction of the mucus. After adding a mucolytic agent, the mucus sample can be mixed and incubated at room temperature.

This liquefaction allows the fungal organisms to present themselves inside the mucus to be released. Once liquefied, the mucus can be isolated by centrifugation or other means since the mucus typically forms a separate layer from the other solutions (ie, the collection solution). Once isolated, the mucus can be mixed and an aliquot placed in contact with a suitable fungal growth medium such as the agar plates of growth medium. A fungal growth medium is any medium that can support the growth of a fungal organism including, without limitation, RPMI-1649, the modified Delbecco's aloe medium (DMEM), inhibitory template agar (I MA) and Bay agar. The fungal growth medium may contain antibacterial agents (eg, chloramphenicol and ciprofloxacin) to prevent the growth of bacteria. Once liquefied, the mucus is placed in contact with an appropriate fungal growth medium, the cultures can be incubated at an optimum temperature, for example, between approximately 20 ° C and 37 ° C, "in some cases, between approximately 25 ° C. C and 35 ° C. Optimal temperature can be assessed by placing duplicate cultures at various temperatures and comparing growth rates Typically, the cultures are incubated between approximately two to thirty-five days at approximately 30 ° C. observe fungal growth, fungal species can be identified using procedures well known in the art and the phenotype and genotype of each fungus isolated, characterized For example, an isolated fungus can be examined to determine any property of drug susceptibility or drug resistance.

Treatment and Prevention of Mucositis Induced by Non-Aggressive Fungi The antifungal agents can be mucoadministered to a mammal in an amount, at a frequency, and for an effective duration to treat or prevent mucositis induced by non-aggressive fungi. An "antifungal agent" is any agent that is active against a fungal organism. For example, an antifungal agent is any agent that prevents the growth of or kills a fungal organism such as polyene antifungal macrolides, tetrane macrolides, pentalenic macrolides, fluorinated pyrimidines, imidazoles, triazoles, azoles, halogenated phenolic ether, thiocarbamates and allylamines. . In addition, antifungal agents can be agents that interpolate the fungal cell wall components or act as sterol inhibitors. Specific antifungal agents within the scope of the invention include, without limitation, amphotericin B, flucytosine, acetoconazole, miconazole, itraconazole, fluconazole, griseofulvin, clotrimazole, econazole, terconazole, butoconazole, oxiconazole, sulconazole, saperconazole, voriconazole, cyclopirox olamine, haloprogine, tolnaftate, naftifine, nystatin, natamycin, terbinafine hydrochloride, morpholines, undecylenic butenafine acid, Whitefield ointment, propionic acid, and caprylic acid as well as those agents that can be identified as antifungal agents using methods well known in the art. It is noted that a particular patient may possess a fungal organism that acts as the etiological agent that is resistant to a particular antifungal agent. In such a case, an important aspect of this invention includes treating that patient with an effective antifungal agent (eg, an antifungal agent that prevents the growth of, or kills the, fungal organism that acts as the etiological agent). Such fungal organisms act as etiological agents that can be identified using the harvest and culture methods described herein. The term "mucoadministration" as used herein refers to any type of administration that places an agent administered in contact with the mucus. In this way, any intravenously administered agent that does not leave the bloodstream is not considered a mucoadministered agent because the agent fails to make contact with the mucus. In addition, the term "mucoadministration" can be subdivided into "direct" and "indirect" mucoadministration. The term "direct mucoadministration" as used herein, refers to any type of administration that places an agent administered in direct contact with a targeted mucus before passing through the epithelium. For the purpose of this invention, it should be understood that injections of an agent into a mucus-containing cavity is considered direct mucoadministration if the agent contacts the mucus even when an injection medium (eg, needle, tube or catheter) can be used. used to traverse the epithelium. In this way, the use of a needle to bypass the tympanic membrane and inject an agent into the middle ear is considered a direct mucoadministration that targets the mucus of the middle ear. What follows is that any intravenously administered agent that subsequently exits the bloodstream penetrates the epithelium, and that contact with the mucus is not considered a mucoadministrated agent directly because the agent passed through the epithelium before contacting the mucus. However, in this case, the intravenously administered agent is considered an indirectly mucoadministered agent since the term "indirect mucoadministration" means any type of administration that places an agent administered in contact with a target mucus after traversing the epithelium. Again, the use of an injection means such as a needle, tube or catheter to deliver an agent beyond the epithelium and in direct contact with the mucus does not necessarily mean that the administration is an indirect mucoadministration. It also follows that an oral administration can be either a direct or indirect mucoadministration, depending on the mucus targeted. For example, an agent can swallow and then pass through the esophagus, stomach and small intestine to come into direct contact with the mucus in a large intestine, without having crossed an epithelium (i.e., direct mucoadministration). At the same time, the orally administered agent could be absorbed through the intestine, accumulate systematically and penetrate the nasal epithelium to come into contact with the nasal mucus (ie, indirect mucoadministration). In this way, the direct or indirect nature of the mucoadministration depends on the specific route of administration as well as the specific location of the targeted mucus. Typical mucoadministration pathways for various locations of mucus from a mammal are described below. An effective amount of an antifungal agent or formulation containing an antifungal agent can be any amount that reduces, prevents or eliminates mucositis induced by non-aggressive fungi after mucoadministration in a mammal without significant toxicity to the mammal. Typically, an effective amount can be any amount greater than or equal to the minimum inhibitory concentration (MIC) for a fungal or isolated organism present within a particular mucus of the individual that does not induce significant toxicity to the individual after mucoadministration. Some antifungal agents may have a relatively large concentration range that is effective while others may have a relatively narrow effective concentration range. In addition, the effective amount may vary depending on the specific or isolated fungal organism since certain organisms and isolates are more or less susceptible to particular antifungal agents. Such effective amounts can be determined by individual antifungal agents using commonly available or easily ascertainable information that includes, concentrations of antifungal efficacy, concentrations of animal toxicity and tissue permeability rates. For example, non-toxic antifungal agents can typically be mucoadministered directly or indirectly in any amount that shows antifungal activity within the mucus. In addition, antifungal agents that do not penetrate the mucosal epithelium, typically can mucoadministered directly in any amount that shows antifungal activity within the mucus. Using the information provided herein, such effective amounts can also be determined by routine experimentation in vitro or in vivo. For example, a patient who has a mucositis condition induced by non-aggressive fungi can receive direct mucoadministration of an antifungal agent in an amount close to the MIC calculated from in vitro analysis. If the patient stops responding, then the amount can be increased by, say, ten times. After receiving this higher concentration, the patient can be monitored for both the ability to respond to treatment and symptoms of toxicity and adjustments made in accordance with the above. For amphotericin B, an effective amount may be from about 0.01 ng to about 1000 mg per kg of body weight of the mammal by administration when directly administered. When used as a nasal irrigation solution, an effective amount may be a volume of about 0.01 mL to about 1 L per nostril per administration of a solution containing about 0.01 mg of Amphotericin B per liter to about 1000 mg of Amphotericin B per liter. Alternatively, an effective amount may be 20 mL per nostril per administration (eg, two to four times per day) of an irrigation solution containing approximately 100 mg of amphotericin B per liter of saline or water. Typically, saline or water is sterile. The effective amount can remain constant or can be adjusted as a sliding scale or variable dose depending on the response of the individual to treatment. The amounts effective for other antifungal agents can be determined by a person of ordinary skill in the art using routine experimentation in view of the many teachings described herein. Typically, an effective amount of any directly mucoadministered antifungal agent (eg, itraconazole, acetoconazole and voriconazole) can be about 0.01 ng to about 1000 mg per kg of body weight of the mammal per administration. The MIC values for voriconazole vary from approximately 0.003 μg / mL to approximately 4 μg / mL, depending on the specific fungal organism or isolated isolate tested. For fluconazole, the MIC values vary from about 0.25 μg / mL to more than about 64 μg / mL. To help determine the effective amounts of different antifungal agents, it may be useful to refer to an equivalent effective amount based on the effective amount of a common antifungal agent. For example, direct mucoadministration of approximately 20 μl per nostril per administration (eg, twice daily) of an amphotericin B irrigation solution containing approximately 1000 mg of amphotericin B per liter is an effective amount as described in FIG. shows in the present. The effects produced by this effective amount can be used as a reference point to compare the effects observed by other antifungal agents used at varying concentrations. Once the equivalent effect is observed, then the specific amount effective for that particular antifungal agent can be determined. In this case, that particular amount would be qualified as an effective amount of amphotericin B equivalent. The different factors can influence the current effective amount used for a particular application. For example, the frequency of mucoadministration, duration of treatment, combination of other antifungal agents, site of administration, degree of inflammation, and the anatomical configuration of the treated area, may require an increase or reduction in the current mucoadministrated effective amount. The frequency of mucoadministration can be any frequency that reduces, prevents or eliminates mucositis induced by non-aggressive fungi in a mammal without producing significant toxicity to the mammal. For example, the mucoadministration frequency may be from about four times per day to about once a month, or more specifically, from about twice a day to about once a week. In addition, the mucoadministration frequency may remain constant or may be variable during the duration of the treatment. As with the effective amount, several factors may influence the current mucoadministration frequency used for a particular application. For example, the effective amount, duration of treatment, combination of other antifungal agents, site of administration, degree of inflammation, and anatomical configuration of the treated area may require an increase or reduction in the frequency of mucoadministration. An effective duration for the mucoadministration of the antifungal agent can be any duration that reduces, prevents or eliminates mucositis induced by non-aggressive fungi in a mammal without producing significant toxicity to the mammal. In this way, the effective duration can vary from several days to several weeks, months, or years. In general, the effective duration for the treatment of mucositis induced by non-aggressive fungi can vary in duration from several days to several months. Once the antifungal applications are stopped, however, mucositis induced by non-aggressive fungi can return. In this way, the effective duration for the prevention of mucositis induced by non-aggressive fungi can last in some cases as long as the individual remains alive. For anatomies that are less susceptible to the repopulation factors of the fungal organism (e.g., a human middle ear with an intact tympanic membrane), an effective duration may range from about 10 days to about 30 days. For less sterile environments such as the nasal-paranasal anatomy, however, an effective duration may range from about 30 days to more than about 80 days. In the respiratory tract or digestive tract, an effective duration can be from about 10 days to more than about 30 days, or even more than about 90 days. Again, prophylactic treatments are typically longer in duration and can last throughout the individual's lifetime. The multiple factors can influence the current effective duration used for a particular treatment or prevention regimen. For example, an effective duration may vary with the frequency of administration of the antifungal agent, the amount of the effective antifungal agent, the combination of the multiple antifungal agents, the site of administration, the degree of inflammation, and the anatomical configuration of the treated area. In addition, the specific antifungal agent used can influence the current effective duration. For example, an effective duration for the treatment of rhinosinusitis induced by non-aggressive fungi may be approximately 30 days for amphotericin B and approximately 7 days for itraconazole. It is noted that the methods of the diagnostic algorithm can be devised to determine or reflect the appropriate frequencies, durations and effective doses.

Formulations Containing at least one Antifungal Agent A formulation containing an antifungal agent can be found in any form provided, the formulation can be mucoadministered to a mammal in an amount, at a frequency, and for an effective duration to prevent, reduce or eliminate a mucositis induced by non-aggressive fungi. For example, a formulation within the scope of the invention may be in the form of a solid, liquid, and / or aerosol including, without limitation, powders, crystalline substances, gels, pastes, ointments, balms, creams, solutions, suspensions , partial liquids, aerosols, nebulas, vapors, atomized vapors, dyes, pills, capsules, tablets and gel capsules. In addition, the formulation may contain a cocktail of antifungal agents. For example, a formulation within the scope of the invention may contain, without limitation, one, two, three, four, five or more different antifungal agents. In addition, formulations within the scope of the invention may contain additional ingredients including, without limitation, pharmaceutically acceptable aqueous vehicles, pharmaceutically acceptable solid carriers, steroids, mucolytic agents, antibacterial agents, anti-inflammatory agents, immunosuppressants, stents, vasoconstrictors , decongestants, leukotriene or anti-cholinergic inhibitors, anti-histamines, therapeutic compounds, and combinations thereof. In addition, a formulation can contain any one or more compounds known to be effective in inhibiting the gagging reflex of a mammal. A pharmaceutically acceptable aqueous vehicle can be, for example, any liquid solution that is capable of dissolving an antifungal agent and is not toxic to the particular individual receiving the formulation. Examples of pharmaceutically acceptable aqueous vehicles include, without limitation, saline, water and acetic acid. Typically, pharmaceutically acceptable aqueous vehicles are sterile. A solid pharmaceutically acceptable carrier can be formulated in such a way that the antifungal agent is suitable for oral administration. For example, the capsules or tablets may contain an antifungal agent in enteric form. The dose delivered by each capsule or tablet may vary, since an effective amount can be achieved by administering either one or multiple capsules or tablets. Any pharmaceutically acceptable material, known such as cellulose derivatives and gelatin, can be used as a solid pharmaceutically acceptable carrier. In addition, a solid pharmaceutically acceptable carrier can be a solid carrier including, without limitation, starch, sugar, or bentonite. In addition, a pill or tablet formulation of an antifungal agent can follow conventional procedures employing solid carriers, lubricants and the like. The steroids can be any compound containing an annular structure of hydrocyclopentanophenanthrene. Examples of steroids include, without limitation, prednisone, dexamethasone and hydrocortisone. The mucolytic agents can be any compound that liquefies the mucus. Suitable mucolytic agents can include, without limitation, N-acetyl-L-cysteine (MUCOSI L ™; Dey Laboratories) and recombinant human DNase (PULMOZYME®; Genentech, I nc.) . An antibacterial agent can be any compound that is active against bacteria, such as penicillin, erythromycin, neomycin, gentamicin and clindamycin. An anti-inflammatory agent can be any compound that counteracts inflammation, such as ibuprofen and salicylic acid. An immunosuppressant can be any compound that suppresses or interferes with normal immune function, such as cyclosporin. A dilator can be any compound that causes the expansion of an orifice, such as albuterol. A vasoconstrictor can be any compound that tightens or narrows blood vessels, such as phenylephrine hydrochloride (N EO-SYNEPHRI NE®).; Sanofi Pharmaceuticals), cocaine and epinephrine. A decongestant can be any compound that acts to reduce nasal-paranasal congestion or swelling, such as pseudoephedrine hydrochloride, phenylpropanolamine and oxymetazoline. A leukotriene inhibitor can be any compound that inhibits the function or synthesis of a leukotriene, such as Azelastine®. An anti-cholinergic can be any compound that blocks impulses from the parasympathetic nerve, such as ipratropium bromide. An anti-histamine can be any compound that opposes the action of histamine or its release from cells (e.g., barley cells), such as terfenadine and astemizole. A therapeutic compound can be any compound that has a therapeutic effect after its administration. For example, a therapeutic compound can be any compound that blocks or interferes with the interaction of an eosinophilic cell with an immunoglobulin binding to a fungal antigen by carrying out, for example, the interactions of the Fc receptor or type lectin factor receptor. S (for example, galectin-3). Such compounds may include, without limitation, antibodies such as IgE, IgA, IgG, IgM and IgD as well as antibody fragments such as Fab, F (ab ') 2, FcγRI, FcγRI, FcaR, FceRI I u FceRI.

Signaling as an objective of the Mucoadministration in Nasal-paranasal Anatomies. The mucoadministration of an agent to nasal-paranasal anatomies can be any type of administration that places the agent in contact with the nasal-paranasal mucus. Direct mucoadministration to nasal-paranasal anatomies may include, without limitation, nasal irrigations, nasal sprays, nasal inhalations, and nasal packs with, for example, saturated gauze that stipulates that the administered agent makes contact with nasal-paranasal mucus before to cross the epithelium. In addition, injections into the nasal-paranasal cavities using, for example, a needle or catheter tube are considered a direct mucoadministration which stipulates that the administered agent makes contact with the nasal-paranasal mucus after removing the needle or catheter tube and before going through the epithelium. Any device can be used to mucoadminister an agent directly to the nasal-paranasal anatomy including, without limitation, a syringe, bulb, inhaler, can, aerosol can, nebulizer and mask. For example, a 20 mL bulb can be used to irrigate the nasal-paranasal anatomy with a liquid form of a formulation containing an antifungal agent. Such a liquid form of a formulation can be stored at -20 ° C, 0 ° C, or at room temperature. If stored below room temperature, the formulation is typically heated before application to the nasal / paranasal cavities. Indirect mucoadministration to nasal-paranasal anatomies may include, without limitation, oral, intravenous, intradermal, and intraperitoneal administrations that stipulate that the administered agent makes contact with the nasal-paranasal mucus. In addition, any device can be used to mucoadminister an agent indirectly to the nasal-paranasal anatomy including, without limitation, a syringe and regulated release capsule. It is noted that the particular route of administration can influence the effective amount and duration of treatment with antifungal agents as well as the frequency of mucoadministration. For example, orally mucoadministered antifungal agents may require higher concentrations to deliver an effective amount to the nasal-paranasal mucus than direct mucoadministration by nasal irrigation.

Signaling as an Objective of Mucoadministration in the Airways of the Lung A respiratory route is any part of the anatomy of the mammal that air passes through during respiration, including the mouth, nasal passages, trachea, bronchi, and bronchial tubes. A lung airway is any air passage of the lung lined by mucosa including the bronchi and bronchial tubes. The mucoadministration of an agent to the airways of the lung can be any type of administration that places the agent in contact with the mucus of the airway of the lung. Direct mucoadministration to the respiratory tract of the lung may include, without limitation, inhalations, nasal sprays, and nasal irrigations that stipulate that the administered agent makes contact with the mucus of the airway before passing through the epithelium. In addition, lung airway injections using, for example, a needle or catheter tube, are considered a direct mucoadministration that stipulates that the administering agent contacts the mucus of the airway after the needle or tube is removed of catheter and before passing through the epithelium. Any device can be used to mucoadminister an agent directly to the airway of the lung including, without limitation, a syringe, bulb, inhaler, nebulizer, aerosol can, aerosol can, and mask. Indirect mucoadministration to the lung airways may include, without limitation, oral administrations, intravenous, intradermal and intraperitoneal stipulating that the agent administered makes contact with the mucus of the airway of the lung. In addition, any device can be used to mucoadminister an agent indirectly to the lung airway including, without limitation, a syringe and regulated release capsule. It is noted that the particular route of administration can influence the effective amount and duration of treatment with antifungal agents as well as the frequency of mucoadministration. For example, the enteric mucoadministration of an antifungal agent may require a higher concentration to deliver an effective amount to the airway mucus of the lung than direct mucoadministration by inhalation through the mouth or nose. It is understood that direct and indirect mucoadministration to the respiratory tract including the trachea, nasal passages, and mouth can be carried out using the methods and materials described herein for lung airway.

Signaling as an objective of Mucoadministration in the Middle Ear The mucoadministration of an agent to the middle ear can be any type of administration that places the agent in contact with the mucus of the middle ear. Direct mucoadministration to the middle ear may include, without limitation, ear drops and ear fluids, which stipulate that the administered agent makes contact with the mucus of the middle ear before traversing the epithelium. For example, if the tympanic membrane is damaged or otherwise punctured, then a flow to the ears could be considered a direct mucoadministration that stipulates that the administered agent makes contact with the mucus of the middle ear. In addition, injections in the middle ear that use, for example, a needle or myringotomy tube, are considered a direct mucoadministration that stipulates that the administered agent makes contact with middle ear mucus after removing the needle or tube and before traverse the epithelium. Any device can be used to mucoadminister an agent directly to the middle ear including, without limitation, a syringe and bulb. Indirect mucoadministration to the middle ear may include, without limitation, oral, intravenous, intradermal, and intraperitoneal administrations which stipulate that the administered agent makes contact with middle ear mucus. In addition, any device can be used to mucoadminister an agent indirectly to the middle ear including, without limitation, a syringe and regulated release capsule.

It is noted that the particular route of administration can influence the effective amount and duration of treatment with antifungal agents as well as the frequency of mucoadministration. For example, orally mucoadministered antifungal agents may require higher concentrations to deliver an effective amount to the middle ear mucus than direct mucoadministration by injection into the middle ear.

Signaling as an objective of Mucoadministration in the intestines The mucoadministration of an agent to the intestines can be any type of administration that places the agent in contact with the intestinal mucus. Direct mucoadministration to the intestines may include, without limitation, oral administrations and enema, which stipulate that the administered agent makes contact with the intestinal mucus before crossing the epithelium. In addition, injections into the digestive tract using, for example, a needle or catheter tube are considered a direct mucoadministration that stipulates that the administered agent makes contact with intestinal mucus after removing the needle or catheter tube and before passing through the epithelium. Any device can be used to mucoadminister an agent directly to the intestines including, without limitation, a syringe and regulated release capsule. For example, an antifungal agent can be formulated in a regulated release capsule such that the antifungal agent is released after passing, for example, the stomach (eg, pH-regulated release capsules and time-regulated release capsules). ) Indirect mucoadministration to the intestines may include, without limitation, oral, intravenous, intradermal, and intraperitoneal administrations that stipulate that the administered agent makes contact with intestinal mucus. In addition, any device can be used to mucoadminister an agent indirectly to the intestines including, without limitation, a syringe. It is noted that the particular route of administration can influence the effective amount and duration of treatment with antifungal agents as well as the frequency of mucoadministration. For example, mucoadministered antifungal agents intravenously may require higher concentrations to deliver an effective amount to the intestinal mucus than direct mucoadministration by an enema.

Additional Treatments Other treatments may be used in combination with a formulation containing an antifungal agent to help improve the treatment or prevention of mucositis conditions induced by non-aggressive fungi. Such additional treatments may include, without limitation, surgeries and the administration of a second formulation. Surgeries may include, without limitation, the removal of growths of polypoids or other tumors, the physical opening of a cavity, and the insertion of catheter tubes and the like. A second formulation may include, without limitation, antifungal agents, mucolytic agents, antibacterial agents, anti-inflammatory agents, immunosuppressants, dilators, vasoconstrictors, decongestants, steroids, anti-cholinergics, leukotriene inhibitors, antihistamines, therapeutic compounds, and combinations thereof. In addition, this second formulation can be administered to a mammal by any route. For example, oral, intraperitoneal, intradermal, intravenous, subcutaneous, intramuscular, topical, intranasal and intrabronchial administration can be used to deliver a second formulation to a mammal.

Treatment and Prevention of Asthma Asthma can be characterized by a paradoxical narrowing of the bronchi (air passages of the lung), so that breathing becomes difficult. Individuals suffering from asthma may show symptoms such as asthmatic breathing, difficulty breathing (particularly exhaling air), dyspnea, and tightness in the chest. Factors that can exacerbate asthma include rapid changes in temperature or humidity, allergies, upper respiratory infections, exercise, stress and smoking. Individuals suffering from asthma can be identified using any of the methods known in the art. In general, asthma can be diagnosed, without limitation, objectively with a pulmonary function test (increased resistance of the airway) with or without causing the airway (for example, metacholine exchange tests), X-ray of the chest, and auscultation of the chest. Individuals at risk of developing asthma may include, without limitation, those individuals who have had a previous episode of asthma. In addition, elderly individuals; individuals who have cystic fibrosis, chronic rhinosinusitis with or without thick nasal-paranasal polyps, sensitivity to aspirin, or a family with a history of respiratory problems or allergies; and individuals who are exposed to significant levels of allergens (eg, fungal spores, pollen and chemicals) or irritants may be at risk of developing asthma. Chronic asthmatic individuals can be treated by muco-administering directly an antifungal agent to at least a portion of the respiratory tract in an amount, at a frequency, and for an effective duration to reduce or eliminate the symptoms of asthma. Such direct mucoadministrations may be similar to the methods and materials described herein for the treatment and prevention of non-aggressive fungal-induced rhinosinusitis since the nasal-paranasal cavities are respiratory tract. For example, nasal sprays and nasal irrigations can be used to mucoadminister antifungal agents directly to airway mucus. In addition, individuals with chronic asthma can be treated by directly administering an antifungal agent to at least a portion of the lung airways in an amount, at a frequency, and for an effective duration to reduce or eliminate the symptoms of asthma. For example, the aerosol or powder forms of an antifungal agent can be used for direct mucoadministration to mucus from the lung airway by inhalation through the mouth or nose. In addition, individuals at risk of developing chronic asthma can be treated prophylactically by mucocognizing an antifungal agent to at least a portion of the respiratory tract., on a frequency, and for an effective duration to avoid asthma symptoms. Again, such prophylactic treatments may be similar to methods and materials described herein for the prophylactic treatment of non-aggressive fungal-induced rhinosinusitis. The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

EXEM PLOS Example 1 - Collection and analysis of mucus samples The following methods and materials were used to collect and analyze mucus from 202 patients. Before collecting mucus, each patient was instructed to inhale and then lower his chin toward his chest to minimize or prevent the flow of a collection solution out of the nasal-paranasal air passages through normal drainage in the back of the throat. The collection solution was either a sterile saline solution or sterile water. In addition, each patient is positioned in such a way that the flow of the collection fluid out of the nasal air passages would be reduced or avoided. Some patients received an administration of a vasoconstrictor, such as phenylephrine hydrochloride (1-2 drops per nostril) or cocaine (powder or topical liquid, less than four mg per kg of body weight). Some patients received a spray of approximately three mL of a 20% solution of N-acetyl-L-cysteine. Patients who receive both are first given the vasoconstrictor and then approximately two minutes later they are given N-acetyl-L-cysteine. Once the patient was prepared, a collection container was placed under the nostril or nostrils, from which the mucus sample was collected. An injection device, such as a syringe-like device having a blunt-covered needle or tube assembly, is then partially placed in one of the patient's nostrils or paranasal anatomy, such that the collection solution could be forced through the nasal-paranasal anatomy of the patient. In some cases, about five mL to about 30 mL of a collection solution was then injected into a nostril for a period of about 0.5 and five seconds. In most cases, approximately ten mL to approximately 20 mL of a collection solution was injected into a nostril for a period of time between about 0.5 and three seconds. In general, each patient forcibly expelled or discharged the collection solution either simultaneously as it was injected or after detecting its entry into the nostril. This forced discharge of the injected collection solution contributed significantly to the loosening of the mucus within the patient's nostril and paranasal passages. Again, special care was taken to reduce or avoid the loss of the volume of the collection solution. Once expelled, the collection solution containing the mucus from the patient's nostril was collected in the collection container placed under the nostril. After the nasal-paranasal mucus was collected, the mucus was cultured using one of the following two methods. In the first method, one mL of a 20% solution of N-acetyl-L-cysteine was added to approximately ten μL of the recovered collection solution containing mucus. This mixture was then stirred for 30 seconds and incubated for 1 5 minutes at room temperature. After incubation, the mixture was centrifuged in a 50 mL tube for five minutes at 4800 rpm. After separation, the supernatant was discarded and the remaining mucus was agitated for 30 seconds. An aliquot of 0.5 mL of the isolated mucus was then added to each culture plate, an IMA plate containing chloramphenicol and an IMA plate containing ciprofloxacin. The plates were then incubated at 30 ° C and read as a routine fungal culture. The growth of the individual isolates was observed from about two days to about 35 days. In a second method, ten mL of DTT was diluted with 90 mL of sterile distilled water. An equal volume of this freshly diluted DTT solution was added to the recovered collection solution containing mucus and the mixture was stirred for 30 seconds. The mixture was then incubated for 15 minutes at room temperature. After the incubation, the mixture was centrifuged in a tube of 50 μl for ten minutes at 3000 x g. After separation, the supernatant was discarded and the remaining mucus was agitated for 30 seconds. An aliquot of 0.5 mL of the isolated mucus was then added to each culture plate, an IMA plate containing chloramphenicol and a Bay agar plate containing ciprofloxacin. The plates were then incubated at 30 ° C and read as a routine fungal culture. The growth of isolates was observed from about two days to about 35 days. Once the fungal growth was observed, the organisms were identified using standard mycology techniques that included visual, histological and immunological techniques. The fungal genus identified and the species included many fungal organism previously isolated from AFS patients, such as Absidia, Aspergillus flavus, Aspergillus fumigatus, Aspergillus glaucus, Aspergillus nidulans, Aspergillus versicolor, Alternaria, Basidiobolus, Bipolaris, Candida albicans, Candida lypolytica, Candida parapsilosis, Cladosporium, Conidiobolus, Cunninahamella, Curvularia, Dreschlera, Exserohilum, Fusarium, Malbranchia, Paecilomvces, Penicillium, Pseudallescheria, Rhizopus, Schizophylum and Sporothrix. In addition, fungal organisms were identified that were not previously identified in mucus samples from patients diagnosed as positive for AFS, such as Acremonium, Arachniotus citrinus, Aurobasidioum, Beauveria, Chaetomium, Chryosporium, Epicoccum, Exophilia jeanselmei, Geotrichum, Oidiodendron, Phoma, Pithomyces. , Rhinocladiella, Rhodoturula, Sagrahamala, Scolebasidium, Scopulariopsis, Ustilago, Trichoderma and Zygomycete. To determine the optimal temperature for culturing fungal organisms that cause mucositis induced by non-aggressive fungi, samples of liquefied mucus collected from two patients were grown on IMA plates containing either chloramphenicol or ciprofloxacin. Two culture cuvettes (one containing chloramphenicol and one containing ciprofloxacin) for each sample were then incubated at 25 ° C, 28 ° C, 30 ° C, 32 ° C, 33 ° C, 35 ° C and 37 ° C. Each plate was visually graded for fungal growth and developed every other day for a period of time from about two days to about 35 days from the time of cultivation. The scores for each temperature were averaged, thus providing an estimate of the optimum temperature for spore germination and the subsequent growth of fungal organisms. The results indicated that the optimum temperature for fungal growth varied depending on the specific or isolated fungal species. In general, it was found that 30 ° C support growth for a large number of fungal and isolated species. The following procedure was used to determine effective antifungal agents as well as effective concentrations of antifungal agents in such a way that the fungal organisms isolated from patients can be prevented from growing or dying. Seventeen fungal isolates were collected from eight patients with rhinosinusitis and tested for susceptibility against amphotericin B, acetoconazole and itraconazole. Each antifungal agent was tested on these fungal isolates using the fluid fluid macro dilution technique according to the National Committee on Clinical Laboratory Standards (NCCLS) procedure. A 48-hour MIC reading was recorded and interpreted using the NCCLS lines to assess each culture as susceptible, intermediate or resistant to the antifungal agent in the concentrations tested. The results of this procedure provided an estimate of the efficacy of antifungal agents against specific fungal isolates in vitro. In general, it was found that MIC values for these antifungal agents for each isolate vary widely between 0.03 and 100 μg / μL (Table I).

Table 1 . Fungal organisms isolated from 64 of 66 patients with rhinosinusitis studied including 17 MIC values of amphotericin B, acetoconazole for selected isolates of eight patients with rhinosinusitis Organism MIC number of MIC of Fungal Species / Isolated Amphotericin B Acetoconazole Itraconazole (μg / mL ) (μg / mL) (μg / mL) Acremoni? M Alternate 40 0.2 1 .56 neg * 0.8 3.1 3 neg > 5 12.5 neg Arachniotus 2 citrinus Aspergillus 21 Aurobasidium 2 Candida 1 3 0.2 50 0.03 0.4 1 .56 neg 0.1 0.39 neg 0.2 > 100 neg Cladosporium 21 3 1 .56 neg 0.4 0.05 neg 0.1 0.05 0.125 Chryosporium 1 Epicoccum 6 Exophilium 2 Jeanselmei Continuous Table Fusarium 1 8 > 5 > 1 00 37 ° C ** 2 100 1 > 5 1 2.5 > 1 6 Geotrichum 5 0.1 0.05 37 ° C Mucor 2 Oididendron 1 Paecilomyces 1 lilacinus Papularia 1 Penicillium 30 0.4 3.1 3 0.5 1 1 .56 0.25 Phoma 1 Pithomyces 2 Rhodoturula 1 Scolebasidium 1 Trichoderma 3 50 37 ° C Ustilago 2 (unidentified, 2 monila, 3 dermatiaceous *, neg means the organism that did not grow in the test medium (PEG 400; **, 37 ° C means the organism that did not grow at 37 ° C.) The following study conducted to determine the frequency of rhinosinusitis conditions that have a non-aggressive fungal etiology.For this study the following criteria were used to determine if a patient does not have rhinosinusitis induced by non-aggressive fungi: (1) presence of observable disease within the nasal-paranasal anatomy, (2) presence of allergic mucus, and (3) presence of fungal organisms within nasal-paranasal mucus.) Each patient had a CT scan using standard procedures to determine the presence of observable disease within their paranasal anatomy. To determine the presence of allergic mucus, a surgical specimen was collected from each patient and evaluated histologically. He took special care to collect each surgical specimen to ensure that mucus samples were not washed away. To determine the presence of fungal organisms within the nasal-paranasal mucus, the methods and materials were used to collect and culture fungal organisms of a patient's mucus described herein. Seventy-three patients with rhinosinusitis were entered into the study. The ages of these patients varied from 1 3 to 73 years, averaging 50.1 years of age. Thirty-nine of the 73 patients were women and 34 were men. The number of previous surgeries in relation to rhinosinusitis for each patient ranged from 0 to 25, with an average of 3.41 surgeries per patient. Seventy of the 73 patients have previously experienced a recurrence of polyposis and rhinosinusitis. Seven patients were subsequently excluded from the study due to the lack of an acceptable mucus specimen. Of the remaining 66 patients, 66 (1 00%) were diagnosed as positive CT-scan, 62 (94%) were diagnosed positive for the presence of allergic mucus, and 64% (97%) had positive fungal cultures. Taken together, 60 of 66 (91%) cases of rhinosinusitis had all three criteria. In other words, 91 percent of the 66 patients with rhinosinusitis evaluated had, based on the previous criteria, rhinosinusitis induced by non-aggressive fungi. This proportion of 91 percent represents a dramatic increase in the number of rhinosinusitis cases that include non-aggressive fungal organisms. For example, numerous medical research articles report that approximately three to eight percent of cases of chronic rhinosinusitis requiring surgery are cases of AFS, a rhinosinusitis condition that has a non-aggressive fungal etiology. In this way, the results presented here indicate that the involvement of non-aggressive fungal organisms in rhinosinusitis conditions is much more frequent than previously appreciated. A total of 25 different fungal species were identified from the mucosal specimens of these patients with non-aggressive fungal-induced rhinosinusitis. Sixteen organisms never before described as present coinciding with AFS, were detected from the 64 mucus samples that showed fungal growth. The range was from approximately one to seven fungal organisms per patient with an average of approximately 2.9 fungal species per patient. Sixty-three percent of the crops included Alternaria, 47 percent included Penicillium, 33 percent included Cladosporium, 33 percent included Aspergillus, 28 percent included Fusarium, and 20 percent included Candida. In a separate study, twelve control individuals (ie, people who do not have chronic rhinosinusitis) had mucus samples collected and analyzed as described herein. The twelve (100%) had positive fungal cultures. Specifically, a total of seven different fungal organisms were grown with an average of approximately 2.25 different fungal organisms per person and a range of one to four. Fifty percent of the crops included Cladosporium, 42 percent included Alternaria, 33 percent included Geotrichum, 33 percent included Aspergillus, 25 percent included Penicillium, 8 percent included Acremonium, and 8 percent included Candida. These results indicate that fungal organisms live in the nasal-paranasal mucus of most, if not all, humans. Example 2 - Treatment and prevention of rhinosinusitis induced by non-aggressive fungi One hundred and thirty two patients with consecutive rhinosinusitis were enrolled in a study to evaluate the use of an antifungal agent to treat non-aggressive fungal-induced rhinosinusitis. After the diagnostic analysis, 1 25 of the 1 32 patients (95%) had the following criteria: (1) presence of observable disease within the nasal-paranasal anatomy as evidenced by a CT scan, (2) presence of mucus allergic as evidenced by histological evaluation of a surgical specimen; and (3) presence of fungal organisms within the nasal-paranasal mucus as evidenced by the ability to culture fungal organisms from a mucus sample. The 1 25 patients with non-aggressive fungal-induced rhinosinusitis initiated an antifungal treatment of approximately 20 mL of amphotericin B solution per nostril, two to four times a day for at least three months. The concentration of the amphotericin B solution was approximately 100 mg per liter of saline or water. A 20 mL bulb was used by the patient to mucoadminister the amphotericin B solution in the patient's nasal-paranasal anatomy. The data was compiled for 53 of the patients who returned for their three-month control analysis. In addition to the patient interview, the CT scan analysis, the visual examination and the fungal culture analysis, two types of evaluation were used to qualify the success of the treatment: an endoscopic evaluation and an evaluation of the patient's symptoms. These evaluations were scored as follows: Endoscopic Evaluation Stage 0: no evidence of disease Stage 1: changes of polypoid / polyps observed only by endoscopy Stage 2: polyps in the middle meatus Stage 3: polyps that fill the nasal cavity Patient's Symptom Assessment 'Stage -2: very bad / much worse Stage -1: bad / worse Stage 0: baseline / no change Stage 1: good / improved Stage 2: very good / free of symptoms The endoscopic evaluation revealed that 33 of the 53 patients passed from stage 2 or 3 to stage 0 after three months. Six of these 33 cases that show no evidence of disease were confirmed by CT scans. For example, a patient who did not have recent surgeries and who did not take steroids was diagnosed with bilateral rhinosinusitis since a CT scan revealed bilateral involvement (Figure 1). The patient was then treated with 20 mL of a solution of amphotericin B (100 mg / L) per nostril twice a day. After four months of continuous antifungal treatment, a CT scan was taken to show the complete disappearance of opacity and characteristic symptoms of rhinosinusitis (Figure 2). Eleven of the 53 patients went from the endoscopy evaluation stage 2 or 3 to stage 1 after three months. The other nine patients did not respond to the treatment. Five of the patients who did not respond had previously collected mucus samples that are available for examination. Analysis of these five available samples revealed that the five patients had fungal organisms within their mucus that were resistant to amphotericin B, the antifungal agent used for the treatment. The evaluation of the patient's symptoms revealed that 44 of the 53 patients gave themselves a stage 2, three of the 53 gave themselves a stage 1, and six of the 53 gave themselves a stage 0 after the treatment. The nine patients who gave themselves a stage 1 or 0 were the same nine patients who had no response as measured by endoscopic evaluation, five of which are shown to contain fungal organisms resistant to amphotericin B. In a review Subsequent to another group of patients, several unresponsive patients were found, which did not contain fungal organisms resistant to amphotericin B. In addition, several patients had mucus samples collected and analyzed before and after antifungal treatment. The comparison of the results of the evaluation of the mucus samples before and after the fungal treatment revealed that the number of different fungal species in those patients was markedly reduced after the antifungal treatments, as determined by the culture techniques of fungal organisms. . In this way, patients with rhinosinusitis were asymptomatic and contained less fungi in their mucus after treatment with an antifungal agent. In a single separate study, a patient with rhinosinusitis was diagnosed in the left paranasal cavities, since a CT scan showed a disease characteristic of rhinosinusitis-related opacification in the left paranasal cavities. A RAST analysis for Alternaria showed 6.23 kilo units per liter (KU / L) and bilateral fungal cultures confirmed the growth of Alternaria in each nostril. Only the left nasal-paranasal side, however, received surgery as well as intra-operative and post-operative treatment with approximately 20 mL of an amphotericin solution (1000 mg / L) two to four times a day. At each post-operative visit, the patient's left paranasal cavities were free of disease. A RAST reading taken eight to ten weeks after the disappearance of rhinosinusitis symptoms in the left cavities of the patient, however, was 7.1 6 KU / L. This represents an increase over the first RAST reading. In six months after the operation, the patient was diagnosed with rhinosinusitis in the right paranasal cavities based on a CT scan and a RAST reading of 10.0 KU / L for Alternaria. After surgery in the right paranasal cavities of the patient and antifungal treatment on both sides used approximately 20 ml of a solution of amphotericin B (1 00 mg / L) per nostril two to four times a day for approximately seven weeks, the patient remained free of symptoms and had a RAST reading of 4.47 KU / L. Six months after this last surgery, the patient remained free of symptoms and free of disease, as evidenced by a CT scan. Taken together, these results indicate that proper irrigation with an antifungal agent suitably administered on one side only resulted in the prevention of inflammatory symptoms on that side. In addition, the fungal load previously detected on the untreated side initially (right side) was sufficient to eventually cause the presentation of visual or palpable rhinosinusitis symptoms on the untreated side initially (right side). In addition, the fungal organisms present on the untreated side initially (right side) induced higher IgE substance concentrations, as shown by the IgE readings of the RAST analyzes, independent of the recurrent reduction of fungal organisms by the antifungal treatment. applied to the left side. In this case, a reduction of the IgE readings of the RAST analyzes was only observed after irrigating both sides with an antifungal agent. In this way, the reduction of IgE and the prevention of the symptoms of the disease coincided with the treatment of both sides with an antifungal agent. To further evaluate the use of an antifungal agent to treat non-aggressive fungal-induced rhinosinusitis, patient information was collected for each patient returning to the physician's office for a period of one week. Only the previously observed patients who were ordered to use nasal irrigations of antifungal amphotericin B were introduced in this study. Over a period of one week, twenty patients returned to the doctor's office (Table I I). The average age of the patients who returned was 47 years (range 16-74 years). The patients used irrigations of amphotericin B for an average duration of approximately six months (range 1-16 months). Some patients had nasal surgery as recently as one month, while others never had such surgery. In addition, some patients used systemic and topical steroid therapy. In addition, some patients used an antibiotic nasal irrigation in addition to antifungal irrigations. The antibacterial solution contained 80 mg of gentamicin per L of saline (Wilson solution). Some patients mixed the antibacterial solution with the antifungal solution and then carried out nasal irrigations while others used each solution separately in a sequential manner. Some patients also had other diseases including asthma (1 5 of the 20 patients) and colitis (2 of the 20 patients). In the endoscopic evaluation, the majority of the patients' had an observable improvement in their condition of rinosinusitis induced by non-aggressive fungi. These observable improvements were correlated with the symptom improvement scores given for each patient. One patient stopped the nasal irrigations of amphotericin B after two months. Eight months later that patient showed recurrent symptoms of the non-aggressive fungal-induced rhinosinusitis condition. Two other patients changed from a solution of amphotericin B (duration: 3 months, frequency: twice a day) to a solution of itraconazole (duration: 1 month, frequency: twice a day). A better condition was reported after using the itraconazole solution for only several days. Taken together, these results indicate that antifungal agents can be used effectively to treat non-aggressive fungal-induced rhinosinusitis. Table I I. Patient data collected over a period of one week B, before the antifungal treatment; A, after antifungal treatment 1 Also irrigated with Wilson's solution (80 mg gentamicin / L saline) twice daily Also irrigated intermittently with Wilson's solution Nasal irrigations were stopped 8 months earlier and the disease has recurred Also irrigated with Wilson's solution (80 mg gentamicin / L saline) once a day Feeling better seven days after switching from nasal irritations of amphotericin B (duration: 3 months, frequency: twice a day) to itraconazole (duration: 1 month, frequency: twice a day) Switched to itraconazole irrigations (duration: 1 month, frequency: twice a day) after 3 months of amphotericin B was also irrigated with Wilson's solution (duration: 1 year) Received Kenalog Medium Valuation Dose Package of 40 IM 1 month earlier Received a Kenalog Charge 6 months earlier Received Prednisone for 1 week Received a systemic steroid treatment micos for 3 years stopped taking theophylline and tilada since they began antifungal irrigations Example 3 - Treatment and prevention of non-aggressive fungal-induced rhinosinusitis in patients without previous nasal surgery The following three patients of non-aggressive fungal-induced rhinosinusitis did not have a previous nasal surgery. A 61-year-old male was diagnosed with non-aggressive fungal-induced rhinosinusitis and was instructed to perform amphotericin B irrigations twice a day. Before starting the treatment, the endoscopic evaluation revealed polyps filling his nasal cavity (endoscopic score 3) and the patient gave himself a symptom score of -1. After using the irrigations of amphotericin B for fourteen months, the endoscopic evaluation revealed no evidence of disease (endoscopic score 0) and the patient gave himself a symptom score of +2. A 64-year-old woman with rhinosinusitis induced by non-aggressive fungi was diagnosed and was instructed to perform amphotericin B irrigations twice a day, which was then increased to four times a day. Before starting treatment, the endoscopic evaluation revealed evidence of polypoid changes (endoscopic score 1) and the patient gave herself a symptom score of -1. After using the irrigations of amphotericin B for sixteen months, the endoscopic evaluation revealed no evidence of disease (endoscopic score 0) and the patient gave herself a symptom score of +2.

A 54-year-old male with rinosinusitis induced by non-aggressive fungi was diagnosed and was instructed to perform irrigations of amphotericin B twice a day. This patient had injections of intramuscular steroids every 3 to 8 months, the last discharge being administered approximately seven months before starting the irrigations of amphotericin B. Before initiating the antifungal treatment, the endoscopic evaluation did not reveal any evidence of disease (endoscopic score 0 ) but the patient gave himself a symptom score of -1. After using the irrigations of amphotericin B for four months, the endoscopic evaluation did not reveal again any evidence of disease (endoscopic score 0) and the patient gave himself a symptom score of +1. Example 4 - Depletion of eosinophilic cells by the use of antifungal treatment A 67-year-old woman was diagnosed with non-aggressive fungal-induced rhinosinusitis and was instructed to perform irrigations of amphotericin B twice a day. After nine months of irrigations of amphotericin B, the patient underwent cavity surgery for further improvement. During the surgery, mucosal biopsies were collected and the eosinophil count was compared with that obtained from the biopsies collected from the patient during a surgery prior to the antifungal treatment. The eosinophil count in all the mucosal biopsies of all the cavities, except the frontal one, decreased after the antifungal treatment (<;5%). The eosinophil count in the biopsy of the frontal cavity was 1 0%. In addition, the allergic mucus appeared to be present in the frontal cavity, presumably because the amphotericin B irrigations did not reach the frontal cavity due to the obstruction of the frontal cavity. Therefore, previously observed hypereosinophilia had decreased to normal in all cavity areas treated. Example 5 - Treatment and Prevention of Chronic Asthma Symptoms Thirty-seven of the 53 patients in the study described in Example 2 had previously been diagnosed with chronic asthma. After three months of antifungal treatment, 28 of the 37 asthmatic patients reported an improvement or complete elimination of asthma symptoms, after being asked. Four of these 28 were analyzed by the use of a pulmonary function test after antifungal treatment as they had undergone a similar examination before antifungal treatment. The comparison of the results before and after the antifungal treatment confirmed that the four patients of this asthma had improved their lung function. In addition, 26 of the 28 patients who no longer exhibited asthma symptoms stopped taking their asthma medication. Twenty-three of these 26 patients were taking systemic steroids for asthma before antifungal treatment, but none have taken steroids subsequently after initiating antifungal treatment. In a separate study, sputum samples were collected from the lung of seven asthma patients. The analysis of the culture of these samples revealed the presence of fungal organisms in each sample. Specifically, Candida albicans were grown, Penicillium, Fusarium, Scopulariopsis, Cryptococcus, Cladosporium, Aspergillus, Aspergillus fumigatus, Aspergillus nidulans and yeast. The number of different fungal species cultured from each sputum sample ranged from one to five. Example 6 - Formulations of Itraconazole The formulations of itraconazole were prepared by dissolving itraconazole in polyethylene glycol (PEG) to form a base solution of itraconazole. Itraconazole was obtained from 100 mg itraconazole capsules (Janssen Pharmaceutica, I nc.). Typically, PEG 400 was used to dissolve itraconazole. Once dissolved, the base solution was filtered to remove any insoluble material. Then, the base solution was prepared to be used by dilution with sterile water. Specifically, twenty 1000 mg capsules of itraconazole were opened and the spheres containing itraconazole were placed in a graduated cylinder. One liter of hot PEG 400 (70 ° C) was added to the graduated cylinder containing itraconazole. The mixture was then placed on a hot stir plate and kept at 70 ° C for 30 minutes. After 30 minutes, the hot suspension was filtered through a urine stone filter in a glass container and allowed to cool to room temperature. Once cooled, 100 mL of the filtered solution was placed in an empty plastic bottle. Then, 900 mL of sterile water was added and the solution mixed. Once mixed, a drop of flavoring (peppermint oil) was added. This procedure typically resulted in a solution containing approximately 98.8 μg to approximately 11.1 μg itraconazole per mL. The following concentrations of itraconazole were determined for each solution indicated by HPLC (Table 11). Table l l l. Concentrations of itraconazole in the solution A formulation of itraconazole containing a steroid was also prepared. Specifically, the content of two 200 μg PULMICORT inhalers (approximately 91 μg of budesonide in total) was added to a stock solution of itraconazole PEG-400 at 70 ° C for about 15 minutes. The budesonide was added approximately 5 minutes after the itraconazole powder was dissolved in the PEG-400. After cooling to room temperature, some precipitation occurred. This insoluble material was removed by filtering the solution through thin filter paper under vacuum. The filter was dried and the captured precipitate (36-40 μg) was measured. In this way, approximately 54 to 50 μg of steroids remained in the solution / fine suspension. Example 7 - Treatment and prevention of non-aggressive fungal-induced rhinosinusitis by the use of itraconazole A three patients of non-aggressive fungal-induced rhinosinusitis (a 33-year-old man, a 70-year-old woman and a 57-year-old woman of age) were instructed to perform nasal irrigations with an itraconazole solution. The tetraconazole solution contained approximately 1 00 mg of itraconazole per L solution (1.0% PEG 400 in sterile water) and was prepared as described herein. Two patients were instructed to perform itraconazole irrigations because they did not respond to irrigations of amphotericin B: Each patient reported a marked improvement in symptoms at two weeks of onset of itraconazole irrigations (symptom scores: -1 to +2 and -1 to + 1). Sixteen days after initiating itraconazole irrigations, one of these two patients exhibited an improvement, as revealed by the endoscopic analysis (endoscopic score: from 1 to 0 for the right side and from 1 to 1 for the left side). In addition, this patient indicated that the symptoms of his asthma had dramatically improved and he reduced his asthma medication (Flovent and Servent) from twice a day to once a day. The third patient was instructed to perform itraconazole irrigations due to a local adverse reaction to amphotericin B (burning sensation). After treatment with itraconazole, that patient reported an improvement in symptoms (symptom score: from -1 to 0). In addition, that patient has no adverse local reaction or problems with traconazole irrigations. Example 8 - Treatment and prevention of chronic asthma symptoms by the use of itraconazole A 32-year-old white male patient with no history or symptoms of chronic rhinosinusitis exhibited significant symptoms of asthma despite medical therapy with systemic and topical steroids and use frequent of a bronchodilator. Sputum and nasal-paranasal mucus samples were collected and analyzed. The analysis of the culture revealed the presence of Candida albicans in the sputum and Penicillium, Geotrichum, Alternaria and Cladosporium species in the nasal-paranasal mucus. The patient was initiated on an antifungal treatment of approximately 20 μL of an itraconazole solution through the nasal cavity, twice a day. The concentration of the itraconazole solution was approximately 1000 mg per liter. After a few weeks, the patient took his last course of systemic steroids. Approximately two months after stopping systemic steroids, the patient also stopped the use of topical steroids as well as the bronchodilator. Since he stopped all steroid therapy, the patient's symptoms improved dramatically. Specifically, the patient did not report episodes of respiratory failure or asthmatic breathing during the period of four to five months since all steroid therapy was stopped. The objective analysis also revealed a dramatic improvement. In a study conducted before antifungal treatment, the patient exhibited abnormal lung function. After seven months of continuous antifungal irrigations, as described in the last four to five months before getting rid of steroid therapy, the patient exhibited improved lung function. Specifically, the forced vital capacity (FVC) of the lung improved from 3.99 liters before treatment to 4.80 liters after treatment, an increase of 20.30%; the forced expiration volume in 1 second (FEV1), a marker for the lower respiratory resistance degree, improved from 3.34 liters before treatment to 4.27 liters after treatment, an increase of 27.84%; the maximum forced expiration flow (FEFmax) improved from 9.1 liters per second before treatment to 1.6 liters per second after treatment, an increase of 38.46%; and maximum voluntary ventilation (MVV) improved from 1 1 9 liters per minute before treatment to 1 56 liters per minute after treatment, an improvement of 31.90%.

In summary, the objective markers revealed an improvement in pulmonary function between 20.3% and 38.46%, despite the absence of any other medical therapy other than nasal irrigation during the previous four to five months. These results indicated that the symptoms of chronic asthma can be treated and prevented by mucoadministration of antifungal agents in the respiratory tract. Sometimes, after this patient's asthma symptoms improved, the patient stopped using itraconazole irrigations. After four to six weeks of not using the itraconazole irrigations, the asthma symptoms returned to the patient. At that time, the patient inhaled steroids only to control the symptoms of asthma. After approximately four to six weeks, the patient switched from using a steroid inhaler to using an itraconazole powder inhaler. Specifically, the patient was instructed to inhale approximately 400 μg of pure itraconazole per day by the use of a powder inhaler. The itraconazole powder was an authentic "AS" substance (Janssen Pharmaceutica, Inc.). The inhaler was a TURBOHALER® of 200 μg of Pulmicort, manufactured by ASTRA Pharmaceuticals. This inhaled product was designed for measured doses of budesonide inhalation powder, but was adapted as an administration of itraconazole. The patient had been asymptomatic for four weeks and continues to use the itraconazole powder treatment. Initially, the patient also had at least one nasal polyp. That polyp was markedly reduced in viability by the second week of treatment. Another asthma patient was also instructed to inhale approximately 200 μg of pure itraconazole per day by the use of a TU RBOHALER® of 200 μg Pulmicort. After approximately two weeks, the patient's condition improved markedly. The patient remains in treatment. An asthma patient who has rhinosinusitis induced by non-aggressive fungi was treated with itraconazole by using a nebulizer. Specifically, approximately two mL of an itraconazole solution (approximately 1.0 mg of itraconazole per mL of PEG-400) per day was applied in a nebulizer. The nebulizer was a PULMO-MATE brand, pressurized by air, manufactured by DeVilIbis. After approximately two weeks, the patient demonstrated an improvement in both asthma conditions and non-aggressive fungal-induced rhinosinusitis, as evidenced by a total improvement in symptom scores. Improvements were also observed in one-week increments. Example 9 - Identification of otitis media induced by non-aggressive fungi Mucus samples were collected from the middle ear by using a suction trap of three patients diagnosed with chronic otitis media. Analysis of the culture of the samples revealed the presence of fungal organisms. Specifically, the mucus sample from the first patient was positive for the Candida and Trichophyton rubrum species, the mucus sample for the second patient was positive for the Penicillium species and the mucus sample from the third patient was positive for the Aspergillus species. In addition, microscopic examination revealed a large number of degenerative eosinophilic cells within each mucus sample. Therefore, these results indicate that chronic otitis media is most likely caused by non-aggressive fungal organisms. In addition, it appears that chronic otitis media is a non-aggressive fungal-induced mucositis that can be treated and prevented through the use of antifungal treatment and prevention approaches. described here. Example 1 0 - Treatment of non-aggressive fungal-induced intestinal mucositis Three out of five consecutive patients with chronic rhinosinusitis reported having a history of colitis. Two patients were initiated on an antifungal treatment of an itraconazole capsule (provided by Janssen Pharmaceutica, I nc.) Per day. The capsule contained 1 00 mg of itraconazole. Each patient was instructed to take the capsule before going to sleep, a minimum of two hours after his last meal and without any cola drink. Foods and cola drinks increase the absorption of the drug. When taken as described, approximately 50 percent of itraconazole should remain in the bowel passage for the treatment of symptoms of intestinal mucositis induced by non-aggressive fungi.

OTHER MODALITIES It should be understood that although the invention has been described in conjunction with the detailed description thereof, the foregoing description attempts to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.

Claims (100)

1. REVIVAL DICTION IS 1. A method for the treatment of a mammal that has rhinosinusitis induced by non-aggressive fungi, characterized in that it comprises the mucoadministration of at least a portion of the nasal-paranasal anatomy of said mammal, of a formulation in an amount, at a frequency and for an effective duration to reduce or eliminate said rhinosinusitis, said formulation comprising an antifungal agent. The method according to claim 1, characterized in that said mammal is a human. 3. The method according to claim 1, characterized in that said mammal is non-atopic. 4. The method according to claim 1, characterized in that said mammal is immunocompetent. The method according to claim 1, characterized in that said rinosinusitis induced by non-aggressive fungi is characterized by the formation of polyps or polypoid changes. 6. The method according to claim 1, characterized in that said rinosinusitis induced by non-aggressive fungi is chronic. The method according to claim 1, characterized in that said formulation is in a solid, liquid or aerosol form. The method according to claim 1, characterized in that said formulation is in a form selected from the group consisting of a powder, crystalline substance, gel, paste, ointment, balsam, cream, solution, suspension, partial liquid, aerosol , nebulae, steam, atomized vapor, aerosol and tincture. The method according to claim 1, characterized in that said mucoadministration is a direct mucoadministration. The method according to claim 9, characterized in that said direct mucoadministration comprises the irrigation of said nasal-paranasal anatomy with a liquid form of said formulation. eleven . The method according to claim 9, characterized in that said direct mucoadministration comprises the application in an aerosol form of said formulation to said nasal-paranasal anatomy. The method according to claim 9, characterized in that said direct mucoadministration comprises the application in a powder form of said formulation to said nasal-paranasal anatomy. 3. The method according to claim 1, characterized in that said antifungal agent comprises a macrolide. The method according to claim 1, characterized in that said antifungal agent comprises an azole. The method according to claim 1, characterized in that said antifungal agent interpolates the components of the fungal cell wall. The method according to claim 1, characterized in that said antifungal agent comprises a sterol inhibitor. 17. The method according to claim 1, characterized in that said antifungal agent comprises an antifungal agent selected from the group consisting of amphotericin B, acetoconazole, itraconazole, saperconazole, voriconazole, flucytosine, miconazole, fluconazole, griseofulvin, clotrimazole, econazole, terconazole, butoconazole, oxiconazole, sulconazole, cyclopirox olamine, haloprogin, tolnaftate, naftifine, terbinafine hydrochloride, morpholines, nystatin, natamycin, butenafine, undecylenic acid, Whitefield ointment, propionic acid and caprylic acid. The method according to claim 1 7, characterized in that said antifungal agent comprises an antifungal agent selected from the group consisting of amphotericin B, acetoconazole, itraconazole, saperconazole, and voriconazole. 1 9, The method according to claim 1, characterized in that said antifungal agent comprises amphotericin B. 20. The method according to claim 1, characterized in that said antifungal agent comprises itraconazole. twenty-one . The method according to claim 1, characterized in that said formulation comprises a pharmaceutically acceptable aqueous vehicle. 22. The method according to claim 21, characterized in that said formulation comprises from about 0.01 mg to about 1000 mg of said antifungal agent per liter. 23. The method according to claim 22, characterized in that said effective amount comprises from about 0.01 mL to about 1 L of said formulation per nostril of said mammal. The method according to claim 22, characterized in that said effective amount comprises from about 5 mL to about 100 mL of said formulation by said nostril of said mammal. 25. The method according to claim 22, characterized in that said effective amount comprises approximately 20 mL of said formulation per nostril of said mammal. 26. The method according to claim 21, characterized in that said formulation comprises from about 1 mg to about 500 mg of said antifungal agent per liter. 27. The method according to claim 21, characterized in that said formulation comprises approximately 1000 mg of said antifungal agent per liter. The method according to claim 1, characterized in that said formulation comprises a plurality of antifungal agents. 29. The method according to claim 1, characterized in that said effective amount of said formulation comprises from about 0.01 ng to about 1000 mg of said antifungal agent per kg of body weight of said mammal. 30. The method according to claim 1, characterized in that said effective amount of said formulation comprises from about 1 ng to about 500 mg of said antifungal agent per kg of body weight of said mammal. 31 The method according to claim 1, characterized in that said effective amount of said formulation remains constant during said effective duration. 32. The method according to claim 1, characterized in that said effective frequency of said mucoadministration is from about four times a day to about once a week. The method according to claim 1, characterized in that said effective frequency of said mucoadministration is from approximately twice a day to approximately once a week. 34. The method according to claim 1, characterized in that said effective frequency of said mucoadministration is more frequent than once a day. 35. The method according to claim 1, characterized in that said effective frequency of said mucoadministration is more frequent than once a week. 36. The method according to claim 1, characterized in that said effective duration is greater than about 7 days. 37. The method according to claim 1, characterized in that said effective duration is greater than about 14 days. 38. The method according to claim 1, characterized in that said effective duration is greater than about 30 days. 39. The method according to claim 1, characterized in that said effective duration is greater than about 60 days. 40. The method according to claim 1, characterized in that said effective duration is greater than 90 days. 41 The method according to claim 1, characterized in that said formulation comprises a compound selected from the group consisting of pharmaceutically acceptable aqueous vehicles, pharmaceutically acceptable solid carriers, mucolytic agents, antibacterial agents, anti-inflammatory agents, immunosuppressants, dilators, vasoconstrictors, steroids and therapeutic compounds. 42. The method according to claim 1, characterized in that said method comprises the administration to said mammal of a second formulation. 43. The method according to claim 42, characterized in that said second formulation comprises a compound selected from the group consisting of antifungal agents, pharmaceutically acceptable aqueous vehicles, pharmaceutically acceptable solid carriers, mucolytic agents, antibacterial agents, anti-inflammatory agents, immunosuppressants. , dilators, vasoconstrictors, steroids and therapeutic compounds. 44. The method according to claim 1, characterized in that said method comprises, after said mucoadministration, the prophylactic mucoadministration to said mammal of a prophylactic formulation in an amount, at a frequency, and for an effective duration to prevent said induced rhinosinusitis. by non-aggressive fungi, said prophylactic formulation comprising an antifungal agent. 45. The method according to claim 44, characterized in that said prophylactic mucoadministration comprises direct mucoadministration. 46. A method for prophylactically treating a mammal at risk of developing non-aggressive fungal-induced rhinosinusitis, comprising the mucoadministration to said mammal of a formulation in an amount, at a frequency and for an effective duration to prevent said induced rhinosinusitis. by non-aggressive fungi, said formulation comprising an antifungal agent. 47. A method for the treatment of a mammal that has non-aggressive fungal-induced rhinosinusitis, comprising the steps of: a) identifying said mammal, and b) muco-administering directly into at least a portion of the nasal-paranasal anatomy of said mammal. mammal a formulation in an amount, at a frequency and for an effective duration to reduce or eliminate said rhinosinusitis induced by non-aggressive fungi, said formulation comprising an antifungal agent. 48. The method according to claim 47, characterized in that said identification comprises the diagnosis. 49. A method for prophylactically treating a mammal at risk of developing non-aggressive fungal-induced rhinosinusitis, characterized in that it comprises the steps of: a) identifying said mammal, and b) muco-administering, in at least a portion of the nasal anatomy -paranasal of said mammal, a formulation in an amount, at a frequency and for an effective duration to prevent said rinosinusitis induced by non-aggressive fungi, said formulation comprising an antifungal agent. 50. A method for the treatment of a mammal having asthma, characterized in that it comprises the mucoadministration, in at least a portion of the respiratory tract of said mammal, of a formulation in an amount, at a frequency and for an effective duration to reduce or eliminate the symptoms of said asthma, said formulation comprising an antifungal agent. 51 The method according to claim 50, characterized in that said mucoadministration comprises a direct mucoadministration. 52. The method according to claim 51, characterized in that said direct mucoadministration comprises the irrigation of the nasal-paranasal anatomy of said mammal with a liquid form of said formulation. 53. The method according to claim 51, characterized in that said direct mucoadministration comprises the inhalation of said formulation through the mouth or nose of said mammal. 54. The method according to claim 50, characterized in that said portion comprises the nasal airways. 55. The method according to claim 50, characterized in that said portion comprises the pulmonary airways. 56. The method according to claim 50, characterized in that said method comprises, after said mucoadministration, the prophylactic mucoadministration to said mammal of a prophylactic formulation in an amount, at a frequency and for an effective duration to avoid the symptoms of said asthma. , said prophylactic formulation comprising an antifungal agent. 57. A method for prophylactically treating a mammal at risk of developing asthma, characterized in that it comprises the mucoadministration, in at least a portion of the respiratory tract of said mammal, of a formulation in an amount, at a frequency and during a effective duration to avoid the symptoms of said asthma, said formulation comprising an antifungal agent. 58. A method for treating a mammal having asthma, characterized in that it comprises the steps of: a) identifying said mammal, and b) directly administering, in at least a portion of said mammal's respiratory tract, a formulation in a amount, at a frequency and for an effective duration to reduce or eliminate the symptoms of said asthma, said formulation comprising an antifungal agent. 59. A method for prophylactically treating a mammal at risk of developing asthma, characterized in that it comprises the steps of: a) identifying said mammal, and b) muco-administering, in at least a portion of the respiratory tract of said mammal, a formulation in an amount, at a frequency and for an effective duration to avoid the symptoms of said asthma, said formulation comprising an antifungal agent. 60. A method for treating a mammal having intestinal mucositis induced by non-aggressive fungi, characterized in that it comprises the mucoadministration in said mammal, of a formulation in an amount, at a frequency and for an effective duration to reduce or eliminate said intestinal mucositis. induced by non-aggressive fungi, said formulation comprising an antifungal agent. 61 A method for prophylactically treating a mammal at risk of developing intestinal mucositis induced by non-aggressive fungi, characterized in that it comprises the mucoadministration, to said mammal, of a formulation in an amount, at a frequency and for an effective duration to avoid said intestinal mucositis induced by non-aggressive fungi, said formulation comprising an antifungal agent. 62. A method for treating a mammal having an intestinal mucositis induced by non-aggressive fungi, characterized in that it comprises the steps of: a) identifying said mammal, and b) muco-administering, in at least a portion of said mammal's digestive tract, a formulation in an amount, at a frequency and for an effective duration to reduce or eliminate the symptoms of said intestinal mucositis induced by non-aggressive fungi, said formulation comprising an antifungal agent. 63. The method according to claim 62, characterized in that said identification comprises the diagnosis. 64. A method for prophylactically treating a mammal at risk of developing intestinal mucositis induced by non-aggressive fungi, characterized in that it comprises the steps of: a) identifying said mammal, and b) mucoadministering, in at least a portion of the digestive tract. of said mammal, a formulation in an amount, at a frequency and for an effective duration to prevent said intestinal mucositis induced by non-aggressive fungi, said formulation comprising an antifungal agent. 65. A method for the treatment of a mammal having otitis media induced by non-aggressive fungi, characterized in that it comprises the mucoadministration in said mammal, of a formulation in an amount, at a frequency and for an effective duration to reduce or eliminate said Otitis media induced by non-aggressive fungi, said formulation comprising an antifungal agent. 66. A method to prophylactically treat a mammal at risk of developing otitis media induced by non-aggressive fungi, characterized in that it comprises the mucoadministration in said mammal, of a formulation in an amount, at a frequency and for an effective duration to avoid said otitis media induced by non-aggressive fungi, said formulation comprising an antifungal agent. 67. A method for the treatment of a mammal having an otitis media induced by non-aggressive fungi, characterized in that it comprises the steps of: a) identifying said mammal, and b) mucoadministering, in at least a portion of the middle ear of said mammal , a formulation in an amount, at a frequency and for an effective duration to reduce or eliminate said otitis media induced by non-aggressive fungi, said formulation comprising an antifungal agent. 68. The method according to claim 67, characterized in that said identification comprises the diagnosis. 69. A method for prophylactically treating a mammal at risk of developing otitis media induced by non-aggressive fungi, characterized in that it comprises the steps of: a) identifying said mammal, and b) mucoadministering, in at least a portion of the ear means of said mammal, a formulation in an amount, at a frequency and for an effective duration to prevent said otitis media induced by non-aggressive fungi, said formulation comprising an antifungal agent. 70. An article of manufacture, characterized in that it comprises packaging material and a formulation contained within said packaging material, wherein said formulation comprises an antifungal agent and wherein said packaging material comprises a label or package insert indicating that said formulation can mucoadministered directly in at least a portion of the nasal-paranasal anatomy of a mammal that has rhinosinusitis induced by non-aggressive fungi, in an amount, at a frequency and for an effective duration to reduce or eliminate said rhinosinusitis induced by non-aggressive fungi. 71 A manufacturing article, characterized in that it comprises packaging material and a formulation contained within said packaging material, wherein said formulation comprises an antifungal agent and wherein said packaging material comprises a label or package insert indicating that said formulation can be muco-administered in at least a portion of the nasal-paranasal anatomy of a mammal at risk of developing rhinosinusitis induced by non-aggressive fungi, in an amount, at a frequency and for an effective duration to prevent said rhinosinusitis induced by non-aggressive fungi. 72. An article of manufacture, characterized in that it comprises packaging material and a formulation contained within said packaging material, wherein said formulation comprises an antifungal agent and wherein said packaging material comprises an insert label or package indicating that said formulation can mucoadministered directly in at least a portion of the airways of a mammal having asthma, in an amount, at a frequency and for an effective duration to reduce or eliminate the symptoms of said asthma. 73. An article of manufacture, characterized in that it comprises packaging material and a formulation contained within said packaging material, wherein said formulation comprises an antifungal agent and wherein said packaging material comprises a label or package insert indicating that said formulation can mucoadministered in at least a portion of the respiratory tract of a mammal at risk of developing asthma, in an amount, at a frequency and for an effective duration to avoid the symptoms of said asthma. 74. An article of manufacture, characterized in that it comprises packaging material and a formulation contained within said packaging material, wherein said formulation comprises an antifungal agent and wherein said packaging material comprises an insert label or package indicating that said formulation can mucoadministered to a mammal that has intestinal mucositis induced by non-aggressive fungi, in a quantity, at a frequency and for an effective duration to reduce or eliminate said intestinal mucositis induced by non-aggressive fungi. 75. An article of manufacture, characterized in that it comprises packaging material and a formulation contained within said packaging material, wherein said formulation comprises an antifungal agent and wherein said packaging material comprises a label or package insert indicating that said formulation can Mucoadministered to a mammal at risk of developing intestinal mucositis induced by non-aggressive fungi, in a quantity, at a frequency and for an effective duration to avoid said intestinal mucositis induced by non-aggressive fungi. 76. An article of manufacture, characterized in that it comprises packaging material and a formulation contained within said packaging material, wherein said formulation comprises an antifungal agent and wherein said packaging material comprises a label or package insert indicating that said formulation can mucoadministered to a mammal that has otitis media induced by non-aggressive fungi, in an amount, at a frequency and for an effective duration to reduce or eliminate said otitis media induced by non-aggressive fungi. 77. An article of manufacture, characterized in that it comprises packaging material and a formulation contained within said packaging material, wherein said formulation comprises an antifungal agent and wherein said packaging material comprises a label or package insert indicating that said formulation can Mucoadministered to a mammal at risk of developing otitis media induced by non-aggressive fungi, in an amount, at a frequency and for an effective duration to prevent said otitis media induced by non-aggressive fungi. 78. The use of an antifungal agent in the preparation of a medicament for the treatment or prevention of rhinosinusitis induced by non-aggressive fungi. 79. The use according to claim 78, characterized in that said medicament is mucoadministered in at least a portion of the nasal-paranasal anatomy of a mammal, in an amount, at a frequency and for an effective duration to reduce, eliminate or avoid said rinosinusitis induced by non-aggressive fungi. 80. The use according to claim 79, characterized in that said mucoadministration is a direct mucoadministration. 81 The use according to claim 80, characterized in that said direct mucoadministration comprises the irrigation of said nasal-paranasal anatomy with a liquid form of said medicament. 82. The use according to claim 80, characterized in that said mucoadministration comprises the application of an aerosol form of said medicament to said nasal-paranasal anatomy. 83. The use according to claim 80, characterized in that said direct mucoadministration comprises the application of a powder form of said medicament to said nasal-paranasal anatomy. 84. The use according to claim 79, characterized in that said effective amount comprises from about 0.01 mL to about 1 L of said medicament per nostril of said mammal. 85. The use according to claim 79, characterized in that said effective amount of said medicament remains constant during said effective duration. 86. The use according to claim 79, characterized in that said effective frequency of said mucoadministration is from approximately four times a day to approximately once a week. 87. The use according to claim 79, characterized in that said effective duration is greater than 7 days. 88. The use according to claim 78, characterized in that said rinosinusitis induced by non-aggressive fungi is characterized by the formation of polyps or polypoid changes. 89. The use according to claim 78, characterized in that said rinosinusitis induced by non-aggressive fungi is chronic. 90. The use according to claim 78, characterized in that said medicament is in a solid, liquid or aerosol form. 91 The use according to claim 78, characterized in that said medicament is in a form selected from the group consisting of a powder, a crystalline substance, gel, paste, ointment, balm, cream, solution, suspension, partial liquid, aerosol, Nebulas, vapor, atomized vapor, aerosol and tincture. 92. The use according to claim 78, characterized in that said antifungal agent comprises a macrolide. 93. The use according to claim 78, characterized in that said antifungal agent comprises an azole. 94. The use according to claim 78, characterized in that said antifungal agent comprises an antifungal agent selected from the group consisting of amphotericin B, acetoconazole, itraconazole, saperconazole, voriconazole, flucytosine, miconazole, fluconazole, g riseofulvin, clotrimazole, econazole, terconazole, butoconazole, oxiconazole, sulconazole, cyclopirox olamine, haloprogin, tolnaftate, naftifine, terbinafine hydrochloride, morpholines, nystatin, natamycin, butenafine, undecylenic acid, Whitefield ointment, propionic acid and caprylic acid. 95. The use according to claim 78, characterized in that said medicament comprises a pharmaceutically acceptable aqueous vehicle. 96. The use according to claim 95, characterized in that said medicament comprises from about 1 ng to about 500 mg of said antifungal agent per liter. 97. The use according to claim 95, characterized in that said medicament comprises approximately 100 mg of said antifungal agent per liter. 98. The use according to claim 78, characterized in that said medicament comprises from about 0.01 ng to about 1000 mg of said antifungal agent per liter. 99. The use according to claim 78, characterized in that said medicament comprises a plurality of antifungal agents. 100. The use according to claim 78, characterized in that said medicament comprises a compound selected from the group consisting of pharmaceutically acceptable aqueous vehicles, pharmaceutically acceptable solid carriers, mucolytic agents, antibacterial agents., anti-inflammatory agents, immunosuppressants, dilators, vasoconstrictors, steroids and therapeutic compounds. 1 01. The use of an antifungal agent in the development of a medication for the treatment or prevention of asthma. 1 02. The use according to claim 1, characterized in that said medicament is mucoadministered in at least a portion of the respiratory tracts of a mammal in an amount, at a frequency and for an effective duration to reduce, eliminate or avoid symptoms of said asthma. 1 03. The use of an antifungal agent in the development of a medication for the treatment or prevention of intestinal mucositis induced by non-aggressive fungi. 104. The use according to claim 103, characterized in that said medicament is mucoadministered to a mammal in an amount, at a frequency and for an effective duration to reduce, eliminate or avoid symptoms of said intestinal mucositis induced by non-aggressive fungi. 1 05. The use of an antifungal agent in the development of a medication for the treatment or prevention of otitis media induced by non-aggressive fungi. 106. The use according to claim 105, characterized in that said medicament is mucoadministered to a mammal in an amount, at a frequency and for an effective duration to reduce, eliminate or avoid symptoms of said otitis media induced by non-aggressive fungi. 07. An antifungal formulation characterized in that it comprises an antifungal agent, a flavoring agent and water, wherein said water comprises at least about 50 percent of said formulation. 108. The antifungal formulation according to claim 1, characterized in that said water comprises at least about 75 percent of said formulation. 109. The antifungal formulation according to claim 107, characterized in that said water comprises at least about 85 percent of said formulation. 10. An antifungal formulation, characterized in that it comprises an antifungal agent, a flavoring agent and water, wherein said water comprises at least about 50 percent of said formulation and wherein said antifungal agent comprises an antifungal agent selected from the group consisting of in amphotericin B, acetoconazole, saperconazole, voriconazole, flucytosine, miconazole, fluconazole, griseofulvin, clotrimazole, econazole, terconazole, butoconazole, oxiconazole, sulconazole, cyclopirox olamine, haloprogin, tolnaftate, naftifine, terbinafine hydrochloride, morpholines, nystatin, natamycin, butenafine, undecylenic acid, Whited ointment, propionic acid and caprylic acid. 1 1 1 An antifungal formulation characterized in that it comprises itraconazole and water, wherein said itraconazole is dissolved in said formulation at a concentration greater than about 25 μg per mL and wherein said water comprises at least about 50 percent of said formulation. The antifungal formulation according to claim 11, characterized in that said formulation comprises polyethylene glycol. The antifungal formulation according to claim 11, characterized in that said formulation comprises a flavoring. 1 14. An antifungal formulation characterized in that it comprises itraconazole and water, wherein said itraconazole is suspended in said formulation at a concentration greater than about 25 μg per mL and wherein said water comprises at least about 50 percent of said formulation. 1 1 5. A method for preparing an antifungal formulation, characterized in that said formulation comprises itraconazole and water, wherein said itraconazole is dissolved in said formulation at a concentration greater than about 25 μg per μL and wherein said water comprises at least about 50 percent of said formulation, said method comprising the addition of said water to a base solution containing said itraconazole 16. A method for cultivating fungi from a mammalian mucus, characterized in that said method comprises: a) the contact of said mucus with a mucolytic agent to reduce the viscosity of said mucus, b) the separation of said fungi from said mucus of reduced viscosity, c) the contact of said separated fungi with fungal development means in order to form a fungal culture, and d) the incubation of said mushroom culture in such a way that said fungi develop separately. A method for obtaining a fungal antigen, characterized in that said method comprises: a) the contact of a mammalian mucus with a mucolytic agent to reduce the viscosity of said mucus, b) the separation of the fungi from said mucus of reduced viscosity, c) the contact of said separated fungi with fungal development means in order to form a fungal culture, d) the incubation of said fungal culture in such a way that said separate fungi develop and e) the isolation of said antigen from said fungi. cultivated mushrooms 1 1 8. A method for producing a fungal-specific antibody, characterized in that said method comprises: a) contacting a mammalian mucus with a mucolytic agent to reduce the viscosity of said mucus; b) separating the fungi from said mucus; mucus of reduced viscosity, c) the contact of said fungi separated with fungal development means in order to form a fungal culture, d) the incubation of said mushroom culture in such a way that said fungi are developed separately, e) the isolation of an antigen from said cultured fungi and f) immunization of an animal with said fungal antigen to produce said antibody. 19. A nasal mucus collection apparatus, characterized in that it comprises: a) a collection retainer, said collection container being suitable for retaining said mucus, b) a collection tube that extends from said collection container, wherein said collection tube defines a distal end and a passage such that the mucus can traverse said passage from said distal end of said collection tube to said collection container, said collection tube generally being flexible over at least a portion of the length of said collection tube such that said collection tube can be selectively manipulated toward a desired configuration by a practitioner during a collection procedure, said collection tube being generally malleable, so that said collection tube generally retains such desired configuration has The practitioner manipulates said collection tube to conform it to a different configuration, and c) a connection portion extending from said collection container, wherein said connection portion defines a second passage that communicates with the inside of the container. said collection container, said connecting portion adapting to receive a vacuum source. The apparatus according to claim 1 1 9, characterized in that said apparatus comprises a valve that adjusts the opening of said second passage. 1 21. The apparatus according to claim 1 1 9, characterized in that said collection container is removable from said collection tube and said connection portion. 22. A pharmaceutical composition characterized in that it comprises an antifungal agent. 1 23. A pharmaceutical composition characterized in that it comprises an antifungal agent and a mucolytic agent. 1 24. A pharmaceutical composition characterized in that it comprises an antifungal agent and a steroid. 125. A pharmaceutical composition characterized in that it comprises an antifungal agent and a decongestant. 1 26. A pharmaceutical composition characterized in that it comprises an antifungal agent and an antibiotic. 1 27. A pharmaceutical composition characterized in that it comprises an antifungal agent and an anti-inflammatory agent. 1 28. A composition for treating an immune response to fungi in a mammal, characterized by an agent configured to direct mucoadministration to mammalian mucus and having antifungal means to eliminate or reduce fungi below a threshold level in where the fungi stop activating the migration of eosinophilic cells to the affected area. 1 29. A pharmaceutical composition for the treatment of a condition related to fungi in the cavity-nasal anatomy, pulmonary anatomy, ear anatomy or intestinal anatomy of a mammalian patient, said composition comprising an effective dose of an antifungal as described in FIG. the present. 130. A pharmaceutical composition for the treatment of a condition related to fungi in the cavity-nasal anatomy, pulmonary anatomy, ear anatomy or intestinal anatomy of a mammalian patient, said composition comprising an effective dose of an antifungal agent and minus another agent or inhibitor as described herein. 1 31. A pharmaceutical composition for the treatment of a condition related to fungi in the cavity-nasal anatomy, pulmonary anatomy, ear anatomy or intestinal anatomy of a mammalian patient, said composition comprising an effective dose of an antifungal suitable for long-term use within of the cavity-nasal anatomy. 32. A medicine for treating sinusitis, asthma, otitis media or colitis of a patient, characterized in that it comprises a mucolytic agent; and an antifungal compound as described herein. 1 33. An irrigation medicine to treat a nasal area, lung area, ear area or intestinal area, inflamed of a patient, originating the nasal area, lung area, ear area or intestinal area, inflamed by the presence of a fungus , the medicament comprising effective doses of an antifungal compound and a steroid as described herein. 1 34. An irrigation drug to treat a nasal area, lung area, ear area or intestinal area, inflamed of a patient, originating the nasal area, lung area, ear area or intestinal area, inflamed by the presence of a fungus , the medicament comprising effective doses of an antifungal compound and a mucolytic agent. 1 35. An irrigation medicine to treat a nasal area, lung area, ear area or intestinal area, inflamed of a patient, originating the nasal area, lung area, ear area or intestinal area, inflamed by the presence of a fungus , the medicament comprising effective doses of a steroid and a mucolytic agent as described herein. 1 36. An irrigation drug to treat a nasal area, lung area, ear area or intestinal area, inflamed of a patient, originating the nasal area, lung area, ear area or intestinal area, inflamed by the presence of a fungus , the medicament comprising effective doses of an antifungal compound, a steroid and a mucolytic agent as described herein. 1 37. An irrigation drug to treat a nasal area, lung area, ear area or intestinal area, inflamed of a patient, originating the nasal area, lung area, ear area or intestinal area, inflamed by the presence of a fungus , the medicament comprising effective doses of at least one medicine selected from the group consisting of an antifungal compound, a steroid, a mucolytic agent and any combination thereof as described herein.