TWI236905B

TWI236905B - Pharmaceutical composition for treating and preventing inflammation of mucosal tissue

Info

Publication number: TWI236905B
Application number: TW87117691A
Authority: TW
Inventors: Jens Ponikau
Original assignee: Jens Ponikau
Priority date: 1997-10-28
Filing date: 1998-10-26
Publication date: 2005-08-01
Also published as: AR017397A1

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 contact 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 otitis media, chronic colitis, and Crohn's disease. Further, the invention involves methods and materials for treating and preventing chronic asthma symptoms.

Description

經濟部中央標準局員工消費合作社印製 1236905 Λ, Β1 五、發明説明q ) 發明領域本發明涉及有關治療和預防非侵襲性真菌誘導的粘膜組織炎症以及哮喘症狀的方法和物質。發明背景粘膜炎，即粘膜組織的炎症是影響全世界數百萬人的嚴重醫學問題。例如，保守估計表明2千至4千萬美國人患慢性鼻竇炎，即一種鼻腔和/或鼻旁竇炎症。對於大多數情況，慢性鼻竇炎的病因不明。然而，在小部份病人中，似乎與生活於粘膜內的非侵襲性真菌生物有關。具有該症狀的現在稱爲過敏性真菌鼻竇炎（AFS ) 的病人最早在八十年代早期被描述（Miller JW等， Prod.Soct.Thor.Soc. 36 : 710(1981)和 Katzenstein ALA 等，過敏臨床免疫學雜誌。72: 89-93 (1983))。具體地說，因爲由息肉形成所導致的鼻阻塞需要手術的約百分之三至八的慢性鼻竇炎病例被分類爲AFS。簡言之，通過鼻旁腔中濃縮粘液的存在而診斷AFS。一般來說，該粘液含有壞死的嗜酸性細胞團（clump)或片（sheets)，夏科一萊登晶體和非侵襲性真菌菌絲。此外，患有AFS的病人一般具有鼻旁息肉病史並且可能經歷過多次手術。炎症不但可影響所有的鼻旁腔，而且可以是非對稱性的，僅涉及一側。患有AFS病人的電腦局部解剖（CT)掃描具有特徵性表象，並且經常顯示相鄰結構中的骨的腐蝕。的確，已報導與竇和鼻區域有百分之十九至百分之八十相鄰的骨被破壞。本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 1236905 Λ, Β1 V. Description of the Invention q) Field of the Invention The present invention relates to methods and substances for the treatment and prevention of non-invasive fungal induced mucosal tissue inflammation and asthma symptoms. BACKGROUND OF THE INVENTION Mucositis, i.e. inflammation of mucosal tissue, is a serious medical problem affecting millions of people worldwide. For example, conservative estimates indicate that 20 to 40 million Americans suffer from chronic sinusitis, an inflammation of the nasal cavity and / or paranasal sinuses. In most cases, the cause of chronic sinusitis is unknown. However, in a small proportion of patients, it appears to be related to non-invasive fungal organisms living in the mucosa. Patients with this condition, now known as allergic fungal sinusitis (AFS), were first described in the early 1980s (Miller JW et al., Prod. Soct. Thor. Soc. 36: 710 (1981) and Katzenstein ALA et al., Allergies Journal of Clinical Immunology. 72: 89-93 (1983)). Specifically, about three to eight percent of cases of chronic sinusitis that require surgery because of nasal obstruction caused by polyp formation are classified as AFS. In short, AFS is diagnosed by the presence of concentrated mucus in the paranasal cavity. Generally, the mucus contains necrotic eosinophil clump or sheets, Charco-Lyden lens and non-invasive fungal hyphae. In addition, patients with AFS generally have a history of paranasal polyps and may have undergone multiple surgeries. Inflammation not only affects all paranasal cavities, but can also be asymmetric, involving only one side. Computerized local anatomy (CT) scans of patients with AFS have characteristic features and often show bone erosion in adjacent structures. Indeed, 19 to 80 percent of the bones adjacent to the sinus and nasal areas have been reported damaged. This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm)

1236905 五、發明説明請先閱讀背之注意事項再雖然真菌生物似乎是AFS的誘因，但仍然缺乏成功的治療。目前，AFS病人以及大多數慢性鼻竇炎病人接受手術治療，伴隨或不伴隨以類固醇治療。當由息肉而阻塞時’手術幫助淸空鼻旁腔，而類固醇治療有助於控制似乎是造成組織和骨毀壞的炎症反應。不幸的是，僅以手術治療的病人幾乎總要經受復發的鼻竇炎症狀和其它的息肉生長。此外，長期使用類固醇伴隨有嚴重的副作用，並且停止類固醇治療後也導致鼻竇炎的復發事件。由於這些原因’患有慢性鼻竇炎症狀的病人一般經歷嚴重炎症，手術和類固醇治療的重覆循環，然後經受復發嚴重的炎症。因此’手術和類固醇治療在長期治療慢性鼻竇炎中均不是特別有效或理想的。發明要旨經濟部中央標準局員工消費合作社印製本發明一般涉及用於治療和預防非侵襲性真菌誘導的粘膜組織炎的方法和物質。本文使用的術語“粘膜炎” 意爲炎症，以區別粘膜感染。本發明基於這樣的發現，即稱爲AFS的病症可通過使用能有效減輕由鼻旁粘液內的真菌所引起的炎症的抗真菌劑量、頻率和時間從而成功的治療。此外，本發明也基於這樣的發現，即以有效維持鼻旁粘液內較低真菌水平的抗真菌劑使用量，頻率和時間而預防AFS症狀。具體的說，本發明涉及給哺乳動物施用抗真菌劑從而使該抗真菌劑接觸哺乳動物粘液並減少在粘液中存在的真菌生物。除了作爲唯一用於成功治療和預防本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）經濟部中央標準局員工消費合作社印製 1236905 B1 __ _____ 五、發明説明<3 ) AFS的已知方法外，當與其它目前可得到的治療AFS的醫學方法如手術治療和類固醇治療相比，抗真菌劑的使用對病人是特別有優勢的。因爲這些醫學方法可能具有副作用，可能較昂貴，且可能與病人的不適有關。本發明也基於這樣的發現，即使不是全部，但大多數慢性鼻竇炎病情也具有真菌病因，並且即使不是全部，但大多數慢性鼻竇炎病例也可通過能有效降低鼻旁粘液內存在的真菌生物的量、頻率和時間內使用抗真菌劑來加以治療。此外，通過能有效維持鼻旁粘液內較低真菌生物水平的量、頻率和時間內使用抗真菌劑可預防慢性鼻竇炎症狀。該發現與目前對慢性鼻竇炎的了解相衝突，並且在醫學中具有深遠的含義。例如，許多醫學硏究論文報導需要手術的慢性鼻竇炎病例中大約百分之三至八爲AFS，即一種具有非侵襲性真菌病因的鼻竇炎病情。實際上，在過去15年的文獻中已報導的AFS不到150個病例。應注意到的是可能缺乏對慢性鼻竇炎病情的非侵襲性真菌病因學的正確鑑別，因爲受影響的個體頻繁發現具有細菌感染 (即非侵襲性細菌）。很可能由非侵襲性真菌誘導炎症所引起的組織損傷導致在這些損傷區域中發現更高幾率的細菌感染。因此，在受影響的個體中表面上的細菌感染可能掩蓋了潛在的病因，即粘液內的真菌生物。爲了達到本發明的目的，術語“非侵襲性真菌誘導的鼻竇炎”包含AFS以及具有非侵襲性真菌病因學的任 -6 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210Χ：297公釐） (請先閱讀背面之注意事項再填寫本頁) r裝·1236905 V. INTRODUCTION OF THE INVENTION Please read the notes and notes first. Although fungal organisms seem to be the cause of AFS, there is still a lack of successful treatment. Currently, patients with AFS and most patients with chronic sinusitis receive surgery with or without steroids. When blocked by a polyp, the 'surgery helps empty the paranasal cavity, and steroid treatment helps control the inflammatory response that appears to cause tissue and bone destruction. Unfortunately, patients treated with surgery alone almost always experience recurrent sinus inflammation and other polyp growths. In addition, long-term use of steroids is accompanied by severe side effects, and the recurrence of sinusitis after discontinuation of steroid therapy. For these reasons, patients with chronic sinusitis symptoms generally experience severe inflammation, repeated cycles of surgery and steroid treatment, and then severe inflammation that recurs. Therefore, neither 'surgery nor steroid therapy is particularly effective or desirable in the long-term treatment of chronic sinusitis. SUMMARY OF THE INVENTION Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics The present invention relates generally to methods and substances for treating and preventing non-invasive fungal-induced mucosal tissue inflammation. The term "mucositis" as used herein means inflammation to distinguish mucosal infections. The present invention is based on the finding that a condition called AFS can be successfully treated by using an antifungal dose, frequency, and time that is effective in reducing inflammation caused by fungi in the paranasal mucus. In addition, the present invention is also based on the finding that AFS symptoms are prevented with the amount, frequency, and duration of antifungal agents effective in maintaining lower fungal levels in paranasal mucus. In particular, the invention relates to administering an antifungal agent to a mammal such that the antifungal agent contacts mammalian mucus and reduces the presence of fungal organisms in the mucus. Except as the only standard for the successful treatment and prevention of this paper, the Chinese National Standard (CNS) A4 specification (210X297 mm) is applied. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. In addition to known methods, the use of antifungal agents is particularly advantageous for patients when compared to other currently available medical methods for the treatment of AFS, such as surgery and steroids. Because these medical methods can have side effects, they can be expensive, and they can be related to patient discomfort. The present invention is also based on the discovery that most, if not all, conditions of chronic sinusitis have fungal causes, and even if not all, most cases of chronic sinusitis can effectively reduce the fungal organisms present in the paranasal mucus The amount, frequency and duration of treatment with antifungal agents. In addition, chronic sinusitis symptoms can be prevented by using antifungal agents in an amount, frequency, and time that can effectively maintain lower levels of fungal organisms in the paranasal mucus. This finding conflicts with current knowledge of chronic sinusitis and has profound implications in medicine. For example, many medical research papers report that about 3 to 8 percent of cases of chronic sinusitis requiring surgery are AFS, a condition of sinusitis with a non-invasive fungal etiology. In fact, fewer than 150 cases of AFS have been reported in the literature over the past 15 years. It should be noted that there may be a lack of correct identification of the non-invasive fungal etiology of chronic sinusitis, as affected individuals frequently find bacterial infections (ie, non-invasive bacteria). It is likely that tissue damage caused by non-invasive fungal-induced inflammation leads to a higher probability of finding bacterial infections in these areas of injury. As a result, bacterial infections on the surface in affected individuals may obscure the underlying cause, the fungal organisms in the mucus. For the purpose of the present invention, the term "non-invasive fungal-induced sinusitis" includes AFS and Ren-6 with non-invasive fungal etiology-this paper applies Chinese National Standard (CNS) A4 specifications (210 ×: 297) Li) (Please read the notes on the back before filling this page)

、1T 1236905 五、發明説明q ) 何其它鼻旁粘膜炎病情。通過用抗真菌劑治療和預防非侵襲性真菌誘導的鼻竇炎’無論是診斷爲AFS或任何其它具有非侵襲性真菌病因學的鼻竇炎病情避免了導致病人很多疼痛和痛苦的手術治療和類固醇治療的必要。此外，用抗真菌劑治療和預防非侵襲性真菌誘導的鼻竇炎實際上是針對病因（即，真菌）的治療，與手術治療、類固醇治療和抗菌素治療不同。本文使用的術語“慢性”是指持續至少三個月的疾病。應該理解按本文所述治療並且變得無症狀的疾病可歸爲慢性的。因此，慢性疾病可以是有症狀的或無症狀的。本發明也基於另一個同樣重要的發現，即慢性哮喘症狀可通過能有效減少呼吸道粘液中真菌生物的量、頻率、在一定時間內使用抗真菌劑從而成功的治療和預防。根據本發現，抗真菌劑可直接施用至肺呼吸道而用於治療慢性哮喘也是顯而易見的。另外，這些發現與目前對慢性哮喘的了解相抵觸並且具有深遠的臨床含義。總的來說，這些重要的突破可能會讓許多民眾過著更爲幸福、健康和更具有成果的日常生活。經濟部中央標準局員工消費合作社印製具體地說，本發明提供通過用抗真菌劑治療和預防各種粘膜炎疾病的方法和物質。抗真菌劑的使用是安全而高效的治療方法，其包含粘膜施用能有效緩解，預防和消除非侵襲性真菌誘導的粘膜炎的量、頻率、在一定時間內使用抗真菌劑。本文使用的術語“粘膜施用”指任何一種將所用的試劑與粘液接觸的施用。本發明也提供可應用於本紙張尺度適用中國國家標準（CNS ) A4規格（2I0X297公釐） 1236905 ΗΊ 五、發明説明‘) 含有粘液的哺乳動物各部份的特異性抗真菌配方。此外，本發明提供可用於施用抗真菌配方的醫療設備。這些設備特別具有優勢，因爲它們可由個體使用，以施用有效劑量的特異性真菌配方至身體的適當區域。此外，本發明提供了用於收集和培養來自粘液樣品中真菌生物的改進方法和物質。這些培養技術可用於監測特定抗真菌治療方案中粘液內的多種真菌種類。此外，這些真菌收集和培養方法以及物質對於鑑定導致非侵襲性真菌誘導性粘膜炎的特異真菌生物的基因型和表型是有用的。對在特定個體粘膜中發現的非侵襲性真菌生物的鑑定和特徵分析可幫助臨床醫生決定適當的治療和預防方法。例如，此信息可幫助決定特異性的抗真菌劑，劑量，用藥模式和待使用的施用數目以及可包含其它醫療方案和方法如類固醇，抗生素和手術的可能的組合治療。經濟部中央標準局員工消費合作社印製一般來說，本發明的特徵在於治療具有非侵襲性真菌誘導的鼻竇炎的哺乳動物（如人）的方法。該方法包含以能緩解或消除非侵襲性真菌誘導的鼻竇炎的量、頻率和時間給至少一部份哺乳動物鼻旁解剖學位置直接粘膜施用一配方。該配方含有一抗真菌劑或多種抗真菌劑，並且可以是固體、液體或氣霧劑形式[如粉末、晶體狀物質、凝膠、糊劑、軟膏劑、油膏、乳膏、溶液、懸液、部份液態、噴劑（spray)、噴霧劑（nebulae)、霧狀物、霧化氣體 (atomized vapor)、氣霧劑和酊劑]。此外，該配方可以爲適於人自我粘膜施用的形式。本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1236905 ____ ]Γ 五、發明説明‘) 經濟部中央標準局員工消費合作社印製此外，該配方可以含有藥用上可接受的含水載體 (如，鹽和水）。例如，該配方的液體形式通過測定每含水體積中抗真菌劑重量，可能含有約0.00001 %至約20% 的抗真菌劑。此外，在本發明的一些實施方案中，配方可含每升約0.01 ng至約1 000 mg的抗真菌劑（如兩性霉素 B)，或在本發明其它實施方案中含每升約1 ng至約500 mg的抗真菌劑，或在本發明另外實施方案中含每升約1 〇〇 mg的抗真菌劑。此外，在本發明一些實施方案中，這些含水的有效量可以爲每鼻孔約0.01 mL至約1 L配方，或者在本發明的其他實施方案中約每鼻孔5 mL至約100 mL 配方，或者在本發明的另一些實施方案中每鼻孔約40 mL 配方。作爲選擇，在本發明的一些實施方案中有效量的配方可以爲約0.01 ng至約1000 mg抗真菌劑每公斤哺乳動物體重或者在本發明的其它實施方案中約1 ng至約500 mg抗真菌劑每公斤哺乳動物體重。在有效持續時間內，配方的有效量可以改變或維持不變。在本發明的一些實施方案中，直接粘膜施用的有效頻率可以從約每天4次至約每隔一週一次，或者在本發明其它的實施方案中從約每天 2次至約每週一次，或者在本發明的另一些實施方案中約每天2次。此外，直接粘膜施用的有效頻率可以大於一天一次或大於一週一次。有效的持續時間可大於約7、14、 30、60 或 90 天。哺乳動物可以是特異反應性或非特異反應性的。並且可以是免疫活性或免疫損傷的。此外，非侵襲性真菌誘 -9 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ”—™ ^ " 1236905 Λ 經濟部中央標準局員工消費合作社印製 __)V五、發明説明‘) 導鼻竇炎以息肉形成或息肉狀改變爲特徵。非侵襲性真菌誘導的鼻竇炎也可以爲慢性病。粘膜用藥可以是用液體形式的配方灌注至少部份的鼻旁解剖位置。作爲選擇，粘膜用藥可以包含施用氣霧劑形式的配方至至少部份的鼻旁解剖位置。抗真菌劑可以是固體、液體或氣霧劑形式。此外，抗真菌劑可以爲多嫌大環內酯、四叉骨針大環內酯、五烯大環內酯、氟化吡啶、咪唑、吡咯、***、鹵代酚醚、硫代氨基甲酸酯、烯丙胺、固醇抑制劑和***真菌細胞壁成分之間的試劑。這些抗真菌劑包含兩性霉素B、5-氟胞嘧啶、酮康唑、咪康唑、伊曲康唑、氟康唑、灰黃霉素、克霉唑、益康唑、特康唑、布康唑、奧昔康唑、硫康唑、沙波康唑、Voriconazole、環匹司胺、鹵普羅近、萘替芬、鹽酸特比萘芬、嗎琳、制霉菌素、游霉素、Butenafine、十一碳烯酸、苯甲酸及水楊酸軟膏、丙酸和辛酸。除了含有抗真菌劑外，該配方可非限制性的含有藥用上可以接受的含水載體、藥用上可接受的固體載體、類固醇、粘液溶解劑、抗菌劑、抗炎劑、免疫抑制劑、稀釋劑、血管收縮劑、去充血劑、白三烯抑制劑、抗膽鹼能藥、抗組胺藥、治療化合物及其組合。該方法也可包含施用第二種非限制性含以下成份的配方，包含抗真菌劑、抗菌劑、類固醇、粘液溶解劑、抗炎劑、免疫抑制劑、稀釋劑、血管收縮劑、去充血劑、白三烯抑制劑、抗膽鹼能藥、抗組胺藥、治療化合物或其組合β同樣，該方法可包含直接粘膜用藥後的附加步驟，該 -10 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） — 一 (請先閱讀背面之注意事項再填寫本頁) r裝. 、11 線 1236905 ir ___ 五、發明説明t ) 附加步驟可以是以能有效預防非侵襲性真菌誘導的鼻竇炎的劑量，頻率和時間預防性粘膜施用預防性配方。該預防性配方也含抗真菌劑，並且可以爲固體、液體、或氣霧劑形式（如，粉末、晶體狀物質、凝膠、糊劑、軟膏劑、油膏、乳膏、溶液、懸液、部份液態、噴劑、噴霧劑、霧狀物、霧化氣體、氣霧劑、酊劑、九劑、膠囊、片劑和膠衣）。此外，預防性粘膜用藥可以爲直接或間接的粘膜用藥。例如，預防性粘膜用藥可以是以液體形式的預防性配方灌注至少部份的鼻旁解剖位置、施用氣霧劑形式的預防性配方至至少部份的鼻旁解剖位置或以固體形式口腔施用預防性配方至晡乳動物。應明白上述本發明的每個額外特徵均可應用至本發明下面的附加實施方案和方面。例如預防性治療具有形成非侵襲性真菌誘導的鼻竇炎風險的哺乳動物的方法和治療哮喘的方法可使用含抗真菌劑約〇_〇〇〇〇1%至約20%重量或體積的配方等。經濟部中央標準局員工消費合作社印製在另一實施方案中，本發明的特徵在於預防性治療具有形成非侵襲性真菌誘導的鼻竇炎風險的哺乳動物的方法。此方法包含以能有效預防非侵襲性真菌誘導的鼻竇炎的量、頻率和時間內給哺乳動物粘膜施用一配方。該配方含有抗真菌劑。本發明的另一實施方案的特徵在於治療患有非侵襲性真菌誘導的鼻竇炎的哺乳動物的方法。該方法包含以下步驟，即鑑定（如診斷）哺乳動物並以能有效緩解或消除 -1 1 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） — 1^ 1236905 五、發明説明& ) 非侵襲性真菌誘導的鼻竇炎的量、頻率和時間內用一配方直接粘膜施用至至少部份的哺乳動物鼻旁解剖位置。該配方含有抗真菌劑。本發明的另一實施方案的特徵在於預防性治療具有形成非侵襲性真菌誘導的鼻竇炎風險的哺乳動物的方法。該方法包含以下步驟’即鑑定哺乳動物（如診斷）和以能有效預防非侵襲性真菌誘導的鼻竇炎的量、頻率和時間內用一配方粘膜施用至哺乳動物鼻旁至少部份解剖位置。該配方含有抗真菌劑。經濟部中央標準局員工消費合作社印製在另一方面，本發明的特徵在於治療患有哮喘的哺乳動物的方法。該方法包含以能有效緩解或消除哮喘症狀的量，頻率和時間內用一配方直接粘膜施用至哺乳動物至少部份的呼吸道（如，鼻旁呼吸道和肺呼吸道）。該配方含有抗真菌劑。直接的粘膜用藥可以是以液體形式的配方灌注哺乳動物鼻旁解剖位置。作爲選擇，直接的粘膜用藥可以經哺乳動物的口或鼻吸入該配方。此外，該方法可包含直接粘膜用藥後的附加步驟。該附加步驟可以爲以能有效預防哮喘症狀的量、頻率和時間內用一種預防性配方預防性粘膜施用至哺乳動物。該預防性配方也含有抗真菌劑。在另一實施方案中，本發明的特徵在於預防性治療具有形成哮喘風險的哺乳動物的方法。該方法包含以能有效預防哮喘症狀的量、頻率和時間內用一配方粘膜施用至哺乳動物至少部份的呼吸道（如，鼻旁呼吸道和肺呼吸 -12 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210、/*297公釐） — 12369051T 1236905 V. Description of the invention q) Any other conditions of paranasal mucositis. By treating and preventing non-invasive fungal-induced sinusitis with antifungal agents, whether it is diagnosed as AFS or any other non-invasive fungal etiology of sinusitis, it avoids surgical and steroid treatments that cause patients a lot of pain and pain Necessary. In addition, the treatment and prevention of non-invasive fungal-induced sinusitis with antifungal agents is actually a treatment for the cause (i.e., fungi), unlike surgery, steroids, and antibiotics. The term "chronic" as used herein refers to a disease that lasts for at least three months. It should be understood that diseases that are treated as described herein and become asymptomatic can be classified as chronic. Therefore, chronic diseases can be symptomatic or asymptomatic. The present invention is also based on another equally important finding that chronic asthma symptoms can be successfully treated and prevented by effectively reducing the amount, frequency, and use of antifungal agents in respiratory mucus in a certain period of time. It is also apparent from the present findings that antifungals can be applied directly to the pulmonary airways for the treatment of chronic asthma. In addition, these findings conflict with current understanding of chronic asthma and have profound clinical implications. Taken together, these important breakthroughs may enable many people to live happier, healthier, and more productive lives. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economics Specifically, the present invention provides methods and substances for treating and preventing various mucositis diseases by using antifungal agents. The use of antifungal agents is a safe and effective treatment method, which includes mucosal administration which can effectively alleviate, prevent, and eliminate the use of antifungal agents within a certain period of time unless the amount and frequency of invasive fungal-induced mucositis. The term "mucosal administration" as used herein refers to any application in which the agent used is brought into contact with mucus. The present invention also provides a specific antifungal formula that can be applied to this paper size to the Chinese National Standard (CNS) A4 specification (2I0X297 mm) 1236905 ΗΊ 5. Description of the invention ‘) mammalian parts containing mucus. In addition, the present invention provides medical devices that can be used to apply antifungal formulations. These devices are particularly advantageous because they can be used by individuals to apply effective doses of specific fungal formulas to appropriate areas of the body. In addition, the present invention provides improved methods and materials for collecting and cultivating fungal organisms from mucus samples. These culture techniques can be used to monitor multiple fungal species in the mucus in specific antifungal treatment regimens. In addition, these fungal collection and culture methods and materials are useful for identifying genotypes and phenotypes of specific fungal organisms that cause non-invasive fungal-induced mucositis. Identification and characterization of non-invasive fungal organisms found in the mucous membranes of specific individuals can help clinicians decide on appropriate treatment and prevention methods. For example, this information can help determine specific antifungal agents, dosages, modes of administration and number of applications to be used, and possible combination treatments that can include other medical protocols and methods such as steroids, antibiotics, and surgery. Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs In general, the present invention features a method for treating mammals (such as humans) with non-invasive fungal-induced sinusitis. The method comprises applying a formulation directly to the mucosa of the paranasal anatomical location of at least a portion of a mammal in an amount, frequency, and time that can alleviate or eliminate non-invasive fungal-induced sinusitis. The formulation contains an antifungal agent or multiple antifungal agents and can be in the form of a solid, liquid or aerosol [such as powder, crystalline substance, gel, paste, ointment, ointment, cream, solution, suspension Liquid, partially liquid, spray, nebulae, mist, atomized vapor, aerosol and tincture]. In addition, the formulation may be in a form suitable for human self-mucosal administration. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 1236905 ____] Γ 5. Description of the invention ') Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs In addition, the formula may contain pharmaceutically acceptable water Carriers (eg, salt and water). For example, the liquid form of the formulation may contain from about 0.00001% to about 20% of the antifungal agent by weight of the antifungal agent per water volume. In addition, in some embodiments of the invention, the formulation may contain from about 0.01 ng to about 1,000 mg of an antifungal agent (such as amphotericin B) per liter, or in other embodiments of the invention about 1 ng per liter Up to about 500 mg of an antifungal agent, or in another embodiment of the present invention, about 100 mg of an antifungal agent per liter. In addition, in some embodiments of the present invention, these aqueous effective amounts can be from about 0.01 mL to about 1 L of formula per nostril, or in other embodiments of the present invention from about 5 mL to about 100 mL of formula per nostril, or in In other embodiments of the invention, the formulation is about 40 mL per nostril. Alternatively, an effective amount of the formulation may be from about 0.01 ng to about 1000 mg of antifungal agent per kilogram of mammal body weight in some embodiments of the invention or from about 1 ng to about 500 mg of antifungal in other embodiments of the invention Dose per kg of mammal body weight. The effective amount of the formula can be changed or maintained for the duration of the effect. In some embodiments of the invention, the effective frequency of direct mucosal administration can be from about 4 times per day to about once every other week, or from about 2 times per day to about once per week in other embodiments of the invention, or In other embodiments of the invention, about twice a day. In addition, the effective frequency of direct mucosal administration can be greater than once a day or greater than once a week. The effective duration can be greater than about 7, 14, 30, 60, or 90 days. Mammals can be specifically or non-specifically reactive. It can be immunologically active or immunocompromised. In addition, non-invasive fungal entrapment-9-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) ”— ™ ^ " 1236905 Λ Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs __) V5 Inventive sinusitis is characterized by polyp formation or polyp-like changes. Non-invasive fungal-induced sinusitis can also be a chronic disease. Mucosal medications can be perfused with at least part of the paranasal anatomy with a liquid formulation. Alternatively, the mucosal medication may include the formulation in the form of an aerosol to be applied to at least part of the paranasal anatomy. The antifungal agent may be in the form of a solid, liquid or aerosol. In addition, the antifungal agent may be in a macrocyclic Esters, tetraketone needle macrolides, pentenyl macrolides, fluorinated pyridine, imidazole, pyrrole, triazole, halogenated phenol ethers, thiourethanes, allylamines, sterol inhibitors and inserts Reagents between fungal cell wall components. These antifungals include amphotericin B, 5-flucytosine, ketoconazole, miconazole, itraconazole, fluconazole, griseofulvin, clotrimazole, Econazole Terconazole, butoconazole, oxconazole, thioconazole, sapoconazole, voriconazole, cyclopiramide, haproxil, naftifine, terbinafine hydrochloride, morphine, nystatin, Natamycin, Butenafine, undecylenic acid, benzoic acid and salicylic acid ointment, propionic acid, and octanoic acid. In addition to containing antifungal agents, the formula may contain, without limitation, pharmaceutically acceptable aqueous carriers, drugs Use of acceptable solid carriers, steroids, mucolytics, antibacterials, anti-inflammatory agents, immunosuppressants, diluents, vasoconstrictors, decongestants, leukotriene inhibitors, anticholinergics, antihistamines Amines, therapeutic compounds, and combinations thereof. The method may also include administering a second non-limiting formulation containing the following ingredients, including an antifungal, antibacterial, steroid, mucolytic, anti-inflammatory, immunosuppressive agent, dilution Agents, vasoconstrictors, decongestants, leukotriene inhibitors, anticholinergics, antihistamines, therapeutic compounds, or combinations thereof. Similarly, the method may include an additional step after direct mucosal administration, the -10 -This paper size Applicable to China National Standard (CNS) Α4 specification (210X297 mm) — one (please read the precautions on the back before filling out this page) r equipment., 11 line 1236905 ir ___ 5. Description of the invention t) Additional steps can be Dosage, frequency, and time to prevent non-invasive fungal-induced sinusitis. Prophylactic formula for prophylactic mucosal administration. This prophylactic formula also contains an antifungal agent and can be in the form of a solid, liquid, or aerosol (eg, powder) , Crystalline substance, gel, paste, ointment, ointment, cream, solution, suspension, partially liquid, spray, spray, mist, atomizing gas, aerosol, tincture, nine (Capsules, tablets, gel coats). In addition, prophylactic mucosal medications can be direct or indirect mucosal medications. For example, prophylactic mucosal medications can be perfused at least part of the paranasal anatomy in a liquid form of the prophylactic formula, administered in the form of an aerosol to at least part of the paranasal anatomy, or administered in the solid form orally Sexual formula to lactating animals. It should be understood that each of the additional features of the invention described above can be applied to additional embodiments and aspects of the invention below. For example, a method for the prophylactic treatment of mammals at risk of forming a non-invasive fungal-induced sinusitis and a method for treating asthma may use an antifungal agent containing from about 0.00% to about 20% by weight or volume of a formulation, etc. . Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economics In another embodiment, the invention features a method for the prophylactic treatment of mammals at risk of developing non-invasive fungal-induced sinusitis. This method involves administering a formulation to a mammalian mucosa in an amount, frequency and time effective to prevent non-invasive fungal-induced sinusitis. The formulation contains an antifungal agent. Another embodiment of the invention features a method of treating a mammal having non-invasive fungal-induced sinusitis. The method includes the steps of identifying (such as diagnosing) mammals and effectively alleviating or eliminating them-1 1-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) — 1 ^ 1236905 5. Description of the invention &) The amount, frequency, and time of non-invasive fungal-induced sinusitis are directly mucosally administered to at least a portion of the paranasal anatomy of a mammal using a formulation. The formulation contains an antifungal agent. Another embodiment of the invention features a method of prophylactically treating mammals at risk of developing non-invasive fungal-induced sinusitis. The method comprises the steps of identifying a mammal (e.g., diagnosing) and administering a formulation of mucosa to at least a portion of the anatomic location near the nose of a mammal in an amount, frequency, and time effective to prevent non-invasive fungal-induced sinusitis. The formula contains antifungal agents. Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs. In another aspect, the invention features a method of treating mammals with asthma. The method includes direct mucosal administration to at least a portion of a mammal's respiratory tract (e.g., paranasal and pulmonary airways) in a formulation in an amount, frequency, and time effective to relieve or eliminate asthma symptoms. The formula contains antifungal agents. Direct mucosal medications can be formulated in a liquid form to infuse a mammal's nasal anatomy. Alternatively, direct mucosal administration can be inhaled through the mouth or nose of a mammal. In addition, the method may include additional steps after direct mucosal administration. This additional step can be prophylactic mucosal administration to a mammal with a prophylactic formula in an amount, frequency and time effective to prevent symptoms of asthma. This preventative formula also contains antifungal agents. In another embodiment, the invention features a method of prophylactically treating a mammal at risk for developing asthma. The method includes administering a formulation of mucosa to at least part of the mammalian respiratory tract (eg, paranasal respiratory tract and lung breathing-12) in an amount, frequency and time effective to prevent asthma symptoms. ) A4 size (210, / * 297 mm) — 1236905

A ___η 五、發明説明k ) 道）。該配方含有抗真菌劑。本發明的另一實施方案的特徵在於治療患有哮喘的哺乳動物的方法。此方法包含以下步驟，即鑑定（診斷）哺乳動物，並且以能有效緩解或消除哮喘症狀的量、頻率和時間內用一配方直接粘膜施用至哺乳動物至少部份的呼吸道（如，鼻旁呼吸道和肺呼吸道）。該配方含有抗真菌劑。本發明的另一實施方案的特徵在於預防性治療具有形成哮喘風險的哺乳動物的方法。該方法包含以下步驟，鑑定哺乳動物（如診斷），和以能有效預防哮喘症狀的量、頻率和時間內用一配方粘膜施用至哺乳動物至少一部份呼吸道（如，鼻旁呼吸道和肺呼吸道）。該配方含有抗真菌劑。經濟部中央標準局員工消費合作社印製在另一方面，本發明的特徵在於治療患有非侵襲性真菌誘導腸道粘膜炎（如，慢性結腸炎和節段性回腸炎）的哺乳動物的方法。該方法包含以能有效緩解或消除非侵襲性真菌誘導的腸道粘膜炎症狀的量、頻率和時間內用一配方粘膜施用至哺乳動物。該配方含有抗真菌劑並且可以是調節釋放膠囊（如，pH或時間調節釋放膠囊）的形式。粘膜用藥可以在哺乳動物消化道內口腔施用該配方。作爲選擇，粘膜用藥可以爲通過灌腸劑方式在哺乳動物消化道內施用該配方。在另一實施方案中，本發明的特徵在於預防性治療具有形成非侵襲性真菌誘導的腸道粘膜炎（如，慢性結腸 -13 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1236905 __ B1 ^' "丨丨丨 I·· I 丨 _·| …i .…-. - - _ _ . 五、發明説明（n ) 炎和節段性回腸炎）風險的哺乳動物的方法。該方法包含以能有效預防非侵襲性真菌誘導的腸道粘膜炎症狀的量、頻率和時間內用一配方粘膜施用至哺乳動物。該配方含有抗真菌劑。在另一方面，本發明的特徵在於治療患有非侵襲性真菌誘導的中耳炎的哺乳動物的方法。該方法包含以能有效緩解或消除非侵襲性真菌誘導的中耳炎的量、頻率和時間內用一配方粘膜施用至哺乳動物。該配方含有抗真菌劑。該粘膜用藥可以在哺乳動物中耳內施用此配方。例如，如果鼓膜被抬高或不完整，可用液體形式的配方灌注中耳。作爲選擇，可將配方注射至中耳或可用鼓膜切開術穿透鼓膜。此外，可使用鼓膜切開術用導管繞過鼓膜。此外，可經鼻和咽鼓管將配方粘膜施用至中耳。在另一實施方案中，本發明的特徵在於預防性治療具有形成非侵襲性真菌誘導的中耳炎風險的哺乳動物的方法。該方法包含以能有效預防非侵襲性真菌誘導的中耳炎症的量、頻率和時間內用一配方粘膜施用至哺乳動物。該此配方含有抗真菌劑。經濟部中央標準局員工消費合作社印製在另一方面，本發明的特徵在於含有包裝材料（如，盒、包裹物、瓶和其它容器）和位於包裝材料中的配方的人工製品。該配方含有抗真菌劑。該包裝材料含有標籤或包裝說明，表明該配方以能有效緩解或消除非侵襲性真菌誘導的鼻竇炎的量、頻率和時間內直接粘膜施用至患有# 侵襲性真菌誘導的鼻竇炎的哺乳動物至少一部份的鼻旁 -14 - 張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）一 '— 1236905 Λ_ 1Γ 五、發明説明k ) 解剖位置。在另一實施方案中，本發明的特徵在於含有包裝材料和位於包裝材料內的配方的人工製品。該配方含有抗真菌劑並且包裝材料含有標籤或包裝說明，表明該配方以能有效預防非侵襲性真菌誘導的鼻竇炎的量、頻率和時間粘膜施用至具有形成非侵襲性真菌誘導的鼻竇炎風險的哺乳動物至少一部份的鼻旁解剖位置。本發明的另一實施方案的特徵在於含有包裝材料和位於包裝材料內的配方的人工製品。該配方含有抗真菌劑。包裝材料含有標籤或包裝說明，表明該配方以能有效緩解或消除哮喘症狀的量、頻率和時間內直接粘膜施用至患有哮喘的哺乳動物的一部份呼吸道中。本發明的另一實施方案的特徵在於含有包裝材料和位於包裝材料內的配方的人工製品。該配方含有抗真菌劑並且包裝材料含有標籤或包裝說明，表明該配方以能有效預防哮喘症狀的量、頻率和時間粘膜施用至具有形成哮喘風險的哺乳動物的一部份呼吸道中。經濟部中央標準局負工消費合作社印繁本發明的另一實施方案的特徵在於含有包裝材料和位於包裝材料內的配方的人工製品。該配方含有抗真菌劑。該包裝材料含有標籤或包裝說明，表明該配方以能有效緩解或消除非侵襲性真菌誘導的腸道粘膜炎症狀的量、頻率和時間粘膜施用至患有非侵襲性真菌誘導的腸道粘膜炎的哺乳動物。本發明的另一實施方案的特徵在於含有包裝材料和 -15 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）一一-~一~ 1236905 五、發明説明“）位於包裝材料內的配方的人工製品。該配方含有抗真菌劑並且包裝材料含有標籤或包裝說明，表明該配方以能有效預防非侵襲性真菌誘導的腸道粘膜炎症狀的量、頻率和時間粘膜施用至具有形成非侵襲性真菌誘導的腸道粘膜炎風險的哺乳動物。本發明的另一實施方案的特徵在於含有包裝材料和位於包裝材料內的配方的人工製品。該配方含有抗真菌劑。包裝材料含有標籤或包裝說明，表明該配方以能有效緩解或消除非侵襲性真菌誘導的中耳炎症狀的量、頻率和時間粘膜施用至患有非侵襲性真菌誘導中耳炎的哺乳動物。本發明的另一實施方案的特徵在於含有包裝材料和位於包裝材料內的配方的人工製品。該配方含有抗真菌劑。包裝材料含有標籟或包裝說明，表明該配方以能有效緩解或消除非侵襲性真菌誘導中耳炎的量、頻率和時間粘膜施用至患有非侵襲性真菌誘導中耳炎的哺乳動物。經濟部中央標準局員工消費合作社印製本發明的另一實施方案的特徵在於含有包裝材料和位於包裝材料內的配方的人工製品。該配方含有抗真菌劑，並且包裝材料含有標籤或包裝說明，表明該配方以能有效預防非侵襲性真菌誘導中耳炎症狀的量、頻率和時間粘膜施用至具有形成非侵襲性真菌誘導中耳炎風險的哺乳動物。在另一方面，本發明的特徵在於抗真菌劑在製備用於治療或預防非侵襲性真菌誘導鼻竇炎的藥劑中的應 -16 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） — '~" 1236905 ______ η1 五、發明説明（14 ) 用。在另一實施方案中，本發明的特徵在於抗真菌劑在製備用於治療或預防哮喘症狀的藥劑中的應用。本發明另一實施方案的特徵在於抗真菌劑在製備用於治療或預防非侵襲性真菌誘導腸道粘膜炎的藥劑中的應用。本發明的另一實施方案的特徵在於抗真菌劑在製備用於治療或預防非侵襲性真菌誘導中耳炎的藥劑中的應用。在另一方面，本發明的特徵在於含有抗真菌劑、調味劑和水的抗真菌配方。水構成配方的至少約50%。例如，水可以構成配方的至少約百分之55、60、65、70、 75、80、85、90、95 $ 99 ° 經濟部中央標準局員工消費合作社印製在另一實施方案中，本發明的特徵在於含有伊曲康唑和水的抗真菌配方。伊曲康唑以大於約25// g/mL的濃度溶解於配方中。例如，伊曲康唑可以以大於約30、40、 50、60、70、80、90、100、110、120、130、140、150、 160、170或180// g/mL的濃度溶解於配方中。此外，水構成配方的至少約50%。例如，水可以構成該配方的至少約 55、60、65、70、75、80、85、90、95 或 99%。該配方也可含有聚乙二醇（如，PEG-200、PEG-400、PEG-800 等）。該配方也可含有調味劑（如，薄荷油、櫻桃調味品、糖漿等）。在另一實施方案中，本發明的特徵在於含有伊曲康 -17 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）經濟部中央標準局員工消費合作社印製 1236905 hr w 五、發明説明（15 ) 唑和水的抗真菌配方。伊曲康唑以大於約25// g/mL的濃度懸浮於配方中。例如，伊曲康唑可以以大於約30、40、 50、60、70、80、90、100、110、120、130、140、150、 160、170或180// g/mL的濃度懸於制劑中。此外，水構成該配方的至少約50%。例如，水可以構成配方的至少約 55、60、65、 70、75、80、85、90、95 或 99%。該配方也可含有聚乙二醇（如，PEG-200、PEG-400、PEG-800 等）。該配方也可含有調味劑（如，薄荷油，櫻桃調味品，糖漿等）。在另一實施方案中，本發明的特徵在於含有抗真菌劑，調味劑和水的抗真菌配方。水構成配方的至少約50 %。例如，水可以構成配方的至少約55、60、65、70、 75、80、85、90、95或99%。此外，抗真菌劑可以爲兩性霉素B、酮康哗、沙波康哩、Voriconazole、5-氟胞嘧啶、咪康唑、氟康唑、灰黃霉素、克霉唑、益康唑、特康唑、布康唑、奧昔康唑、硫康唑、環吡司胺、鹵丙炔氧苯、托萘酯、萘替芬、鹽酸特比萘芬、嗎琳、制霉菌素、游霉素、布替那芬、十一碳烯酸、苯甲酸及水楊酸軟膏、丙酸和辛酸。在另一方面，本發明的特徵在於製備抗真菌配方的方法。該配方含有伊曲康唑和水。伊曲康唑以大於約25 // g/mL的濃度溶解於該配方中。例如，伊曲康唑可以大於約 30、40、50、60、70、80、90、100、110、120、130、 140、150、160、170或180/zg/mL的濃度溶解於配方中。 -18 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁)A ___ η 5. Invention Description k) Road). The formula contains antifungal agents. Another embodiment of the invention features a method of treating a mammal having asthma. This method includes the steps of identifying (diagnosing) a mammal and applying it directly to at least part of the mammal's respiratory tract (eg, paranasal respiratory tract) with a formula in an amount, frequency, and time effective to relieve or eliminate asthma symptoms. And lung airways). The formula contains antibacterial agents. Another embodiment of the invention features a method of prophylactically treating a mammal at risk for developing asthma. The method comprises the steps of identifying a mammal (if diagnosed) and administering a formulation of mucosa to at least a portion of a mammal's respiratory tract (eg, paranasal and pulmonary respiratory tract) in an amount, frequency, and time effective to prevent symptoms of asthma ). The formula contains antibacterial agents. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. In another aspect, the invention features a method of treating mammals with non-invasive fungal-induced intestinal mucositis (eg, chronic colitis and segmental ileitis) . The method comprises administering a prescribed mucosa to a mammal in an amount, frequency, and time effective to alleviate or eliminate symptoms of non-invasive fungal-induced intestinal mucosal inflammation. The formulation contains an antifungal agent and may be in the form of a modified release capsule (e.g., a pH or time adjusted release capsule). Mucosal medications can be administered orally in the mammalian digestive tract. Alternatively, the mucosal administration may be by administering the formulation to the mammalian digestive tract. In another embodiment, the present invention is characterized by prophylactic treatment of non-invasive fungal-induced intestinal mucositis (eg, chronic colon-13-this paper size applies Chinese National Standard (CNS) A4 specification (210X297) 1236905 __ B1 ^ '" 丨丨丨 I ·· I 丨 _ · |… i.…-.--_ _. V. Description of the invention (n) inflammation and segmental ileitis) mammals at risk Methods. The method comprises administering a formulation of mucosa to a mammal in an amount, frequency, and time effective to prevent non-invasive fungal-induced symptoms of intestinal mucosal inflammation. The formula contains antifungal agents. In another aspect, the invention features a method of treating a mammal having a non-invasive fungal-induced otitis media. The method comprises administering to a mammal with a formulated mucosa in an amount, frequency, and time effective to alleviate or eliminate non-invasive fungal-induced otitis media. The formula contains an antifungal agent. The mucosal medication can be administered in the mammal's middle ear. For example, if the eardrum is raised or incomplete, the middle ear can be perfused with a liquid formulation. Alternatively, the formulation can be injected into the middle ear or the tympanic membrane can be penetrated by tympanostomy. In addition, a tympanostomy catheter can be used to bypass the tympanic membrane. In addition, the formula can be applied to the middle ear via the nose and eustachian tube. In another embodiment, the invention features a method of prophylactically treating a mammal at risk of developing non-invasive fungal-induced otitis media. The method comprises administering to a mammal a mucosal formulation in an amount, frequency, and time effective to prevent non-invasive fungal-induced middle ear inflammation. This formulation contains an antifungal agent. Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. In another aspect, the invention features artefacts containing packaging materials (e.g., boxes, wraps, bottles, and other containers) and formulas located in the packaging materials. The formula contains antifungal agents. This packaging contains a label or packaging instructions indicating that the formula is applied directly to a mammal with # invasive fungal-induced sinusitis in an amount, frequency and time effective to alleviate or eliminate non-invasive fungal-induced sinusitis. At least a part of the paranasal -14-sheet scale is in accordance with the Chinese National Standard (CNS) A4 specification (210X 297 mm)-'1236905 Λ_ 1Γ 5. Description of the anatomy k). In another embodiment, the invention features an artefact containing a packaging material and a formulation located within the packaging material. The formulation contains an antifungal agent and the packaging contains a label or packaging instructions indicating that the formulation is applied mucosally to the risk of forming a non-invasive fungal-induced sinusitis in an amount, frequency and time that is effective in preventing non-invasive fungal-induced sinusitis. Anatomical location of at least part of a mammal. Another embodiment of the invention is characterized by an artefact containing a packaging material and a formulation located within the packaging material. The formula contains an antifungal agent. The packaging material contains a label or packaging instructions indicating that the formula is applied directly to a portion of the respiratory tract of a mammal with asthma in an amount, frequency and time effective to alleviate or eliminate asthma symptoms. Another embodiment of the invention is characterized by an artefact containing a packaging material and a formulation located within the packaging material. The formulation contains an antifungal agent and the packaging contains a label or packaging instructions indicating that the formulation is administered mucosally to a portion of the respiratory tract of a mammal at risk of developing asthma, in an amount, frequency, and time that is effective in preventing asthma symptoms. Printed by the Central Standards Bureau, Ministry of Economic Affairs, Consumer Cooperatives Another embodiment of the present invention is characterized by an artificial product containing a packaging material and a formula located in the packaging material. The formula contains antifungal agents. The packaging material contains a label or packaging instructions indicating that the formula is administered to the patient with non-invasive fungal-induced intestinal mucositis in an amount, frequency, and time that is effective to alleviate or eliminate symptoms of non-invasive fungal-induced intestinal mucosal inflammation. Mammal. Another embodiment of the present invention is characterized by containing packaging materials and -15-this paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X 297 mm)-one-~ one ~ 1236905 V. Description of the invention ") Located in the packaging Artifact of a formula within the material. The formula contains an antifungal agent and the packaging material contains a label or packaging instructions indicating that the formula is applied to the mucosa in an amount, frequency and time that is effective in preventing non-invasive fungal-induced intestinal mucosal inflammation. Mammals at risk of forming non-invasive fungal-induced intestinal mucositis. Another embodiment of the present invention is characterized by an artefact containing a packaging material and a formulation located within the packaging material. The formulation contains an antifungal agent. Packaging material Contains label or packaging instructions indicating that the formulation is administered to a mammal with a non-invasive fungal-induced otitis media in a quantity, frequency, and time that is effective to alleviate or eliminate the symptoms of non-invasive fungal-induced otitis media. Another Practice of the Invention The program is characterized by a person who contains the packaging material and a formulation located in the packaging material The formulation contains antifungal agents. The packaging material contains label or packaging instructions, indicating that the formula is applied to the patient with non-invasive fungal-induced otitis media in an amount, frequency, and time that is effective to relieve or eliminate non-invasive fungal-induced otitis media. Another embodiment of the present invention printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economics is characterized by an artificial product containing a packaging material and a formula located in the packaging material. The formula contains an antifungal agent and the packaging material contains a label Or packaging instructions indicating that the formulation is administered to a mammal at risk, non-invasive fungal-induced otitis media symptoms, in a frequency, and time, to a mammal that is at risk of forming non-invasive fungal-induced otitis media. In another aspect, the invention features The application of antifungal agents in the preparation of a medicament for the treatment or prevention of non-invasive fungal-induced sinusitis-16-This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) — '~ " 1236905 ______ η1 5. Description of the Invention (14) Use In another embodiment, The invention is characterized by the use of an antifungal agent in the preparation of a medicament for treating or preventing asthma symptoms. Another embodiment of the invention is characterized by the antifungal agent in the preparation of a non-invasive fungal-induced intestinal mucositis. Use of a medicament. Another embodiment of the present invention is characterized by the use of an antifungal agent in the preparation of a medicament for the treatment or prevention of non-invasive fungal-induced otitis media. In another aspect, the present invention is characterized by containing an antifungal Antifungal formulations of fungi, flavors and water. Water makes up at least about 50% of the formula. For example, water can make up at least about 55, 60, 65, 70, 75, 80, 85, 90, 95 of the formula $ 99 ° Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. In another embodiment, the invention features an antifungal formulation containing itraconazole and water. Itraconazole is dissolved in the formulation at a concentration greater than about 25 // g / mL. For example, itraconazole can be dissolved in a concentration greater than about 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, or 180 / g / mL. In the recipe. In addition, water constitutes at least about 50% of the formulation. For example, water may constitute at least about 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99% of the formulation. The formulation may also contain polyethylene glycols (eg, PEG-200, PEG-400, PEG-800, etc.). The formula may also contain flavoring agents (eg, peppermint oil, cherry flavoring, syrup, etc.). In another embodiment, the present invention is characterized by containing Itracon-17-this paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1236905 hr w 5 2. Description of the invention (15) An antifungal formulation of azole and water. Itraconazole is suspended in the formulation at a concentration greater than about 25 // g / mL. For example, itraconazole can be suspended at a concentration greater than about 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, or 180 / g / mL. In the preparation. In addition, water constitutes at least about 50% of the formulation. For example, water may constitute at least about 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99% of the formulation. The formulation may also contain polyethylene glycol (eg, PEG-200, PEG-400, PEG-800, etc.). The formula may also contain flavoring agents (eg, peppermint oil, cherry flavoring, syrup, etc.). In another embodiment, the invention features an antifungal formulation comprising an antifungal agent, a flavoring agent and water. Water makes up at least about 50% of the formulation. For example, water may constitute at least about 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99% of the formulation. In addition, the antifungal agent can be amphotericin B, ketoconazole, sapoconazole, Voriconazole, 5-fluorocytosine, miconazole, fluconazole, griseofulvin, clotrimazole, econazole, Terconazole, butoconazole, oxconazole, thioconazole, cyclopyramine, halopropynyloxybenzene, tolnaftate, naftifine, terbinafine hydrochloride, morphine, nystatin, swim Mycin, butenafine, undecylenic acid, benzoic acid and salicylic acid ointment, propionic acid and caprylic acid. In another aspect, the invention features a method of making an antifungal formulation. The formula contains itraconazole and water. Itraconazole is dissolved in the formulation at a concentration greater than about 25 // g / mL. For example, itraconazole can be dissolved in the formulation at a concentration greater than about 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, or 180 / zg / mL. . -18-This paper size applies to Chinese National Standard (CNS) A4 (210X297mm) (Please read the precautions on the back before filling this page)

、1T 1236905 Λ? Η- — … I 1 1 —I%· η. l_ _1冷朴 W-urj 一— W—一W «·· ..- ·ΙΙΙ·Ι I I ——.11·· 五、發明説明（^ ) 水構成該配方的至少約50%。例如，水可以構成該配方的至少約 55、60、65、70、75、80、85、90、95 或 99% ° 該方法包含添加水至含有伊曲康唑的貯備溶液中。在另一方面，本發明的特徵在於培養來自哺乳動物粘液的真菌的方法。該方法包含（1 )將粘液與粘液溶解劑接觸以降低粘液的粘度，（2 )從降低粘度的粘液中分離真菌，（3)將分離的真菌與真菌培養基接觸以形成真菌培養物，（4 )培養真菌培養物從而使分離的真菌生長。在另一方面，本發明的特徵在於用於獲得真菌抗原的方法。該方法包含（1 )將哺乳動物的粘液與粘液溶解劑接觸以降低粘液的粘性，（2 )從降低粘性的粘液中分離真菌，（3)將分離的真菌與真菌培養基接觸以形成真菌培養物，（4 )培養真菌培養物從而使分離的真菌生長，和 (5)從培養的真菌中分離抗原。經濟部中央標準局員工消費合作社印製在另一方面，本發明的特徵在於製備真菌特異性抗體的方法。該方法包含（1 )將哺乳動物粘液與粘液溶解劑接觸以降低粘液的粘性，（2 )從降低粘性的粘液中分離真菌，（3)將分離的真菌與真菌培養基接觸以形成真菌培養物，（4 )培養真菌培養物從而使分離的真菌生長，（5 ) 從培養的真菌中分離抗原和（6 )以該真菌抗原免疫動物製備抗體。在另一方面，本發明的特徵在於鼻粘液收集器。該收集器含有收集容器（collection retainer)，收集管和連接部份。此收集容器適用於容納粘液。收集管從收集容器處 -19 _ 本紙張尺度適用巾國國家標準（CNS ) A4規格（210X2^7公釐) ' " 1236905 Λ? —____ 五、發明説明（17 ) 延伸並限定了遠末端和一個管腔從而使粘液從收集管的遠末端穿越管腔至收集容器。收集管全長的至少一部份是彈性的，從而在收集過程中該管可由醫生選擇性彎成所需的構型。進一步的說，收集管一般是有韌性的從而使收集管一般維持所需的構型直至醫生操縱收集管以適應不同的構型。連接部份從收集容器延伸並限定了一個與收集容器內部相通的第二管腔。調整連接部份以接受真空源 (vacuum source)。此外，該收集器可進一步含有調整第二管腔開口的閥門。收集容器可從收集管和連接部份上除下。在另一方面，本發明的特徵在於含有抗真菌劑的藥用組合物。在另一實施方案中，本發明的特徵在於含有抗真菌劑和粘液溶解劑的藥用組合物。另一實施方案的特徵在於含有抗真菌劑和類固醇的藥用組合物。另一實施方案的特徵在於含有抗真菌劑和去充血劑的藥用組合物。經濟部中央標準局員工消費合作社印製另一實施方案的特徵在於含有抗真菌劑和抗生素的藥用組合物。另一實施方案的特徵在於含有抗真菌劑和抗炎劑的藥用組合物。另一實施方案的特徵在於含有抗真菌劑和抗組胺劑的藥用組合物。 -20 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）一 1236905 五、發明説明（18 ) 另一實施方案的特徵在於含有抗真菌劑和抗膽鹼能劑的藥用組合物。另一實施方案的特徵在於含有抗真菌劑和白三烯抑制劑的藥用組合物。方面’本發明的特徵在於治療哺乳動物對真 ®免疫s應的組合物，其特徵在於構建用於直接粘膜施用至哺乳動物粘液並且具有消除或降低真菌至閾値以下水平的抗真菌方法的試劑，其中在該閾値水平下真菌停止激活嗜酸性細胞遷移至受影響的區域。 ’本發明的特徵在於治療哺乳動物患者鼻竇解剖' 0市解剖、耳解剖或腸解剖位置中與真菌有關的病情的藥用組合物’該組合物包含一有效劑量的本文所述的一抗真菌劑。在另一方面’本發明的特徵在於治療哺乳動物患者鼻s解剖'肺解剖、耳解剖或腸解剖位置中與真菌有關的病情的藥用組合物’其中該組合物包含一有效劑量的本文所述的一抗真菌劑和至少一種其它試劑或抑制劑。經濟部中央標準局員工消費合作社印製在另一方面’本發明的特徵在於用於治療哺乳動物病人鼻竇解剖’肺解剖，耳解剖或腸解剖位置中與真菌有關的病情的藥用組合物，該組合物包含適於長期在鼻竇解剖位置中使用的一有效劑量的一抗真菌劑。在另一方面’本發明的特徵在於治療病人鼻竇炎、哮喘、中耳炎或結腸炎的藥劑，包含粘液溶解劑；和本文所述的一抗真菌化合物。 _________-21- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（ ----------" 1236905 _ ·、一一 _ "--一 —… >· , I ·.〜·. 五、發明説明（】9 ) 在另一方面，本發明的特徵在於治療病人發炎鼻區、肺區、耳區或腸區的灌注藥劑，該發炎的鼻區、肺區、耳區或腸區是由於真菌的存在所致，該藥劑包含有效劑量的本文所述的一抗真菌化合物和一類固醇。在另一方面，本發明的特徵在於治療病人發炎鼻區、肺區、耳區或腸區的灌注藥劑，該發炎的鼻區、肺區、耳區或腸區是由於真菌的存在所致，該藥劑包含有效劑量的一抗真菌化合物和一粘液溶解劑。在另一方面，本發明的特徵在於治療病人發炎鼻區、肺區、耳區或腸區的灌注藥劑，該發炎的鼻區、肺區、耳區或腸區是由於真菌的存在所致，該藥劑包含有效劑量的本文所述的一類固醇和一粘液溶解劑。在另一方面，本發明的特徵在於治療病人發炎鼻區、肺區、耳區或腸區的灌注藥劑，該發炎的鼻區、肺區、耳區或腸區是由於真菌的存在所致，該藥劑包含有效劑量的本文所述的一抗真菌化合物、一類固醇和一粘液溶解劑。經濟部中央標準局員工消費合作社印製在另一方面，本發明的特徵在於治療病人發炎鼻區、肺區、耳區或腸區的灌注藥劑，該發炎的鼻區、肺區、耳區或腸區是由於真菌的存在所致，該藥劑包含一有效劑量的本文所述的至少一選自由一抗真菌化合物、一類固醇、一粘液溶解劑及其組合所組成的藥物。如果沒有特別說明，本文所用的技術和科學術語與本發明涉及的領域的普通技術人員的常規理解具有相同的 -22 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐) " 1236905 _______ 五、發明説明ς。）意義。儘管在實踐或測試本發明中可以使用與本文所述類似或等同的方法與材料，但適當的方法與材料描述如下。本文提及的所有出版物、專利申請、專利和其它文獻以其全文作爲參考文獻引用。在衝突情況時，以本說明書，包含定義爲準。此外，材料、方法和實施例僅僅是說明性的而不是爲了限制。本發明的其他特徵和優勢從下面的詳細描述和申請專利範圍來看將是顯而易見的。圖示之簡單說明圖1爲具有兩側慢性鼻竇炎病人的CT掃描。圖2爲圖1的病人在以抗真菌灌注治療四個月後的 CT掃描。圖3爲描述用於收集粘液裝置的圖。圖4爲描述用於收集粘液裝置的圖。發明之詳細說明經濟部中央標準局員工消費合作社印製本發明包含用於治療和預防非侵襲性真菌誘導粘膜炎的方法和物質。具體地說，本發明包含以能有效預防、緩解或消除慢性非侵襲性真菌誘導的鼻竇炎的量、頻率和時間粘膜施用抗真菌劑。本發明也提供用於診斷慢性非侵襲性真菌誘導的鼻竇炎和培養來自哺乳動物粘液樣品的非侵襲性真菌的方法和物質以及用於治療和預防非侵襲性真菌誘導鼻竇炎的特導性抗真菌配方和醫療裝置。此 -23 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1236905 — )\η ~~ _________________ __________ ___________ 五、發明説明（21 ) 外，本發明提供用於治療和預防其它非侵襲性真菌誘導的粘膜炎病情如慢性中耳炎、慢性結腸炎、和節段性回腸炎的方法和物質。經濟部中央標準局員工消費合作社印製儘管不受任何特定的作用模式限制，但包含通過用抗真菌劑治療和預防粘膜組織非侵襲性真菌誘導炎症的本發明是基於下面提出的來自本文所報導發現的疾病進展機制。一般來說，即使不是全部，但大多數個體有生活於其粘液中的真菌生物。通常，大多數個體忍受這些非侵襲性生物並且過著正常的無病生活。由於未知的原因，有些個體不能忍受這些真菌生物並且開始形成對其的免疫反應。隨著免疫反應的進展，嗜酸性細胞在局部組織中聚集。嗜酸性細胞的聚集可促進阻擋性組織塊（如息肉和息肉狀結構）的形成以及激活的嗜酸性細胞從組織（身體內部）遷移至粘液（身體外部）。這些阻擋性組織塊似乎阻止正常的孔腔淸潔並且因而可利於其它的真菌生長。一旦嗜酸性細胞位於粘液內，它們很可能在表面FC受體激活時釋放其嗜酸性粒的內容物。嗜酸性粒含有許多毒性分子如嗜酸性陽離子蛋白（ECP)、嗜酸性細胞過氧化物酶（ΕΡΟ)和主要基本蛋白（MB Ρ)。釋放時，這些毒性分子可損傷靶向的外源微生物（如真菌）以及自身組織。由嗜酸性細胞聚積和嗜酸性脫顆粒（degranulation)所致的損害程度變化明顯，以輕微的炎病疼痛和不適應嚴重結構異常如組織和骨毀壞以及息肉、息肉狀結構和其它腫瘤的形成。一旦自身組織受到損傷，該個體對細菌感染等的易感性也可增加。因 -24 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1236905 五、發明説明ς2 ) 此，在即使不是全部，但也是大多數的慢性鼻竇炎中所觀察到的特徵性炎症反應，所致的損害和所致的細菌感染實際上是由非侵襲性真菌生物所誘發的。已注意到真菌生物可以在極端粘膜炎狀態和骨毀壞情況下在組織內觀察到，僅僅因爲身體內部和外部之間的屏障（即，表皮）已被毀壞或損傷了。在這些情況中，在損害組織的局部區域內僅僅觀察到的少量真菌生物的存在沒有排除這樣的事實，即該痛苦爲非侵襲性真菌誘導的粘膜炎並且不是一種感染。經濟部中央標準局員工消費合作社印製如果不是全部，但大多數慢性鼻竇炎病例是由非侵襲性真菌生物所致的發現表明其它慢性炎症病情如慢性中耳炎、慢性結腸炎和節段性回腸炎最可能是由生活於粘液中的非侵襲性真菌生物所致。此外，非侵襲性真菌誘導的鼻竇炎當粘膜施用有效量、有效頻率和有效時間的抗真菌劑時可被成功地治療和預防的發現表明這些其它非侵襲性真菌誘導的粘膜炎病情也可以按本文所述適當的使用抗真菌劑進行治療和預防。此外，慢性哮喘症可以通過鼻旁灌注方式直接粘膜施用抗真菌劑至呼吸道進行治療和預防的發現表明當經過鼻或嘴吸入直接粘膜施用該抗真菌劑至呼吸道時可能是有效的。因此，本文該方法和物質具有治療數百萬患慢性鼻竇炎、慢性中耳炎、慢性結腸炎、節段性回腸炎和任何其它非侵襲性真菌誘導的粘膜炎病情以及慢性哮喘患者的潛能。如上所述，非侵襲性真菌誘導的粘膜炎爲發炎而不是 -25 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公f] 1236905 1Γ I I ___ *—*^^"** 111 _·."*· '1 I. I . .1,1. I ..- . -w».- ： — .1·'·»'-—·· . . ---------- ----1,1 ,| mv___ 五、發明説明L ) 感染。一般來說，發炎在本質上和臨床上不同於感染。感染定義爲生物在組織內的生長。此外，感染的特徵爲侵襲性疾病，意指感染的生物進入宿主組織內，然後誘導發出宿主免疫反應和/或導致損傷。因此，感染性生物的作用一般爲侵襲性病原體的作用。此外，感染的個體可以爲免疫活性的或免疫損傷的。當感染的個體受到免疫損傷時，該感染常稱爲“機會”感染。此外，依據多種因素如感染個體免疫系統的能力、侵襲性病原體的性質和醫療處理的有效性，感染可爲急性或慢性的。相反，發炎爲用於破壞、稀釋和/或隔離有害物質或侵襲的局部保護性反應。此外，炎症反應一般導致發紅、腫脹、發熱、和疼痛。在非侵襲性真菌誘導粘膜炎病例中，局部保護性反應是針對生活在組織（如粘膜內）外部的非侵襲性真菌生物。一般地，患非侵襲性真菌誘導粘膜炎的一些個體爲特異反應性和/或免疫活性的。此外，有害物質（如真菌）的作用爲非侵襲性過敏原的作用。因此’非侵襲性真菌誘導粘膜炎爲由個體的免疫系統產生的抵抗生活於個體組織外部真菌生物的過敏反應。經濟部中央標準局員工消費合作社印製如本文所述，本發明提供了將粘液內的真菌生物降低至一定水平和一定時間內的方法和物質’從而終止、治療或預防與粘膜炎有關的特徵性炎症反應和所產生的損傷。爲了淸楚的目的’降低真菌生物在粘液內的存在以治療或預防粘膜炎類似於從患過敏反應（如’枯草熱）的個體中去除過敏原（如，花粉）。另外’對，例如，花粉的過敏 -26 - 本紙張尺度適用中國國家標準（CNS ) A4規格（2丨〇><297公釐） 1236905 經濟部中央標準局員工消費合作社印製 Λ_ ΙΓ 五、發明説明L ) 反應不是感染而是發炎。此外，本發明的簡易性強調了這些發現後深遠的臨床應用。例如，一旦臨床醫生明白雖不是全部，但大多數慢性鼻竇炎是由非侵襲性真菌生物所致並且此炎症疾病可通過用本文該方法和物質降低鼻旁粘液內非侵襲性真菌生物的水平而治愈和預防，那麼數百萬人們將能夠過上更爲健康、幸福和卓有成效的生活。鑑定非侵襲性真菌誘導的粘膜炎非侵襲性真菌誘導的粘膜炎定義爲由非侵襲性真菌生物誘導的任何粘膜組織的炎症。粘膜組織的實例非限定性地包含口腔、腸道、鼻道、鼻旁竇、肺呼吸道、氣管、中耳、咽鼓管、***和尿道的粘膜。一般來說，粘膜組織的炎症可用技術人員通常熟知的任何一種方法測定。例如，通過組織活檢以及視覺檢查、內窺鏡分析和圖像分析技術（如，X-射線，CT掃描和磁共振成像（MRI)掃描）可鑑定個體是否患有粘膜組織炎症，因爲各種發炎的粘膜解剖位置可顯示出可觀察到的異常特徵。可用多種診斷方法測定是否特定的粘膜炎爲非侵襲性真菌誘導的粘膜炎。一般來說，這種診斷方法非限制性地包含復查患者以前的醫療條件及治療、訪問和評估患者，以及從患者中收集和分析生物樣品。復查患者的病史可有助於測定是否特定的粘膜炎爲非侵襲性真菌誘導的粘膜炎，因爲此類炎症一般爲復發性和慢性的。因此，以前有非侵襲性真菌誘導粘膜炎事件的 -27 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閱讀背面之注意事項再填寫本頁) r裝·, 1T 1236905 Λ? Η- —… I 1 1 —I% · η. L_ _1 Lengpu W-urj One — W—One W «·· ..- · ΙΙΙ · Ι II ——. 11 ·· V. DESCRIPTION OF THE INVENTION (^) Water constitutes at least about 50% of the formulation. For example, water may constitute at least about 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99% of the formula. The method includes adding water to a stock solution containing itraconazole. In another aspect, the invention features a method of culturing a mucus from a mammalian mucus. The method includes (1) contacting mucus with a mucolytic agent to reduce the viscosity of the mucus, (2) separating the fungus from the viscosity-reducing mucus, (3) contacting the isolated fungus with a fungal culture medium to form a fungal culture, (4) ) Cultivating the fungal culture to grow the isolated fungus. In another aspect, the invention features a method for obtaining a fungal antigen. The method comprises (1) contacting mammalian mucus with a mucus solubilizing agent to reduce the viscosity of the mucus, (2) separating the fungus from the mucus that reduces the viscosity, and (3) contacting the isolated fungus with a fungal culture medium to form a fungal culture (4) cultivating the fungal culture to grow the isolated fungus, and (5) isolating the antigen from the cultured fungus. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. In another aspect, the invention features a method for preparing fungal-specific antibodies. The method comprises (1) contacting a mammalian mucus with a mucus solubilizing agent to reduce mucus viscosity, (2) separating a fungus from the mucus reducing viscosity, (3) contacting the isolated fungus with a fungal culture medium to form a fungal culture, (4) cultivating the fungal culture so that the isolated fungus grows, (5) isolating the antigen from the cultured fungus and (6) immunizing animals with the fungal antigen to prepare antibodies. In another aspect, the invention features a nasal mucus collector. The collector contains a collection retainer, a collection tube and a connection part. This collection container is suitable for holding mucus. Collecting tube from the collecting container-19 _ This paper size applies the national standard (CNS) A4 size of the towel (210X2 ^ 7 mm) '" 1236905 Λ? —____ 5. Description of the invention (17) extends and defines the far end And a lumen to allow mucus to pass from the distal end of the collection tube to the collection container. At least a portion of the total length of the collection tube is elastic, so that the tube can be selectively bent by the doctor into the desired configuration during the collection process. Further, the collection tube is generally flexible so that the collection tube generally maintains the desired configuration until the doctor manipulates the collection tube to adapt to a different configuration. The connecting portion extends from the collection container and defines a second lumen communicating with the inside of the collection container. Adjust the connection to accept the vacuum source. In addition, the collector may further include a valve that adjusts the opening of the second lumen. The collection container can be removed from the collection tube and connection. In another aspect, the invention features a pharmaceutical composition containing an antifungal agent. In another embodiment, the invention features a pharmaceutical composition comprising an antifungal agent and a mucolytic agent. Another embodiment is characterized by a pharmaceutical composition comprising an antifungal agent and a steroid. Another embodiment is characterized by a pharmaceutical composition comprising an antifungal agent and a decongestant. Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Another embodiment is characterized by a pharmaceutical composition containing antifungal agents and antibiotics. Another embodiment is characterized by a pharmaceutical composition comprising an antifungal agent and an anti-inflammatory agent. Another embodiment is characterized by a pharmaceutical composition comprising an antifungal agent and an antihistamine. -20-This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 1123690 5. Description of the invention (18) Another embodiment is characterized by a medicinal combination containing an antifungal agent and an anticholinergic agent Thing. Another embodiment is characterized by a pharmaceutical composition comprising an antifungal agent and a leukotriene inhibitor. Aspect 'The present invention is characterized by a composition for treating mammalian immune response to true®, characterized by constructing an agent for direct mucosal administration to mammalian mucus and having an antifungal method for eliminating or reducing fungi to a level below threshold, Where the fungus stops activating eosinophils to migrate to the affected area at this threshold level. 'The invention is characterized by the treatment of a sinus anatomy in a mammalian patient' 0 A pharmaceutical composition for fungal-related conditions in anatomy, ear anatomy or intestinal anatomy 'This composition comprises an effective dose of an antifungal as described herein Agent. In another aspect, the invention features a pharmaceutical composition for treating a mammalian patient's nasal anatomy, a fungal-related condition in a lung anatomy, ear anatomy, or intestinal anatomy location, wherein the composition comprises an effective dose as described herein. A primary antifungal agent and at least one other agent or inhibitor. In another aspect, the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed a medicinal composition of the present invention which is used to treat mammalian patients with sinus anatomy, lung anatomy, ear anatomy, or intestinal anatomy in relation to fungal conditions, The composition contains an effective dose of an antifungal agent suitable for long-term use in anatomic locations of the sinuses. In another aspect, the invention features an agent for treating sinusitis, asthma, otitis media, or colitis in a patient, comprising a mucolytic agent; and an antifungal compound described herein. _________- 21- This paper size applies the Chinese National Standard (CNS) Λ4 specification (---------- " 1236905 _ · 、一一 _ "-一 ——… > ·, I ·. ~ ·. V. Description of the invention (9) In another aspect, the present invention is characterized by infusion agent for treating patients with inflamed nasal, lung, ear or intestinal area, the inflamed nasal, pulmonary, ear area Or the intestinal area is caused by the presence of a fungus, and the agent comprises an effective dose of an antifungal compound and a steroid described herein. In another aspect, the invention features treating the patient's inflamed nasal, lung, and ear areas Or intestinal infusion agent, the inflamed nasal, lung, ear, or intestinal area is caused by the presence of fungi, the agent comprises an effective dose of an antifungal compound and a mucolytic agent. In another aspect, The invention is characterized by an infusion agent for treating an inflamed nasal, lung, ear or intestinal area of a patient. The inflamed nasal, pulmonary, ear or intestinal area is caused by the presence of a fungus, and the agent contains an effective dose. A steroid and a mucus dissolve as described herein In another aspect, the invention features an infusion agent for treating an inflamed nasal, pulmonary, ear, or intestinal region of a patient, the inflamed nasal, pulmonary, ear, or intestinal region due to the presence of a fungus The medicament contains an effective dose of an antifungal compound, a steroid, and a mucolytic agent described herein. Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs. In another aspect, the present invention is characterized by the treatment of inflammation in the nose area , Lung, ear, or intestine infusion agent, the inflamed nose, lung, ear, or intestine is caused by the presence of fungi, the agent contains an effective dose of at least one selected from the group consisting of A drug consisting of an antifungal compound, a steroid, a mucolytic agent, and a combination thereof. Unless otherwise specified, the technical and scientific terms used herein have the same -22 as the conventional understanding of those skilled in the art to which the present invention relates. -This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) " 1236905 _______ V. Description of the invention.) Meaning. 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, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description and the scope of the patent application. Brief illustration of the figure Figure 1 is a CT scan of a patient with chronic sinusitis on both sides. Figure 2 is a CT scan of the patient of Figure 1 after four months of antifungal perfusion treatment. FIG. 3 is a diagram describing a device for collecting mucus. FIG. 4 is a diagram describing a device for collecting mucus. Detailed description of the invention Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics The present invention contains methods and substances for the treatment and prevention of non-invasive fungal-induced mucositis. Specifically, the present invention comprises the administration of antifungal agents in a mucosal amount, frequency, and time effective to prevent, alleviate or eliminate chronic non-invasive fungal-induced sinusitis. The invention also provides methods and materials for diagnosing chronic non-invasive fungal-induced sinusitis and culturing non-invasive fungi from mammalian mucus samples, as well as specific resistances for treating and preventing non-invasive fungal-induced sinusitis. Fungal formulas and medical devices. This-23-This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210X297 mm) 1236905 —) \ η ~~ _________________ __________ ___________ 5. Description of the invention (21) In addition, the invention provides for the treatment and prevention of other non- Methods and substances for invasive fungal-induced mucositis conditions such as chronic otitis media, chronic colitis, and segmental ileitis. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, although not subject to any specific mode of action, the present invention, which includes treatment and prevention of non-invasive fungal-induced inflammation of mucosal tissues with antifungal agents, is based on the following report from this article Discovered disease progression mechanisms. In general, if not all, most individuals have fungal organisms that live in their mucus. Generally, most individuals endure these non-invasive organisms and lead a normal disease-free life. For unknown reasons, some individuals cannot tolerate these fungal organisms and begin to develop an immune response to them. As the immune response progresses, eosinophils accumulate in local tissues. The accumulation of eosinophils promotes the formation of blocking tissue masses (such as polyps and polyp-like structures) and the migration of activated eosinophils from tissue (inside the body) to mucus (outside the body). These blocking tissue blocks appear to prevent normal porosity from being contaminated and thus may facilitate the growth of other fungi. Once the eosinophils are in the mucus, they are likely to release the contents of their eosinophils when the surface FC receptor is activated. Eosinophils contain many toxic molecules such as eosinophilic cationic protein (ECP), eosinophil peroxidase (EPO), and major basic proteins (MBP). When released, these toxic molecules can damage targeted foreign microorganisms (such as fungi) and their own tissues. The degree of damage caused by the accumulation of eosinophils and eosinophilic degranulation varies significantly, with mild inflammatory pain and maladjustment, severe structural abnormalities such as tissue and bone destruction, and the formation of polyps, polypoid structures, and other tumors. Once the self tissue is damaged, the individual's susceptibility to bacterial infections and the like can also increase. Yin-24-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1236905 V. Description of invention ς 2) This is the characteristic observed in most chronic sinusitis, if not all The inflammatory response, the damage caused, and the bacterial infections are actually induced by non-invasive fungal organisms. It has been noted that fungal organisms can be observed in tissues under conditions of extreme mucositis and bone destruction, simply because the barrier (ie, epidermis) between the inside and outside of the body has been destroyed or damaged. In these cases, the presence of only a small number of fungal organisms observed in a localized area of the damaged tissue does not rule out the fact that the pain is non-invasive fungal induced mucositis and is not an infection. Printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs, if not all, but most cases of chronic sinusitis are caused by non-invasive fungal organisms. Findings indicate other chronic inflammatory conditions such as chronic otitis media, chronic colitis, and segmental ileitis. Most likely caused by non-invasive fungal organisms that live in mucus. In addition, the discovery that non-invasive fungal-induced sinusitis can be successfully treated and prevented when an effective amount, frequency, and duration of antifungal agents are administered to the mucosa indicates that these other non-invasive fungal-induced mucositis conditions can also be treated as follows: The appropriate use of antifungals described herein for treatment and prevention. In addition, the discovery that chronic asthma can be treated and prevented by mucosal administration of an antifungal agent directly to the respiratory tract by paranasal infusion means that the antifungal agent may be effective when administered directly mucosally to the respiratory tract by inhaling through the nose or mouth. Therefore, the methods and materials herein have the potential to treat millions of patients with chronic sinusitis, chronic otitis media, chronic colitis, segmental ileitis, and any other non-invasive fungal-induced mucositis and chronic asthma. As mentioned above, non-invasive fungal-induced mucositis is inflammation instead of -25-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 male f) 1236905 1Γ II ___ * — * ^^ " ** 111 _ ·. &Quot; * · '1 I. I. .1,1. I ..-. -W ».-: — .1 ·' ·» '-— ··.. ------- --- ---- 1,1, | mv___ 5. Description of the Invention L) Infection. In general, inflammation is different from infections in nature and clinically. Infection is defined as the growth of organisms in tissues. In addition, infection is characterized by an invasive disease, meaning that the infected organism enters the host tissue and then induces a host immune response and / or causes damage. Therefore, the role of infectious organisms is generally the role of invasive pathogens. In addition, infected individuals can be immunologically active or immunocompromised. When an infected individual is immunocompromised, the infection is often referred to as an "opportunistic" infection. In addition, infections can be acute or chronic depending on factors such as the ability to infect the individual's immune system, the nature of the invasive pathogen, and the effectiveness of the medical treatment. In contrast, inflammation is a local protective response used to destroy, dilute and / or isolate harmful substances or attacks. In addition, inflammatory reactions generally cause redness, swelling, fever, and pain. In cases of non-invasive fungal-induced mucositis, the local protective response is directed at non-invasive fungal organisms that live outside the tissue (eg, inside the mucosa). Generally, some individuals suffering from non-invasive fungal-induced mucositis are specifically reactive and / or immunologically active. In addition, the effects of harmful substances such as fungi are the effects of non-invasive allergens. Therefore, 'non-invasive fungal-induced mucositis is an allergic reaction produced by an individual's immune system against a fungal organism living outside the individual tissue. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs As described herein, the present invention provides a method and substance for reducing fungal organisms in mucus to a certain level and within a certain period of time, thereby terminating, treating, or preventing features associated with mucositis Sexual inflammatory response and the resulting damage. For succinct purposes' reducing the presence of fungal organisms in the mucus to treat or prevent mucositis is similar to removing allergens (eg, pollen) from individuals suffering from an allergic reaction (eg, 'hay fever'). In addition, allergies to, for example, pollen-26-This paper size applies Chinese National Standard (CNS) A4 specifications (2 丨〇 < 297 mm) 1236905 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Λ_ ΙΓ 5 Explanation of the invention L) The reaction is not infection but inflammation. In addition, the simplicity of the present invention highlights the profound clinical application of these discoveries. For example, once the clinician understands that although not all, most chronic sinusitis is caused by non-invasive fungal organisms and this inflammatory disease can be reduced by using the methods and substances described herein to reduce the level of non-invasive fungal organisms in the paranasal mucus. Cure and prevent, then millions of people will be able to lead healthier, happier and more productive lives. Identification of non-invasive fungal-induced mucositis Non-invasive fungal-induced mucositis is defined as inflammation of any mucosal tissue induced by non-invasive fungal organisms. Examples of mucosal tissue include, but are not limited to, the mucous membranes of the oral cavity, intestinal tract, nasal tract, paranasal sinuses, pulmonary airways, trachea, middle ear, eustachian tube, vagina, and urethra. In general, inflammation of mucosal tissue can be measured by any method commonly known to the skilled person. For example, tissue biopsy and visual inspection, endoscopic analysis, and image analysis techniques (such as X-rays, CT scans, and magnetic resonance imaging (MRI) scans) can be used to identify individuals with inflammation of mucosal tissues because of various The anatomical location of the mucosa may show observable abnormal features. Various diagnostic methods can be used to determine whether a particular mucositis is non-invasive fungal induced mucositis. Generally, this diagnostic method includes, without limitation, reviewing a patient's previous medical conditions and treating, interviewing and evaluating the patient, and collecting and analyzing biological samples from the patient. A review of the patient's medical history can help determine if a particular mucositis is non-invasive fungal-induced mucositis, as such inflammation is generally recurrent and chronic. Therefore, there have been non-invasive fungal-induced mucositis incidents in the past. -27-This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page) r Pack ·

、1T 經濟部中央標準局員工消費合作社印製 1236905 Η"7 五、發明説明（25 ) 跡象可提示目前的粘膜炎也爲非侵襲性真菌誘導的粘膜炎。患者病史中其它有用的信息將非限制性地包含過敏、手術和其它疾病如囊性（cystic)纖維變性和睫狀不動性綜合症（ciliary dismotility Syndromes)。訪問和評估患者也可有助於鑑定非侵襲性真菌誘導的粘膜炎。例如，患慢性粘膜炎症狀如呼吸道阻塞、味覺喪失、聽力喪失、哮喘、呼吸困難、咳嗽、頭痛和面部緊張（pressure)的個體可能患有非侵襲性真菌誘導的粘膜炎。此外，可根除表現出感染症狀如發熱、真菌散播、真菌血症、多形核白細胞的增加和急性發作個體中的非侵襲性真菌誘導的粘膜炎。應注意到復發的細菌感染可能暗示著構成其基礎的非侵襲性真菌誘導的粘膜炎病情，因爲慢性炎症可導致上皮的毀壞並且因此增加了個體對細菌感染的易感性。此外，可進行多種診斷測試以幫助鑑定出非侵襲性真菌誘導的粘膜炎。例如，可用一組真菌和非真菌抗原進行常規過敏篩選測定是否個體爲特異反應性的，因爲有些非侵襲性真菌誘導的粘膜炎病例包含特異反應性的個體。此外，可用用以測定是否存在抗真菌抗原抗體的基於免疫的測試、使用或不用乙醯甲基膽鹼（methacholine) 的異常肺功能測試、聽力圖（audiogram)和鼓膜圖 (tym pa nog rams)鑑定非侵襲性真菌誘導的粘膜炎。收集和分析來自患者的生物樣品可有助於鑑定非侵襲性真菌誘導的粘膜炎。一般來說，可收集和分析生物樣品如粘液、糞便、尿、痰和血以找出表明有非侵襲性真菌 -28 - 本紙張尺度適用中國國家標準（CNS ) A4規格（2!OX 297公釐） ―― (請先閱讀背面之注意事項再填寫本頁)Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the 1T. 1236905 Η " 7 V. Description of the invention (25) The signs can indicate that the current mucositis is also non-invasive fungal induced mucositis. Other useful information in the patient's medical history will include, without limitation, allergies, surgery, and other diseases such as cystic fibrosis and ciliary dismotility syndromes. Interviewing and evaluating patients can also help identify non-invasive fungal-induced mucositis. For example, individuals suffering from chronic mucosal inflammation symptoms such as airway obstruction, taste loss, hearing loss, asthma, dyspnea, cough, headache, and facial pressure may suffer from non-invasive fungal-induced mucositis. In addition, non-invasive fungal-induced mucositis in individuals exhibiting symptoms of infection such as fever, fungal spread, bacteremia, increase in polymorphonuclear leukocytes, and acute attacks can be eradicated. It should be noted that recurrent bacterial infections may imply non-invasive fungal-induced mucositis conditions that underlie it, as chronic inflammation can cause destruction of the epithelium and thus increase an individual's susceptibility to bacterial infections. In addition, a variety of diagnostic tests can be performed to help identify non-invasive fungal-induced mucositis. For example, a group of fungal and non-fungal antigens can be used for routine allergy screening to determine whether an individual is specifically reactive, as some cases of non-invasive fungal-induced mucositis include specifically reactive individuals. In addition, immune-based tests to determine the presence of antifungal antibodies, abnormal lung function tests, audiograms, and tympanograms (tym pa nog rams) with or without methacholine Identification of non-invasive fungal-induced mucositis. Collecting and analyzing biological samples from patients can help identify non-invasive fungal-induced mucositis. In general, biological samples such as mucus, feces, urine, sputum, and blood can be collected and analyzed to identify non-invasive fungi-28-This paper size applies to China National Standard (CNS) A4 (2! OX 297) Li) —— (Please read the notes on the back before filling in this page)

經濟部中央標準局員工消費合作社印製 1236905 Λ ' ΙΓ 五、發明説明（26 ) 生物參與的跡象。這些跡象可非限制性地包含非侵襲性真菌誘導粘膜炎任何抗原性標記的存在；嗜酸性細胞、嗜酸性細胞產物（如，MBP和ECP)、抗體、真菌抗原或真菌生物在粘液、糞便、尿、或痰樣品中的存在；和真菌生物在血液樣品中的不存在。例如，對過敏性粘膜（即，含有嗜酸性細胞存在跡象的粘膜）的鑑定可指示非侵襲性真菌誘導的粘膜炎。這種嗜酸性細胞存在的跡象非限制性地包含完整嗜酸性細胞、壞死嗜酸性細胞和嗜酸性細胞產物的存在。用於檢測這些各種這些跡象和標記在生物樣品中存在的多種方法在本領域是眾所周知的並且可以使用。例如，可用蘇木精/曙紅染色然後顯微鏡檢查測定過敏粘膜內嗜酸性細胞的存在。此外，可收集，分析組織活檢材料查出是否有侵襲性真菌。如上所述，當檢查組織活檢材料時可觀察到在極端組織粘膜炎條件和骨毀壞時組織中有真菌生物，這僅僅是因爲身體內部和外部的屏障（如上皮）已被破壞或損傷。在這些情況下，僅僅在組織損傷局部區域內少量真菌生物的存在並不一定意味著病疼不是非侵襲性真菌誘導的粘膜炎。此外，可用基於免疫的分析檢測生物樣品中各種非侵襲性真菌誘導粘膜炎的跡象。許多基於免疫的分析在本領域是眾所周知的，非限定性地包含酶聯免疫吸附分析 (ELISA)和放射過敏性吸附測試（radioallergosorbant tests)(RAST)。使用RAST的方法描述於，例如，McRury -29 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐) (請先閱讀背面之注意事項再填寫本頁) r裝· II, 1236905Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 1236905 Λ 'ΙΓ 5. Description of the invention (26) Signs of biological participation. These signs may include, without limitation, the presence of any antigenic marker of non-invasive fungal-induced mucositis; eosinophils, eosinophilic products (eg, MBP and ECP), antibodies, fungal antigens, or fungal organisms in mucus, feces, Presence in urine, or sputum samples; and absence of fungal organisms in blood samples. For example, identification of an allergic mucosa (ie, a mucous membrane containing signs of the presence of eosinophils) may indicate non-invasive fungal-induced mucositis. Signs of the presence of such eosinophils include, without limitation, the presence of intact eosinophils, necrotic eosinophils, and eosinophilic products. A variety of methods for detecting the presence of these various signs and labels in biological samples are well known in the art and can be used. For example, hematoxylin / eosin staining followed by microscopy can be used to determine the presence of eosinophils in allergic mucosa. In addition, tissue biopsy materials can be collected and analyzed for invasive fungi. As mentioned above, when examining tissue biopsy materials, fungal organisms can be observed in the tissue during extreme tissue mucositis conditions and bone destruction, simply because the internal and external barriers, such as the epithelium, have been destroyed or damaged. In these cases, the presence of a small amount of fungal organisms only in the localized area of tissue damage does not necessarily mean that the pain is not non-invasive fungal-induced mucositis. In addition, immune-based assays can be used to detect signs of mucositis induced by various non-invasive fungi in biological samples. Many immune-based assays are well known in the art and include, without limitation, enzyme-linked immunosorbent assays (ELISA) and radioallergosorbant tests (RAST). The method using RAST is described in, for example, McRury -29-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

IP ~ - I 1- - — -_- «. —.· , » I —«,_* --------------------— ---... ......J 一 m_ui . -I -」」五、發明説明k ) J等（臨床實驗免疫學65 : 631-638(1 986))、Mabry RL和 Manning S(Otolaryngol Head Neck Surg.113 ： 721 -723(1 995))，和 Lynch NR 等(Int Arch Allergy Immunol 114: 59-67(1997))。基於免疫的分析可使用對可作爲非侵襲性真菌誘導粘膜炎診斷標記的抗原具有特異性的多克隆抗體、單克隆抗體及其片段。例如，可製備和使用對已知導致非侵襲性真菌誘導粘膜炎的真菌生物具有特異性的單克隆抗體篩選生物樣品。該抗體可用別處該方法 [Zeidan等，生化和分子生物學實驗方法，William C· Brown出版社（1996)和Seaver，單克隆抗體的商業製備： Scale-Up 指南，Marcel Dekker 公司，紐約，NY(1987)] 製備。簡言之，以真菌生物分離物樣品免疫小鼠。數週後從免疫小鼠的脾臟中回收淋巴細胞並與骨髓瘤細胞融合以製備雜交瘤細胞。然後可分離對免疫的真菌分離物顯示出特異性的雜交瘤細胞並製備單克隆抗體製品。由於用於鑑定非侵襲性真菌誘導的粘膜炎的特異性方法和物質可隨粘膜炎的特異性位置而改變，故下面提供幾種舉例粘膜組織的詳細描述。經濟部中央標準局員工消費合作社印製 1 .鼻旁腔鼻的外部骨性骨架由2根橢圓形鼻骨所組成。兩根鼻骨各位於中線的一側，2根鼻骨形成弓形的交叉部份。鼻中隔將鼻腔一分爲二。鼻的側壁具有增加鼻腔或前庭粘膜表面積的三根鼻甲骨。鼻的前庭由鼻中隔和側壁所界 -30 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X291公釐） 1236905 Η17 五、發明説明Q ) 定。鼻甲骨和鼻中隔的大的表面積促進了與吸入空氣的廣泛接觸，從而促進加濕、顆粒去除和吸入空氣的溫度調節。鼻旁竇爲通過開口或孔與鼻腔相通的含有空氣的空間。儘管它們是成對的，鼻旁竇在形狀和位置上一般爲非對稱的，並且包含上頜、額、篩骨和蝶骨竇。鼻旁塞被認爲起到包含減輕頭骨重量、提供鼻腔粘膜和作爲聲音產生的共振腔的作用。上頜竇爲最大的鼻旁竇。每個上頜竇都位於上頜中並開口於中道（middle meatus)。額竇位於額骨中並且在眼窩的上方或中部。額竇也開口於中道。篩骨竇的數目眾多並且爲開口於中道和上道（superior meatuses) 的不規則形氣室。蝶竇位於蝶骨中並且位於眼和鼻腔上部的後部。蝶竇通入上道中。粘膜組織（粘膜）位於鼻腔和鼻旁竇的裡邊，一般包含上皮層、結締組織和粘液腺。粘膜層一般覆蓋粘膜、粘膜分泌的粘液用於捕捉顆粒和防止暴露於空氣中的鼻和鼻旁組織的脫水。粘液一般由纖毛向鼻咽方向運輸且然後被呑咽。經濟部中央標準局員工消費合作社印製用本領域已知的方法鑑定患鼻竇炎的個體。鼻竇炎症狀非限定性地包含鼻呼吸道阻塞、味覺的喪失、面部的疼痛、頭痛、後鼻滴注（drip)、和鼻溢（rhinorrhea)。檢查時，稠粘液的存在或視覺鑑定出具有粘液或息肉的鼻或鼻旁阻塞常表示有鼻竇炎病情。鼻息肉從鼻旁粘膜向外生長，其一般爲光滑、凝膠狀、半透明、圓形或梨形及灰白 1 3 1 - ^紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） ^ 1236905 Λ'7 _____ Η" 五、發明説明（29 ) 色。一般地，鼻息肉位於鼻側壁，通常位於中道或沿著中鼻甲或上鼻甲。大多數鼻息肉產生自篩骨竇但有些息肉起源於上頜蝶骨竇。鼻息肉塊主要由含少量纖維細胞的水腫液（edematous liquid)和少數粘液腺所組成。鼻和鼻旁息肉的表面上皮一般表現出鱗狀的組織變形。嗜酸性細胞通常以適中到大量存在於息肉中，並且現已知鼻息肉液含有大於正常濃度的IgA、IgE、IgG和IgM抗體以及異常高濃度的丨L-5，其爲促進嗜酸性細胞激活和存活的細胞因子。如本文所示，鼻息內的存在不是鼻竇炎的風險因子，而是慢性炎症的晚期。經濟部中央標準局員工消費合作社印製可用下面的方法和物質鑑定患非侵襲性真菌誘導的鼻竇炎的個體。如上述，稱爲AFS的病情爲非侵襲性真菌誘導的鼻竇炎病情。因此，可用用於鑑定AFS的本領域中任何已知的方法鑑定非侵襲性真菌誘導的鼻竇炎（Cody ΌΎ mm 1〇4： 1074-1079(1994)¾ Kupferberg SB # > Oto I a ryngol· Head Neck Surg 117 : 35-41(1997))。例如，可通過含有壞死嗜酸性細胞團或片、夏科-萊登 (Charcot-Leyden)晶體和非侵襲性真菌菌絲的濃縮粘液的存在鑑定出非侵襲性真菌誘導的鼻竇炎。此外，可用圖像分析如MRI和CT掃描鑑定非侵襲性真菌誘導的鼻竇炎因爲這種病情一般表現出特徵性表象並且可導致相鄰結構中骨的腐蝕（Quraishi 等，Otolaryngol_Head Neck Surg.117 : 29-34(1997) ; Manning 等，喉鏡 107 : 170_ 176(1997) ; Kinsella 等，頭和頸 18 : 211-217(1 996); -32 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） ~ ' 1236905 Η"7 五、發明説明Q )IP ~-I 1--— -_- «. —. ·,» I — «, _ * --------------------— --- .. ...... J-m_ui .-I-"" V. Description of the invention k) J et al. (Clinical Laboratory Immunology 65: 631-638 (1 986)), Mabry RL and Manning S (Otolaryngol Head Neck Surg .113: 721-723 (1 995)), and Lynch NR et al. (Int Arch Allergy Immunol 114: 59-67 (1997)). Immuno-based assays can use Doklon antibodies, monoclonal antibodies, and fragments thereof that are specific for antigens that can be used as diagnostic markers for non-invasive fungal-induced mucositis. For example, biological samples can be prepared and screened using monoclonal antibodies specific for fungal organisms known to cause non-invasive fungal-induced mucositis. This antibody can be used elsewhere [Zeidan et al., Experimental Methods in Biochemical and Molecular Biology, William C. Brown (1996) and Seaver, Commercial Preparation of Monoclonal Antibodies: A Scale-Up Guide, Marcel Dekker, New York, NY ( 1987)] preparation. Briefly, mice were immunized with fungal biological isolate samples. After several weeks, lymphocytes were recovered from the spleens of immunized mice and fused with myeloma cells to prepare hybridoma cells. Hybridoma cells that show specificity for immune fungal isolates can then be isolated and monoclonal antibody preparations made. Since the specific methods and substances used to identify non-invasive fungal-induced mucositis can vary with the specific location of mucositis, detailed descriptions of several exemplary mucosal tissues are provided below. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1. Paranasal cavity The outer bone of the nose is composed of 2 oval nose bones. The two nasal bones are located on one side of the midline, and the two nasal bones form an arched intersection. The nasal septum divides the nasal cavity into two. The side wall of the nose has three turbinates that increase the surface area of the nasal cavity or vestibular mucosa. The vestibule of the nose is bounded by the nasal septum and the side wall. -30-This paper size applies the Chinese National Standard (CNS) A4 specification (210X291 mm) 1236905 Η17 V. Description of the invention Q). The large surface area of the turbinate and nasal septum promotes extensive contact with the inhaled air, which promotes humidification, particle removal, and temperature adjustment of the inhaled air. Paranasal sinuses are air-containing spaces that communicate with the nasal cavity through openings or holes. Although they are paired, the paranasal sinuses are generally asymmetric in shape and location and include the maxillary, frontal, ethmoid, and sphenoid sinuses. Paranasal plugs are thought to play a role including reducing the weight of the skull, providing nasal mucosa, and acting as a resonant cavity for sound production. The maxillary sinus is the largest paranasal sinus. Each maxillary sinus is located in the upper jaw and opens in the middle meatus. The frontal sinus is located in the frontal bone and above or in the middle of the eye socket. The frontal sinus also opens in the middle canal. The ethmoid sinus is numerous and is an irregularly shaped air chamber opening in the middle and superior meatuses. The sphenoid sinus is located in the sphenoid bone and posterior to the eyes and upper nasal cavity. The sphenoid sinus leads into the upper canal. Mucosal tissue (mucosa) is located inside the nasal cavity and paranasal sinuses, and generally contains the epithelium, connective tissue, and mucus glands. The mucosal layer generally covers the mucous membranes and the mucus secreted by the mucous membranes is used to capture particles and prevent dehydration of the nose and paranasal tissues exposed to the air. Mucus is generally transported by the cilia toward the nasopharynx and is then choked. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics Individuals with sinusitis are identified using methods known in the art. Sinusitis symptoms include, but are not limited to, nasal airway obstruction, loss of taste, facial pain, headache, posterior nasal drip (drip), and rhinorrhea. During inspection, the presence of thick mucus or visual identification of nasal or paranasal obstructions with mucus or polyps often indicates a sinusitis condition. Nasal polyps grow outward from the paranasal mucosa, which are generally smooth, gelatinous, translucent, round or pear-shaped, and off-white 1 3 1-^ Paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) ) ^ 1236905 Λ'7 _____ Η " V. Invention Description (29) Color. Generally, nasal polyps are located on the side of the nose, usually in or along the middle turbinate or upper turbinate. Most nasal polyps originate from the ethmoid sinus but some polyps originate from the maxillary sphenoid sinus. Nasal polyps consist mainly of edematous liquid with a small amount of fibroblasts and a small number of mucous glands. The surface epithelium of the nasal and paranasal meats generally exhibits squamous tissue deformation. Eosinophils are usually found in polyps in moderate to large amounts, and it is now known that nasal polyp fluids contain greater than normal concentrations of IgA, IgE, IgG, and IgM antibodies and abnormally high concentrations of L-5, which promotes eosinophil activation And surviving cytokines. As shown in this article, the presence in the nose is not a risk factor for sinusitis, but rather an advanced stage of chronic inflammation. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs The following methods and substances can be used to identify individuals with non-invasive fungal-induced sinusitis. As mentioned above, the condition called AFS is a non-invasive fungal-induced sinusitis condition. Therefore, any method known in the art for identifying AFS can be used to identify non-invasive fungal-induced sinusitis (Cody ΌΎ mm 104: 1074-1079 (1994) ¾ Kupferberg SB # > Oto I a ryngol · Head Neck Surg 117: 35-41 (1997)). For example, non-invasive fungal-induced sinusitis can be identified by the presence of concentrated mucus containing necrotic eosinophils or pellets, Charcot-Leyden crystals, and non-invasive fungal hyphae. In addition, image analysis such as MRI and CT scans can be used to identify non-invasive fungal-induced sinusitis because this condition generally displays a characteristic appearance and can cause bone erosion in adjacent structures (Quraishi et al., Otolaryngol_Head Neck Surg. 117: 29-34 (1997); Manning et al., Laryngoscope 107: 170_176 (1997); Kinsella et al., Head and Neck 18: 211-217 (1 996); -32-This paper size applies to the Chinese National Standard (CNS) A4 Specifications (210X 297 mm) ~ '1236905 Η " 7 V. Description of the invention Q)

Allbery 等，放射圖（RadioGraphics)15 : 1311· 1327(1995) ； Roth MR，耳、鼻和喉雜誌 73 : 928-930(1994);和 Bartynski 等 » Otolaryngol. Head Neck Surg.103: 32-39(1990))。此外，具有非侵襲性真菌誘導鼻竇炎的個體可能具有鼻旁息肉病史並且可能經過多次手術。經濟部中央標準局員工消費合作社印裝使用現有診斷方法學的結果表明約百分之三到八的需要手術的慢性鼻竇炎病例爲AFS病例。一般地，這些目前的AFS診斷方法包含以下標準如CT掃描中特徵性表象的存在、過敏粘液的存在和由組織學或真菌在培養物中生長所證實的真菌生物在粘液樣品中的存在。本發明顯示了大於約90%的所有慢性鼻竇炎病例具有真菌病因，這基於對慢性鼻竇炎更多的理解、改進的診斷方法和本文所述抗真菌治療方法很高的成功率獲得。此外，本發明顯示了從粘液樣品中培養真菌生物的能力對於診斷非侵襲性真菌誘導的鼻竇炎病情如AFS並不是有用的標準，因爲如果不是全部，但大多數人在其鼻旁粘液中具有真菌生物（見實施例1)。然而，已注意到從鼻旁粘液樣品中收集、分析和/ 或培養真菌生物可提供有用的診斷信息。這種信息可非限制性地包含有關存在於特定粘液樣品中真菌生物水平和不同真菌種類數目的信息。似乎由於數種原因發生了對慢性鼻竇炎病情非侵襲性真菌病因學理解的缺乏。首先，依賴於不充足的粘液收集和真菌培養技術似乎導致對陰性真菌生長結果的誤 -33 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X2G公釐） " 經濟部中央標準局員工消費合作社印製 1236905 A*7 五、發明説明（31 ) 解。如本文所顯示的，這些陰性結果最有可能爲假陰性結果因爲真菌生物可在從，如果不是全部，但是大多數人中收集的鼻旁粘液樣品中生長。因此，從鼻旁粘液樣品中培養真菌生物的能力作爲非侵襲性真菌誘導鼻竇炎病情包含AFS的診斷標準基本上是無意義的。其次，臨床大夫在手術期間在過敏性粘液存在下去除和檢查息肉之前，常常從鼻旁腔中洗去或丟棄粘液。因此，未能檢測到過敏性粘液最可能是由於未能收集到待測的適當介質。這反過來又導致廣泛認可和醫學上接受的理論，即息肉病是鼻旁解剖位置中一些炎症病情的原因。如上所述，息肉病可能認爲是慢性炎症晚期結果。第三，如本文所述，慢性炎症病情可導致復發的細菌感染，其可能掩蓋了潛在的非侵襲性真菌誘導鼻竇炎病情。此外，抗菌素治療後觀察到的暫時緩解可使具有非侵襲性真菌病因學病情的診斷復雜化。無論如何，本發明教導了應採取特別的注意以保護用於分析的粘液並且可用過敏性粘液的存在鑑定非侵襲性真菌誘導的鼻竇炎。此外，在鼻旁解剖位置中復發的細菌感染可暗示非侵襲性真菌誘導的鼻竇炎。任何以前具有鼻竇炎病史的個體都有發展爲非侵襲性真菌誘導的鼻竇炎的風險。此外，較老齡的個體以及具有囊性纖維變性、哮喘和鼻問題或過敏家史的個體可能有發展爲非侵襲性真菌誘導的鼻竇炎的風險。此外，暴露於高過敏原（如，真菌孢子、花粉和化學藥品）水平的個體可能有發展爲非侵襲性真菌誘導的鼻竇炎的風險。 -34 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐) " — (請先閱讀背面之注意事項再填寫本頁)Allbery et al., RadioGraphics 15: 1311 · 1327 (1995); Roth MR, Journal of Ear, Nose, and Throat 73: 928-930 (1994); and Bartynski et al. »Otolaryngol. Head Neck Surg. 103: 32-39 (1990)). In addition, individuals with non-invasive fungal-induced sinusitis may have a history of paranasal polyps and may undergo multiple surgeries. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Results from existing diagnostic methodologies indicate that approximately 3 to 8% of cases of chronic sinusitis requiring surgery are AFS cases. Generally, these current AFS diagnostic methods include criteria such as the presence of characteristic appearances on CT scans, the presence of allergic mucus, and the presence of fungal organisms in mucus samples as evidenced by histology or fungal growth in culture. The present invention shows that more than about 90% of all cases of chronic sinusitis have a fungal cause, which is based on a better understanding of chronic sinusitis, improved diagnostic methods, and a high success rate of antifungal treatment methods described herein. In addition, the invention shows that the ability to cultivate fungal organisms from mucus samples is not a useful criterion for diagnosing non-invasive fungal-induced sinusitis conditions such as AFS, because if not all, most people have Fungal organisms (see Example 1). However, it has been noted that collecting, analyzing, and / or cultivating fungal organisms from paranasal mucus samples can provide useful diagnostic information. This information can include, without limitation, information about the level of fungal organisms and the number of different fungal species present in a particular mucus sample. There appears to be a lack of understanding of the etiology of non-invasive fungi of chronic sinusitis for several reasons. First of all, reliance on inadequate mucus collection and fungal culture techniques seems to lead to errors in negative fungal growth results. Printed by the Consumer Cooperative 1236905 A * 7 V. Explanation of the Invention (31). As shown herein, these negative results are most likely false negative results because fungal organisms can grow in paranasal mucus samples collected from, if not all, most people. Therefore, the ability to cultivate fungal organisms from paranasal mucus samples is essentially useless as a diagnostic criterion for non-invasive fungal-induced sinusitis including AFS. Second, clinicians often wash or discard mucus from the paranasal cavity before removing and examining polyps in the presence of allergic mucus during surgery. Therefore, the failure to detect allergic mucus is most likely due to the failure to collect the appropriate medium to be tested. This in turn has led to widely accepted and medically accepted theories that polyposis is the cause of some inflammatory conditions in the paranasal anatomic location. As mentioned above, polyposis may be considered a late result of chronic inflammation. Third, as described herein, chronic inflammatory conditions can lead to recurrent bacterial infections, which may mask potentially non-invasive bacterial-induced sinusitis conditions. In addition, the temporary relief observed after antibiotic treatment can complicate the diagnosis of non-invasive fungal etiology. In any case, the present invention teaches that special care should be taken to protect the mucus used for analysis and the presence of allergic mucus can be used to identify non-invasive fungal-induced sinusitis. In addition, recurrent bacterial infections in the paranasal anatomic location may suggest non-invasive fungal-induced sinusitis. Any individual with a previous history of sinusitis is at risk of developing non-invasive fungal-induced sinusitis. In addition, older individuals and individuals with a family history of cystic fibrosis, asthma and nasal problems or allergies may be at risk for developing non-invasive fungal-induced sinusitis. In addition, individuals exposed to high levels of allergens (eg, fungal spores, pollen, and chemicals) may be at risk for developing non-invasive fungal-induced sinusitis. -34-This paper size is applicable to China National Standard (CNS) A4 (210X297mm) " — (Please read the precautions on the back before filling this page)

1236905 Λ" 五、發明説明k ) ~ 一"" 2.中耳耳朵可分爲三部份：外耳道、中耳和內耳。中耳是通過咽鼓管連接至鼻咽腔的。此外，中耳通過鼓膜與外^ 道開口分開並且含有連接鼓膜與內耳的三個聽小骨的鏈。粘膜組織覆蓋了大多數的中耳表面。患中耳粘膜組織炎症（中耳炎）的個體可根據中耳病史、視覺檢查、組織活檢和症狀如聽力喪失、耳液溢和中耳液溢出（effusion)加以鑑定。一般來說’可通過以下方法鑑定非侵襲性真菌誘導的中耳炎病情（1)收集和分析中耳中的液體或粘液樣品中，以找出是否有真菌生物或嗜酸性細胞存在，（2)組織活檢分析以找出非侵襲性真菌生物，（3)與傳導聽力喪失相一或的聽力圖’和（4)扁平鼓膜圖（fiattympanogram)。與鼻旁粘液不同，從中耳收集到的樣品中鑑定出真菌生物的存在可暗示非侵襲性真菌誘導的炎症病情，因爲中耳一般是相當無菌的。經濟部中央標準局員工消費合作社印製任何以前具有中耳炎病史的個體都有發展爲非侵襲性真菌誘導中耳炎的風險。此外，年輕的個體（如，嬰兒和學步的小孩）以及具有耳問題或過敏家史的個體可能具有發展爲非侵襲性真菌誘導中耳炎的風險。 3·腸道粘膜組織覆盖於小腸和大腸。患腸炎（如，潰瘍性結 -35 - 本紙張尺度適用中國國家標準（CNS ) Α4^Τ^_χ 297公麓）-—· ™ 1236905 __ ir 五、發明説明（33 ) 腸炎和節段性回腸炎）的年體可用本領域常規的方法和物質加以鑑定。例如。可用組織活檢分析以及內窺鏡分析鑑定腸道粘膜炎病情如腸道息肉病。此外，症狀如腹瀉、腹部疼痛性痙攣、產氣和噁心可暗示腸道炎症。一般來說，可通過真菌生物、嗜酸性粒細胞、或嗜酸性細胞產物在糞便樣品中的存在鑑定非侵襲性真菌誘導的腸道粘膜炎病情。此外，顯示非侵襲性真菌生物存在的組織活檢可暗示非侵襲性真菌誘導的腸道粘膜炎狀況。任何以前具有腸道炎症病情的個體都有發展爲非侵襲性真菌誘導腸道粘膜炎的風險。此外，較老的個體以及具有消化問題 '腸道息肉病或過敏家史的個體可能具有發展爲非侵襄性真困誘導腸道粘膜炎的風險。真菌生物經濟部中央標準局員工消費合作社印製任何生活於哺乳動物粘液中的真菌生物都可能是能夠誘導粘膜炎的非侵襲性真菌生物，因爲正是由該生物在不耐受個體粘液中的存在才導致了炎症。例如，以前在 AFS病人粘液樣品中鑑定出的所有真菌生物可能是能夠誘導非侵襲性真菌誘導粘膜炎的非侵襲性真菌生物，其非限制性地包含犁頭霉屬，黃色曲霉，煙曲霉，灰綠曲霉，構巢曲霉，雜色曲霉，鏈格孢屬，團擔子菌屬，Bipolaris，白色假絲酵母，Candida lypolytica，***滑假絲酵母，枝 ?包屬，耳霉屬，Cunninahamella，彎孢屬，Dreschlera， -36 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） >’ ’ 1236905 _____ Βη 五、發明説明（34 )1236905 Λ " V. Description of the invention k) ~ One " " 2. Middle ear The ear can be divided into three parts: the external ear canal, middle ear and inner ear. The middle ear is connected to the nasopharynx via the eustachian tube. In addition, the middle ear is separated from the external canal opening by the eardrum and contains a chain of three ossicles connecting the eardrum and the inner ear. Mucosal tissue covers most of the middle ear surface. Individuals with inflammation of the middle ear mucosal tissue (otitis media) can be identified based on middle ear history, visual inspection, tissue biopsy, and symptoms such as hearing loss, ear fluid, and effusion. Generally speaking, 'non-invasive fungal-induced otitis media can be identified by (1) collecting and analyzing liquid or mucus samples in the middle ear to find out if fungal organisms or eosinophils are present, (2) tissue Biopsy analysis was performed to find non-invasive fungal organisms, (3) audiograms that are equivalent to conductive hearing loss, and (4) fiatympanograms. Unlike paranasal mucus, the presence of fungal organisms in samples collected from the middle ear may suggest a non-invasive fungal-induced inflammatory condition, as the middle ear is generally quite sterile. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Any individual with a previous history of otitis media is at risk of developing non-invasive fungal-induced otitis media. In addition, young individuals (such as infants and toddlers) and individuals with a family history of ear problems or allergies may be at risk for developing non-invasive fungal-induced otitis media. 3. Intestine Mucosal tissue covers the small and large intestines. Suffering from enteritis (eg, ulcerative nodules -35-This paper size applies Chinese National Standard (CNS) Α4 ^ Τ ^ _χ 297 gong)--™ 1236905 __ir V. Description of the invention (33) Enteritis and segmental gyrus Enteritis) can be identified by methods and substances conventional in the art. E.g. Tissue biopsy analysis and endoscopic analysis can be used to identify intestinal mucositis conditions such as intestinal polyposis. In addition, symptoms such as diarrhea, painful cramps in the abdomen, gas production, and nausea may suggest intestinal inflammation. In general, non-invasive fungal-induced intestinal mucositis can be identified by the presence of fungal organisms, eosinophils, or eosinophilic products in stool samples. In addition, tissue biopsies showing the presence of non-invasive fungal organisms may suggest non-invasive fungal-induced conditions of intestinal mucositis. Any individual who has previously had an intestinal inflammatory condition is at risk of developing non-invasive fungal-induced intestinal mucositis. In addition, older individuals, as well as individuals with a family history of digestive problems' intestinal polyposis or allergies, may be at risk of developing intestinal mucositis as a non-invasive drowsiness. Any fungal organism that lives in mammalian mucus may be a non-invasive fungal organism that can induce mucositis, because it is the organism that is in the mucus of intolerant individuals. Presence causes inflammation. For example, all fungal organisms previously identified in mucus samples from AFS patients may be non-invasive fungal organisms capable of inducing non-invasive fungal-induced mucositis, which include, without limitation, Phytophthora, Aspergillus flavus, Aspergillus fumigatus, Aspergillus griseus, Aspergillus nidulans, Aspergillus versicolor, Alternaria, Basidiomyces, Bipolaris, Candida albicans, Candida lypolytica, Candida pseudosmoothus, Cladophora, Otococcus sp Droschlera, -36-This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) > '' 1236905 _____ Βη V. Description of the invention (34)

Exserohilum，鐮孢屬，Malbranchia，Paecilomvces，青霉屬，Pseudallescheria，根霉屬，裂褶菌屬和 Sporothrix，此外，在診斷爲AFS陽性病人的粘液樣品中至今仍未鑑定出的真菌生物可能是能夠導致非侵襲性真菌誘導粘膜炎的非侵襲性真菌生物，其非限制性地包含，枝頂孢屬（Acremonium)，黃珠網霉（Arachniotus citrinus)，Aurobasidioum，白僵菌屬（Beauveria)，無殼屬（Chaetomium)，Chryosporium，附球屬（Epicoccum)， Exophilia jeanselmei，地絲菌屬（Geotrichum)， Oidiodendeon，莖點霉屬（Phoma)，Pithomyces， Rhinocladiella，Rhodoturula，Sagrahamala， Scolebasidium，帚霉（Scopulariopsis)，黑粉菌 (1^丨丨39〇)，木霉（丁1^〇110€^^13)，和接合菌（779〇阳乂0616)。能夠誘導非侵襲性真菌誘導粘膜炎的可能爲非侵襲性真囷生物的其它真囷生物目錄可發現於大多數分類的真菌學教科書中。收集粘液樣品經濟部中央標準局員工消費合作社印製一般地，可通過用收集液衝洗含粘液的腔從任何粘膜組織表面收集粘液。適當的粘液收集技術應通過充分滲透適當的解剖腔和降低個體吸收的收集液量而最大程度地回收含有粘液的收集液。可用血管收縮劑最大程度地進行粘液收集並且可用粘液溶解劑溶解障礙粘液 (obstructive mucus)從而增強收集液的滲透。 -37 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐) — 1236905 五、發明説明（35 ) 因此，在收集粘液樣品之前，可用血管收縮劑和/或粘液溶解劑處理個體從而在適當的區域中誘導充分的血管收縮和/或粘液溶解作用。適當的血管收縮劑可非限制性地包含脫氫腎上腺素鹽酸（NEO-SYNEPHRINE® ; Sanofi 製藥）、***、和腎上腺素。粘液溶解劑是任何使粘液液化從而可從病人中回收粘液的試劑。適當的粘液溶解劑可非限定性地包含N-乙醯-L-半胱氨酸（MUCOSILTM ; Dey 實驗室）和重組的人DNA酶（PULMOZYME® ;基因技術公司）。應允許在施用後等待足夠的時間如大約2到5分鐘使任何施用的血管收縮劑或粘液溶解劑發生作用。可用下面的方法和物質收集鼻旁粘液樣品。首先，經濟部中央標準局員工消費合作社印製通過指導個體吸氣和降低下頜，或以一些其它方式限制液體流出口外和流下食管的通路，準備個體在至少一個鼻孔或鼻旁腔中接受收集液。在垂直坐或站著的個體中，這些方法趨於最大限度地減少收集液的損失或攝入。如果達到此目的，其它方法也是可能的。其次，建立注射和收集系統。一般來說，其設計是這樣的，即可施用收集液至個體的鼻孔，然後有效地被收集於容器中。注射系統可非限定性地爲具有彎曲鈍針或管裝置的注射器。該容器可以是容納液體的任何一種容器。此外，該容器可非限制性地爲貯存容器，其適於用作運輸器或可封閉的裝置從而可處理或運輸所收集的樣品。這些容器依據粘液樣品的所需用途也可含有如防腐劑或抗生素的藥劑。第三，施用收集液至個體的鼻腔並收集之。施用前，可告誡該個體當感受到有液 -3 8 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）一 — 1236905Exserohilum, Fusarium, Malbranchia, Paecilomvces, Penicillium, Pseudallescheria, Rhizopus, Schizophyllum and Sporothrix. In addition, fungal organisms that have not yet been identified in mucus samples from patients diagnosed with AFS may be able A non-invasive fungal organism that causes non-invasive fungal-induced mucositis, which includes, without limitation, Acremonium, Arachniotus citrinus, Aurobasidioum, Beauveria, no Chaetomium, Chryosporium, Epicoccum, Exophilia jeanselmei, Geotrichum, Oidiodendeon, Phoma, Pithomyces, Rhinocladiella, Rhodoturula, Sagrahamala, Scolebasidium, Scopulariopsis ), Ustilago spp. (1 ^ 丨 39〇), Trichoderma spp. (Ding 1 ^ 11010 ^^ 13), and Zygomycetes (7790 impotence 0616). Catalogues of other true eel organisms that may be non-invasive eel organisms that can induce non-invasive fungal-induced mucositis can be found in most classified mycology textbooks. Collecting Mucus Samples Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics Generally, mucus can be collected from the surface of any mucosal tissue by flushing the mucus-containing cavity with the collection fluid. Proper mucus collection techniques should maximize the recovery of mucus-containing collection fluids by adequately penetrating the appropriate anatomical cavity and reducing the amount of collection fluid absorbed by the individual. A vasoconstrictor can be used to maximize mucus collection and a mucolytic agent can be used to dissolve obstructive mucus to enhance the permeation of the collected fluid. -37-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) — 1236905 V. Description of the invention (35) Therefore, before collecting mucus samples, individuals can be treated with vasoconstrictors and / or mucolytic agents to thereby Inducing adequate vasoconstriction and / or mucolysis in the appropriate area. Suitable vasoconstrictors may include, without limitation, DHEA (NEO-SYNEPHRINE®; Sanofi Pharmaceuticals), ***e, and epinephrine. A mucolytic is any agent that liquefies mucus so that it can be recovered from a patient. A suitable mucolytic agent may include, without limitation, N-acetamidine-L-cysteine (MUCOSILTM; Dey Labs) and recombinant human DNase (PULMOZYME®; Gene Technology Corporation). Allow sufficient time after administration, such as about 2 to 5 minutes, for any administered vasoconstrictor or mucolytic agent to function. The following methods and materials can be used to collect paranasal mucus samples. First, the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed the preparation for individuals to receive collections in at least one nostril or paranasal cavity by instructing the individual to inhale and lower the jaw, or in some other way restrict access to the fluid outflow and down the esophagus. liquid. In individuals sitting or standing vertically, these methods tend to minimize the loss or intake of collected fluids. If this is achieved, other methods are possible. Second, establish an injection and collection system. Generally, the design is such that the collection liquid is applied to the individual's nostrils and then effectively collected in a container. The injection system may be, without limitation, a syringe with a curved blunt needle or tube device. The container may be any container that holds a liquid. Furthermore, the container may be, without limitation, a storage container suitable for use as a transporter or a closable device so that the collected samples can be processed or transported. These containers may also contain agents such as preservatives or antibiotics depending on the intended use of the mucus sample. Third, the collection fluid is applied to the individual's nasal cavity and collected. Before application, the individual may be cautioned to feel fluid -3 8-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 1 — 1236905

A ____ ηη 五、發明説明“）體在其鼻旁解剖位置中時排出收集液。作爲選擇，可告誡該個體在施用的同時排除收集液。施用期間，可強制性將收集液注射入至少一個鼻孔或一側鼻旁解剖位置。收集液的體積可根據個體和粘膜炎的狀態而改變。例如，液體體積可非限制性地在約0.1 mL至約1 00 mL或更多之間，並且特別是在約0.1 mL至約25 mL之間。收集液可非限制性地爲鹽溶液、水、和任何其它合適的適於接觸粘膜組織的溶液，此外，收集液可含有可用於收集粘液的任何其它試劑如粘液溶解劑。經濟部中央標準局員工消費合作社印製收集液的一個用途是移走和去除含有粘液腔內的粘液。除了作爲天然衝洗液而起作用的收集液外，粘液溶解劑在收集液中的滲透效應可有助於液化障礙性的粘液。此外，聯合施用與由個體幾乎同時的高壓排出可幫助移走和收集粘液。一般來說，可以不到約5秒每側的時間施用收集液。此外，可在不到3秒的時間內施用收集液。作爲選擇，依據特異的因素如炎症程度、障礙的存在和個體的身材可將收集液的施用時間延長超過5秒。此外，當需要很小體積或流動（stream)的收集液時可使用長於5秒的施用。特別是個體不能夠遵循或適應液體收集方法時也可用其它的收集方法收集粘液樣品。這些其它的方法在本領域中是眾所周知的，並且非限制性地包含手術去除粘液、棉拭或機械性粘液提取方法以及提取粘液的壓力或真空系統。此外，可對本文該方法和物質，以及其它收集步驟 -39 - 本紙張尺度適用中國國家標準（CNS ) 規格（ 210X 297公釐） " 1236905 ________________ ηη 五、發明説明) 加以修改或調整以從如中耳和腸道等的其它身體區域中獲得生物學液體。收集粘液樣品後，可分析樣品中是否有顯示有關非侵襲性真菌誘導粘膜炎的標記存在。例如，可檢查粘液樣品以檢定過敏粘液的存在。此外，可用本文該技術以及本領域已知的技術從粘液樣品中培養和分析真菌生物。經濟部中央標準局員工消費合作社印製圖3和4描述了用於吸收和收集粘液以及其它液體的舉例性裝置1 〇。裝置1 0包含上部構件1 2，收集容器 (collection retainer)14和收集管16。上部部件12依次廣泛包含中間部份22、線性部份24、連接部份26和管接收部件28。中間部份22 —般可限定開口 29於其中。閥門 30可操作地位於開口 29中。線性部份24可從中間部份 22向下延伸。連接部份26從中間部份22發散性地延伸， 26在本實施方案中的交叉部份一般是環形的，並且限定了內徑32。內徑32連接裝置10的外部與其內部。在該實施方案中，容器1 4呈線性地連接到線性部份24上。然而，可通過其它已知的方法將容器14固定至中間部份22上。儘管描繪了圓錐形底部構型，但容器14可以採用多種構型且在本發明的範圍之內。收集管1 6從孔徑34處延伸並位於其中。管1 6的一節可位於容器1 4的內部以利於收集物質的放置。收集管1 6限定了收集的粘液在其中流過的管腔36。在一個實施方案中’管彳6包含彈性的內存貯 (memory)手段以利於適應不同的患者解剖位置。即’管16 保持所需的彈性構型，如由圖3中剖式圖線所繪製的構型 -40 - 本紙「張尺度適用中國國家標準（CNS ) A4規格（21〇X^97公釐） " — 1236905 ν' _____ ηη 五、發明説明) ^ 相一致。利於粘液經收集管和裝置1 0運輸的進一步方法可包含具有設計成最大程度減小粘液在其中吸附的材料特徵的管或裝置管腔壁（Liner)。在一個實施方案中，裝置10被設計成單一的用途。然而，裝置10可由許多材料，合成樹脂製備，如可使用聚乙烯。連接部份26連接裝置10至真空管（hose)38。因此，連接部份26可具有外部構型從而產生適於真空管38 的不透氣性（air tight)。閥30調節管腔36中所通的真空度。通過調整閥門30，逐漸增加或降低真空度可應用於其中。在此實例中，閥門30包含一般性延長的狹縫（slit)，其配上一滑塞（sliding member)。使用者可調整滑塞從而暴露所有、部份或不暴露該延長的狹縫，因而調整了管腔 36所通上的真空度。然而，用於調節真空度的多種其它調節方法也在本發明的範圍之內。另一實施例包含“IV”型閥門，其利用滾動閥門以可調地收縮拉桿（draw)或收集管。經濟部中央標準局員工消費合作社印製與其它裝置相反，接收部件管28和收集管1 6 —般是從容器14縱軸垂直延伸。這使得使用者在回收粘液和其它液體時更好地定位收集管16。應認識到可舒適地與病人的面部解剖位置相一致，以及可由病人或保健醫生容易放好位置的其它收集容器可能也在本發明的範圍內。如果其能夠達到注射至病人中的液體而同時又能夠從病人排出或取出液體和粘液，那麼該實施方案可依賴於空間、重力或其它收集機制。 -4 1 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐)—— ―― -- 1236905 ______ ΙΓ 五、發明説明“）在該實施方案中，管腔36直徑在大約1 mm與10mm 之間，並且總長度在約5 cm至50 cm之間。舉例性容器 14直徑一般在約1到3之間，高度在3至6之間，儘管各種其它的尺寸可能是有用的。優先使用裝置1 0從病人的鼻、鼻旁或肺解剖位置中獲得粘液或液體樣本，在獲得粘液或液體樣品時，按照需要將裝置1 〇連接至真空源並調整閥門30。將管1 6設計成所需的位置。然後將管1 6***到粘液或液體從其中獲得的病人解剖位置部份。必要時進一步調整閥門30以獲得樣品，然而需確保病人的安全。將得到的粘液或液體收集於容器14中。一旦收集完成，可從上部部件12處拆分容器14用於貯藏或運輸獲得的粘液或液體樣品。培養來自粘液樣品的真菌生物經濟部中央標準局員工消費合作社印製通過以粘液溶解劑如N-乙醯-L-半胱氨酸或二硫蘇糖醇（DTT)處理樣品以增強或促進粘液進一步液化，可製備粘液樣品用於真菌生物培養。添加粘液溶解劑後，可於室溫混合並孵育粘液樣品。此液化過程使存在於粘液內的真菌生物釋放。一旦被液化，可通過離心或其它方式分離粘液因爲粘液一般形成與其它溶液（即，收集液）分離的層。一旦被分離，可混合粘液並將一等份與適當的真菌培養基如培養基瓊脂板接觸。真菌培養基爲任何可支持真菌生長的培養基，非限制性地包含RPMM649、Delbecco’s 改進的eagle培養基（DMEM)、抑制性霉菌瓊脂（IMA)和 -42 - 本紙張尺度適用中關家標準（CNS ) A4規格（21GX297公釐) —— 1236905 ΙΓ 五、發明説明“）A ____ ηη 5. Description of the invention ") The body drains the collection fluid when it is in its anatomical position next to the nose. As an option, the individual can be warned to exclude the collection fluid at the same time as the application. During the application, the collection fluid can be forcibly injected into at least one Anatomical location of the nostril or one side of the nose. The volume of the collected fluid may vary depending on the individual and the status of the mucositis. For example, the volume of the fluid may be non-limiting between about 0.1 mL to about 100 mL or more, and particularly Is between about 0.1 mL to about 25 mL. The collection solution may be, but is not limited to, saline solution, water, and any other suitable solution suitable for contacting mucosal tissues. In addition, the collection solution may contain any Other reagents such as mucus dissolving agents. One use of printed collection fluids printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs is to remove and remove mucus containing the mucus cavity. In addition to the collecting liquid that functions as a natural flushing solution, mucus dissolves The penetrating effect of the agent in the collection fluid can help to liquefy the obstructed mucus. In addition, the combined application and high-pressure discharge by the individual at about the same time can help remove Collect mucus. Generally speaking, the collection fluid can be applied in less than about 5 seconds on each side. In addition, the collection fluid can be administered in less than 3 seconds. Alternatively, it depends on specific factors such as the degree of inflammation, the presence of an obstacle And the body of the individual can extend the application time of the collection liquid for more than 5 seconds. In addition, when a small volume or stream of collection liquid is required, an application longer than 5 seconds can be used. In particular, the individual cannot follow or adapt to the liquid collection Other methods of collection may be used to collect mucus samples. These other methods are well known in the art and include, without limitation, surgical mucus removal, cotton swabs or mechanical mucus extraction methods, and pressure or vacuum systems for mucus extraction. In addition, the method and substance in this article, and other collection steps -39-This paper size applies the Chinese National Standard (CNS) specifications (210X 297 mm) " 1236905 ________________ ηη 5. Description of the invention) Obtain biological fluids from other areas of the body such as the middle ear and intestine. Collect mucus samples The sample can be analyzed for the presence of a marker showing non-invasive fungal-induced mucositis. For example, a mucus sample can be examined to detect the presence of allergic mucus. In addition, the technique herein and techniques known in the art can be used to remove mucus samples from the mucus sample. Cultivation and analysis of fungal organisms. Printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, Figures 3 and 4 depict an exemplary device 10 for absorbing and collecting mucus and other liquids. The device 10 contains the upper component 12 and a collection container ( collection retainer) 14 and collection tube 16. The upper part 12 includes a middle part 22, a linear part 24, a connection part 26, and a tube receiving part 28. The middle part 22 generally defines an opening 29 therein. The valve 30 is operatively located in the opening 29. The linear portion 24 may extend downward from the middle portion 22. The connecting portion 26 extends divergently from the middle portion 22, and the intersection portion 26 in this embodiment is generally annular and defines an inner diameter 32. The inner diameter 32 connects the outside of the device 10 with its inside. In this embodiment, the container 14 is linearly connected to the linear portion 24. However, the container 14 may be fixed to the middle portion 22 by other known methods. Although a conical bottom configuration is depicted, the container 14 can take a variety of configurations and is within the scope of the present invention. The collection tube 16 extends from the aperture 34 and is located therein. A section of the tube 16 may be located inside the container 14 to facilitate the placement of the collected material. The collection tube 16 defines a lumen 36 through which collected mucus flows. In one embodiment, the 'tubule 6' includes flexible internal memory means to facilitate adaptation to different patient anatomy locations. That is, the tube 16 maintains the required elastic configuration, such as the configuration drawn by the cross-sectional diagram in Figure 3-40-This paper "sheet size applies Chinese National Standard (CNS) A4 specification (21〇X ^ 97 mm) ) &Quot; — 1236905 ν '_____ ηη 5. Description of the invention) ^ Consistent. Further methods to facilitate the transport of mucus through collection tubes and devices 10 may include tubes or materials with features designed to minimize the adsorption of mucus in the material. Device lumen wall (Liner). In one embodiment, the device 10 is designed for a single use. However, the device 10 can be made of many materials, synthetic resin, such as polyethylene can be used. The connecting portion 26 connects the device 10 to the vacuum tube (Hose) 38. Therefore, the connecting portion 26 may have an external configuration to generate air tightness suitable for the vacuum tube 38. The valve 30 adjusts the degree of vacuum passing through the lumen 36. By adjusting the valve 30, gradually Increasing or decreasing the degree of vacuum can be applied therein. In this example, the valve 30 includes a generally elongated slit with a sliding member. The user can adjust the slider to expose all, The length of the vacuum passing through the lumen 36 is adjusted or not exposed, so that various other adjustment methods for adjusting the vacuum are also within the scope of the present invention. Another embodiment includes " IV "type valve, which uses a rolling valve to adjust the draw or collection tube. The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economics prints. In contrast to other devices, the receiving part tube 28 and the collection tube 16 are generally from The longitudinal axis of the container 14 extends vertically. This allows the user to better position the collection tube 16 when recovering mucus and other liquids. It should be recognized that it can be comfortably aligned with the patient's facial anatomy and can be easily placed by the patient or health practitioner Other collection containers at the location may also be within the scope of the present invention. This embodiment may rely on space, gravity, or other collections if it can reach the liquid injected into the patient while at the same time being able to discharge or remove the liquid and mucus from the patient. Mechanism -4 1 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) —— ——-1236905 ______ ΙΓ 5 Description of the Invention ") In this embodiment, the lumen is between about between 1 mm and 10mm, and total length Approximately 5 cm to 50 cm 36 diameter. Exemplary containers 14 are generally between about 1 to 3 in diameter and 3 to 6 in height, although various other sizes may be useful. The device 10 is preferably used to obtain a mucus or liquid sample from the patient's nose, paranasal or lung anatomic location. When obtaining a mucus or liquid sample, connect the device 10 to a vacuum source and adjust the valve 30 as needed. Design the tube 16 to the desired position. The tube 16 is then inserted into the part of the patient's anatomy where mucus or liquid is obtained. The valve 30 is further adjusted if necessary to obtain a sample, however, the patient's safety needs to be ensured. The obtained slime or liquid is collected in a container 14. Once the collection is complete, the container 14 can be split from the upper part 12 for storage or transportation of the obtained mucus or liquid sample. Cultivate fungi from mucus samples Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Bioeconomy by strengthening or promoting mucus by treating samples with a mucolytic agent such as N-acetamidine-L-cysteine or dithiothreitol (DTT) Further liquefaction, a mucus sample can be prepared for fungal biological culture. After adding the mucus dissolving agent, the mucus sample can be mixed and incubated at room temperature. This liquefaction process releases the fungal organisms present in the mucus. Once liquefied, the mucus can be separated by centrifugation or other means because mucus generally forms a layer separate from other solutions (i.e., the collection liquid). Once isolated, the mucus can be mixed and an aliquot contacted with an appropriate fungal medium such as a medium agar plate. Fungal medium is any medium that can support the growth of fungi, and includes, without limitation, RPMM649, Delbecco's modified eagle medium (DMEM), inhibitory mold agar (IMA), and -42-This paper standard applies to Zhongguanjia Standard (CNS) A4 Specification (21GX297 mm) —— 1236905 ΙΓ 5. Description of the invention ")

Bay瓊脂。真菌培養基可含有抗菌素（如，氯霉素和環丙沙星）以防止細菌生長。一旦液化的粘液與適當的真菌培養基接觸，可以最佳的溫度，如約20°C與37°C之間，並且在有些情況下如 25°C與35t之間培養培養物。通過將2份培養物放置在不同的溫度下並比較生長速率而估計最佳溫度。一般來說，培養物於30°C培養約20至35天。一旦觀察到真菌生長，可用本領域眾所周知的方法和每種真菌分離物特徵描述過的表型和基因型鑑定真菌種類。例如，可檢查真菌分離物以測定其任何藥物抗性或藥物易感性。治療和預防非侵襲性真菌誘導的粘膜炎經濟部中央標準局員工消費合作社印製抗真菌劑可以能有效治療或預防非侵襲性真菌誘導的粘膜炎的量、頻率和時間內經粘膜施用至哺乳動物。 “抗真菌劑”是有抗真菌生物活性的任何試劑。例如，抗真菌劑是防止真菌生物生長或殺死真菌生物的任何試劑，如抗真菌多烯大環內酯、四叉骨針大環內酯、五烯大環內酯、氟化嘧啶、咪唑、***、吡咯、鹵化酚醚、硫代氨基甲酸酯和烯丙胺。此外，抗真菌劑可以是***真菌細胞壁組分之間或作爲固醇抑制劑而起作用的試劑。本發明範圍中的特異性抗真菌劑非限制性地包含兩性霉B、5-氟胞嘧啶、酮康唑、咪康唑、伊曲康唑、氟康唑、灰黃霉素、克霉唑、益康唑、特康唑、布康唑、奧昔康唑、硫康唑、沙波康唑、voriconazole、環吡司胺、鹵普羅近、托萘酯、 -43 - 本紙張尺度適用中國國家標準（CNS ) Μ規格（210X297公釐） — - 1236905 B1 五、發明説明L ) 萘替芳、制霉菌素、游霉素、鹽酸、特比萘芬、嗎啉、布替那芬、十一烯酸、懷德菲爾特軟膏、丙酸和辛酸以及用本領域眾所周知的方法鑑定爲抗真菌劑的物質。已注意到特定的病人可具有這樣的真菌生物，即其作爲對特定抗真菌劑有抗性的病原。在這種情況，本發明重要的方面包含以有效的抗真菌劑（如，防止作爲病原的真菌的生長或殺死真菌的抗真菌劑）治療病人。可用本文該收集和培養的方法鑑定作爲病原而起作用的此種真菌生物。經濟部中央標準局員工消費合作社印裂本文使用的術語“粘膜施用”指將施用的試劑與粘液接觸的任何一種施用方法。因此，任何只在血流中存在的靜脈內施用試劑都不被認爲是粘膜施用的試劑因爲該試劑未能接觸粘液。此外，術語“粘膜施用”可分成“直接”和“間接”的粘膜施用。這裡使用的術語“直接粘膜施用”指在穿過上皮之前將施用的試劑與靶粘液直接接觸的任何一種施用。爲了本發明的目的，應該理解的是只要試劑接觸粘液，甚至是可用注射方法（如，針、管或導管）穿過上皮，也將此試劑注射至含有粘液的腔內認爲是直接的粘膜施用。因此，用針頭繞過鼓膜並注射試劑至中耳被認爲是靶向中耳粘液的直接粘膜施用。應理解隨後存在於血流中、滲出上皮並且接觸粘液的任何靜脈內施用試劑都不被認爲是直接粘膜施用的試劑，因爲該試劑在接觸粘液之前已穿過上皮。然而，在此情況，該靜脈內施用的試劑認爲是間接的粘膜施用試劑因爲術語“間接粘膜施用”意爲在穿過上皮後將施用的試 -44 - 本紙張尺度適用中關家標準（CNS ) A4規格（210X297公嫠) '" 1236905 A"7 H*7 五、發明説明ς2 ) 劑與靶向粘液接觸的任何一種施用。同樣，使用注射手段如針頭、管或導管運輸試劑穿過上皮並與粘液直接接觸不一定意味著該施用爲間接的粘膜施用。也應理解，依據靶向的粘液，口腔施用可以或者爲直接、或者爲間接的粘膜施用。例如，可吞下試劑且然後穿過食道、胃和小腸而與大腸粘液直接接觸而不穿過上皮 (即，直接的粘膜施用）。同時，口腔施用的試劑可由腸道吸收、系統積累、並滲透出鼻上皮以達到與鼻粘液的接觸 (即，間接的粘膜施用）。因此，直接和間接性質的粘膜施用依賴於特定的施用途徑以及靶粘液的特定位置。哺乳動物各種粘液位置的典型直接和間接粘膜施用描述如下。經濟部中央標準局員工消費合作社印製抗真菌劑或含有抗真菌劑的配方的有效量可以是當粘膜施用至哺乳動物時不對其產生明顯毒性並且能減輕、預防或消除非侵襲性真菌誘導的粘膜炎的任何量。一般來說，有效量可以爲粘膜施用時對個體沒有顯著的毒性，且大於或等於對存在於特定個體粘液內的真菌生物或分離物的最小抑制濃度（MIC)的任何量。有些抗真菌劑可具有相對較大的有效濃度範圍而其它抗真菌劑可能具有相對較窄的有效濃度範圍。此外’該有效的量可根據特異性真菌生物或分離物而改變，因爲有些生物和分離物對特定抗真菌劑較多或較少敏感。可用常規可得到或容易查明的信息包含抗真菌有效濃度、動物毒性濃度和組織通透率，測定單個抗真菌劑的有效量。例如’非毒性的抗真菌劑一般可以在粘液中以顯示出抗真菌活性的任何量直接 -45 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1236905 經濟部中央標準局員工消費合作社印製 i、發明説明（43 ) 或間接粘膜施用。此外，不能滲透入粘膜上皮的抗真菌劑一般可以在粘液中顯示出抗真菌活性的任何量直接粘膜施用。用本文提供的信息，這種有效的量也可通過體外或體內常規的實驗加以測定。例如，具有非侵襲性真菌誘導的粘膜炎病情的病人可接受接近從體外分析而算的MIC 量直接粘膜施用抗真菌劑。如果病人沒有反應，那麼可增加，例如，1 〇倍的量，接受此更高濃度後，可監測該病人對治療的反應和毒性症狀並相應作出調整。對於兩性霉素B，當直接粘膜施用時，有效量可爲每次施用每公斤哺乳動物體重約0.01 ng至約1 000 mg。當用作鼻灌注溶液時，有效量可爲每鼻孔每次施用約0.01 mL至約1升體積，每升含有約0.01 mg兩性霉素B至每升約1000 mg兩性霉素B。作爲選擇，有效量可以爲每次施用（如，每日2到4次）每鼻孔20 mL的含有每升鹽水或水約1 00 mg兩性霉素B的灌注射。一般來說，鹽或水爲無菌的。該有效量可維持恆定或可根據個體對治療的反應而調整爲比例可調（sliding scale)或可變的劑量。用於其它抗真菌劑的有效量可根據本文該多種方法，用常規的實驗由本領域中一般的技術人員加以測定。一般來說，直接粘膜施用任何抗真菌劑（如，伊曲康唑、酮康哩、和vor icon azole)的有效量可爲約每次施用每公斤體重哺乳動物約爲0·01 ng至約1000 mg。依據測試的特異性真菌生物或分離物，voriconazole的MIC値在約 0.0 03 // g/mL至約4 // g/m L之間。對於氟康唑，ΜIC値 -46 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ 297公f ) (請先閲讀背面之注意事項再填寫本頁) :裝· 、11 -齡- 經濟部中央標準局員工消費合作社印製 1236905 Λ7 ΙΓ 五、發明説明（44 ) 在約0·25 // g/mL至大於約64 // g/mL之間。爲了幫助測定不同抗真菌劑的有效量，參考根據常規抗真菌劑有效量的等效量可能是有用的。例如，直接粘膜施用每鼻孔每次施用（如，一日2次）約20 mL含有每升約1 00 mg兩性霉素B的兩性霉素B灌注液爲本文所證實的有效量。由此有效量產生的效果可用作參照點以比較用不同濃度觀察到的所用其它抗真菌劑的效果。一旦觀察到相同的效果，那麼可測定出該特定抗真菌劑的特定有效量。在此情況下，特定的量將稱爲兩性霉素B有效量的等效果。多種因素可影響特定施用所用的實際有效量。例如，粘膜施用的頻率、治療的時間、與其它抗真菌劑的組合、施用位點、炎症程度，和治療區域的解剖學形態可需要增加或降低實際粘膜施用有效量。粘膜施用的頻率可爲減輕、預防或消除哺乳動物中非侵襲性真菌誘導的粘膜炎而對該哺乳動物不產生顯著毒性的任何頻率。例如，粘膜施用的頻率可爲約每日4次至約每月一次，或更爲特異性地從約每日2次至每週一次。此外，粘膜施用的頻率在治療期間可維持恆定或可以是變化的。與有效量一樣，多種因素可影響用於特定施用的實際粘膜施用頻率。例如，有效的量、治療時間、與其它抗真菌劑合用、施用位點、炎症程度和治療區域的解剖學形態可需要增加或降低粘膜施用頻率。抗真菌劑粘膜施用的有效時間可爲減輕、預防或消 -47 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)Bay agar. Fungal media may contain antibiotics (eg, chloramphenicol and ciprofloxacin) to prevent bacterial growth. Once the liquefied mucus is contacted with a suitable fungal culture medium, the culture can be cultured at optimal temperatures, such as between about 20 ° C and 37 ° C, and in some cases, between 25 ° C and 35t. The optimal temperature was estimated by placing two cultures at different temperatures and comparing growth rates. Generally, cultures are grown at 30 ° C for about 20 to 35 days. Once fungal growth is observed, fungal species can be identified by methods well known in the art and characterized by the phenotypes and genotypes of each fungal isolate. For example, fungal isolates can be examined to determine any drug resistance or susceptibility to them. Treatment and prevention of non-invasive fungal-induced mucositis. The anti-fungal agent printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs can effectively treat or prevent non-invasive fungal-induced mucositis by mucosal administration to mammals in an amount, frequency and time. . An "antifungal agent" is any agent that has antifungal biological activity. For example, an antifungal agent is any agent that prevents the growth of or kills fungal organisms, such as antifungal polyene macrolides, tetrapod needles macrolides, pentaene macrolides, fluorinated pyrimidines, imidazoles , Triazole, pyrrole, halogenated phenol ether, thiourethane and allylamine. In addition, the antifungal agent may be an agent that is interposed between fungal cell wall components or functions as a sterol inhibitor. Specific antifungal agents within the scope of the present invention include, without limitation, amphoteric mold B, 5-fluorocytosine, ketoconazole, miconazole, itraconazole, fluconazole, griseofulvin, clotrimazole , Econazole, ticonazole, butoconazole, oxconazole, thioconazole, sapoconazole, voriconazole, ciclopirox, haproxil, tonaclide, -43-This paper size applies to China National Standards (CNS) M specifications (210X297 mm) —-1236905 B1 V. Description of the invention L) Naphthyridine, nystatin, natamycin, hydrochloric acid, terbinafine, morpholine, butenafine, ten Monoenoic acid, Whitefield ointment, propionic acid and caprylic acid, and substances identified as antifungal agents by methods well known in the art. It has been noted that a particular patient may have a fungal organism that acts as a pathogen resistant to a particular antifungal agent. In this case, an important aspect of the present invention includes treating the patient with an effective antifungal agent (e.g., an antifungal agent that prevents the growth or kills fungi as a pathogen). The collection and cultivation methods described herein can be used to identify such fungal organisms that function as pathogens. Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs The term "mucosal application" as used herein refers to any method of application in which the applied agent is contacted with mucus. Therefore, any intravenously administered agent that is only present in the bloodstream is not considered a mucosal agent because the agent fails to contact the mucus. In addition, the term "mucosal administration" can be divided into "direct" and "indirect" mucosal administration. The term " direct mucosal administration " as used herein refers to any application in which the agent to be administered is in direct contact with the target mucus before passing through the epithelium. For the purposes of the present invention, it should be understood that as long as the reagent comes into contact with mucus, it may even be injected through the epithelium by injection methods (eg, needles, tubes, or catheters), and this reagent is also injected into the cavity containing mucus as a direct mucosa. Apply. Therefore, bypassing the tympanic membrane with a needle and injecting the agent into the middle ear is considered to be a direct mucosal application targeting the middle ear mucus. It is understood that any intravenously administered agent that is subsequently present in the bloodstream, exudates the epithelium, and contacts mucus is not considered a reagent for direct mucosal administration, as the agent has passed through the epithelium before contacting the mucus. However, in this case, the intravenously administered agent is considered to be an indirect mucosal administration agent because the term "indirect mucosal administration" means a test to be administered after passing through the epithelium -44-This paper standard applies the Zhongguan standard ( CNS) A4 specification (210X297 male) "" 1236905 A " 7 H * 7 V. Description of the invention (2) Any application of the agent in contact with the targeted mucus. Similarly, the use of injection means such as needles, tubes or catheters to transport reagents through the epithelium and in direct contact with mucus does not necessarily mean that the application is an indirect mucosal application. It should also be understood that oral administration may be either direct or indirect mucosal administration depending on the targeted mucus. For example, the agent can be swallowed and then passed directly through the esophagus, stomach, and small intestine into the large intestinal mucus without passing through the epithelium (i.e., direct mucosal administration). At the same time, the agents for oral administration can be absorbed by the intestine, accumulated systematically, and penetrate the nasal epithelium to reach contact with nasal mucus (i.e., indirect mucosal administration). Therefore, the mucosal application of direct and indirect nature depends on the specific route of application and the specific location of the target mucus. Typical direct and indirect mucosal administrations at various mucus locations in mammals are described below. An effective amount of an antifungal agent or an antifungal agent-containing formula printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs may be that mucosa does not cause significant toxicity when applied to mammals and can reduce, prevent, or eliminate non-invasive fungal induction Any amount of mucositis. Generally, an effective amount can be any amount that is not significantly toxic to an individual when administered mucosally and is greater than or equal to the minimum inhibitory concentration (MIC) of a fungal organism or isolate present in the mucus of a particular individual. Some antifungals may have a relatively large effective concentration range while other antifungals may have a relatively narrow effective concentration range. In addition, this effective amount can vary depending on the specific fungal organism or isolate, as some organisms and isolates are more or less sensitive to a particular antifungal agent. The effective amount of a single antifungal agent can be determined using conventionally available or easily identifiable information including effective antifungal concentrations, animal toxic concentrations, and tissue permeability. For example, 'non-toxic antifungal agents can generally be directly in the mucus to show any amount of antifungal activity -45-This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1236905 employees Printed by Consumer Cooperatives i, Description of Invention (43) or indirect mucosal administration. In addition, antifungal agents that cannot penetrate into the mucosal epithelium can generally be applied directly to the mucosa in any amount that exhibits antifungal activity in the mucus. Using the information provided herein, this effective amount can also be determined by routine experiments in vitro or in vivo. For example, patients with a non-invasive fungal-induced mucositis condition may receive direct mucosal administration of antifungal agents close to the MIC amount calculated from in vitro analysis. If the patient does not respond, it can be increased, for example, by a factor of 10, and after receiving this higher concentration, the patient's response to treatment and symptoms of toxicity can be monitored and adjusted accordingly. For amphotericin B, when administered directly mucosally, the effective amount may be from about 0.01 ng to about 1,000 mg per kilogram of mammal body weight per application. When used as a nasal perfusion solution, an effective amount may be from about 0.01 mL to about 1 liter per administration per nostril, containing about 0.01 mg of amphotericin B per liter to about 1000 mg of amphotericin B per liter. Alternatively, the effective amount may be a perfusion (e.g., 2 to 4 times per day) of 20 mL per nostril containing about 100 mg of amphotericin B per liter of saline or water. Generally, salt or water is sterile. This effective amount can be maintained constant or adjusted to a sliding scale or a variable dose depending on the individual's response to the treatment. Effective amounts for other antifungal agents can be determined by one of ordinary skill in the art by routine experimentation in accordance with the various methods herein. In general, an effective amount of any antifungal agent (eg, itraconazole, ketoconazole, and vor icon azole) for direct mucosal administration can be about 0.01 ng to about 0.001 per kg of body weight mammal per application 1000 mg. Depending on the specific fungal organism or isolate tested, the MIC 値 of voriconazole is between about 0.0 03 // g / mL and about 4 // g / m L. For fluconazole, MIC 値 -46-This paper size applies Chinese National Standard (CNS) Α4 specification (210 × 297 male f) (Please read the precautions on the back before filling out this page): Packing ·, 11-age-economic Printed by the Consumers' Cooperative of the Ministry of Standards, Ministry of Standards, 1236905 Λ7 ΙΓ 5. Description of the invention (44) is between about 0.25 // g / mL and greater than about 64 // g / mL. To help determine the effective amount of different antifungal agents, it may be useful to refer to an equivalent amount based on the effective amount of a conventional antifungal agent. For example, approximately 20 mL of amphotericin B perfusion containing about 100 mg of amphotericin B per liter per nasal nostril (e.g., twice a day) is an effective amount as demonstrated herein. The effect produced by this effective amount can be used as a reference point to compare the effects of other antifungal agents used at different concentrations. Once the same effect is observed, a specific effective amount of the specific antifungal agent can be determined. In this case, a specific amount will be called an equivalent effect of an effective amount of amphotericin B. A number of factors can affect the actual effective amount used for a particular application. For example, the frequency of mucosal administration, the duration of treatment, the combination with other antifungal agents, the site of application, the degree of inflammation, and the anatomical morphology of the treated area may require increasing or decreasing the effective amount of actual mucosal administration. The frequency of mucosal administration may be any frequency that reduces, prevents, or eliminates non-invasive fungal-induced mucositis in a mammal without causing significant toxicity to the mammal. For example, the frequency of mucosal administration may be from about 4 times a day to about once a month, or more specifically from about 2 times a day to once a week. In addition, the frequency of mucosal administration may be maintained constant or may vary during treatment. As with the effective amount, a number of factors can affect the actual frequency of mucosal application for a particular application. For example, an effective amount, duration of treatment, combination with other antifungal agents, site of application, degree of inflammation, and anatomical morphology of the treated area may require increased or decreased frequency of mucosal administration. The effective time of antifungal mucosal application can be reduced, prevented or eliminated -47-This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

1236905 _____ ΙΓ 五、發明説明L ) 除哺乳動物中非侵襲性真菌誘導的粘膜炎而不在該哺乳動物中產生顯著毒性的任何時間。因此，有效的時間可以數天至數週、數月或數年間變化。一般來說，用於治療非侵襲性真菌誘導粘膜炎的有效時間可從幾天至幾個月。然而，一旦終止抗真菌施用，非侵襲性真菌誘導的粘膜炎可復發。因此，用於防止非侵襲性真菌誘導粘膜炎的有效時間在有時候可持續長達終生。對於對真菌生物種群恢復（repopulation)因素敏感性較小的解剖位置（如，具有完整鼓膜的人中耳），有效的時間可以約1 0天至約30天。然而，對於不太無菌的部份如鼻旁解剖位置，有效的時間可從約30天至大於約80天。在呼吸道或消化道中，有效的時間可從約1 0天至大約大於30天，或甚至大於約90天。同樣，預防性治療一般時間可更長並且可能持續終生。經濟部中央標準局負工消費合作社印t 多種因素可影響用於特定治療或預防方案中的實際有效時間。例如，有效的時間可隨抗真菌劑施用頻率、有效抗真菌劑的量、多種抗真菌劑的合用、施用位點和炎症程度以及治療區域的解剖形狀而改變。此外，所用的特定抗真菌劑可影響實際有效的時間。例如，用於治療非侵襲性真菌誘導鼻竇炎的有效時間對於兩性霉素B爲約3〇天’而對伊曲康唑爲約7天。已注意到可設計診斷的算術方法以測定或反映適當的有效劑量、時間和頻率。 -4 8 - 本紙張尺度適财Η國家標準（〇叫八4規格（210\7^釐） 1236905 hr'1236905 _____ ΙΓ 5. Description of the invention L) Any time other than non-invasive fungal-induced mucositis in mammals without significant toxicity in the mammal. Therefore, the effective time can vary from days to weeks, months, or years. In general, the effective time for treating non-invasive fungal-induced mucositis can range from several days to several months. However, once the antifungal application is discontinued, non-invasive fungal-induced mucositis can recur. Therefore, the effective time for preventing non-invasive fungal-induced mucositis sometimes lasts for life. For less anatomical locations that are less sensitive to fungal biological population repopulation factors (eg, human middle ear with intact eardrum), the effective time can be from about 10 days to about 30 days. However, for less sterile parts such as the paranasal anatomic location, the effective time can be from about 30 days to more than about 80 days. In the respiratory or digestive tract, the effective time can be from about 10 days to about greater than 30 days, or even greater than about 90 days. Similarly, preventive treatments are generally longer and may last a lifetime. A number of factors can affect the actual effective time used in a particular treatment or prevention program. For example, the effective time can vary with the frequency of antifungal application, the amount of effective antifungal, the combination of multiple antifungals, the site of application and the degree of inflammation, and the anatomical shape of the area being treated. In addition, the particular antifungal agent used can affect the actual effective time. For example, the effective time for treating non-invasive fungal-induced sinusitis is about 30 days' for amphotericin B and about 7 days for itraconazole. It has been noted that diagnostic arithmetic can be designed to determine or reflect the appropriate effective dose, time, and frequency. -4 8-This paper is suitable for national standards (〇叫八 4〇（210 \ 7 ^ ％） 1236905 hr '

____ }V 五、發明説明匕）含有至少一抗真菌劑的配方只要該配方以能有效預防、減輕或消除非侵襲性真菌誘導的粘膜炎的量，頻率，時間粘膜施用至哺乳動物，那麼含有抗真菌劑的配方可以爲任何一種形式。例如，本發明範圍內的配方可以爲固體、液體和/或氣溶膠的形式，非限制性地包含粉劑、晶形物質、凝膠、糊劑、軟膏、油膏、乳膏、溶液、懸液、部份液態形式、噴劑、噴霧劑、霧狀物、霧化氣、酊劑、九劑、膠囊、片劑和膠衣。此外，該配方可含有抗真菌劑的雞尾酒（cocktail)。例如，本發明範圍內的配方可非限制性地含有一種，二種、三種、四種、五種或更多種不同的抗真菌劑。此外，本發明範圍內的配方可含有其它成分，非限制性地包含藥用上可接受的含水載體、載體、藥用上可接受的固體載體，類固醇類、粘液溶解劑、抗生素、抗炎劑、免疫抑制劑、擴張劑、血管收縮劑、去充血劑、白三烯抑制劑，抗膽鹼能劑、抗組胺劑、治療性化合物和其組合。此外，配方可含有任何一種或更多種已知對抑制哺乳動物嘔吐反射（gag reflex)有效的化合物。經濟部中央標準局員工消費合作社印製藥用上可接受的含水載體可以爲，例如，能夠溶解抗真菌劑並且對接受該配方的特定個體是無毒的任何溶液。藥用上可接受的含水載體實例非限制性地包含鹽水，水和醋酸。一般來說，藥用上可接受的含水載體爲無菌的。可製備藥用上可接受的固體載體從而使該抗真菌劑適於口腔施用。例如，膠囊或片劑可含有腸衣形式的抗真菌 -4 9 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1236905____} V V. Description of the invention D) Formula containing at least one antifungal agent as long as the formula is effective for preventing, reducing or eliminating non-invasive fungal-induced mucositis to the mammal, then containing Antifungal agents can be formulated in any form. For example, the formulations within the scope of the present invention may be in the form of a solid, liquid, and / or aerosol and include, without limitation, powders, crystalline substances, gels, pastes, ointments, ointments, creams, solutions, suspensions, Partial liquid form, sprays, sprays, mists, mists, tinctures, nine doses, capsules, tablets and gel coats. In addition, the formula may contain a cocktail of antifungals. For example, a formulation within the scope of the present invention may include, but is not limited to, one, two, three, four, five or more different antifungals. In addition, the formulations within the scope of the present invention may contain other ingredients, including, without limitation, pharmaceutically acceptable aqueous carriers, carriers, pharmaceutically acceptable solid carriers, steroids, mucolytics, antibiotics, and anti-inflammatory agents , Immunosuppressants, dilators, vasoconstrictors, decongestants, leukotriene inhibitors, anticholinergics, antihistamines, therapeutic compounds, and combinations thereof. In addition, the formulation may contain any one or more compounds known to be effective in suppressing gag reflex in mammals. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economics A pharmaceutically acceptable aqueous carrier may be, for example, any solution that is capable of dissolving antifungal agents and is non-toxic to the particular individual receiving the formulation. Examples of pharmaceutically acceptable aqueous carriers include, without limitation, saline, water, and acetic acid. Generally, pharmaceutically acceptable aqueous carriers are sterile. A pharmaceutically acceptable solid carrier can be prepared to make the antifungal agent suitable for oral administration. For example, capsules or tablets may contain antifungal in the form of casings-4 9-This paper size applies to China National Standard (CNS) A4 (210X297 mm) 1236905

經濟部中央標準局員工消費合作社印製五、發明説明ς7 ) 劑。由每種膠囊或片劑提供的劑量是可改變的因爲有效的量可通過施用一個或多個膠囊或片劑而得的。任何熟知的藥用上可接受的物質如明膠和纖維素衍生物都可用作藥用上可接受的固體載體。此外，藥用上可接受的固體載體可爲固體的載體，其非限制性地包含澱粉、糖或皂土。此外，抗真菌劑的片劑或九劑配方可遵循使用固體載體、潤滑劑等的常規方法。類固醇可爲含有環戊烷多氫菲環結構的任何化合物。類固醇的實例非限制性地包含強的松、***和氫化可的松。粘液溶解劑可爲使粘液液化的任何化合物。適當的粘液溶解劑可非限制性地包含N-乙醯-L-半胱氨酸 (MUCOSILtm，Dey實驗室）和重組的人DNA酶 (PULMOZYME®，基因技術公司）。抗菌素可爲對細菌有活性的任何化合物，如青霉、紅霉素、新霉素、慶大霉素和氯林可霉素。抗炎劑可爲抵抗炎症的任何化合物，如異丁苯丙酸和水楊酸。免疫抑制劑可爲抑制或干擾正常免疫功能的任何化合物，如環孢素。擴張劑可爲任何導致開口張大的化合物，如沙丁胺醇、血管收縮劑可爲收縮或縮窄血管的任何化合物，如脫氫腎上腺素鹽酸^巳0-SYNEPHRINE® ; Sanofi藥物），***和腎上腺素。去充血劑可爲減輕鼻旁充血或腫脹的任何化合物，如假麻黃鹼鹽酸、鹽酸去甲麻黃鹼和羥甲唑啉，白三烯抑制劑可爲抑制白三烯功能或合成的任何化合物，如氮斯汀。抗膽鹼能劑可爲阻止副交感神經衝動的任何化合物，如異丙托溴 -50 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂 1236905 ______ )Γ 五、發明説明L ) 4 〇銨。抗組胺劑可爲阻止組胺作用或其從細胞（如乳腺細胞）釋放的任何化合物，如特非那定和阿司咪唑。治療性化合物可爲施用時具有治療效應的任何化合物。例如，治療性化合物可爲阻止或干擾嗜酸性細胞與結合到真菌抗原上的免疫球蛋白之間相互作用，例如靶向Fc 受體或S-型凝集素因子受體（如，galectin-3)相互作用的任何化合物。這些化合物可非限制性地包含抗體如IgE、 IgA、IgG、IgM、IgO 以及抗體片段如 Fab、F(at〇2、Fc rFU、FcrRH、FcaR、FceRII 和 FceR 卜靶向鼻旁解剖位置的粘膜施用經濟部中央標準局員工消費合作社印製粘膜施用試劑至鼻旁解剖位置可通過任何一種將該試劑與鼻旁粘液接觸的施用方式進行。只要該施用的試劑在穿過上皮之前接觸鼻旁粘液，直接粘膜施用至鼻旁解剖位置可非限制性地包含鼻灌注液、鼻噴劑、鼻吸入劑和具有，例如，孢和薄紗（saturated gauze)的鼻塞劑（nasal packs)。此外，只要施用的試劑在離開針頭或導管後和穿過上皮之前接觸鼻旁粘液，用，例如，針頭或導管注射至鼻旁腔被認爲是直接的粘膜施用。可用任何的裝置直接的粘膜施用。試劑至鼻旁解剖位置，其非限制性地包含注射器、吸耳球、吸入器、小罐（canister)、噴哂罐（spray can)、噴霧器和面具。例如，可用20 mL吸耳球以含有抗真菌劑的液體配方形式灌注鼻旁解剖位置。這種液體的配方形式可貯存於-20°C、0°C或室溫。如果貯存於室溫以下，該配 -51 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）~ ' 1236905 Λ?Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. The dosage provided by each capsule or tablet is variable because the effective amount can be obtained by administering one or more capsules or tablets. Any well-known pharmaceutically acceptable substance such as gelatin and cellulose derivatives can be used as a pharmaceutically acceptable solid carrier. In addition, the pharmaceutically acceptable solid carrier may be a solid carrier, which includes, without limitation, starch, sugar or bentonite. In addition, the tablet or nine-dose formulation of the antifungal agent may follow a conventional method using a solid carrier, a lubricant and the like. The steroid may be any compound containing a cyclopentane polyhydrophenanthrene ring structure. Examples of steroids include, without limitation, prednisone, dexamethasone, and hydrocortisone. The mucolytic agent can be any compound that liquefies mucus. A suitable mucolytic agent may include, without limitation, N-acetamidine-L-cysteine (MUCOSILtm, Dey Labs) and recombinant human DNase (PULMOZYME®, Gene Technology Corporation). The antibiotic can be any compound that is active against bacteria, such as penicillium, erythromycin, neomycin, gentamicin, and clindamycin. The anti-inflammatory agent may be any compound that fights inflammation, such as ibuprofen and salicylic acid. An immunosuppressant can be any compound that inhibits or interferes with normal immune function, such as cyclosporine. The dilating agent can be any compound that causes dilation, such as salbutamol, and the vasoconstrictor can be any compound that constricts or constricts the blood vessels, such as DHEA 0-SYNEPHRINE®; Sanofi drugs), ***e and epinephrine. Decongestants can be any compound that reduces paranasal congestion or swelling, such as pseudoephedrine hydrochloride, norephedrine hydrochloride, and oxymetazoline. Leukotriene inhibitors can be any compound that inhibits leukotriene function or synthesis Compounds such as azelastine. Anticholinergic agent can be any compound that prevents parasympathetic nerve impulses, such as ipratropium bromide-50-this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling This page) Order 1236905 ______) Γ 5. Description of the invention L) 4 〇 Ammonium. An antihistamine can be any compound that prevents the action of histamine or its release from cells such as breast cells, such as terfenadine and astemizole. A therapeutic compound can be any compound that has a therapeutic effect when administered. For example, a therapeutic compound may be to prevent or interfere with the interaction between eosinophils and an immunoglobulin bound to a fungal antigen, such as targeting an Fc receptor or an S-type lectin factor receptor (eg, galectin-3) Any compound that interacts. These compounds can include, but are not limited to, antibodies such as IgE, IgA, IgG, IgM, IgO, and antibody fragments such as Fab, F (at〇2, Fc rFU, FcrRH, FcaR, FceRII, and FceR). The application of printed mucosal application reagents to the nasal anatomy by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics can be performed by any application method that contacts the reagent with the nasal mucus. As long as the applied reagent contacts the nasal mucus before passing through the epithelium Direct mucosal administration to the paranasal anatomic location may include, without limitation, nasal perfusate, nasal sprays, nasal inhalants and nasal packs with, for example, spores and saturated gauze. In addition, as long as The applied agent contacts the paranasal mucus after leaving the needle or catheter and before passing through the epithelium. Injection into the paranasal cavity with, for example, a needle or catheter is considered a direct mucosal application. The mucosal application can be performed directly with any device. To the paranasal anatomical location, which includes, without limitation, syringes, ear bulbs, inhalers, canisters, spray cans, sprays And masks. For example, a 20 mL earball can be used to infuse the paranasal anatomic location in a liquid formulation containing an antifungal. This liquid formulation can be stored at -20 ° C, 0 ° C, or room temperature. If stored at Below room temperature, this paper is -51-This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) ~ '1236905 Λ?

IP 五、發明説明ς9 ) 方在施用至鼻旁腔之前一般要加熱。間接粘膜施用至鼻旁解剖位置可非限制性地包含口腔、靜脈內、皮內和腹膜內施用，只要該施用的試劑接觸鼻旁粘液。此外，可使用任何裝置以間接粘膜施用試劑至鼻旁解剖位置，這些裝置非限制性地包含注射器和調節釋放膠囊。已注意到特定的施用途徑可影響抗真菌劑的有效量和治療時間以及粘膜施用的頻率。例如，口腔粘膜施用抗真菌試劑較通過鼻灌注的直接粘膜施用會需要更高的濃度以運輸有效的量到鼻旁粘液。靶向肺呼吸道的粘膜施用經濟部中央標準局員工消費合作社印製呼吸道爲呼吸過程中空氣穿過的哺乳動物解剖位置的任何部份，包含口腔、鼻通道、導管、支氣管和分支氣管（bronchial tubes)。肺呼吸道爲管腔壁是粘膜的肺的任何呼吸道，包含支氣管和分支氣管。粘膜施用試劑至肺呼吸道可以爲將該試劑與肺呼吸道粘液接觸的任何一種施用。只要施用的試劑在穿過上皮之前接觸肺呼吸道粘液，直接粘膜施用至肺呼吸道可非限制性地包含吸入、鼻噴灑和鼻灌注。此外，如果施用的試劑在離開針頭或導管後和穿過上皮之前接觸肺呼吸道粘液，用，例如，針頭或導管注射至肺呼吸道被看作是直接粘膜施用。可用任何裝置直接粘膜施用試劑至肺呼吸道，這些裝置可非限制性地包含注射器、吸耳球、吸入器、噴霧器、氣溶膠罐（aerosol -52 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） " 1236905 Λ· ΙΓ 五、發明説明“） canieter)、噴灑罐和面具。只要施用的試劑在穿過上皮之後接觸肺呼吸道粘液，那麼間接粘膜施用至肺呼吸道可非限制性地包含口腔、靜脈內、皮內和腹膜內施用。此外，可用任何裝置間接粘膜施用試劑至肺呼吸道，這些裝置可非限定性地包含注射器和調節釋放膠囊。已注意到特定的施用途徑可影響抗真菌劑的有效量和治療時間以及粘膜施用的頻率。例如，小腸粘膜施用抗真菌劑較經口腔或鼻通過吸入的真接粘膜施用會需要更高的濃度以運輸有效量至肺呼吸道粘液。應該明白直接和間接粘膜施用至呼吸道包含氣管、和□腔’可用本文該用於肺呼吸道的方法和物質加以完成。靶向中耳的粘膜施用經濟部中央標準局員工消費合作社印製粘膜施用試劑至中耳可爲將該試劑與中耳粘液接觸的任何一種施用。直接的粘膜施用至中耳可非限制性地包 #耳滴液和耳衝洗，只要該施用的試劑在穿過上皮之前接觸中耳粘液’例如，如果鼓膜受損或穿孔，只要施用的試齊!ί接觸中耳粘液，那麼此耳衝洗將被認爲是直接的粘膜施 °此外’只要施用的試劑在離開針頭或針管後且在穿過上皮之前接觸中耳粘液，那麼使用針頭或注射針管注射至中耳被認爲是直接的粘膜施用。可用任何裝置直接粘膜施用試劑至中耳，這些裝置包含注射器和吸耳球。 _______________ _ 5 3 _ 本紙張尺騰釐） 1236905 五、發明説明q 請閱讀背 ιέ 意事項再填寫本頁間接粘膜施用至中耳可非限定性地包含口腔、靜脈內、皮內和腹膜內施用，只要該施用的試劑在穿過上皮之後接觸中耳粘液。此外，可用任何的裝置間接粘膜施用試劑至中耳，這些裝置非限定性地包含注射器和調節釋放的膠囊。已注意到特定的施用途徑可影響抗真菌劑有效量和治療時間以及粘膜施用的頻率。例如，口腔粘膜施用抗真菌劑較直接通過中耳注射的粘膜施用會需要更高濃度以運輸有效量至中耳粘液。靶向腸道的粘膜施用經濟部中央標準局員工消費合作社印製粘膜施用試劑至腸道可爲將該試劑與腸道粘液接觸的任何一種施用。直接粘膜施用至腸道可非限制性地包含口腔和灌腸施用，只要施用的試劑在穿過上皮之前接觸腸道粘液。此外，只要施用的試劑在離開針頭或導管後且穿過上皮之前接觸腸道粘液，用，例如，針頭或導管注射至消化道被認爲是直接的粘膜施用。可作任何的裝置直接粘膜施用試劑至腸道，這些裝置非限制性地包含注射器和調節釋放膠囊。例如，抗真菌劑可製成調節釋放膠囊從而使該抗真菌劑在穿過，例如，胃之後得以釋放（如，pH調節釋放膠囊和時間調節釋放膠囊）。間接粘膜施用至腸道可非限制性地包含靜脈內、皮內和腹膜內施用，只要施用的試劑接觸腸道粘液。此外，可用任何的裝置間接粘膜施用試劑至腸道，這些裝置非限 54 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 1236905 to _ ΙΓ 五、發明説明（52 ) 制性地包含注射器。已注意到施用的特定途徑可影響抗真菌劑有效的量和治療時間以及粘膜施用的頻率。例如，靜脈內粘膜施用抗真菌劑可能較通過灌腸法的直接粘膜施用需要更高的濃度以運輸有效的量至腸道粘液。其它的治療可與含有抗真菌劑的配方合用其它治療以幫助增強治療或預防非侵襲性真菌誘導的粘膜炎病情。這些附加治療可非限制性地包含手術和施用第二種配方。手術可非限制性地包含去除息肉狀生長或其它腫瘤、打開身體的一個腔和***導管等。第二種配方可非限制性地包含抗真菌劑、粘液溶解劑、抗生素、抗炎劑、免疫抑制劑、擴張劑、血管縮窄劑、去充血劑、類固醇、抗膽鹼能劑、白三烯抑制劑、抗組胺劑、治療性化合物及其組合。此外，該第二種配方可通過任何途徑施用至哺乳動物。例如，口腔、腹膜內、皮內、靜脈內、皮下、肌肉內、表面、鼻內和支氣管內施用可用於運輸第二種配方至哺乳動物。經濟部中央標準局員工消費合作社印製治療和預防哮喘哮喘的特徵在於支氣管（肺通道）的反常變窄從而呼吸變得困難，患哮喘的個體可表現出如下症狀，如喘氣、呼吸困難（尤其呼氣）、呼吸困難（dyspnee)和胸部緊張 (tightness)。可使哮喘加重的因素包含溫度或濕度的快速 -55 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）經濟部中央標準局員工消費合作社印製 1236905 -_________________^ ........................ ........ 五、發明説明（53 ) 變化、過敏、上呼吸道感染、訓練、應激和吸煙。患哮喘的個體可用本領域已知的任何一種方法加以鑑定。一般來說，哮喘可非限制性地用或不用激發呼吸道的肺功能測試 (增加的呼吸道阻力）（如，乙醯甲基膽鹼攻擊測試、胸部X-射線、和胸部）聽診進行客觀診斷。具有形成哮喘風險的個體可非限制性地包含哪些具有哮喘病史的個體。此外，較老齡的個體；患有囊性纖維化、具有或不具有總的鼻旁息肉的慢性鼻竇炎、阿司匹林敏感或呼吸道問題或過敏家史的個體；和暴露至很大過敏原（如，真菌孢子、花粉和化學藥品）或刺激劑水平的個體可能具有形成哮喘的風險。慢性哮喘個體可通過以能有效減輕或消除哮喘症狀的量、頻率和時間直接粘膜施用試劑至至少部份的呼吸道而加以治療。這種直接的粘膜施用可類似於本文所述用於治療和預防非侵襲性真菌誘導鼻竇炎的方法和物質，因爲鼻旁腔也是呼吸道。例如，可用鼻噴劑和鼻灌注劑直接粘膜施用抗真菌劑至呼吸道粘液。此外，可通過以能有效減輕或消除哮喘症狀的量、頻率時間直接粘膜施用抗真菌劑至至少肺呼吸道的一部份治療慢性哮喘的個體。例如，可經口腔或鼻的吸入用抗真菌劑的氣霧劑或粉劑形式直接粘膜施用至肺呼吸道粘液。此外，可通過以能有效預防哮喘症狀的量、頻率時間粘膜施用抗真菌劑至至少呼吸道的一部份而預防治療具有形成慢性哮喘風險的個體。同樣，這種預防性治療可 -56 - 本紙張尺度適用中國國家標準（CNS ) 規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)IP V. INTRODUCTION OF THE INVENTION 9) The prescription is generally heated before application to the paranasal cavity. Indirect mucosal administration to the paranasal anatomical location may include, without limitation, oral, intravenous, intradermal, and intraperitoneal administration, as long as the agent to be administered contacts the paranasal mucus. In addition, any device may be used for indirect mucosal administration of the agent to the paranasal anatomical site, these devices include, without limitation, a syringe and a modified release capsule. It has been noted that the particular route of administration can affect the effective amount and duration of treatment of the antifungal agent and the frequency of mucosal administration. For example, oral mucosal application of antifungal agents may require a higher concentration to transport effective amounts to the paranasal mucus than direct mucosal application via nasal infusion. Mucosal application targeted to the lung and respiratory tract Printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs, any part of a mammal's anatomical location through which the air passes during breathing, including the oral cavity, nasal passages, catheters, bronchial tubes, and branched trachea ). The pulmonary airway is any airway of the lung whose lumen wall is a mucosa, including the bronchi and branched trachea. The mucosal administration of the agent to the respiratory tract of the lung may be any one of the application of the agent to the pulmonary respiratory mucus. As long as the administered agent contacts the pulmonary airway mucus before passing through the epithelium, direct mucosal administration to the pulmonary airway may include, without limitation, inhalation, nasal spray, and nasal perfusion. In addition, if the administered agent contacts the pulmonary airway mucus after leaving the needle or catheter and before passing through the epithelium, injection into the pulmonary airway with, for example, a needle or catheter is considered a direct mucosal administration. Any device can be used for mucosal administration directly to the pulmonary airway. These devices can include, without limitation, syringes, ear bulbs, inhalers, nebulizers, aerosol cans (aerosol -52-this paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) " 1236905 Λ · ΙΓ V. Description of the invention ") canieter), spray cans and masks. As long as the applied agent contacts the pulmonary airway mucus after passing through the epithelium, the indirect mucosal application to the pulmonary airway can be non-limiting It includes oral, intravenous, intradermal, and intraperitoneal administration. In addition, the agent can be indirectly mucosally administered to the pulmonary airway with any device, and these devices can include, without limitation, syringes and modified release capsules. It has been noted that specific routes of administration can affect An effective amount of antifungal agent and the duration of treatment and the frequency of mucosal administration. For example, administration of antifungal agents in the small intestinal mucosa may require higher concentrations to transport effective amounts to the pulmonary respiratory mucus than in true mucosal administration by inhalation via the mouth or nose. It should be understood that direct and indirect mucosal administration to the respiratory tract contains the trachea, and The 'cavity' can be completed with the methods and substances described herein for the pulmonary airways. Targeting to the mucosa of the middle ear Application of printed mucosal application reagents to the middle ear by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs can be achieved by contacting the reagent with the middle ear mucus Either application. Direct mucosal application to the middle ear can include, without limitation, ear drops and ear irrigation, as long as the applied agent contacts the middle ear mucus before passing through the epithelium, for example, if the tympanic membrane is damaged or perforated, As long as the application is correct! Ί contact with middle ear mucus, then this ear flush will be considered a direct mucosal application. In addition, 'as long as the applied agent contacts the middle ear mucus after leaving the needle or tube and before passing through the epithelium, Then using a needle or injection needle to inject the middle ear is considered to be a direct mucosal application. The agent can be applied directly to the middle ear by any device, including a syringe and a suction ball. _______________ _ 5 3 _ This paper ruler) 1236905 V. Description of the invention q Please read the notes before filling out this page. Indirect mucosal application to the middle ear can include the mouth without limitation , Intravenous, intradermal, and intraperitoneal administration, as long as the administered agent contacts the middle ear mucus after passing through the epithelium. In addition, the agent can be indirectly mucosally administered to the middle ear with any device, these devices include, without limitation, syringes and adjustments Released capsules. It has been noted that specific routes of administration can affect the effective amount and duration of treatment of antifungal agents and the frequency of mucosal administration. For example, oral mucosal administration of antifungal agents will require higher concentrations than mucosal administration injected directly through the middle ear. Transport an effective amount to the middle ear mucus. Targeted intestinal mucosal application Mucosal application reagents printed to the intestine by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs can be any application that contacts the agent with intestinal mucus. Direct mucosal application to The intestinal tract may include, but is not limited to, oral and enema administration, as long as the applied agent contacts the intestinal mucus before passing through the epithelium. In addition, as long as the administered agent contacts the intestinal mucus after leaving the needle or catheter and before passing through the epithelium, injection into the digestive tract with, for example, a needle or catheter is considered a direct mucosal administration. Any device may be used for the direct mucosal administration of the agent to the intestine. These devices include, without limitation, a syringe and a modified release capsule. For example, an antifungal agent can be made into a modified release capsule such that the antifungal agent is released after passing through, for example, the stomach (e.g., pH-adjusted release capsules and time-adjusted release capsules). Indirect mucosal administration to the intestinal tract may include, without limitation, intravenous, intradermal, and intraperitoneal administration, as long as the agent administered contacts the intestinal mucus. In addition, any device can be used for indirect mucosal administration of reagents to the intestinal tract. These devices are not limited to 54-This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1236905 to _ ΙΓ 5. Description of the invention (52) Sexually contains a syringe. It has been noted that the particular route of administration can affect the effective amount and duration of treatment of the antifungal agent and the frequency of mucosal administration. For example, intravenous antimucosal administration of antifungal agents may require a higher concentration to transport an effective amount to the intestinal mucus than direct mucosal administration by an enema method. Other treatments Other treatments can be combined with antifungal formulations to help enhance the treatment or prevention of non-invasive fungal-induced mucositis conditions. These additional treatments may include, without limitation, surgery and administration of a second formulation. Surgery can include, without limitation, the removal of polyp-like growths or other tumors, opening a cavity in the body, and inserting a catheter. The second formulation may include, without limitation, antifungal agents, mucolytic agents, antibiotics, anti-inflammatory agents, immunosuppressive agents, dilators, vasoconstrictors, decongestants, steroids, anticholinergics, white trioxide Ene inhibitors, antihistamines, therapeutic compounds, and combinations thereof. In addition, this second formulation can be administered to mammals by any route. For example, oral, intraperitoneal, intradermal, intravenous, subcutaneous, intramuscular, topical, intranasal and intrabronchial administration can be used to transport the second formulation to mammals. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs for the treatment and prevention of asthma. Asthma is characterized by abnormal narrowing of the bronchi (lung passages) and difficulty in breathing. Individuals with asthma can show symptoms such as wheezing, difficulty breathing (especially Exhale), dyspnee, and tightness in the chest. Factors that can exacerbate asthma include rapid temperature or humidity -55-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 1236905 -_________________ ^ .... ................. 5. Description of the invention (53) Changes, allergies, upper respiratory infections, training, stress and smoking. Individuals with asthma can be identified by any method known in the art. In general, asthma can be objectively diagnosed with or without aspirating lung function tests (increased airway resistance) (eg, acetylcholine challenge tests, chest X-rays, and chest) without the need to challenge the respiratory tract. Individuals at risk for developing asthma may include, without limitation, individuals with a history of asthma. In addition, older individuals; individuals with cystic fibrosis, chronic sinusitis with or without total paranasal polyps, aspirin sensitivity or respiratory problems or family history of allergies; and exposure to large allergens (eg, Individuals with fungal spores, pollen and chemicals) or stimulant levels may be at risk for developing asthma. Individuals with chronic asthma can be treated by directly mucosal administration of the agent to at least a portion of the respiratory tract in an amount, frequency, and time effective to reduce or eliminate asthma symptoms. This direct mucosal administration can be similar to the methods and substances described herein for treating and preventing non-invasive fungal-induced sinusitis, since the paranasal cavity is also the respiratory tract. For example, nasal sprays and nasal infusions can be used to apply antifungal agents directly to the mucous membranes of the respiratory tract. In addition, individuals with chronic asthma can be treated by direct mucosal administration of an antifungal agent to at least a portion of the pulmonary airway in an amount, frequency, and time effective to reduce or eliminate asthma symptoms. For example, the oral or nasal inhalation antifungal aerosol or powder form can be applied directly mucosally to the pulmonary airway mucus. In addition, individuals at risk of developing chronic asthma can be prevented by administering antifungal agents to at least a portion of the respiratory tract in a quantity and frequency effective to prevent asthma symptoms. Similarly, this preventative treatment can be -56-This paper size applies to the Chinese National Standard (CNS) specifications (210X297 mm) (Please read the precautions on the back before filling this page)

1236905 經濟部中央標準局員工消費合作社印m ___ B1五、發明説明（54 ) 類似於本文該用於預防性治療非侵襲性真菌誘導鼻竇炎的方法和物質。本發明將進一步以下面的實施例加以描述，這些實施例沒有限制申請專利範圍中該本發明的範圍。實施例實施例1-收集和分析粘液樣品用下面的方法和物質收集和分析202個病人的粘液。收集粘液之前，指導每位病人吸氣並降低其下頜至其胸部以最大程度減少或防止收集液經喉背部的下正常通道流出鼻旁通道。該收集液或者爲無菌鹽水或者爲無菌水。此外，對每個病人進行一定的定位從而最大程度地減少或防止收集液流出鼻通道。有些病人接受血管收縮劑，如脫氫腎上腺素鹽酸（1 -2噴劑/鼻孔）或***（表面的液體或粉劑，不到每公斤體重4 mg)。有些病人接受約3 mL 20%的N-乙醯-L-半胱氨酸溶液的噴劑。接受這2種試劑的病人首先施以血管收縮劑，而後在約2分鐘後施以N-乙醯串胱氨酸。一旦病人準備好，將收集容器置於一個或兩個鼻孔下粘液樣品將從其中收集，然後將注射裝置，如具有管裝配或鈍而彎曲的針頭和注射器樣裝置部份地置於病人的一個鼻孔或鼻旁解剖位置從而可迫使收集液經過病人的鼻旁解剖位置。在有些情況下，然後在約0.5和5秒的時間內將大約5 mL·至約30 mL的收集液注射至鼻孔。在大 -57 - ^本紙張尺度適用中國國家標準（CNS)A4規格（210x^97公釐） — (請先閱讀背面之注意事項再填寫本頁) 衣·1236905 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ___ B1 V. Description of the Invention (54) Similar to the methods and substances used in this article for the prophylactic treatment of non-invasive fungal-induced sinusitis. The invention will be further described by the following examples, which do not limit the scope of the invention in the scope of the patent application. EXAMPLES Example 1-Collection and analysis of mucus samples The following methods and substances were used to collect and analyze mucus from 202 patients. Before collecting mucus, instruct each patient to inhale and lower their jaw to their chest to minimize or prevent the collected fluid from flowing out of the paranasal passage through the lower normal passage of the larynx. The collection solution is either sterile saline or sterile water. In addition, each patient is positioned to minimize or prevent collection fluid from flowing out of the nasal passages. Some patients receive vasoconstrictors such as DHEA (1-2 spray / nostril) or ***e (liquid or powder on the surface, less than 4 mg per kilogram of body weight). Some patients receive approximately 3 mL of a 20% spray of N-acetamidine-L-cysteine. Patients receiving these two agents were first given a vasoconstrictor and then about 2 minutes later N-acetamidine cystine. Once the patient is ready, place the collection container in one or both of the nostrils. The mucus sample will be collected from it, and then the injection device, such as a tube fitting or blunt and curved needle and syringe-like device, will be partially placed in the patient's one. The nostril or paranasal anatomical position can thus force the collected fluid to pass through the patient's paranasal anatomical position. In some cases, about 5 mL to about 30 mL of the collected solution is then injected into the nostrils over a period of about 0.5 and 5 seconds. In Da -57-^ This paper size applies Chinese National Standard (CNS) A4 (210x ^ 97 mm) — (Please read the precautions on the back before filling this page)

、1T 泉經濟部中央標準局員工消費合作社印f 1236905 _______ Βη 五、發明説明（55 ) 多數情況下，在約0.5和3秒之間的時間內將約1 0 mL至 20 mL的收集液注射至鼻孔。一般來說，每個病人在注射收集液的同時或當感受收集液進入鼻孔時會噴出或強行吐出收集液。此強行吐出注射的收集液很大程度的造成了病人鼻和鼻旁腔中粘液的疏松。同樣，採取特殊護理以減少或防止收集液體積的減少，一旦被吐出，將含有病人鼻孔粘液的收集液收集於置於鼻孔下的收集容器中。收集鼻旁粘液後，用下面的二種方法之一培養粘液。在第一種方法中，加入1 mL 20% 的N-乙醯-L-半胱氨酸的溶液至約10 mL回收的含有粘液的收集液中。然後將此混合物攪拌30秒並且於室溫孵育 15分鐘。毈育後，將混合物於50 mL管中以480 rpm離心5分鐘。分離後，棄上淸並對餘下的粘液攪拌30秒。然後將0.5 mL等份的分離的粘液加入到每個培養板，一個丨Μ A板含有氯霉素，一個IΜ A板含有環丙沙星。然後將這些板於30°C孵育，並作爲常規真菌培養物進行觀察。從約2天至約35天後觀察到單個分離物的生長。在第二種方法中，1〇 mL DTT以90 mL無菌蒸餾水稀釋，將等積的該新鮮稀釋的DTT溶液加入到含有粘液的回收收集液中並將混合物攪拌30秒。然後將此混合物於室溫孵育15分鐘。孵育後，在50 mL管中以300xg將此混合物離心1 〇分鐘。分離後’棄上淸並將剩餘的粘液攪拌3 0秒。然後將〇 · 5 m L等份的分離粘液加入到每個培養板，一個IMA板含有氯霉素’一個Bay瓊脂板含有環丙沙 -58 - 本紙張尺度適用中國國家標準（CNS ΓΧ4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) ·€衣- »1 1236905 A"? — H*7 五經濟部中央標準局員工消費合作社印製發明説明（56 ) 星。然後將該板於30°C培養並按常規真菌培養物觀察。從約2天到約35天後觀察到單個分離物的生長。一旦觀察到真菌的生長，用標準的真菌學技術，包含視覺、組織學和免疫學技術鑑定這些生物。鑑定出的真菌屬和種包含許多以前從AFS病人中分離的真菌生物，如梨頭霉屬、黃色曲霉、煙曲霉、灰綠曲霉、構巢曲霉、雜色曲霉菌、鏈格孢屬、團擔子菌屬、Bipolaris、白色假絲醇母、Candida Lypolytica、***滑假絲酵母、枝孢屬、耳霉屬、小克銀漢霉屬、彎孢屬、Dreschlera、Exserohilum、鐮孢霉屬、Malbranchia、擬青霉菌屬、青霉屬、 Pseudallescheria、根霉屬、裂褶菌屬和孢子絲屬。此外，鑑定出一些以前在診斷爲AFS陽性病人的粘液樣品中沒有鑑定出的真菌生物，如枝頂孢屬、檸檬珠網霉 (Arachniorus citrinus)、Aurobasidioum、白僵菌屬、毛殻屬、Chryosporium、附球屬、Exophilia jeanselmei、地絲菌屬、Oidiodendron、莖點菌病、Pithomyces、 Rhinocladiella、Rhodoturula、Sagrahamala、 Scolebasidium、帚霉屬、黑粉菌霉、木霉屬和接合菌。爲了測定培養導致非侵襲性真菌誘導粘膜炎的真菌生物的最佳溫度，將從兩份病人中收集的液化粘液樣品培養於或者含有氯霉素或者含有環丙沙星的IMA平板上。然後將每個樣品2碟（一個含氯霉素且另一個含有環丙沙星）孵育於 25〇C、28〇C、30〇C、32〇C、33〇C、35 和 37〇C ° 從開始培養起約2天至約35天的時間內每隔一天用眼計數 -59 - 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇χ 297公釐） 1236905 B*7 五、發明説明（57 ) 每個平板的真菌生長和形成。每個溫度下的計數被平均’ 從而提供了孢子萌發和真菌生物隨後生長或形成的最佳溫度估計。結果顯示真菌生長的最佳溫度依據特定的真菌種類或分離物而改變。一般來說，發現3CTC爲支持最大數目真菌種類和分離物的生長。可用下面的方法以確定有效的抗真菌劑以及抗真菌劑的有效濃度從而防止生長從病人分離出的真菌生物或殺死這些真菌生物。從8個鼻竇炎病人中收集到1 7個真菌分離物並測試其對兩性霉素B、酮康唑和伊曲康唑的易感性。用大肉湯 (macro broth)稀釋技術根據國家臨床實驗室標準委員會 (NCCLS)方法在這些真菌分離物中測試每種抗真菌劑。記錄48小時MIC讀數並用NCCLS指南將其解析以將分爲對待測濃度的抗真菌劑易感、居間或抗性的。該方法的結果提供了體外抗特定真菌分離物的抗真菌劑有效性的評價。一般來說，發現這些抗真菌劑對於每種分離物的MIC 値變化較大，從〇·〇3至100// g/mL之間（表I)。衣-- (請先閱讀背面之注意事項再填寫本頁)、 1T Quanzhou Bureau of Standards, Ministry of Economic Affairs, Consumer Consumption Cooperatives f 1236905 _______ Βη V. Description of the Invention (55) In most cases, about 10 mL to 20 mL of the collected solution is injected within a time between about 0.5 and 3 seconds To the nostrils. In general, each patient will spit out or forcefully spit out the collection fluid while injecting the collection fluid or when the collection fluid enters the nostril. The forced spitting of the collected fluid caused the loosening of mucus in the patient's nose and paranasal cavity. Similarly, special care is taken to reduce or prevent a decrease in the volume of the collected fluid. Once it is spit out, collect the collected fluid containing the patient's nostril mucus in a collection container placed under the nostril. After collecting the paranasal mucus, culture the mucus in one of two ways. In the first method, add 1 mL of a 20% N-acetamidine-L-cysteine solution to about 10 mL of the recovered mucus-containing collection solution. This mixture was then stirred for 30 seconds and incubated at room temperature for 15 minutes. After incubation, the mixture was centrifuged in a 50 mL tube at 480 rpm for 5 minutes. After separation, discard the palate and stir the remaining mucus for 30 seconds. 0.5 mL aliquots of the separated mucus were then added to each culture plate, one M A plate containing chloramphenicol and one IM A plate containing ciprofloxacin. These plates were then incubated at 30 ° C and observed as regular fungal cultures. The growth of individual isolates was observed after about 2 days to about 35 days. In the second method, 10 mL of DTT was diluted with 90 mL of sterile distilled water, an equal volume of the freshly diluted DTT solution was added to the recovery collection solution containing the mucus, and the mixture was stirred for 30 seconds. This mixture was then incubated at room temperature for 15 minutes. After incubation, the mixture was centrifuged at 300 xg for 10 minutes in a 50 mL tube. After separation ', discard the palate and stir the remaining mucus for 30 seconds. Then add 0.5 m L aliquots of separated mucus to each culture plate, one IMA plate contains chloramphenicol, and one Bay agar plate contains ciprofloxacin-58-This paper size applies Chinese national standards (CNS Γχ4 specification ( 210X297 mm) (Please read the precautions on the back before filling out this page) · Clothing-»1 1236905 A "? — H * 7 Printed the invention description (56) star by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. The plate was incubated at 30 ° C and observed as a conventional fungal culture. The growth of individual isolates was observed from about 2 days to about 35 days. Once the growth of the fungus was observed, use standard mycological techniques, including visual, Histological and immunological techniques have identified these organisms. The identified fungal genus and species include many fungal organisms previously isolated from patients with AFS, such as Pythora, Aspergillus flavus, Aspergillus fumigatus, Aspergillus grayus, Aspergillus nidulans, Aspergillus crassa, Alternaria, Basidiomycetes, Bipolaris, Candida albicans, Candida Lypolytica, Candida subsp., Cladosporium, Oleomyces, Pleurotus spp., Curvularia, Dreschl era, Exserohilum, Fusarium, Malbranchia, Paecilomyces, Penicillium, Pseudallescheria, Rhizopus, Schizophyllum, and Sporothrix. In addition, some mucus samples from patients previously diagnosed with AFS were identified Fungal organisms not identified in the genus, such as Acremonium, Arachniorus citrinus, Aurobasidioum, Beauveria bassiana, Chaetomium, Chryosporium, Epididium, Exophilia jeanselmei, Geotrichum, Oidiodendron, Phytophthora, Pithomyces, Rhinocladiella, Rhodoturula, Sagrahamala, Scolebasidium, Limonium, Trichoderma, Trichoderma, and Zygomycetes. To determine the optimal temperature for culturing fungal organisms that cause non-invasive fungal-induced mucositis, Liquefied mucus samples collected from two patients were cultured on IMA plates containing either chloramphenicol or ciprofloxacin. Then 2 discs of each sample (one with chloramphenicol and the other with ciprofloxacin ) Incubate at 25 ° C, 28 ° C, 30 ° C, 32 ° C, 33 ° C, 35, and 37 ° C. Every 2 days to about 35 days from the start of the culture. Sky Eye Count-59-This paper size is in accordance with Chinese National Standard (CNS) A4 (21〇χ 297 mm) 1236905 B * 7 5. Description of the invention (57) Fungal growth and formation on each plate. Each temperature The counts below are averaged 'thus providing an optimal temperature estimate for spore germination and subsequent growth or formation of fungal organisms. The results show that the optimal temperature for fungal growth varies depending on the particular fungal species or isolate. In general, 3CTC was found to support the growth of the largest number of fungal species and isolates. The following methods can be used to determine effective antifungal agents and effective concentrations of antifungal agents to prevent the growth or kill of fungal organisms isolated from patients. Seventeen fungal isolates were collected from eight patients with sinusitis and tested for susceptibility to amphotericin B, ketoconazole, and itraconazole. Each antifungal agent was tested in these fungal isolates using a macro broth dilution technique according to the National Committee for Clinical Laboratory Standards (NCCLS) method. A 48-hour MIC reading was recorded and interpreted using the NCCLS guidelines to classify the antifungal as susceptible, intervening, or resistant at the concentration to be tested. The results of this method provide an evaluation of the effectiveness of antifungals against specific fungal isolates in vitro. In general, it was found that the MIC (R) of these antifungal agents varied greatly for each isolate, from 0.03 to 100 // g / mL (Table I). Clothing-(Please read the precautions on the back before filling this page)

、1T 經濟部中央標準局員工消費合作社印製 -60- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1236905 五、發明説明（58 ) 表I、從接受硏究的66位鼻竇炎病人中的64個中分離出的真菌生物，包含對從8位鼻竇炎病人中選出的分離物的 17個兩性霉素B、酮康唑和伊曲康唑的MIC値_ 首獅物種類/分離物兩性霉素B 酮康哗伊曲康唑一囷十J 數目 MIC(//g/mL) MIC(//g/mL) MIC(//g/mL) 枝頂孢屬鏈格孢屬 40 檸檬珠網霉曲霉屬 Aurobasidium 假絲酵母屬 2212 2 8 5 0.0.> 1.56 3.13 12.5 neg* neg neg 3 枝孢屬 21 SSM23 50 1.56 0.39 >100 1.56 0.05 0.05 0.03 neg neg neg neg neg 0.125 (請先閱讀背面之注意事項再填寫本頁)， 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-60- This paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) 1236905 V. Description of the invention (58) Table I Fungal organisms isolated from 64 patients with sinusitis, including MIC of 17 amphotericin B, ketoconazole, and itraconazole from isolates selected from 8 patients with sinusitis Species / Isolates Amphotericin B Ketocontra itraconazole 囷 10J Number MIC (// g / mL) MIC (/ g / mL) MIC (/ g / mL) Acremonium chain 40 spp. Aspergillus aurobasidium Candida 2212 2 8 5 0.0. &1.5; 3.56 1 3.13 12.5 neg * neg neg 3 Cladosporium 21 SSM23 50 1.56 0.39 > 100 1.56 0.05 0.05 0.03 neg neg neg neg neg neg neg 0.125 (Please read the notes on the back before filling this page)

Chryosporium 附球屬 Exophilium Jeanselmei 鐮孢霉屬 16 2 8 經濟部中央標準局員工消費合作社印製地絲菌屬生霉屬 Oididendron 淡紫擬青霉 Papularia 青霉屬莖點霉屬 Pithomyces Rhodoturula Scolebasidium 木霉屬黑粉菌屬沒有鑑定(2 monila， 3 dermaitiaceous) 5 2 12 1 30 12 1 3 2 >52>50.1 4 1 0.1 >100 100 12.5 0.05 3.13 1.56Chryosporium Exophilium Jeanselmei 16 2 8 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, printed by Geotrichum Oididendron Paecilomyces papularia Penicillium Pithomyces Rhodoturula Scolebasidium Trichoderma Ustilago was not identified (2 monila, 3 dermaitiaceous) 5 2 12 1 30 12 1 3 2 > 52 > 50.1 4 1 0.1 > 100 100 12.5 0.05 3.13 1.56

37〇C** 1 >16 37〇C 0.5 0.25 *，neg意爲該生物在測試培養基（PEG 400)中不生長； μ，37t意爲該生物在37t不生長。本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） #f -61 - 1236905 五、發明説明（59 ) 進行下面的硏究以測定具有非侵襲性真菌病因學的鼻竇炎的出現率。爲了達到此目的，用正同的標準測定病人是否具有非侵襲性真菌誘導的鼻竇炎：（1)在鼻旁解剖位置中可觀察到疾病的存在，（2)過敏性粘液的存在，和（3)真菌生物在鼻旁粘液中的存在。每位病人都做了使用標準方法的CT掃描從測定其鼻旁解剖位置中可觀察疾病的存在。爲了測定過敏性粘液的存在，收集每位病人的手術標本並進行組織學評價。已注意到用特定的措施收集每次的手術標本從而確保粘液樣品不被洗去。爲了測定真菌生物在鼻旁粘液中的存在，使用本文該用於收集和培養病人粘液中真菌生物的方法和物質。 73位鼻竇炎病人參與此硏究。這些病人的年齢從13 到73歲，平均年齢50.1。73位病人中的39位爲女性， 34位爲男性。每位病人以前與鼻竇炎有關的手術次數從〇到25次，平均每位病人3_41次手術。73位病人的70位以前經受過息肉病和鼻竇炎的復發。經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 由於缺乏可接受的粘液標本，隨後在硏究中放棄了 7 位病人。剩下的66位病人中，66位（100%)診斷爲CT-掃描陽性，62(94%)診斷爲過敏性粘液陽性，並且64位（97%) 具有陽性真菌培養物。加起來，66位鼻竇炎病例中的60 位（91%)具有所有這三個標準。換句話說，根據上述標準，評價的66位鼻竇炎病人中的91 %具有非侵襲性真菌誘導的鼻竇炎。這91 %的比例代表有關非侵襲性真菌生物鼻竇炎病例數目的巨大增加。例如，眾多的醫學硏究論文報導 _ - 62 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐) — 1236905 經濟部中央標準局員工消費合作社印製〜____________________............——____— 五、發明説明（60 ) 約3%-8%需要手術的慢性鼻竇炎病例爲AFS病例，即一種具有非侵襲性真菌病原學的鼻竇炎病情。因此，本文列出的結果表明在鼻竇炎病情中非侵襲性真菌生物的參與大大多於先前注意到的數目。從這些非侵襲性真菌誘導的鼻竇炎病人的粘液樣品中總共鑑定出25種不同的真菌種類。在表現出真菌生長的64個粘液樣品中檢測到以前從末描述過與AFS相一致的1 6種生物。該範圍約每位病人1到7種真菌生物，平均每位病人約2.9種真菌。63%的培養物包含鏈格孢屬， 47%包含青霉屬，33%包含枝孢屬，33%包含曲霉素，28% 包含鐮孢霉屬，以及20%包含假絲酵母屬。在單獨的硏究中，1 2位對照個體（即，沒有慢性鼻竇炎的人）的粘液樣品按本文所述被收集和分析。所有12位個體（100%)具有陽性的真菌培養物。具體地說，培養出總共7種不同的真菌生物，平均約每人2-25種不同的真菌生物，範圍爲1到4。50%的培養物包含枝孢屬，42%包含鏈格孢屬，33%包含地絲菌屬，33%包含曲霉屬，25% 包含青霉屬，8%包含枝頂孢屬並且8%包含假絲酵母屬。這些結果表明真菌生物生活於雖不是全部，但在大多數人的鼻旁粘液中。實施例2-治療和預防非侵襲性真菌誘導的鼻竇炎 1 32位連續鼻竇炎病人參與硏究以評價抗真菌劑治療非侵襲性真菌誘導的鼻竇炎的用途。診斷分析以後，1 32 -63 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 衣·37 ° C ** 1 > 16 37 ° C 0.5 0.25 *, neg means that the organism does not grow in the test medium (PEG 400); μ, 37t means that the organism does not grow at 37t. This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) #f -61-1236905 V. Description of the invention (59) The following investigation was performed to determine the occurrence of sinusitis with non-invasive fungal etiology rate. To achieve this, the same criteria are used to determine whether a patient has non-invasive fungal-induced sinusitis: (1) the presence of disease can be observed in the paranasal anatomic location, (2) the presence of allergic mucus, and 3) The presence of fungal organisms in the paranasal mucus. Each patient underwent a CT scan using standard methods to determine the presence of observable disease in their anatomical location near the nose. To determine the presence of allergic mucus, surgical specimens from each patient were collected and histologically evaluated. It has been noted that specific measures are used to collect each surgical specimen to ensure that mucus samples are not washed away. To determine the presence of fungal organisms in the paranasal mucus, the methods and materials used herein to collect and culture fungal organisms in patient mucus are used. Seventy-three patients with sinusitis participated in the study. These patients ranged in age from 13 to 73, with an average age of 50.1. Of the 73 patients, 39 were female and 34 were male. The number of previous sinusitis-related operations per patient ranged from 0 to 25, with an average of 3_41 operations per patient. 70 of the 73 patients had previously experienced a recurrence of polyposis and sinusitis. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling out this page). Due to the lack of acceptable mucus specimens, 7 patients were subsequently abandoned in the investigation. Of the remaining 66 patients, 66 (100%) were diagnosed with a positive CT-scan, 62 (94%) were diagnosed with an allergic mucus, and 64 (97%) had a positive fungal culture. Taken together, 60 (91%) of the 66 sinusitis cases had all three criteria. In other words, according to the above criteria, 91% of the 66 patients evaluated for sinusitis had non-invasive fungal-induced sinusitis. This 91% ratio represents a huge increase in the number of cases of non-invasive fungal biological sinusitis. For example, many medical research papers reported _-62-This paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) — 1236905 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ~ ______________________ ......——____— V. Description of the invention (60) About 3% -8% of cases of chronic sinusitis that require surgery are AFS cases, which is a sinusitis condition with non-invasive fungal etiology. Therefore, the results presented here indicate that the involvement of non-invasive fungal organisms in sinusitis conditions is largely greater than previously noted. A total of 25 different fungal species were identified from mucus samples from patients with non-invasive fungal-induced sinusitis. Sixteen organisms previously consistent with AFS have been detected in 64 mucus samples showing fungal growth. This range is about 1 to 7 fungal organisms per patient, with an average of about 2.9 fungi per patient. 63% of the cultures include Alternaria, 47% of Penicillium, 33% of Cladosporium, 33% of Aspergillus, 28% of Fusarium, and 20% of Candida. In a separate study, mucus samples from 12 control individuals (ie, people without chronic sinusitis) were collected and analyzed as described herein. All 12 individuals (100%) had positive fungal cultures. Specifically, a total of 7 different fungal organisms were cultivated, with an average of about 2-25 different fungal organisms per person, ranging from 1 to 4. 50% of the cultures contained Cladosporium and 42% contained Alternaria 33% contains Geotrichum, 33% contains Aspergillus, 25% contains Penicillium, 8% contains Acrospora and 8% contains Candida. These results indicate that fungal organisms live in paranasal mucus, although not all, in most people. Example 2-Treatment and prevention of non-invasive fungal-induced sinusitis 1 Thirty-two consecutive patients with sinusitis participated in a study to evaluate the use of antifungal agents to treat non-invasive fungal-induced sinusitis. After diagnosis and analysis, 1 32 -63-This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page).

、1T •f 經濟部中央標準局員工消費合作社印製 1236905 Η"7 五、發明説明（61 ) 位病人中的125位（95%)具有下面的標準：（1)由CT掃描所證實的鼻旁解剖位置中的可觀察疾病的存在，（2)由組織學評價手術標本所證實的過敏性粘液的存在，和（3)從粘液樣品中培養出真菌生物所證實的鼻旁粘液中真菌生物的存在。1 25位非侵襲性真菌誘導的鼻竇炎病人以每鼻孔約 20 mL兩性霉素B溶液每日2到4次持續至少3個月的抗真菌治療而開始。兩性霉素B溶液的濃度約每升鹽水或水 100 mg。病人用20 mL的吸耳球粘膜施用兩性霉素B溶液至病人的鼻旁解剖位置。當53位病人三個月後返回進行繼續分析時，收集了 53位病人的數據。除了病人訪談、CT掃描分析、肉眼檢查、和真菌培養分析之外，用2種評價計數治療的成功：內窺鏡評價和病人症狀評價。這些評價計數如下：內窺鏡評價〇期：無疾病跡象 1期：僅由內窺鏡見到的息肉狀改變/息肉 2期：中部腔中的息肉 3期：充滿鼻腔的息肉病人症狀評價 -2期：極壞/很壞 -1期：壞/較壞〇期：基線/無變化 1期：好/改進 -64 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） (請先閱讀背面之注意事項再填寫本頁)1T • f Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 1236905 Η " 7 V. Description of Invention 125 (95%) of the 61 patients had the following criteria: (1) Nose confirmed by CT scan Presence of observable disease in para-anatomical locations, (2) presence of allergic mucus confirmed by histological evaluation of surgical specimens, and (3) fungal organisms in paranasal mucus confirmed by culture of fungal organisms from mucus samples The presence. 1 25 non-invasive fungal-induced sinusitis patients started with an antifungal treatment of about 20 mL of amphotericin B solution per nostril 2 to 4 times daily for at least 3 months. The concentration of amphotericin B solution is approximately 100 mg per liter of saline or water. The patient used a 20 mL ear ball mucosa to apply amphotericin B solution to the patient's nasal anatomy. When 53 patients returned for analysis three months later, data for 53 patients were collected. In addition to patient interviews, CT scan analysis, macroscopic examination, and fungal culture analysis, the success of treatment was counted with two evaluations: endoscopic evaluation and patient symptom evaluation. These evaluation counts are as follows: Endoscopic evaluation Stage 0: No signs of disease Phase 1: Polyp-like changes seen only by endoscope / Polyposis 2: Polyp in the middle cavity Phase 3: Symptom evaluation of polyp patients with nasal cavity- Phase 2: Extremely Bad / Very Bad Phase 1: Bad / Worse Phase 0: Baseline / No Change Phase 1: Good / Improved-64-This paper size applies to China National Standard (CNS) A4 (210X 297 mm) (Please read the notes on the back before filling this page)

、-口經濟部中央標準局員工消費合作社印製 1236905 H*7 五、發明説明（62 ) 2期：很好/無症狀內窺1¾評價顯不二個月後5 3位病人中的3 3位從2 期或3期過渡到0期。通過CT掃描證實了 33個病例中的 6位沒有顯币疾病跡象。例如，最近沒有手術和沒有攝入類固醇的一位病人被診斷的2側鼻竇炎，因爲CT掃描顯示與/2側有關（圖1)。該病人然後每日2次每鼻孔接受20 mL兩性霉素B溶液（1〇〇 mg/L)的治療。經過4個月的連續抗真菌治療後，進行CT掃描顯示作爲鼻竇炎特徵的不透明性和症狀完全消失（圖2)。 3個月後53位病人中的11位從內窺鏡評價2期或3 期過渡到1期。其它9位病人對此治療沒有反應。9位無反應的病人中的5位具有可用於檢測的以前收集到的粘液樣品。對這5份可得到的樣品的分析顯示所有5位病人的粘液中具有抗兩性霉素B(用於該治療的抗真菌劑）的真菌生物。病人症狀評價顯示治療後，53位病人中的44位病人進入2期，53位病人中的3位進入1期並且53位病人中的6位進入0期。進入1期或〇期的9位病人爲內窺鏡評價測定而沒有任何反應的相同9位病人，其中的5位顯示有對兩性霉素B具有抗性的真菌生物。在對另一群病人的隨後復查中，發現有數個無反應的病人不含有對兩性霉素 B抗性的真菌生物。此外，收集和分析數位病人在抗真菌治療前和治療 -65 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） — (請先閱讀背面之注意事項再填寫本頁)Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China 1236905 H * 7 V. Description of the invention (62) Phase 2: Very good / asymptomatic endoscope 1¾ After 2 months of evaluation, 3 of 3 patients 3 3 The bit transitions from Phase 2 or 3 to Phase 0. CT scans confirmed that 6 of the 33 cases had no signs of significant disease. For example, a patient with no recent surgery and no steroid intake was diagnosed with 2-sided sinusitis because a CT scan showed a / 2-sided relationship (Figure 1). The patient was then treated with 20 mL of amphotericin B solution (100 mg / L) per nostril twice daily. After 4 months of continuous antifungal treatment, a CT scan showed complete opacity and symptoms that were characteristic of sinusitis (Figure 2). Eleven of the 53 patients transitioned from endoscopic evaluation stage 2 or 3 to stage 1 after 3 months. Nine other patients did not respond to this treatment. Five of the nine non-responsive patients had previously collected mucus samples available for testing. Analysis of these five available samples revealed that all five patients had amphotericin-resistant fungal organisms (antifungal agents for this treatment) in their mucus. Patient symptom evaluation showed that after treatment, 44 of the 53 patients entered Phase 2, 3 of 53 patients entered Phase 1, and 6 of 53 patients entered Phase 0. Nine patients who entered phase 1 or 0 were endoscopic evaluations of the same 9 patients without any response, and 5 of them showed fungal organisms resistant to amphotericin B. In a subsequent review of another group of patients, several non-responding patients were found not to contain amphotericin B-resistant fungal organisms. In addition, collect and analyze digital patients before and after antifungal treatment -65-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) — (Please read the precautions on the back before filling this page)

、訂 1236905 __ ΗΊ 五、發明説明（63 ) 後的粘液樣品。比較抗真菌治療前和治療後粘液樣品評價的結果顯示由真菌生物培養技術所測定的不同真菌的數目在抗真菌治療後在這些病人中顯著地降低。因此，在抗真菌劑治療後鼻竇炎病人爲無症狀的且在其粘液中含有較少的真菌。經濟部中央標準局員工消費合作社印製在單獨的硏究中，病人被診斷爲左側鼻旁竇鼻竇炎，因爲CT掃描顯示出左側鼻旁竇中有炎症疾病特徵性的鼻竇炎相關的混濁化（opacification)。對鏈格孢屬的 RAST分析顯示每升6.23千單位（KV/L)並且雙側真菌培養證實了鏈格孢屬在每個鼻孔中生長。然而，僅僅左側鼻旁接受過手術，並用約20 mL兩性霉素B溶液（100 mg/L) 每曰2到4次進行手述中和手術後治療。在每次手術後的訪談中，病人左側鼻旁竇內都沒有。然而，在病人左竇中鼻竇炎症狀消失後8到10週而得到的RAST讀數爲7.16 KU/L。這代表了較第一次RAST讀數的增加。手術後6個月後，病人的右側鼻旁竇中根據CT掃描被診斷爲鼻竇炎，並且具有1〇.〇 KU/L RAST的鏈格孢屬讀數。在對病人右側鼻旁竇手術治療並用每鼻孔約20 mL的兩性霉素B 溶液（100 mg/L)每日2到4次約7週的抗真菌治療後，病人保持無症狀並且具有4.47 KU/L的RAST讀數。最後一次手術6個月後，CT掃描證實病人保持無症狀和無疾病。總之，這些結果表明使用適當的抗真菌劑至單一側的適當灌注能防止該側的炎症症狀。此外，以前檢測到的負載於起始未治療一側（右側）的真菌足以最終導致在該起 -66 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ^ 經濟部中央標準局員工消費合作社印製 1236905 __ Βη 五、發明説明（64 ) 始未治療一側中存在可見到或明顯的鼻竇炎症狀。此外，如RAST分別的IgE讀數顯示，存在於起始未治療一側（右側）中的真菌生物誘導高的IgE滴度，這與施用至左側抗真菌治療所致的真菌生物的復發減少了無關。在此情況， RAST分析IgE讀數的減少僅僅在以抗真菌齊"瞿注2側後才觀察到。因此，IgE的減少和此疾病症狀的預防與以抗真菌劑對兩側的治療相一致。爲了進一步評價抗真菌劑在治療非侵襲性真菌誘導鼻竇炎中的使用。在一週內收集返回醫師辦公室的每位病人的信息。僅僅以前見到的被指導使用抗真菌兩性霉素B 鼻灌注的病人參與此硏究。在一週期間內，20位病人返回醫生的辦公室（表II)。返回病人的平均年齡爲47歲範圍（16-74歲）。病人用兩性霉素B灌注平均約6個月（範圍1-1 6個月）。有些病人在近一個月進行了鼻手術而其它病人從來末進行過此手術。此外，有些病人用局部和全身性的類固醇治療。此外，除了抗真菌灌注外，有些病人用抗生素進行鼻灌注。該抗菌素溶液每升鹽水（Wilson氏溶液）含有80 mg慶大霉素。有些病人混合此抗菌素溶液與抗真菌溶液，然後進行鼻灌注，而其它病人以順序方式單獨使用每種溶液。有些病人同時也患有其它疾病包含哮喘（20位病人中的15位）和結腸炎 (20位病人中的2位）。當內窺鏡評價的，大多數病人在其非侵襲性真菌誘導的鼻竇炎病情中具有可觀察到的改進。這些可觀察到的 -67 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ' (請先閱讀背面之注意事項再填寫本頁)Order 1236905 __ ΗΊ V. Mucus sample after invention description (63). Comparing the evaluation of mucus samples before and after antifungal treatment showed that the number of different fungi determined by the fungal bioculture technique was significantly reduced in these patients after antifungal treatment. Therefore, patients with sinusitis after antifungal treatment are asymptomatic and contain less fungi in their mucus. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. In a separate study, the patient was diagnosed with left paranasal sinus sinusitis because a CT scan revealed turbidity associated with sinusitis characteristic of inflammatory diseases in the left paranasal sinus (Opacification). RAST analysis of Alternaria spp. Showed 6.23 thousand units per liter (KV / L) and bilateral fungal cultures confirmed Alternaria spp. Growth in each nostril. However, surgery was performed only on the left side of the nose and manual postoperative neutralization was performed with approximately 20 mL of amphotericin B solution (100 mg / L) 2 to 4 times per day. In each post-operative interview, the patient had no left paranasal sinuses. However, the RAST reading 8 to 10 weeks after the disappearance of sinusitis symptoms in the patient's left sinus was 7.16 KU / L. This represents an increase from the first RAST reading. Six months after the operation, the patient's right paranasal sinus was diagnosed with sinusitis based on a CT scan and had an Alternaria reading of 10.0 KU / L RAST. After surgical treatment of the patient's right paranasal sinuses and antifungal treatment with approximately 20 mL of amphotericin B solution (100 mg / L) per nostril 2 to 4 times daily for approximately 7 weeks, the patient remained asymptomatic and had a 4.47 KU / L RAST reading. Six months after the last operation, a CT scan confirmed that the patient remained asymptomatic and disease-free. Taken together, these results indicate that proper infusion of the appropriate antifungal agent to a single side can prevent the symptoms of inflammation on that side. In addition, the previously detected fungus loaded on the untreated side (right side) was sufficient to eventually lead to this -66-This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) ^ Central Standard of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperatives 1236905 __ Βη V. Description of the Invention (64) There are visible or obvious symptoms of sinusitis in the untreated side. In addition, as the respective IgE readings of RAST show, fungal organisms present in the initial untreated side (right side) induce high IgE titers, which is not related to a reduction in the recurrence of fungal organisms caused by application to the left antifungal treatment . In this case, the reduction in IgE readings in the RAST analysis was only observed after antifungal quotation on Qu Qu 2 side. Therefore, the reduction of IgE and the prevention of the symptoms of this disease are consistent with the treatment of both sides with antifungal agents. To further evaluate the use of antifungal agents in the treatment of non-invasive fungal-induced sinusitis. Collect information about each patient returning to the physician's office within a week. Only previously seen patients who were instructed to use antifungal amphotericin B nasal perfusion were involved in this study. During the week, 20 patients returned to the doctor's office (Table II). The average age of returning patients was in the 47-year range (16-74 years). The patients were perfused with amphotericin B for an average of about 6 months (range 1 to 16 months). Some patients have had nasal surgery in the past month while others have never had this surgery. In addition, some patients are treated with local and systemic steroids. In addition, in addition to antifungal perfusion, some patients use antibiotics for nasal perfusion. This antibiotic solution contains 80 mg of gentamicin per liter of saline (Wilson's solution). Some patients mix this antibiotic solution with an antifungal solution and then perform nasal infusion, while others use each solution individually in a sequential manner. Some patients also have other conditions including asthma (15 of 20 patients) and colitis (2 of 20 patients). When evaluated endoscopically, most patients had observable improvements in their non-invasive fungal-induced sinusitis condition. These observable -67-This paper size applies to China National Standard (CNS) A4 (210X297 mm) '(Please read the precautions on the back before filling this page)

1236905 ______ h1 五、發明説明（65 ) 改進與由每位病人得到的症狀改進計分相關。一位病人在 2個月後停止了鼻兩性霉素B的灌注。8個月後該病人表現出非侵襲性真菌誘導鼻竇炎病情的復發症狀。2位其它的病人從兩性霉素B溶液（時間：3個月；頻率··一日2次) 轉變至伊曲霉素溶液（時間：1個月；頻率：一日2次）。用伊曲霉素溶液僅僅7天後有一位報告感覺變好。總之，這些結果顯示抗真菌可用於有效地治療非侵襲性真菌誘導的鼻竇炎。經濟部中央標準局員工消費合作社印製本紙張尺度適用中國國家標準（CNS ) A4規格（210XM7公釐） 1236905 五、發明説明（66 ) 經濟部中央標準局員工消費合作社印裂表II、在一週中收集的病人數據年齡時間頻Φ 最後一次手術類固醇治療其它疾病內窺鏡計分症狀計分 Β A Β A 59 3月1 2天 2月 Μ j \\\ 哮喘 ΝΑ ΝΑ Λ 1 40 1月 2天 Μ j \\\ 有8 哮喘結腸炎 2 1 -1 +2 63 4月 1天 4月並 J \\\ 結節腸炎 1 0 Λ + 1 16 12月2 1天 26月表面哮喘 2 0 -1 + 1 44 12月2 2天 9月 Μ j\\\ 哮喘 3 0 -1 + 1 40 2月3 2天 12月 Μ j \\\ j\w 3 3 -1 0 23 16月 2天 10月 ftE J \\\ 哮喘 3 0 -1 + 1 48 4月 2天 >10年表面 Μ j \ \\ 2 0 -1 0 50 4月 2天 4月 J \ \N 哮喘 1 0 -1 + 1 45 2月 2天 Μ j\\\ 表面哮喘 1 ΝΑ -1 0 74 2月 2天 >4年表面 Μ 2 ΝΑ -1 +1 57 2月 2天 1月系統表面哮喘 2 0 -1 +2 16 12月4 1天 12月 Μ j\\\ 哮喘12 3 0 -1 +2 71 7月 2天 >6年 Μ 哮喘 3 3 -2 -2 38 12月 2天 >6年有9 哮喘 3 3 -1 0 38 5月 2天 28月 Μ J ϊ ΛΛ 哮喘 0 0 -2 +2 66 13月 2天 >4年表面 Μ j \\\ 3 3 -2 0 70 3月5 2天 >2年系統1U 表面哮喘 3 3 -2 + 1 32 3月6 2天 5月 Μ j\\\ 哮喘 3 1 -2 +2 47 2月7 2天 >3年系統” 表面哮喘 3 0 一 2 0 -69 - (請先閱讀背面之注意事項再填寫本頁) 、\呑本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）經濟部中央標準局員工消費合作社印製 1236905 Λ] 1Γ 五、發明説明（67 ) B，抗真菌治療前；A，抗真菌治療後 1 同樣以Wilson氏溶液（80 mg慶大霉素/L鹽水）一天2 次灌注 2 同樣間斷性地以Wilson氏溶液灌注 3 提前8個月終止鼻灌注，並且疾病已復發 4 同時以Wilson氏溶液（80 mg慶大霉素/L鹽水）一天1 次灌注 5 以兩性霉素B(時間：3個月；頻率：一天2次）再換至伊曲康唑（時間：1個月，頻率：1天2次）鼻灌注7天後感覺變好 6 兩性霉素B3個月後更換至伊曲康唑灌注（時間：1個月；頻率：一天2次） 7 同時以Wilson氏溶液灌注（時間：1年） 8 提前一個月接受 Kenalog 40 IM Medval Dose Pack 1 9 提前6個月接受Kenalog Shot 6 1 〇接受強的松1週 11接受系統性類固醇治療3年 12自從開始抗真菌灌注後放棄攝入茶鹼和tylade 實施例3-治療和預防以前未經過鼻手術病人的非侵襲性真菌誘導的鼻竇炎下面的三位非侵襲性真菌誘導的鼻竇炎病人以前未經過鼻手術。一位61歲男患者被診斷爲非侵襲性真菌誘導的鼻竇 -70 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公鰲） (請先閲讀背面之注意事項再填寫本頁) 衣· 、1Τ 經濟部中央標準局員工消費合作社印製 1236905 一·· ------- - — . __________ 五、發明説明（68 ) 炎並告誡其每日2次進行兩性霉素B灌注。開始治療之前，內窺鏡評價顯示有塡滿其鼻腔的息肉（內窺鏡計數分3) 並且病人給自己症狀計分爲-1。用兩性霉素B灌注1 4個月後，內窺鏡評價顯示沒有疾病的跡象（內窺鏡計數爲〇) 並且病人給自己症狀數爲+2。一位64歲女患者被診斷爲非侵襲性真菌誘導的鼻竇炎並告誡其一日2次，後來增至一日4次進行兩性霉素B 灌注。開始治療之前，內窺鏡評價顯示息肉狀病變的跡象 (內窺鏡計分爲1)並且病人給自己計分爲-1。用兩性霉素B 灌注16個月後，內窺鏡評價顯示設有疾病的跡象（內窺鏡計分爲0)並且病人給自己症狀計分爲+2。一位54歲男患者被診斷爲非侵襲性真菌誘導的鼻竇炎開告誡其以一日2次進行兩性霉素B灌注。此病人已進行了每3至8個月一次的肌內類固醇注射，最後一次注射在兩性霉素B灌注開始前約7個月時給予的。抗真菌治療開始前，內窺鏡評價顯示沒有疾病跡象（內窺鏡計分爲〇) 但病人給其自身症狀計分爲-1。用兩性霉素B灌注4個月後，內窺鏡評價再次顯示設有疾病跡象（內窺鏡計分爲〇) ’ 然而，該病人給其自身症狀計分爲+1。實施例4-用抗真菌治療減少嗜酸性細胞一位67歲女患者被診斷爲非侵襲性真菌誘導的鼻竇炎並告誡其進行一日2次的兩性霉素B灌注。兩性霉素B 灌注9個月後，病人進行竇手術用於進一步改進。手術期 -71 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 、-口 1236905 一________________________^ _______ ___ 五、發明説明（69 ) 間，收集手術粘液活檢材料並將嗜酸性細胞計數與從抗真菌治療前手術期間從病人處收集到活檢材料中得到的計數相比較。抗真菌治療後，除了前額竇外，所有竇中粘液活檢材料中的嗜酸性細胞計數均下降（< 5 %)。額竇活檢材料中嗜酸性細胞的計數爲1 〇%。此外，過敏性粘液似乎存在於額竇中，這可能是因爲由於額竇的阻塞，兩性霉素B灌注沒有到達額竇。因此，在所有治療過的竇區域中以前觀察到的嗜酸性細胞過多都已降至正常水平。實施例5-治療和預防慢性哮喘症狀經濟部中央標準局員工消費合作社印製在實施例2中所描述硏究中的53病人中的37位以前被診斷爲慢性哮喘。經過三個月的抗真菌治療後，當接受詢問時，37位哮喘病人中的28位宣稱哮喘症狀的改進或完全消除。抗真菌治療後用肺功能測試分析這28位病人中的4位，因爲他們在抗真菌治療前進行了類似的測試。比較抗真菌治療前和治療，後的結果證實了所有這4 位哮喘病人具有改進的肺功能。此外，28位不再表現出哮喘症狀的病人中的26位停止他們的哮喘治療。在抗真菌治療前這26位病人中的23位服用了系統性固醇，但開始抗真菌治療後沒有人繼續服用類固醇。在單獨的硏究中，從7位哮喘病人的肺中到痰的樣品。對這些樣品的培養分析顯示真菌生物在每種樣品中存在。具體地說，培養了白色假絲酵母、青霉屬、鐮孢霉屬、 -72 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） ' 經濟部中央標準局肩工消費合作社印製 1236905 ___ ΙΓ 五、發明説明（70 )1236905 ______ h1 5. Description of the Invention (65) The improvement is related to the symptom improvement score obtained by each patient. One patient stopped nasal amphotericin B infusion after 2 months. After 8 months, the patient showed recurring symptoms of non-invasive fungal-induced sinusitis. Two other patients switched from amphotericin B solution (time: 3 months; frequency · twice a day) to itramycin solution (time: 1 month; frequency: twice a day). One person reported feeling better after only 7 days with the itramycin solution. Taken together, these results show that antifungal can be used to effectively treat non-invasive fungal-induced sinusitis. Printed by the Central Consumers ’Cooperative of the Ministry of Economic Affairs. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210XM7 mm) 1236905 V. Description of the invention (66). Patient data collected in the age time frequency Φ last surgery steroid treatment other diseases endoscopic score symptom score Β A Β A 59 March 1 2 days 2 months Μ j \\\ asthma ΝΑ ΝΑ Λ 1 40 January 2 TianM j \\\ has 8 asthma colitis 2 1 -1 +2 63 April 1 day April and J \\\ nodular enteritis 1 0 Λ + 1 16 December 2 1 day 26 months surface asthma 2 0 -1 + 1 44 December 2 2 days September Μ j \\\ Asthma 3 0 -1 + 1 40 February 3 2 days December Μ j \\\ j \ w 3 3 -1 0 23 16 days 2 October ftE J \\\ Asthma 3 0 -1 + 1 48 April 2 days > 10 years surface M j \ \\ 2 0 -1 0 50 April 2 days April J \ \ N Asthma 1 0 -1 + 1 45 February 2 days Μ j \\\ surface asthma 1 ΝΑ -1 0 74 February 2 days > 4 years surface Μ 2 ΝΑ -1 +1 57 February 2 days January systemic surface asthma 2 0 -1 +2 16 December 4 1 day December Μ j \\\ Asthma 12 3 0 -1 +2 71 2 days in July > 6 years asthma 3 3 -2 -2 38 2 days in December > 9 years in asthma 3 3 -1 0 38 May 2 days 28 months M J ϊ ΛΛ asthma 0 0 -2 +2 66 13 days 2 days> 4 years surface M j \\\ 3 3 -2 0 70 March 5 2 days> 2 years system 1U surface asthma 3 3 -2 + 1 32 March 6 2 days May Μ j \\\ Asthma 3 1 -2 +2 47 February 7 2 days > 3-year system "Surface asthma 3 0-2 0 -69-(Please read the precautions on the back before filling this page) 、 \ 呑This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 1236905 Λ] 1Γ 5. Description of the invention (67) B, before antifungal treatment; A, antifungal treatment The latter 1 was also infused with Wilson's solution (80 mg of gentamicin / L saline) twice a day. 2 The patient was also infused with Wilson's solution intermittently. 3 The nasal perfusion was stopped 8 months earlier and the disease had recurred. 4 Solution (80 mg gentamicin / L saline) perfusion 5 amphotericin B (time: 3 months; frequency: 2 times a day) and then itraconazole (time: 1 month, frequency) :1 2 times) Feeling better after 7 days of nasal perfusion 6 Amphotericin B changed to itraconazole perfusion after 3 months (time: 1 month; frequency: 2 times a day) 7 Simultaneous perfusion with Wilson's solution (Time: 1 Year) 8 Receive Kenalog 40 IM Medval Dose Pack 1 one month in advance 9 Receive Kenalog Shot 6 6 months in advance 1 〇 Receive prednisone for 1 week 11 Receive systemic steroid treatment for 3 years 12 Give up tea intake after starting antifungal infusion Alkali and tylade Example 3-Treating and preventing non-invasive fungal-induced sinusitis in patients who have not previously undergone nasal surgery The three non-invasive fungal-induced sinusitis patients below have not previously undergone nasal surgery. A 61-year-old male patient was diagnosed with non-invasive fungal-induced sinuses -70-This paper size applies to Chinese National Standard (CNS) A4 (210X297). (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the People's Republic of China. 12369905 I.. Before the start of treatment, an endoscopic evaluation revealed polyps that filled his nasal cavity (endoscopy count of 3) and the patient scored himself a score of -1. After 14 months of perfusion with amphotericin B, endoscopic evaluation showed no signs of disease (endoscopic count was 0) and the patient gave himself a symptom count of +2. A 64-year-old female patient was diagnosed with non-invasive fungal-induced sinusitis and warned twice a day, then increased to four times a day for amphotericin B infusion. Before starting treatment, endoscopic evaluation showed signs of a polypoid lesion (endoscopic score of 1) and the patient scored himself -1. After 16 months of infusion with amphotericin B, an endoscopic evaluation showed signs of disease (endoscopic score of 0) and the patient scored +2 on his symptoms. A 54-year-old male patient was diagnosed with non-invasive fungal-induced sinusitis and warned that he should undergo amphotericin B infusion twice a day. This patient has been given an intramuscular steroid injection every 3 to 8 months, with the last injection being given approximately 7 months before the start of amphotericin B perfusion. Before the start of the antifungal treatment, an endoscopic evaluation showed no signs of disease (endoscopy scored 0) but the patient gave his symptoms a score of -1. After 4 months of infusion with amphotericin B, the endoscopic evaluation again showed signs of disease (endoscopy score of 0) 'However, the patient scored +1 on his own symptoms. Example 4-Reduction of eosinophils with antifungal treatment A 67-year-old female patient was diagnosed with non-invasive fungal-induced sinusitis and warned to perform amphotericin B perfusion twice a day. Nine months after amphotericin B infusion, the patient underwent sinus surgery for further improvement. Surgical period -71-This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page),-口 1236905 一 ________________________ ^ _______ ___ 5. Description of the invention ( 69), collect surgical mucus biopsy material and compare the eosinophil count with the count obtained from the biopsy material collected from the patient during surgery before antifungal treatment. After antifungal treatment, eosinophil counts in mucus biopsy materials in all sinuses except for the frontal sinus decreased (< 5%). The eosinophil count in the frontal sinus biopsy material was 10%. In addition, allergic mucus appears to be present in the frontal sinus, which may be because amphotericin B perfusion did not reach the frontal sinus due to frontal sinus obstruction. As a result, previously observed excess eosinophils have fallen to normal levels in all treated sinus areas. Example 5-Treatment and Prevention of Chronic Asthma Symptoms Printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs. 37 of the 53 patients in the study described in Example 2 were previously diagnosed with chronic asthma. After three months of antifungal treatment, 28 of 37 asthma patients reported improvement or complete elimination of asthma symptoms when questioned. Four of these 28 patients were analyzed by anti-fungal therapy with a lung function test because they performed similar tests before anti-fungal treatment. Comparison of antifungal treatment before and after treatment confirmed that all four asthma patients had improved lung function. In addition, 26 of the 28 patients who no longer showed asthma symptoms stopped their asthma treatment. Twenty-three of these 26 patients took systemic steroids before antifungal treatment, but no one continued to take steroids after starting antifungal treatment. In a separate study, samples from the lungs of seven asthmatic patients were obtained from sputum. Culture analysis of these samples revealed the presence of fungal organisms in each sample. Specifically, Candida albicans, Penicillium, Fusarium, -72-This paper size applies to China National Standard (CNS) A4 (210X 297 mm) Printed by the cooperative 1236905 ___ ΙΓ 5. Description of the invention (70)

Scopulariopsis、Cryptococcus 、枝孢屬、曲霉屬、煙曲屬、構巢曲霉和醇母。從每種痰樣品中培養的不同真菌種類數目範圍爲1到5種。實施例6-伊曲康唑配方通過將伊曲康唑溶解至聚乙二醇（PEG)以形成伊曲康唑貯備液而製備伊曲康唑制劑。從1 00 mg伊曲康唑膠囊中（Janssen藥物公司）獲取伊曲康唑，一般來說，用 PEG400溶解伊曲康唑。一旦溶解後，過濾貯備液以去除任何不可溶的物質。然後，通過無菌水稀釋而製備貯備液待用。具體地說，打開20粒100 mg的伊曲康唑膠囊並將具有伊曲康唑的球體置於梯度圓柱體（graduated cylinder) 中。將1升加熱的（70°C )PEG-400加入到含有伊曲康唑的梯度圓柱體中。然後將此混合物置於攪拌的熱平板上並於 7 0°C維持30分鐘。30分鐘後，將此熱懸液經尿石過濾器過濾至玻璃容器中並讓其冷卻至室溫。一旦冷卻，將100 mL過濾液置於空塑料瓶中。然後，加入900 mL無菌水並且混合此溶液。一旦混合後，加入一滴調味劑（薄荷油）。此方法一般得到每mL含約98 8 // g至約111 // g伊曲康唑的溶液。通過HPLC測定每種所示溶液的伊曲康唑濃度（表 III)。 -73 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閱讀背面之注意事項再填寫本頁)Scopulariopsis, Cryptococcus, Cladosporium, Aspergillus, Aspergillus, Aspergillus nidulans, and Alcohol. The number of different fungal species cultivated from each sputum sample ranged from 1 to 5. Example 6-Itraconazole Formula Itraconazole formulation was prepared by dissolving itraconazole into polyethylene glycol (PEG) to form itraconazole stock solution. Itraconazole was obtained from a 100 mg itraconazole capsule (Janssen Pharmaceuticals). Generally, itraconazole was dissolved with PEG400. Once dissolved, the stock solution is filtered to remove any insoluble material. Then, a stock solution was prepared by dilution with sterile water for use. Specifically, 20 100 mg itraconazole capsules were opened and a sphere having itraconazole was placed in a graduated cylinder. One liter of heated (70 ° C) PEG-400 was added to a gradient cylinder containing itraconazole. This mixture was then placed on a stirred hot plate and maintained at 70 ° C for 30 minutes. After 30 minutes, this hot suspension was filtered through a urinary stone filter into a glass container and allowed to cool to room temperature. Once cooled, place 100 mL of filter solution in an empty plastic bottle. Then, add 900 mL of sterile water and mix the solution. Once mixed, add a drop of flavoring agent (menthol oil). This method generally results in a solution containing about 98 8 // g to about 111 // g itraconazole per mL. The itraconazole concentration of each of the indicated solutions was determined by HPLC (Table III). -73-This paper size applies to Chinese National Standard (CNS) Α4 size (210 × 297 mm) (Please read the precautions on the back before filling this page)

、1T 1236905 ΙΓ 五、發明説明（71 ) 表IΜ、溶液中伊曲康唑的濃度溶液可溶性伊曲康唑濃度 (β g/mL) 200 mg來自膠囊的伊曲康唑加入1 L PEG400(貯備液)中以900 mL無菌水稀釋的100 mL貯備液 1839 113 500 mg伊曲康唑粉劑“AS”加入到250 mL PEG400(貯備液)中以900 mL無菌水稀釋的100 mL貯備液 1951 85 來自膠囊的2000 mg伊曲康唑加入到1 L PEG-400(貯備液)中以750 mL無菌稀釋100 mL貯備液和150 mL PGE-400 179 來自膠囊的2000 mg伊曲康唑加入到1 L PEG-400(貯備液)中以875 mL無菌稀釋100 mL貯備液和25 mL PGE-400 155 (請先閱讀背面之注意事項再填寫本頁) • —衣 _1T 1236905 ΙΓ V. Description of the invention (71) Table IM, Concentration of itraconazole in solution Soluble itraconazole concentration (β g / mL) 200 mg Itraconazole from capsules Add 1 L PEG400 (storage 100 mL of stock solution diluted with 900 mL of sterile water in 1839 113 500 mg of itraconazole powder "AS" was added to 250 mL of PEG400 (stock solution). 100 mL of stock solution diluted with 900 mL of sterile water 1951 85 from 2000 mg of itraconazole in capsules was added to 1 L of PEG-400 (stock solution). 100 mL of stock solution and 150 mL of PGE-400 were sterile diluted in 750 mL of 179 mg of itraconazole from capsules was added to 1 L of PEG. -400 (stock solution) with 875 mL of sterile diluted 100 mL stock solution and 25 mL PGE-400 155 (please read the precautions on the back before filling this page)

、1T 也製備了含有類固醇的伊曲康唑配方。具體地說，將來自2個PULMICORT 200 // g吸入器的內容物（約總共91 經濟部中央標準局員工消費合作社印製 // 9布地萘德）加入到70°C的伊曲康唑PEG-400貯備液中維持約15分鐘。在伊曲康唑粉劑溶解於PEG-400 5分鐘後加入布地萘德。冷卻至室溫後，出現一些沉澱。通過經真空精細濾紙過濾該溶液而去除此不溶性物質。將濾紙乾燥並將得到的沉澱物加以測定（36-40 // g)。因此，約54 至50// g的類固醇存在於該溶液/精製（fine)的懸液中。 -74 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公漦）經濟部中央標準局員工消費合作社印製 1236905 Λ? 五、發明説明（72 ) 實施例7-用伊曲康唑治療和預防非侵襲性真菌誘導的鼻竇炎告誡三位非侵襲性真菌誘導的鼻竇炎病人（33歲的男性，70歲的男性和57歲的女性）進行用伊曲康唑溶液的鼻灌注。伊曲康唑溶液含有約每L溶液（無菌水中10%的 PEG-400) 100 mg的伊曲康唑並按本文所述製備。告誡2 位病人進行伊曲康唑灌注因爲他們對兩性霉素B灌注沒有反應。每位病人報告在伊曲康唑灌注開始後的2週內症狀有顯著好轉（症狀計分爲：至+2和-1到+1)。開始伊曲康唑灌注後1 6天時，內窺鏡分析顯示這2位病人中的一位顯示出改進（內窺鏡計分：右側爲從1到〇，左側爲從1 到1)。此外，該病人顯示其哮喘症狀顯著好轉並且她的哮喘用藥（Flovent和Servent)從一日2次降至一日1次。告誡第三位病人進行伊曲康唑灌注因爲他對兩性霉素B的有不良局部反應（灼燒感）。以伊曲康唑治療後，該病人報告有症狀改善（症狀計分··從-1至〇)。此外，該病人用伊曲康唑灌注沒有任何的不良局部反應或問題。實施例8-用伊曲康唑治療和預防慢性哮喘症狀沒有慢性鼻竇炎病史或症狀的32歲白種男性病人儘管以系統性和局部的類固醇和頻繁使用支氣管擴張藥治療，仍顯示出顯著的哮喘症狀。收集和分析痰和鼻旁粘液樣品。培養分析顯示在痰中有白色假絲酵母存在並且在鼻 -75 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） (請先閲讀背面之注意事項再填寫本頁) 、11 經濟部中央標準局負工消費合作社印製 1236905 ΛΊ ΗΊ, 1T also prepared itraconazole formula containing steroids. Specifically, the contents of 2 PULMICORT 200 // g inhalers (approximately a total of 91 printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economics // 9 budesonide) were added to itraconazole PEG at 70 ° C -400 stock solution for about 15 minutes. 5 minutes after itraconazole powder was dissolved in PEG-400, budesonide was added. After cooling to room temperature, some precipitation appeared. This insoluble material was removed by filtering the solution through a vacuum fine filter paper. The filter paper was dried and the resulting precipitate was measured (36-40 // g). Therefore, about 54 to 50 / g of steroids are present in this solution / fine suspension. -74-This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 cm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1236905 Λ? 5. Description of the invention (72) Example 7-Treatment with itraconazole And prevention of non-invasive fungal-induced sinusitis caution three patients (33-year-old men, 70-year-old men, and 57-year-old women) with nasal perfusion with itraconazole solution. Itraconazole solution contains approximately 100 mg of itraconazole per L of solution (10% PEG-400 in sterile water) and is prepared as described herein. Two patients were cautioned for itraconazole infusion because they did not respond to amphotericin B infusion. Each patient reported a significant improvement in symptoms within 2 weeks after the start of itraconazole infusion (symptom score: to +2 and -1 to +1). Sixteen days after the start of itraconazole infusion, endoscopic analysis showed improvement in one of the two patients (endoscopy score: 1 to 0 on the right and 1 to 1 on the left). In addition, the patient showed a marked improvement in her asthma symptoms and her asthma medications (Flovent and Servent) were reduced from twice a day to once a day. The third patient was cautioned for itraconazole infusion because he had an adverse local reaction (burning sensation) to amphotericin B. After treatment with itraconazole, the patient reported improvement in symptoms (symptom score ... from -1 to 0). In addition, the patient was infused with itraconazole without any adverse local reactions or problems. Example 8-Treatment and prevention of chronic asthma symptoms with itraconazole A 32 year old white male patient with no history or symptoms of chronic sinusitis shows significant asthma despite treatment with systemic and local steroids and frequent use of bronchodilators symptom. Collect and analyze sputum and paranasal mucus samples. Cultivation analysis showed the presence of Candida albicans in the sputum and nasal-75-This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page), 11 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 1236905 ΛΊ ΗΊ

------__·_ - 一 II II, ,| I--— ..一一-.丨· .->〜丨······» W I 五、發明説明（73 ) 旁竇的粘液中有青霉屬、地絲菌屬、鏈格孢屬、和枝孢屬的存在。該病人開始以每日2次每鼻孔約20 mL的伊曲康唑溶液的進行抗真菌治療。伊曲康唑溶液的濃度約爲每升 1 00 mg。幾週後，該病人進行了最後一個系統性類固醇療程。停止系統性類固醇約2個月後，該病人也停止使用局部類固醇和支氣管擴張劑。自從停止所有的類固醇治療’ 病人的症狀改善明顯。具體地說，該病人報告自從終止所有的類固醇治療後的4到5個月間沒有呼吸急促和喘氣事件。客觀分析也顯示出劇烈的改善。在抗真菌治療前進行的硏究中，該病人顯示出異常的肺功能。按本文所述進行7個月的連續抗真菌灌注後，其中的後4到5個月沒有所有的類固醇治療，該病人顯示出改進的肺功能。具體地說，力竭性肺活量（forced vital capacity)(FVC)從治療前的3.99升增至治療後的4· 80升，增加20.30% ; 1秒鐘力竭性呼氣體積（FEV1)即降低呼吸道阻力程度的指標’從治療前的3.34升增至治療後的4_27升，增加27.84% ;最大力竭性呼氣流（FEFmax)從治療前的每秒9.1升增至治療後的每秒12 _6升，增加38 _46% ;最大自主換氣量 (maximum voluntary ventilation ; MVV)從治療前的每分鐘119升增加至治療後的每分鐘156升，增加31.90%。總之，儘管在前4至5個月間除了抗真菌鼻灌注以外沒有其它治療，但客觀指標顯示肺功能改善20_3%到 -76 -------__ · _-一 II II,, | I --— .. 一一-. 丨 · .- > ~ 丨 ····· »WI V. Next to the description of the invention (73) Penicillium, Geotrichum, Alternaria, and Cladosporium are present in the mucus of the sinuses. The patient started antifungal therapy with about 20 mL of itraconazole solution per nostril twice daily. The concentration of itraconazole solution is about 100 mg per liter. A few weeks later, the patient underwent the last systemic steroid treatment. About 2 months after stopping systemic steroids, the patient also stopped using local steroids and bronchodilators. Symptoms have improved significantly in patients who have stopped all steroid therapy. Specifically, the patient reported no shortness of breath and asthma between 4 and 5 months after discontinuing all steroid treatment. Objective analysis has also shown dramatic improvements. During the study of antifungal therapy, the patient showed abnormal lung function. After 7 months of continuous antifungal perfusion as described herein, the last 4 to 5 months of which were not treated with all steroids, the patient showed improved lung function. Specifically, the exhausted vital capacity (FVC) increased from 3.99 liters before treatment to 4.80 liters after treatment, an increase of 20.30%; the exhausted expiratory volume (FEV1) decreased in 1 second. The index of the degree of respiratory resistance increased from 3.34 liters before treatment to 4_27 liters after treatment, an increase of 27.84%; the maximum exhaustive expiratory flow (FEFmax) increased from 9.1 liters per second before treatment to 12 per second after treatment _6 litres, an increase of 38_46%; the maximum voluntary ventilation (MVV) increased from 119 litres per minute before treatment to 156 litres per minute after treatment, an increase of 31.90%. In summary, although there were no treatments other than antifungal nasal perfusion during the first 4 to 5 months, objective indicators showed an improvement in lung function of 20_3% to -76-

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）經濟部中央標準局員工消費合作社印製 1236905 五、發明説明（74 ) 38.46%。這些結果表明慢性哮喘症狀可通過粘膜施用抗真菌劑至呼吸道而加以治療和預防。該哮喘病人症狀改善後一段時間，該病人停止用伊曲康唑灌注。停止使用伊曲康唑灌注4-6週後，該病人的哮喘症狀復發。此時，病人攝入類固醇僅僅是爲了控制哮喘症狀。約4-6週後，該病人從使用類固醇變爲使用伊曲康唑粉劑吸入器。具體地說，告誡該病人用粉劑吸入器每天吸入約400 // g的純伊曲康唑。伊曲康唑粉劑爲可靠 (authentic)物質“AS”（Janssen藥物公司）。吸入器爲 ASTRA藥物公司生產的Pulmicort 200 // g TURBO HALER®。該吸入器（in haled)被設計用於布地萘德吸入粉劑的測定過的劑量，但被調整以施用伊曲康唑。病人4週無症狀，並繼續使用伊曲康唑粉劑治療。該病人開始也至少具有一個鼻息肉。治療2週後，該息肉生存力顯著下降。也告誡另一位哮喘病人以調整過的Pulmic〇rt 200 /z g TURBO HALER®每天吸入約200 // g純伊曲康唑。約2 週後，該病的病情明顯改善。該病人一直保持治療。用噴霧器以伊曲康唑治療具有非侵襲性真菌誘導鼻竇炎的哮喘病人。具體地說，每天以噴霧器施用約2 m L 的伊曲康唑溶液（約每mL PEG-400 10 mg伊曲康唑）。該噴霧器爲由Devi lib is生產的氣壓PULMO-M ATE商品。約 2週後，由整體症狀計分的改善證實了該病人在哮喘病情以及非侵襲性真菌誘導的鼻竇炎病情上有確實改進。在延 -77 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ 297公釐） (請先閱讀背面之注意事項再填寫本頁) 、-口 1236905 -____ 丨―·_·Μ I II ..λ. I B I I·...— M..I ·ΙΙ· Ι^·Ι«·,ΙΙ ^. .·.«—-> ,> · . —·. . .-M—^ _ 丨 _ . 五、發明説明（75 ) 長一週的治療也注意到改善。實施例9-鑑定非侵襲性真菌誘導的中耳炎用吸收式捕捉器（suction trap)從三位診斷爲慢性中耳炎的病人中耳中收集粘液樣品。該樣品的培養分析顯示了真菌生物的存在。具體地說，來自第一位病人的粘液樣品爲假絲酵母和Trichophyton rub rum陽性，來自第二位病人的粘液樣品爲青霉菌陽性，並且來自第三位病人的粘液樣品爲曲霉菌陽性。此外，顯微鏡檢查顯示在每種粘液樣品中有大量正在退化的嗜酸性細胞。因此，這些結果表明慢性中耳炎最可能是由非侵襲性真菌生物所致。此外，似乎慢性中耳炎爲可由本文該抗真菌治療和預防方法加以治療和預防的非侵襲性真菌誘導的粘膜炎。實施例1 〇-治療非侵襲性真菌誘導的腸道粘膜炎經濟部中央標準局員工消費合作社印製 5位具有慢性連續鼻竇炎的病人中的3位報告有結腸炎病史。2位病人以每日一粒伊曲康唑膠囊（由Janssen 藥物公司提供）的抗真菌治療開始。該膠囊含有100 mg伊曲康唑。告誡每位病人在其晚餐後至少2小時的睡覺前服用此膠囊並且不攝入任何可樂。食物和可樂飮料增加此藥物的吸收。當按所述施用時，約5 0 %的伊曲康π坐應留在腸腔中用於治療非侵襲性真菌誘導的腸粘膜炎症狀° 其它實施方案 -78 - 度適用中國國家標準（CNS ) Α4規格（210Χ 297公釐） "~ 1236905 Λ? 1Γ 五、發明説明（ 76 應明白雖然結合其詳細描述已經描述了本發明，但前面的描述意在說明並不是限制本發明的範圍，該範圍由所附的申請專利範圍進行限定。其它的方面，優勢和修飾也在下面的申請專利範圍內。 (請先閱讀背面之注意事項再填寫本頁) -1¾.This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 1236905 V. Description of Invention (74) 38.46%. These results indicate that chronic asthma symptoms can be treated and prevented by mucosal administration of antibacterial agents to the respiratory tract. Some time after the asthma patient's symptoms improved, the patient stopped injecting itraconazole. Four to six weeks after stopping itraconazole infusion, the patient's asthma symptoms returned. At this time, patients are taking steroids only to control asthma symptoms. After about 4-6 weeks, the patient switched from steroid use to itraconazole powder inhaler. Specifically, the patient was cautioned to use a powder inhaler to inhale approximately 400 // g of pure itraconazole per day. Itraconazole powder is an authentic substance "AS" (Janssen Pharmaceuticals). The inhaler is a Pulmort 200 // g TURBO HALER® manufactured by ASTRA Pharmaceuticals. The inhaler was designed for the measured dose of budesonide inhaled powder, but adjusted to administer itraconazole. The patient was asymptomatic for 4 weeks and continued to be treated with itraconazole powder. The patient also initially had at least one nasal polyp. After 2 weeks of treatment, the viability of the polyp decreased significantly. Also warn another asthma patient to inhale about 200 // g pure itraconazole per day with adjusted Pulmicor 200 / z g TURBO HALER®. After about 2 weeks, the condition of the disease improved significantly. The patient remains on treatment. Itraconazole is used to treat asthma patients with non-invasive fungal-induced sinusitis using a nebulizer. Specifically, about 2 ml of itraconazole solution (approximately 10 mg of itraconazole per mL of PEG-400) was applied daily with a sprayer. The sprayer is a commercial product of pneumatic PULMO-M ATE manufactured by Devi lib is. After about 2 weeks, the improvement in overall symptom score confirmed the patient's definite improvement in asthma and non-invasive fungal-induced sinusitis. In Yan-77-This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back before filling out this page),-口 1236905 -____ 丨 ― ― ∙ Μ I II ..λ. IBII · ...— M..I · ΙΙ · Ι ^ · Ι «·, ΙΙ ^. ..« —- >, >丨 _. V. Description of the Invention (75) One week's treatment has also noticed improvement. Example 9-Identification of non-invasive fungal-induced otitis media Mucus samples were collected from the middle ears of three patients diagnosed with chronic otitis media using a suction trap. Culture analysis of this sample revealed the presence of fungal organisms. Specifically, the mucus sample from the first patient was positive for Candida and Trichophyton rub rum, the mucus sample from the second patient was positive for penicillium, and the mucus sample from the third patient was positive for aspergillus. In addition, microscopy revealed a large number of degraded eosinophils in each mucus sample. Therefore, these results indicate that chronic otitis media is most likely caused by non-invasive fungal organisms. In addition, chronic otitis media appears to be non-invasive fungal induced mucositis that can be treated and prevented by the antifungal treatment and prevention methods described herein. Example 1-Treatment of non-invasive fungal-induced intestinal mucositis Printed by the Consumer Cooperative of the Central Standards Bureau, Ministry of Economic Affairs, 3 of 5 patients with chronic continuous sinusitis reported a history of colitis. Two patients started antifungal therapy with one itraconazole capsule (provided by Janssen Pharmaceuticals) daily. This capsule contains 100 mg of itraconazole. Advise each patient to take this capsule and not to take any cola before going to bed at least 2 hours after dinner. Food and cola sauce increase the absorption of this medicine. When administered as described, about 50% of itracon π should be left in the intestinal lumen for the treatment of non-invasive fungal-induced symptoms of intestinal mucosal inflammation ° Other embodiments -78-Degrees are subject to Chinese national standards (CNS ) Α4 specification (210 × 297 mm) " ~ 1236905 Λ? 1Γ 5. Description of the invention (76 It should be understood that although the invention has been described in conjunction with its detailed description, the foregoing description is intended to illustrate and not limit the scope of the invention, The scope is defined by the scope of the attached patent application. In other respects, advantages and modifications are also within the scope of the patent application below. (Please read the precautions on the back before filling out this page) -1¾.

'1T 經濟部中央標準局員工消費合作社印製 -79 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）'1T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs -79 This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Claims

1236905 A8B8C8D8 i:.i lr 4 * 泰 4 年六、申請專利範圍 1 _一種用於治療或預防非侵襲性真菌誘導鼻竇炎的醫藥組成物，包含一治療學上有效量的抗真菌劑作爲有效成分。 2.如申請專利範圍第彳項的醫藥組成物，其中該醫藥組成物適於以能有效減輕、消除或預防該非侵襲性真菌誘導鼻竇炎的量、頻率和時間粘膜施用至哺乳動物的至少一部份鼻旁解剖位置。 3·如申請專利範圍第2項的醫藥組成物，其中該粘膜施用爲直接的粘膜施用。 4·如申請專利範圍第3項中的醫藥組成物，其中該直接粘膜施用包含以液體形式之該醫藥組成物灌注至該鼻旁解剖位置。 5. 如申請專利範圍第3項中的醫藥組成物，其中該直接粘膜施用包含施用氣溶膠形式之該醫藥組成物至該鼻旁解剖位置。 6. 如申請專利範圍第3項中的醫藥組成物，其中該直接粘膜施用包含施用粉劑形式之該醫藥組成物至該鼻旁解剖位置。 -80- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -— — — — — — II > — — — — — — 1— — — — — — — — — — — — — — — — — — — — — — I. 1236905 韶 C8 ___(2005 年 4 月修正) 六、申請專利範圍 7·如申請專利範圍第2項中的醫藥組成物，其中該有效量包含該哺乳動物每鼻孔0_01 mL至1 L之該醫藥組成物。 8. 如申請專利範圍第2項中的醫藥組成物，其中該醫藥組成物之該有效量在該有效時間內維持恆定。 9. 如申請專利範圍第2項中的醫藥組成物，其中該粘膜施用之該有效頻率從一日4次至每隔一週1次。 10. 如申請專利範圍第2項中的醫藥組成物，其中該有效時間大於7天。 11 _如申請專利範圍第1項中的醫藥組成物，其中該非侵襲性真菌誘導的鼻竇炎的特徵在於息肉形成或息肉狀病變。 12_如申請專利範圍第1項中的醫藥組成物，其中該非侵襲性真菌誘導的鼻寶炎爲慢性的。 13·如申請專利範圍第1項中的醫藥組成物，其中該醫藥組成物爲固體、液體或氣溶膠的形式。 14.如申請專利範圍第1項中的醫藥組成物，其中該 -81 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 - ϋ I ϋ I ϋ I ϋ ϋ ϋ ϋ ϋ I ϋ I ϋ ϋ 1 ϋ ϋ ϋ I ϋ I ϋ n H ϋ H ϋ ^1 ϋ n ϋ ^1 ϋ ϋ 1236905 截 C8 _P8_(2005年4月修正）六、申請專利範圍醫藥組成物的形式爲一選自由粉劑、晶體狀物質、凝膠、糊劑、軟膏、油膏、乳膏、溶液、懸液、半液體、噴劑、噴霧劑、霧狀物、霧化的氣體、氣溶膠和酊劑所組成之族群。 15·如申請專利範圍第1項中的醫藥組成物，其中該抗真菌劑包含大環內酯。 16.如申請專利範圍第1項中的醫藥組成物，其中該抗真菌劑包含鏰咯。 17·如申請專利範圍第1項中的醫藥組成物，其中該抗真菌劑包含一選自由兩性霉素B、酮康唑、伊曲康唑、沙皮康唑、voriconazole、5-氟胞嘧啶、咪康唑、氟康嗤、灰黃霉素、clotrimazole、益康哇、terco n azole、布康π坐、奧昔康唑、硫康唑、環鏞司乙醇胺、鹵代丙炔氧苯 (haloprogin)、tolnaftate、萘替芳、鹽酸特比萘芬、嗎啉、制霉菌素、游霉素、布替那芬、十一碳烯酸、苯甲酸、水楊酸油膏、丙酸和辛酸所組成之族群。 18. 如申請專利範圍第1項中的醫藥組成物，其中該醫藥組成物包含藥用上可接受的含水載體。 19. 如申請專利範圍第18項中的醫藥組成物，其中該 -82- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 I I I I ^ I ^ I I I I I I I I I I I I I I I I I I I I I I I 1236905 頜 C8 _™_(2005 年 4 月修TF、經濟部智慧財產局員工消費合作社印製六申請專利範圍醫藥組成物包含每升中1 ng至500 mg之該抗真菌劑。 20. 如申請專利範圍第18項中的醫藥組成物，其中該醫藥組成物包含每升中1〇〇 mg該抗真菌劑。 21. 如申請專利範圍第1項中的醫藥組成物，其中該醫藥組成物包含每升中〇.〇1 ng至1000 mg該抗真菌劑。 22. 如申請專利範圍第1項中的醫藥組成物，其中該醫藥組成物包含多種抗真菌劑。 23. 如申請專利範圍第1項中的醫藥組成物，其中該醫藥組成物包含一選自由藥用上可接受的含水載體、藥用上可接受的固體載體、粘液溶解劑、抗細菌劑、抗炎劑、免疫抑制劑、擴張劑、血管收縮劑、類固醇、和治療性化合物所組成之族群的化合物。 24. —種用於治療或預防哮喘的醫藥組成物，包含一治療學上有效量的抗真菌劑作爲有效成分。 25. 如申請專利範圍第24項中的醫藥組成物，其中該醫藥組成物適於以能有效減輕、消除或防止該哮喘症狀的量、頻率和時間粘膜施用至哺乳動物的至少一部份呼吸道。 -83- (請先閱讀背面之注意事項再填寫本頁) -# ^OJI ϋ ϋ ϋ ·ϋ I ϋ _1 I I ϋ ϋ ϋ i·— -1-i .^1 ϋ ^1 ϋ ϋ ^1 ϋ 1 ^1 ϋ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1236905 A8 B8 C8 D8 申請專利範圍 (2005年4月修正） 26. —種用於治療或預防非侵襲性真菌誘導的腸道粘膜炎的醫藥組成物，包含一治療學上有效量的抗真菌劑作爲有效成分。 27. 如申請專利範圍第26項中的醫藥組成物，其中該醫藥組成物適於以能有效減輕、消除或預防該非侵襲性真菌誘導腸道粘膜炎的量、頻率和時間粘膜施用至哺乳動物。 28. —種用於治療或預防非侵襲性真菌誘導中耳炎的醫藥組成物，包含一治療學上有效量的抗真菌劑作爲有效成分。 29.如申請專利範圍第28項中的醫藥組成物，其中該醫藥組成物適於以能有效減輕、消除或預防該非侵襲性真菌誘導中耳炎症狀的量、頻率和時間粘膜施用至哺乳動物。 (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製本紙張尺度逋用中國國家梯準（CNS ) A4規格（210¾妙7»兼)1236905 A8B8C8D8 i: .i lr 4 * Thai 4 years 6. Application scope 1_ A pharmaceutical composition for treating or preventing non-invasive fungal-induced sinusitis, comprising a therapeutically effective amount of an antifungal agent as effective ingredient. 2. The pharmaceutical composition according to item (1) of the scope of patent application, wherein the pharmaceutical composition is suitable for mucosal administration to at least one of mammals in an amount, frequency and time effective to reduce, eliminate or prevent the non-invasive fungal-induced sinusitis. Partial nasal anatomy. 3. The pharmaceutical composition according to item 2 of the application, wherein the mucosal application is a direct mucosal application. 4. The pharmaceutical composition according to item 3 of the scope of patent application, wherein the direct mucosal administration comprises infusion of the pharmaceutical composition in a liquid form to the paranasal anatomic location. 5. The pharmaceutical composition according to item 3 of the scope of the patent application, wherein the direct mucosal application comprises applying the pharmaceutical composition in the form of an aerosol to the paranasal anatomic location. 6. The pharmaceutical composition according to item 3 of the patent application scope, wherein the direct mucosal application comprises applying the pharmaceutical composition in the form of a powder to the paranasal dissection position. -80- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs----- — — II > — — — — — — 1— — — — — — — — — — — — — — — — — — — — I. 1236905 Shao C8 ___ (Amended in April 2005) VI. Application Patent scope 7. The medical composition as described in the second item of the patent application scope, wherein the effective amount comprises the pharmaceutical composition of 0 to 1 mL per nostril of the mammal. 8. The pharmaceutical composition as described in item 2 of the scope of patent application, wherein the effective amount of the pharmaceutical composition remains constant within the effective time. 9. The pharmaceutical composition according to item 2 of the scope of patent application, wherein the effective frequency of the mucosal administration is from 4 times a day to once every other week. 10. The pharmaceutical composition according to item 2 of the scope of patent application, wherein the effective time is greater than 7 days. 11 _ The pharmaceutical composition as described in item 1 of the scope of patent application, wherein the non-invasive fungal-induced sinusitis is characterized by polyp formation or a polypoid lesion. 12_ The pharmaceutical composition according to item 1 of the scope of patent application, wherein the non-invasive fungal-induced rhinitis is chronic. 13. The pharmaceutical composition according to item 1 of the scope of the patent application, wherein the pharmaceutical composition is in the form of a solid, liquid or aerosol. 14. For the medicinal composition in item 1 of the scope of patent application, where -81-This paper size applies to China National Standard (CNS) A4 (210 X 297 public love) (Please read the precautions on the back before filling in this Page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs-ϋ I ϋ I ϋ I ϋ ϋ ϋ ϋ ϋ I ϋ I ϋ ϋ 1 ϋ ϋ ϋ I ϋ I ϋ n H ϋ H ϋ1 1 n ϋ ^ 1 ϋ ϋ 1236905 Section C8 _P8_ (Amended in April 2005) Sixth, the scope of patent application The pharmaceutical composition is in a form selected from the group consisting of powders, crystalline substances, gels, pastes, ointments, ointments, creams, solutions, suspensions , Semi-liquid, spray, spray, mist, atomized gas, aerosol and tincture. 15. The pharmaceutical composition according to item 1 of the application, wherein the antifungal agent comprises a macrolide. 16. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the antifungal agent comprises fluorene. 17. The pharmaceutical composition according to item 1 of the scope of the patent application, wherein the antifungal agent comprises a compound selected from the group consisting of amphotericin B, ketoconazole, itraconazole, sapiticonazole, voriconazole, 5-fluorocytosine , Miconazole, fluconazole, griseofulvin, clotrimazole, econazole, terco n azole, butan π, oxoxiconazole, thioconazole, cyclopentazolamine, halopropynyloxybenzene ( haloprogin), tolnaftate, naftifine, terbinafine hydrochloride, morpholine, nystatin, natamycin, butenafin, undecylenic acid, benzoic acid, salicylic acid ointment, propionic acid and caprylic acid The group of people. 18. The pharmaceutical composition according to item 1 of the patent application scope, wherein the pharmaceutical composition comprises a pharmaceutically acceptable aqueous carrier. 19. For the medicinal composition in item 18 of the scope of patent application, where -82- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling in this Page) Printed by IIII ^ I ^ IIIIIIIIIIIIIIIIIIIII II 1236905 Jaw C8 _ ™ _ (revised in April 2005, printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs and printed by the Consumer Cooperatives) 1 ng to 500 mg of the antifungal agent per liter. 20. The pharmaceutical composition according to item 18 of the scope of patent application, wherein the pharmaceutical composition comprises 100 mg of the antifungal agent per liter. 21. Such as The pharmaceutical composition according to item 1 of the scope of the patent application, wherein the pharmaceutical composition comprises the antifungal agent in an amount of 0.01 ng to 1000 mg per liter. 22. The pharmaceutical composition according to the scope of patent application, wherein The medicinal composition comprises a plurality of antifungal agents. 23. The medicinal composition according to item 1 of the patent application scope, wherein the medicinal composition comprises a member selected from the group consisting of pharmaceutically acceptable Carriers, pharmaceutically acceptable solid carriers, mucolytic agents, antibacterial agents, anti-inflammatory agents, immunosuppressants, dilators, vasoconstrictors, steroids, and compounds of the group consisting of therapeutic compounds. 24. — A medicinal composition for treating or preventing asthma comprises a therapeutically effective amount of an antifungal agent as an active ingredient. 25. The medicinal composition according to item 24 of the application for a patent, wherein the medicinal composition is suitable for The amount, frequency, and time that can effectively reduce, eliminate, or prevent the symptoms of asthma are applied to at least part of the respiratory tract of mammals. -83- (Please read the precautions on the back before filling this page)-# ^ OJI ϋ ϋ ϋ · ϋ I ϋ _1 II ϋ ϋ ϋ i · — -1-i. ^ 1 ϋ ^ 1 ϋ ϋ ^ 1 ϋ 1 ^ 1 ϋ This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ) 1236905 A8 B8 C8 D8 patent application scope (revised in April 2005) 26.-a pharmaceutical composition for treating or preventing non-invasive fungal-induced intestinal mucositis, comprising a therapeutically effective amount of antifungal Agent as effective 27. The pharmaceutical composition as described in item 26 of the scope of the patent application, wherein the pharmaceutical composition is suitable for mucosal administration to the mucosa in an amount, frequency and time effective to reduce, eliminate or prevent the non-invasive fungus-induced enteric Mammals 28. A pharmaceutical composition for treating or preventing non-invasive fungal-induced otitis media, comprising a therapeutically effective amount of an antifungal agent as an active ingredient. 29. The pharmaceutical composition according to item 28 of the scope of application for a patent, wherein the pharmaceutical composition is suitable for mucosal administration to mammals in an amount, frequency and time effective to reduce, eliminate or prevent the symptoms of middle ear inflammation induced by the non-invasive bacteria. (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper size is in accordance with China National Standards (CNS) A4 (210 ¾ 7)