TW516957B

TW516957B - Composition for use in reducing nitric oxide levels and inactivating or inhibiting the formation of species that induce the expression of nitric oxide synthase

Info

Publication number: TW516957B
Application number: TW85114207A
Authority: TW
Inventors: Ching-San Lai
Original assignee: Medinox Inc
Priority date: 1995-11-21
Filing date: 1996-11-19
Publication date: 2003-01-11

Abstract

A composition for use in (a) reducing nitric oxide levels, or (b) inactivating or inhibiting the formation of species that induce the expression of nitric oxide synthase, comprising a nitric oxide scavenger in combination with an agent which inactivates or inhibits the formation of species that induce the expression of nitric oxide synthase in a pharmactucially acceptable carrier therefor, wherein said species is selected from cytokines, cytokine receptors, endotoxins, platelet activating factor, bradykinin, bradykinin receptor, bacteria, coagulation factors, arachidonate metabolites or nitric oxide synthase. Stimulus of nitric oxide synthase expression inactive (or inhibit the production thereof), and nitric oxide harmless. The resulting complexes are eventually excreted in the urine of the host. Further in accordance with the present invention, there are provided compositions and formulations useful for carrying out the above-described methods.

Description

516957 A7 B7 五、發明説明（1 ) 發明領域本發明係有關一種直接或間接處理可於哺乳類中謗發一氧化氮合成酶表現之物種產生之方法。於特別目標中，本發明係有關一種使此種物種去活化或抑制此種物種產生而同時降低一氧化氮量之方法，係使可令此物種去活化（或抑制其產生）之藥劑與過度產生之一氧化氮之去除劑一起投藥。於進一步目標中，本發明係有關一種可用於本文揭示方法中之組合物及調配物。發明背景 1987年，於人類中發現一氧化氮（· NO)(—種氣態游離基) (參見例如，Ignarro等人於 Proc· Natl· Acad· Sci·，USA 84: 9265·69(1987)及 Palmer等人於 Nature 327 : 524-26(1987))。如此發現可用以了解人類生理及病理學之重要指標，科學雜誌選擇一氧化氮作爲1992年之分子。一氧化氮係藉一氧化氮合成酶由L -精氨酸之端胍基之氮原子所形成（NOS ;參見例如，Rodeberg等人於Am. J. Surg. 170:292-303(1995)，及 Bredt及 Snyder於 Ann· Rev. Biochem. 63:175-95(1994))。已鑑定出兩種主要型態之一氧化氮合成酶，構成及可謗發酵素。經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 在生理狀況下，· NO低輸出係由存在於數種細胞（包含内皮及神經單位）中之構成之鈣依存性N 0 S異型態（c N 0 S)所產生。此低量之一氧化氮係涉及多種調節製程如血管等穩，神經單元通訊及免疫系統功能。另一方面，在病理狀況下，高輸出· NO係由可於數種細胞型態（包含内皮細胞，平滑 -4- 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇><297公釐） 516957 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（3 ) 炎及感染性疾病有關聯。發炎性細胞素（如TNF，介白質或干擾素）及感染劑（如内毒素）藉由謗發可謗發之一氧化氮合成酶基因之轉錄，引致可謗發之一氧化氮合成酶製造，隨後導致一氧化氮之過度製造，因而謗發一氧化氮過度製造。經上述路徑之一氧化氮製造可以各種方式瓦解，例如已嘗試努力發展單株抗體（如抗内皮素抗體，抗細胞素抗體，抗細胞素受體抗體等）以在轉錄程度阻斷· NO製造路徑。但不幸地此種努力成功性有限（參見例如 Glauser等人於 Clin· Infect. Dis· 18:S205-16(1994)及 St. John & Dorinsky，於 Chest 103:932-943(1993)) 。此領域中相對缺乏成功性之至少一個原因爲事實上發炎性細胞素之製造爲短存活者（參見例如Wange及Steinsham於 Eur. J· Haematol· 50:243-249(1993))，而一氧化氮之過度製造則持續數天，引起全身性低血壓，不足之組織灌流及器官衰竭。因此例如内毒素症期間TNF製造高峰在約1 - 2小時。因而爲求有效，抗-TNF抗體需在感染早期投藥。確實，在許多臨床設定中，病患在被許可之前以乎已被細菌感染。據此，此種方法僅具有限之成功率。目前，許多醫藥公司已將其注意力轉移至設計並發展酵素NOS之基質或產物類似物抑制劑，以努力處理· NO之過度製造。但近來數據顯示NOS之抑制作用對目標物有害，例如對齧齒類研究顯示抑制一氧化氮之製造引起大鼠中子宮内生長受阻及後腿破裂（例如參見Diket等人於Am. J. -6- 本紙張尺度適用中國國家標準（CNS ) A4規格（2K)X297公釐） (請先閲讀背面之注意事項再填寫本頁) # 訂 516957 經濟部中央標準局員工消費合作衽印製 A7 B7 五、發明説明（4 )516957 A7 B7 V. Description of the Invention (1) Field of the Invention The present invention relates to a method for directly or indirectly treating the generation of species that can spur the expression of nitric oxide synthase in mammals. In a particular object, the present invention relates to a method for deactivating or inhibiting the production of such species while reducing the amount of nitric oxide. It relates to an agent and an agent that can deactivate (or inhibit the production of) this species. The remover which produces a nitric oxide is administered together. In a further object, the present invention relates to a composition and formulation useful in the methods disclosed herein. BACKGROUND OF THE INVENTION Nitric oxide (· NO) (a gaseous free radical) was found in humans in 1987 (see, for example, Ignarro et al. In Proc. Natl. Acad. Sci., USA 84: 9265 · 69 (1987) and Palmer et al. Nature 327: 524-26 (1987)). This discovery can be used to understand important indicators of human physiology and pathology. The scientific journal selected nitric oxide as the molecule of 1992. Nitric oxide is formed by nitric oxide synthase from the nitrogen atom of the terminal guanidino group of L-arginine (NOS; see, for example, Rodeberg et al. Am. J. Surg. 170: 292-303 (1995), And Bredt and Snyder in Ann. Rev. Biochem. 63: 175-95 (1994)). Nitric oxide synthetase, one of two main types, has been identified, which constitutes and defies fermentin. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Under physiological conditions, the low NO output is composed of several types of cells (including endothelial cells and neural units). Calcium-dependent N 0 S isoform (c N 0 S). This low amount of nitric oxide is involved in a variety of regulatory processes such as vascular stabilization, neuronal communication, and immune system function. On the other hand, under pathological conditions, high output and NO are produced by several cell types (including endothelial cells, smooth -4- This paper is in accordance with the Chinese National Standard (CNS) A4 specification (21〇 > < 297 mm) 516957 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (3) Inflammation and infectious diseases are related. Inflammatory cytokines (such as TNF, white matter or interferon) and infectious agents ( (Such as endotoxin) by defamating the transcription of a nitric oxide synthase gene, leading to the production of catastrophic nitric oxide synthase, which subsequently leads to the excessive production of nitric oxide, and thus stigmatizing the excessive production of nitric oxide The production of nitric oxide via one of the above pathways can be disrupted in various ways. For example, efforts have been made to develop monoclonal antibodies (such as anti-endothelin antibodies, anti-cytokine antibodies, anti-cytokine receptor antibodies, etc.) to block transcription at the level of NO Manufacturing path. But unfortunately such efforts have had limited success (see, for example, Glauser et al. Clin · Infect. Dis · 18: S205-16 (1994) and St. John & Dorinsky, Chest 103: 932-943 (1993 )) At least one reason for the relative lack of success in this field is the fact that the production of inflammatory cytokines is short-lived (see, eg, Wange and Steinsham in Eur. J. Haematol. 50: 243-249 (1993)), and one The excessive production of nitric oxide lasts for several days, causing systemic hypotension, insufficient tissue perfusion, and organ failure. Therefore, for example, the peak of TNF production during endotoxin disease is about 1-2 hours. Therefore, to be effective, anti-TNF antibodies need Dosing early in the infection. Indeed, in many clinical settings, patients seem to have been infected by bacteria before being licensed. As such, this method has only a limited success rate. At present, many pharmaceutical companies have turned their attention To design and develop enzyme NOS matrix or product analogue inhibitors in an effort to deal with the excessive production of NO. However, recent data show that the inhibitory effect of NOS is harmful to the target, for example, rodent studies have shown that inhibition of nitric oxide production causes Intrauterine growth retardation and hind leg rupture in rats (see, for example, Diket et al. Am. J. -6- This paper size applies to Chinese National Standard (CNS) A4 (2K) X 297 mm) (Please read the notes on the back before filling out this page) # OR 516957 Printed by the Consumers ’Cooperative Standards of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of Invention (4)

Obstet. Gynecol. 171:1243-1250(1994))。再者，在内毒素症期間抑制一氧化氮合成亦顯示有害（例如參見Minnard等人於 Arch· Surg. 129:142-148(1994); Luss等人於 Biochem· Biophys. Res. Commun. 204:635-640(1994);及 Hargrecht等人於J. Leuk. Biol. 52:390-394(1992))。類似結果已報導於對較大動物之研究中如狗及豬（參見例如Statman等人於J. Surg. Res. 57:93-98(1994); Mitaka等人 Am. J. Physiol. 268:Η2017· H2023(1994); Robertson等人 Arch· Surg. 129:149-156(1994); 及Henderson等人Arch· Surg· 129:1271-1275(1994))。由於各種刺激謗發一氧化氮合成酶之表現，其接著引致一氧化氮過度產生（其限隨著有害效果），因此在本技藝中需要可同時有效處理一氧化氮合成酶表現之初刺激及所得之一氧化氮過度表現。發明簡單敘述依據本發明，發展一種結合治療方法，可用於活體内使可謗發一氧化氮合成酶（係可謗發者）表現之物種去活化或抑制其形成（直接或間接）並減少因· NO合成酶表現所產生之一氧化氮量。與習知技藝用以解決一氧化氮過度產生問題所述之抑制方法（例如參見Aisaka等人Biochem. Biophys. Res. Commun. 60:881-886(1989); Rees·等人 Proc. Natl. Acad. Sci. USA 86:3375-3379 (1989)); Henderson 等人於 Arch·Obstet. Gynecol. 171: 1243-1250 (1994)). Furthermore, inhibition of nitric oxide synthesis during endotoxin disease has also been shown to be harmful (see, for example, Minnard et al., Arch · Surg. 129: 142-148 (1994); Luss et al., Biochem. Biophys. Res. Commun. 204: 635-640 (1994); and Hargrecht et al. J. Leuk. Biol. 52: 390-394 (1992)). Similar results have been reported in studies of larger animals such as dogs and pigs (see e.g. Statman et al. J. Surg. Res. 57: 93-98 (1994); Mitaka et al. Am. J. Physiol. 268: Η2017 H2023 (1994); Robertson et al. Arch Surg. 129: 149-156 (1994); and Henderson et al. Arch Surg. 129: 1271-1275 (1994)). As various stimuli flaunt the performance of nitric oxide synthase, which in turn leads to excessive production of nitric oxide (which is limited by harmful effects), it is necessary in this art to simultaneously deal with the initial stimulus and performance of nitric oxide synthase. One of the resulting nitric oxides was overexpressed. Brief description of the invention In accordance with the present invention, the development of a combined treatment method that can be used in vivo to deactivate or inhibit the formation of direct and indirect species that can manifest nitric oxide synthase (the defamator) and reduce the causes · The amount of nitric oxide produced by NO synthase performance. Inhibition methods described with conventional techniques to solve the problem of excessive nitric oxide production (see, for example, Aisaka et al. Biochem. Biophys. Res. Commun. 60: 881-886 (1989); Rees · et al. Proc. Natl. Acad Sci. USA 86: 3375-3379 (1989)); Henderson et al.

Surg. 129:1271-1275(1994); Hambrecht 等人於 J. Leuk. Biol· 52: 390-394(1992); Luss 等人於 Biochem.及 Biophys. Res. Comm. 204:635-640(1994); Robertson等人於 Arch. Surg. 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) # 訂經濟部中央標準局員工消費合作社印製 516957 A7 B7 五、發明説明（5 ) 129:149-156(1994); Statman等人於 J. Surg. Res. 57:93-98(1994);及Minnard等人於Arch· Surg· 129:142-148(1994))相反，本發明利用去活化（及/或抑制）作用及去除方法之結合，由而使一氧化氮合成酶表現之刺激去活化及/或抑制其表現，且過度產生之一氧化氮於活體内結合至適宜之一氧化氮去除劑上。所得複合物使一氧化氮合成酶表現之刺激去活化（或抑制其產生），同時亦使所得一氧化氮無害。所得複合物最後排至宿主尿液中。又依據本發明，發展一種可用以進行上述方法之組合物及調配物。 • NO合成酶之數種刺激爲本技藝已知。使可令· NO合成酶表現之刺激去活化（或抑制其製造）之試劑與前述之一氧化氮去除劑組合而共同投藥，可提供比本技藝先前所述之方法更有效之處理各種指標之方法。欲用於本發明實務中之一氧化氮去除劑例如二硫代胺基甲酸亞鐵鹽-鐵複合物。此複合物結合至· NO，形成具有特徵化之三線光譜（表示單亞硝基-鐵複合物）之安定水可溶二硫代胺基甲酸酯-鐵-NO複合物，該光譜易在常溫下藉電子常磁共振（EPR)光度計偵測（參見Komarov等人Biochem. Biophys. Res· Commun. 195:1191-1198(1993);及Lai與Komarov， FEBS Lett·，345:120-124(1994))。此於確實時間内偵測體液中· NO之方法近來已由Lai述於美國專利號5,358,703，其全部併於本文供參考。本發明係有關一種結合之治療方法，用以處理可於哺乳類中謗發一氧化氮合成酶表現之物種之製造。因而，對可 -8 - 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X297公釐） (請先閱讀背面之注意事項再填寫本頁) ·#·Surg. 129: 1271-1275 (1994); Hambrecht et al. J. Leuk. Biol 52: 390-394 (1992); Luss et al. Biochem. And Biophys. Res. Comm. 204: 635-640 (1994 ); Robertson et al. In Arch. Surg. This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back before filling out this page) # Order Staff Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Printed 516957 A7 B7 V. Description of the Invention (5) 129: 149-156 (1994); Statman et al. J. Surg. Res. 57: 93-98 (1994); and Minnard et al. Arch · Surg · 129 : 142-148 (1994)) In contrast, the present invention utilizes a combination of deactivation (and / or inhibition) action and removal method, thereby deactivating and / or inhibiting the expression of nitric oxide synthase, and excessively The nitric oxide produced is bound in vivo to a suitable nitric oxide remover. The resulting complex deactivates (or inhibits) the stimulus manifested by nitric oxide synthase, while also rendering the resulting nitric oxide harmless. The resulting complex is finally excreted into the urine of the host. In accordance with the present invention, a composition and a formulation that can be used to perform the above method are developed. • Several stimuli for NO synthase are known in the art. The combination of a reagent capable of deactivating (or inhibiting the production of) NO synthase performance and one of the aforementioned nitric oxide removers can provide a more effective treatment of various indicators than the method previously described in this technology. method. One of the nitric oxide removing agents to be used in the practice of the present invention is, for example, a dithioaminoformate-iron complex. This complex binds to · NO to form a stable water-soluble dithiocarbamate-iron-NO complex with a characteristic three-line spectrum (indicating a mononitroso-iron complex). Detection at room temperature by electronic ordinary magnetic resonance (EPR) photometer (see Komarov et al. Biochem. Biophys. Res. Commun. 195: 1191-1198 (1993); and Lai and Komarov, FEBS Lett., 345: 120-124 (1994)). This method of detecting NO in body fluids within a certain time has recently been described by Lai in U.S. Patent No. 5,358,703, all of which is incorporated herein by reference. The present invention relates to a combined therapeutic method for treating the manufacture of species that can shed the expression of nitric oxide synthase in mammals. Therefore, the applicable national standard (CNS) A4 size (21 × 297 mm) is applicable to this paper size (Please read the precautions on the back before filling this page) · # ·

、1T 516957 經濟部中央標準局員工消費合作社印製、發明説明（發可謗發之一氧化氮合成酶表現之物種製造之結合治療方法。本方法包括：對目標物共同投與有效量之至少一種可直接或間接使該物種去活化或抑制該物種之製造之藥劑及至少一種一氧化氮去除劑之結合。如熟悉本技藝者已悉知者，多種藥劑可使用於去除一氧化氮。適於此目的之藥劑實例包含非血紅素之含鐵胜肽或蛋白質，卟啉（porphyrins)，金屬卟啉，二硫代胺基甲酸酯類’ 一筑基琥ί白酸’菲繞p林，desferriioxamine，ρ比多酸異菸驗醯腙（PIH)，1，2-二甲基_3_羥基吡啶_4·酮（L1)，[+]1,2· 雙（3,5-二氧代六氫吡畊-1-基）丙烷（ICrf-187)等。可用於此目的之較佳類化合物爲二硫代胺基甲酸酯類。意欲用於本發明實務之含二硫代胺基甲酸酯之一氧化氮去除劑包含二硫代胺基甲酸酯部份之任何生理可相容衍生物（即（R)2N-C(S)-SH)。此化合物可參考下列一般結構（I)加以説明： M+1+2+3 (I) 其中：各1^及112分別選自（^至。^烷基，經取代之烷基，環烷基，經取代環烷基，雜環基，經取代雜環基，烯基，經取代烯基，炔基，經取代炔基，芳基，經取代芳基，雜芳基，經取代雜芳基，烷芳基，經取代烷芳基，芳烷基，經取代芳烷基，芳烯基，經取代芳烯基，芳炔基，經取代芳炔基，芳醯基，經取代芳醯基，醯基，經取代醯基，或化1與R2可合而形成包 10- 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)1T 516957 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, and a description of the invention (Combined treatment method for the production of species that expresses the expression of nitric oxide synthase. This method includes: jointly administering at least an effective amount of the target substance to at least A combination of an agent that can directly or indirectly deactivate the species or inhibit the manufacture of the species and at least one nitric oxide remover. As known to those skilled in the art, various agents can be used to remove nitric oxide. Examples of pharmaceuticals for this purpose include non-heme iron-containing peptides or proteins, porphyrins, metalloporphyrins, dithiocarbamates, 'a-based succinic acid, phenoxylan, phenanthrene, desferriioxamine, PIH, PIH, 1,2-dimethyl-3_hydroxypyridine_4 · one (L1), [+] 1,2 · bis (3,5-dioxo Hexahydropyrine-1-yl) propane (ICrf-187), etc. The preferred class of compounds that can be used for this purpose are dithiocarbamates. Dithioamine-containing groups intended for use in the practice of this invention One of the formate nitric oxide removers contains any of the dithiocarbamate moieties Physiologically compatible derivative (ie (R) 2N-C (S) -SH). This compound can be described with reference to the following general structure (I): M + 1 + 2 + 3 (I) where: 1 ^ and 112 are respectively selected from (^ to. ^ Alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, alkenyl, substituted alkenyl, alkynyl, and Substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, substituted aralkyl, arylalkenyl, substituted arene Group, arylalkynyl, substituted arylalkynyl, arylfluorenyl, substituted arylfluorenyl, fluorenyl, substituted fluorenyl, or CH1 and R2 can be combined to form package 10-Applicable to China National Standard (CNS) A4 Specifications (210X297mm) (Please read the notes on the back before filling this page)

516957 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（8 ) 含N，R#R2之5·，6-或7-員環， X爲1或2 ’及當X爲1時，Μ爲單價陽離子或當X爲2時Μ爲生理可相容之二價或三價過渡金屬陽離子。具有上述一般結構（I)之較佳化合物爲其中：各化1及112=(：1至(：12烷基，經取代烷基，烯基，經取代烯基，块基或經取代炔基，其中取代基係選自羧基， C(0)H，氧醯基，酚，苯氧基，吡啶基，吡咯啶基，胺基，醯胺基，羥基，硝基或硫醯基，及 M=Fe+2 或 Fe+3 者。具有上述一般結構之特佳化合物爲其中： 1^=(：2至C8烷基或經取代烷基，其中取代基係選自羧基，乙醯基，吡啶基，吡洛啶基，胺基，醯胺基，經基或硝基，尺2係選自C#C6烷基或經取代烷基，或R2可與Rl合而形成包含N，，6_或7_員環，及 M=Fe+2 者。具有上述一般結構之最佳化合物爲其中：至Cs烷基或經取代烷基，其中取代基係選自複基 ’乙醯基，醯胺基或經基，燒基或經取代烷基，及 M=Fe+2 者。當Ri與及2合而形成5-，6·或7-員環時，1^與尺2之組合可爲各種飽和或不飽和4，5或6原子聯連物種，係選自伸烯基， -11 _ 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516957 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (8) Contains N, R # R2 of 5 ·, 6- or 7-member ring, X is 1 or 2 'and when X is 1 M is a monovalent cation or when X is 2, M is a physiologically compatible divalent or trivalent transition metal cation. Preferred compounds having the above general structure (I) are among them: 1 and 112 = (: 1 to (: 12 alkyl, substituted alkyl, alkenyl, substituted alkenyl, bulk or substituted alkynyl) Where the substituent is selected from the group consisting of carboxyl, C (0) H, oxonyl, phenol, phenoxy, pyridyl, pyrrolidinyl, amine, sulfonylamino, hydroxyl, nitro, or thiosulfanyl, and M = Fe + 2 or Fe + 3. Particularly preferred compounds having the above general structure are: 1 ^ = (: 2 to C8 alkyl or substituted alkyl, where the substituent is selected from the group consisting of carboxyl, acetamyl, and pyridine Group, pyrrolidinyl group, amine group, amido group, via group or nitro group, the ruler 2 is selected from C # C6 alkyl group or substituted alkyl group, or R2 can be combined with R1 to form N, 6_ Or 7-membered ring, and M = Fe + 2. The best compounds having the above general structure are among them: to Cs alkyl or substituted alkyl, wherein the substituent is selected from the group consisting of the compound 'ethylamyl, amidine Or a radical, an alkyl group or a substituted alkyl group, and M = Fe + 2. When Ri and 2 are combined to form a 5-, 6 ·, or 7-membered ring, the combination of 1 ^ and ruler 2 may be Various saturated or unsaturated 4, 5 or 6 atom linked species Selected from alkenylene group, -11 _ this paper scale applicable Chinese National Standards (~ CNS) A4 size (210X297 mm) - (Please read the back of the precautions to fill out this page) Order #

經濟部中央標準局員工消費合作社印製 516957 A7 B7 五、發明説明（9 ) 或含-S-’ -C(0)-及/或-N(R)_之伸燒基部份，其中r爲氫或低碳烷基部份。意欲併入結構（I)化合物之單價陽離子包含H+，Na+，NH4+ ，四燒按等。意欲併入上述化合物之生理可相容二價或三價過渡金屬陽離子包含帶電荷態之鐵、鈷、銅、錳等（如 Fe+2，Fe+3，Co+2，Co+3，Cu+2，Mn+2或 Mn+3)。依據本發明，二硫代胺基甲酸酯物種對平衡離子M之比例可廣泛變化。因而，含二硫代胺基甲酸醋之一氧化氮去除劑可予以投藥而不需任何添加之金屬平衡離子（即Μ=Η+或過渡金屬陽離子對二硫代胺基甲酸酯物種比例爲〇，以過渡金屬陽離子對二硫代胺基甲酸酯物種比例高達約1 : 2 (即2 : 1之二硫代胺基甲酸酯：過渡金屬陽離子複合物）較適宜。本文所用之”經取代烷基”包括又帶有一或多個選自下列取代基之烷基：羥基，烷氧基（低碳烷基之烷氧基，其中低碳燒基具有約1-4個碳原子）’（低碳燒基之）戴基，環燒基，經取代環烷基，雜環基，經取代雜環基，芳基，經取代芳基，雜芳基，經取代雜芳基，芳氧基，經取代芳氧基，函素，三氟甲基，氰基，硝基，亞硝基，胺基，醯胺基， C(0)H，酿基，氧醯基，羧基，胺甲酸g旨，橫醯基，續酿胺基，硫醯基等。本文所用之"環烷基”表示含約3至8個碳原子之含環狀環基，及”經取代雜環基”表示又帶有一或多個前述取代基之環燒基。本文所用之”烯基”表示含有至少一個碳-碳雙鍵且含有約 -12- 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) -訂Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 516957 A7 B7 V. Description of the Invention (9) or a base part containing -S- '-C (0)-and / or -N (R) _, where r Is hydrogen or a lower alkyl moiety. The monovalent cations intended to be incorporated into the compound of structure (I) include H +, Na +, NH4 +, tetrazolium and the like. Physiologically compatible divalent or trivalent transition metal cations intended to incorporate the above compounds include charged iron, cobalt, copper, manganese, etc. (such as Fe + 2, Fe + 3, Co + 2, Co + 3, Cu +2, Mn + 2 or Mn + 3). According to the present invention, the ratio of the dithiocarbamate species to the counter ion M can vary widely. Therefore, a nitrogen oxide remover containing dithiocarbamate can be administered without any additional metal counter ion (ie, M = Η + or transition metal cation to dithiocarbamate species ratio is 〇, the transition metal cation to dithiocarbamate species ratio is as high as about 1: 2 (that is, 2: 1 dithiocarbamate: transition metal cation complex) is more suitable. "Used herein" "Substituted alkyl" includes an alkyl group further bearing one or more substituents selected from: hydroxy, alkoxy (alkoxy of a lower alkyl group, wherein the lower alkyl group has about 1 to 4 carbon atoms) '(Low-carbon alkyl group) Daiyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl Oxy, substituted aryloxy, functional group, trifluoromethyl, cyano, nitro, nitroso, amine, amido, C (0) H, alcohol, oxo, carboxy, amine Formic acid g, sulfonyl, continuous amino, thiosulfanyl, etc. As used herein, "cycloalkyl" means a ring-containing group containing about 3 to 8 carbon atoms. A cyclic group, and "substituted heterocyclic group" means a cycloalkyl group further bearing one or more of the aforementioned substituents. As used herein, "alkenyl" means containing at least one carbon-carbon double bond and containing about -12- Standards are applicable to China National Standard (CNS) A4 specifications (210x297 mm) (Please read the precautions on the back before filling this page)-Order

516957 A7 B7 五、發明説明（1〇 ) 經濟部中央標準局員工消費合作社印製 2至1 2個碳原子之直鏈或支鏈烴基，及"經取代烯基”表示又帶有一或多個前述取代基之烯基。本文所用之”炔基"表示含有至少一個碳-碳叁鍵且含約2 至1 2個碳原子之直鏠或支鏈烴基，及"經取代炔基"表示又帶有一或多個前述取代基之炔基。本文所用之”芳基”表示含6至14個碳原子之芳香基，及” 經取代芳基”表示又帶有一或多個前述取代基之芳基。本文所用之”烷芳基，，表示經烷基取代之芳基，及”經取代坑芳基”表示又帶有一或多個前述取代基之烷芳基。本文所用之”芳烷基”表示經芳基取代之烷基，及”經取代芳坑基表示又帶有一或多個前述取代基之芳坑基。本文所用之”芳烯基”表示經芳基取代之烯基及”經取代之芳烯基'’表示又帶有一或多個前述取代基之芳烯基。本文所用之”芳炔基”表示經芳基取代之炔基及”經取代芳炔基”表不又帶有一或多個前述取代基之芳炔基。本文所用之芳醯基"表示芳羰基如苯甲醯基及"經取代芳醯基"表7F又帶有一或多個前述取代基之芳醯基。本文所用之”雜環基"表示含一或多個雜原子（如N，〇，S 等）作爲環結構部份且含3至14個碳原子之環狀（即含有環）基，且’’經取代雜環基”表示又帶有一或多個上述取代基之雜環基。本文所用之”醯基”表示烷羰基。本文所用之” _素，，表示氟，氯，溴或碘原子。可謗發之一氧化氮合成酶表現之謗發且因此過度產生一516957 A7 B7 V. Description of the invention (10) The consumer cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed a straight or branched chain hydrocarbon group of 2 to 12 carbon atoms, and "substituted alkenyl" means that it has one or more "Alkynyl" of the foregoing substituents. As used herein, "alkynyl" means a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and containing about 2 to 12 carbon atoms, and "substituted alkynyl" " means an alkynyl group further bearing one or more of the aforementioned substituents. As used herein, "aryl" means an aromatic group containing 6 to 14 carbon atoms, and "substituted aryl" means an aryl group further bearing one or more of the aforementioned substituents. As used herein, "alkaryl" refers to an aryl group substituted with an alkyl group, and "substituted aryl group" refers to an alkaryl group having one or more of the aforementioned substituents. As used herein, "aralkyl group" means An aryl-substituted alkyl group, and "substituted aryl aryl group" means an aryl aryl group further bearing one or more of the foregoing substituents. As used herein, "arylalkenyl" means an aryl-substituted alkenyl group and "substituted arylalkenyl" means an arylalkenyl group having one or more of the aforementioned substituents. As used herein, "arylalkynyl" means An aryl-substituted alkynyl group and a "substituted aryl-alkynyl group" refer to an aryl-alkynyl group further bearing one or more of the foregoing substituents. As used herein, "aryl" refers to an arylcarbonyl group such as benzyl and " Substituted arylfluorenyl groups "Table 7F also bears one or more of the foregoing substituents." Heterocyclyl "as used herein means one or more heteroatoms (such as N, 0, S, etc.) as A cyclic (ie, ring-containing) group having 3 to 14 carbon atoms in a ring structure portion, and "substituted heterocyclic group" means a heterocyclic group having one or more of the above-mentioned substituents. As used herein " "Amidino" means an alkylcarbonyl group, as used herein, means a fluorine, chlorine, bromine or iodine atom. May blame the expression of nitric oxide synthase and therefore excessively produce a

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訂 #· ^16957 A7 B7 五、發明説明（ 11 經濟部中央標準局員工消費合作社印製氧化氮伴隨廣範圍之疾病狀態及/或徵候，如敗血性休克，出血性休克，過敏性休克，毒性休克徵候群，絕血，腦絕血，細胞素投藥，細胞素過度表現，潰瘍，發炎性腸疾病（如潰瘍性結腸炎或柯隆氏疾病），糖尿病，關節炎，氣喘，阿茲海默氏疾病，帕金森氏疾病，多發性硬化，硬變，異體移植排斥作用，腦脊髓炎，腦膜炎，胰炎，腹膜炎，脈管炎，淋巴球性脈絡叢腦膜炎，絲球體性腎炎，葡萄膜炎，迴腸炎，發炎（如肝發炎，腎發炎等），灼傷，感染（包含細菌、病毒、眞菌及寄生性感染），血液滲析，慢性疲勞徵候群，中風，癌症（如乳癌，黑瘤，癌瘤等），心肺旁通，絕血/再灌注損傷，胃炎，成人呼吸痛苦徵候群，惡病質，心肌炎，自動免疾失調，濕療，牛皮癖，心臟衰竭，心臟疾病，動脈硬化，皮膚炎，蓴蔴療，全身性紅斑性狼瘡， AIDS，AIDS癡呆，慢性神經退化疾病，慢性疼痛，異常 ***，囊腫纖維變性，肌萎縮性側索硬化，精神***症，抑鬱，行經前徵候群，焦慮，成癮，偏頭痛，亨丁頓氏疾病，癲痼，神經退化失調，胃腸能動性失調，肥胖症，攝食過度，實心腫瘤（如神經母細胞瘤），瘧疾，血癌，脊髓纖維變性，肺損傷，移植對宿主疾病，頭損傷，CNs創傷，肝炎，腎衰竭，肝疾病（如慢性肝炎c)，藥物謗發之肺損傷（如paraquat)，重症肌無力（MG)，眼疾病等。此種病況之處理可以藥劑進行如抗細胞素抗體，抗細胞素受體抗體，抗内毒素抗體，緩激肽拮抗劑，合成胜肽阻斷緩激肽受體，殺菌/滲透性增加之蛋白質，對血小板活化Order # · ^ 16957 A7 B7 V. Description of the invention (11 NOx printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs accompanies a wide range of disease states and / or symptoms, such as septic shock, hemorrhagic shock, anaphylactic shock, toxicity Shock syndrome, hemorrhage, brain hemorrhage, cytokine administration, cytokine overexpression, ulcers, inflammatory bowel disease (such as ulcerative colitis or Cologne's disease), diabetes, arthritis, asthma, Alzheimer's Disease, Parkinson's disease, multiple sclerosis, sclerosis, allograft rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choroid meningitis, filamentous nephritis, grapes Meningitis, ileitis, inflammation (such as liver inflammation, kidney inflammation, etc.), burns, infections (including bacteria, viruses, bacillus, and parasitic infections), hemodialysis, chronic fatigue syndrome, stroke, cancer (such as breast cancer, black (Tumor, cancer, etc.), cardiopulmonary bypass, hemorrhage / reperfusion injury, gastritis, respiratory distress syndrome in adults, cachexia, myocarditis, autoimmune disorders, wet therapy, cattle Addiction, heart failure, heart disease, arteriosclerosis, dermatitis, ramie therapy, systemic lupus erythematosus, AIDS, AIDS dementia, chronic neurodegenerative diseases, chronic pain, abnormal erectile, cystic fibrosis, amyotrophic lateral sclerosis , Schizophrenia, depression, premenstrual syndrome, anxiety, addiction, migraine, Huntington's disease, epilepsy, neurodegenerative disorders, gastrointestinal motility disorders, obesity, overeating, solid tumors (such as neuroblasts Tumors), malaria, blood cancer, spinal fibrosis, lung injury, transplantation to host disease, head injury, CNs trauma, hepatitis, renal failure, liver disease (such as chronic hepatitis c), drug-induced lung injury (such as paraquat), Myasthenia gravis (MG), eye diseases, etc. Treatment of this condition can be carried out with agents such as anti-cytokine antibodies, anti-cytokine receptor antibodies, anti-endotoxin antibodies, bradykinin antagonists, and synthetic peptides to block bradykinase Peptide receptor, a bactericidal / increased protein, activates platelets

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訂 # 516957 A7 B7 五、發明説明（12 ) 經濟部中央標準局員工消費合作社印製因子之抗體等。此種藥劑可用於各種徵候，例如抗内毒素治療（如對内毒素之抗體，對LPS-結合蛋白質之抗體母可溶CD14蛋白質，殺菌/滲透性增加之蛋白質，多粘^素^ 等），細胞素合成/釋出之抑制作用（如使用磷醯二酯^抑制劑，IL-4, IL-10, a-u，TGF_々，皮質崔醇等），抗細胞素治療（如使用對TNF之抗體，可溶TNF受體，江一受體抄抗劑，對IL-1受體之抗體，對IL-6之抗體，對干擾素_/之抗體，可落之干擾素-r受體等），凝集級聯之抑制作用（及補充活化作用，使用如抗因子χΠ抗體，對C 5 a之抗體， C1-酯酶抑制劑，可溶crl等之藥劑），血小板活化因子之抑制作用（PAF，使用如PAF受體拮抗劑之藥劑），花生四烯酸酯代謝之抑制作用（如使用例如環氧酶抑制劑，脂氧酶抑制劑’白二晞抑制劑，凝血崎燒八2抑制劑，***素等藥劑）’ 一氧化氮合成酶酵素之抑制作用（如利用N _甲基_ L-精氨酸，亞胺乙基-L·賴氨酸，胺基胍，s_甲基異硫脲硫酸鹽等），免疫抑制作用（如利用如環孢子素a，OKT3 ’ FK506等），糖尿病治療（如利用例如游離胰島，包囊之胰島’ 口服胰島素’靜脈内胰島素，澱粉經絡質激素等藥劑） ’二氫峨呢鈣槽道阻斷劑（如利用如硝苯吡啶（nifedipine)，硝烯吡哫（nitrendipine)，尼索吡啶（nisoldipine)等），發炎疾病/口療（如利用硫p塞p井（sulfasalazine)，美沙明（mesalamine) ，皮質甾醇類，吖嘧平（azathi〇prine)，6_巯基嘌呤，滅滴靈（metronidazole)，阿斯匹靈，苯基丁基硝酸靈（phenyl butyl nitrone(PBN)，等藥劑）。 -15- 本紙張尺度適财關家標準（CNS ) A4規格（210x^97公釐) (請先閱讀背面之注意事項再填寫本頁) # 訂 # I ! 1 1 - 516957 經濟部中央標準局員工消費合作社印製 A7 B7__ _五、發明説明（13 ) 此外，許多治療劑之投藥可引致可謗發之一氧化氮合成酶表現之謗發，因此過度產生一氧化氮。例如，一氧化氮過度產生亦會伴隨下列處理，如免疫抑制劑之投藥，如葡糖皮質素（甲基去氫潑尼松（methylprednisolone))，髓磷脂驗性蛋白質（如7_卡帕酮（7_capaxone))，抗-Fc受體單株抗體，氫乳清酸酯去氫酶抑制劑，抗-IL2單株抗體（如CHI_621及達可利美（dacliximab))，布p比酮（buspirone)，栗普明 (castanospermine)，CD-59(互補因子抑制劑），5·脂氧酶抑制劑（如CMI-3 92)，磷脂酸合成拮抗劑，依西林（ebselen)，依弗辛（edelfosine)，依利莫美（enlimomab)，葛拉鍚 (galaptin)，血小板活化因子拮抗劑，選擇素（selectin)抬抗劑（如ICAM-4)，介白素-10激動劑，巨環内酯酮，甲氧酮 (methoxatone)，咪峻利賓（mizoribine)，OX-19，肽原 (peptigen)劑，PG-27，蛋白質激酶C抑制劑，磷醯二醋酶IV 抑制劑，單鏈抗原結合蛋白質，互補因子抑制劑，唾弗林 (sialophorin)，希洛利馬（sirolimus)，螺環狀内醯胺，5·#呈基色胺拮抗劑，抗_TCR單株抗體，CD5 gelonin，TOK-8801 等。引起一氧化氮過度表現之其他處理包含投與抗代謝物胞毒素（如吖噻平，氯磷醯胺），C5a釋出抑制劑，炎痛靜 (benzydamine)，配達辛（peldesine)，片斯達汀（pentostatin) ，SDZ-ASM-981，g太胺旅淀酮（thalidomide)，苯并口卜淋 (benzoporphyrin)衍生物，花生四晞酸醋拮抗劑（如鹵美他松 (halometasone)，鹵氟美松（halobetasol)丙酸鹽），皮質甾醇（ -16- ^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 # 516957 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（14 ) 丙酸氯氟美松（clobetasol propionate))，生長激素拮抗劑（八胜肤索美托斯達汀（octapeptide somatostatin)類似物，藍利太（lanreotide)，安琪喊汀（angiopeptin)，及德莫咬汁 (dermopeptin))，胸片订（thymopetin)等。引起一氧化氮過度表現之其他處理包含投與神經保護劑，如α -腎上腺素受體拮抗劑（如α -二氫麥角卡里驗）， NMDA拮抗劑（如5,6,7-三氯_THQTQ，雷馬酿胺（remacemide) ，2-六氫吡啶羧酸，N-啕哚甘醯胺衍生物，螺[苯幷（b)噻吩 -4(5H)]衍生物，CP-101606，利普淀（eliprodil)，丹森必# (dexanabinol)，GV-150526，L-695902，L-701324，金岡丨J 燒胺（amantadine)衍生物，代峻西平（dizocilpine)，苯幷嗎非 (benzomorphan)衍生物，p丫替兼耐（aptiganel)，（S)_a_苯基-2-吡啶乙醯胺二鹽酸鹽，1-胺基-環戊烷羧酸等），鈉槽道拮抗劑（如619C89)，甘氨酸拮抗劑（如甘斯達辛（glystasins))，鈣槽道拮抗劑（如3,5-吡啶二羧酸衍生物，可諾胜肽 (conopeptide)，1-六氫说p井乙醇，遠吩幷[2,3_b]p比淀-5·瘦酸衍生物，NS-3034，尼巴地平（nilvadipine)，尼索地平 (nisoldipine)，替利拉齊（tirilazad)甲績酸鹽，2H-1_晞峻峨喃-6·醇（2H-l-enzopyran-6-ol)，硝酮旋轉牌，依希地平 (iacidipine)，依歐姆_ (iomeerzine)鹽酸鹽，列明地平 (lemildipine)，利伐利 p井（lifarizine)，CPC-304，依弗尼地平 (efonidipine)，F-0401，六氫外b 哨1 衍生物等，卡痛（calpain) 抑制劑，纖維蛋白原拮抗劑（如恩夸（ancrod))，integrin拮抗劑（如安替忍（antegren))，凝血崎燒A2拮抗劑（如9Η·卡巴峻- -17- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閲讀背面之注意事項再填寫本頁) #· 訂 # 經濟部中央標準局員工消費合作社印製 516957 A7 B7 五、發明説明（15) 9-丙酸衍生物，5-庚烯酸衍生物，1-奠磺酸衍生物等），得自腦之神經營養因子，腎上腺素激導傳遞吸收抑制劑（如 -1-丁胺），内皮素A受體拮抗劑（如苯磺醯胺衍生物）， GABA A受體抬抗劑（如三峻幷p密淀衍生物，環己少充乙酸衍生物等），GPIIb Ilia受體拮抗劑（如G68-22)，血小板凝集拮抗劑（如2(1H)-喹啉酮衍生物，1H·峨咯-1-乙酸衍生物，芊丙酮香豆素鈉（coumadin)等），因子Xa抑制劑，CPC-211，促皮質素釋出因子激動劑，凝血酶抑制劑（如輔凝血酶，發西帕林（fraxiparine)，硫酸皮膚素，類肝素等），彡塔畊 (dotarizine)，細胞内#5螯合劑（如BAPTA衍生物），游離基形成拮抗劑（如EPC-K1，3-吡啶叛醯胺衍生物，過氧歧化酶，拉索非拉斯特（raxofelast)，盧貝盧峻（lubeluzole)，3Η·ρ比峻-3 -酮衍生物，犬尿p奎淋酸衍生物，高六氫p比p井衍生物，聚硝醯白蛋白等），蛋白質激酶抑制劑（如m-i，4-二吖庚因），神經生長激動劑（如底板因子-5)，谷氨酸@旨拮抗劑（如環己燒丙酸，利盧峻（riluzole)，NS-409，乙醯胺衍生物等），脂質過氧酶抑制劑（如2,5-環己二烯-1，4-二酮衍生物），ε受體激動劑（如環丙烷甲胺衍生物，SA-4503等），促甲狀腺釋放激素激動劑（如JTP-2942，L-脯醯胺，普沙泰啉 (posatirelin)等），脯氨醯内胜肽酶抑制劑，單唾神經節替脂 (monosialoganglioside)CMl，蛋白水解酶抑制劑（如那發莫斯特（nafamostat))，嗜中性抑制因子，血小板活化因子拮抗劑（如魯帕凡特（nupafant))，單胺氧化酶B抑制劑（如對氟哂列齊淋（parafluoroselegiline)，苯甲腈衍生物等），PARS抑 -18- 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)Order # 516957 A7 B7 V. Description of the invention (12) The staff of the Central Standards Bureau of the Ministry of Economic Affairs consumes antibodies printed on factors by cooperatives. Such agents can be used for various symptoms, such as anti-endotoxin therapy (such as antibodies to endotoxin, antibodies to LPS-binding protein, soluble CD14 protein, proteins with increased bactericidal / permeability, polyadhesin ^, etc.), Inhibition of cytokine synthesis / release (such as the use of phosphodiester inhibitors, IL-4, IL-10, au, TGF_々, cortisol, etc.), anti-cytokine therapy (such as the use of Antibodies, soluble TNF receptors, Jiangyi receptor antagonists, antibodies to IL-1 receptors, antibodies to IL-6, antibodies to interferon_ /, interferon-r receptors, etc. ), The inhibitory effect of the agglutination cascade (and supplementary activation, using agents such as anti-factor χΠ antibodies, antibodies to C 5 a, C1-esterase inhibitors, soluble crl, etc.), platelet activating factor inhibition ( PAF, using agents such as PAF receptor antagonists), Inhibitory effects of arachidonic acid ester metabolism (such as using cyclooxygenase inhibitors, lipoxygenase inhibitors, 'white diazepam inhibitors, clotting sakiyaki 2 inhibitors, Prostaglandins and other agents) 'inhibitory effect of nitric oxide synthase enzyme (such as Use N_methyl_L-arginine, iminoethyl-L·lysine, aminoguanidine, s_methylisothiourea sulfate, etc.), immunosuppressive effects (such as using cyclosporine a OKT3, FK506, etc.), diabetes treatment (such as the use of free islets, cystic islets, oral insulin, intravenous insulin, starch meridian hormones and other agents) 'dihydroanine calcium channel blocker (such as the use of Nifedipine, nitrendipine, nisoldipine, etc.), inflammatory diseases / oral treatments (such as the use of sulfasalazine, mesalamine, corticosteroids , Azathioprine, 6-mercaptopurine, metronidazole, aspirin, phenyl butyl nitrone (PBN), etc. -15- This paper Standards for Financial Standards (CNS) A4 (210x ^ 97mm) (Please read the notes on the back before filling out this page) # ## I! 1 1-516957 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7__ _ V. Description of the Invention (13) In addition, the investment of many therapeutic agents It can lead to slander of the expression of nitric oxide synthase, and therefore excessive production of nitric oxide. For example, excessive production of nitric oxide is accompanied by the following treatments, such as the administration of immunosuppressive drugs, such as glucocorticoid (a Methylprednisolone), myelin test protein (such as 7_capaxone), anti-Fc receptor monoclonal antibody, hydrogen orotate dehydrogenase inhibitor, anti- IL2 monoclonal antibodies (such as CHI_621 and dacliximab), buspirone, castanospermine, CD-59 (complementary factor inhibitor), 5. Lipase inhibitors (such as CMI -3 92), phosphatidic acid synthesis antagonist, ebselen, edelfosine, enlimomab, galaptin, platelet activating factor antagonist, selectin Antibodies (such as ICAM-4), interleukin-10 agonists, macrolides, methoxatone, mizoribine, OX-19, peptigen, PG -27, Protein Kinase C Inhibitor, Phosphodiacetate IV Inhibitor, Single Chain Antigen Binding Egg Substances, Complementary Factor Inhibitors, sialophorin, sirolimus, Spirocyclic Lactamine, 5 · # Serotonin Antagonist, Anti-TCR Monoclonal Antibody, CD5 gelonin, TOK- 8801 etc. Other treatments that cause excessive manifestations of nitric oxide include the administration of antimetabolites cytotoxins (such as azathiapine, clodoxamine), inhibitors of C5a release, benzydamine, peldesine, and tablets Dentin (pentostatin), SDZ-ASM-981, g-thalidomide, benzoporphyrin derivatives, arachidonic acid antagonists (such as halometasone, halogen Flumeson (halobetasol) propionate), cortisol (-16- ^ paper size applies Chinese National Standard (CNS) A4 size (210X297 mm) (Please read the precautions on the back before filling out this page) # # 516957 A7 B7 printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (14) Clobetasol propionate (clobetasol propionate)), growth hormone antagonist (octapeptide somatostatin) Analogs, lanreotide, angiopeptin, dermopeptin, thymopetin, etc. Other treatments that cause excessive manifestations of nitric oxide include administration of neuroprotective agents, such as alpha-adrenergic receptor antagonists (such as alpha-dihydroergocariin), and NMDA antagonists (such as 5, 6, 7-III Chlorine_THQTQ, remacemide, 2-hexahydropyridinecarboxylic acid, N-indoleglycinamine derivative, spiro [phenylhydrazone (b) thiophene-4 (5H)] derivative, CP-101606 , Eliprodil, Dansenbi # (dexanabinol), GV-150526, L-695902, L-701324, Jingang 丨 J amantadine derivatives, dizocilpine, phenamidine (benzomorphan) derivatives, aptiganel, (S) _a_phenyl-2-pyridineacetamidamine dihydrochloride, 1-amino-cyclopentanecarboxylic acid, etc.), sodium channel Antagonists (such as 619C89), glycine antagonists (such as glystasins), calcium channel antagonists (such as 3,5-pyridine dicarboxylic acid derivatives, conopeptide, 1-hexa Hydrogen, p-well ethanol, phenofluorene [2,3_b] p biyodo-5 · leptate derivative, NS-3034, nilvadipine, nisoldipine, tirilazad Formate salt, 2H-1_ -6 · ol (2H-l-enzopyran-6-ol), nitrone spin card, iacidipine, iomeerzine hydrochloride, lemildipine, rivalip well (Lifarizine), CPC-304, efonidipine, F-0401, hexahydroouter 1 derivative, etc., calpain inhibitor, fibrinogen antagonist (such as ancrod) ), Integrin antagonists (such as antigren), coagulation sakiyaki A2 antagonists (such as 9Η · carbajun--17- This paper size applies Chinese National Standard (CNS) A4 specifications (210 × 297 mm) (Please Read the notes on the back before filling this page) # · 定 # Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 516957 A7 B7 V. Description of the invention (15) 9-propionic acid derivatives, 5-heptenoic acid derivatives, 1-sulfonic acid derivatives, etc.), neurotrophic factors derived from the brain, inhibitors of epinephrine-induced transmission absorption (such as 1-butamine), endothelin A receptor antagonists (such as benzsulfamide derivatives ), GABA A receptor antagonists (such as San Jun 密 p dense lake derivatives, cyclohexanone less acetic acid derivatives, etc.), GPIIb Ilia receptor Antagonists (such as G68-22), platelet aggregation antagonists (such as 2 (1H) -quinolinone derivatives, 1H · erole-1-acetic acid derivatives, acetoacetone coumarin sodium (coumadin), etc.), factors Xa inhibitor, CPC-211, corticotropin-releasing factor agonist, thrombin inhibitor (such as cothrombin, fraxparine, dermatan sulfate, heparinoid, etc.), dotarizine Intracellular # 5 chelator (such as BAPTA derivatives), free radical formation antagonists (such as EPC-K1,3-pyridine betamine derivatives, peroxo dismutase, raxofelast), Lu Lubeluzole, 3Η · ρ bijun-3 -one derivative, canine urine p-lycolate derivative, high hexahydrop-specific p-well derivative, polynitrosalbumin albumin, etc.), protein kinase inhibitor (Such as mi, 4-diazepine), nerve growth agonists (such as floor factor-5), glutamate @animation antagonists (such as cyclohexanoic acid, riluzole, NS-409, Acetylamine derivatives, etc.), Lipid peroxidase inhibitors (such as 2,5-cyclohexadiene-1,4-dione derivatives), ε receptor agonists (such as those derived from cyclopropanemethylamine) Substances, SA-4503, etc.), thyroid-stimulating hormone agonists (such as JTP-2942, L-proline, posatirelin, etc.), proline endopeptidase inhibitors, monosial ganglia Monosialoganglioside CML, proteolytic enzyme inhibitors (such as nafamostat), neutrophil inhibitors, platelet activating factor antagonists (such as nupafant), monoamine oxidase B inhibitors (Such as parafluoroselegiline, benzonitrile derivatives, etc.), PARS -18- This paper size applies to China National Standard (CNS) A4 size (210X 297 mm) (Please read the note on the back first (Fill in this page again)

516957 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（16 ) 制劑，血管緊張素I轉化酶抑制劑（如普利多p比（perindopril) ，雷米吡（ramipril)等），乙醯膽鹼激動劑（如帕咪雷西泰 (pramiracetam))，蛋白質合成拮抗劑（如原半胱氨酸），璘醯二酯酶抑制劑（如丙晞托飛林（propentofylline))，opioid kappa受體凌動劑^如10H_苯嘍畊-2-羧胺衍生物），互補因子抑制劑（如sCRI片段），somatomedin-Ι肉驗乙醯轉化酶刺激劑（如乙酸肉驗）等。引致一氧化氮過度產生之又進一步處理包含投與T細胞抑制劑，如合成白細胞抗原衍生之胜肽，介白素-1受體拮抗劑，MG/AnergiX，抗-CD3單株抗體，抗-CD23單株抗體，抗-CD28抗體，抗-CD2單株抗體，CD4拮抗劑，抗-E選擇素抗體，MHC抑制劑，單原，霉紛酸醋莫非替（mycophenolate mofetil)等。引致一氧化氮過度產生之其他處理包含投與antimigraine 劑如 MK-462，324C91，植物藥物，（S)·氣呼汀（fluoxetine) 5槽道拮抗劑（如尼莫地平（nimodipine)/尼莫塔（Nimotop) ，氟那 _(flunarizine)，多塔口井（dotarizine)/FI-6026，依莫利畊（iomerizine)HCL/KB-2796，CPC-304，CPC-317等），α -二氫麥角卡里鹼，5_ΗΤ1激動劑，（如舒嗎三泰 (Sumatriptan)/依咪催（Imitrex)，依咪瑞（Imigran)，GR-85548，311C，GR-127607，等），5-HT1D激動劑，5-HT1A 拮抗劑，5-HT1B拮抗劑（如CP-93129)，5-HT1D拮抗劑（如 1H-啕哚-5_乙磺醯胺衍生物，1H-嘀哚-5_甲磺醯胺等），5-HT1D受體柯隆（cloned)(如5-HT1D劑），2-嘧吩羧醯胺，3-六 l_____-19-__ 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)516957 A7 B7 printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (16) Preparations, angiotensin I converting enzyme inhibitors (such as perindopril, ramipril, etc.), B醯 Choline agonists (such as pramiracetam), protein synthesis antagonists (such as procysteine), phosphodiesterase inhibitors (such as propofofylline), opioid kappa receptor agonist ^ such as 10H_benzidine-2-carboxamide derivative), complementary factor inhibitors (such as sCRI fragments), somatomedin-1 glycosyl acetate conversion enzyme stimulants (such as acetic acid meat test), etc. . Further processing that leads to excessive production of nitric oxide includes administration of T cell inhibitors, such as synthetic leukocyte antigen-derived peptides, interleukin-1 receptor antagonists, MG / AnergiX, anti-CD3 monoclonal antibodies, anti- CD23 monoclonal antibody, anti-CD28 antibody, anti-CD2 monoclonal antibody, CD4 antagonist, anti-E-selectin antibody, MHC inhibitor, monogen, mycophenolate mofetil, etc. Other treatments that cause excessive production of nitric oxide include administration of antimigraine agents such as MK-462, 324C91, phytopharmaceuticals, (S) fluoxetine, 5-channel antagonists such as nimododipine / nimod Nimotop, flunarizine, dotarizine / FI-6026, iomerizine HCL / KB-2796, CPC-304, CPC-317, etc.), α-II Dihydroergocarnitine, 5-HT1 agonist, (such as Sumatriptan / Imitrex, Imigran, GR-85548, 311C, GR-127607, etc.), 5- HT1D agonist, 5-HT1A antagonist, 5-HT1B antagonist (such as CP-93129), 5-HT1D antagonist (such as 1H-pyridin-5_ethanesulfonamide derivative, 1H-pyridin-5_ Methanesulfonamide, etc.), 5-HT1D receptor cloned (such as 5-HT1D agent), 2-pyrimidylcarboxamide, 3-hexal _____- 19 -__ This paper size applies to Chinese national standards (CNS ) A4 size (210X297mm) (Please read the notes on the back before filling this page)

訂 # 516957 A7 B7 五、發明説明（17 ) 氫叶b p井胺，二氯吩那卸（diclofenac potassium)，二氫麥角胺 (如DHE 45®)，多拉西通米西莱特（dolasetron mesilate)，多塔畊（dotarizine)，氟峨汀（flupirtine)，組胺-H3受體激動劑，峭噪布芬（indobufen)，1_莫績酸衍生物，膽驗酯酶抑制劑（如S-9977)，緩激肽拮抗劑，一氧化氮原酶抑制劑（BN· 52296)，一氧化氮受體拮抗劑，物質Ρ拮抗劑（如辣椒辣素/ 那索卡布（Nasocap)，内胜肽酶抑制劑（如中性内胜肽酶，柯隆（cloned))，六氫峨畊衍生物，神經激肽1拮抗劑，美替葛林（metergoline)，多巴胺D2拮抗劑（如美托羅帕驢胺 (metoclopramide)+離氨酸乙醯），腦啡肽酶抑制劑（如中性内胜肽酶），5-HT2拮抗劑（如LY-053857)，5-HT3拮抗劑（如多拉嗎通美西萊特（Dolasetron mesilate)/MDL-73147，4H-卡巴峻-4-酮衍生物等），tenosal，托驗那酸（tolfenamic acid)，環氧酶抑制劑（如卡巴沙雷特（carbasalate)/卡巴斯必林 (carbaspirin)#5，tenosal/MR-Y134等），α 腎上腺素受體拮抗劑（如阿羅替諾醇（arotinolol)，二氫麥角卡里驗等）， opioid激動劑（如氟说汀* /D-9998)，/?腎上腺激素拮抗劑（如心得安（propranolol))，拔普特（valproate)半鋼等。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) 引致一氧化氮過度產生之其他處理包含投與抗關節炎藥，如抗-CD4單株抗體，磷脂酶A1抑制劑，羅泰比諾 (loteprednol)，妥布黴素，羅泰比諾與妥布黴素組合，沙那西淀（salnacedin)，安咪卩比羅（amiprilose)，安那齊拉 (anakinra)，anergiX，抗-B7抗體，抗-CD3H，抗 _gp39，抗· MHC MAbs，抗風濕胜肽，抗-Tac(Fv)_PE40，AP-1抑制劑 -20- 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X 297公釐）經濟部中央標準局員工消費合作社印製 516957 A7 B7 五、發明説明（18 ) ，AR-324，嘌呤核甞磷醯酶抑制劑（如BCX-5)，拜大利特 (bindarit)，CD2拮抗劑（如 BTI-322)，坎帕斯（campach)_lH， CD4拮抗劑（如CE9.1，SB-210396等），腫瘤壞死因子拮抗劑 (如 p80 TNFR，rhTNFbp，胜肽 T，CenTNF，g太胺口辰淀酮， CDP-571，TBP-1等），眼鏡蛇毒液因子，介白素la激動劑（如胞質素（cytogenin))，介白素2受體拮抗劑（如達利西美 (dacliximab)，ICAM 1拮抗劑（如伊利莫美（enlimomab)，介白素1 yS轉化酶抑制劑（如ICE-抑制劑），干擾素（如胸卡汀 (thymocartin))，介白素-10，介白素-13，介白素1拮抗劑（如 SR_31747，TJ-114等），介白素_2拮抗劑（如希羅利莫 (sirolimus))，嶙脂酶C抑制劑，神經激肽1拮抗劑（如L-733060)，拉氟尼莫（laflunimus)，列麥（leflunomide)，白三晞拮抗劑，利巴米索（levamisole)，LFA3TIP，巨環内酉旨酮，MHC類II抑制劑，咪唑利濱（mizoribine)，麥可酚那莱特莫芬替（mycophenolate mofetil)，NfkB抑制劑，oncolysin CD6，配得辛（peldesine)，外匕多替模（pidotimod)，PKC-RACK抑制劑，PNP抑制劑，雷嗎康（reumacon)，CD28拮抗劑，羅昆美克斯（roquinimex)，RWJ-50271，沙布利 (subreum)，T7載體，塔羅利模（tacrolimus)，VLA拮抗劑（如 TBC-772)，轉形生長因子激動劑，蛋氨酸合成酶抑制劑（如維他命B12拮抗劑），腺甞A2受體激動劑（如YT_146)， CD5拮抗劑（如峻利莫美（zolimomab))，5_脂氧酶抑制劑（如齊路通（zileuton)，田尼代（tenidap)，ABT-761等），環氧酶抑制劑（如田諾西坎（tenoxicam)，塔美塔辛（talmetacin)，口比 -21- 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 # 516957 A7 B7 V. Description of the invention (17) Hydrochloride bp well amine, dilofenac potassium, dihydroergotamine (such as DHE 45®), dorasitone mesilate (dolasetron mesilate ), Dotarizine, flupirtine, histamine-H3 receptor agonist, indobufen, 1-molaric acid derivative, bile esterase inhibitor (such as S -9977), bradykinin antagonists, nitric oxide protase inhibitors (BN · 52296), nitric oxide receptor antagonists, substance P antagonists (such as capsaicin / Nasocap, internal Peptidase inhibitors (such as neutral endopeptidases, cloned), hexahydrogeno derivatives, neurokinin 1 antagonists, metergoline, dopamine D2 antagonists (such as US Toropaparamide (metoclopramide + lysine acetamidine), enkephalinase inhibitor (such as neutral endopeptidase), 5-HT2 antagonist (such as LY-053857), 5-HT3 antagonist ( Such as Dolasetron mesilate / MDL-73147, 4H-carbazone-4-one derivatives, etc.), tenosal, tolfenamic acid, ring Enzyme inhibitors (such as carbasalate / carbaspirin # 5, tenosal / MR-Y134, etc.), alpha adrenergic receptor antagonists (such as arotinolol, arotinol, two Ergot erucine test, etc.), opioid agonists (such as fluoxetine * / D-9998), /? Adrenal hormone antagonists (such as propranolol), valproate semi-steel, etc. Economy Printed by the Ministry of Standards and Staff ’s Consumer Cooperatives (please read the notes on the back before filling this page) Other treatments that cause excessive nitric oxide production include administration of anti-arthritis drugs such as anti-CD4 monoclonal antibodies, phospholipase A1 Inhibitors, loteprednol, tobramycin, combination of rotebino and tobramycin, salnacedin, amipirose, anakira ), AnergiX, anti-B7 antibody, anti-CD3H, anti-gp39, anti-MHC MAbs, anti-rheumatic peptide, anti-Tac (Fv) _PE40, AP-1 inhibitor-20- This paper applies Chinese national standards (CNS) A4 size (21 × 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 516957 A7 B7 V. Description of the invention (18), AR-324, purine nuclear phosphatase inhibitor (such as BCX-5), bindarit, CD2 antagonist (such as BTI-322), Campas ( campach) _lH, CD4 antagonists (such as CE9.1, SB-210396, etc.), tumor necrosis factor antagonists (such as p80 TNFR, rhTNFbp, peptide T, CenTNF, g-Teramine Ketamine, CDP-571, TBP -1, etc.), cobra venom factor, interleukin la agonists (such as cytogenin), interleukin 2 receptor antagonists (such as dacliximab, ICAM 1 antagonists (such as irimonide) (Enlimomab), interleukin 1 yS converting enzyme inhibitor (such as ICE-inhibitor), interferon (such as thymocartin), interleukin-10, interleukin-13, interleukin-1 antagonist (Such as SR_31747, TJ-114, etc.), interleukin_2 antagonists (such as sirolimus), lipase C inhibitors, neurokinin 1 antagonists (such as L-733060), laflux Laflunimus, Leflunomide, Lepinomide Antagonist, Levamisole, LFA3TIP, Macrolide, A MHC Class II Inhibitor, Mizoribi ne), mycophenolate mofetil, NfkB inhibitor, oncolysin CD6, peldesine, pidotimod, PKC-RACK inhibitor, PNP inhibitor, thunder Reumacon, CD28 antagonist, roquinimex, RWJ-50271, subreum, T7 vector, tacrolimus, VLA antagonist (such as TBC-772), transfection Growth factor agonist, methionine synthase inhibitor (such as vitamin B12 antagonist), adenosine A2 receptor agonist (such as YT_146), CD5 antagonist (such as zolimomab), 5_lipoxygenase Inhibitors (such as zileuton, tenidap, ABT-761, etc.), cyclooxygenase inhibitors (such as tenoxicam, talmetacin, mouth ratio -21 -This paper size applies to China National Standard (CNS) A4 (210X297mm) (Please read the precautions on the back before filling this page)

516957 A7 B7 經濟部中央標準局員工消費合作衽印製五、發明説明（19) 咯西坎（piroxicam)桂皮酸鹽，嘮普畊（oxaprozin)，ΝΧΊΉΙΟ ’ ML_3000 ’ 莫非峻拉（mofezolac)，那布美通（nabumetone) ’氟布普芬（flurbiprofen)，叮西羅芬那（aceclofenac)，二羅务那（diclofenac) ’地西布普芬（dexibuprofen)等，金屬蛋白酶抑制劑（如XR-168，TNF轉化酶抑制劑，GI-155704A， AG-3340，BB-2983等），一氧化氮合成酶抑制劑（如ARL-16556)，磷脂酶A2抑制劑（如ARL-67974)，選擇素拮抗劑（如CAM抑制劑），白三烯B4拮抗劑（如CGS-25019C)，膠原酶抑制劑（如GR-129574A)，環氧酶2抑制劑（如美羅西坎 (meloxicam))，凝血吟烷合成酶抑制劑（如姜黃素），半胱氨酸蛋白酶抑制劑（如GR-373)，金屬蛋白酶抑制劑（D-5410) ，脂腎上腺皮質素合成激動劑（如利美索酮（rimexolone)，去氫潑尼松（predonisolone)21·法呢酸酯，HYC-141，地非峻夸（deflazacort)等），螯合劑（如代希林（diacerein))，彈性酶抑制劑，DNA有關之RNA聚合酶抑制劑（如***），氧基形成拮抗劑（如葡糖胺硫酸鹽），凝血酶抑制劑（如GS-522) ，膠原抑制劑（如鹵富胍酮（halofuguinone))，透明質酸激動劑（如NRD-101，亥蘭（hylan)，地斯帕山（Dispasan)，亥呀拉特（Hyalart)等，一氧化氮拮抗劑（如維生素B 12a)，思托美來辛（stromelysin)抑制劑（如L-758354)，***素E1激動劑（如咪索普托（misoprostol)，咪索普托十地羅芬那（diclofenac)等），二氫葉酸S旨還原酶抑制劑（如三美催西特（trimetrexate)， MX-68等），opioid拮抗劑（如那美芬（nalmefene))，促皮質素釋出因子拮抗劑（如NBI-103，NBI-104等），水解蛋白酶抑 -22- 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) _#· 訂516957 A7 B7 Consumption cooperation with employees of the Central Bureau of Standards of the Ministry of Economic Affairs 衽 Printing 5. Description of invention (19) Piroxicam cinnamate, oxaprozin, ΝχΙΙΟ 'ML_3000' mofezolac, that Nabumetone 'flurbiprofen, aceclofenac, dilofenac, dexibuprofen, etc., metalloproteinase inhibitors (such as XR- 168, TNF converting enzyme inhibitor, GI-155704A, AG-3340, BB-2983, etc.), nitric oxide synthase inhibitor (such as ARL-16556), phospholipase A2 inhibitor (such as ARL-67974), selectin Antagonists (such as CAM inhibitors), leukotriene B4 antagonists (such as CGS-25019C), collagenase inhibitors (such as GR-129574A), cyclooxygenase 2 inhibitors (such as meloxicam), Thrombin synthase inhibitors (such as curcumin), cysteine protease inhibitors (such as GR-373), metalloprotease inhibitors (D-5410), and adrenocortical hormone synthesis agonists (such as risomone) (Rimexolone), dehydroprednisolone (predonisolone) 21 · farnesate, HYC -141, deflazacort, etc.), chelating agents (such as diacerein), elastase inhibitors, DNA-related RNA polymerase inhibitors (such as estrogen), and oxygen-forming antagonists (such as Glucosamine sulfate), thrombin inhibitors (such as GS-522), collagen inhibitors (such as halfuguinone), hyaluronic acid agonists (such as NRD-101, hylan, ground Dispasan, Hyalart, etc., nitric oxide antagonists (such as vitamin B 12a), stromelysin inhibitors (such as L-758354), prostaglandin E1 agonists (Such as misoprostol, diclofenac, etc.), dihydrofolate S reductase inhibitors (such as trimetrexate, MX-68, etc.) , Opioid antagonists (such as nalmefene), corticotropin-releasing factor antagonists (such as NBI-103, NBI-104, etc.), hydrolytic protease inhibitors-22- This paper applies Chinese national standards (CNS) A4 size (210 X 297 mm) (Please read the notes on the back before filling this page) _ # · Order

516957 A7 B7 五、發明説明（20 ) 制劑（如蛋白酶尼辛（nexin)-l，NCY-2010等），緩激肽拮抗劑（如促激肽拮抗劑，NPC-17731等），生長激素拮抗劑（如辛利泰（octreotide))，磷醯二酯酶IV抑制劑（如PDEIV抑制劑），明膠酶抑制劑（如REGA-3G12)，游離基去除劑（如SIDR- 1026) ’***素合成酶抑制劑（如硫P塞p井（sulfasalazine))等〇引致一氧化氮過度產生之其他處理包含投與用以治療敗血性休克之藥劑，如血管生成抑制劑（如OLX-514)，緩激肽拮抗劑（如CP-0502，NPC-17731等），互補因子抑制劑（如C3 轉化酶抑制劑），C5a釋出抑制劑（如CAB-2.1)，多巴胺激動劑（如多配胺（dopexamine))，彈性酶抑制劑（如ONO-5046)，經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) E選擇素拮抗劑（如CY-1787)，法呢基轉移酶抑制劑（如RBE 檸檬烯），免疫刺激劑（如CGP-19835A，脂質A疫苗，依多貝可美（edobacomab)，尼巴庫美（nebacumab)，StaphGAM，逮阿波地（diabodies)等），免疫抑制劑（如CytoTAB，轉環戊醯嘌呤類似物等），介白素1拮抗劑（如介白素1受體），介白素1受體拮抗劑（如阿那齊拉（anakinra))，介白素lb拮抗劑（如介白素-1 /?)，介白素1 Θ轉化酶抑制劑（如ICE_抑制劑），介白素8拮抗劑（如IL-8受體），介白素13激動劑（如介白素-I3)，ITF-1697，脂酶清除因子抑制劑（如SC_；59735)，膜滲透性增強劑（如殺菌劑滲透性增加蛋白質/BPI)，一氧化氮拮抗劑（如維生素B12a)，一氧化氮合成酶抑制劑（如L-NMMA，從-甲基-Νβ-亞胺乙基鳥氨酸等），P2受體刺激劑（如ATP類似物），磷脂酸合成拮抗劑（如利索發淋（lisofylline))，嶙脂 -23 - 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 516957 A7 B7 五、發明説明（21 ) 酶A2抑制劑（如S-448，醯基吡咯烷酸衍生物，吲哚乙酸衍生物等），血小板活化因子拮抗劑（如ABT-299，TCV_309， SM-12502，（2RS，4R)-3-(2_吡啶基）嘍唑啉_4_醯基）啕哚類， UR-12670。E-5880等），前列環素（prostacyclin)激動劑（如塔普烯（taprostene))，***素E1激動劑（如TLC C53)，蛋白質激酶抑制劑（如SB-203580)，蛋白質激酶C抑制劑，蛋白質合成拮抗劑（如原半胱氨酸），水解蛋白酶抑制劑（如那發莫斯特（nafamostat))，SDZ-PMX-622，選擇素拮抗劑（如硫酸化糖脂細胞黏附抑制劑），凝血酶抑制劑（如GS-522)， TNF受體_Ig，腫瘤壞死因子拮抗劑（如抗-TNF MAbs， MAK_195F，TBP-I，Yeda，rhTNFbp，CDP-571等），腫瘤壞死因子α拮抗劑（如E-5531)等。引致一氧化氮過度產生之又其他處理包含投與用以治療多發性硬化之藥劑，如4·胺基p比淀，15 土去氧司帕胍琳（15 ± deoxyspergualin)，ACTH，金剛燒胺，抗體佐劑（如聚 ICLC，聚-IC+聚-L-賴氨酸+羧甲基纖維素等），抗細胞素 MAb(如 CDP-835)，消炎劑（如 CY-1787，CY-1503等），抗選擇素 MAb(如 CY-1787)，抗-TCRMAb(如 NBI-114，NBI-115 ，NBI-116，等），氣苯胺丁酸（bacloten)，氯化胺甲醯甲膽鹼，胺甲醯氮革，碳水合物藥物（如CY-1503)，可樂那齊平 (clonazepam)，CNS及免疫系統功能調節劑（如NBI-106， NBI-107等），環磷醯胺，環孢子素A，細胞素（如IFN-從，以-法隆（alfaferone)，IFN-ySlb，>3西隆（betaseron)，TGF-y32 ，PEG-TGF-/52，貝他金（betakine)，IFN-y5/Rebif，法隆， -24- 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)516957 A7 B7 V. Description of the invention (20) Preparations (such as protease nexin-1, NCY-2010, etc.), bradykinin antagonists (such as kinin antagonists, NPC-17731, etc.), growth hormone antagonists Agents (such as octreotide), phosphodiesterase IV inhibitors (such as PDEIV inhibitors), gelatinase inhibitors (such as REGA-3G12), free-radical removers (such as SIDR-1026) 'prostaglandin synthase Inhibitors (such as sulfasalazine), etc. Other treatments that cause excessive nitric oxide production include administration of agents used to treat septic shock, such as angiogenesis inhibitors (such as OLX-514), and Peptide antagonists (such as CP-0502, NPC-17731, etc.), complementary factor inhibitors (such as C3 invertase inhibitors), C5a release inhibitors (such as CAB-2.1), and dopamine agonists (such as dopexamine )), Elastase inhibitor (such as ONO-5046), printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) E-selectin antagonist (such as CY-1787), method Insulin transferase inhibitors (eg RBE limonene), immunostimulants (eg C GP-19835A, Lipid A vaccine, edobacomab, nebacumab, StaphGAM, diabodies, etc., immunosuppressants (such as CytoTAB, transcyclopentanine analogs Etc.), interleukin 1 antagonists (such as interleukin 1 receptor), interleukin 1 receptor antagonists (such as anakira), interleukin lb antagonists (such as interleukin- 1 /?), Interleukin 1 Θ converting enzyme inhibitor (such as ICE_ inhibitor), interleukin 8 antagonist (such as IL-8 receptor), interleukin 13 agonist (such as interleukin-I3 ), ITF-1697, Lipase clearance factor inhibitors (such as SC_; 59735), membrane permeability enhancers (such as fungicide permeability increasing protein / BPI), nitric oxide antagonists (such as vitamin B12a), nitric oxide Synthetase inhibitors (such as L-NMMA, from -methyl-Nβ-imineethyl ornithine, etc.), P2 receptor stimulators (such as ATP analogs), and phosphatidic acid synthesis antagonists (such as Lissofaline ( lisofylline)), 嶙 zhi-23-This paper size applies to China National Standard (CNS) A4 (210X297 mm) — ~ Employee Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Printed 516957 A7 B7 5. Description of the invention (21) Enzyme A2 inhibitor (such as S-448, fluorenylpyrrolidic acid derivative, indoleacetic acid derivative, etc.), platelet activating factor antagonist (such as ABT-299, TCV_309 , SM-12502, (2RS, 4R) -3- (2-pyridyl) oxazoline_4-fluorenyl) pyridines, UR-12670. E-5880, etc.), prostacyclin agonists (such as taprostene), prostaglandin E1 agonists (such as TLC C53), protein kinase inhibitors (such as SB-203580), protein kinase C inhibition Agents, protein synthesis antagonists (such as procysteine), protease inhibitors (such as nafamostat), SDZ-PMX-622, selectin antagonists (such as sulfated glycolipid cell adhesion inhibition Agents), thrombin inhibitors (such as GS-522), TNF receptor_Ig, tumor necrosis factor antagonists (such as anti-TNF MAbs, MAK_195F, TBP-I, Yeda, rhTNFbp, CDP-571, etc.), tumor necrosis Factor alpha antagonists (such as E-5531) and so on. Other treatments that lead to excessive production of nitric oxide include administration of agents used to treat multiple sclerosis, such as 4.amino p-pyridine, 15 ± deoxyspergualin, ACTH, amantadine , Antibody adjuvants (such as poly ICLC, poly-IC + poly-L-lysine + carboxymethyl cellulose, etc.), anti-cytokine MAb (such as CDP-835), anti-inflammatory agents (such as CY-1787, CY-1503 Etc.), anti-selectin MAb (such as CY-1787), anti-TCRMAb (such as NBI-114, NBI-115, NBI-116, etc.), aniline butyric acid (bacloten), amine methacholine chloride Carbamazepine, carbohydrate drugs (such as CY-1503), clonazepam, CNS and immune system function modifiers (such as NBI-106, NBI-107, etc.), cyclophosphamide, Cyclosporin A, cytokines (such as IFN-from, alfaferone, IFN-ySlb, > 3 betaseron, TGF-y32, PEG-TGF- / 52, betakine ), IFN-y5 / Rebif, Falun, -24- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

516957 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（22 ) 干擾素-卢，IFN-/3等），CD4+T細胞抑制劑（如AnergiX)， CD28拮抗劑（如B7-1，B7_2，CD28等），直接細胞毒素治療 (如苯幷普外淋（benzoporphyrin)衍生物（BPD))，FK-506，生長因子（如神經膠生長因子，GCF，神經生長因子，TGF-卢2 ，PEG-TGF· y52，貝他金，等），人類 4匕 MAb(：^ 抗-TNF- r MAb ，靈敏之抗-IFN-r MAb，抗_Tac抗體，靈敏之抗_Tac抗體等），人類化抗_CD4 MAb(如抗-CD4 MAb，聖塔拉（centara) 等），水解酶刺激劑（如卡司通司伯明（castanospermine))， IFN- a，IFN- r 拮抗劑(如抗_IFN- rMAb，靈敏之抗-IFN r MAb 等），IL-2拮抗劑（如塔羅利模（tacrolimus)，FK-506，FR-900506，富士黴素，普葛福（Prograf)，IL-2融合毒素， DAB389JL-2等），IL-4拮抗劑（如 IL-4融合毒素，DAB389IL-4 等），免疫調節之神經元損害抑制劑（如NBI-114，NBI-115 ，NBI-116等），免疫球蛋白，免疫刺激劑（如聚ICLC，依地氟辛（edelfosine)，ALP，ET-18-OCH3，ET-18-OME，NSC-24,聚-IC+聚-L·賴氨酸+羧甲基纖維素等），免疫抑制劑（如吖嘧平（azathioprine)，AI-100動物蛋白質，rDMA人類蛋白質AI-101，胜肽，AI-102，卡司通司伯明，塔羅利模，FK· 506，FR-900506，富士黴素，普葛福，抗白 integrin MAb ，Hu23F2G，靈長類抗-CD4抗體，CE9.1，葛拉汀 (Galaptin)14-1，GL14-1，外源凝集素-1，重組體IML-1，亞麻醯胺，魯峡尼美（roquinimex)，LS-2616，反環戊醯嘌呤類似物，MS_6044，司班ί丁（spanidin)，15-去氧司伯胍淋，去氧司帕胍啉，蓋司伯莫（gusperimus)HCL，NSC-356894， -25- (請先閱讀背面之注意事項再填寫本頁)516957 A7 B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (22) Interferon-Lu, IFN- / 3, etc., CD4 + T cell inhibitors (such as AnergiX), CD28 antagonists (such as B7- 1, B7_2, CD28, etc.), direct cytotoxic therapy (such as benzoporphyrin derivative (BPD)), FK-506, growth factors (such as glial growth factor, GCF, nerve growth factor, TGF- Lu 2, PEG-TGF-y52, Betakin, etc.), human 4D MAb (: ^-TNF-r MAb, sensitive anti-IFN-r MAb, anti-Tac antibody, sensitive anti-Tac antibody Etc.), humanized anti-CD4 MAb (such as anti-CD4 MAb, centara, etc.), hydrolase stimulants (such as castanospermine), IFN-a, IFN-r antagonist Agents (such as anti-IFN-rMAb, sensitive anti-IFN r MAb, etc.), IL-2 antagonists (such as tacrolimus, FK-506, FR-900506, Fujimycin, and Prograf) , IL-2 fusion toxin, DAB389JL-2, etc.), IL-4 antagonists (such as IL-4 fusion toxin, DAB389IL-4, etc.), immunomodulatory neuronal damage inhibitors (such as NBI-114, N BI-115, NBI-116, etc.), immunoglobulins, immunostimulants (such as polyICLC, edelfosine, ALP, ET-18-OCH3, ET-18-OME, NSC-24, poly- IC + poly-L·lysine + carboxymethyl cellulose, etc.), immunosuppressive agents (such as azathioprine, AI-100 animal protein, rDMA human protein AI-101, peptide, AI-102, card Stone Sparming, Talorimol, FK 506, FR-900506, Fujimycin, Pugford, Anti-integrin MAb, Hu23F2G, Primate Anti-CD4 Antibody, CE9.1, Galaptin 14-1, GL14-1, Exogenous Lectin-1, Recombinant IML-1, Linolepine, Roquinimex, LS-2616, Anticyclopentanine Purine Analogue, MS_6044, Span Spanidin, 15-deoxysperguanide, desporaguanide, gusperimus HCL, NSC-356894, -25- (Please read the precautions on the back before filling this page)

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本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）經濟部中央檩準局員工消費合作社印製 516957 A7 B7 五、發明説明（23) NKT-01，TCR，CD3/Ti，環孢子素（cyclosporine)，OL-27-400，Sandimmune，人類 IL-10，單原，抗-TCR MAbs， TCAR MAbs，單原T19，單原TM27，單原TM29，單原 TM31，胜肽原 TP12，抗-CD4 MAb，卡塔拉（cantara)，免疫菲啉（immunophilins)，VX-10367，VX-10393，VX-10428，合成鹼性胺基酸聚合物，共聚物-1，COP-1，T淋巴細胞免疫融合（TIF)蛋白質，環磷醯胺等），integrin拮抗劑（如抗-integrin單株抗體，AN-100225，AN-100226等），干擾素激動劑（如聚-ICLC，聚-IC+聚_L-賴氨酸+羧甲基纖維素等），干擾素-yS -16，異丙肌苷，IV甲基去氧潑尼松，大環内酯族（如塔羅利模，FK-506，FR-900506，富士黴素，普葛福等），MAO B抑制劑（如塞利齊淋（selegiline)，帕金（Parkinyl) 等），胺甲噪呤（methotrexate)，麥托山通（mitoxantrone)，肌肉舒緩劑（如RGH-5002)，毒覃鹼拮抗劑（如RGH-5002)，神經類醇（如NBI-106，NBI-107等），八胜肽（如胜肽T)，氧丁寧氣化物，氧游離基拮抗劑（如特船君（tetrandrine)，生物爷基異p奎淋類驗等），胜肽激動劑（如胜肽T)，苯氧爷胺，嶙月旨酶C抑制劑（如依代氟辛（edelfosine)，ALP，ET-18-OCH3 ，ΕΤ-18·ΟΜΕ，NSC_24等），光動力治療（如苯幷普菲林衍生物（BPD)，質體電泳，血小板活化因子拮抗劑（如銀杏苦内酯B，BN-52021等），鉀槽道拮抗劑（如胺二喹 (aminodiaquine)，EL-970等），心得安，***素合成酶抑制劑（如硫 p塞 _ (sulfasalazine)，沙峻硫（salazosulfa)_^ 淀， PJ_3〇6，SI-88，柳氮磺胺吡啶（azulfidine)，水楊酸偶氮磺 -26- 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)This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs 516957 A7 B7 V. Description of Invention (23) NKT-01, TCR, CD3 / Ti, cyclospore (Cyclosporine), OL-27-400, Sandimmune, Human IL-10, Monogen, Anti-TCR MAbs, TCAR MAbs, Monogen T19, Monogen TM27, Monogen TM29, Monogen TM31, Protopeptide TP12, Anti-CD4 MAb, cantara, immunophilins, VX-10367, VX-10393, VX-10428, Synthesis of basic amino acid polymer, copolymer-1, COP-1, T Lymphocyte immune fusion (TIF) protein, cyclophosphamide, etc.), integrin antagonists (such as anti-integrin monoclonal antibodies, AN-100225, AN-100226, etc.), interferon agonists (such as poly-ICLC, poly- IC + poly_L-lysine + carboxymethylcellulose, etc.), interferon-yS-16, isoprinosine, IV methyldeoxydnisone, macrolides (such as tarotlimide, FK- 506, FR-900506, Fujimycin, Puerfos, etc.), MAO B inhibitors (such as selegiline, Parkinyl, etc.), methotrexate (Methotrexate), mitoxantrone, muscle relaxant (such as RGH-5002), toxin antagonist (such as RGH-5002), neuroloids (such as NBI-106, NBI-107, etc.), eight Peptide (such as peptide T), Oxybutyn gas, Oxygen free radical antagonists (such as tetrandrine, bio-based iso-p-quinine, etc.), peptide agonists (such as peptide T) , Phenoxymamine, leucocyte enzyme C inhibitors (such as edelfosine, ALP, ET-18-OCH3, ET-18 · OME, NSC_24, etc.), photodynamic therapy (such as phenprofiline Derivatives (BPD), plastid electrophoresis, platelet activating factor antagonists (such as Ginkgolide B, BN-52021, etc.), potassium channel antagonists (such as aminodiaquine, EL-970, etc.), experience Ann, prostaglandin synthetase inhibitors (such as sulfasalazine, salazosulfa_ ^ lake, PJ_306, SI-88, azulfidine, salicylic acid azosulfide -26- This paper size applies to Chinese National Standard (CNS) A4 (210X297mm) (Please read the precautions on the back before filling this page)

516957 A7 B7 經濟部中央橾準局員工消費合作衽印製五、發明説明（24) 胺P比淀（salazopyrin)等），蛋白酶拮抗劑（如銀杏苦内酯B， BN-52021等），重組體可溶IL-1受體，司伯胍啉類似物（如司班啶，15-去氧司伯胍啉，去氧司帕胍啉，蓋司伯莫HC1 ，NSC-356894，NKT-01等），TCR胜肽德夸（decoys)(^αΝΒΙ· 114，NBI-115，NBI-116等），TCR 擬胜肽德夸（如 NBI-114， NBI-115，NBI-116等），TCR胜肽疫苗（如 AI-208(Vy3 6.2/6.5 表現型）），選擇素拮抗劑（如外源凝集素-1，重組體IML_1等），可溶TNF受體I，TCARs(如TCR，CD3/Ti，月生肽原TP12等），TNF抬抗劑（如g太胺旅淀酮|，TNF抑制劑等），三環抗抑欝劑等。引致一氧化氮過度產生之其他處理包含投與器官移植劑，如抗-CD25MAbs，抗-Tac抗體，抗-TNFMAb(如 CDP571) ，艾普托辛（apoptosin)，。丫 p塞平（azathioprines)(如硫峻續呤) ，BCX-34，CA3，CD28，互補抑制因子（如 CD59)， CTLA4Ig，環司伯淋（如CsA)，FK-506/雷帕黴素，結合蛋白質（FKBP)，糖皮質激素，0KT3之人類變體（如huOKT3-185) ，氫乳清酸醋去氫酶抑制劑（如布雷夸（Brcquinar))，正柯隆 (orthoclone)OKT3(如IgG2a抗·Τ細胞老鼠單株抗體，姆羅莫奈（muromonab)_CD3等），雷帕黴素（如AY-22989)，鏈黴素單離物（如 FR-900520, FR-900523 等）等。引致一氧化氮過度產生之其他處理包含投與用以治療全身性狼瘡紅斑（SLE)之藥劑，如雄性素衍生之類固醇（如 Org_4094)，抗-CD4人類抗體，抗-DNA/V_88，抗特異型老鼠MAb(如對3E10/MAblC7之抗-特異型抗體），CD2拮抗劑（ -27- (請先閲讀背面之注意事項再填寫本頁)516957 A7 B7 Consumption cooperation with employees of the Central Bureau of Standards of the Ministry of Economic Affairs. Printing 5. Description of the invention (24) Amine P than lake (salazopyrin, etc.), protease antagonists (such as Ginkgolide B, BN-52021, etc.), reorganized Body-soluble IL-1 receptors, spiguanoline analogs (such as spanidine, 15-deoxyspiguanoline, despoguanoline, gaespermo HC1, NSC-356894, NKT-01 Etc.), TCR peptide decoy (^ αΝΒΙ · 114, NBI-115, NBI-116, etc.), TCR pseudo peptide decoy (such as NBI-114, NBI-115, NBI-116, etc.), TCR Peptide vaccines (such as AI-208 (Vy3 6.2 / 6.5 phenotype)), selectin antagonists (such as exogenous lectin-1, recombinant IML_1, etc.), soluble TNF receptor I, and TCARs (such as TCR, CD3 / Ti, peptidyl TP12, etc.), TNF antagonists (such as g tyramine triptonone |, TNF inhibitors, etc.), tricyclic anti-suppressive agents and so on. Other treatments that cause excessive nitric oxide production include administration of organ transplants, such as anti-CD25MAbs, anti-Tac antibodies, anti-TNFMAb (such as CDP571), and Aptosin. Azathioprines (such as thiojunine), BCX-34, CA3, CD28, complementary inhibitors (such as CD59), CTLA4Ig, cyclosporine (such as CsA), FK-506 / rapamycin, Binding protein (FKBP), glucocorticoids, human variants of 0KT3 (such as huOKT3-185), hydrogen orotate dehydrogenase inhibitors (such as Brcquinar), orthoclone OKT3 (such as IgG2a anti-T cell mouse monoclonal antibodies, muromonab (CD3, etc.), rapamycin (such as AY-22989), streptomycin isolated (such as FR-900520, FR-900523, etc.), etc. . Other treatments that cause excessive nitric oxide production include administration of agents to treat systemic lupus erythematosus (SLE), such as androgen-derived steroids (such as Org_4094), anti-CD4 human antibodies, anti-DNA / V_88, anti-specific Mouse MAb (such as anti-specific antibodies to 3E10 / MAblC7), CD2 antagonist (-27- (Please read the precautions on the back before filling this page)

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本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X 297公釐） 516957 A7 B7 五、發明説明（25) 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 如CD2)，互補抑制劑（如重組體mcp爲主之互補抑制劑），環孢子素（如Sandimmune，環孢子素類似物，〇g-37325，環孢子素-G，NVal-CyA等），細胞素（如IL_4融合毒素），細胞素受體拮抗劑（如免疫調節細胞素），E-選擇素拮抗劑（如抗-ELAM，CY-1787等），FK506/塔羅利模（如普葛福），高血鈣劑（如KH-1060)，IFN· r拮抗劑（如抗-IFN- r MAb，靈敏抗_IFN_ r MAb等），IL-1 0轉化酶抑制劑（ice)，大腸桿菌產生之IL_2(如西莫利金（celmoleukin)，IL-2，TGP-3，希利克（Celeuk)等），免疫球蛋白（如抗_ELAM，CY-1788，人類CY-1787等）’免疫刺激劑（如胸催南（thymotrinan)，RGH-0205，TP3，等），免疫抑制劑（如雷帕黴素，AY-22989， NSC-226080，NSC-606698，抗-CD4，Τ·細胞抑制劑，抗-tac MAb，靈敏抗-tac MAb，密吉斯（Migis)(膜免疫球蛋白同位素特異性）抗體，SM-8849，免疫菲啉，VX-10367， VX-10393，VX-10428，霉酚酸酯莫非替，ME-MPA，RS-61444，環孢子素，OL-27-400，Sandimmune，IL_4融合毒素，錐蟲抑制因子（TIF)，Τ·細胞受體，CD3/Ti，Org-4094 ，抗-TBM，CP17193，利福麥（Leflunomide)/A-77_1726， ELAM-1，AnergiX，司班i丁，15-去氧司伯胍淋，去氧司帕胍啉，蓋司伯莫HQ，NSC-356894，ΝΚΤ-01，雷S昆尼美 (Roquinimex)，LS-2616，利諾麥（linomide)，LJP-394，CD-59抗原等），免疫毒素（如唑利莫美亞利托斯（Zolimomab aritox)，xmmly-h65_rta，xanazyme-lym/CD5-Plus 9 OrthoZyme-CD5+，XomaZyme-H65-rta，Xomazyme_CD5Plus等），靜脈 -28 - 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X297公釐） 516957 A7 B7 五、發明説明（26 ) 内免疫球蛋白（如IVIG)，integrin拮抗劑（如integrin阻斷劑），密吉斯™抗體，單株抗體治療劑，老鼠MAb(如抗-SLE疫苗，MAb 3E10，等），靈長類抗-CD4抗體（如CE9.1)，蛋白酶抑制劑（如母質金屬蛋白酶（MMP)抑制劑，思托美來辛等），蛋白質合成拮抗劑（如抗-CD6-bR，抗-T12-bR，oncolysin CD6等），嘌呤核苷磷醯酶抑制劑（如BCX-25，BCX-14等），選擇素拮抗劑（如CY1503，Cylexin等），司伯胍啉類似物（如司班汀，15-去氧司伯胍淋，去氧司帕胍琳，蓋司伯莫HC1 ，NSC-356894，NKT_01等），T細胞抑制劑（如 AnergiX)，腫瘤壞死因子（TNF)拮抗劑等。經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 引致一氧化氮過度產生之其他處理包含投與用以治療阿茲海默氏疾病之藥劑，如ACh釋出增強劑（如T_588(苯幷嘧吩衍生物），乙醯膽鹼刺激劑（如DUP-996及類似物），ΑΜΡΑ 激動劑（如AMAlex，異崎峻化合物系列等）’ AMPA GluR激動劑（如 IDRA-21[7-氯-3-甲基-3,4-二氫-2H-1，2,4_苯幷嘍二畊])，AMPA GluR拮抗劑（如S-18986及相關喹諾酮衍生物），抗膽驗S旨酶（如E-2020)，Ga-拮抗劑（如NS-649，物妹毒液衍生之ICM胜肽及類似物，經取代之2-胺基茚滿化合物系列等），組合之抗膽鹼酯酶及毒覃鹼AChR拮抗劑（如 PD142676)，K-槽道阻斷劑（如反-R-4-(4-甲氧苯基甲基）環己基苯胺及類似物，馬加毒素（margatoxin)爲主之官能性及 /或結構類似物等），MI毒覃驗受體激動劑（如Xanomeline)， NMDA拮抗劑（如某種㈣哚衍生物（R^R^S1))-以，（4-羥苯基）-/?-甲基-4-(苯蓋基）-1-六氫p比淀丙醇及其類似物等），於驗 -29 - 本紙張尺度適用中國國家標準（CNS ) Μ規格（210X297公釐） 516957 A7 B7___ 五、發明説明（27 ) 酸AChR激動劑（如ABT-418[異嘮唑，3-甲基-5-(1-甲基_2_吡咯啶基）]等）等。引致一氧化氮過度產生之其他處理包含投與用以治療乾癖之藥劑，如5_L0抑制劑（如Wy-50295，Wy-49232，羅那帕林（Lonapalene)，RS-43179，MK-886，L-663536，ΕΤΗ-615，DUP-654，吉列通（Zileuton)，依布卡唑啉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) (epocarbazolin)-A，A-64077等），5-L0/C0抑制劑（如 BF_397 ，Tenidap，CP-309，CP-66248等），血管形成抑制劑（如血小板因子4)，抗腫瘤抗生素（如AGM-1470，TNP-470等），消炎細胞色素P450氧還原酶抑制劑（如DuP-630，DuP-983等），抗增生化合物（如Zyn-聯結劑），花生四烯酸類似物（如 CD581，CD554，等），花生四烯酸拮抗劑（如羅那帕林， RS-43179，具滲透增強劑Azone之三西諾酮乙酸奈 (triamcinolone acetonide)，倍他米松二丙酸鹽類藥，G-202 ，鹵貝他索丙酸鹽，超貝特（ultravate)，鹵美他松，C-48401-Ba，西可田（Sicorten)等），/?-葡聚糖受體拮抗劑，貝他米松類藥，躬代謝調節劑（如塔可西托（Tacalcitol)，朋尼發（Bonealfa)，TV-02軟膏，Ro-23-6474，KH-1060，鈣普三醇（Calcipotriol)，BMS-181161，BMY-30434，道莫耐斯 (Dovonex)，地莫耐斯（Divonex)等），CD4結合抑制劑（如PIC 060)，細胞黏附化合物（如 CY-726，VCAM_1，ELAM-1， ICAM等），細胞黏附抑制劑（如選擇素抑制劑，GM-1930等) ，細胞老化抑制劑（如因子X)，皮質甾醇（如鹵倍他索丙酸鹽，超貝特，鹵美他松，C-48401-Ba，西可田等），環孢子 _ -30- 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇><297公釐） 516957 A7 B7 五、發明説明（28) 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) 素類似物（如IMM-125)，二氫葉酸酯還原酶抑制劑（如G-301，二氯苯幷卩比林（dichlorobenzoprim)，美索催西特 (methotrexate)，於巨海綿體輸送系統中之美索催西特等）， E-選擇素抑制劑（如ISIS 4730)，維他命D3内源活化態（如鈣三醇（Calcitriol)，Du-026325等），纖維母細胞生長因子拮抗劑（如司伯啉米托毒素，Steno-Stat等），煙麴黴素類似物（如 AGM-1470，TNP-470等），G-蛋白質及單一轉導化合物（如 CPC_A) ’痤瘡之凝膠調酉己物（如於驗醯胺，N-547，Papulex 等），生長激素拮抗劑（如歐催泰（Octreotide)，山多斯達汀 (Sandostatin)，藍利歐泰（Lanreotide)，血管肽素，BIM-23〇14，索烏突淋（Somatuline)等），人類抗體（如抗-CD4抗體），氫乳清酸酯二氫酶抑制劑（如布雷奈鈉，雙苯醌酯 (bipenquinate)，DuP-785，等），ICAM-1抑制劑（如 ISIS 939) ，IL及其他細胞素抑制劑（如塞田尼爾（Septanil))，IL-1轉化酶抑制劑，IL_1受體拮抗劑（如安替拉（Antril))，IL-2拮抗劑 (如塔羅利模，普葛福，FK_5〇6等），IL·2受體目標之融合毒素（如DAB 389 IL_2)，IL_8受體，免疫刺激劑（如胸配汀 (Thymopentin)，提莫諾（Timunox)等），免疫抑制劑（如 XomaZyme-CD5 Plus，環孢子素，Sandimmune，SR-31747 ，抗-CD11，18MAb，塔羅利模，普葛福，FK-506，FK-507等），免疫抑制劑目標FK506(如免疫菲啉，VX_10367， VX-10428等），免疫毒素MAb有關之抗CD抗原（如 XomaZyme-CD5 Plus)，白三烯拮抗劑（如 Sch_40120，Wy_ 50295，Wy-49232等），白三晞 B4拮抗劑（如 SC-41930，SC- -31 - 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X297公釐） 516957 A7 B7 五、發明説明（29 ) (請先閲讀背面之注意事項再填寫本頁) 50605，SC-48928，ONO-4057，LB-457，LY_255283，LY-177455，LY-223982，LY-223980，LY-255253等），白三烯合成抑制劑（如MK-886，L-663536等），脂酶清除因子抑制劑（如1-廿二碳醇，利達可（lidakol)等），脂質包封還原劑（如地催諾（Dithranol))，微脂質凝膠（如地催諾），L0抑制劑（如 CD581，CD554，美索普可（Masoprocol)，安替尼斯（Actinex) 等），琥珀酸鋰軟膏（如鋰鹽，伊發鋰（Efalith)，等），LO/CO 抑制劑（如 P-8892，P-8977，CHX-108，FPL-62064等），膜整體激動劑（如鋰鹽，伊發鋰等），微細管抑制劑（如含婆索葉毒素（Posophyliotoxin)化合物，Psorex等），八胜肽生長激素釋放抑制因子類似物（如藍利歐泰，血管肽素，BIM-23014，索馬突啉等），寡核甞（如ISIS 4730，ISIS 3801， ISIS 193 9，IL-1抑制劑等），胜肽激動劑（如八胜肽，胜肽T 等），PKC抑制劑，磷脂質Α2化合物，磷脂質D化合物，光動力抗腫瘤劑（如5-胺基乙醯丙酸，5-ALA等），光動力治療 (如苯幷普非啉衍生物，合成氯，合成普非啉，EF-9等）光敏劑（如波福馬（Porfirmer)納），PKC抑制劑（如山非諾 (Safingol)，Kynac等），血小板活化因子拮抗劑（如TCV-309) ，血小板凝集抑制劑（如CPC-A)，前藥NSAIDs(如G-201)，經濟部中央標準局員工消費合作社印製 ***素激動劑（如廿碳五烯酸+ r -亞麻酸組合，伊發莫馬啉等），蛋白質抑制劑（如SPC-103600，SPC-101210，等），蛋白質激酶 C(PKC)抑制劑（如 R〇_31_7549，Ro-31-8161， Ro-31-8220等），蛋白質合成拮抗劑（如卡西三醇，Du-026325 ， LG-1069 ， LG-1064 ， AGN-190168 ，鈉咪羅替 -32- 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X297公釐） 516957 A7 B7 五、發明説明（30) (Namirotene)，CBS_211A等），嗓呤核甞璘醯酶抑制劑（如 BCX-34)，游離基形成激動劑（如苯幷普非啉衍生物），重組體抗白蛋白酶（如ALP-242)，類視黃素（如BMY-30123，LG_ 1069，LG-1064等），類視黃素衍生物（如AGN-190168)，雷帕黴素結合蛋白質（FKBP)(如免疫非啉，VX-10367，VX_ 10428等），二代單芳族類視黃素（如安西催汀（Acitretin)，尼歐替加松（Neotigason)等），可溶之IL_1，IL-4及IL-7受體，經濟部中央標準局員工消費合作衽印製 (請先閱讀背面之注意事項再填寫本頁) 生長激素釋放抑制因子類似物（如歐催泰，山多斯達汀等），類固醇（如AGN-191743)，鏈黴素環狀單離物（如依波卡唑淋（epocarbazolin)_A)，過氧歧化酶（如 EC-SOD-B)，胸腺口密啶脱氧核甞酸酯合成酶抑制劑（如AG-85，MPI_5002，於生物可降解之似凝膠母質中之5-FU，5-FU及於生物可降解似凝膠母質中之腎上腺素，Accusite等），局部調配物（如？-0751，P-0802等），轉谷氨醯酶抑制劑，tyrphostin EGF受體激酶阻斷劑（如AG-18，AG-555等），VCAM-1抑制劑（如ISIS 3801)，維他命D類似物（如Ro-23-6474，KH-1060，鈣普三醇，BMS-181161，BMY-30434，道莫耐斯，地莫耐斯等），維他命D3類似物（如塔可西托，朋尼發，TV_02軟膏等），維他命D3衍生物（如1，2-二幾_維他命D3)等。引致一氧化氮過度產生之又其他處理包含投與用以治療糖尿病之藥劑，如ACE抑制劑（如蓋托必（captopril))，澱粉素激動劑及拮抗劑（如諾麥林（Normylin™)，AC137, GC747) ，AC253，AC625，等），自動免疫化合物（如AI-401)，辣椒辣素（如Zostrix-HP)，細胞調節劑（如蛋白質激酶C抑制劑， -33- 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X 297公釐） 516957 A7 B7 五、發明説明（31) 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) 巴南醇（Balanol)等），多普酮（domperidone)(如莫替林 (Motilium)®)，弗巴斯達汀（fluvasatins)(如 Lescol)，FOX 988 ，融合毒素（如DAB389IL-2，DAB486IL_2等），基因治療（如轉核治療），高血糖糖原分解因子（如重組體酵母高血糖糖原分解因子），IL-10化合物，iloprost，免疫抑制劑（如塔可利模，普葛福，FK-506等），胰島素類似物（如AI-401，Nu·胰島素化合物，富姆琳（Humulin)，依利汀（Iletin)，富馬隆 (Humalog)™，LYs-Pro，阿馬利（Amaryl)等），似胰島素生長因子（如希隆（Chiron)/汽巴嘉基化合物，Fujisawa化合物， Genentech化合物等），促胰島素（如Pfizer/Scios Nova化合物) ，神經生長因子（如Genentech化合物），口服降血糖劑（如 AS_6，glimepiride，阿馬利，CL 316，243，阿卡糖 (acarbosc)，米利托（miglitol)，垂組體酵母高血糖糖原分解因子，GlucaGen™，NovoNorm™，葛利峨 p塞（glipizide)，促騰島素’ CI_991/CS-045等），血小板衍生之生長因子（如 ZymoGenetics/NovoNordisk化合物），橫醯脈（如妥布醯胺 (tolbutamide)，乙感己醯胺，托π 丫醯胺（tolazamide)，氯丙醯胺等），T細胞方法（如卩丫尼卩井（anergize)，AnergiX™，普塞特（Procept)化合物，T細胞科學化合物等），托雷斯特（如 Alredase®，ARI-509等）等。引致一氧化氮過度產生之其他處理包含投與用以治療中風之藥劑，如5-HT拮抗劑（如六氫吡畊衍生物），5-HT再攝取抑制劑（如 Milnacipran，Dalcipran等），5_HT 1A激動劑（如 SR-57746A，SR-57746等），5-HT3 激動劑（如 SR-57227), 5· -34- 本張尺度適用中國國家標準（ CNS ) A4規格（210X297公釐） 516957 A7 B7 五、發明説明（32 ) 經濟部中央標準局員工消費合作衽印製 (請先閲讀背面之注意事項再填寫本頁) HT 4拮抗劑，5-脂氧酶抑制劑（如低MW雙重5·脂氧酶及PAF 抑制劑CMI_392) ’ ACH激動劑（如派味拉西坦（pramiracetam) ，膽驗-L-阿法西瑞（alfoscerate)，L_從_甘油基磷酿膽驗，代利塞（Delecit)，等），腺苷激動劑（如GP-1-4683，ARA-100 ，arasine類似物等），腺甞A1受體激動劑（如吖異特 (Azaisotere，2·氯-Ν-[4·(苯硫基）-1·六氫吡啶]腺苷， 2120136等），腺苷再攝取抑制劑（如二苯基嘮唑衍生物），腎上腺素轉遞再攝取抑制劑（如必芬美南（Bifemelane)，Ε_ 0687，MCI-2016，阿耐特（Alnert)，西拉波（Celeport)等），酸糖還原酶抑制劑（如螺-3'p比哈琳衍生物），從拮抗劑（如 Drotaverine acephyllinate，戴布原（Depogen)等），α 2激動劑（如 SNAP-5083，SNAP-5608，SNAP-568.2等），ΑΜΡΑ受體激動劑（如雜環化合物SYM-1207，雜環化合物SYM-1252等），AMPA受拮抗劑（如 LY-293558，LY-215490等），安口 (Ancord)/啊維（Arvin)，阿斯匹靈，苯幷p塞峻（如魯貝盧峻 (Lubeluzole)，R87926等），苯幷二吖庚因受體拮抗劑（如3-吟二唑基-1，6-茬利啶衍生物，四環咪唑二吖庚因系列咪唑尼，FID-02-023，Ro_23-1412等），血液取代物，緩激肽拮抗劑（如CP-0127,在萊地可（Bradycor)，塞替可（Septicor)等) ，C5a釋出抑制劑（如蛋白質衍生物CMI-46000)，#5拮抗劑（如利米地平（Lemildipine)，NB-818，NPK-1886，三美塔啶 (Trimetazidine)衍生物，依馬口井（Iomerizine)KP-2796，地替忍（Diltiazem)類似物克來替忍（Clentiazem)順丁晞二酸鹽， TA-3 090等），#5槽道拮抗劑（如似耐催地平（nitrendipine)化 -35- 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衽印製 516957 A7 B7 五、發明説明（33 ) 合物代帕地平（diperdipine)，YS-201，U-92032，地替忍衍生物，1058，SM-6586，KP-840，F-0401，D-31-D，四氫莕衍生物，發舒地（fasudil)，AT-877，H_7，HA-1044，HA-1077，伊利爾（Eril)，代羅地平（darodipine)，代峻地平 (dazodipine)，PY-108-068，皮利莫（Plimo)，二氬被淀，AE 0047，GJ-0956，菜西地平（1^(^出？1狀），011-43659，011· 43659X，GX-1048，S-312-d，S-312，S-830312，尼巴地平 (Nilvadipine)，FK-235等），卡痛抑制劑（如 AK-275，CX-275 等），卡尼ί丁椋欄酸轉移酶抑制劑，卡貝地醇（carvedilol)，細胞黏附分子技術，腦鈣拮抗劑血管擴張劑（如尼莫地平 (Nimodipine)，尼莫塔（Nimotop)等），膽驗酯酶抑制劑（如吲嗓及W丨峻衍生物，塔琳（Tacrine)類似物等），互補因子抑制劑（如 TK9C，蛋白質衍生物 TP16，compinact A，compinact C，因子D抑制劑，可溶重組體MCP爲主之互補抑制劑等) ，互補抑制劑（如sCRI/BRL-55730，YM-203等），冠狀血管擴張劑（如尼可雷地（Nicorandil)，RP-46417，SG-75，安丹可（Adancor)等），CPC-111，胞甞醯二磷醯膽驗/胞二嶙膽驗，細胞素（如NBI-117)，代仙必醇（Dexanabiol)，多巴胺激動劑，EAA受體，内皮素拮抗劑（如SB 209670)，内皮素受體拮抗劑，激發胺基酸激動劑（如醯化多胺類似物，N-(4-羥苯基丙醯基）司伯明類似物等），激發胺基酸拮抗劑（如色氨酸，4,6-二取代之中風及犬尿氨酸衍生物，1^1>(：-17742， CPC-701，CPC-702等），谷氨酸拮抗劑（如紅藻氨酸酯使君子氨酸酯 NNC-07-9202，NPC-17742，小分子 CNS-1237， __ -36- 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)This paper size applies to Chinese National Standard (CNS) A4 specification (21 × X 297 mm) 516957 A7 B7 V. Description of invention (25) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling in) (This page) such as CD2), complementary inhibitors (such as recombinant McP-based complementary inhibitors), cyclosporine (such as Sandimmune, cyclosporine analogs, 0g-37325, cyclosporin-G, NVal-CyA Etc.), cytokines (such as IL_4 fusion toxins), cytokine receptor antagonists (such as immunomodulating cytokines), E-selectin antagonists (such as anti-ELAM, CY-1787, etc.), FK506 / Taroteli (such as Pu Ge Fu), hypercalcemia (such as KH-1060), IFN · r antagonists (such as anti-IFN-r MAb, sensitive anti-IFN_r MAb, etc.), IL-1 0 invertase inhibitor (ice) , IL_2 produced by E. coli (such as celmoleukin, IL-2, TGP-3, Celeuk, etc.), immunoglobulins (such as anti-ELAM, CY-1788, human CY-1787, etc. ) 'Immune stimulants (such as thymotrinan, RGH-0205, TP3, etc.), immunosuppressants (such as rapamycin, AY- 22989, NSC-226080, NSC-606698, anti-CD4, T · cytokine, anti-tac MAb, sensitive anti-tac MAb, Migis (membrane immunoglobulin isotope-specific) antibody, SM- 8849, immunophenanthroline, VX-10367, VX-10393, VX-10428, mycophenolate mofetil, ME-MPA, RS-61444, cyclosporine, OL-27-400, Sandimmune, IL_4 fusion toxin, cone Insect Inhibitory Factor (TIF), T · Cell Receptor, CD3 / Ti, Org-4094, Anti-TBM, CP17193, Leflunomide / A-77_1726, ELAM-1, AnergiX, Spantin, 15 -Deoxysperguanide, Desparguanide, Gespermo HQ, NSC-356894, NKT-01, Roquinimex, LS-2616, Linomide, LJP -394, CD-59 antigen, etc.), immunotoxins (such as Zolimomab aritox, xmmly-h65_rta, xanazyme-lym / CD5-Plus 9 OrthoZyme-CD5 +, XomaZyme-H65-rta, Xomazyme_CD5Plus, etc. ), Vein-28-This paper size is applicable to Chinese National Standard (CNS) A4 (21 × 297 mm) 516957 A7 B7 V. Description of the invention (26) Immunoglobulin (such as IVIG), i ntegrin antagonists (such as integrin blockers), Myggis ™ antibodies, monoclonal antibody therapeutics, mouse MAbs (such as anti-SLE vaccine, MAb 3E10, etc.), primate anti-CD4 antibodies (such as CE9.1 ), Protease inhibitors (such as maternal metalloproteinase (MMP) inhibitors, tomelin, etc.), protein synthesis antagonists (such as anti-CD6-bR, anti-T12-bR, oncolysin CD6, etc.), purine nuclei Inosine phosphatase inhibitors (such as BCX-25, BCX-14, etc.), selectin antagonists (such as CY1503, Cylexin, etc.), sparguanoline analogs (such as spantine, 15-deoxysperguanide, etc.) , Deoxysparguanine, gaispermo HC1, NSC-356894, NKT_01, etc.), T cell inhibitors (such as AnergiX), tumor necrosis factor (TNF) antagonists, etc. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Other treatments that cause excessive nitric oxide production include administration of drugs used to treat Alzheimer's disease, such as ACh release Enhancers (such as T_588 (phenylpyrimidine derivatives), acetylcholine stimulants (such as DUP-996 and the like), AMPA agonists (such as AMAlex, isozaki compound series, etc.) 'AMPA GluR agonist (Such as IDRA-21 [7-chloro-3-methyl-3,4-dihydro-2H-1,2,4_phenylhydrazone), AMPA GluR antagonists (such as S-18986 and related quinolones) Derivatives), anticholinergic enzymes (such as E-2020), Ga-antagonists (such as NS-649, ICM peptides and analogs derived from Wumei Venom, and substituted 2-aminoindane compounds Etc.), a combination of anti-cholinesterase and toxin AChR antagonists (such as PD142676), K-channel blockers (such as trans-R-4- (4-methoxyphenylmethyl) cyclohexylaniline And analogs, margatoxin-based functional and / or structural analogs, etc.), MI toxin receptor agonists (such as Xanomeline), NMDA antagonists (such as a certain Derivatives (R ^ R ^ S1))-(4-hydroxyphenyl)-/?-Methyl-4- (benzyl) -1-hexahydrop-pyridine propanol and its analogs Etc.), Yuyan-29-This paper size applies Chinese National Standard (CNS) M specifications (210X297 mm) 516957 A7 B7___ V. Description of the invention (27) Acid AChR agonists (such as ABT-418 [isoxazole, 3 -Methyl-5- (1-methyl-2-pyrrolidinyl)] etc.). Other treatments that cause excessive nitric oxide production include administration of agents to treat dryness, such as 5_L0 inhibitors (such as Wy-50295, Wy-49232, Lonapalene, RS-43179, MK-886, L-663536, ΕΤΗ-615, DUP-654, Zileuton, printed by the Employees' Cooperatives of the Central Standards Bureau of the Ibucarbazoline Ministry of Economics (please read the precautions on the back before filling this page) (epocarbazolin) -A, A-64077, etc.), 5-L0 / C0 inhibitors (such as BF_397, Tenidap, CP-309, CP-66248, etc.), angiogenesis inhibitors (such as platelet factor 4), antitumor antibiotics (such as AGM- 1470, TNP-470, etc.), anti-inflammatory cytochrome P450 oxygen reductase inhibitors (such as DuP-630, DuP-983, etc.), antiproliferative compounds (such as Zyn-linking agents), arachidonic acid analogs (such as CD581, CD554, etc.), arachidonic acid antagonists (eg, Ronaparin, RS-43179, triamcinolone acetonide with penetration enhancer Azone, betamethasone dipropionate, G -202, Halbetasol propionate, ultraravate, Halmetaxone, C-48401-Ba, Xico (Sicorten, etc.), /?-Glucan receptor antagonists, betamethasones, bowel metabolism regulators (such as Tacalcitol, Bonealfa, TV-02 ointment, Ro -23-6474, KH-1060, Calcipotriol, BMS-181161, BMY-30434, Dovonex, Divonex, etc., CD4 binding inhibitors (such as PIC 060), cell adhesion compounds (such as CY-726, VCAM_1, ELAM-1, ICAM, etc.), cell adhesion inhibitors (such as selectin inhibitors, GM-1930, etc.), cell aging inhibitors (such as factor X), cortex Sterols (such as halobetasol propionate, superfibrate, lomethasone, C-48401-Ba, Xiketian, etc.), cyclospores _ 30- This paper size applies to China National Standard (CNS) A4 specifications (21〇 > < 297 mm) 516957 A7 B7 V. Description of Invention (28) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Prime analogs (such as IMM -125), dihydrofolate reductase inhibitors (such as G-301, dichlorobenzoprim, methotrexa te), mexoxetine in giant cavernous body delivery system, etc.), E-selectin inhibitors (such as ISIS 4730), vitamin D3 endogenous activated states (such as calcitriol, Du-026325, etc.), Fibroblast growth factor antagonists (such as Spoline Mitotoxin, Steno-Stat, etc.), Nicotinin analogs (such as AGM-1470, TNP-470, etc.), G-proteins, and single transduction compounds (such as CPC_A) 'Acne gels (such as Acetamine, N-547, Papulex, etc.), growth hormone antagonists (such as Octreotide, Sandostatin, Langley Lanreotide, vasopeptin, BIM-23〇14, Somatuline, etc.), human antibodies (such as anti-CD4 antibodies), hydrogen orotate dihydrogenase inhibitors (such as brenat Sodium, bipenquinate, DuP-785, etc.), ICAM-1 inhibitors (such as ISIS 939), IL and other cytokine inhibitors (such as Septanil), IL-1 conversion Enzyme inhibitors, IL_1 receptor antagonists (such as Antril), IL-2 antagonists (such as talimide, Pugford, FK_506, etc.), I L · 2 receptor target fusion toxins (such as DAB 389 IL_2), IL_8 receptors, immunostimulants (such as thymopentin, Timunox, etc.), immunosuppressants (such as XomaZyme-CD5 Plus , Cyclosporin, Sandimmune, SR-31747, anti-CD11, 18MAb, tarotlimo, Pugford, FK-506, FK-507, etc., immunosuppressant targets FK506 (such as immunophenanthroline, VX_10367, VX-10428 Etc.), anti-CD antigens related to immunotoxin MAb (such as XomaZyme-CD5 Plus), leukotriene antagonists (such as Sch_40120, Wy_ 50295, Wy-49232, etc.), leukotriol B4 antagonists (such as SC-41930, SC-- 31-This paper size applies Chinese National Standard (CNS) A4 specification (21 × 297 mm) 516957 A7 B7 V. Description of invention (29) (Please read the precautions on the back before filling this page) 50605, SC-48928, ONO-4057, LB-457, LY_255283, LY-177455, LY-223982, LY-223980, LY-255253, etc.), leukotriene synthesis inhibitors (such as MK-886, L-663536, etc.), lipase clearance factor Inhibitors (such as 1-fluorenol, lidakol, etc.), lipid-encapsulating reducing agents (such as Dit hranol)), microlipid gel (such as Desanos), L0 inhibitors (such as CD581, CD554, Masoprocol, Actinex, etc.), lithium succinate ointment (such as lithium salt, Efalith, etc.), LO / CO inhibitors (such as P-8892, P-8977, CHX-108, FPL-62064, etc.), membrane agonists (such as lithium salts, efalith, etc.), Microtubule inhibitors (such as compounds containing Posophyliotoxin, Psorex, etc.), octapeptide growth hormone release inhibiting factor analogs (such as Blue Leotech, vasopeptin, BIM-23014, somatoline, etc.) ), Oligonucleotides (such as ISIS 4730, ISIS 3801, ISIS 193 9, IL-1 inhibitors, etc.), peptide agonists (such as octapeptide, peptide T, etc.), PKC inhibitors, phospholipid A2 compounds, Phospholipids D compounds, photodynamic antitumor agents (such as 5-aminoacetamidopropionic acid, 5-ALA, etc.), photodynamic therapy (such as benzamprofen derivatives, synthetic chlorine, synthetic prafolin, EF- 9) Photosensitizers (such as Porfirmer), PKC inhibitors (such as Safiningol, Kynac, etc.), platelet activating factor antagonists Agents (such as TCV-309), platelet aggregation inhibitors (such as CPC-A), prodrugs NSAIDs (such as G-201), and prostaglandin agonists (such as pentapentaenoic acid) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs + r-linolenic acid combination, imamonoline, etc.), protein inhibitors (such as SPC-103600, SPC-101210, etc.), protein kinase C (PKC) inhibitors (such as Ro-31_7549, Ro-31- 8161, Ro-31-8220, etc.), protein synthesis antagonists (such as calcitriol, Du-026325, LG-1069, LG-1064, AGN-190168, sodium milotti-32-) Standard (CNS) A4 specification (21 × 297 mm) 516957 A7 B7 V. Description of invention (30) (Namirotene), CBS_211A, etc.), Thyroid ribozyme inhibitor (such as BCX-34), free radical formation Agonists (such as benzamprofen derivatives), recombinant anti-albumin (such as ALP-242), retinoids (such as BMY-30123, LG_1069, LG-1064, etc.), retinoid derivatives (Such as AGN-190168), rapamycin binding protein (FKBP) (such as immunononline, VX-10367, VX_ 10428, etc.), second-generation monoaromatic retinoids Such as Acitretin, Neotigason, etc.), soluble IL_1, IL-4 and IL-7 receptors, printed by the consumer cooperation agreement of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the back first) Note for refilling this page) Growth hormone release inhibiting factor analogs (such as euthymine, sandostatin, etc.), steroids (such as AGN-191743), streptomycin ring-shaped single species (such as epoca Epocarbazolin_A), peroxo dismutase (such as EC-SOD-B), thymidine deoxyribonucleotide synthase inhibitor (such as AG-85, MPI_5002, biodegradable like gel 5-FU, 5-FU in parent material and adrenaline, Accusite, etc. in biodegradable gel-like parent material, local formulations (eg? -0751, P-0802, etc.), transglutaminase inhibitors, tyrphostin EGF receptor kinase blockers (such as AG-18, AG-555, etc.), VCAM-1 inhibitors (such as ISIS 3801), vitamin D Analogs (such as Ro-23-6474, KH-1060, calcitriol, BMS-181161, BMY-30434, Damonas, Demonas, etc.), Vitamin D3 analogs (such as Tacosito, Pennyfat, TV_02 ointment, etc.), Vitamin D3 derivatives (such as 1,2-Digui_Vitamin D3), etc. Other treatments that cause excessive nitric oxide production include administration of agents used to treat diabetes, such as ACE inhibitors (such as captopril), amyloid agonists and antagonists (such as Normylin ™) , AC137, GC747), AC253, AC625, etc.), autoimmune compounds (such as AI-401), capsaicin (such as Zostrix-HP), cell regulators (such as protein kinase C inhibitors, -33- this paper standard Applicable to Chinese National Standard (CNS) A4 specification (21 × X 297 mm) 516957 A7 B7 V. Description of invention (31) Printed by the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Balanol, etc.), domperidone (such as Motilium®), fluvasatins (such as Lescol), FOX 988, fusion toxins (such as DAB389IL-2, DAB486IL_2, etc.), gene therapy (such as nuclear transfer therapy), hyperglycemic glycogenolytic factor (such as recombinant yeast hyperglycemic glycogenolytic factor), IL-10 compounds, iloprost, immunosuppressants (such as tacrolimus, general Ge Fu, FK-506, etc.), islets Analogs (such as AI-401, Nu · insulin compounds, Humulin, Iletin, Humalog ™, LYs-Pro, Amaryl, etc.), insulin-like growth Factors (such as Chiron / cibagee compounds, Fujisawa compounds, Genentech compounds, etc.), insulin-promoting agents (such as Pfizer / Scios Nova compounds), nerve growth factors (such as Genentech compounds), oral hypoglycemic agents (such as AS_6 , Glimepiride, amali, CL 316, 243, acarbosc, miglitol, pituitary yeast hyperglycemic glycogenolytic factor, GlucaGen ™, NovoNorm ™, Glipizide, nootropic Tengdaosu 'CI_991 / CS-045, etc.), platelet-derived growth factors (such as ZymoGenetics / NovoNordisk compounds), transverse veins (such as tolbutamide, acetamidine, tropamidine) ( tolazamide), chlorpromazine, etc.), T-cell methods (such as anergize, AnergiX ™, Procept compounds, T-cell scientific compounds, etc.), Torrest (such as Alredase®, ARI -509 etc. Wait. Other treatments that cause excessive production of nitric oxide include administration of agents used to treat stroke, such as 5-HT antagonists (such as hexahydropyrine derivatives), 5-HT reuptake inhibitors (such as Milnacipran, Dalcipran, etc.), 5_HT 1A agonist (such as SR-57746A, SR-57746, etc.), 5-HT3 agonist (such as SR-57227), 5 · -34- This standard applies to China National Standard (CNS) A4 specification (210X297 mm) 516957 A7 B7 V. Description of the invention (32) Printed by the Consumer Co-operation of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) HT 4 antagonist, 5-lipoxygenase inhibitor (such as low MW Double 5.lipoxygenase and PAF inhibitor CMI_392) 'ACH agonist (such as piracetam (pramiracetam), bile test-L-alfascerate (alfoscerate), L_ from _ glyceryl phosphate brewed bile test , Delecit, etc.), adenosine agonists (such as GP-1-4683, ARA-100, arasine analogs, etc.), adenosine A1 receptor agonists (such as Azaisotere, 2. · Chloro-N- [4 · (phenylthio) -1 · hexahydropyridine] adenosine, 2120136, etc.), adenosine reuptake inhibitors (such as diphenyloxazolyl Substances), epinephrine re-uptake inhibitors (such as Bifemelane, E_ 0687, MCI-2016, Alnert, Celeport, etc.), acid sugar reductase inhibitors ( Such as Spiro-3'p biharine derivatives), from antagonists (such as Drotaverine acephyllinate, Depogen, etc.), alpha 2 agonists (such as SNAP-5083, SNAP-5608, SNAP-568.2, etc.), AMPA receptor agonists (such as heterocyclic compounds SYM-1207, heterocyclic compounds SYM-1252, etc.), AMPA receptor antagonists (such as LY-293558, LY-215490, etc.), Ancord / Arvin , Aspirin, benzodiazepine (such as Lubeluzole, R87926, etc.), benzodiazepine receptor antagonists (such as 3-indoxazolyl-1,6-stigmaline) Pyridine derivatives, tetracyclic imidazole diazepene series imidazolidine, FID-02-023, Ro_23-1412, etc.), blood substitutes, bradykinin antagonists (such as CP-0127, in Bradycor), Septicor, etc.), C5a release inhibitors (such as protein derivative CMI-46000), # 5 antagonists (such as Lemildipine, NB-818, NPK-1886, Trimetazidine derivatives, Iomerizine KP-2796, Diltiazem analogs Clentiazem maleate, TA-3 090, etc.), # 5 Slot antagonists (such as nitrendipine-35-) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm). Consumption cooperation with employees of the Central Standards Bureau of the Ministry of Economic Affairs. Printed 516957 A7 B7 5 2. Description of the invention (33) Compound diperdipine, YS-201, U-92032, ditetopine derivatives, 1058, SM-6586, KP-840, F-0401, D-31-D, four Hydrofluorene derivatives, fasudil, AT-877, H_7, HA-1044, HA-1077, Eril, darodipine, dazodipine, PY-108- 068, Plimo, argon is deposited, AE 0047, GJ-0956, caesipine (1 ^ (^ 出? 1 form), 011-343659, 011 · 43659X, GX-1048, S-312-d, S-312, S-830312, Nilvadipine, FK-235, etc.), and pain inhibitors (such as AK -275, CX-275, etc.), carnitil inhibitors, carvedilol, cell adhesion molecule technology, brain calcium antagonist vasodilators (such as Nimododipine, Nimotop, etc.), bile esterase inhibitors (such as indole and W derivatives, Tacrine analogs, etc.), complementary factor inhibitors (such as TK9C, protein derivative TP16, compinact A, compinact C, factor D inhibitors, soluble recombinant MCP-based complementary inhibitors, etc.), complementary inhibitors (such as sCRI / BRL-55730, YM-203, etc.), coronary vasodilators (such as nicole Ground (Nicorandil), RP-46417, SG-75, Adancor (Adancor, etc.), CPC-111, cytosine diphosphate test / cytosine test, cytokines (such as NBI-117), Dexanabiol, dopamine agonist, EAA receptor, endothelin antagonist (such as SB 209670), endothelin receptor antagonist, stimulating amino acid agonist Such as tritiated polyamine analogs, N- (4-hydroxyphenylpropanyl) sparmine analogs, etc.), stimulating amino acid antagonists (such as tryptophan, 4,6-disubstituted stroke and canine) Uric acid derivatives, 1 ^ 1 > (: -17742, CPC-701, CPC-702, etc.), glutamate antagonists (such as kainic acid esters make gentisine esters NNC-07-9202, NPC- 17742, Small molecule CNS-1237, __ -36- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page)

經濟部中央標準局員工消費合作社印製 516957 A7 B7 五、發明説明（34 ) NS-257，NS-072，BW-619C，CGS 19755，利盧唑（Riluzole) ，PK-26124，RP-54274等），谷氨酸受體拮抗劑（如阿拉辛 (Araxin)化合物，喹嘮啉衍生物，YM-90K，YM-900等），甘氨酸拮抗劑，甘氨酸NMDA激動劑（如3-羥基-2,5-二氧代-1H-苯幷[b]吖庚因），甘氨酸NMDA聯合之拮抗劑（如5,6-二氫-1H-吡咯[l，2,3-de]喹哼啉-2,3·二酮，NMDA受體L-687414之番木鱉鹼不敏感之甘氨酸結合位置，甘氨斯達辛 (Glystasins)，ALEA-2011，ACEA-3031，AC-1021，ACPC ，伊利普地（eliprodil)等），生長因子拮抗劑（如非胜肽吲嗓卡峻嗜中性分子，CEP-075等），GPIIb/IIIa拮抗劑（如胜肽 C68-22)，血流力學劑（如 Drotaverine acephyllinate，戴布原等），肝素，羥基形成抑制劑（如高六氫吡畊衍生物K-7259) ，高血鈣劑（如降血鈣素胜肽，相關於hCGRP胜肽），低體溫劑/BMY-20862，ICAM-1化合物（如尹利莫美（Enlimomab)) ，免疫抑制劑（如小分子化合物，NBI-117等），integrin—般拮抗劑（如單株抗體AN-100225，單株抗體AN-100226等），介白素-1拮抗劑（如環狀硝酸靈），鐵依存之脂質過氧化反應抑制劑（如2-(胺甲基）色滿），乳酸蓄積作用抑制劑（如小分子 CPC_211)，白三烯 B4拮抗劑（如 Ebselcn，DR-3305， PZ-25，PZ-51，RP-60931，RP-61605等），月旨質過氧酶抑制劑（如依代貝酮（Idebenone)，艾文（Avan)等），低分子量小分子，甲基轉移酶刺激劑（如4·甲基苯磺酸鹽，阿代美替寧 (ademetionine)硫酸鹽甲苯續酸鹽，FO-156，色利旦（Ceritan) 等），單胺氧化酶B抑制劑（如MD_280040，MD-200243， — -37- 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 516957 A7 B7 V. Description of Invention (34) NS-257, NS-072, BW-619C, CGS 19755, Riluzole, PK-26124, RP-54274, etc. ), Glutamate receptor antagonists (such as Araxin compounds, quinoline derivatives, YM-90K, YM-900, etc.), glycine antagonists, glycine NMDA agonists (such as 3-hydroxy-2, 5-dioxo-1H-phenylhydrazone [b] azepine), an antagonist of glycine NMDA (such as 5,6-dihydro-1H-pyrrole [l, 2,3-de] quinhumline-2 , 3 · Diketone, NMDA receptor L-687414, the insensitive glycine binding site of pupalin, Glystasins, ALEA-2011, ACEA-3031, AC-1021, ACPC, Ilipide (Eliprodil), etc., growth factor antagonists (such as non-peptide indoxacarb neutrophil, CEP-075, etc.), GPIIb / IIIa antagonists (such as peptide C68-22), hemodynamic agents (such as Drotaverine acephyllinate, Debogen, etc.), heparin, hydroxyl formation inhibitors (such as homohexahydropyrine derivatives K-7259), hypercalcemia (such as calcitonin peptide, related to hCGRP peptide), low body temperature / BMY-20862, ICAM-1 compounds (such as Enlimomab), immunosuppressants (such as small molecule compounds, NBI-117, etc.), integer-like antagonists (such as the monoclonal antibody AN-100225, single Strain AN-100226, etc.), interleukin-1 antagonists (such as cyclic nitrate), iron-dependent lipid peroxidation inhibitors (such as 2- (aminemethyl) chroman), lactic acid accumulation inhibitors (Such as small molecule CPC_211), leukotriene B4 antagonists (such as Ebselcn, DR-3305, PZ-25, PZ-51, RP-60931, RP-61605, etc.) Idebenone, Avan, etc.), low-molecular-weight small molecules, methyltransferase stimulants (such as 4-methylbenzenesulfonate, ademetionine sulfate, toluene acid) Salt, FO-156, Ceritan, etc.), monoamine oxidase B inhibitors (such as MD_280040, MD-200243,--37- This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) (Please (Read the notes on the back before filling out this page)

516957 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（35) MD-280080，拉峻貝麥（Lazabemide)，Ro-19-6327等），MS-153，MS-424，Na+/H+，Na+/Li+交換抑制劑（如吡畊衍生物），那多帕林（nadroparin)(如弗雷西帕林（Fraxiparin))，拿法酿 /那替多吱利（nafronyl/naftidrofuryl)(如帕希林（Praxilene)) ，神經生長因子激動劑（如小分子化合物，CNTF，BDNF， 2.5S NGF，單唾神經節苷脂GM1，塞忍/西忍（Sigen/Sygen) 等），神經朊鈣槽道阻斷劑（如CPC-304，CPC-317，等），神經朊分化化合物（如F-司伯淀），神經胜肽激動劑（如趨神經性胜肽托弗辛（Trofexin))，嗜中性抑制因子（如小分子化合物），一氧化氮激動劑（如輕基衍生物N-33 93，經基衍生物 Ν·3 3 98，尼可雷地，瑟拉ρ比可（Therapicon)等），一氧化氮拮抗劑，NMD A拮抗劑（如螺異旧哚/二唑西平衍生物，氧吲哚化合物，CP-112116，LY-104658，LY-235959，FR-115427，水楊酸衍生物，N-棕搁醯乙基糖苷唾液酸， ND-37, Ro-01-6794 , 706，右經嗎喃，伊芬普地（Ifenprodil) 類似物伊利普地，SL_82.0715，親脂性分子，HU-211，雷西麥（Remacemide)，934-423，12495，12859，12942AA，西發泰（Selfotel)，CGS-19755，SDZ-EAA-494，CGP-40116 ，CGP-37849，CGP-39551，CGP-43487，等），NMDA拮抗劑邵份激動劑（如可那托金（Conantokin)G胜肽SYM-1010)， NMDA槽道阻斷劑（如安替眞耐（Aptiganel)，CERESTAT， CNS 1102等），NMDA受體拮抗劑，NMDA受體亞型（如紅藻氨酸酯使君子氨酸酯NNC-07-9202)，非競爭性NMDA拮抗劑（如FPL-15896)，非離子共聚物RheothRx，吡烷酮醋胺/乙 __ -38- 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)516957 A7 B7 printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (35) MD-280080, Lazabemide, Ro-19-6327, etc., MS-153, MS-424, Na + / H +, Na + / Li + exchange inhibitors (such as Picolin derivatives), nadroparin (such as Fraxiparin), nafronyl / naftidrofuryl ( Such as Praxilene), nerve growth factor agonists (such as small molecule compounds, CNTF, BDNF, 2.5S NGF, monosialganglioside GM1, Sigen / Sygen, etc.), neural crest Calcium channel blockers (such as CPC-304, CPC-317, etc.), neural crest differentiation compounds (such as F-Spartan), neuropeptide agonists (such as trofexin) ), Neutrophil inhibitors (such as small molecule compounds), nitric oxide agonists (such as the light-based derivative N-33 93, the radical-based derivative N · 3 3 98, Nicoredi, Seraphim (Therapicon), etc., nitric oxide antagonists, NMD A antagonists (such as spiroisodole / diazocepine derivatives, oxindole compounds, CP-112116 LY-104658, LY-235959, FR-115427, salicylic acid derivative, N-brown ethylglycoside sialic acid, ND-37, Ro-01-6794, 706, dextran morphan, ifenprid (Ifenprodil) Analogs Ilipide, SL_82.0715, lipophilic molecule, HU-211, Remacemide, 934-423, 12495, 12859, 12942AA, Selfotel, CGS-19755, SDZ -EAA-494, CGP-40116, CGP-37849, CGP-39551, CGP-43487, etc.), NMDA antagonist Shao agonists (such as Conantokin G peptide SYM-1010), NMDA channel Blocking agents (such as Aptiganel, CERESTAT, CNS 1102, etc.), NMDA receptor antagonists, NMDA receptor subtypes (such as kainic acid ester make gentisine ester NNC-07-9202), Non-competitive NMDA antagonists (such as FPL-15896), non-ionic copolymer RhothRx, pyridone acetate / ethyl __ -38- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please (Read the notes on the back before filling out this page)

516957 A7 _____ _B7__ 五、發明説明（36 ) 醯膽鹼激動劑（如歐西雷泰（Oxiracetam)，CT-848，努拉替 (Ncuractiv)等），去甲腎上腺素抑制劑（如咪達西班 (Midalcipran)，N-型鈣槽道拮抗劑（如 NS-626，NS-638等）， opioid拮抗劑（如那美芬（Nalmefene)，那美晞（Nalmetrcne)， JF-1 ’ ORF-11676，色維（Cervene)，v5l p塞晞（Incysten)等）， opioid kappa受體激動劑（如丙晞乙醯胺啕多啉（enad〇line)， CI-997等），有機硒（如伊塞林（Ebselen)，DR-3305，PZ-25， PZ-51，RP60931，RP61605等），氧去除劑（如替利萊 (Tirilazad)甲續酸鹽，拉峻德（Lazaroids)，弗利多斯 (Freedox)等），PA2抑制劑（如抱磷脂酶A2抑制劑），P AF指抗劑（如努帕芬（nupafant)，BB_2113等），部份甘氨酸NMDA 激動劑（如ACPC)，胜肽/GPIIb/IIIa拮抗劑（如引特葛林 (Integrelin))，胜肽神經特異之鈣槽道拮抗劑（如SNX-111) ，嶙酸二酯酶抑制劑（如黃嘌呤衍生物，丙托飛林經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) (propentofylline)，Hoe-285，亥斯托（Hextol)等），磷脂酶A2 抑制劑（如小有機分子CEP-217)，纖維蛋白溶酶原活化劑（如pProUK(重組體原尿激酶）），血小板活化因子拮抗劑（如 UK-74505)，血小板黏附抑制劑（如胜肽），血小板凝集拮抗劑（如西羅塔峻（cilostazol)，胜肽劑，GPHb-IIIA抑制劑， TP-9201等），血小板凝集抑制劑（如二胺基烷酸衍生物），鉀槽道激動劑（如尼可雷地，RP-46417，SG-75，安丹可 (Adancor)等），脯氨醯内胜肽酶（PEP)抑制劑（如JTP-4819)，蛋白質激酶C抑制劑（如單唾神經節苷脂衍生物Liga-20)，水解蛋白酶抑制劑（如蛋白酶尼辛-1，引塞（Incyte)，PN-1， ___-39-__ 本紙張尺度適用中國國家標準（CNS ) A4規格（2丨〇'乂297公釐） 516957 A7 B7 五、發明説明（37 ) PN_2，那法莫斯特（Nafamostat)，PUT-175，杜山（Duthan) ，冨山（Futhan)等，嘧啶衍生物，喹諾畊衍生物（如KF- 17329，KF-19863，等），游離基形成拮抗劑（如EPC-K1)，重組體組織纖維蛋白溶酶原活化劑（如歐泰酶（altepiase)，活化酶等），史旺（Schwann)細胞衍生之分子/促進劑，ε拮抗劑（如ε配位基），ε受體拮抗劑（如四氫吡啶異噚唑啉，異嘮唑PD-144418等），鈉/鉀槽道調節劑（如利法畊 [Lifarizine，RS-87476等），鈉槽道拮抗劑，鏈激酶（如鏈酶），經取代之胍（如小分子CNS-1237)，過氧歧化酶刺激劑（如 PEG共輛之酶過氧歧化酶/Dismutec，PEG-SOD，等），凝血酶抑制劑（如非胜肽），凝血嘮烷合成酶抑制劑（如尼諾托班 (Linotroban)，HN-11500等），促甲狀腺素釋放激素激動劑（如TRH激動劑，促甲狀腺素釋放激素類胸腺貝啉，RX_ 77368等），替羅 p比淀(ticlopidine)(如替克來（Ticlid))，TJ-8007，TRH激動劑（如促甲狀腺素釋放激素，JTP-2942等），泰拉查（trilazard)，尿激酶（如哈胺激酶（Abbokinase))，w-可諾胜肽（conopeptide)(如SNX-111)，爷丙酮香豆素（如爷丙酮香豆素鈉）等。經濟部中央標準局員工消費合作衽印製 (請先閲讀背面之注意事項再填寫本頁) 據此，依據本發明處理之較佳病徵包含敗血性休克，絕血，潰瘍，潰瘍性結腸炎，糖尿病，關節炎，氣喘，阿茲海默氏疾病，帕金森氏疾病，多發性乾癖，硬變或異體移植排斥等。依據本發明特定目標，一氧化氮去除劑與一或多種上述藥劑組合投藥，視情況包含抗生素（如慶大黴素，妥布黴素 ___-40-__ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 516957 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（38 ) ，丁胺卡那黴素，胡椒黴素（piperacillin)，氯林可黴素 ’頭孢遠吩或萬古黴素或其混合物），血管活化劑（如兒茶酚胺，去甲腎上腺素，多巴胺或多巴酚丁胺）或其混合物。此方法中’許多上述醫藥劑之有害副作用及/或欲解決之病徵（如全身性低血壓）可藉共同投與包含一氧化氮去除劑之組合藥劑而予以預防或降低。熟悉本技藝者將了解可使可謗發一氧化氮表現之物種去活化之藥劑（或可抑制此物種產生之藥劑）與本文所述之一氧化氮去除劑組合可以各種方式輸送，例如口服，靜脈内 ’皮下，非經腸道，直腸，吸入等方式。由於個別目標物可提出廣泛變化之病徵嚴重性且各藥物具有其獨特治療特徵，因此用於各目標物之投藥精確模式、使用劑量及治療方式需留待醫師決定。依據本發明又其他具體例，提供一種生理活性組合物，包括治療劑’’（本文所述）及一氧化氮去除化合物（如具有前述結構I之化合物），於可賦與該組合物可口服輸送，經皮輸送，靜脈内輸送，肌肉内輸送，局部輸送，鼻内輸送等之適宜載劑中。視所用輸送模式而定，上述組合物可以多種醫藥可接受形式輸送，例如，上述組合物可以固體、溶液、乳液、分散液、微胞，微脂等形式輸送。本發明之醫藥組合物可以固體、溶液、乳液、分散液、微胞、微脂等形式使用，其中所得組合物含有一或多種各一氧化氮去除劑及欲用於本發明實務中之治療活性化合物 (請先閲讀背面之注意事項再填寫本頁)516957 A7 _____ _B7__ 5. Description of the invention (36) 醯 Choline agonists (such as Oxiracetam, CT-848, Ncuractiv, etc.), norepinephrine inhibitors (such as midasylban (Midalcipran), N-type calcium channel antagonists (such as NS-626, NS-638, etc.), opioid antagonists (such as Nalmefene, Nalmetrcne, JF-1 'ORF-11676 , Cervene, v5l p-cysteine (Incysten, etc.), opioid kappa receptor agonist (such as acetamidine, poly-line (enad〇line), CI-997, etc.), organic selenium (such as Iraq Ebselen, DR-3305, PZ-25, PZ-51, RP60931, RP61605, etc., oxygen removers (such as Tirilazad formate, Lazaroids, Fridos (Freedox, etc.), PA2 inhibitors (such as phospholipase A2 inhibitors), P AF refers to antagonists (such as nupafant, BB_2113, etc.), some glycine NMDA agonists (such as ACPC), peptides / GPIIb / IIIa antagonists (such as Integrelin), peptide-specific calcium channel antagonists (such as SNX-111), and gallate diesterase inhibitors (such as xanthine) Derivatives, printed by the Consumer Cooperative of the Central Standards Bureau of Propofelin Ministry of Economic Affairs (please read the precautions on the back before filling this page) (propentofylline), Hoe-285, Hextol, etc.), phospholipase A2 inhibitors (such as the small organic molecule CEP-217), plasminogen activators (such as pProUK (recombinant protourokinase)), platelet activating factor antagonists (such as UK-74505), and platelet adhesion inhibitors (such as Peptides), platelet aggregation antagonists (such as cilostazol, peptides, GPHb-IIIA inhibitors, TP-9201, etc.), platelet aggregation inhibitors (such as diaminoalkanoic acid derivatives), potassium Channel agonists (such as Nicoredil, RP-46417, SG-75, Adancor, etc.), prolysin endopeptidase (PEP) inhibitors (such as JTP-4819), protein kinase C Inhibitors (such as monosialganglioside derivative Liga-20), hydrolytic protease inhibitors (such as protease Nixin-1, Incyte, PN-1, ___- 39 -__ This paper is applicable to China Standard (CNS) A4 specification (2 丨〇 '乂 297 mm) 516957 A7 B7 V. Description of invention (37 ) PN_2, Nafamostat, PUT-175, Duthan, Futhan, etc., pyrimidine derivatives, quinolomin derivatives (such as KF-17329, KF-19863, etc.), Free radical formation antagonists (such as EPC-K1), recombinant tissue plasminogen activators (such as altepiase, activating enzymes, etc.), Schwann cell-derived molecules / promoters, ε Antagonists (such as ε ligands), ε receptor antagonists (such as tetrahydropyridine isoxazoline, isoxazole PD-144418, etc.), sodium / potassium channel regulators (such as rifagen [Lifarizine, RS -87476, etc.), sodium channel antagonists, streptokinase (such as streptase), substituted guanidine (such as small molecule CNS-1237), peroxo dismutase stimulants (such as PEG co-enzyme peroxo dismutase / Dismutec, PEG-SOD, etc.), thrombin inhibitors (such as non-peptide), thromboxane synthase inhibitors (such as Linotroban, HN-11500, etc.), thyrotropin-releasing hormone agonists (Such as TRH agonist, thyrotropin-releasing hormone thymosin, RX_77368, etc.), tirolopidine (ticlopidine) (such as tic (Ticlid)), TJ-8007, TRH agonist (such as thyrotropin releasing hormone, JTP-2942, etc.), trilazard, urokinase (such as Abbokinase), w-conoxol Peptides (conopeptide) (such as SNX-111), cetoacetone coumarin (such as cetoacetone coumarin sodium) and so on. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page). According to this, the better symptoms to be treated according to the present invention include septic shock, hemorrhage, ulcer, ulcerative colitis, Diabetes, arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple dry addiction, sclerosis or allograft rejection, etc. According to a specific objective of the present invention, a nitric oxide remover is administered in combination with one or more of the above-mentioned agents, and optionally includes antibiotics (such as gentamicin, tobramycin ___- 40 -__ This paper size applies to Chinese national standards (CNS ) A4 size (210X297 mm) 516957 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (38), amikacin, piperacillin, clindamycin 'cephalosporin Telephene or vancomycin or mixtures thereof), vascular activators (such as catecholamines, norepinephrine, dopamine or dobutamine) or mixtures thereof. The harmful side effects of many of the aforementioned pharmaceutical agents and / or the symptoms to be resolved (such as systemic hypotension) in this method can be prevented or reduced by co-administration of a combination agent containing a nitric oxide remover. Those skilled in the art will understand that a combination of a deactivating agent (or an agent that inhibits the production of this species) that can slap nitric oxide performance and a nitric oxide removing agent described herein can be delivered in various ways, such as orally, Intravenous' subcutaneous, parenteral, rectal, inhalation, etc. Because individual targets can suggest widely varying severity of symptoms and each drug has its own unique therapeutic characteristics, the precise mode of administration, dosage and treatment of each target need to be determined by the physician. According to still other specific examples of the present invention, a physiologically active composition is provided, which includes a therapeutic agent (as described herein) and a nitric oxide removal compound (such as a compound having the aforementioned structure I), which can be orally administered to the composition. Suitable carriers for delivery, percutaneous delivery, intravenous delivery, intramuscular delivery, local delivery, intranasal delivery, etc. Depending on the delivery mode used, the above composition can be delivered in a variety of pharmaceutically acceptable forms. For example, the above composition can be delivered in the form of a solid, solution, emulsion, dispersion, microcellular, microlipid, and the like. The pharmaceutical composition of the present invention can be used in the form of solid, solution, emulsion, dispersion, microcellular, microlipid, etc., wherein the obtained composition contains one or more of each nitric oxide removing agent and the therapeutic activity to be used in the practice of the present invention Compounds (please read the notes on the back before filling this page)

、1T -41 - 516957 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（39 ) 作爲其活性成份，與適於食用或非經腸道使用之有機或無機载體或賦形劑混合。活性成份可與用於錠劑，粒片，膠囊，栓劑，溶液，乳液，懸浮液及任何適用形式之尋常非毒性醫藥可接受性載體混合。可使用之載體包含葡萄糖，乳糖，***膠，明膠，甘露糖醇，澱粉糊，三矽酸鍰，滑石’玉米澱粉’角蛋白，膠體氧化碎，馬铃薯殿粉，尿素，中度鏈長之三酸甘油酯，葡聚糖及其他適於製造固態、半固態或液態製劑之載體。此外，亦可使用佐劑、安定劑、增稠劑及著色劑及香料。活性化合物（即”治療劑"及— 氧化氮去除化合物（如本文所述之結構I化合物））於醫藥組合物中之量爲足以產生依目標製程、病況或疾病而定之所需效果之量。含本文活性成份之醫藥組合物可呈適於口服使用之形式 ’例如錠劑，扁錠，糖錠，水性或油性懸浮液、可分散粉劑或顆粒，乳液，硬或軟膠囊，或糖漿或酣酏劑。用於口服之組合物可依據製造醫藥組合物之領域悉知之任何方法製備。此外，此種組合物可含有一或多種選自甜味劑（如薦糖，乳糖或糖精），矯味劑（如薄荷油，白珠樹及櫻桃油），著色劑及保存劑等之試劑，以提供醫藥上可口之製劑。含活性成份與非毒性醫藥可接受賦形劑之混合物之錠劑亦可藉已知方法製備。所用賦形劑可爲例如（1 )惰性稀釋劑如碳酸鈣，乳糖，磷酸鈣，磷酸鈉等；（2)粒化及崩解劑如玉米澱粉，馬鈐薯澱粉，藻朊酸等；結合劑如西黃蓍樹膠，玉米澱粉，明膠，***膠等；及（4)潤滑劑如硬脂酸鎂， 42- (請先閱讀背面之注意事項再填寫本頁}1T -41-516957 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (39) As its active ingredient, organic or inorganic carriers or excipients suitable for edible or parenteral use mixing. The active ingredient can be mixed with lozenges, granules, capsules, suppositories, solutions, emulsions, suspensions and any suitable form of a non-toxic pharmaceutically acceptable carrier. Carriers that can be used include glucose, lactose, gum arabic, gelatin, mannitol, starch pastes, trisilicate, talc 'cornstarch' keratin, colloidal oxidized particles, potato powder, urea, moderate chain length Triglycerides, dextran and other carriers suitable for the manufacture of solid, semi-solid or liquid preparations. In addition, adjuvants, stabilizers, thickeners, colorants and perfumes can also be used. The amount of active compound (ie, "therapeutic agent" and "therapeutic agent", such as the structure I compound described herein) in the pharmaceutical composition is an amount sufficient to produce the desired effect depending on the target process, condition, or disease Pharmaceutical compositions containing the active ingredients herein may be in a form suitable for oral use 'for example, lozenges, lozenges, dragees, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Liniments. Compositions for oral administration may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. In addition, such compositions may contain one or more selected from sweeteners (such as recommended sugars, lactose or saccharin), Flavoring agents (such as peppermint oil, white pearl tree and cherry oil), colorants and preservatives, etc. to provide pharmaceutical delicious preparations. Lozenges containing a mixture of active ingredients and non-toxic pharmaceutically acceptable excipients are also available Prepared by known methods. The excipients used can be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate, sodium phosphate, etc .; (2) granulating and disintegrating agents such as corn starch Potato starch, alginic acid, etc .; binders such as gum tragacanth, corn starch, gelatin, gum arabic, etc .; and (4) lubricants such as magnesium stearate, 42- (please read the precautions on the back first) Fill out this page}

經濟部中央標準局員工消費合作社印製 516957 發明説明（4〇) 硬脂酸’滑石等。疑劑可武古a、士田 j馬未包衣或可藉已知技術包衣以在同腸道内延長崩解及吸收 α 收因而提供較長期間之持續活性。例如可使用時間延長物、處如单硬舳鉍甘油酯或二硬脂甘油醋。亦可以Α Τ Τ。 0曰 τ τ Μ 於 USP 4,256，108 ; 416〇 452及 4,265，m之技術包衣以形成可控制釋出之渗透治療錠劑。某些例中’ Π服用途之調配物可呈硬明膠膠囊形式，立中活性成份與惰性固體稀釋劑例如碳酸鈣，磷酸鈣，高嶺土等混合。亦可呈軟明膠膠囊形式，其中活性成份與水或油性介質例如花生油、液態石犧或橄欖油混合。此醫藥组合物可呈殺菌可注射懸浮液形式。此懸浮液可依據已知方法使適宜分散劑或溼潤劑及懸浮劑調配。此殺菌可注射懸浮液亦可呈㈣毒性非經腸道可接受之稀釋劑或溶劑中之殺菌可注射溶液或懸浮液，例如於13_ 丁二醇中之溶液。殺菌之固定油爲習知使用之溶劑或懸浮介質。對此目的而言，可使用任何溫和之固定油包含合成單-或二甘油酯，脂肪酸（包含油酸），天然植物油如芝麻油，椰子油，花生油，棉籽油等，或合成脂肪載劑如油酸乙酯等。若需要，可併入緩衝劑，保存劑、抗氧化劑等。欲用於本發明實務之組合物亦可以供活性成份直腸投藥之栓劑形式投藥。該等組合物可藉由使活性成份與適宜之非刺激性賦形劑如可可脂'聚乙二醇之合成甘油酯（其在常溫爲固體但在直腸内液化及/或溶解以釋出活性成份）等混合而製備。由於個別目標物存在有廣泛變化之病徵嚴重性且各活性 -43- 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 516957 Description of the invention (40) Stearic acid 'talc and so on. Suspects may be uncoated with Wugu a, Shitian j horse or may be coated by known techniques to prolong disintegration and absorption in the intestinal tract and thus provide continuous activity over a longer period. For example, a time extender such as bismuth glyceryl monostearate or distearyl glycerol vinegar can be used. Can also be ATOT. 0% τ τ Μ coated with the technology of USP 4,256,108; 4160,452 and 4,265, m to form a osmotic therapeutic tablet with controlled release. In some cases, the formulations for use in the formulation may be in the form of hard gelatin capsules, and the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, kaolin and the like. It may also be in the form of a soft gelatin capsule in which the active ingredient is mixed with water or an oily medium such as peanut oil, liquid stone sacrifices or olive oil. This pharmaceutical composition may be in the form of a sterilizable injectable suspension. This suspension may be formulated according to known methods with suitable dispersing or wetting agents and suspending agents. This sterilizable injectable suspension may also be a sterilizable injectable solution or suspension in a toxic parenterally acceptable diluent or solvent, such as a solution in 13-butanediol. Bactericidal fixed oils are conventionally used solvents or suspension media. For this purpose, any mild fixed oil can be used containing synthetic mono- or diglycerides, fatty acids (including oleic acid), natural vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fat carriers such as oil Acid ethyl ester and so on. If necessary, buffers, preservatives, antioxidants, etc. may be incorporated. The composition to be used in the practice of the present invention may also be administered in the form of suppositories for rectal administration of the active ingredient. These compositions can release the activity by synthesizing the active ingredient with a suitable non-irritating excipient, such as a synthetic glyceride of cocoa butter 'polyethylene glycol (which is solid at ordinary temperatures but liquefies and / or dissolves in the rectum). Ingredients) and so on. Due to the wide variation of the severity of symptoms of individual targets and their respective activities -43- This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm (please read the precautions on the back before filling this page)

516957 A7 B7___ 五、發明説明（41 ) 成份具有其獨特治療特徵，因此由醫師決定目標物對治療之反應而據此改變劑量。通常，一氧化氮去除劑之典型曰劑量在每公斤體重約10 微克至約100毫克之範園，較好每公斤體重約50微克至10 毫克之範圍且每曰可投藥達4次。每曰之IV劑量爲每公斤體重約1微克至約100毫克之範圍，且較好爲每公斤體重自 10微克至10毫克之範圍。通常，使用於本發明實務之一氧化氮去除劑劑量落於約 0 . 〇 1毫莫耳/目標物公斤體重/小時至約0 · 5毫莫耳/公斤/小時之範圍。本發明現在將參考下列非限制性實例更加詳細敘述。實例1 由西蒙森（Simonson)實驗室（Gilroy，CA)供應威士達鼠（雄性，230-300克）。由 Sigma(St· Louis, MO)得脂多糖（LPS ; S. typhosa，内毒素）。經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 由Aldrich(Milwaukee，WI)獲得N-甲基葡萄糖胺及二硫化碳。以 Shinobu等人之方法（Acta Pharmacol. Toxicol. 54:189-194(1984))合成N-甲基-D-葡萄糖胺二硫代胺基甲酸酉旨（MGD) 〇實例2 如前所述（參見 Lai及 Komarov於 FEBS Lett· 345:120-124 (I994))，一 [(MGD2/Fe]複合物結合至一分子一氧化氮上以形成[(MGD)2/Fe-NO]複合物。雖然游離之一氧化氮爲強力 -44- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 516957 A7 B7 五、發明説明（42 ) 之血管擴張素，但結合至[(MGD)2/Fe]之一氧化氮則否。所得複合物接著於尿中自體内排出，因而減少活體内一氧化氮量。 [(MGD)2/Fe]處理對大鼠中内毒素症之平均動脈壓之影響示於圖1。當大鼠以致死劑量之LPS處理時，平均動脈壓隨時間逐漸降低並在2小時後達7 5 m m H g。於對照組中，當動物以食鹽水灌注時，其平均動脈壓維持非常低；確實，實驗終了前16隻動物中有11雙死亡。另一方面，當LPS-處理之動物以[(MGD)2/Fe]灌注時，其平均動脈壓逐漸恢復至正常値，在實驗終了前16隻動物僅3隻死亡。因此，灌注[(MGD)2/Fe]不僅恢復血壓，亦會降低内毒素謗發之敗血休克大鼠之致死率。概言之，[(MGD)2/Fe]爲潛在可用以治療因一氧化氮異常升高量引起之全身性低血壓（血壓極降）；該病況伴隨有許多發炎及感染性疾病。此外，動物注射達其體重之1 %量後仍存活而無明顯副作用顯示[(MGD)2/Fe]爲安全者（Lai及 Komarov，同上）〇實例3 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) 如前所述（參見 Komarov及 Lai之 Biochim. Biophys. Acta 1272 ; 29-36(1995))，皮下投與[(MGD)2/Fe]複合物降低 LPS-處理之小鼠活體内之·ΝΟ量。由於過量之·ΝΟ產生已知可謗發全身性低血壓，因此注射可降低活體内·Ν0量之[(MGD)2/Fe]複合物亦可恢復因LPS處理所謗發之低血壓動物之血壓。爲了測試此概念，進行實驗以測定投與 -45- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 516957 A7 B7 五、發明説明（46 ) (4) 同時灌注[(MGDh/FeK 〇· 1毫莫耳/公斤/小時）及抗·tnf (7.5晕克/公斤/小時）3小時，接著食鹽水灌注3小時。 (5) [(MGDh/Fe](在5比1之比例>〇 j毫莫耳/公斤/小時灌注 3小時接著以抗_TNF(7·5毫克/公斤/小時）灌注3小時。灌注完畢時，使大鼠回至其蘢子供觀察。比較由該等各種處理產生之2 4 -小時殘活率。由於使用致死劑量之Lp s ’因此預期對照組1中所有動物在2 4小時内將死亡。基於圖1 (實例2 )所提出之結果，預期處理組（即以[(MGD)2/Fe]處理之組3)在24小時後約2/3之大鼠將存活。如上所討論，於内毒素症中，TNF製造爲短暫存活且高峰在J _2小時。因此，如组3所示之以L P S挑戰2小時後灌注抗_ τNF抗體無法阻斷可謗發一氧化氮合成酶基因之謗發，其導致 iNOS產生，導致一氧化氮過度產生。於組4中，共同灌注抗-TNF抗體及[(MGD)2/Fe]預期可產生如組2之僅使用 [(MGDh/Fe]灌注之類似殘活率。另一方面，預期灌注 [(MGDh/Fe] 3小時接著灌注抗_TNF抗體（如組5所處理）將比組2具改良之殘活率，係由於在後來小時内灌注抗_ 抗體將抑制可謗發NO合成酶基因之進一步活化，因而減少過量NO產生之增進。經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) [(MGD^Fe]及其他治療劑（如抗内毒素抗體，其他抗-細胞素抗體’抗-細胞素受體抗體及其他藥劑，如抗緩激肽胜肽，一氧化氮合成酶抑制劑等）之組合治療效果可藉本文所述之類似方式證明。實例5 -49- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 516957 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（47 ) 在大鼠中急性心臟異體移植排斥期間NO製造會增加，如由進行期間及排斥時升高之尿及血漿硝酸鹽/亞硝酸鹽量增加可看出（例如參見Winlaw等人之Transplantati〇n 1〇31(1"4))。異常升高量之No似乎係由活化浸潤宿主巨噬細胞及排斥異體移植之心臟肌細胞所產生（例如參見 Yang等人之J· Clin· Invest· 94:714-721(1994))。環孢子素係廣泛使用作爲免疫抑制劑以避免異體移植排斥’主要係經由T細胞活化之抑制作用。但使用環孢子素伴隨有多發性副作用，例如腎毒性，肝毒性及高血壓（參見例如 Atkinson等人之Transplantation 38:34(1984))。進行實驗以評估本組合治療對預防大鼠之心臟異體移植排斥（使用低劑量之環孢子素及MGD/Fe)之效果，器官損贈者爲重約160至3 00克之雄性威士達-富舒（wf)系大鼠。器官接受者爲重約210至340克之雄性路易士（Lew)系大鼠。路易士大鼠經歷同種（即Lew-Lew)或異種（即WF-Lew)異型心臟移植至腹至動脈及腔靜脈，係以標準微血管手術技術使用戊巴必妥鈉麻醉（5 0毫克/公斤）進行。所有心臟移植均觀察到具有良好收縮功能且手術完成後無早期死亡。每日兩次經由腹壁觸診追腙移植功能。異體移植排斥定義爲可觸知之收縮活性喪失且藉開腹術直接視診而確認。藉由將MGD溶於蒸餾水且接著添加適宜量之Fes〇4水溶液以產生具MGD/Fe莫耳比例爲約1〇 ·· 1之溶液而每日製備新鮮之MGD/Fe複合物。製備足量體積之MGD/Fe溶液以進行皮下注射。製備環孢子素A(CsA，Sandoz醫藥公司）於市售 -50- (請先閱讀背面之注意事項再填寫本頁)516957 A7 B7___ 5. Description of the Invention (41) The ingredients have their unique therapeutic characteristics, so the physician determines the response of the target to the treatment and changes the dosage accordingly. Generally, the typical dosage of nitric oxide remover is in the range of about 10 micrograms to about 100 milligrams per kilogram of body weight, preferably about 50 micrograms to 10 milligrams per kilogram of body weight and can be administered up to 4 times per day. The IV dose per day ranges from about 1 microgram to about 100 milligrams per kilogram of body weight, and preferably ranges from 10 micrograms to 10 milligrams per kilogram of body weight. Generally, the dosage of the nitric oxide remover used in one practice of the present invention falls in the range of about 0.01 millimolar / kg of target body weight / hour to about 0.5 millimolar / kg / hour. The invention will now be described in more detail with reference to the following non-limiting examples. Example 1 Wright rats (male, 230-300 g) were supplied by Simonson Laboratories (Gilroy, CA). Lipopolysaccharide (LPS; S. typhosa, endotoxin) was obtained from Sigma (St. Louis, MO). Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page). N-methylglucamine and carbon disulfide were obtained from Aldrich (Milwaukee, WI). N-methyl-D-glucosamine dithiocarbamate (MGD) was synthesized by the method of Shinobu et al. (Acta Pharmacol. Toxicol. 54: 189-194 (1984)) Example 2 As previously described ( See Lai and Komarov in FEBS Lett. 345: 120-124 (I994)), a [(MGD2 / Fe] complex is bound to a molecule of nitric oxide to form a [(MGD) 2 / Fe-NO] complex. Although one of the free nitrogen oxides is strong-44- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 516957 A7 B7 V. Description of the invention (42) of angiotensin, but it is bound to [(MGD) 2 / Fe] is not nitric oxide. The resulting complex is then excreted from the body in the urine, thereby reducing the amount of nitric oxide in the living body. [(MGD) 2 / Fe] treatment averages endotoxin in rats The effect of arterial pressure is shown in Figure 1. When rats were treated with a lethal dose of LPS, the mean arterial pressure gradually decreased with time and reached 75 mm H g after 2 hours. In the control group, when the animals were perfused with saline At that time, the mean arterial pressure remained very low; indeed, 11 of the first 16 animals died at the end of the experiment. On the other hand, when LPS-treated When [(MGD) 2 / Fe] was perfused, the average arterial pressure gradually returned to normal, and only 3 of the 16 animals died before the end of the experiment. Therefore, perfusion [(MGD) 2 / Fe] not only restored blood pressure, It will also reduce the fatality rate of septic shock rats with endotoxin slurries. In summary, [(MGD) 2 / Fe] is potentially useful for treating systemic hypotension (blood pressure caused by abnormally elevated amounts of nitric oxide). This condition is accompanied by many inflammatory and infectious diseases. In addition, animals survived to 1% of their body weight without significant side effects, showing that [(MGD) 2 / Fe] is safe (Lai and Komarov, Same as above. Example 3 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) as described above (see Biochim. Biophys. Acta 1272 by Komarov and Lai; 29-36 (1995 )), Subcutaneous administration of [(MGD) 2 / Fe] complex reduces the amount of NO in vivo in LPS-treated mice. Injections can reduce systemic hypotension due to excessive amounts of NO, which are known to provoke systemic hypotension [(MGD) 2 / Fe] complex in the amount of N0 in vivo can also restore hypotension due to LPS treatment Blood pressure in animals. In order to test this concept, experiments were performed to determine the dosing. -45- This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) 516957 A7 B7 V. Description of the invention (46) (4) Simultaneously Perfusion [(MGDh / FeK 0.1 mmol / kg / hr) and anti-tnf (7.5 hag / kg / hr) for 3 hours, followed by saline perfusion for 3 hours. (5) [(MGDh / Fe] (at a ratio of 5 to 1)> 0j millimoles / kg / hour perfusion for 3 hours followed by anti-TNF (7.5 mg / kg / hour) perfusion for 3 hours. Perfusion When finished, return the rats to their mules for observation. Compare the 24-hour residual survival rate produced by these various treatments. Since the lethal dose of Lp s' is used, all animals in control group 1 are expected to be within 24 hours Will die. Based on the results presented in Figure 1 (Example 2), it is expected that about 2/3 of the rats in the treatment group (ie, group 3 treated with [(MGD) 2 / Fe]) will survive 24 hours later. As mentioned above In discussion, in endotoxin, TNF is made to survive for a short time and its peak is at J_2 hours. Therefore, as shown in Group 3, challenge with LPS for 2 hours after perfusion of anti-τNF antibody fails to block the liberation of nitric oxide synthase Gene blaming, which results in iNOS production and excessive nitric oxide production. In group 4, co-perfusion of anti-TNF antibodies and [(MGD) 2 / Fe] is expected to produce as in group 2 using only [(MGDh / Fe] perfusion has similar residual survival rate. On the other hand, it is expected that perfusion with [(MGDh / Fe] for 3 hours followed by perfusion with anti-TNF antibody (as treated in group 5) will be more effective than group 2. The residual survival rate is because the injection of anti-antibodies in the following hours will inhibit the further activation of the NO synthase gene, thereby reducing the increase in excess NO production. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read first Note on the back, please fill out this page) [(MGD ^ Fe] and other therapeutic agents (such as anti-endotoxin antibodies, other anti-cytokine antibodies' anti-cytokine receptor antibodies and other agents, such as anti-bradykinin) Peptides, nitric oxide synthase inhibitors, etc.) can be proven in a similar way as described herein. Example 5 -49- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 516957 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (47) NO production will increase during acute heart allograft rejection in rats, such as increased urine and plasma nitrate / nitrite nitrite during and during rejection. An increase in the amount of salt can be seen (see, for example, Transplantati 0n 1031 (1 " 4) of Winlaw et al.). The abnormally elevated amount of No appears to be activated by infiltration of host macrophages and rejection of foreign bodies Produced by implanted cardiac muscle cells (see, for example, J. Clin. Invest. 94: 714-721 (1994) of Yang et al.). Cyclosporine is widely used as an immunosuppressant to avoid rejection of allografts. Inhibition of cell activation. However, the use of cyclosporine is accompanied by multiple side effects such as nephrotoxicity, hepatotoxicity, and hypertension (see, eg, Transplantation 38:34 (1984) by Atkinson et al.). Experiments were performed to evaluate the effectiveness of this combination therapy in preventing rejection of heart allografts in rats (using low doses of cyclosporine and MGD / Fe). The organ donor was a male Vistar-Fo weighing approximately 160 to 300 grams. Shu (wf) is a rat. Organ recipients were male rats of the Lew line weighing approximately 210 to 340 grams. Lewis rats undergo allogeneic (ie Lew-Lew) or heterogeneous (ie WF-Lew) heterotypic heart transplantation to the abdominal to arteries and vena cava, and are anesthetized with sodium pentobarbital (50 mg / kg) using standard microvascular surgery techniques )get on. All heart transplants were observed to have good contractile function and no early death after surgery. Twice a day, the transplant function was followed by palpation of the abdominal wall. Allograft rejection is defined as palpable loss of contractile activity and is confirmed by direct inspection of the laparotomy. Fresh MGD / Fe composites are prepared daily by dissolving MGD in distilled water and then adding a suitable amount of Fes04 aqueous solution to produce a solution with a MGD / Fe mole ratio of about 10 ·· 1. A sufficient volume of the MGD / Fe solution was prepared for subcutaneous injection. Preparation of Cyclosporin A (CsA, Sandoz Pharmaceutical Co., Ltd.) is commercially available -50- (Please read the precautions on the back before filling in this page)

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本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 516957 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（49) 所有研究組中，移植後第7天體重降低8 -1 4 %，但所有組中，在第7天後體重回復，顯示研究期間體重最初降低係由於大鼠手術之影響，而非大鼠接受結果。未接受處理之同種移植對照組，與各種處理組相較，顯現類似之體重傾向。在接受本發明組合治療之組別中觀察到體重增加似乎爲研究中增加存活之結果，其是由於改良之移植存活。本文報導之移植存活係以天數之平均存活時間（MST 士 SE) 表示（見表3)。 -52- 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)This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 516957 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (49) In all the research groups, weight loss on the 7th day after transplantation 8 -14%, but in all groups, body weight recovered after day 7, indicating that the initial weight loss during the study was due to the effects of rat surgery, not the rats receiving results. The untreated allograft control group showed similar weight trends compared to the various treatment groups. Observation of weight gain in the group receiving the combination treatment of the present invention appeared to be the result of increased survival in the study due to improved transplant survival. The graft survival reported in this article is expressed as the average survival time in days (MST ± SE) (see Table 3). -52- This paper size applies to Chinese National Standard (CNS) A4 (210X 297mm) (Please read the precautions on the back before filling this page)

516957 A7516957 A7

7 B 五、發明説明（50 ) 表3 經濟部中央標準局員工消費合作社印製組別捐贈者接受者 n 處理移植存活天數 (n)+ MSP 土 SEM，天 1 LEW LEW 5 無 >100(5) ΝΑ 2 WF LEW 17 無 6.5(11)，7.0(1)， 7.5(3)，8.0(1)， 8.5(1) 6·9±0·2 3 WF LEW 16 MGD-Fe， 400mg/kg sc bid，直至排斥作用 9.5(1)，10.0(2)， 10.5(2)，11.0(1)， 11.5(3)，12.5(2)， 13.0(2)，13.5(2)， 14.0(1) 11·8±0·4 4 WF LEW 17 CsA, 2.5 mg/kgim 每曰X7天 11.0(11)，11.5(3)， 12.0(2)，12.5(5)， 13.0(2)，19.5(1)， 22.0(1)，23.0(1)， 24.0(1) 14·5 土 1.1 5 WF LEW 11 CsA，2·5 mg/kg im 每日X 7天加上 MGD-Fe，400 mg/kg sc bid 每日X30天 31.0(1)，32.5(2)， 37.0(1，，38.0(1)， 57.0(1)，44.5(1)， 42.0(1)，86.0(1)， 51.5(1)，43.0(1) 45·0±4·7 +(n)=大鼠數 1MST)=平均存活時間（天） * 移植至功能化 * *由於心旁膿腫而犧牲，移植功能化在未處理對照組中第6.9 ±0.2天發生急性異體移植排斥。以MGD-Fe或CsA單獨單次藥物治療，與未處理之異體移植 -53- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）丨.丨./I丨%、玎# (請先閲讀背面之注意事項再填寫本頁) 516957 需經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（51 相較，明顯地延長異體移植存活（分別爲n 8土〇 4及14 5士 1.1天）。但本發明之組合藥物治療導致戲劇性之移植存活延長性（即45·0±4·7天）。 MGD-Fe治療在移植後第3 〇天中斷以測定是否可達到盔限存活（即>100天）。在接受本發明組合治療之組別中所有 11隻大鼠中移植功能持續超過3〇天（參見表3)。此組中之一隻大鼠具有超過50天之功能性異體移植接著停止組合= 療。治療期間所有動物均呈健康態且無死亡。、口〜综言之，一氧化氮量之調節作用，特別是與次治心標準免疫抑制劑組合時，導致細菌性地延長異體里活。 7値辱雖然本發明已參考其某些較佳具體例更詳細説了解修飾及變化均在本發明之精神及範園内。仁 -54 本紙張尺度適用中關家標準（CNS ) Α1ϋ_(训幻97公楚） (請先閱讀背面之注意事項再填寫本頁)7 B V. Description of the invention (50) Table 3 Printed Group Donor Recipients of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs n Number of days for transplantation survival (n) + MSP soil SEM, day 1 LEW LEW 5 None > 100 ( 5) ΝΑ 2 WF LEW 17 None 6.5 (11), 7.0 (1), 7.5 (3), 8.0 (1), 8.5 (1) 6 · 9 ± 0 · 2 3 WF LEW 16 MGD-Fe, 400mg / kg sc bid, until rejection 9.5 (1), 10.0 (2), 10.5 (2), 11.0 (1), 11.5 (3), 12.5 (2), 13.0 (2), 13.5 (2), 14.0 (1) 11 · 8 ± 0 · 4 4 WF LEW 17 CsA, 2.5 mg / kgim X7 days per day 11.0 (11), 11.5 (3), 12.0 (2), 12.5 (5), 13.0 (2), 19.5 (1) , 22.0 (1), 23.0 (1), 24.0 (1) 14.5 soil 1.1 5 WF LEW 11 CsA, 2.5 mg / kg im daily X 7 days plus MGD-Fe, 400 mg / kg sc bid Daily X30 days 31.0 (1), 32.5 (2), 37.0 (1 ,, 38.0 (1), 57.0 (1), 44.5 (1), 42.0 (1), 86.0 (1), 51.5 (1), 43.0 (1) 45 · 0 ± 4 · 7 + (n) = number of rats 1MST) = mean survival time (days) * transplantation to functionalization * * sacrificed due to paracardial abscess, functionalization of transplantation in untreated control group Acute allograft rejection occurred on day 6.9 ± 0.2. Take MGD-Fe or CsA alone for a single drug treatment and untreated allograft -53- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 丨. 丨 ./I 丨% 、玎 # (Please read the precautions on the back before filling this page) 516957 A7 B7 printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (51 Compared with that, it significantly prolongs the survival of allogeneic transplants (n 8 and 0 4 respectively) And 14 5 ± 1.1 days). However, the combination drug treatment of the present invention resulted in dramatic prolonged graft survival (ie 45.0 ± 4 · 7 days). MGD-Fe treatment was discontinued at 30 days after transplantation to determine if it was possible Reached helmet limit survival (i.e.,> 100 days). Transplantation function persisted for more than 30 days in all 11 rats in the group receiving the combination treatment of the present invention (see Table 3). One rat in this group had Functional allogeneic transplantation over 50 days and then stop combination = therapy. All animals were healthy and did not die during the treatment period. In summary, the regulating effect of the amount of nitric oxide, especially the immunosuppression with the secondary treatment standard Combination of agents Prolonged allogeneic activity by bacteria. 7 Disgrace Although the present invention has been referred to some of its preferred specific examples to understand in more detail that modifications and changes are within the spirit and scope of the present invention. Ren-54 This paper is applicable to Zhongguanjia Standard (CNS) Α1ϋ_ (Xunyu 97 Gongchu) (Please read the precautions on the back before filling this page)

Claims

A BCD 516957 ^ 弟〇851142〇7號專利申請案申請專利範圍修正本（91年1〇月）六、申請專利範圍 1 · 種用於⑻降低一氧化氮濃度或(b)去活化或抑制可謗發一氧化氮酶表現之物種形成之組合物，其包含一氧化氮去除劑與可去活化或抑制謗發一氧化氮酶表現之物種形成之藥劑之組合於醫藥上可接受之載劑，其中該物種係選自細胞素，細胞素受體，内毒素，血小板活化因子，緩激肽，緩激肽受體，細菌，凝聚因子，花生四埽酸酯代謝物或一氧化氮合成酶。 2·根據申請專利範圍第1項之組合物，其中該一氧化氮去除劑為具有結構（I)之化合物’其中該具結構（I)之化合物如下： [R^N.CCS)^-]^^3 (I) 其中：各1^及R2分別選自（^至c18燒基，經取代之垸基，環燒基，經取代環烷基，雜環基，經取代雜環基，晞基，經取代烯基，炔基，經取代炔基，芳基，經取代芳基，雜芳基，經取代雜芳基，烷芳基，經取代燒芳基’芳燒基，經取代芳垸基，或1^與r2 可合而形成包含N，1^及112之5-，6-或7-員環， X為1或2，及當X為1時，Μ為單價陽離子或當X為2時Μ為生理可相容之二價或三價過渡金屬陽離子。 3. 根據申請專利範圍第2項之組合物，其中Μ係選自Η+， Na+，ΝΗ4+或四烷銨。 4. 根據申請專利範圍第2項之組合物，其中Μ係選自Fe+2，本纸張尺度適用中國國家標準(CNS)A4規格(210 x297公釐)A BCD 516957 ^ Brother No. 0851142〇7 Patent Application Amendment of Patent Scope (October 91) 6. Application for Patent Scope 1 · It is used to reduce nitric oxide concentration or (b) deactivation or inhibition can be A composition forming a speculative manifestation of nitric oxide enzyme comprising a combination of a nitric oxide remover and an agent which can deactivate or inhibit the formation of a speculative manifestation of nitric oxide enzyme in a pharmaceutically acceptable carrier, The species is selected from cytokine, cytokine receptor, endotoxin, platelet activating factor, bradykinin, bradykinin receptor, bacteria, coagulation factor, arachidate metabolite or nitric oxide synthase. 2. The composition according to item 1 of the scope of patent application, wherein the nitric oxide removing agent is a compound having the structure (I) 'wherein the compound having the structure (I) is as follows: [R ^ N.CCS) ^-] ^^ 3 (I) where: 1 and R2 are each selected from (^ to c18 alkyl, substituted amidino, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, 晞, Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted aryl ', aryl, substituted aryl Fluorenyl, or 1 ^ and r2 can be combined to form a 5-, 6- or 7-membered ring containing N, 1 ^ and 112, X is 1 or 2, and when X is 1, M is a monovalent cation or when When X is 2, M is a physiologically compatible divalent or trivalent transition metal cation. 3. The composition according to item 2 of the scope of patent application, wherein M is selected from the group consisting of ++, Na +, NΗ4 + or tetraalkylammonium. 4 The composition according to item 2 of the scope of patent application, where M is selected from Fe + 2, and the paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm)

、申請專利範圍 Fe+3，Co+2，Co+3，Cu+2，Mn+2或 Mn+3。 5·根據申請專利範圍第2項之組合物，其中過渡金屬離子對二硫代胺基甲酸酯部份之比例在〇至約1 : 2之範圍。 6·根據申請專利範圍第2項之組合物，其中：各111及112==<：1至（：12烷基，經取代烷基，烯基，經取代婦基，炔基或經取代炔基，其中取代基係選自羧基，-C(0)H，氧醯基，g分，苯氧基，ρ比症基，外匕咯啶基，胺基，醯胺基，羥基，硝基或硫醯基，及 M=Fe+2或 Fe+3。 7·根據申請專利範圍第2項之組合物，其中：尺广心至心烷基或經取代烷基，其中取代基係選自羧基，乙酿基，说淀基，批洛淀基，胺基，醯胺基，羥基或硝基， R2係選自Ci至C6烷基或經取代烷基，或r2可與Ri合而形成包含N，及之5-，6-或7-員環，及 M = Fe+2。 8. 根據申請專利範圍第2項之組合物，其中： 1^=(：2至(：8烷基或經取代烷基，其中取代基係選自羧基，乙醯基，醯胺基或羥基，尺^心至匕烷基或經取代烷基，及 M = Fe+2。 9. 根據申請專利範圍第2項之組合物，其中該藥劑係選自抗-内毒素劑，細胞素合成/釋出抑制劑，抗-細胞素劑， -2- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) A8 B8 C8Scope of patent application: Fe + 3, Co + 2, Co + 3, Cu + 2, Mn + 2 or Mn + 3. 5. The composition according to item 2 of the patent application range, wherein the ratio of the transition metal ion to the dithiocarbamate moiety is in the range of 0 to about 1: 2. 6. The composition according to item 2 of the scope of patent application, wherein: each of 111 and 112 == <: 1 to (: 12 alkyl, substituted alkyl, alkenyl, substituted amidyl, alkynyl or substituted Alkynyl, wherein the substituent is selected from the group consisting of carboxyl, -C (0) H, oxyfluorenyl, g, phenoxy, rhozoyl, exopyridinyl, amine, amido, hydroxyl, nitrate Group or thiosulfanyl group, and M = Fe + 2 or Fe + 3. 7. The composition according to item 2 of the scope of the application for patent, wherein: Chi Guangxin to heart alkyl or substituted alkyl, wherein the substituent is selected From carboxyl, ethyl, ethyl, ethyl, amine, amine, hydroxy, or nitro, R2 is selected from Ci to C6 alkyl or substituted alkyl, or r2 can be combined with Ri Form a 5-, 6-, or 7-membered ring containing N, and M = Fe + 2. 8. The composition according to item 2 of the scope of patent application, wherein: 1 ^ = (: 2 to (: 8 alkane) Or substituted alkyl, wherein the substituent is selected from the group consisting of carboxyl, ethyl, amido, or hydroxy, from alkyl to substituted or substituted alkyl, and M = Fe + 2. 9. According to the patent application The composition of the second item, wherein the agent is selected Anti - endotoxin agent, cytokine synthesis / release inhibitors, anti - cytokine agents, -2-scale paper suitable for the present Chinese National Standard (CNS) A4 size (210 X 297 mm) A8 B8 C8

516957 凝聚級聯抑_，互補活化作用抑_，血小板活化因子抑制劑，花生四烯酸酯代謝物抑制劑，一氧化氮合成酶酵素抑制劑’免疫抑制劑’糖尿病治療劑，發炎^病治療劑或柯隆氏疾病治療劑，抗-細胞素抗體，抗_細胞素受體抗體，抗-内毒素抗體，緩激肽拮抗劑，合成胜肽阻斷缓激肽受體，殺菌/滲透性増加蛋白質，對血小板活化因子之抗體，或治療眼疾病之治療劑。 10·根據申請專利範圍第9項之组合物，其%該抗内毒素劑係選自對内毒素之抗體，對LPS_結合蛋白質之抗體，可命CD 14蛋白質，殺菌/滲透性增加蛋白質或多枯菌素B。 11. 根據中請專利範圍第9項之组合物，其中該細胞素合成/ 釋出抑制劑係選自磷醯二酯酶抑制劑，IL_4，il_i〇，化_ 13，TGF-沒，阿斯匹靈，苯基丁基硝酸靈或皮質崔醇。 12. 根據中請專利範圍第9項之组合物，其中該抗細胞素劑係選= TNF抗體，可溶TNF受體，受體拮抗劑，對 IL-1受體之抗體，對IL_6之抗體，對干擾素-丫之抗體或可溶干擾素受體。 13. 根據申请專利範圍第9項之組合物，其中該凝集級聯抑制劑係選自抗-因子ΧΙΙ抗體，對C5a之抗體，c卜酯酶抑制劑或可溶Cri。 14·根據中請專利範圍第9項之組合物，其中該血小板活化因子抑制劑為PAF受體拮抗劑。 15·^據中請專利範圍第9項之組合物，其中該花生四缔酸酯代謝物抑制劑係選自環氧酶抑制劑，脂氧酶抑制劑，516957 Coagulation cascade inhibitory, complementary activation inhibitory inhibitor, platelet activating factor inhibitor, arachidonic acid metabolite inhibitor, nitric oxide synthase enzyme inhibitor 'immunosuppressant' diabetes treatment, inflammation treatment Agent or therapeutic agent for Cologne's disease, anti-cytokine antibody, anti-cytokine receptor antibody, anti-endotoxin antibody, bradykinin antagonist, synthetic peptide blocking bradykinin receptor, bactericidal / permeability Add protein, antibodies to platelet activating factors, or therapeutic agents for treating eye diseases. 10. The composition according to item 9 of the scope of the patent application, wherein the anti-endotoxin agent is selected from antibodies against endotoxin, antibodies against LPS-binding protein, CD 14 protein, bactericidal / permeability increasing protein, or Polybactin B. 11. The composition according to item 9 of the patent claim, wherein the cytokine synthesis / release inhibitor is selected from the group consisting of a phosphodiesterase inhibitor, IL_4, il_i〇, Hua_13, TGF-N, Aspen Piling, phenylbutyl nitrate or cortisol. 12. The composition according to item 9 of the patent claim, wherein the anti-cytokine agent is selected as TNF antibody, soluble TNF receptor, receptor antagonist, antibody to IL-1 receptor, and antibody to IL_6. , Interferon-A antibody or soluble interferon receptor. 13. The composition according to item 9 of the scope of patent application, wherein the agglutination cascade inhibitor is selected from the group consisting of an anti-factor XII antibody, an antibody to C5a, a c-esterase inhibitor or soluble Cri. 14. The composition according to item 9 of the patent application, wherein the platelet activating factor inhibitor is a PAF receptor antagonist. 15. The composition according to item 9 of the patent, wherein the arachidonic acid metabolite inhibitor is selected from the group consisting of a cyclooxygenase inhibitor, a lipoxygenase inhibitor,

% 訂 -3- 516957 A8 B8 C8 -一------ -£8 申請專利範圍白三烯抑制劑，凝血嘮烷&抑制劑或***素。 16·根據中請專利範圍第9項之組合物，其中該—氧化氮合成酶酵素抑制劑係選自N_甲基_L.精氨酸，ε養亞胺基L賴氨敗，胺基脈或^ _甲基異硫腿硫酸鹽。 Π.根據中请專利範圍第9項之組合物，其中該免疫抑制劑係選自環孢子素，0KT3，FK5〇6,胸球蛋白或霉紛酸。 18·根據申請專利範圍第9項之組合物，其中該糖尿病治療劑係選自游離胰島，包囊胰島，口服胰島素，靜脈内膜島素，澱粉經絡質激素。 19·根據申請專利範圍第9項之組合物，其中發炎疾病治療劑係選自硫噻畊（sulfasalazine)，美沙明加㈣丨咖丨㈣，皮質留醇，吖嘍平（azathioprine)，巯基嘌呤或滅滴靈 (metronidazole) 〇 20·根據申請專利範圍第9項之組合物，其中該發炎疾病治療劑為—風17比槽道阻斷劑 21.根據申請專利範圍第9項之組合物，其中該藥劑係選自 k -内母素劑’細胞素合成/釋出抑制劑，抗-細胞素劑，凝聚級聯抑制劑，互補活化作用抑制劑，血小板活化因子抑制劑，花生四烯酸酯代謝物抑制劑，一氧化氮合成酶酵素抑制劑，免疫抑制劑，糖尿病治療劑，發炎疾病治療劑或柯隆氏疾病治療劑’抗-細胞素抗體，抗-細胞素受體抗體’抗内毒素抗體’缓激肤拮抗劑，合成胜肽阻斷缓激肤受體’殺菌/滲透性增加蛋白質或對血小板活化因子之抗體。 -4 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 516957 ^ A8 B8 C8 — ______ _ D8 六、申請專利範圍 22·根據申請專利範圍第1項之組合物，其中該醫藥可接受載體係選自固體、溶液、乳液、分散液、微胞或微脂粒。 23.根據申請專利範圍第1項之組合物，其中該組合物又包括腸包衣膜。 24·根據申請專利範圍第9項之組合物，其中該眼疾病治療劑為局部皮質留醇，免疫抑制劑，抗生素，吖嘍平，滴液氣劑’人工淚液’局邵羅多醯胺（l〇d〇xamide)，乙峰α坐醯胺（acetazolamide) ’ 皮羅卡平（pii〇carpine)，替莫拉 (timolal) ’列伯班諾拉（levobunolal)，美替心得安 (metipranolol)，堅西羅必爾（ganeici〇vir)，發斯卡耐特 (fascarnet) ’ 甲基去氫潑尼松（methyiprednisolone)，去氫 /¾尼松’辱:戊托來特（CyCl〇pent〇late)，水楊酸酉旨，引多美砂辛（indomethacin)，苯丁膝（phenybutazone)或地沙美沙酮（dexamethazone)。 25.根據申請專利範圍第1項之組合物，係可用於治療上瘾、細胞素投藥、成人呼吸窘迫徵候群、aiDS、aids癡呆、異體移植排斥、阿茲海默氏疾病、肌萎縮性側索硬化、過敏性休克、焦慮、關節炎、氣喘、動脈硬化、自體免疫疾病、細菌移轉、灼傷、惡質病、癌症、心肺旁通、心血管疾病、腦溢血、慢性疲勞徵候群、慢性疾病、循環休克、肝硬化、C N S損傷、克隆氏疾病、囊纖維變性、抑鬱、皮膚炎、糖尿病、藥物誘發之肺損傷、渔療、細脊fe炎、癲癎、增進生育力、胃炎、胃腸螺動 -5- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 516957 A8 B8 C8 广 —_____ D8 六、申請專利範圍障礙、血管球形胃炎、移植對宿主疾病、頭損傷、聽力喪失、心疾病、心臟衣竭、血癌、血液滲析、出血性休克、肝炎、亨丁頓氏症、攝食過度、迴腸炎、腸疫塞、感染、發炎、發炎性腸疾病、絕血、絕血/再灌注損傷、肝疾病、肝發炎、肺損傷、淋巴球性脈絡叢腦膜炎、癔疾、腦膜炎、偏頭痛、多發性硬化症、骨髓纖維變性、心肌梗塞、心肌炎、神經退化障礙、肥胖症、器官保存、細胞素過度表現、眼疾病、胰炎、帕金森氏疾病、腹膜炎、異¥***、乾癬、胃衰竭、腎發炎、精神 ***症、敗血性休克、實心腫瘤、中風、全身性紅斑狼瘡、毒性休克徵候群、移植排斥及保存、外傷休克、癀瘍、結腸潰瘍、蓴麻療、葡萄膜炎、疫苗接種或脈；炎。 -6- 本紙張尺度適用中國国家標準(CNS) A4規格(21〇x 297公釐)% Order -3- 516957 A8 B8 C8 -A -------£ 8 Patent application scope Leukotriene inhibitor, thromboxane & inhibitor or prostaglandin. 16. The composition according to item 9 of the patent claim, wherein the nitric oxide synthase enzyme inhibitor is selected from N_methyl_L. Arginine, ε-imino group L lysine, amine group Vein or ^ _ methyl isosulfide leg sulfate. Π. The composition according to item 9 of the patent application, wherein the immunosuppressive agent is selected from the group consisting of cyclosporin, 0KT3, FK506, thymosin, or mycolic acid. 18. The composition according to item 9 of the scope of the patent application, wherein the diabetes treatment agent is selected from the group consisting of free islets, cystic islets, oral insulin, intravenous insulin, and starch meridian hormone. 19. The composition according to item 9 of the scope of the patent application, wherein the agent for treating an inflammatory disease is selected from the group consisting of sulfasalazine, methasamine, coffee, cortisol, azathioprine, and mercaptopurine Or metronidazole 〇20. The composition according to item 9 of the scope of the patent application, wherein the therapeutic agent for inflammatory diseases is -wind 17 ratio channel blocker 21. The composition according to item 9 of the scope of patent application, Wherein the agent is selected from the group consisting of k-endogens' cytokine synthesis / release inhibitors, anti-cytokine agents, aggregation cascade inhibitors, complementary activation inhibitors, platelet activation factor inhibitors, arachidonic acid Ester metabolite inhibitors, nitric oxide synthase enzyme inhibitors, immunosuppressants, therapeutic agents for diabetes, therapeutic agents for inflammatory diseases or therapeutic agents for Cologne's 'anti-cytokine antibodies, anti-cytokine receptor antibodies' anti Endotoxin antibody 'bradystimulant antagonist, synthetic peptide blocking bradykinin receptor' bactericidal / permeability increase protein or antibody to platelet activating factor. -4-This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 516957 ^ A8 B8 C8 — ______ _ D8 VI. Scope of patent application 22. The composition according to item 1 of the scope of patent application, in which the medicine Acceptable carriers are selected from the group consisting of solids, solutions, emulsions, dispersions, micelles, or liposomes. 23. The composition according to item 1 of the patent application scope, wherein the composition further comprises an enteric coating film. 24. The composition according to item 9 of the scope of the patent application, wherein the eye disease treatment agent is topical cortisol, an immunosuppressant, an antibiotic, acridine, a liquid drop agent 'artificial tears', and sulopolamine ( lOdOxamide), acetazolamide, piocarpine, timolal, levobunolal, metipranolol , Ganeicivir, fascarnet 'methyiprednisolone, dehydrogenation / ¾nisone' humiliation: Cyclopentol late), salicylic acid, indomethacin, phenybutazone or dexamethazone. 25. The composition according to item 1 of the scope of patent application, which can be used for the treatment of addiction, cytokine administration, adult respiratory distress syndrome, aiDS, aids dementia, allograft rejection, Alzheimer's disease, amyotrophic lateral cord Sclerosis, anaphylactic shock, anxiety, arthritis, asthma, arteriosclerosis, autoimmune disease, bacterial migration, burns, malignant disease, cancer, cardiopulmonary bypass, cardiovascular disease, cerebral hemorrhage, chronic fatigue syndrome, chronic disease , Circulatory shock, cirrhosis, CNS injury, Crohn's disease, cystic fibrosis, depression, dermatitis, diabetes, drug-induced lung injury, fishing therapy, spinal cord inflammation, epilepsy, fertility enhancement, gastritis, gastrointestinal spiral -5- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 516957 A8 B8 C8 Guang — _____ D8 VI. Patent application disorder, vascular spheritis, transplantation to host disease, head injury, hearing loss , Heart disease, heart failure, blood cancer, hemodialysis, hemorrhagic shock, hepatitis, Huntington's disease, overeating, ileitis, and enterococcus , Infection, inflammation, inflammatory bowel disease, hemostasis, hemorrhage / reperfusion injury, liver disease, liver inflammation, lung injury, lymphocytic choroid plexus meningitis, dysentery, meningitis, migraine, multiple sclerosis , Bone marrow fibrosis, myocardial infarction, myocarditis, neurodegenerative disorder, obesity, organ preservation, cytokine overexpression, eye disease, pancreatitis, Parkinson's disease, peritonitis, isoerectomy, psoriasis, stomach failure, kidney inflammation, Schizophrenia, septic shock, solid tumors, stroke, systemic lupus erythematosus, toxic shock syndrome, transplant rejection and preservation, traumatic shock, ulcers, colon ulcers, ramie therapy, uveitis, vaccination or pulse; inflammation. -6- This paper size applies to China National Standard (CNS) A4 (21 × 297 mm)