TWI291872B

TWI291872B - Compositions including modafinil for treatment of attention deficit hyperactivity disorder and multiple sclerosis fatigue

Info

Publication number: TWI291872B
Application number: TW89116415A
Authority: TW
Inventors: S Miller Matthew; E Scammell Thomas
Original assignee: Cephalon Inc
Priority date: 1999-08-16
Filing date: 2000-08-15
Publication date: 2008-01-01
Also published as: ZA200200807B; AR031525A1; MY126607A

Description

1291872 A7 B7 五、發明說明（l ) 發明背景 1·發明領域本發明是有關於神經藥理作用劑的領域，包括有效於治療注意力不集中的過度反應症及多發性硬化相關的疲勞之作用劑。 2·相關技藝之說明注意力不集中/過度反應症（ADHD)是一種孩童中的慢性神經精神病症狀，其特徵在於發育性不適當的過度反應、衝動以及不注意。估計ADHD影響的學齡孩童。在歷史上，ADHD被認爲不會持續到青春期之後；然而，目前的硏究顯示，在10%到60%發生於幼年時期的例子中，ADHD可持續至成年期。ADHD的持續是與學業及職業上的官能障礙之高發生率，以及與精神病的共同發病 (例如，行爲、主要的抑鬱以及焦慮症）之高發生率有關。據估計大約1%到3%的成年人具有ADHD的症候群。患有ADHD的成年人，具有人口統計學的、心裡社會學的、精神病學的以及認知上的特徵之類型，其反映了在患有此症狀的孩童中所妥善記載之發現。這更支持成年人診斷的正當性。在成年人中，核心的ADHD症候群包括經常性或持續性的不注意/分心及/或過度反應-衝動之類型。在 ADHD成年人中所表現出之最常見的症候群，是明顯的不注意、不專心、容易分心、作白日夢、健忘以及活動力的經常轉移。也有報導指出，ADHD成年人具有明顯的衝動 3 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) 0. 經濟部智慧財產局員工消費合作社印製 mb n n H 一》0、· n n ϋ n ϋ ϋ n I n n n ϋ n ϋ ϋ n n 1291872 A7 B7 五、發明說明（，）、侵入性（intrusiveness)、低的挫折/壓力耐受性、易發怒的脾氣、易怒以及相當的不耐煩。在成年人中，較不常被報導的症候群包括過度反應，其可侷限於煩躁不安，或緊張不安或心神不定的內心感覺。除了核心的ADHD症候群之外，患有ADHD的成年人通常顯示相關的臨床特徵，例如厭倦、社會的不適應以及在社會環境中的慢性衝突。這些特徵可能反映：（1)分居及離婚；以及（2)儘管具有適當的智力能力，但仍然存在有不佳的學業表現及職業成就之高發生率。此外，患有ADHD的成年人，具有高的物質濫用症狀之發生率。雖然ADHD的發病原因仍是不淸楚的，但多巴胺（ dopaminergic)及正腎上腺（noradrenergic)的功能之改變，似乎是此疾病的神經化學基礎。在患有ADHD的成年人之腦部陽電子發散的X光斷層攝影中，已顯示大腦皮層區域中葡萄糖代謝的改變，其中，此區域是牽涉到注意及運動的能力，像是額葉（frontal lobe)。對於成年人及小兒科的ADHD之最常見的治療是刺激劑（例如，右旋安非它命（dextroamphetamine )、苯呢陡乙酸甲基酯（ methylphenidate)以及比瑪林（pemoline))。刺激劑被視爲藉由增加可在神經元突觸（synapses)中獲得的多巴胺的量而發生作用。刺激劑似乎在多個大腦結構上的位置執行這個工作。其他已使用的療法包括：抗抑鬱劑（例如，三環類的抗抑鬱劑，例如丙咪U秦（imipramine)及丙代n秦 (desipramine ):新穎的抗抑鬱劑，例如布普利昂（ 4 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 tr---------,·----------------------- 經濟部智慧財產局員工消費合作社印制衣 1291872 A7 ---—_____Β7_ 五、發明說明（3 ) buproorion)及泛拉法素（venlafaxine))、抗高血壓劑（例如，克龍陡（clonidine )及狐發素（guanfacine ))、單胺基氧化酶抑制劑（[MAO’s]，例如，賽拉林（selegiline ))、胺基酸（例如，左旋多巴、苯丙胺酸及L-酪胺酸）以及組合的藥學治療劑（例如，同時使用血淸素選擇性的再攝取抑制劑以及刺激劑藥物；或刺激劑及鄰苯二酚胺類的抗抑鬱劑療法）（Bhandary 等人，Psychiatric Annals 27 • 545-555，1997 ; Wilens 等人，J. Clin· Psychopharmacol. 15 : 270-279，1995 ; Finkel，The Neurologist 3 : 31-44， 1997 ; Miller 及 Catellanos，Pediatrics in Review 19 ·· 373-384，1998 ) 〇雖然刺激劑是最常使用的治療方法，但大約30%-50 %患有ADHD的成年人對於刺激劑沒有陽性的反應、會有不可接受的副作用或同時發生的抑鬱或焦慮症狀，此刺激性藥劑可使治療惡化或是在治療中變得無效。長期不利的效果以及它們在ADHD高危險物質濫用亞群上的使用，仍是未硏究的並且是關心的因此，仍有需要非刺激性的藥物治療，以用於注意力不集中過度反應症。對於非刺激性的藥物治療也有長期性需要的其他症狀，是與多發性硬化（MS)有關的疲勞。在美國，多發性硬化是年輕人最常見的失能神經性疾病之一，其中估計約 400,000人患有此疾病。雖然多發性硬化可造成各種失能神經性的損傷，例如，失明、癱瘓、共濟官能喪失（ incoordination)以及腸或膀胱官能障礙，但也會嚴重失會g 5 (請先閱讀背面之注意事項再填寫本頁) 職 an I n ϋ n n n 一：eJ n n n n n l 線丨ft 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 1291872 經濟部智慧財產局員工消費合作社印制衣 A7 B7 五、發明說明（γ) 之較不明顯的症狀是疲勞。在一項牽涉到656位患有多發性硬化病患的硏究中，78%抱怨有疲勞，60%每天感受到疲勞，以及22%受苦於他們每日活動力的中斷（Freal等人，Arch· Phys. Med· Rehabil· 65 : 135，1984)。國際多發性硬化學會評估839位病患，其雖然患有多發性硬化長達10以上，但是僅患有輕微的神經性損傷，在這些輕微影響的病患族群中，疲勞是最常被報導的症狀（Jones ’紐約 :國際多發性硬化學會，健康服務硏究報告’ 1991)。在另一項硏究中，40%的多發性硬化患者列出疲勞是他們的疾病之最嚴重的症狀（Murray ’ Can. J· Neurol· Sci· 12 · 251，1985 )。據報導，在多達75%患有多發性硬化的病患中，疲勞至少是臨時性失能的成因；並且，英國多發性硬化學會發現，疲勞是在這個族群中導致失業的最重要症狀（Rolak，Curr· Neurol. 9 : 109，1989)。在美國，與多發性硬化疲勞相關的失能之流行程度，是在社會安全管理局所發佈之指導方針下，藉由其納入爲失能津貼發放的標準而被強調。多發性硬化疲勞的機轉仍不是很淸楚的了解。它曾被歸因於中樞神經系統內的神經傳導異常，以及由神經性失能所引起之增加的能量需求之結果。多發性硬化疲勞的數種特徵，是每日生活的生理功能發揮及活動力相衝突，受熱而惡化，並且在一天結束時惡化（Kmpp等人，八1^11· Neurol·. 45 : 435，1988 )。爲了治療多發性硬化疲勞所開的處方藥劑包括胺基三環癸烷（amantadine)、比瑪林及 6 (請先閱讀背面之注意事項再填寫本真) • 了 ^ 0 i I n ϋ ϋ ϋ ϋ ^ J · ϋ 1 n ϋ n ί I H ϋ n n ϋ ϋ ϋ n n n n n n an n an n n ϋ «I ϋ 1 n 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 1291872 A7 B7 五、發明說明（<) 其他的刺激劑。在雙盲、隨機的硏究中已證實，胺基三環癸烷在79%的患者中，對於多發性硬化疲勞是有益的，但其有益的作用機轉仍不淸楚（Krupp等人，Neurology 45 : 1956, 1995 )。雖然胺基三環癸烷已以精確的方式證實有益於多發性硬化疲勞，但這個益處對大多數病患而言，只是部份而已，並且仍有非常多的病患說沒有獲益。對於通常用於治療多發性硬化疲勞之比瑪林所進行的相同硏究，並沒有顯示有益的效果，因此，對於這種失能症狀之安全且有效的治療，仍有其強烈的需求。發明槪述本發明提供一種莫塔夫尼（modafinil)之新穎用途，以治療注意力不集中過度反應症（ADHD)以及改善由於多發性硬化（MS)而引起的疲勞症狀。形成本揭露之基礎的硏究意外地證明，將促進淸醒（ wake-promoting)劑量的莫塔夫尼給藥至大鼠，導致後卞視丘的管乳突狀核（TMN)之選擇性的增加。給藥莫塔夫尼可降低在下視丘之前外側視葉前區（VLPO)的神經元之活性，其已知是可以在睡眠期間，抑制在管乳突狀核中促進淸醒的組織胺神經元之活性。藉由莫塔夫尼，此組織胺途徑的活化，導致皮質層的活化以及淸醒。因此，其顯示出對於莫塔夫尼之促進淸醒作用的生理基礎是牽涉到，藉由對VLPO的抑制作用，而不去抑制TMN的組織胺神經元。這代表了第一種藉由TMN之選擇性的活化而產生淸 7 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 _*:!訂---------ί----------------------- 1291872 A7 - ---—-___B7__ 五、發明說明（V ) 醒的藥物作用劑’並且這是根據在此領域中的先前文獻所意想不到的。根據這些機轉的硏究，相較於經常使用於注意力不集中過度反應症及多發性硬化疲勞的刺激劑，莫塔夫尼具有明顯不同的活性。這些是非常不同的藥物，如同此處所揭露的，莫塔夫尼可藉由將涉及正常淸醒的下視丘核作選擇性地活化而促進淸醒；相反地，經常使用的精神刺激劑（例如，安非它命），主要是藉由增強多巴胺至皮質及其他的腦部區域的輸入而作用，多巴胺的輸入是藉由促進在中間邊緣（mesolimbic )、管漏斗狀（tuberoinfundibular )及黑條紋（nigrostdatal)系統中，多巴胺神經元的神經傳導而增強。在這些主要的多巴胺途徑中，源自於腹蓋膜的中間邊緣系統，可能最直接涉及到皮質活化，而管漏斗狀及黑條紋系統則是分別牽涉到腦垂體及運動的功能。藉由安非它命而同時促進這些途徑導致非常具有特徵的皮質刺激，以及給藥安非它命的相關過度反應。相對於涉及正常淸醒的下視丘系統，多巴胺神經傳導的促進，似乎可誘導一種異常的淸醒狀態，在此狀態中，它是有關於安樂幸福的情緒及感覺上的改變，以及運動活動力的增加。因爲對於莫塔夫尼在後下視丘之管漏斗狀神經元的活化有令人驚訝的發現，因此如同此處所揭露的，顯示對於莫塔夫尼之新穎的用途，並且這樣的用途是本發明的一種形態。例如，本發明的一種形態是，莫塔夫尼是一種新穎的治療作用劑，其可對於患有注意力不集中過度反應症的 8 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印制衣 _________f #_____________________ 1291872 A7 __B7 ___ 五、發明說明（q ) 病患提供重要的益處。因爲莫塔夫尼活化下視丘，更因爲來自抑制的伽碼-胺基丁酸（GABA)前葉中間神經元上的下視丘胞突之抑制的組織胺神經途徑，所以下視丘的活化可促成後續錐狀細胞的活化，並提供莫塔夫尼有效用於注意力不集中過度反應症的機轉。此外，管乳突狀核的活化，也藉由直接的組織胺激發而導致增強的皮質作用。換句話說，管乳突狀核神經元的活化，是直接或間接的刺激皮質。在前皮質之不充足的活性已被暗示於ADHD的病原學中（Castellanos，F.X.，Clinical Pediatrics，381_393 ( 1997 );Swanson，J.等人，Current Opinion in Neurobiology，8 :263-271 ( 1998 ) ; Barkley，R.A·，Scientific American， 66_71 ( 1998 ))。本發明的一種形態因此可說明爲一種治療注意力不集中過度反應症的方法，其中，治療包括將一組成物給藥至患有注意力不集中過度反應症或易受其發展而影響的病患，此組成物包括一有效量的莫塔夫尼化合物，以在該病患中改善或預防注意力不集中過度反應的症狀。本發明的另一形態是一種治療與多發性硬化有關的疲勞之方法，包括將一組成物給藥至患有多發性硬化疲勞的病患，此組成物包含一有效量的莫塔夫尼化合物，以在該病患中改善或預防多發性硬化疲勞的症狀。此處所使用的名詞“疲勞”包括力氣或對刺激反應的能力之減損。就其本身而論，莫塔夫尼在此處顯示可有效於作爲減輕與多發性硬化有關的倦怠或睡意之治療，並可有效於作爲促進多 9 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印制衣 ---------線— ·_______________________ 1291872 A7 B7 五、發明說明（g) 發性硬化病患淸醒的方法。本發明的另一形態是一種治療患有注意力不集中過度反應症或多發性硬化疲勞之症狀的病患之方法，包括將一藥學組成物給藥至該病患，此藥學組成物包括一有效量的莫塔夫尼化合物，以刺激在該病患的腦部管漏斗狀神經元中之活性。仍是本發明的另一形態是一種單位劑量形式的藥學組成物，以用於在患有注意力不集中過度反應症或易受其發展而影響的病患中，治療注意力不集中過度反應症，此藥學組成物包括一有效量的莫塔夫尼化合物，使得其一個或多個單位劑量，可在週期性的給藥期間，在該病患中，有效於穩定或改善病患之注意力不集中過度反應症之症狀。本發明的一種形態也是一種單位劑量形式的藥學組成物，以用於治療在多發性硬化的病患中之疲勞，其中此組成物包括一有效量的莫塔夫尼化合物，使得其一個或多個單位劑量，可在週期性給藥期間，在該病患中，有效於穩定或改善病患之多發性硬化疲勞的症狀。如同此處所揭露的，以及如同使用於本發明的組成物及方法中，莫塔夫尼化合物可包括一消旋混合物，並可能是存在於一種酸的形式之中（例如，莫塔夫尼的代謝酸或二苯甲基亞擴醯醋酸）、碾（sulfone)形式、羥基化形式、共軛形式（例如，共軛連結至一蛋白質、多醣類、葡萄糖苷酸或硫酸鹽的莫塔夫尼化合物）或多形性形式，其可包括含有莫塔夫尼苯基同位質取代物之化合物，以及莫塔 10 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) 鳓· 經濟部智慧財產局員工消費合作社印製 ^---------爷II---------------------- 1291872 A7 B7 五、發明說明（') 夫尼之多形性物種或類似物’或是同種物（ccmgeners)及前藥物（prodrug)之衍生物，特別是當給藥至哺乳動物時，可剌激TMN活性的那些製劑。在一較佳具體實施例中，莫塔夫尼化合物是莫塔夫尼。前藥物在此技藝中是已知爲，可在病患體內轉換成活性作用劑（莫塔夫尼）的化合物。此處所揭露的組成物及方法，較佳地是有效於治療哺乳動物的病患，更特別地是人類。因爲已知多發性硬化及注意力不集中過度反應症會使得成年人及青少年或孩童痛苦，因此，此處所揭露的方法及組成物是針對那些族群。雖然對於人類口服給藥而言，有效劑量可用毫克/日爲單位，但應了解的是，除非有其他不同的指明，否則劑量可針對成年人的治療，並對孩童的劑量而適當的調整。本發明之目的是提供治療方法，其包括用於治療注意力不集中過度反應症及多發性硬化疲勞之有效劑量的莫塔夫尼化合物，莫塔夫尼化合物的有效量，較佳是從每曰劑量大約1毫克到大約400毫克。例如，在此技藝中之人士所知的是，從大約200毫克/日到大約400毫克/日的劑量，是有效的促進淸醒劑量，以及，這樣的劑量被認爲對於治療注意力不集中過度反應症及多發性硬化疲勞是有效的。也已知的是，大約100毫克/日的劑量，是在促進淸醒劑量的較低閾値上，但這樣的劑量也被認爲對於治療注意力不集中過度反應症及多發性硬化疲勞是有用的。其他的硏究報告也顯示了在次促進淸醒劑量之莫塔夫尼的有利的'活 11 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） (請先閱讀背面之注意事項再填寫本頁} > I n ϋ n n I I n 一σι> · ϋ i>M— n n n ϋ n I I · 經濟部智慧財產局員工消費合作社印製 1291872 A7 B7 五、發明說明（、〇 ) 性，特別是在於認知官能的改善。就其本身而論，本發明的一種形態是，用於此處所揭露之方法的莫塔夫尼化合物之有效量，包括從大約1毫克/日到大約400毫克/日，或每日劑量從大約100到大約400毫克，或每日劑量從大約 2〇〇到大約400毫克，或甚至每日劑量200毫克。也應了解的是，在那些範圍之內但並沒有明確指出的劑量，例如，30毫克、50毫克、75毫克等，也是包括在所陳述的範圍之內，相同地，稍微超過所陳述的範圍限制之外的量，也是在本發明的範疇之內。在較佳具體實施例中，將一種包括莫塔夫尼化合物的組成物賦形以用於口服給藥，並且更佳地是賦形爲錠劑（ tablet)以用於口服給藥。含有莫塔夫尼之錠劑的配方是在此技藝中之人士所熟知，如下所述，並且這樣的錠劑較佳地可包含各種惰性成份，例如，乳糖、玉米澱粉、矽酸鎂、克羅卡糖鈉（croscarmellose sodium)、聚乙烯|]比略院酮 (povidone)硬脂酸鎂或滑石粉或其任何的組合物。本發明的一種形態也可說明爲一種治療包裝（package )，用以配藥或用以使用配藥給要治療注意力不集中過度反應症或多發性硬化疲勞的哺乳動物，其中該包裝包括： (1) 一個或多個單位劑量，每一個這樣的單位劑量包含一莫塔夫尼化合物的量，使得該一個或多個單位劑量，可在週期性給藥或該單位劑量週期性給藥的期間，有效於穩定或改善哺乳動物之注意力不集中過度反應症或多發性硬化疲勞之症狀；以及（2) —使用於此之最終的藥物容器，該 12 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 ·:!!!丨訂________線丨·_____________________ 1291872 經濟部智慧財產局員工消費合作社印制取 A7 B7 五、發明說明（u ) 容器包含··（a)該單位劑量；以及（b)指示此包裝用於治療該哺乳動物之標籤。在較佳具體實施例中，此包裝是適合於口服給藥。雖然此處所揭露的組成物及方法已按照特定的較佳具體實施例而說明，但應了解的是，此處所說明的莫塔夫尼化合物可以與，例如，一惰性稀釋劑或可吸收食用的載體而口服地給藥。組成物也可以包裹在硬質或軟質外殼的動物明膠膠囊內，壓成錠劑，或直接與餐飮食物合倂。雖然錠劑是一般較佳的給藥莫塔夫尼的方法，但對於口服的治療性給藥而言，活性化合物（例如，莫塔夫尼）可與賦形劑合併，並以可攝取的錠劑、頰錠劑、喉片、膠囊、萬能藥、懸浮液、糖漿、薄片及其類似物的形式而使用。這樣的組成物及製劑應至少包含0.1%的活性化合物。當然，可以改變組成物及製劑的百分比，並且可以合宜地介於大約 2至大約60%的單位重量百分比。錠劑、喉片、片劑、膠囊及其類似物，也可以包含下列成份中的任何一種：例如，黏結劑（例如，特拉加康斯樹膠、阿拉伯膠、玉米澱粉或動物明膠）；賦形劑（例如，磷酸氫二鈉）；崩散劑（例如，玉米澱粉、馬鈴薯澱粉、藻酸及其類似物）；潤滑劑（例如，硬脂酸鎂）；以及甘味劑（例如，可加入蔗糖、乳糖或糖精）或香味劑（例如，薄荷、冬青油或櫻桃香料）。當劑量單位形式是膠囊時，除了上述類型的材料之外，其可包含一液體載體。可出現各種其他的材料作爲包膜，或在其方面修飾劑量單位 13 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) ·&δ,屮 1·— ϋ _1 n an n Mu I -ϋ i-i flu n n n n n in n n 1291872 A7 B7 五、發明說明（〆）的物理形式。例如，錠劑、片劑或膠囊可藉由蟲膠淸漆（ shellac)、糖類或兩者而包覆。糖漿或萬能藥可包含活性化合物、蔗糖（作爲甘味劑）、對-羥基苯甲酸甲基酯及對 -羥基苯甲酸丙基酯（作爲防腐劑）、染劑及香味劑（例如 ’櫻桃或柳橙香料）。當然，用於製備任何劑量單位形式的任何材料，在其所使用的量而言，應是藥學上純的以及本質上無毒的。此外，可將活性化合物倂入至持續釋放的製劑及配方中。在特定的具體實施例中，可將本發明之組成物賦形，以藉由使用皮膚貼片，或經皮傳遞系統而給藥。此處所說明之經皮地將莫塔夫尼組成物給藥，可藉由在此技藝中所熟知的任何系統而完成。可適合於使用此處所說明之組成物的系統之實例，包括那些說明於下列文獻中之經皮給藥的系統：美國專利第4,816,252號；美國專利第5，122,382 號；美國專利第5，198,223號；美國專利第5,〇23,084號；美國專利第4,906，169號；美國專利第5，145,682號；美國專利第4,62七665號；美國專利第4,687,481號；美國專利第4,834,978號；以及美國專利第4,810,499號（其完整的內容在此納入爲參考資料）。這些方法典型地包括一黏性基質或藥物儲存系統，並可包括一皮膚穿透增進劑，例如，乙醇、200月桂酸聚乙二醇酯、肉宣蔻酸異丙基酯、三油酸甘油酯、亞麻脂酸飽和醇、單油酸甘油酯、單月桂酸甘油酯、正-十二烷基醇、癸酸，以及特定的飽和及不飽和脂肪酸，及其酯類、醇類 14 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 x 297公釐） (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製1291872 A7 B7 V. INSTRUCTION DESCRIPTION (1) BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the field of neuropharmacological agents, including agents for treating hyperreactivity disorder and multiple sclerosis-related fatigue agents. . 2. Description of Related Techniques Attention Deficit/Overreaction (ADHD) is a chronic neuropsychiatric condition in children characterized by developmental inappropriate overreaction, impulsivity, and inattention. Estimated age-related children affected by ADHD. Historically, ADHD has been thought to not persist until after puberty; however, current studies have shown that in cases where 10% to 60% occur in early childhood, ADHD can persist into adulthood. The persistence of ADHD is associated with a high incidence of academic and occupational dysfunction and a high incidence of psychosocial co-morbidities (eg, behavior, major depression, and anxiety). It is estimated that approximately 1% to 3% of adults have ADHD syndrome. Adults with ADHD have demographic, psychosocial, psychiatric, and cognitive traits that reflect well-documented findings in children with this condition. This more supports the legitimacy of adult diagnosis. In adults, the core ADHD syndrome includes frequent or persistent types of inattention/distraction and/or overreaction-impulsivity. The most common syndromes exhibited by adults with ADHD are significant inattention, distraction, distraction, daydreaming, forgetfulness, and frequent shifting of activity. It has also been reported that ADHD adults have significant impulses. The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). (Please read the notes on the back and fill out this page.) 0. Ministry of Economics Intellectual Property Bureau employee consumption cooperative printed mb nn H a 0, · nn ϋ n ϋ ϋ n I nnn ϋ n ϋ ϋ nn 1291872 A7 B7 V. Invention description (,), intrusiveness, low frustration / pressure resistance Sexual, irritating temper, irritability, and considerable impatience. Among adults, the less frequently reported syndromes include overreaction, which can be limited to irritability, or nervous or uneasy inner feelings. In addition to the core ADHD syndrome, adults with ADHD often show relevant clinical characteristics such as boredom, social discomfort, and chronic conflicts in the social environment. These characteristics may reflect: (1) separation and divorce; and (2) despite the appropriate intellectual abilities, there is still a high incidence of poor academic performance and professional achievement. In addition, adults with ADHD have a high incidence of substance abuse symptoms. Although the cause of ADHD is still unclear, the changes in the function of dopaminergic and noradrenergic appear to be the neurochemical basis of the disease. Changes in glucose metabolism in the cerebral cortex have been shown in X-ray tomography of the brain's electronic divergence in adults with ADHD, which is the ability to note and exercise, such as the frontal lobe ). The most common treatment for ADHD in adults and pediatrics is stimulating agents (e.g., dextroamphetamine, methylphenidate, and pemoline). Stimulants are thought to act by increasing the amount of dopamine available in neuronal synapses. The stimulator seems to perform this work at multiple locations on the brain structure. Other therapies that have been used include: antidepressants (eg, tricyclic antidepressants such as imipramine and desipramine: novel antidepressants such as Bupleon ( 4 The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the note on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs, employee consumption cooperatives tr------ ---,·----------------------- Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed clothing 1291872 A7 ----_____Β7_ V. Invention Description (3) buproorion) and venlafaxine, antihypertensive agents (eg, clonidine and guanfacine), monoamine oxidase inhibitors ([MAO's], eg , selegiline, amino acids (eg, levodopa, phenylalanine, and L-tyrosine) and a combination of pharmaceutical therapeutics (eg, simultaneous use of heparin selective reuptake inhibitors and Stimulant drugs; or stimulants and catecholamines for antidepressant therapy) (Bhandary et al., Psychiatric An) Nals 27 • 545-555, 1997; Wilens et al, J. Clin· Psychopharmacol. 15 : 270-279, 1995 ; Finkel, The Neurologist 3 : 31-44, 1997 ; Miller and Catellanos, Pediatrics in Review 19 · 373 -384,1998) 〇Although stimulants are the most commonly used treatment, approximately 30%-50% of adults with ADHD have no positive response to stimulants, unacceptable side effects or concurrent depression or Anxious symptoms, this irritating agent can worsen treatment or become ineffective in treatment. Long-term adverse effects and their use in the subgroup of ADHD high-hazard substance abuse are still unexplored and of concern. Therefore, there is still a need for non-irritating drug therapy for attention deficit hyperactivity disorder. . Other symptoms that are also chronically needed for non-irritating medications are fatigue associated with multiple sclerosis (MS). In the United States, multiple sclerosis is one of the most common disability neurological diseases in young people, with an estimated 400,000 people suffering from the disease. Although multiple sclerosis can cause various destructive neurological damage, such as blindness, paralysis, incoordination, and intestinal or bladder dysfunction, it can also be severely lost. 5 (Please read the notes on the back first) Fill in this page) Job an I n ϋ nnn One: eJ nnnnnl 丨 ft This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 1291872 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print clothing A7 B7 V. The less obvious symptom of the invention (γ) is fatigue. In a study involving 656 patients with multiple sclerosis, 78% complained of fatigue, 60% felt fatigue every day, and 22% suffered from interruptions in their daily activities (Freal et al., Arch · Phys. Med· Rehabil· 65 : 135, 1984). The International Multiple Sclerosis Society evaluated 839 patients who, although suffering from multiple sclerosis for more than 10 years, had only mild neurological damage, and fatigue was the most frequently reported among these slightly affected patient populations. Symptoms (Jones 'New York: International Multiple Sclerosis Society, Health Services Research Report' 1991). In another study, 40% of patients with multiple sclerosis listed fatigue as the most serious symptom of their disease (Murray' Can. J. Neurol Sci 12 251, 1985). It has been reported that in up to 75% of patients with multiple sclerosis, fatigue is at least a cause of temporary disability; and the UK Multiple Sclerosis Society found that fatigue is the most important symptom of unemployment in this group ( Rolak, Curr. Neurol. 9: 109, 1989). In the United States, the prevalence of disability associated with multiple sclerosis fatigue is highlighted by the guidelines issued by the Social Security Administration, which are included in the criteria for disability allowances. The mechanism of multiple sclerosis fatigue is still not very understanding. It has been attributed to abnormalities in nerve conduction in the central nervous system and to the increased energy requirements caused by neurological disability. Several characteristics of multiple sclerosis fatigue are the daily physiological functions of the living and the conflict of activity, which are exacerbated by heat and deteriorate at the end of the day (Kmpp et al., VIII 1^11· Neurol·. 45: 435, 1988). Prescriptions for the treatment of multiple sclerosis include amantadine, bimarin and 6 (please read the notes on the back and fill in the original) • ^ 0 i I n ϋ ϋ ϋ ϋ ^ J · ϋ 1 n ϋ n ί IH ϋ nn ϋ ϋ ϋ nnnnnn an n an nn ϋ «I ϋ 1 n This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 1291872 A7 B7 Invention Description (<) Other stimulating agents. In a double-blind, randomized study, it has been demonstrated that in 18% of patients, aminotricyclodecane is beneficial for multiple sclerosis fatigue, but its beneficial effects are still unclear (Krupp et al. Neurology 45: 1956, 1995). Although aminotricyclodecane has been shown to be beneficial in multiple sclerosis fatigue in a precise manner, this benefit is only partial for most patients, and there are still many patients who say no benefit. The same study of Bimaline, which is commonly used to treat multiple sclerosis fatigue, does not show beneficial effects, so there is still a strong need for safe and effective treatment of this disabling symptom. SUMMARY OF THE INVENTION The present invention provides a novel use of modafinil for the treatment of attention deficit hyperactivity disorder (ADHD) and for the improvement of fatigue symptoms due to multiple sclerosis (MS). The study that forms the basis of this disclosure unexpectedly demonstrates that the wake-promoting dose of motafni is administered to rats, resulting in the selectivity of the ductal papillary nucleus (TMN) of the posterior sacral hypothalamus. Increase. Administration of Motafni reduces the activity of neurons in the lateral preoptic area (VLPO) before the hypothalamus, which is known to inhibit histamine nerves that promote wakefulness in the ductal mammary nucleus during sleep. Yuan activity. Activation of this histamine pathway leads to activation and wakefulness of the cortical layer by Mottafni. Therefore, it has been shown that the physiological basis for the promotion of awakening of Motaffini is involved in the inhibition of VLPO without inhibiting the histamine neurons of TMN. This represents the first generation of 淸7 by selective activation of TMN. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public). (Please read the back note and fill out this page) Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative _*:!订--------- ί----------------------- 1291872 A7 - -----___B7__ V. Invention Description (V) Awakened drug agent' and this is unexpected according to previous literature in this field. According to these studies, Motaffini has significantly different activities than irritants that are often used in attention deficit hyperactivity and multiple sclerosis fatigue. These are very different drugs, and as disclosed herein, Mottafni can promote wakefulness by selectively activating the hypothalamic nucleus involved in normal wakefulness; conversely, a frequently used psychostimulant ( For example, amphetamines, mainly by enhancing the input of dopamine to the cortex and other brain regions, dopamine input by promoting mesolimbic, tuberoinfundibular and black streaks In the (nigrostdatal) system, dopamine neurons are enhanced by nerve conduction. Among these major dopamine pathways, the intermediate marginal system derived from the abdominal cap membrane may be most directly involved in cortical activation, while the funnel-shaped and black-striped system is involved in the function of the pituitary gland and movement, respectively. Simultaneous promotion of these pathways by amphetamine results in very characteristic cortical irritation and associated hyperreactivity of amphetamine. The promotion of dopaminergic nerve conduction seems to induce an abnormal state of awakening relative to the hypothalamus system involved in normal wakefulness, in which it is an emotional and sensory change in euthanasia, as well as athletic activity. Increase in force. Because of the surprising discovery of the activation of the funnel-shaped neurons of Motivini in the posterior hypothalamus, as disclosed herein, the novel use of Mottafni is shown, and such use is One form of the invention. For example, in one embodiment of the invention, Motaffini is a novel therapeutic agent that is applicable to the Chinese National Standard (CNS) A4 specification (210 X) for 8 paper sizes with attention deficit hyperactivity disorder. 297 mm) (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives Printed Clothing _________f #_____________________ 1291872 A7 __B7 ___ V. Invention Description (q) Patients provide important benefits. Activation of the hypothalamus is due to the activation of the hypothalamus by Mottafni and the histamine neuropathy from inhibition of the hypothalamic process on the gamma-aminobutyric acid (GABA) anterior interneuron It can contribute to the activation of subsequent cone cells and provide a mechanism for Mottafni to be effectively used for attention deficit hyperactivity disorder. In addition, activation of the ductile mammary nucleus results in enhanced cortical effects by direct histamine stimulation. In other words, the activation of the ductal nucleus neurons is a direct or indirect stimulation of the skin. Insufficient activity in the anterior cortex has been implicated in the etiology of ADHD (Castellanos, FX, Clinical Pediatrics, 381_393 (1997); Swanson, J. et al., Current Opinion in Neurobiology, 8: 263-271 (1998) Barkley, RA·, Scientific American, 66_71 (1998)). One aspect of the present invention can thus be described as a method of treating attention deficit hyperactivity disorder, wherein the treatment comprises administering a composition to a disease suffering from inattention overreaction or susceptible to its development. Suffering from this composition, an effective amount of Motafni compound is included to improve or prevent the symptoms of attention deficit hyperactivity in the patient. Another aspect of the invention is a method of treating fatigue associated with multiple sclerosis comprising administering a composition to a patient suffering from multiple sclerosis, the composition comprising an effective amount of a Motafni compound To improve or prevent the symptoms of multiple sclerosis fatigue in this patient. The term "fatigue" as used herein includes impairment of strength or ability to respond to stimuli. For its part, Mottafni has shown here that it can be effective as a treatment for reducing burnout or drowsiness associated with multiple sclerosis, and can be effectively used as a Chinese National Standard (CNS) A4 for promoting more than 9 paper scales. Specifications (210 X 297 mm) (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Clothing --------- Line — ·_______________________ 1291872 A7 B7 V. DESCRIPTION OF THE INVENTION (g) A method of awakening a patient with a sclerosis. Another aspect of the invention is a method of treating a patient suffering from symptoms of attention deficit hyperactivity disorder or multiple sclerosis fatigue comprising administering a pharmaceutical composition to the patient, the pharmaceutical composition comprising a An effective amount of Motafni compound to stimulate activity in the funnel-shaped neurons of the brain of the patient. Still another aspect of the invention is a pharmaceutical composition in unit dosage form for use in treating insufficiency of overreaction in a patient suffering from or at least being affected by the development of attention deficit hyperactivity disorder The pharmaceutical composition comprises an effective amount of a Motaftan compound such that one or more unit doses thereof are effective in stabilizing or improving the patient's attention during the periodic administration period in the patient. The effect is not concentrated on the symptoms of overreaction. One form of the invention is also a pharmaceutical composition in unit dosage form for the treatment of fatigue in a patient suffering from multiple sclerosis, wherein the composition comprises an effective amount of a Motafni compound such that one or more A unit dose that is effective in stabilizing or improving the symptoms of multiple sclerosis in a patient during periodic administration. As disclosed herein, and as used in the compositions and methods of the present invention, a Motafni compound may comprise a racemic mixture and may be present in an acid form (eg, Motaffini's) Metabolic acid or diphenylmethyl stilbene acetate, sulfone form, hydroxylated form, conjugated form (eg, Motaf conjugated to a protein, polysaccharide, glucuronide or sulfate) Nie compound) or a polymorphic form, which may include a compound containing a Motafni phenyl isotopic substitution, and a Mota 10 paper size applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ( Please read the notes on the back and fill out this page. 鳓· Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed ^---------Ye II-------------- -------- 1291872 A7 B7 V. Inventive Note (') Finnish polymorphic species or analogues' or derivatives of the same species (ccmgeners) and prodrugs, especially when given Those agents that stimulate TMN activity when administered to a mammal. In a preferred embodiment, the Motafni compound is Motafani. The prodrug is known in the art as a compound which can be converted into an active agent (Motafny) in a patient. The compositions and methods disclosed herein are preferably effective for treating mammals, and more particularly humans. Because multiple sclerosis and attention deficit hyperreactivity are known to cause pain in adults and adolescents or children, the methods and compositions disclosed herein are directed to those ethnic groups. Although effective doses can be administered in milligrams per day for human oral administration, it should be understood that unless otherwise indicated, the dosage may be administered to an adult and adjusted appropriately for the child's dosage. It is an object of the present invention to provide a method of treatment comprising an effective amount of a Motafni compound for the treatment of attention deficit hyperactivity disorder and multiple sclerosis fatigue, an effective amount of a Motafni compound, preferably from each The dose is about 1 mg to about 400 mg. For example, it is known to those skilled in the art that doses from about 200 mg/day to about 400 mg/day are effective to promote wake-up doses, and such doses are considered to be inattentive for treatment. Hyperreactivity and multiple sclerosis fatigue are effective. It is also known that a dose of about 100 mg/day is on the lower threshold of promoting the wake-up dose, but such a dose is also considered useful for treating attention deficit hyperactivity disorder and multiple sclerosis fatigue. of. Other research reports also show that the Motivni's favorable 'live 11' paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public). (Please read the back Note: Please fill out this page again} > I n ϋ nn II n σι> · ϋ i>M- nnn ϋ n II · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1291872 A7 B7 V. Invention Description (, 〇) Sex, particularly in the improvement of cognitive faculty. As such, one aspect of the invention is an effective amount of a Motafani compound for use in the methods disclosed herein, including from about 1 mg/day to about 400. MG/day, or daily dose from about 100 to about 400 mg, or daily dose from about 2 〇〇 to about 400 mg, or even 200 mg per day. It should also be understood that within those ranges but Dosages not specifically indicated, for example, 30 mg, 50 mg, 75 mg, etc., are also included in the stated range, and, similarly, slightly outside the stated range limits, are also within the scope of the present invention. It In a preferred embodiment, a composition comprising a Motafni compound is shaped for oral administration, and more preferably as a tablet for oral administration. Formulations containing lotions of Motafni are well known to those skilled in the art, as described below, and such tablets may preferably contain various inert ingredients such as lactose, corn starch, magnesium citrate, grams. Croscarmellose sodium, polyethylene|] povidone magnesium stearate or talc or any combination thereof. One form of the invention may also be described as a therapeutic package, For the purpose of dispensing or for dispensing a medicament for treating a mammal suffering from attention deficit hyperactivity disorder or multiple sclerosis fatigue, wherein the package comprises: (1) one or more unit doses, each such unit dose comprising one The amount of Motavny compound is such that the one or more unit doses are effective to stabilize or improve the attention of the mammal during periodic administration or periodic administration of the unit dose. Symptoms of degree of response or multiple sclerosis fatigue; and (2) - the final drug container used in this 12-sheet scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read first Note on the back side of this page.) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives.: !!! ________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ Description (u) The container contains (a) the unit dose; and (b) a label indicating that the package is used to treat the mammal. In a preferred embodiment, the package is suitable for oral administration. Although the compositions and methods disclosed herein have been described in terms of specific preferred embodiments, it will be appreciated that the motafini compounds described herein can be, for example, an inert diluent or absorbable. The carrier is administered orally. The composition may also be enclosed in a mechanical gelatin capsule in a hard or soft outer shell, compressed into a lozenge, or directly combined with a meal. While lozenges are a generally preferred method of administering motafoni, for therapeutic administration orally, the active compound (eg, motafoni) can be combined with excipients and ingestible. It is used in the form of tablets, buccal tablets, throat tablets, capsules, panacea, suspensions, syrups, flakes and the like. Such compositions and preparations should contain at least 0.1% of active compound. Of course, the percentage of the composition and formulation can be varied, and may conveniently range from about 2 to about 60% by weight. Tablets, guillotine, tablets, capsules and the like, may also comprise any of the following ingredients: for example, a binder (for example, Tragacons gum, gum arabic, corn starch or animal gelatin); a tablet (for example, disodium hydrogen phosphate); a disintegrating agent (for example, corn starch, potato starch, alginic acid, and the like); a lubricant (for example, magnesium stearate); and a sweetener (for example, can be added with sucrose) , lactose or saccharin) or a fragrance (for example, mint, wintergreen or cherry). When the dosage unit form is a capsule, it may contain a liquid carrier in addition to materials of the above type. Various other materials may be used as the envelope, or the dosage unit may be modified in this respect. 13 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the back note before completing this page) ·&δ,屮1·—ϋ_1 n an n Mu I -ϋ ii flu nnnnn in nn 1291872 A7 B7 V. Physical description of the invention (〆). For example, lozenges, tablets or capsules may be coated with shellac, sugar or both. A syrup or panacea may comprise the active compound, sucrose (as a sweetener), methyl p-hydroxybenzoate and propyl p-hydroxybenzoate (as a preservative), a dye and a fragrance (eg 'cherry or willow' Orange spice). Of course, any material used in the preparation of any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound can be incorporated into sustained release formulations and formulations. In a particular embodiment, the compositions of the invention may be shaped for administration by the use of a dermal patch, or a transdermal delivery system. Administration of the Motafni composition percutaneously as described herein can be accomplished by any of the systems well known in the art. Examples of systems that may be suitable for use with the compositions described herein include those systems that are described in the following documents for transdermal administration: U.S. Patent No. 4,816,252; U.S. Patent No. 5,122,382; U.S. Patent No. 5,198,223 U.S. Patent No. 5, No. 4,906,169; U.S. Patent No. 5,145,682; U.S. Patent No. 4,62,767; U.S. Patent No. 4,687,481; U.S. Patent No. 4,834,978; U.S. Patent No. 4,810,499, the entire disclosure of which is incorporated herein by reference. These methods typically include a viscous matrix or drug storage system and may include a skin penetration enhancer such as ethanol, 200 lauric acid polyethylene glycol ester, isopropyl myristate, triolein Ester, linolenic acid saturated alcohol, glycerol monooleate, glycerol monolaurate, n-dodecyl alcohol, decanoic acid, and specific saturated and unsaturated fatty acids, and esters and alcohols thereof 14 paper The scale applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm) (please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

-- -I m n ^^0 —^1 ·ϋ n _ ϋ_1 I— ·1· ϋ n n —Ml I ϋ n ϋ— an n n ·1 ϋ n n In n in n n i^i n n n n n l I 1291872 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（\3) 、單甘油酯、醋酸酯、二乙醇醯胺以及N，N-二甲基醯胺（例如，參見美國專利第4,9〇6，169號）。本發明更有關於一種鑑定化合物之方法’此化合物可刺激後下視丘之管乳突狀核（TMN)的活性。此方法牽涉到使用標準的篩選技術，其應用於如上所述的新穎發現。因此，本發明提供藉由此方法所鑑定的化合物，以及作爲藥物的使用，其中，在後下視丘之管乳突狀核的刺激，對於要治療的動物或病患的安樂幸福，將具有有益的效果。發明詳述莫塔夫尼是一種在中樞神經系統中具有活性的作用劑，並已被發展爲嗜眠病（narcolepsy)相關的過度白天睡眠的治療。莫塔夫尼之主要的藥理活性，像是類安非他命的作用劑一般，係用以促進淸醒。莫塔夫尼在以下實例中促進淸醒：大鼠（Touret 等人，Neuroscience Letters，189 : 43-46 ( 1995 ) ; Edger and Seidel，J. Pharmacol. Exp.-- -I mn ^^0 —^1 ·ϋ n _ ϋ_1 I—·1· ϋ nn —Ml I ϋ n ϋ— an nn ·1 ϋ nn In n in nni^innnnnl I 1291872 Ministry of Economic Affairs Intellectual Property Office staff Consumer Cooperatives Print A7 B7 V. Invention Notes (\3), Monoglycerides, Acetate, Diethanolamine, and N,N-Dimethylguanamine (See, for example, U.S. Patent No. 4,9,6,169 number). More particularly, the present invention relates to a method of identifying a compound which stimulates the activity of the ductal papillary nucleus (TMN) of the posterior hypothalamus. This method involves the use of standard screening techniques that apply to the novel findings as described above. Accordingly, the present invention provides a compound identified by this method, and as a medicament, wherein the stimulation of the papillary nucleus of the posterior hypothalamic tube will have an happiness for the animal or patient to be treated. Beneficial effect. DETAILED DESCRIPTION OF THE INVENTION Motafni is an active agent in the central nervous system and has been developed as a treatment for narcolepsy-related excessive daytime sleep. Mottafni's main pharmacological activity, like amphetamine-like agents, is used to promote wakefulness. Motaffini promotes wakefulness in the following examples: rats (Touret et al, Neuroscience Letters, 189: 43-46 (1995); Edger and Seidel, J. Pharmacol. Exp.

Ther. ^ 283 ： 757-769 ( 1997 ))、貓（Lin 等人，Brain Research，591 : 319-326 ( 1992 ))、狗（Shelton 等人， Sleep，18(10) : 817-826 ( 1995 ))及非人類的靈長類（ DS-93-023 ， 180-181 頁；Hernant 等人，Ther. ^ 283 : 757-769 ( 1997 )), Cat (Lin et al., Brain Research, 591: 319-326 (1992)), Dog (Shelton et al., Sleep, 18(10): 817-826 (1995) )) and non-human primates (DS-93-023, pp. 180-181; Hernant et al.

Psychopharmacology，103 : 28-32 ( 1991 ))，以及在模擬臨床環境的模式，例如，睡眠性窒息（英國牛頭犬睡眠症狀的呼吸模式）（Panckeri等人，1996 )及嗜眠病（嗜眠的狗）（Shelton 等人，Sleep，18(10) : 817-826 ( 1995 ) 15 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） (請先閱讀背面之注意事項再填寫本頁) --------訂i 11 stem n n n I— I 線丨栅---------------------- 經濟部智慧財產局員工消費合作社印製 1291872 A7 __B7 _____ 五、發明說明（、欠） )。莫塔夫尼也已證實對於以下情況而言，是有用的作用劑··治療帕金森氏症（美國專利第5，180,745號）、保護腦部組織避免缺血（美國專利第5,391，576號）、治療大小便失禁（美國專利第5,4〇1，776號）以及治療中樞起源之睡眠性窒息（美國專利第5,612,378號）。美國專利第 5,618,845號說明一小於200毫米之特定顆粒大小的莫塔夫尼製劑，是比包含大部分較大顆粒的製劑，更具有效力及安全性。已經對於各種神經結構途徑在誘導及維持淸醒的角色上進行硏究，並且，其中一些成果已指出管乳突狀核（ TMN)的潛在角色（Sherrin 等人，Science，271 : 216-219 ，1996)。一項由Lin等人所作的硏究（PNAS，USA，93 :14128-14133，1996 )證實前下視丘經由莫塔夫尼的選擇性活化，並且，該硏究的作者也證實，在促進淸醒的劑量下，將莫塔夫尼給藥至貓，不會引起後下視丘之管乳突狀核的活化。一項相似的硏究，將促進淸醒劑量的莫塔夫尼給藥至大鼠（Engber 等人，Neuroscience，87 : 905-911 ( 1998 ))，也證實由莫塔夫尼所誘導的淸醒與管乳突狀核的活化無關。因此，雖然管乳突狀核的活化已暗示涉及正常的淸醒，但這些硏究者的硏究卻已淸楚地教示，管乳突狀核的活化是無涉於由莫塔夫尼所誘導的淸醒。本發明部份是由於一項發現而產生的，這個發現是當以促進淸醒的劑量給藥時，莫塔夫尼的確造成後下視丘之管乳突狀核中的活性刺激。在大鼠中給藥莫塔夫尼，氏 16 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) -· • m ϋ ^1· n n I n —am ϋ I ·ί n n 1· I ·ϋ ϋ n I n I n n n n ϋ n ϋ n ·ϋ n ϋ n n n n 1 1291872 A7 B7 五、發明說明) 在下視丘之前外側視葉前區（VLPO)的神經元之活性’其已知是可以在睡眠期間，抑制在管乳突狀核中促進淸醒的組織胺神經元之活性。藉由莫塔夫尼，這個組織胺途徑的活化，導致皮質層的活化以及淸醒。因此’其顯示莫塔夫尼之促進淸醒作用的生理基礎是牽涉到，藉由對VLP0的抑制作用，而不去抑制TMN的組織胺神經元。這代表了第一種藉由TMN之選擇性的活化而產生淸醒的藥物作用劑。此外，因爲莫塔夫尼可活化下視丘，更因爲來自抑制的伽碼-胺基丁酸（GABA)前葉中間神經元上的下視丘胞突之抑制的組織胺神經途徑，所以下視丘的活化可促成後續錐狀細胞的活化，因此，本發明之發明者考量到下視丘的活化可促成後續錐狀細胞的活化，並提供莫塔夫尼有效用於注意力不集中過度反應症，以及多發性硬化疲勞的機聿專（Swanson，J·等人，Current Opinion in Neurobiology 5 8 ：263-271 ( 1998 ) ; Roelke，U.等人，Neurobiology，48 : 1566-1571 ( 1997 ) ) 〇在此處所揭示或宣示的任何發明之前，莫塔夫尼在此技藝中已知是以治療包裝的形式存在，並以Provigil®的名稱販售。Provigil®是一種由Cephalon公司（西轍斯特，賓州）所製造的藥學產品，並且也是由Cephalon公司所販售。Provigil®是以含有100毫克或200毫克莫塔夫尼的錠劑而供應。在商業上的用途中，含有莫塔夫尼的治療包裝，在先前技藝中是標示、不然就是標示爲用於嗜眠病的患者〇 17 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製一：口 1 · tmt ·ϋ ϋ IV ϋ— i^i I n n ϋ— -ϋ an Hi -ϋ n n I n n I— n n ϋ ϋ ϋ Hi n n n I — 1291872 A7 Γ____— _Β7 _____ 五、發明說明（) 因此，在先前技藝中所已知的是治療包裝，其提供一個或多個單位劑量的莫塔夫尼作爲其活性成份，在包含該單位劑量之最終藥物容器中供應，並包含或包括指示該包裝用於治療上述人類疾病或症狀的標籤。附在藥物容器中所提供的文件，是每日劑量200毫克/日莫塔夫尼的指示，提供作爲早晨的單一劑量。雖然400毫克/日在臨床試驗中是可以完全忍受的，但200毫克/日是在成年人中最適的促進淸醒之劑量。所有在此處所揭示或宣示的組成物及方法，都可根據本發明之揭露而製作或實施，而無須不適當的實驗。雖然本發明的組成物及方法已藉由較佳具體實施例而說明，但熟悉於此技藝者將可了解，在不脫離本發明的槪念、精神及範疇之外，可對於組成物及/或方法，以及步驟或步驟的順序，進行各種的更動。更特別地，化學及生理學相關的特定作用劑，明顯地可用於取代此處所說明的作用劑，而仍然可達到相同或相似的結果。對於熟悉於此技藝者，所有這樣相似的取代物以及改質物，明顯地可視爲是在本發明的精神、範疇及槪念之內，如同附隨的申請專利範圍所定義。實施例本發明將藉由以下的實施例而加以說明。所提供的實施例僅是用於舉例說明，而並非用以限定本發明之範疇或槪念。 18 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) 躑經濟部智慧財產局員工消費合作社印制衣訂---------線---------------------- 1291872 A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明（\\) 實驗設計：在以下的實施例中’在處理2小時之後將大鼠犧牲，並使用免疫組織化學法，以分析大腦中的。在實施例1及2中，將大鼠裝置儀器以記錄腦電波圖（ EEG)及肌電波圖（EMG)。爲了避免在給藥莫塔夫尼或賦形劑的期間之處理上的壓力，將慢性的導管置於腹膜腔，以用於給藥莫塔夫尼或賦形劑。動物及記錄環境：將65隻重270-330克，雄性的史薄拉格-達力（Sprague-Dawley)大鼠（Harlan)，個別圏養在無病原菌的障礙設施中，置於一房間，溫度維持在21.5-22.5°C，上午7點開燈，下午7點關燈。大鼠有隨意可獲得的食物及飮水。在每個實驗之前至少3天，將大鼠放入在一隔離房間內的不透光、消音的記錄腔室（Biocube)。在每個籠子內部中層的光強度是100-150勒克斯（hix)。以色列醫學中心（Beth Israel Deaconess Medical Center) 及哈佛醫學院的動物照護及使用委員會（Institutional Animal Care and Use Committees)核准戶斤有的程序。動物手術：在水合三氯乙醛的麻醉下（ 350毫克/公斤，靜脈注射），將實施例1及2的大鼠手術植入4個腦電波圖螺桿（從前囪（bregma)，AP ·· +3，-4 ; RL : +2，-2 )，並輕輕接觸硬膜，以及在頸背肌肉下方植入2個肌電波圖金屬線（Plastics One，Roanoke，VA)。將導線連接到6個通路的連接器（Plastics One)，其附在具有齒丙烯酸（ dental acrylic)的頭蓋骨上。除了 5隻大鼠以外，將遙測裝置的溫度傳輸器（TA 10TA-F40，數據科學國際， 19 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) .0.Psychopharmacology, 103: 28-32 (1991)), and models that mimic clinical settings, such as sleep apnea (breathing patterns in English bulldog sleep symptoms) (Panckeri et al., 1996) and narcolepsy (sleepy dogs) (Shelton et al., Sleep, 18(10): 817-826 (1995) 15 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public). (Please read the notes on the back and fill out this page. ) --------Book i 11 stem nnn I— I Line ----------------------- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printed 1291872 A7 __B7 _____ V. Description of invention (, owed)). Motaffini has also proven to be a useful agent for the treatment of Parkinson's disease (US Patent No. 5,180,745), protecting brain tissue from ischemia (US Patent No. 5,391,576) The treatment of incontinence (U.S. Patent No. 5,4,1,776) and the treatment of centrally-occurring sleep apnea (U.S. Patent No. 5,612,378). U.S. Patent No. 5,618,845 teaches that a certain particle size of a motafine formulation of less than 200 mm is more effective and safer than a formulation containing most of the larger particles. Studies have been conducted on the role of various neural pathways in inducing and maintaining wakefulness, and some of these results have indicated the potential role of the ductal nucleus (TMN) (Sherrin et al., Science, 271: 216-219, 1996). A study by Lin et al. (PNAS, USA, 93: 14128-14133, 1996) confirmed the selective activation of the anterior hypothalamus via Mottafni, and the author of the study also confirmed that it was promoting At a dose of awake, administration of Motafni to the cat does not cause activation of the papillary nucleus of the posterior hypothalamic tube. A similar study will promote the administration of awakening doses of Motafni to rats (Engber et al., Neuroscience, 87: 905-911 (1998)), as well as 淸 induced by Mottafni. Wake up is not associated with activation of the ductal nucleus. Therefore, although the activation of the ductal mammary nucleus has been implicated in the involvement of normal wakefulness, the study of these investigators has succinctly taught that the activation of the ductile nucleus is not involved by Motaffni. Induced wakefulness. The present invention is in part due to a finding that when administered at a dose that promotes wakefulness, Mottafni does cause an active stimulus in the papillary nucleus of the posterior hypothalamic tube. Mottafni is administered in rats, and the paper size of 16 is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) -· • m ϋ ^1· nn I n —am ϋ I ·ί nn 1· I ·ϋ ϋ n I n I nnnn ϋ n ϋ n ·ϋ n ϋ nnnn 1 1291872 A7 B7 V. Inventive Note) Before the lower view of the hypothalamus The activity of the neurons of the region (VLPO) is known to inhibit the activity of histamine neurons that promote wakefulness in the ductal mammary nucleus during sleep. With Motaffini, activation of this histamine pathway leads to activation and wakefulness of the cortical layer. Therefore, it shows that the physiological basis of Motaffini's promotion of wakefulness is involved in the inhibition of VLP0 without inhibiting the histamine neurons of TMN. This represents the first drug agent that produces wakefulness by selective activation of TMN. In addition, because Motafni can activate the hypothalamus, and more because of the histamine neural pathway from the inhibition of the inferior colliculus on the gamma-aminobutyric acid (GABA) anterior interneurons, Activation of the mounds may contribute to the activation of subsequent cone cells, and thus the inventors of the present invention have determined that activation of the inferior colliculus may contribute to subsequent activation of the cone cells and provide Mottafni for effective attention deficit hyperactivity. Disease, and the mechanism of multiple sclerosis fatigue (Swanson, J. et al., Current Opinion in Neurobiology 5 8: 263-271 (1998); Roelke, U. et al., Neurobiology, 48: 1566-1571 (1997) Prior to any invention disclosed or claimed herein, Motaffini is known in the art to be in the form of a therapeutic package and is sold under the name Provigil®. Provigil® is a pharmaceutical product manufactured by Cephalon (West West, Pennsylvania) and is also sold by Cephalon. Provigil® is supplied as a tablet containing 100 mg or 200 mg of motavni. For commercial use, the treatment package containing Mottafni is labeled in the prior art, otherwise it is labeled as a patient for narcolepsy. 17 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Co., Ltd. Printed one: mouth 1 · tmt · ϋ ϋ IV ϋ — i^i I nn ϋ — -ϋ an Hi - ϋ nn I nn I nn ϋ ϋ ϋ Hi nnn I — 1291872 A7 Γ ____ — _ Β 7 _____ V. Description of the invention () Accordingly, what is known in the prior art is a therapeutic package that provides one or more unit doses. Mottafni as its active ingredient is supplied in a final pharmaceutical container containing the unit dose and contains or includes a label indicating that the package is used to treat the above-mentioned human disease or condition. The documentation provided in the drug container is an indication of a daily dose of 200 mg/day Motafni, provided as a single dose in the morning. Although 400 mg/day is fully tolerable in clinical trials, 200 mg/day is the most appropriate dose to promote wakefulness in adults. All of the compositions and methods disclosed or claimed herein can be made or carried out in accordance with the teachings of the present invention without undue experimentation. Although the compositions and methods of the present invention have been described in terms of preferred embodiments, those skilled in the art will appreciate that the compositions and/or Or methods, and the order of steps or steps, to make various changes. More particularly, chemically and physiologically-specific agents are clearly available to replace the agents described herein while still achieving the same or similar results. All such similar substitutes and modifications are apparent to those skilled in the art and are apparent to the scope of the invention as defined by the scope of the appended claims. EXAMPLES The present invention will be illustrated by the following examples. The examples are provided for illustration only and are not intended to limit the scope or concept of the invention. 18 The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the note on the back and fill out this page) 踯Ministry of Commerce, Intellectual Property Bureau, Staff Consumer Cooperative, Printed Clothing Order---- -----Line---------------------- 1291872 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (\\) experiment Design: In the following examples, the rats were sacrificed after 2 hours of treatment and immunohistochemistry was used to analyze the brain. In Examples 1 and 2, the rat device was recorded to record an electroencephalogram (EEG) and an electromyogram (EMG). In order to avoid pressure on the treatment during the administration of motafni or excipients, a chronic catheter is placed in the peritoneal cavity for administration of motafani or an excipient. Animal and record environment: 65 rats weighing 270-330 grams, male Sprague-Dawley rats (Harlan), individually raised in a pathogen-free barrier facility, placed in a room, The temperature was maintained at 21.5-22.5 ° C, the lights were turned on at 7 am, and the lights were turned off at 7 pm. Rats have freely available food and drowning. At least 3 days prior to each experiment, the rats were placed in an opaque, silencing recording chamber (Biocube) in an isolated room. The light intensity in the inner layer of each cage is 100-150 lux. The Beth Israel Deaconess Medical Center and the Institutional Animal Care and Use Committees of Harvard Medical School approved the procedures for households. Animal Surgery: Rats of Examples 1 and 2 were surgically implanted with 4 EEG screws under anesthesia with hydrated trichloroacetaldehyde (350 mg/kg, iv) (from the bregma, AP ·· +3,-4; RL: +2,-2), and gently contact the dura mater, and implant 2 myoelectric wave wires (Plastics One, Roanoke, VA) under the nape muscles. Connect the lead to a 6-way connector (Plastics One) attached to a skull with dental acrylic. In addition to 5 rats, the temperature transmitter of the telemetry device (TA 10TA-F40, Data Science International, 19 paper scales apply to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the back Please fill out this page again) .0.

-------訂-I I WR W· I 1 l ι ϋ ·ϋ ·ϋ ϋ n n I an n n ϋ I n n n n n n n n 1291872 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（V$) 聖保羅，明尼蘇達州）置於其他的大鼠腹膜腔中。爲了避免觸摸大鼠而能給藥，將80公分矽橡膠（silastic)導管（ 1毫米內徑，Baxter Scientific Products)插入至腹膜腔中，從皮下打開至頭皮，在適當的地方以齒丙烯酸黏牢，並藉由彈簧而外部地保護。將腹膜內的導管裝塡滿肝素化、無熱原的食鹽水，並且在每週及實驗前3天沖洗。使動物復原至少14天，然後在生理記錄開始之即，使其適應記蠢線纜3天。藥物的給藥：將莫塔夫尼（批號：PA 〇〇8 ; Cephalon 公司，西辙斯特，賓州）懸浮在0·9%無熱原的食鹽水中之 0.25%甲基纖維素溶液（PH= 7·4，Dow化學公司，米蘭，密西根）。將藥物以2.0毫升/公斤的體積，150毫克/公斤的劑量而給藥。對照組動物接受等體積的甲基纖維素載體。然後將導管以1毫升〇·9%食鹽水沖洗，以確保藥物傳遞至腹膜腔中。使用紅色閃光信號燈以協助在黑暗中所執行的注射。組織學及免疫組織化學：藥物注射後2小時，以水合三氯乙酸（ 600毫克/公斤，靜脈注射）將動物強烈地麻醉，並以1〇0毫升0.9%食鹽水穿過心臟而灌流，然後再以 5 〇〇毫升鱗酸鹽緩衝的10%福馬林灌流（pH 7.0，Sigma) 。將腦部移除，在福馬林中後固定4小時，然後使其在4 t：平衡於20%蔗糖溶液，此蔗糖溶液係溶解於0.1 Μ磷酸鹽緩衝溶液（PBS)之中’其含有〇.〇2%疊氮化鈉（sigma )。將腦部在冷凍切片機上切片（1:5列，3〇微米），並 20 (請先閱讀背面之注意事項再填寫本頁) 麝. 訂---------線-Φ---------------------- 本紙張尺度適用中國國家標準（CNS)A4規格⑽X 297公爱） A7 B7 1291872 五、發明說明（q) 在4°C儲存於磷酸鹽緩衝溶液-疊氮化物中。來自每個腦中的連續切片，使用先前說明的方法而對F〇s染色（ Elmquist等人，1996)。簡言之，將切片放在抗-Fos的兔子多株抗血淸（Ab-5，Oncogene Research Products ’ 1 ·· 100,000 稀釋）、3% 驢子血淸（Jackson ImmunoResearch )以及含有〇.25%Ti*iton X-100 (PBT-Az)的磷酸鹽緩衝溶液-疊氮化物中，以4°C培育48小時。然後將組織在磷酸鹽緩衝溶液中潤洗，在室溫下，在生物素化的驢子抗兔子 IgG ( 1 : 1，000 稀釋；Jackson ImmunoResearch)中培育 1小時，以過氧化酶共軛連結的抗生物素蛋白（avidin) -生物素-複合物（ABC，Vector)培育1小時，然後在0.05 %二胺基聯苯胺四氫氯化物（DAB)及0.01%過氧化氫、1 %硫酸鎳及0.5%氯化鈷中培育，以在細胞核中產生黑色的反應產物。細胞計數：對於所選擇的腦部區域檢驗Fos-免疫反應性的類型。爲了定量這些差異，在具有可能由莫塔夫尼所誘導的Fos之區域中，由不知實驗條件的檢驗者計數Fos-IR神經元。對於所有的核，對連續3個切片進行兩側的計數，間隔120微米，其包含最大的核區域，並且將6個計數値加以平均。在實施例1中，在與行爲狀態控制有關的區域：前外側視葉前區（VLPO)、管乳突狀核（TMN) 、腹蓋膜區域（VTA)以及前扣帶皮層（anteri〇r cingulate cortex ).中，計數 Fos-IR 核。統計分析：使用Mann-Whitney排列-總和試驗，配合 21 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） (請先閱讀背面之注意事項再填寫本頁) 0. 經濟部智慧財產局員工消費合作社印製訂——------線----------------------- 經濟部智慧財產局員工消費合作社印制衣 1291872 A7 ____B7__ 五、發明說明（/ )-------Book-II WR W· I 1 l ι ϋ ·ϋ ·ϋ ϋ nn I an nn ϋ I nnnnnnnn 1291872 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention Description (V$ ) St. Paul, Minnesota) was placed in the peritoneal cavity of other rats. To avoid contact with the rat, 80 cm of a silastic catheter (1 mm id, Baxter Scientific Products) was inserted into the peritoneal cavity, opened from the skin to the scalp, and glued to the tooth in place. And externally protected by a spring. The intraperitoneal catheter was filled with heparinized, pyrogen-free saline and rinsed weekly and 3 days prior to the experiment. The animals were allowed to recover for at least 14 days and then adapted to the stupid cable for 3 days at the beginning of the physiological record. Drug administration: Mottafni (batch number: PA 〇〇8; Cephalon, Westchester, Pennsylvania) suspended in 0.29% methylcellulose solution in 0.99% pyrogen-free saline solution ( PH=7.4, Dow Chemical Company, Milan, Michigan). The drug was administered in a volume of 2.0 ml/kg and a dose of 150 mg/kg. Control animals received an equal volume of methylcellulose carrier. The catheter was then rinsed with 1 ml of 〇·9% saline to ensure delivery of the drug into the peritoneal cavity. Use a red flashing light to assist with the injections performed in the dark. Histology and immunohistochemistry: 2 hours after drug injection, animals were strongly anesthetized with hydrated trichloroacetic acid (600 mg/kg, iv) and perfused through the heart with 1 〇 0 ml of 0.9% saline. The cells were perfused with 10% sulphate buffered 10% fumarine (pH 7.0, Sigma). The brain was removed, fixed in formalin for 4 hours, and then allowed to equilibrate at 4 t: in 20% sucrose solution, which was dissolved in 0.1 Μ phosphate buffer solution (PBS). .〇2% sodium azide (sigma). Slice the brain on a cryostat (1:5 columns, 3 μm), and 20 (please read the notes on the back and fill out this page) 麝. Order---------Line-Φ ---------------------- This paper scale applies to China National Standard (CNS) A4 specification (10) X 297 public interest) A7 B7 1291872 V. Invention description (q) Store at 4 ° C in phosphate buffered solution - azide. Serial sections from each brain were stained for F〇s using the previously described method (Elmquist et al., 1996). Briefly, sections were placed in anti-Fos rabbits with multiple anti-blood (Ab-5, Oncogene Research Products '1 ··100,000 dilution), 3% scorpion blood (Jackson ImmunoResearch) and containing 〇.25% Ti *iton X-100 (PBT-Az) phosphate buffer solution - azide, incubated at 4 ° C for 48 hours. The tissue was then rinsed in phosphate buffer solution and incubated for 1 hour at room temperature in biotinylated scorpion anti-rabbit IgG (1:1,000 dilution; Jackson ImmunoResearch) conjugated with peroxidase Avidin-biotin-complex (ABC, Vector) was incubated for 1 hour, then 0.05% diaminobenzidine tetrahydrochloride (DAB) and 0.01% hydrogen peroxide, 1% nickel sulfate and Incubation in 0.5% cobalt chloride to produce a black reaction product in the nucleus. Cell Count: The type of Fos-immunoreactivity tested for the selected brain region. In order to quantify these differences, Fos-IR neurons were counted by a tester who did not know the experimental conditions in a region having Fos that may be induced by Motafni. For all nuclei, three consecutive slices were counted on both sides, spaced 120 microns apart, containing the largest nuclear region, and the six counts were averaged. In Example 1, the area associated with behavioral state control: anterior lateral optic lobes (VLPO), ductal papillary nucleus (TMN), ventral capsular area (VTA), and anterior cingulate cortex (anteri〇r In the cingulate cortex), count the Fos-IR core. Statistical analysis: Use Mann-Whitney alignment-sum test, with 21 paper scales applicable to China National Standard (CNS) A4 specification (210 x 297 mm) (please read the notes on the back and fill out this page) 0. Ministry of Economic Affairs Intellectual Property Bureau staff consumption cooperatives printed and developed ------- line----------------------- Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed衣1291872 A7 ____B7__ V. Description of invention (/ )

Bonferroni校正，以比較Fos-IR細胞計數；p値如果小於 0.05則視爲顯著。實施例1:爲了測量由莫塔夫尼所誘導的神經元活化之類型，我們將莫塔夫尼（150毫克/公斤）或載體，在午夜、正常的淸醒期間而給藥。數據顯示在以下的表1中。Bonferroni correction to compare Fos-IR cell counts; p値 is considered significant if less than 0.05. Example 1: To measure the type of neuronal activation induced by Motafni, we administered Motafni (150 mg/kg) or vehicle during midnight, normal wakefulness. The data is shown in Table 1 below.

載體莫塔夫尼 150毫克/公斤 Kruskal-Wallis Wit η 6 6 扣帶皮層 52 土 13 191 ±38 0.008 管乳突狀核 13±7 46±4 0,005 腹蓋膜區域 8土2 12±3 NS 表1 :對於在午夜以莫塔夫尼或載體治療的大鼠之細胞計數。數値是以平均値土標準差表示。相較於載體’粗體字的數値是統計上顯著的（藉由post-hoc Scheffe試驗計算）在莫塔夫尼（150毫克/公斤）的給藥之後’相較於在對照組中所觀察到的數目，管乳突狀核具有4倍的F〇S-IR 神經元（表1)。前外側視葉前區的神經元’在睡眠期間是活躍的（Sherin 等人，271 : 216_9 ( 1996 ) ’Carrier Motafni 150 mg / kg Kruskal-Wallis Wit η 6 6 Buckle with cortex 52 Soil 13 191 ± 38 0.008 Tube papillary nucleus 13 ± 7 46 ± 4 0,005 Abdominal cap membrane area 8 soil 2 12 ± 3 NS table 1 : Cell counts for rats treated with Mottafni or vehicle at midnight. The number is expressed as the average standard deviation of the soil. The number of bold words compared to the vector is statistically significant (calculated by the post-hoc Scheffe test) after administration of Mottafni (150 mg/kg) as compared to the control group. The observed number of tube papillary nucleus has 4 fold F〇S-IR neurons (Table 1). Neurons in the anterior lateral optic anterior region are active during sleep (Sherin et al., 271: 216_9 (1996) ’

Alam等人，神經科學學會年會，華盛頓特區，1996)，以及因爲所有的動物大部分都是淸醒的，所以並不意外的® 22 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） -1--------------------訂----------線丨 (請先閱讀背面之注意事項再填寫本頁) 1291872 A7 B7 五、發明說明（) ，在所有的大鼠中，Fos-IR前外側視葉前區的神經元是罕見的。相較於對照組，莫塔夫尼治療的大鼠在皮層中具有更多的Fos免疫反應性。這個Fos的誘導在多數的皮層間是明顯的，但在扣帶及梨狀皮層中通常是更明確的’其在額骨及顱頂骨皮層中具有中等的量。實施例2 :莫塔夫尼（150毫克/公斤）在中午、正常的睡眠期間而給藥。數據顯示在以下的表2中。載體莫塔夫尼 Mann-Whitney 150毫克/公斤 Wit η 6 7 前外側視葉前區 52土7 26 土 3 0.007 管乳突狀核 8±4 43 土 5 0.003 (請先閱讀背面之注意事項再填寫本頁) » 經濟部智慧財產局員工消費合作社印製表2 :在LD或DD條件下，對於以莫塔夫尼或載體在中午治療的大鼠之細胞計數。相較於載體，粗體字的數値是統計上不同於載體（使用P〇st-h〇C Scheffe試驗計算）。在維持於正常LD週期的動物中，在中午莫塔夫尼（ 150毫克/公斤）的給藥，明顯地在管乳突狀核中增加Fos-IR神經元的數目，而在前外側視葉前區中是減少的。莫塔夫尼的治療也增加在額骨及扣帶皮層中的表現。 23 訂---------線-· 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） -- · iAlam et al., Annual Meeting of the Society for Neuroscience, Washington, DC, 1996), and because most of the animals are awakened, it is not surprising that the 22 paper scale applies to the Chinese National Standard (CNS) A4 specification (210). χ 297 mm) -1-------------------- Order----------Line 丨 (please read the notes on the back and fill in This page) 1291872 A7 B7 V. INSTRUCTIONS () In all rats, neurons in the anterior and posterior anterior lobes of Fos-IR are rare. Motafni-treated rats had more Fos immunoreactivity in the cortex than the control group. This induction of Fos is evident between most cortical layers, but is usually more pronounced in the cingulate and piriform cortex 'which has a moderate amount in the frontal and cranial cortex. Example 2: Motafny (150 mg/kg) was administered during noon, normal sleep. The data is shown in Table 2 below. Carrier Motaffny Mann-Whitney 150 mg / kg Wit η 6 7 Anterior lateral optic lobes 52 soil 7 26 Soil 3 0.007 Tube papillary nucleus 8 ± 4 43 Soil 5 0.003 (Please read the note on the back first Fill in this page) » Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Print Table 2: Cell counts for rats treated with Motafni or vehicle at noon under LD or DD conditions. The number of bold characters is statistically different from the vector (calculated using the P〇st-h〇C Scheffe test) compared to the vector. In animals maintained in the normal LD cycle, administration of nod mottafni (150 mg/kg) significantly increased the number of Fos-IR neurons in the ductal mammary nucleus, while in the anterolateral lobes The front area is reduced. Mottafni's treatment also increased in the frontal and ligament cortex. 23 Order---------Line-· This paper size applies to China National Standard (CNS) A4 specification (210 x 297 mm) -- · i

Claims

1291872 U .α. 4.ό ϋ Άΐ m 95. ί2. 26 I-1::=:—·.—....—one” ------ VI. Patent application scope 1. A treatment with attention A pharmaceutical composition of a patient who does not concentrate on symptoms of hyperreactivity or multiple sclerosis fatigue, including an effective amount of motafinil (modafinil) that stimulates activity in a brain canal-like neuron of a patient ) compound. 2. A pharmaceutical composition according to claim 1 of the scope of the patent application, which comprises an effective amount of Motaftan compound which can improve or prevent symptoms of inattention and overreaction in a patient. 3. A pharmaceutical composition according to claim 1 of the patent application, which comprises an effective amount of a Motaftan compound which can ameliorate or prevent the symptoms of multiple sclerosis in a patient. 4. The pharmaceutical composition according to item 1 of the scope of the patent application is in the form of a unit dose. The pharmaceutical composition according to any one of claims 1 to 4, wherein the Motafni compound is Mottafni. 6- The pharmaceutical composition according to any one of claims 1 to 4, wherein the patient is an adult. The pharmaceutical composition according to any one of claims 1 to 4, wherein the patient is a human child. The pharmaceutical composition according to any one of claims 1 to 4, wherein the effective amount is from about 1 to about 400 mg per day. The pharmaceutical composition according to any one of claims 1 to 4, wherein the effective amount is from about 1 〇〇 to about 400 mg per day. 10 according to the scope of claims 1 to 4 Any one of the medical group 1 (please read the note on the back and write this page first) The standard paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1291872 A8B8C8D8 VI. Wherein the effective amount is from about 200 to about 400 mg per day. The pharmaceutical composition according to any one of claims 1 to 4, wherein the effective amount is about 200 mg per day. The pharmaceutical composition according to any one of claims 1 to 4, wherein the composition comprising the Motafni compound is formulated for oral administration. The pharmaceutical composition according to any one of claims 1 to 4, wherein the composition comprising the Motafni compound is formulated as a tablet. 14. The pharmaceutical composition according to claim 13 wherein the tablet comprises lactose, corn starch, magnesium citrate, croscarmellose sodium, povidone, and hard Magnesium oleate or talc or any combination thereof. 2 (Please read the note on the back and fill out this page.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm).