TWI839725B - 致幻劑在製備治療運動障礙的藥物之用途 - Google Patents
致幻劑在製備治療運動障礙的藥物之用途 Download PDFInfo
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- TWI839725B TWI839725B TW111116663A TW111116663A TWI839725B TW I839725 B TWI839725 B TW I839725B TW 111116663 A TW111116663 A TW 111116663A TW 111116663 A TW111116663 A TW 111116663A TW I839725 B TWI839725 B TW I839725B
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Abstract
揭露了一種治療運動障礙之方法，該方法藉由如下進行：將有效量的致幻劑投與於患有運動障礙之個體以及治療該運動障礙。
Description
本發明關於用於治療運動障礙之組成物和方法。更特別地，本發明關於用致幻劑治療運動障礙之方法。
震顫係身體部位不隨意的、有節律的和振盪的運動，並且係最常見的運動障礙。它們係由拮抗肌之交替或同步收縮引起的。當身體處於靜止狀態(身體部位得到完全支撐、放鬆或不隨意激活)或處於活動狀態(在隨意運動期間、在特定姿勢期間或在肌肉收縮對抗靜止物體期間)時，可能發生震顫。
帕金森氏症係一種常見的靜止性震顫，並且還引起僵硬、緩慢減少的運動和不平衡。靜止性震顫通常使用抗帕金森劑(如抗膽鹼藥、金剛烷胺、多巴胺促效劑、左旋多巴或唑尼沙胺)進行治療。
自發性震顫(ET)係一種常見的動作性震顫，並且最常影響手和手臂，也可影響頭部、嗓音、面部或軀幹。ET由隨意運動或當手臂保持在固定姿勢對抗重力時激活。ET具有很強的遺傳組分，並且在家族中傳遞。全世界1%的人口患有ET，並且5%的成人大於60歲。由於焦慮、興奮或其他腎上腺素能刺激可能加重震顫。ET等動作性震顫可以使用心得安或乙苯嘧啶二酮作為兩種
主要治療，或使用托吡酯、加巴噴丁(gapapentin)、肉毒桿菌毒素注射劑、以及深層腦刺激和單側丘腦切開術進行治療。乙苯嘧啶二酮具有急性不良反應(鎮靜、嗜睡、疲勞、憂鬱、噁心、嘔吐、運動失調、不適、暈眩、意志輕佻、意識錯亂、眩暈和急性毒性反應)，而心得安具有慢性副作用(頭暈目眩、疲勞、陽痿和心搏過緩)。
震顫亦為某些藥物之副作用。可能引起震顫的藥物包括沙利竇邁和阿糖胞苷等癌症藥物，丙戊酸和丙戊酸鈉等癲癇藥物，茶鹼和沙丁胺醇等氣喘藥物，環孢素和他克莫司等免疫抑制藥物，碳酸鋰等情緒穩定劑，咖啡因和安非他命等興奮劑，選擇性血清素再吸收抑制劑(SSRI)和三環類等抗憂鬱藥，胺碘酮、普魯卡因胺等心臟藥物，某些抗生素，無環鳥苷和阿糖腺苷等某些抗病毒藥，酒精，菸鹼，某些高血壓藥物，腎上腺素和去甲腎上腺素，減肥藥物(替拉曲考)，過多的甲狀腺藥物(左旋甲狀腺素)，或丁苯那嗪(一種治療過度運動障礙的藥物)。個體對這種副作用感到尷尬，但除非他們停止服用藥物或調整劑量，否則副作用不會消失。
致幻劑係能夠誘導異常主體效應(exceptional subjective effect)之物質，例如像夢一樣的意識改變、情感變化、增強的內省能力、視覺心像、假幻覺、聯覺、改變的時間和特殊感知、神秘型體驗(mystical-type experience)、去形體化(disembodiment)和自我解離(ego dissolution)(Liechti,2017；Passie,Halpern,Stichtenoth,Emrich和Hintzen,2008)。致幻劑可用於輔助針對許多適應證(包括焦慮、憂鬱、成癮、人格障礙等)之心理療法，還可以用於治療叢集性頭痛和偏頭痛等其他障礙(Passie等人，2008；Hintzen等人，2010；Nichols,2016；Liechti,2017)。
仍然需要對運動障礙之有效治療。
本發明提供了一種治療運動障礙之方法，該方法藉由如下進行：將有效量的致幻劑投與於患有運動障礙之個體以及治療該運動障礙。
在與以下附圖結合考慮時，參照以下詳細描述，會容易認識到並更好地理解本發明之其他優點：[圖1]係來自二氫野芸香鹼(harmaline)誘導的大鼠震顫模型的自發活動/運動數據之圖表；以及[圖2]係來自二氫野芸香鹼誘導的大鼠震顫模型的震顫功率比數據之圖表。
本發明提供了一種治療運動障礙之方法，該方法藉由如下進行：將有效量的致幻劑投與於患有運動障礙之個體以及治療該運動障礙。
如本文使用的，「運動障礙」可以指導致身體運動異常增加、運動減少或運動緩慢的任何神經系統病症。運動可為隨意的或不隨意的。本文治療的運動障礙可以包括但不限於運動失調、頸部肌肉緊張不足、舞蹈症、肌肉緊張不足、功能性運動障礙、杭丁頓氏舞蹈症、多系統萎縮、肌陣攣、帕金森氏症、帕金森綜合症、進行性核上神經麻痺症、不寧腿症候群、遲發性運動障礙、妥瑞症、震顫(包括自發性震顫)或威爾森氏病。運動障礙可為靜止性震顫或動作性震顫。運動障礙也可能是由於個體正在服用的藥物之副作用引起的。
本發明之致幻劑可為但不限於麥角酸二乙胺(LSD)、賽洛西賓、二甲-4-羥色胺(psilocin)、仙人球毒鹼、3,4-亞甲基二氧基甲基苯丙胺(MDMA，包括其單獨的鏡像異構物形式R-MDMA或S-MDMA)、5-甲氧基-N,N-二甲基色胺(5-MeO-DMT)、二甲基色胺(DMT)、2,5-二甲氧基-4-碘苯丙胺(DOI)、2,5-二甲氧基-4-溴苯丙胺(DOB)、其鹽、其酒石酸鹽、其溶劑合物、其異構物、其類似物、其同系物、或其氘化形式。較佳的是，致幻劑之劑量係提供有意義的臨床效應的劑量，或可為知覺劑量或亞知覺劑量之劑量。致幻藥物可以作為單次劑量或作為在多日、多週、多月或多年內的重複劑量投與。LSD可以使用0.05-1mg(10-1000μg)的劑量。賽洛西賓之劑量可為1-50mg，二甲-4-羥色胺之劑量可為1-100mg，仙人球毒鹼之劑量可為10-1000mg，5-MeO-DMT之劑量可為0.2-20mg，DMT之劑量可為10-100mg，DOI之劑量可為0.1-10mg，並且DOB之劑量可為0.1-5mg。單次劑量的致幻藥物之效應可以在投與後持續1-12小時，並且在此期間個體可以由精神病醫師等醫務人員監督。如果投與較低的劑量，則可能不需要進行醫療監督。
從機制上講，致幻劑充當非特異性血清素促效劑。LSD強效刺激5-HT2A受體，但也刺激5-HT2B/C、5-HT1和D1-3受體(Rickli等人，2016)。血清基能致幻劑藉由對血清素5-HT2A受體之激動作用而具有其精神活性/迷幻效應。LSD主要藉由刺激5-HT2A受體而在人類中誘導其致幻效應(Kraehenmann等人，2017；Preller等人，2017；Barrett等人，2018)。賽洛西賓(3-(2-二甲基胺基乙基)-1H-吲哚-4-基]二氫磷酸鹽)係一種由裸蓋菇(psilocybin mushroom)(例如但不限於蔚藍裸蓋菇(P.azurescens)、半裸蓋菇(P.semilanceata)和藍柄裸蓋菇(P.cyanescens))產生的致幻藥物。二甲-4-羥色胺係賽洛西賓之活性代謝物，抑制5-HT運輸蛋白(SERT)，而LSD刺激D1-3受體但不與SERT相互作用(Rickli等人，2016)。與LSD相比，賽洛西賓和仙人球毒鹼顯示出對D2受體沒有親和
力。LSD之強效多巴胺能受體促效劑特性與延遲的LSD效應有關，這種效應可能與其他迷幻劑不同，並且可能更像興奮劑(Mittman等人，1991；Marona-Lewicka等人，2005；Marona-Lewicka等人，2007；Nichols,2016)。LSD和色胺DMT及二甲-4-羥色胺係5-羥色胺5-HT1受體之強效促效劑，而其他迷幻劑(如仙人球毒鹼)對該受體表現出低效能(Rickli等人，2016)。雖然沒有臨床研究明確記錄5-HT1受體(Strassman,1996；Nichols,2016)在致幻劑作用中的角色，但物質之間可能存在差異。與其他不與SERT相互作用的致幻劑相比，當使用賽洛西賓時，賽洛西賓對SERT之抑制(Rickli等人，2016)及血清素之增加可能與更大的血清基能毒性(包括噁心和嘔吐)相關。仙人球毒鹼與5-HT2A、5-HT1A和腎上腺素能α2A受體結合之濃度範圍相似(Rickli等人，2016)。在治療運動障礙中，致幻劑之效應可為CNS效應、直接周圍效應或兩者之組合。與治療其他障礙一樣，關於致幻劑如何發揮其效應存在多種觀點。根據藥物對5HT2A受體的直接效應之經驗，有證據表明它們藉由心理機制係有效的。還有證據表明它們在腦中具有直接神經生物學效應，而且它們增強全腦連通性並在皮層神經元中引入新程度的神經可塑性。此外，有證據表明，除了脊髓外的周圍神經系統效應外，還有腦外的由中樞神經系統結合驅動的效應。雖然針對運動障礙之確切作用機制仍未完全明確，但可能是該等假定機制之某種組合。
在本發明之方法中，治療運動障礙可以包括減少和/或消除不希望的運動或震顫，或將任何異常運動恢復到正常狀態。該方法可以進一步包括減少焦慮以及因此減少由於焦慮引起的異常運動。該方法可以進一步減少由於個體正在服用的藥物之副作用引起的震顫。
考慮到個體患者之臨床狀況，投與的部位和方法，投與的時間安排，患者年齡、性別、體重，以及開業醫師已知的其他因素，根據良好的醫學實踐投與和給藥本發明之化合物。因此，用於本文目的的藥學上「有效量」由本領
域已知的該等考慮來確定。該量必須有效實現改善，包括但不限於改善的生存率或更快的恢復，或者改善或消除症狀和熟悉該項技術者根據適當措施選擇的其他指標。
在本發明之方法中，本發明之化合物能以各種方式投與。應注意，它們可作為化合物投與，並且可單獨投與或作為活性成分與藥學上可接受的載體、稀釋劑、佐劑和媒介物組合投與。化合物可以經口、經皮膚、經皮下或經胃腸外投與，包括舌下、口腔、吸入、靜脈內、肌內和鼻內投與。所治療的患者係溫血動物，特別是哺乳動物，包括人。藥學上可接受的載體、稀釋劑、佐劑和媒介物以及植入物載體通常係指不與本發明之活性成分反應的惰性、無毒固體或液體填充劑、稀釋劑或封裝材料。
劑量可為單次劑量或者在數小時、數日、數週、數月或數年內的多次劑量或連續劑量。
當經口投與本發明之化合物時，它通常被配製成直接釋放膠囊劑、直接釋放片劑、修飾釋放膠囊劑或片劑(包含腸溶衣)、溶液劑或混懸劑。當經胃腸外投與本發明之化合物時，它通常被配製成舌下或口腔經口溶解片劑、溶解薄膜劑、鼻內粉劑、鼻內溶液劑、吸入粉劑、吸入溶液劑、透皮貼劑、帶有微針或其他滲透增強劑的透皮貼劑、或作為單位劑量可注射形式(溶液劑、混懸劑、乳劑)。適於注射的藥物配製物包括無菌水性溶液劑或分散劑和用於重構成無菌可注射溶液劑或分散劑的無菌粉劑。載體可為含有例如水、乙醇、多元醇(例如甘油、丙二醇、液體聚乙二醇等)、它們的合適的混合物和植物油之溶劑或分散介質。
可以例如藉由使用如卵磷脂的包衣、藉由在分散劑的情況下保持所需粒度以及藉由使用界面活性劑來保持適當的流動性。非水性媒介物如棉籽油、芝麻油、橄欖油、大豆油、玉米油、葵花油或花生油和酯(如肉豆蔻酸異丙
酯)也可用作化合物組成物之溶劑系統。另外，可添加增強組成物之穩定性、無菌性和等滲性的各種添加劑，包括抗微生物防腐劑、抗氧化劑、螯合劑和緩沖劑。可藉由各種抗菌劑和抗真菌劑，例如對羥苯甲酸酯、氯丁醇、苯酚、山梨酸等來確保防止微生物作用。在許多情況下，希望包括等滲劑，例如糖、氯化鈉等。可藉由使用延遲吸收劑(例如，單硬脂酸鋁和明膠)來實現可注射藥物形式之延長的吸收。然而，根據本發明，所用的任何媒介物、稀釋劑或添加劑必須與化合物相容。
無菌可注射溶液劑可藉由將用於實施本發明之化合物摻入所需量的適當溶劑與所需的各種其他成分來製備。
本發明之藥物配製物能以含有任何相容載體(如各種媒介物、佐劑、添加劑和稀釋劑)的可注射製劑之形式投與於患者；或者，本發明中使用的化合物能以緩釋皮下植入物或靶向遞送系統(如單株抗體、載體遞送、離子電滲、聚合物基質、脂質體和微球)之形式經胃腸外投與於患者。可用於本發明的遞送系統之實例包括：5,225,182；5,169,383；5,167,616；4,959,217；4,925,678；4,487,603；4,486,194；4,447,233；4,447,224；4,439,196；和4,475,196。許多其他這樣的植入物、遞送系統和模組係熟悉該項技術者公知的。
藉由參考以下實驗實例進一步詳細描述本發明。提供該等實例僅用於說明的目的，除非另有說明，否則無意為限制性的。因此，本發明決不應被解釋為限於以下實例，而是應該被解釋為涵蓋由於本文提供的傳授內容而變得明顯的任何和所有變化。
實例1
實驗程序
該實驗在大鼠(CD/SD)中進行，來源：查理斯河實驗室(Charles River Labs)，年齡或體重：到達時180-200克，性別：雄性。隨機分組：動物被隨機分配至各處理組。
二氫野芸香鹼之投與途徑係IP，TA之投與途徑係PO。劑量體積係3mL/kg。一或多種配製物：二氫野芸香鹼：0.9%鹽水；TA：PBS用作TA之媒介物。劑量水平：二氫野芸香鹼：30mg/kg；LSD-100ug/kg PO，R-MDMA-25mg/kg。劑量頻率：1x。研究持續時間：1天。預處理時間(最多2小時)：15分鐘。組之數量：4。每組之動物數量：10。動物之總數量：40。研究設計總結在表1中。
方法
使用雄性CD/SD大鼠(CRL)，到達時180-200g。它們在測試前適應了5-7天。每隻大鼠僅測試一次，然後對其進行安樂死以收集腦組織。
藥物
二氫野芸香鹼(二氫野芸香鹼HCl二水合物；西格瑪公司(Sigma)H1392-1)由米利爾(Melior)獲得，並且使用1.33的游離鹼校正因子在鹽水中以10mg/mL(校正後為13.3mg/mL)配製，並以3ml/kg藉由IP途徑投與。
使用無菌過濾水在米利爾配製鹽水(0.9%NaCl)。
測試程序
對於組1-4，每隻動物間隔15分鐘接受兩次處理(見表1)。第一次處理係TA或媒介物。第二次處理係二氫野芸香鹼或鹽水。在第二次給藥後，立即將動物放入測力計(actimeter)(BASi測力板測力計(BASi Force Plate Actimeter))中。測力計由含有剛性板的封閉容器(41.6×41.6cm)組成，該板位於每個角落的四個力換能器上。換能器測量動物走動時所施加的力之分佈。
在該研究中評估四個處理組，表1中列出了每組的測試劑、劑量水平和N。在投與第二測試劑(二氫野芸香鹼或鹽水)後，監測運動活動60分鐘。TPR計算為在二氫野芸香鹼投與後0分鐘開始的六個連續10分鐘時間段(即，從0分鐘至60分鐘)的期間或10分鐘時間段的震顫之平均值。
使用比率TPR=(P2)/(P1+P3)來評估震顫功率，其中Pn=(1)1.5-8Hz，(2)8-13Hz，和(3)13-25Hz的綜合功率(頻率範圍可以根據測試時的實際數據進行優化)。震顫功率比藉由三因素變異數分析(3-factor ANOVA)(時間、頻率、處理)進行評估。
作為分析之一部分，測量了二氫野芸香鹼之腦水平。從分析中排除具有低腦二氫野芸香鹼水平之異常值(大於2個標準差)。
組織樣本和安樂死
在60分鐘(測試結束)時，從用二氫野芸香鹼處理的所有動物中收穫腦。將那些大鼠之腦取出，沿正中矢狀平面分成兩個半球，稱重，然後在乾冰上快速冷凍。藉由HPLC質譜法在左半球評估二氫野芸香鹼之濃度。
結果和討論
二氫野芸香鹼誘導的模型係一種經典的動作性震顫之動物模型。(Pan等人，Animal models of tremor：relevance to human tremor disorders[震顫之動物模型：與人類震顫障礙的相關性].Tremor Other Hyperkinet Mov.[震顫和其他多動運動]，2018；8.)單次劑量的二氫野芸香鹼可以藉由增強下橄欖核(IO)神經元之間的偶合來誘導動作性震顫。二氫野芸香鹼誘導的震顫主要係一種對心得安、乙苯嘧啶二酮和酒精有反應的動作性震顫。因此，長期以來一直假定二氫野芸香鹼誘導的震顫係ET之動物模型。二氫野芸香鹼屬於一組天然存在的化合物，稱為β-生物鹼。在ET患者之血液和腦中，已觀察到增加的二氫野芸香鹼相關的β-生物鹼(如哈爾鹼)，表明環境因子可有助於ET患者的橄欖小腦系統之振盪活動。已證明二氫野芸香鹼可在多種動物(包括小鼠、大鼠、貓、猴子和豬)中誘導動作性震顫，表明進化上保守的橄欖小腦回路可產生震顫。二氫野芸香鹼誘導的震顫模型已在ET之臨床前研究中進行了測試，用於開發縫隙連接阻斷劑卡本諾索隆和T型鈣通道阻斷劑。該模型之轉換有效性(Translational validity)在臨床研究中得到證實。因此，在該模型中獲得的結果可以預測受試化合物在人類中的臨床療效。
圖1示出了在用心得安(15mg/kg，IP)作為陽性對照的大鼠中來自二氫野芸香鹼誘導的震顫模型的自發活動/運動數據之實例。在二氫野芸香鹼投與後60分鐘內，每隔10分鐘進行測量。每組10隻大鼠。*-P<0.05，**-P<0.01，三因素變異數分析(時間、頻率、處理)。
圖2示出了在用心得安(15mg/kg，IP)作為陽性對照的大鼠中來自二氫野芸香鹼誘導的震顫模型的震顫功率比數據之實例。在二氫野芸香鹼投與後60分鐘內，每隔10分鐘進行測量。每組10隻大鼠。*-P<0.05，**-P<0.01，***-P<0.001，三因素變異數分析(時間、頻率、處理)。
在整個申請中，將包括美國專利在內的各種出版物均藉由作者和年份以及專利案號進行援引。下面列出了該等出版物之完整引文。該等出版物和專利之揭露內容以其全文藉由援引特此併入本申請中，以便更全面地描述本發明所屬領域之現狀。
已經以示例性的方式描述了本發明，並且應理解，已經使用的術語意在具有說明性詞語的性質，而非限制性的。
顯而易見地，能夠根據以上傳授內容進行本發明之很多修改和變化。因此，應當理解，在所附申請專利範圍之範圍內可以用不同於具體描述的方式來實踐本發明。
參考文獻
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Claims (6)
- 一種致幻劑在製備治療運動障礙的藥物之用途，該用途包括以下步驟：將有效量的致幻劑投與於患有運動障礙之個體，該致幻劑選自由麥角酸二乙胺(LSD)及3,4-亞甲基二氧基甲基苯丙胺(R-MDMA)所組成之群組；以及治療該運動障礙。
- 如請求項1所述之用途，其中該運動障礙選自由以下組成之群組：運動失調、頸部肌肉緊張不足、舞蹈症、肌肉緊張不足、功能性運動障礙、杭丁頓氏舞蹈症、多系統萎縮、肌陣攣、帕金森氏症、帕金森綜合症、進行性核上神經麻痺症、不寧腿症候群、遲發性運動障礙、妥瑞症、震顫和威爾森氏病。
- 如請求項1所述之用途，其中所述治療步驟進一步包括減少和/或消除不希望的運動或震顫之步驟。
- 如請求項1所述之用途，其中所述治療步驟進一步包括將異常運動恢復到正常狀態之步驟。
- 如請求項1所述之用途，其中所述治療步驟進一步包括減少焦慮以及減少由於焦慮引起的異常運動之步驟。
- 如請求項1所述之用途，其中所述治療步驟進一步包括減少由於個體正在服用的藥物之副作用引起的震顫之步驟。
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| TW111116663A TWI839725B (zh) | 2021-05-04 | 2022-05-03 | 致幻劑在製備治療運動障礙的藥物之用途 |
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| WO2023168022A1 (en) | 2022-03-04 | 2023-09-07 | Reset Pharmaceuticals, Inc. | Co-crystals or salts comprising psilocybin |
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| WO2020212952A1 (en) * | 2019-04-17 | 2020-10-22 | Compass Pathfinder Limited | Treatment of depression and other various disorders with psilocybin |
| US20200397752A1 (en) * | 2017-10-26 | 2020-12-24 | Consejo Superior de Investigacions Cientificas (CSIS) | Combination product for the treatment of neurological and/or psychiatric disorders |
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| NL2018190B1 (en) * | 2017-01-18 | 2018-07-26 | Procare Beheer B V | Psilocybin or psilocin in combination with cannabinoid |
| MX2022009527A (es) * | 2020-02-04 | 2022-11-16 | Mindset Pharma Inc | Derivados de la psilocina como agentes psicodelicos serotoninergicos para el tratamiento de trastornos del snc. |
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| US20200397752A1 (en) * | 2017-10-26 | 2020-12-24 | Consejo Superior de Investigacions Cientificas (CSIS) | Combination product for the treatment of neurological and/or psychiatric disorders |
| WO2020212952A1 (en) * | 2019-04-17 | 2020-10-22 | Compass Pathfinder Limited | Treatment of depression and other various disorders with psilocybin |
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| TW202428274A (zh) | 2024-07-16 |
| WO2022235531A1 (en) | 2022-11-10 |
| TW202245765A (zh) | 2022-12-01 |
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