TWI726355B - 苯甲酸或其鹽及衍生物用於預防或治療抗n-甲基-d-天冬胺酸受體腦炎之用途 - Google Patents
苯甲酸或其鹽及衍生物用於預防或治療抗n-甲基-d-天冬胺酸受體腦炎之用途 Download PDFInfo
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- TWI726355B TWI726355B TW108124912A TW108124912A TWI726355B TW I726355 B TWI726355 B TW I726355B TW 108124912 A TW108124912 A TW 108124912A TW 108124912 A TW108124912 A TW 108124912A TW I726355 B TWI726355 B TW I726355B
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Abstract
本揭露內容提供一種預防或治療有此需求的個體的抗N-甲基-D-天冬胺酸受體腦炎的方法,包括向該個體投予有效量的苯甲酸鹽及其衍生物。
Description
本揭露內容係有關抗N-甲基-D-天冬胺酸受體(anti-N-methyl-D-aspartate receptor,NMDAR)腦炎的預防或治療,特別是藉由使用苯甲酸鹽預防或治療抗NMDAR腦炎的方法。
抗N-甲基-D-天冬胺酸受體(NMDAR)腦炎是由自體抗體相關的NMDAR功能障礙引起的自體免疫性腦炎。在過去十年中,發現越來越多NMDAR腦炎。自體抗體穿過血腦屏障並選擇性地與NMDA受體交聯,導致興奮性和抑制性海馬神經元中的NMDA受體內化,最終導致經NMDAR介導的突觸神經傳遞的功能減退。
大多數患有抗NMDAR腦炎的患者首先發現精神病症狀,其次是癲癇等神經系統症狀。通常,抗癲癇藥和抗精神病藥物在抗NMDAR腦炎患者中效果較差。此外,藉由甲基培尼皮質醇(methylprednisolone) 和靜脈內免疫球蛋白的免疫療法,或藉由血漿交換而去除自體抗體的療法,也用於治療患有抗NMDAR腦炎的患者。然而,即使在免疫療法和抗精神病藥物治療後,仍有一些患者難以治癒。
因此,對抗NMDAR腦炎的預防或治療仍有需求。
鑑於前述內容,本揭露提供一種在有此需求的個體中預防或治療抗NMDAR腦炎的方法,包括向該個體投予有效量的苯甲酸或其鹽及其衍生物以及醫藥上可接受之賦形劑。
在本揭露內容的一具體實施例中,苯甲酸鹽及其衍生物是苯甲酸鈉、苯甲酸鉀、苯甲酸鈣、苯甲酸鎂、2-胺基苯甲酸酯、3-胺基苯甲酸酯、4-胺基苯甲酸酯、4-羥基苯甲酸乙酯、4-羥基苯甲酸乙酯鈉、4-羥基苯甲酸丙酯、4-羥基苯甲酸丙酯鈉、4-羥基苯甲酸甲酯、4-羥基苯甲酸鈉、苯甲酸芐酯或苯甲酸甲酯,但不限於此。
在本揭露內容的另一個具體實施例中,苯甲酸鹽是苯甲酸鈉。
在本揭露內容的一個具體實施例中,醫藥上可接受的賦形劑係選自由填充劑、黏合劑、防腐劑、崩解劑、潤滑劑、懸浮劑、潤濕劑、溶劑、介面活性劑、酸、調味劑、聚乙二醇(PEG)、烷二醇、癸二酸、二甲亞碸、醇及其任何組合所組成的群組。
在本揭露內容的一個具體實施例中,抗NMDAR腦炎是由NMDAR的功能減退引起的。在另一個具體實施例中,抗NMDAR腦炎中之細胞破壞係由自體抗體所引起。
在本揭露內容的一個具體實施例中,苯甲酸或其鹽和衍生物係以有效量投予於個體,以增強或活化NMDAR的功能,進而預防或治療抗NMDAR腦炎。
在本揭露內容的一個具體實施例中,苯甲酸或其鹽及衍生物可以對個體投予200毫克/天至2000毫克/天的量,例如,400毫克/天至1800毫克/天、600毫克/天至1500毫克/天、及800毫克/天到1200毫克/天的量。
在本申請的一個具體實施例中,苯甲酸或其鹽及衍生物可以投予至個體為期1個月至2年,例如4週至12個月。在本申請的另一個具體實施例中,苯甲酸鹽或其鹽及衍生物投予於個體為期約2個月。
在本揭露內容的一個具體實施例中,苯甲酸或其鹽和衍生物係組成物中作為預防或治療抗NMDAR腦炎的唯一活性成分,或苯甲酸或其鹽和衍生物係與其他活性成分合併用於預防或治療抗NMDAR腦炎。在一個具體實施例中,該其他的活性成分是抗精神病藥。在另一個具體實施例中,該抗精神病藥係選自由阿立哌唑(aripiprazole)、氯氮平(clozapine)、帕潘立酮(paliperidone)、理思必妥(risperidone)、布瑞哌唑(brexpiprazole)、奧氮平(olanzapine)、喹硫平(quetiapine)、齊拉西酮(ziprasidone)、氨磺必利(amisulpride)、阿塞那平(asenapine)、伊潘立酮(iloperidone)、魯拉西酮(lurasidone)、卡利拉嗪(cariprazine)、 絡篤平(zotepine)、氟哌啶醇(haloperidol)、氯丙嗪(chlorpromazine)、氯噻平(clotiapine)、氟哌噻吨(flupentixol)、康朗舒(clopixol)、舒必利(sulpiride)、氯噻嗪(chlorprothixene)、左旋美丙嗪(levomepromazine)、美索達嗪(mesoridazine)、哌氰嗪(periciazine)、普力馬林(promazine)、硫利達嗪(thioridazine)、洛沙平(loxapine)、嗎啉吲酮(molindone)、奮乃靜(perphenazine)、硫次克辛(thiothixene)、氟哌啶醇(droperidol)、氟奮乃靜(fluphazine)、匹莫齊特(pimozide)、丙氯拉嗪(prochlorperazine)、硫丙拉嗪(thioproperazine)、三氟拉嗪(trifluoperazine)、珠氯噻醇(zuclopenthixol)所組成的群組。
在本揭露內容的一個具體實施例中,苯甲酸或其鹽和衍生物之投予與其他用於預防或治療抗NMDAR腦炎的療法合併。在一個具體實施例中,其他的療法包括,但不限於,心理療法、電痙攣療法(electroconvulsive therapy,ECT)和其他腦刺激(諸如,重複經顱磁刺激(rTMS)和經顱直流電刺激(tDCS))、免疫療法、血漿分離術、類固醇脈衝療法及其任何組合。在一個具體實施例中,類固醇脈衝療法是用甲基普賴蘇穠(methylprednisolone)進行脈衝療法。
除上述之外,本揭露內容還提供了有效量的苯甲酸或其鹽和衍生物用於製備預防或治療有此需求的個體中的抗N-甲基-D-天冬胺酸受體(NMDAR)腦炎的藥物的用途。此外,本揭露內容還提供有效量的苯甲酸或其鹽和衍生物於預防或治療有此需求的個體的抗N-甲基-D-天冬氨酸受體(NMDAR)腦炎的用途。
以下實施例用於舉例說明本揭露內容。基於本說明書的揭露內容,所屬技術領域中具有通常知識者可以理解本揭露內容的其他優點。本揭露內容還可如不同的具體實施例中所描述的而實現或應用。
還應注意,如本說明書中所使用的單數形式「一(a)」、「一(an)」和「該(the)」包括複數個指涉物,除非明確且毫無疑義地限於一個指涉物。除非上下文另有明確說明,否則術語「或」可與術語「及/或」互換使用。
抗NMDAR腦炎是一種自體免疫性疾病,肇於自體抗體穿過血腦屏障,導致NMDA受體在興奮性和抑制性海馬神經元中的選擇性交聯和內化,導致經NMDAR介導的突觸電流減少和NMDAR的功能減退。
本揭露內容提供了預防或治療有此需求的個體中抗NMDAR腦炎的方法,包括向個體投予有效量的苯甲酸或其鹽及其衍生物。
如本文所使用,術語「治療(treating)」或「治療(treatment)」是指向有此需求的個體投予有效量的苯甲酸或其鹽及其衍生物,目的是治癒、緩解、紓解、補救、改善或預防該疾病、其症狀、或對其之傾向(predisposition)。此個體可藉由醫療保健專業人員基於來自任何合適的診斷方法的結果而識別。
在本揭露內容的一個具體實施例中,藉由本揭露內容的方法所治療的個體患有抗NMDAR腦炎。被診斷患有抗NMDAR腦炎的個體可具有頭痛和暈眩,首先表現出精神病症狀,其次是神經功能障礙。在本揭露內容的進一步具體實施例中,精神病症狀包括激躁、認知惡化、重複解 離性記憶障礙以及與思覺失調症相關的精神病症狀等。在本揭露內容的另一個具體實施例中,被診斷患有抗NMDAR腦炎的個體中的神經功能障礙包括癲癇。在另一個具體實施例中,被診斷患有抗NMDAR腦炎的個體在其腦脊髓液(cerebrospinal fluid,CSF)和血清中經鑑別出具有抗NMDAR的抗體。在另一個具體實施例中,抗NMDAR腦炎中的細胞損傷係由自體抗體引起,該自體抗體穿過血腦屏障進入腦中,在興奮性和抑制性海馬神經元兩者中選擇性地交聯和內化NMDAR。在一個具體實施例中,待本揭露內容的方法治療的個體患有抗NMDAR腦炎,並且可以在本揭露的方法之前、之後或同時採用其他的療法治療。在進一步的具體實施例中,與本揭露的方法合併治療的其他療法係心理療法、電痙攣療法(ECT)、免疫療法、血漿分離術、類固醇脈衝療法及其任何組合。在另一個具體實施例中,待本揭露內容的方法治療的個體患有抗NMDAR腦炎並且表現出差的反應,或者對其他療法沒有反應。
苯甲酸天然存在於許多植物和動物中。因此,它是許多食品的天然成分,包括奶製品(IPCS 1993)。苯甲酸和苯甲酸鈉也是美國(Joint FAO/WHO Expert Committee on Food Additives,1965、1973)、台灣(衛福部)和世界衛生組織(IPCS 1993)的合法食品添加劑,並廣泛用於製造果凍、奶油、醬油、加工肉等。
D-型胺基酸氧化酶(D-amino acid oxidase,DAAO)是一種存在於哺乳動物的腦、腎臟和肝臟中的過氧化體的黃素酶(flavoenzyme),其負責降解D-絲胺酸、D-丙胺酸和其他D型胺基酸。在本揭露內容中,投予如苯甲酸鈉之苯甲酸鹽以抑制DAAO的活性,進而 提高D-絲胺酸和其它D型胺基酸的突觸濃度(synaptic concentration)。在本揭露內容中,苯甲酸鹽係以有效量投予個體,經由增強或活化NMDAR的功能來預防或治療抗NMDAR腦炎。在本揭露內容的一個具體實施例中,苯甲酸或其鹽及衍生物係藉由抑制患有抗NMDAR腦炎個體中的DAAO活性來增強NMDA的功能。
如本文所使用,術語「有效量」是指足以導致預防抗NMDAR腦炎及其一種或多種症狀的發展、復發或發作的治療量,足以增強或改善另一種療法之預防效果、減輕病症的嚴重程度、持續時間、改善病症的一種或多種症狀、防止抗NMDAR腦炎的進展,及/或增強或改善另一種療法的治療效果的治療量。
在本揭露內容的一些具體實施例中,苯甲酸鹽的有效量可為200毫克/天至2000毫克/天。在一個具體實施例中,該劑量的下限值可以是200毫克/天、225毫克/天、250毫克/天、275毫克/天、300毫克/天、325毫克/天、350毫克/天、400毫克/天、450毫克/天、500毫克/天、550毫克/天、600毫克/天、700毫克/天、750毫克/天、或800毫克/天,且該劑量的上限值可以是2000毫克/天、1800毫克/天、1500毫克/天、1200毫克/天、1000毫克/天、900毫克/天、800毫克/天、750毫克/天、700毫克/天、或600毫克/天。例如,苯甲酸或其鹽及衍生物的劑量可以是225毫克/天至2000毫克/天、250毫克/天至1800毫克/天、450毫克/天至1500毫克/天、500毫克/天至1200毫克/天、500毫克/天至1000毫克/天、550毫克/天至1000毫克/天、600毫克/天至800毫克/天、約1000毫克/天、約900毫克/天、約750毫克/天、或約500毫克/天。
如本文所使用,當述及數字或範圍時,所屬技術領域中具有通常知識者可理解,其意圖涵蓋與本揭露內容相關的特定領域的適當的合理範圍。
藉由敘述至少200毫克至2000毫克,這意味著該範圍內的所有整數的單位量可作為本揭露內容的一部分而具體揭露。因此,包括200、201、202、......250、251、252、......1000、1001、1002、......1997、1998、1999和2000單位量皆為本揭露內容所涵蓋的具體實施例。
在本揭露內容的一些具體實施例中,苯甲酸或其鹽及衍生物的投予可以是例如每天一次、每天兩次、每天3次或每天4次。在一個具體實施例中,苯甲酸鹽的投予可以每天進行一次。
在本揭露內容的一些具體實施例中,苯甲酸或其鹽及衍生物可以在足以預防或治療抗NMDAR腦炎的期間內向個體投予。該足夠的期間可取決於個體的物種、性別、體重或年齡、疾病的階段、症狀或嚴重程度、以及投予的途徑、時間或頻率。在本揭露內容的一些具體實施例中,苯甲酸或其鹽及衍生物的投予是每天投予,並持續至少1個月。例如,苯甲酸或其鹽及衍生物的投予期間可持續1、2、3、4或6個月,或1、2、3或4年,或甚至更長,只要在該治療期間不發生副作用。在本揭露內容的例示性具體實施例中,該期間可以在1個月到2年的範圍內。在另一個具體實施例中,該期間為4週至12個月。在另一個具體實施例中,苯甲酸其鹽及衍生物是每日投予,並維持2個月的期間。
在本揭露內容的某些具體實施例中,該方法涉及使用苯甲酸、苯甲酸鹽或其衍生物,其可以選自由苯甲酸、苯甲酸鈉、苯甲酸鉀、 苯甲酸鈣、苯甲酸鎂、2-胺基苯甲酸酯、3-胺基苯甲酸酯、4-胺基苯甲酸酯、4-羥基苯甲酸乙酯、4-羥基苯甲酸乙酯鈉、4-羥基苯甲酸丙酯、4-羥基苯甲酸丙酯鈉、4-羥基苯甲酸甲酯、4-羥基苯甲酸鈉、苯甲酸芐酯或苯甲酸甲酯所組成之群組。
在本揭露內容的一個具體實施例中,苯甲酸或其鹽及衍生物係以口服劑型投予。在本揭露內容的一個具體實施例中,向個體投予的苯甲酸鹽可以包含在醫藥組成物中。本揭露內容的醫藥組成物包含苯甲酸或其鹽及衍生物和其醫藥上可接受的賦形劑。在一個具體實施例中,將本揭露內容的組成物配製成適於口服投予的形式,因此可以藉由口服遞送而向個體投予該組成物。或者,該組成物可以配製成乾粉劑、片劑、錠劑、囊劑、粒劑或丸劑的形式。醫藥上可接受的賦形劑包括,但不限於,填充劑、黏合劑、防腐劑、崩解劑、潤滑劑、懸浮劑、潤濕劑、溶劑、界面活性劑、酸、調味劑、聚乙二醇(PEG)、烷二醇、癸二酸、二甲亞碸、醇或其任何組合。
本揭露內容的醫藥組成物可以僅包含苯甲酸或其鹽及衍生物作為用於預防或治療抗NMDAR腦炎的活性成分。換句話說,苯甲酸鹽是作為本揭露內容之醫藥組成物中用於預防或治療抗NMDAR腦炎的唯一活性成分。在該具體實施例中,本揭露內容提供了藉由單獨使用苯甲酸或其鹽及其衍生物作為活性成分來預防或治療抗NMDAR腦炎的一種安全和有效的療法。
或者,在另一個具體實施例中,除非抑制本揭露內容的效果,否則可以將組成物與另一種活性成分合併而向個體投予。苯甲酸或其鹽及 衍生物和另一種活性成分可以作為單一組成物或個別的組成物提供。
在一個具體實施例中,本揭露內容所提供方法中的苯甲酸或其鹽及衍生物的投予可以與用於抗NMDAR腦炎的任何合適的常規療法合併。在一個具體實施例中,用於抗NMDAR腦炎的常規療法包括,但不限於,第一或第二線免疫療法、類固醇的脈衝療法、電痙攣療法和抗精神病藥療法。
本揭露內容已藉由許多實施例而闡釋。以下具體實施例不應視為對本揭露內容範圍的任何限制。
本揭露內容檢測了苯甲酸鈉用於治療抗NMDAR腦炎的功效和安全性。
一名原本健康的17歲男性出現頭痛和噁心,但沒有發燒。一週後,他逐漸出現了激躁、認知惡化,需要精神病評估。由於疑似思覺失調症和重複分離性記憶障礙,患者3次入住急性精神科病房。
患者接受了大劑量的抗精神病藥物和電痙攣療法(ECT)治療,但即使在高劑量下,對抗精神病藥物(阿立哌唑20至30毫克,氯氮平300至500毫克,及氯氮平500毫克加帕潘立酮9毫克)和電痙攣療法(一週三次,持續三週)的反應仍非常差。然後在腦脊液(CSF)和血清中發現抗NMDAR抗體,並確診為抗NMDAR腦炎。腦磁振造影結果正常。
在使用甲基普賴蘇穠脈衝治療後,立即以靜脈內免疫球蛋白(intravenous immunoglobulin,IVIg)和血漿分離術治療患者。然而,在兩個月的免疫療法和抗精神病藥物治療後,沒有顯著的臨床改善。
之後,以每天1000mg的劑量向患者投予苯甲酸鈉,為期2個月。包括解離症狀和激躁在內的精神病症狀減少,在患者身上觀察到臨床上的明顯改善,且能夠恢復正常生活。
上述詳盡的具體實施例僅用於揭露本揭露內容之原理和作用之闡釋,而非用於限制本揭露內容之範疇。所屬技術領域中具有通常知識者應了解,根據本揭露內容中之精神和原理之所有修飾和改變應落入附加之申請專利範圍之範疇內。說明書和具體實施例應認定為僅具例示性,而本揭露內容之完整範疇係由如下申請專利範圍表示。本案中如下所列之參考文獻係如同個別併入之方式,各自以引用方式併入本文。
DALMAU, J. (2016) NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: The 2016 Cotzias Lecture. Neurology, 87, 2471-2482.
DALMAU, J., LANCASTER, E., MARTINEZ-HERNANDEZ, E., ROSENFELD, M. R. & BALICE-GORDON, R. (2011) Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol., 10, 63-74.
LEYPOLDT, F., ARMANGUE, T. & DALMAU, J. (2015) Autoimmune encephalopathies. Annals of the New York Academy of Sciences, 1338, 94-114.
TITULAER, M. J., MCCRACKEN, L., GABILONDO, I., ARMANGUE, T., GLASER, C., IIZUKA, T., HONIG, L. S., BENSELER, S. M., KAWACHI, I., MARTINEZ-HERNANDEZ, E., AGUILAR, E., GRESA-ARRIBAS, N., RYAN-FLORANCE, N., TORRENTS, A., SAIZ, A., ROSENFELD, M. R., BALICE-GORDON, R., GRAUS, F. & DALMAU, J. (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol., 12, 157-165.
TSUTSUI, K., KANBAYASHI, T., TAKAKI, M., OMORI, Y., IMAI, Y., NISHINO, S., TANAKA, K. & SHIMIZU, T. (2017) N-methyl-D-aspartate receptor antibody could be a cause of catatonic symptoms in psychiatric patients: case reports and methods for detection. Neuropsychiatr. Dis. Treat., 13, 339-345.
Claims (14)
- 一種有效量的苯甲酸鹽或苯甲酸衍生物用於製備預防或治療有此需求的個體中之抗N-甲基-D-天冬胺酸受體腦炎藥物之用途,其中,該苯甲酸鹽或該苯甲酸衍生物是苯甲酸鈉、苯甲酸鉀、苯甲酸鈣、苯甲酸鎂、2-胺基苯甲酸酯、3-胺基苯甲酸酯、4-胺基苯甲酸酯、4-羥基苯甲酸乙酯、4-羥基苯甲酸乙酯鈉、4-羥基苯甲酸丙酯、4-羥基苯甲酸丙酯鈉、4-羥基苯甲酸甲酯、4-羥基苯甲酸鈉、苯甲酸芐酯或苯甲酸甲酯。
- 如申請專利範圍第1項所述之用途,其中,該苯甲酸鹽是苯甲酸鈉。
- 如申請專利範圍第1項所述之用途,其中,該抗N-甲基-D-天冬胺酸受體腦炎是由N-甲基-D-天冬胺酸受體的功能減退所引起的。
- 如申請專利範圍第1項所述之用途,其中,該苯甲酸鹽或該苯甲酸衍生物增強或活化該個體中N-甲基-D-天冬胺酸受體的功能。
- 如申請專利範圍第1項所述之用途,其中,該苯甲酸鹽或該苯甲酸衍生物係以範圍為200毫克/天至2000毫克/天的量向該個體投予。
- 如申請專利範圍第1項所述之用途,其中,該苯甲酸鹽或該苯甲酸衍生物係以範圍為400毫克/天至1800毫克/天的量向該個體投予。
- 如申請專利範圍第1項所述之用途,其中,該苯甲酸鹽或該苯甲酸衍生物係以範圍為450毫克/天至1500毫克/天的量向該個體投予。
- 如申請專利範圍第1項所述之用途,其中,該苯甲酸鹽或該苯甲酸衍生物係以範圍為500毫克/天至1000毫克/天的量向該個體投予。
- 如申請專利範圍第1項所述之用途,其中,該苯甲酸鹽或該苯甲酸衍生物投予該個體的期間範圍為1個月至2年。
- 如申請專利範圍第1項所述之用途,其中,該苯甲酸鹽或該苯甲酸衍生物投予該個體的期間範圍為4週至12個月。
- 如申請專利範圍第1項所述之用途,其中,該苯甲酸鹽或該苯甲酸衍生物係與其他的活性成分合併投予該個體,以預防或治療抗N-甲基-D-天冬胺酸受體腦炎。
- 如申請專利範圍第11項所述之用途,其中,該其他的活性成分是抗精神病藥。
- 如申請專利範圍第1項所述之用途,其中,該苯甲酸鹽或該苯甲酸衍生物係與其他療法合併投予該個體,以預防或治療抗N-甲基-D-天冬胺酸受體腦炎。
- 如申請專利範圍第1項所述之用途,其中,該其他療法包括心理療法、電痙攣療法、免疫療法、血漿分離術、類固醇脈衝療法、或其任何組合。
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