CN112437661A - 苯甲酸或其盐用于预防或治疗抗n-甲基-d-天冬氨酸受体脑炎的用途 - Google Patents
苯甲酸或其盐用于预防或治疗抗n-甲基-d-天冬氨酸受体脑炎的用途 Download PDFInfo
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- CN112437661A CN112437661A CN201980042941.2A CN201980042941A CN112437661A CN 112437661 A CN112437661 A CN 112437661A CN 201980042941 A CN201980042941 A CN 201980042941A CN 112437661 A CN112437661 A CN 112437661A
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- Prior art keywords
- benzoic acid
- derivatives
- salts
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 title claims abstract description 93
- 239000005711 Benzoic acid Substances 0.000 title claims abstract description 44
- 235000010233 benzoic acid Nutrition 0.000 title claims abstract description 44
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- 238000002560 therapeutic procedure Methods 0.000 claims description 17
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- 238000002635 electroconvulsive therapy Methods 0.000 claims description 9
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- 235000010234 sodium benzoate Nutrition 0.000 claims description 9
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- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 6
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 6
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 6
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- 150000001558 benzoic acid derivatives Chemical class 0.000 claims description 5
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- XFDUHJPVQKIXHO-UHFFFAOYSA-M 3-aminobenzoate Chemical compound NC1=CC=CC(C([O-])=O)=C1 XFDUHJPVQKIXHO-UHFFFAOYSA-M 0.000 claims description 3
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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- A—HUMAN NECESSITIES
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Abstract
本公开提供一种预防或治疗有此需求的受试者的抗NMDAR脑炎的方法,包括向该受试者给药有效量的苯甲酸或其盐及衍生物。
Description
技术领域
本公开涉及抗N-甲基-D-天冬氨酸受体(anti-N-methyl-D-aspartate receptor,NMDAR)脑炎的预防或治疗,特别是使用苯甲酸盐预防或治疗抗NMDAR脑炎的方法。
背景技术
抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎是由自体抗体相关的NMDAR功能障碍引起的自体免疫性脑炎。在过去十年中,发现越来越多的NMDAR脑炎。自体抗体穿过血脑屏障并选择性地与NMDA受体交联,导致兴奋性和抑制性海马神经元中的NMDA受体内化,最终导致经NMDAR介导的突触神经传递的功能减退。
大多数患有抗NMDAR脑炎的患者首先发现精神病症状,其次是癫痫等神经系统症状。通常,抗癫痫药和抗精神病药物在抗NMDAR脑炎患者中效果较差。此外,通过甲泼尼龙(methylprednisolone)和静脉内免疫球蛋白的免疫疗法,或通过血浆交换而去除自体抗体的疗法,也用于治疗患有抗NMDAR脑炎的患者。然而,即使在免疫疗法和抗精神病药物治疗后,仍有一些患者难以治愈。
因此,对抗NMDAR脑炎的预防或治疗仍有需求。
发明内容
鉴于前述内容,本公开提供一种在有此需求的受试者中预防或治疗抗NMDAR脑炎的方法,包括向该受试者给药有效量的苯甲酸或其盐及衍生物以及医药上可接受的赋形剂。
在本公开的一个具体实施例中,苯甲酸盐及其衍生物是苯甲酸钠、苯甲酸钾、苯甲酸钙、苯甲酸镁、2-氨基苯甲酸酯、3-氨基苯甲酸酯、4-氨基苯甲酸酯、4-羟基苯甲酸乙酯、4-羟基苯甲酸乙酯钠、4-羟基苯甲酸丙酯、4-羟基苯甲酸丙酯钠、4-羟基苯甲酸甲酯、4-羟基苯甲酸钠、苯甲酸苄酯或苯甲酸甲酯,但不限于此。
在本公开的另一个具体实施例中,苯甲酸盐是苯甲酸钠。
在本公开的一个具体实施例中,药学上可接受的赋形剂选自由填充剂、粘合剂、防腐剂、崩解剂、润滑剂、悬浮剂、润湿剂、溶剂、表面活性剂、酸、调味剂、聚乙二醇(PEG)、烷二醇、癸二酸、二甲亚砜、醇及其任何组合所组成的组。
在本公开的一个具体实施例中,抗NMDAR脑炎是由NMDAR的功能减退引起的。在另一个具体实施例中,抗NMDAR脑炎中的细胞破坏是由自体抗体引起的。
在本公开的一个具体实施例中,苯甲酸或其盐和衍生物以有效量给药至受试者,以增强或活化NMDAR的功能,进而预防或治疗抗NMDAR脑炎。
在本公开的一个具体实施例中,苯甲酸或其盐及衍生物可以对受试者给药的量的范围为200毫克/天至2000毫克/天,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。
在本申请的一个具体实施例中,苯甲酸或其盐及衍生物可以给药至受试者为期1个月至2年,例如4周至12个月。在本申请的另一个具体实施例中,苯甲酸或其盐及衍生物给药于受试者为期约2个月。
在本公开的一个具体实施例中,苯甲酸或其盐和衍生物为组合物中作为预防或治疗抗NMDAR脑炎的唯一活性成分,或苯甲酸或其盐和衍生物与用于预防或治疗抗NMDAR脑炎的其他活性成分合并使用。在一个具体实施例中,所述其他活性成分是抗精神病药。在另一个具体实施例中,该抗精神病药选自由阿立哌唑(aripiprazole)、氯氮平(clozapine)、帕潘立酮(paliperidone)、利培酮(risperidone)、布瑞哌唑(brexpiprazole)、奥氮平(olanzapine)、喹硫平(quetiapine)、齐拉西酮(ziprasidone)、氨磺必利(amisulpride)、阿塞那平(asenapine)、伊潘立酮(iloperidone)、鲁拉西酮(lurasidone)、卡利拉嗪(cariprazine)、络笃平(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)、美索达嗪(mesoridazine)、哌氰嗪(periciazine)、普力马林(promazine)、硫利达嗪(thioridazine)、洛沙平(loxapine)、吗啉吲酮(molindone)、奋乃静(perphenazine)、硫次克辛(thiothixene)、氟哌啶醇(droperidol)、氟奋乃静(fluphazine)、匹莫齐特(pimozide)、丙氯拉嗪(prochlorperazine)、硫丙拉嗪(thioproperazine)、三氟拉嗪(trifluoperazine)及珠氯噻醇(zuclopenthixol)所组成的组。
在本公开的一个具体实施例中,苯甲酸或其盐和衍生物的给药与用于预防或治疗抗NMDAR脑炎的其他疗法合并使用。在一个具体实施例中,其他疗法包括,但不限于,心理疗法、电休克疗法(electroconvulsive therapy,ECT)和其他脑刺激(诸如,重复经颅磁刺激(rTMS)和经颅直流电刺激(tDCS))、免疫疗法、血浆分离术、类固醇脉冲疗法及其任何组合。在一个具体实施例中,类固醇脉冲疗法是用甲泼尼龙(methylprednisolone)进行脉冲疗法。
除上述之外,本公开还提供了有效量的苯甲酸或其盐和衍生物用于制备预防或治疗有此需求的受试者中的抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎的药物的用途。此外,本公开还提供有效量的苯甲酸或其盐和衍生物于预防或治疗有此需求的受试者的抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎的用途。
具体实施方式
以下实施例用于举例说明本公开。基于本说明书的公开,本领域技术人员可以理解本公开的其他优点。本公开还可如不同的具体实施例中所描述的而实现或应用。
还应注意,如本说明书中所使用的单数形式“一(a)”、“一(an)”和“该(the)”除非明确且毫无疑义地限于一个指涉物,包括多个指涉物。除非上下文另有明确说明,否则术语“或”可与术语“及/或”互换使用。
抗NMDAR脑炎是一种自体免疫性疾病,肇于自体抗体穿过血脑屏障,导致NMDA受体在兴奋性和抑制性海马神经元中的选择性交联和内化,导致经NMDAR介导的突触电流减少和NMDAR的功能减退。
本公开提供了预防或治疗有此需求的受试者中抗NMDAR脑炎的方法,包括向受试者给药有效量的苯甲酸或其盐及其衍生物。
如本文所使用,术语“治疗(treating)”或“治疗(treatment)”是指向有此需求的受试者给药有效量的苯甲酸或其盐及其衍生物,目的是治愈、缓解、纾解、补救、改善或预防该疾病、其症状、或对其的预先倾向性(predisposition)。此受试者可由医疗保健专业人员基于来自任何合适的诊断方法的结果而识别。
在本公开的一个具体实施例中,通过本公开的方法所治疗的受试者患有抗NMDAR脑炎。被诊断患有抗NMDAR脑炎的受试者可具有头痛和晕眩,首先表现出精神病症状,其次是神经功能障碍。在本公开的其他具体实施例中,精神病症状包括焦虑、认知恶化、重复解离性记忆障碍以及与精神分裂症相关的精神病症状等。在本公开的另一个具体实施例中,被诊断患有抗NMDAR脑炎的受试者中的神经功能障碍包括癫痫。在另一个具体实施例中,被诊断患有抗NMDAR脑炎的受试者在其脑脊液(cerebrospinal fluid,CSF)和血清中经鉴别出具有抗NMDAR的抗体。在另一个具体实施例中,抗NMDAR脑炎中的细胞损伤是由自体抗体引起的,该自体抗体穿过血脑屏障进入脑中,在兴奋性和抑制性海马神经元两者中选择性地交联和内化NMDAR。在一个具体实施例中,待使用本公开的方法治疗的受试者患有抗NMDAR脑炎,并且可以在本公开的方法之前、之后或同时采用其他的疗法治疗。在进一步的具体实施例中,与本公开的方法合并治疗的其他疗法为心理疗法、电休克疗法(ECT)、免疫疗法、血浆分离术、类固醇脉冲疗法及其任何组合。在另一个具体实施例中,待使用本公开的方法治疗的受试者患有抗NMDAR脑炎,并且对其他疗法表现出差的反应,或者没有反应。
苯甲酸天然存在于许多植物和动物中。因此,它是许多食品的天然成分,包括奶制品(IPCS 1993)。苯甲酸和苯甲酸钠也是美国(Joint FAO/WHO Expert Committee on FoodAdditives,1965、1973)、中国台湾(卫生局)和世界卫生组织(IPCS 1993)的合法食品添加剂,并广泛用于制造果冻、奶油、酱油、加工肉等。
D-氨基酸氧化酶(D-amino acid oxidase,DAAO)是一种存在于哺乳动物的脑、肾脏和肝脏中的过氧化体的黄素酶(flavoenzyme),其负责降解D-丝氨酸、D-丙氨酸和其他D-氨基酸。在本公开中,给药如苯甲酸钠的苯甲酸盐以抑制DAAO的活性,进而提高D-丝氨酸和其它D-氨基酸的突触浓度(synaptic concentration)。在本公开中,苯甲酸盐以有效量给药至受试者,通过增强或活化NMDAR的功能来预防或治疗抗NMDAR脑炎。在本公开的一个具体实施例中,苯甲酸或其盐及衍生物通过抑制患有抗NMDAR脑炎受试者中的DAAO活性来增强NMDA的功能。
如本文所使用,术语“有效量”是指足以导致预防抗NMDAR脑炎及其一种或多种症状的发展、复发或发作的治疗量,足以增强或改善另一种疗法的预防效果、减轻病症的严重程度、持续时间、改善病症的一种或多种症状、防止抗NMDAR脑炎的进展,及/或增强或改善另一种疗法的治疗效果的治疗量。
在本公开的一些具体实施例中,苯甲酸或其盐及衍生物的有效量可为200毫克/天至2000毫克/天。在一个具体实施例中,该剂量的下限值可以是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,且该剂量的上限值可以是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,苯甲酸或其盐及衍生物的剂量可以是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、约1000毫克/天、约900毫克/天、约750毫克/天、或约500毫克/天。
如本文所使用,当述及数字或范围时,本领域技术人员可理解,其意图涵盖与本公开相关的特定领域的适当的合理范围。
至少200毫克至2000毫克的表述意味着该范围内的所有整数的单位量可作为本公开的一部分而具体公开。因此,包括200、201、202……250、251、252……1000、1001、1002……1997、1998、1999和2000单位量全部为本公开所涵盖的具体实施例。
在本公开的一些具体实施例中,苯甲酸或其盐及衍生物的给药可以例如每天一次、每天两次、每天3次或每天4次。在一个具体实施例中,苯甲酸或其盐及衍生物的给药可以每天进行一次。
在本公开的一些具体实施例中,苯甲酸或其盐及衍生物可以向受试者给药一段足够预防或治疗抗NMDAR脑炎的期间。该足够的期间可取决于受试者的物种、性别、体重或年龄、疾病的阶段、症状或严重程度、以及给药的途径、时间或频率。在本公开的一些具体实施例中,苯甲酸或其盐及衍生物的给药是每天给药,并持续至少1个月。例如,苯甲酸或其盐及衍生物的给药期间可持续1、2、3、4或6个月,或1、2、3或4年,或甚至更长,只要在该治疗期间不发生副作用。在本公开的例示性具体实施例中,该期间可以在1个月到2年的范围内。在另一个具体实施例中,该期间为4周至12个月。在另一个具体实施例中,苯甲酸其盐及衍生物是每日给药,并维持2个月的期间。
在本公开的某些具体实施例中,该方法涉及使用苯甲酸、苯甲酸盐或其衍生物,其可以选自苯甲酸、苯甲酸钠、苯甲酸钾、苯甲酸钙、苯甲酸镁、2-氨基苯甲酸酯、3-氨基苯甲酸酯、4-氨基苯甲酸酯、4-羟基苯甲酸乙酯、4-羟基苯甲酸乙酯钠、4-羟基苯甲酸丙酯、4-羟基苯甲酸丙酯钠、4-羟基苯甲酸甲酯、4-羟基苯甲酸钠、苯甲酸芐酯及苯甲酸甲酯所组成的组。
在本公开的一个具体实施例中,苯甲酸或其盐及衍生物以口服剂型给药。在本公开的一个具体实施例中,向受试者给药的苯甲酸或其盐及衍生物可以包含在医药组合物中。本公开的医药组合物包含苯甲酸或其盐及衍生物和其医药上可接受的赋形剂。在一个具体实施例中,本公开的组合物配制成适于口服给药的形式,因此可以通过口服递送而向受试者给药该组合物。或者,该组合物可以配制成干粉剂、片剂、锭剂、囊剂、粒剂或丸剂的形式。医药上可接受的赋形剂包括,但不限于,填充剂、粘合剂、防腐剂、崩解剂、润滑剂、悬浮剂、润湿剂、溶剂、表面活性剂、酸、调味剂、聚乙二醇(PEG)、烷二醇、癸二酸、二甲亚砜、醇或其任何组合。
本公开的医药组合物可以仅包含苯甲酸或其盐及衍生物作为用于预防或治疗抗NMDAR脑炎的活性成分。换句话说,苯甲酸盐是作为本公开的医药组合物中用于预防或治疗抗NMDAR脑炎的唯一活性成分。在该具体实施例中,本公开通过单独使用苯甲酸或其盐及其衍生物作为活性成分来提供一种预防或治疗抗NMDAR脑炎的安全和有效的疗法。
或者,在另一个具体实施例中,除非抑制本公开的效果,否则可以将组合物与另一种活性成分合并而向受试者给药。苯甲酸或其盐及衍生物和另一种活性成分可以作为单一组合物或个别的组合物提供。
在一个具体实施例中,本公开所提供方法中的苯甲酸或其盐及衍生物的给药可以与用于抗NMDAR脑炎的任何合适的常规疗法合并。在一个具体实施例中,用于抗NMDAR脑炎的常规疗法包括,但不限于,第一或第二线免疫疗法、类固醇的脉冲疗法、电休克疗法和抗精神病药疗法。
本公开已通过许多实施例而阐释。以下具体实施例不应视为对本公开范围的任何限制。
实施例
本公开检测了苯甲酸钠用于治疗抗NMDAR脑炎的功效和安全性。
一名原本健康的17岁男性出现头痛和恶心,但没有发烧。一周后,他逐渐出现了焦虑、认知恶化,需要精神病评估。由于疑似精神分裂症和重复解离性记忆障碍,患者3次入住急性精神科病房。
患者接受了大剂量的抗精神病药物和电休克疗法(ECT)治疗,但即使在高剂量下,对抗精神病药物(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)和电休克疗法(一周三次,持续三周)的反应仍非常差。然后在脑脊液(CSF)和血清中发现抗NMDAR抗体,并确诊为抗NMDAR脑炎。脑磁振造影结果正常。
在使用甲泼尼龙脉冲治疗后,立即以静脉注射免疫球蛋白(intravenousimmunoglobulin,IVIg)和血浆分离术治疗患者。然而,在两个月的免疫疗法和抗精神病药物治疗后,没有显著的临床改善。
之后,以每天1000mg的剂量向患者给药苯甲酸钠,为期2个月。包括解离症状和焦虑在内的精神病症状减少,在患者身上观察到临床上的明显改善,且能够恢复正常生活。
上述详尽的具体实施例仅用于公开本公开的原理和作用的阐释,而非用于限制本公开的范畴。本领域技术人员应了解,根据本公开中的精神和原理的所有修饰和改变应落入附加的权利要求书的范畴内。说明书和具体实施例应认定为仅具例示性,而本公开的完整范畴由权利要求书表示。本申请中如下所列的参考文献如同个别并入的方式,各自以引用方式并入本文。
DALMAU,J.(2016)NMDA receptor encephalitis and other antibody-mediateddisorders 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 patientswith anti-NMDAR encephalitis.Lancet Neurol.,10,63-74.
LEYPOLDT,F.,ARMANGUE,T.&DALMAU,J.(2015)Autoimmuneencephalopathies.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:anobservational 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 acause of catatonic symptoms in psychiatric patients:case reports and methodsfor detection.Neuropsychiatr.Dis.Treat.,13,339-345.
Claims (15)
1.一种有效量的苯甲酸或其盐及衍生物的用途,用于制备预防或治疗有此需求的受试者的抗N-甲基-D-天冬氨酸受体脑炎的药物。
2.根据权利要求1所述的用途,其中,所述苯甲酸盐为苯甲酸钠、苯甲酸钾、苯甲酸钙、苯甲酸镁、2-氨基苯甲酸酯、3-氨基苯甲酸酯、4-氨基苯甲酸酯、4-羟基苯甲酸乙酯、4-羟基苯甲酸乙酯钠、4-羟基苯甲酸丙酯、4-羟基苯甲酸丙酯钠、4-羟基苯甲酸甲酯、4-羟基苯甲酸钠、苯甲酸芐酯或苯甲酸甲酯。
3.根据权利要求1所述的用途,其中,所述苯甲酸盐为苯甲酸钠。
4.根据权利要求1所述的用途,其中,所述抗N-甲基-D-天冬氨酸受体脑炎是由N-甲基-D-天冬氨酸受体的功能减退引起的。
5.根据权利要求1所述的用途,其中,所述苯甲酸或其盐及衍生物增强或活化所述受试者的N-甲基-D-天冬氨酸受体的功能。
6.根据权利要求1所述的用途,其中,所述苯甲酸或其盐及衍生物以200毫克/天至2000毫克/天范围内的量给药至所述受试者。
7.根据权利要求1所述的用途,其中,所述苯甲酸或其盐及衍生物以400毫克/天至1800毫克/天范围内的量给药至所述受试者。
8.根据权利要求1所述的用途,其中,所述苯甲酸或其盐及衍生物以450毫克/天至1500毫克/天范围内的量给药至所述受试者。
9.根据权利要求1所述的用途,其中,所述苯甲酸或其盐及衍生物以500毫克/天至1000毫克/天范围内的量给药至所述受试者。
10.根据权利要求1所述的用途,其中,所述苯甲酸或其盐及衍生物给药至所述受试者的期间范围为1个月至2年。
11.根据权利要求1所述的用途,其中,所述苯甲酸或其盐及衍生物给药至所述受试者的期间范围为4周至12个月。
12.根据权利要求1所述的用途,其中,所述苯甲酸或其盐及衍生物与用于预防或治疗抗N-甲基-D-天冬氨酸受体脑炎的其他活性成分合并给药至所述受试者。
13.根据权利要求1所述的用途,其中,所述其他活性成分为抗精神病药。
14.根据权利要求1所述的用途,其中,所述苯甲酸或其盐及衍生物与用于预防或治疗抗N-甲基-D-天冬氨酸受体脑炎的其他疗法合并给药至所述受试者。
15.根据权利要求1所述的用途,其中,所述其他疗法包括心理疗法、电休克疗法、免疫疗法、血浆分离术、类固醇脉冲疗法、或其任何组合。
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---|
HERESCO-LEVY等: "Clinical and Electrophysiological Effects of D-Serine in a Schizophrenia Patient Positive for Anti-NMethyl- D-Aspartate Receptor Antibodies" * |
HONG-ZHI GUAN等: "D-cycloserin, a NMDA-agonist may be a treatment option for anti-NMDAR encephalitis" * |
HSIEN-YUAN LANE等: "Add-on Treatment of Benzoate for Schizophrenia A Randomized, Double-blind, Placebo-Controlled Trial of D-Amino Acid Oxidase Inhibitor" * |
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