CN105188400A - 用于预防、减轻、缓解或治疗特发性呕吐的组合物和方法 - Google Patents
用于预防、减轻、缓解或治疗特发性呕吐的组合物和方法 Download PDFInfo
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- CN105188400A CN105188400A CN201480025593.5A CN201480025593A CN105188400A CN 105188400 A CN105188400 A CN 105188400A CN 201480025593 A CN201480025593 A CN 201480025593A CN 105188400 A CN105188400 A CN 105188400A
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Abstract
含有对5-HT3a和/或NK-1受体具有抑制作用的一种或多种化合物的组合物对预防或治疗哺乳动物的特发性呕吐有效。
Description
发明领域
本发明涉及通过使用对5-羟色胺-3血清素(5-HT3a)和/或神经激肽-1(NK-1)受体具有抑制作用的一种或多种化合物,来预防或治疗哺乳动物特别是家猫的特发性呕吐的膳食组合物或方法。
发明背景
猫的慢性/周期性特发性呕吐(emesis)或呕吐(vomiting)综合征在十九世纪晚期得到确认。虽然猫在某些情况下偶尔呕吐是可以接受的,例如在进食过快或过多或在胃中存在过量毛发或其它异物时,但是没有原因的频繁呕吐或反胃(regurgitation)(“特发性呕吐”)可导致猫的重度营养不良,并导致对猫的胃肠(GI)健康的损害。定义特发性呕吐或反胃的四个主要特征是:1)三个或更多的呕吐或反胃的复发性分隔期(recurrentseparatedepisode);2)各期之间完全正常、健康的状态的间隔不同;3)在发作时间、症状和持续时间方面,各期是模式化的(stereotypical);以及4)呕吐或反胃的原因未知。易患特发性呕吐的个体无法通过包括体检和/或血检在内的标准医学检查确认。在人类中,特发性呕吐可被描述为周期性呕吐综合征(CyclicVomitingSyndrome,CVS),并且可能与脱水、胃肠道(特别是食道)损伤和龋齿(呕吐物可能是酸性的)有关。
特发性呕吐的确切原因尚未完全清楚。然而,近期被公认的是猫中的潜在原因之一与中枢神经系统(CNS)紊乱有关。在猫的脑中有若干种神经递质受体,其可被触发以刺激或激活不同的导致呕吐的生物学途径(biologicalpathways)。这类受体的实例包括神经激肽(NK)受体、组胺受体、乙酰胆碱受体、血清素受体、μ-阿片样物质受体(mu-opioidreceptor)和多巴胺-2受体。因此,预防或减轻特发性呕吐的潜在方法是抑制或部分阻滞这类受体。
某些5-HT3a受体拮抗剂如多拉司琼、格拉司琼、昂丹司琼和帕诺司琼已显示作为人的止吐剂的有效性,并已被用于处理癌症患者中的由化疗诱发的恶心和呕吐。而且,已知作为NK-1受体拮抗剂的新类型的药物在近期被开发用于控制人的呕吐,所述药物包括阿瑞匹坦(aprepitant)和马罗皮坦(maropitant)等等。然而,这些化合物常常导致副作用。并且,由于其不良的味道而难以通过喂食给药这类化合物。遗憾的是,注射并不是给药止吐剂的适当的替代方式。在治疗动物如猫或狗时,注射可能需要兽医辅助,特别是如果动物抵抗注射。
对用于预防、减轻、缓解或治疗特发性呕吐的有效且更易利用的治疗有持续的需求。还对可通过例如喂食或其它口服给药容易给予的具有较小副作用的治疗有需求。这些需求对于具有特发性呕吐病史的家猫而言尤其急迫。
发明内容
本发明的一个方面是通过提供一种用于预防、减轻、缓解或治疗伴侣动物的特发性呕吐的膳食组合物来满足上述需求,所述膳食组合物以对抑制5-羟色胺-3a血清素(5-HT3a)受体和/或神经激肽-1(NK-1)受体有效的量包含一种或多种化合物。具体而言,所述化合物选自以下所组成的组中:泛醌-O(CAS号605-94-7)、白藜芦醇(CAS号501-36-0)、1,4-苯二酚,2,3-二甲基-(9CI)(CAS号608-43-5)、岩兰草醇(CAS号89-88-3)、3,6-二羟黄酮(CAS号92439-20-8)、香草壬酰胺(CAS号2444-46-4)、DL-氯化棕榈酰肉碱(DL-palmitoylcarnitinechloride)(CAS号6865-14-1)、积雪草酸(CAS号464-92-6)、法呢醛(CAS号19317-11-4)、诺卡酮(CAS号4674-50-4)、α-戊基肉桂醇(CAS号101-85-9)、δ-十二内酯(CAS号713-95-1)、γ-十二内酯(CAS号2305-05-7)、α-紫罗兰酮(CAS号127-41-3)、鹰嘴豆芽素A(CAS号491-80-5)、δ-十一内酯(CAS号104-67-6)、δ-十四内酯(CAS号2721-22-4)、2-(3-苯丙基)吡啶(CAS号2110-18-1)、1,14-十四烷二醇(CAS号19812-64-7)、(+)-雪松醇(CAS号77-53-2)、3-庚基二氢-5-甲基-2(3H)-呋喃酮(CAS号40923-64-6)、δ-十一内酯(CAS号710-04-3)、二氢茉莉酮酸甲酯(CAS号24851-98-7)、乙氧喹(CAS号91-53-2)、岩芹酸(CAS号593-39-5)、甲基异丁香酚(CAS号93-16-3)、香兰基丁醚(CAS号82654-98-6)、愈疮木油(CAS号8016-23-7)、藤黄菌素(CAS号491-70-3)、18-β-甘草次酸(18-beta-glycyrrheticacid)(CAS号471-53-4)、柠檬酸三丁酯(CAS号77-94-1)、棕榈油酸(CAS号373-49-9)、红没药醇(bisabolol)(CAS号515-69-5)、姜黄素(CAS号458-37-7)、胡椒碱(CAS号94-62-2)、黄酮(CAS号525-82-6)、薄荷氧基丙二醇(CAS号87061-04-9)、4-羟基查耳酮(CAS号2657-25-2)、N-丙基-4-羟基苯甲酸酯(CAS号94-13-3)、胆钙化醇维生素D3(cholecalciferolVD3)(CAS号67-97-0)、姜油树脂(CAS号8002-60-6)、二十碳五烯酸(CAS号10417-94-4)、核黄素维生素B2(CAS号83-88-5)、根皮素(CAS号60-82-2)、甲萘醌(CAS号58-27-5)、3,3’-二吲哚甲烷(CAS号1968-05-4)、反式,反式-2,4-庚二烯醛(CAS号4313-03-5)、反式-2,顺式-6-壬二烯醇(CAS号557-48-2)、反式,反式-2,4-壬二烯醛(CAS号5910-87-2)、反式-4-甲氧基肉桂醛(CAS号24680-50-0)、4’-羟基查耳酮(CAS号2657-25-2)、2,2’,4’-三羟基查耳酮(CAS号26962-50-5)、血卟啉二盐酸盐(CAS号17696-69-4)、植物鞘氨醇(CAS号554-62-1)、苯亚甲基丙酮(CAS号122-57-6)、染料木黄酮(CAS号446-72-0)、芹黄素(CAS号520-36-5)、查耳酮(CAS号614-47-1)、桂皮油(CAS号8015-91-6),及它们的衍生物,以及它们的组合。
在另一方面,本发明涉及用于预防、减轻、缓解或治疗伴侣动物的特发性呕吐的方法,其包括以对抑制5-HT3a受体和/或NK-1受体有效的量对所述伴侣动物口服给药一种或多种化合物的步骤,同时所述一种或多种化合物选自以下所组成的组中:泛醌-O(CAS号605-94-7)、白藜芦醇(CAS号501-36-0)、1,4-苯二酚,2,3-二甲基-(9CI)(CAS号608-43-5)、岩兰草醇(CAS号89-88-3)、3,6-二羟黄酮(CAS号92439-20-8)、香草壬酰胺(CAS号2444-46-4)、DL-氯化棕榈酰肉碱(CAS号6865-14-1)、积雪草酸(CAS号464-92-6)、法呢醛(CAS号19317-11-4)、诺卡酮(CAS号4674-50-4)、α-戊基肉桂醇(CAS号101-85-9)、δ-十二内酯(CAS号713-95-1)、γ-十二内酯(CAS号2305-05-7)、α-紫罗兰酮(CAS号127-41-3)、鹰嘴豆芽素A(CAS号491-80-5)、δ-十一内酯(CAS号104-67-6)、δ-十四内酯(CAS号2721-22-4)、2-(3-苯丙基)吡啶(CAS号2110-18-1)、1,14-十四烷二醇(CAS号19812-64-7)、(+)-雪松醇(CAS号77-53-2)、3-庚基二氢-5-甲基-2(3H)-呋喃酮(CAS号40923-64-6)、δ-十一内酯(CAS号710-04-3)、二氢茉莉酮酸甲酯(CAS号24851-98-7)、乙氧喹(CAS号91-53-2)、岩芹酸(CAS号593-39-5)、甲基异丁香酚(CAS号93-16-3)、香兰基丁醚(CAS号82654-98-6)、愈疮木油(CAS号8016-23-7)、藤黄菌素(CAS号491-70-3)、18-β-甘草次酸(CAS号471-53-4)、柠檬酸三丁酯(CAS号77-94-1)、棕榈油酸(CAS号373-49-9)、红没药醇(CAS号515-69-5)、姜黄素(CAS号458-37-7)、胡椒碱(CAS号94-62-2)、黄酮(CAS号525-82-6)、薄荷氧基丙二醇(CAS号87061-04-9)、4-羟基查耳酮(CAS号2657-25-2)、N-丙基-4-羟基苯甲酸酯(CAS号94-13-3)、胆钙化醇维生素D3(CAS号67-97-0)、姜油树脂(CAS号8002-60-6)、二十碳五烯酸(CAS号10417-94-4)、核黄素维生素B2(CAS号83-88-5)、根皮素(CAS号60-82-2)、甲萘醌(CAS号58-27-5)、3,3’-二吲哚甲烷(CAS号1968-05-4)、反式,反式-2,4-庚二烯醛(CAS号4313-03-5)、反式-2,顺式-6-壬二烯醇(CAS号557-48-2)、反式,反式-2,4-壬二烯醛(CAS号5910-87-2)、反式-4-甲氧基肉桂醛(CAS号24680-50-0)、4’-羟基查耳酮(CAS号2657-25-2)、2,2’,4’-三羟基查耳酮(CAS号26962-50-5)、血卟啉二盐酸盐(CAS号17696-69-4)、植物鞘氨醇(CAS号554-62-1)、苯亚甲基丙酮(CAS号122-57-6)、染料木黄酮(CAS号446-72-0)、芹黄素(apigenin)(CAS号520-36-5)、查耳酮(CAS号614-47-1)、桂皮油(CAS号8015-91-6),及它们的衍生物,以及它们的组合。
在另一方面,本发明涉及一种用于预防、减轻、缓解或治疗伴侣动物的特发性呕吐的组合物,其以对抑制5-HT3a受体和/或NK-1受体有效的量含有如上所述的一种或多种化合物。
在又一方面,本发明涉及用于处理预防、减轻、缓解或治疗伴侣动物的特发性呕吐的试剂盒,其包括:
(a)膳食组合物;和
(b)用所述膳食组合物对所述伴侣动物喂食的说明书。
具体而言,所述说明书可包括选自以下所组成的组中的信息:评价所述伴侣动物的特发性呕吐病症的严重性;喂食频率;喂食持续时间;喂食方式;和监控所述伴侣动物的特发性呕吐病症以确定何时改变喂食频率和/或喂食持续时间。
本发明的又一方面涉及一种制备膳食组合物的方法,其包括将能够抑制5-羟色胺-3a血清素(5-HT3a)受体和/或神经激肽-1(NK-1)受体的一种或多种化合物与适用于伴侣动物的一种或多种膳食营养物混合的步骤。
在阅读本发明的以下详细描述和实施例后,本发明的这些和其它方面将变得更明显。
附图简要说明
图1-44示出具有出人意料的高5-HT3a抑制作用的本发明的化合物的5-HT3a剂量反应曲线。
图45-70示出具有出人意料的高NK-1抑制作用的本发明的化合物的NK-1剂量反应曲线。
发明详述
除非另有说明,冠词“一(a)”、一(an)和“该(the)”的意思是“一个(种)或多个(种)”。术语“包含(comprising)”的意思是可加入不影响最终结果的其它步骤和其它成分,并且该术语包括术语“由……组成”和“基本由……组成”。本发明的组合物和方法/过程可包括以下、由以下组成、并基本由以下组成:本文所述的本发明的基本要素和限定以及任何本文所述的额外或任选的成分、组分、步骤或限定。除非另有说明,所有百分比、份数(part)和比(ratio)是基于本发明的组合物的总重量。关于所列成分的所有这类重量是基于活性水平,并因此不包括在市售材料中可包括在内的载体或副产品。除非另有具体说明,所有比为重量比。除非另有具体说明,所有温度为摄氏度。本文所公开的所有尺寸和值(例如量、百分比、份额(portion)和比例(proportion))不应理解为被严格限定于所列举的确切数值。相反,除非另有说明,每个这种尺寸或值意指所列举的值和在该值附近的功能等价范围。例如,按“40mm”公开的尺寸意指“约40mm”。
在本文中,术语“治疗(treat)”、“治疗(treating)”或“治疗(treatment)”涵盖治疗目标动物的疾病或病症的所有方式,其包括:(i)抑制疾病或病症,即完全阻止其发展;(ii)减轻疾病或病症,即使疾病或病症消退;和(iii)缓解或舒缓疾病或病症所导致的症状,即在未解决根本疾病或病症的情况下舒缓疼痛或痛苦。
术语“有效的”的意思是为提供待治疗病症的显著积极变化的足够高的主体活性的量。主体活性的有效量将随所治疗的具体病症、病症的严重性、治疗的持续时间、同期治疗的性质等因素而变化。
本文所使用的术语“呕吐(vomit)”或“呕吐(vomiting)”涵盖来自某个体的胃或食道的内容物向口且有时是向鼻中的任何自发性或非自发性排出。这类行为可不同地被称为呕吐(vomiting)、反胃(regurgitation)、呕吐(emesis)、呕出(throwingup)、呕吐(puking)、恶心等,但在本文中由相同术语“呕吐(vomit)”或“呕吐(vomiting)”统一涵盖。
本文所使用的术语“猫科伴侣动物”或“猫科”广泛地涵盖猫科(Felidea)家族中有可能被人类接纳作为室内或户外伴侣的所有动物,其包括但不限于:家猫、美洲狮、猎豹、猞猁、豹猫、老虎、狮子、美洲虎、黑豹、美洲豹等。本文所使用的术语“伴侣动物”包括但不限于:如上文所述的猫科伴侣动物;犬科(Canidea)家族中有可能被人类接纳作为室内或户外伴侣的所有动物,如家养犬(家犬(Canisfamiliaris))、狼、狐狸、豺、郊狼(coyote)等;以及其它更小型家养哺乳动物,如雪貂、浣熊、兔、小鼠、大鼠、仓鼠、豚鼠等。本文所述的化合物也可被用于控制或治疗哺乳动物包括人类的特发性呕吐。
本发明鉴定出在伴侣动物中作为5-HT3a和/或NK-1受体的抑制剂特别有效且具有很小的或没有细胞毒性的特定组的化合物,其可被容易地用于配制控制和治疗如上所述的伴侣动物的特发性呕吐的膳食组合物或食谱(regiment)。
本文所使用的术语“作为5-HT3a和/或NK-1受体的抑制剂有效的”意思是5-HT3a和/或NK-1受体的亲和力(IC50)小于100ppm,优选小于50ppm,更优选小于10ppm。为了测定5-HT3a和/或NK-1受体亲和力,可以容易地使用本领域熟知的各种受体亲和力试验。
具有5-HT3a受体抑制作用的化合物
本发明的发明人已发现了具有出人意料的高5-HT3a受体抑制作用并具有很小细胞毒性或没有细胞毒性的以下化合物:
·泛醌-O(CAS号605-94-7);
·白藜芦醇(CAS号501-36-0);
·2,3-二甲基-1,4-苯二酚(CAS号608-43-5);
·岩兰草醇(CAS号89-88-3);
·3,6-二羟黄酮(CAS号92439-20-8);
·香草壬酰胺(CAS号2444-46-4);
·DL-氯化棕榈酰肉碱(CAS号6865-14-1);
·积雪草酸(CAS号464-92-6);
·法呢醛(CAS号19317-11-4);
·诺卡酮(CAS号4674-50-4);
·α-戊基肉桂醇(CAS号101-85-9);
·δ-十二内酯(CAS号713-95-1);
·γ-十二内酯(CAS号2305-05-7);
·α-紫罗兰酮(CAS号127-41-3);
·鹰嘴豆芽素A(CAS号491-80-5);
·δ-十一内酯(CAS号104-67-6);
·δ-十四内酯(CAS号2721-22-4);
·皮质吡啶(CAS号2110-18-1);
·1,14-十四烷二醇(CAS号19812-64-7);
·(+)-雪松醇(CAS号77-53-2);
·3-庚基二氢-5-甲基-2(3H)-呋喃酮(CAS号40923-64-6);
·δ-十一内酯(CAS号710-04-3);
·二氢茉莉酮酸甲酯(CAS号24851-98-7);
·乙氧喹(CAS号91-53-2);
·岩芹酸(CAS号593-39-5);
·甲基异丁香酚(CAS号93-16-3);
·香兰基丁醚(CAS号82654-98-6);
·愈疮木油(CAS号8016-23-7);
·藤黄菌素(CAS号491-70-3);
·18-β-甘草次酸(CAS号471-53-4);
·柠檬酸三丁酯(CAS号77-94-1);
·棕榈油酸(CAS号373-49-9);
·红没药醇(CAS号515-69-5);
·姜黄素(CAS号458-37-7);
·胡椒碱(CAS号94-62-2);
·黄酮(CAS号525-82-6);
·薄荷氧基丙二醇(CAS号87061-04-9);
·4-羟基查耳酮(CAS号2657-25-2);
·N-丙基-4-羟基苯甲酸酯(CAS号94-13-3);
·胆钙化醇维生素D3(CAS号67-97-0);
·姜油树脂(CAS号8002-60-6);
·二十碳五烯酸(CAS号10417-94-4);
·核黄素维生素B2(CAS号83-88-5);和
·根皮素(CAS号60-82-2)。
具有NK-1受体抑制作用的化合物
本发明的发明人已发现了具有出人意料的高NK-1受体抑制作用并具有很小细胞毒性或没有细胞毒性的以下化合物:
·泛醌-O(CAS号605-94-7);
·白藜芦醇(CAS号501-36-0);
·甲萘醌(CAS号58-27-5);
·3,3’-二吲哚甲烷(CAS号1968-05-4);
·反式,反式-2,4-庚二烯醛(CAS号4313-03-5);
·反式-2,顺式-6-壬二烯醇(CAS号557-48-2);
·反式,反式-2,4-壬二烯醛(CAS号5910-87-2);
·反式-4-甲氧基肉桂醛(CAS号24680-50-0);
·姜油树脂(CAS号8002-60-6);
·3,6-二羟黄酮(CAS号92439-20-8);
·4-羟基查耳酮(CAS号2657-25-2);
·DL-氯化棕榈酰肉碱(CAS号6865-14-1);
·积雪草酸(CAS号464-92-6);
·2,2’,4’-三羟基查耳酮(CAS号26962-50-5);
·血卟啉二盐酸盐(CAS号17696-69-4);
·植物鞘氨醇(CAS号554-62-1);
·藤黄菌素(CAS号491-70-3);
·18-β-甘草次酸(CAS号471-53-4);
·姜黄素(CAS号458-37-7);
·苯亚甲基丙酮(CAS号122-57-6);
·染料木黄酮(CAS号446-72-0);
·芹黄素(CAS号520-36-5);
·胡椒碱(CAS号94-62-2);
·查耳酮(CAS号614-47-1);
·桂皮油(CAS号8015-91-6);和
·二十碳五烯酸(CAS号10417-94-4)。
给药方法
上面列举的化合物可通过任何熟知的递送方法给药,所述方法包括但不限于:口服递送、吸入、直肠注射,或肠胃外递送,例如局部施用、经皮施用、静脉注射、皮下注射、肌内注射等。这类化合物可单独给药,或与任何可接受的载体或稀释剂组合给药,以形成组合物如干粗粒食物(drykibble)、湿罐头食品、肉汁、零食(treat)、片剂、胶囊剂、锭剂、糖锭、硬糖果、粉剂、喷雾剂、乳膏、油膏、栓剂、胶冻剂、凝胶剂、糊剂、洗剂、软膏、水性混悬剂、注射液、酏剂、糖浆剂等。
在本发明的优选但并非必要的实施方案中,将所述化合物口服给药至伴侣动物,例如作为用于伴侣动物的膳食组合物的一部分。这种膳食组合物可以是液体、固体或半固体。并且,所述膳食组合物可配制成在进食时间喂给动物的宠物食品,或者与用于动物的宠物食品分开或组合而喂给动物的宠物食品补充剂。
作为宠物食品,膳食组合物可包括用于目的伴侣动物接受者的营养全面的饮食(nutritionallycompletediet)。除了水以外,营养全面的饮食以基于公认权威机构的建议的合适的量和比例包含维持伴侣动物的生命所需的已知营养物,所述公认权威机构包括政府机构如美国食品药品管理局兽医中心、美国饲料控制官员协会。
例如,本发明的宠物食品组合物可至少包括碳水化合物源、蛋白质源和任选的脂肪源。更优选的是,所述宠物食品组合物为伴侣动物提供了营养全面且均衡的饮食,其可以包括:约1重量%至约99重量%、优选地约1重量%至约90重量%、且更优选地约5重量%至约45重量%的碳水化合物;约5重量%至约99.9重量%、优选地约10重量%至约90重量%、且更优选地约20重量%至约60重量%的蛋白质;约0.1重量%至约50重量%、优选地约1重量%至约40重量%、且更优选地约5重量%至约20重量%的脂肪;约0.01重量%至约20重量%、优选地约1重量%至约11重量%的膳食纤维;约0.01重量%至约重量15%、优选地约0.1重量%至约10重量%、且更优选地1重量%至8重量%的维生素、矿物质、抗氧化剂和支持伴侣动物需要的其它营养物。所述碳水化合物可由谷物如水稻、玉米、买罗高梁(milo)、高粱、大麦、小麦、燕麦等来提供。所述蛋白质可由动物衍生来源如肉(牛肉、猪肉、羊肉、家禽肉、鱼肉等)、鸡蛋和牛奶,或植物衍生来源如大豆、谷类、棉籽、花生等来提供。所述膳食纤维可由纤维素、半纤维素、果胶、木质素和树胶来提供。并且,本发明的宠物食品组合物可包含在宠物食品中通常使用的各种成分,如填充剂、调味剂、结合剂、增稠剂、稳定剂、乳化剂、甜味剂、食品级着色剂、缓冲剂、盐等。特别优选的结合剂和/或增稠剂是明胶、纤维素醚、淀粉、淀粉酯、淀粉醚和改性淀粉。
所述宠物食品组合物配制成干粗粒食物、湿罐头食品、肉汤或零食。可以每日对伴侣动物进行喂食,或者以规律的进食时间(例如每日一次直到每日六次)或按需要全天连续地喂食(例如,通过自动喂食器(automaticfeeder)或简单地通过提供过量食物)。所述组合物可随意喂食。
在某些实施方案中,所述宠物食品组合物是零食。本文所使用的零食是指给予伴侣动物以诱导动物在非进食时间食用的宠物食品组合物。零食也可具有营养价值,且具有类似食品的成分,其包括一种或多种如上所述的营养物,但其自身并不是营养全面的食物。
本发明的膳食组合物还可作为宠物食品补充剂提供,其与另一饲料同期或分开使用,以改善伴侣动物的营养平衡或表现。除其它饲料外,宠物食品补充剂包括但不限于未经稀释而喂食的任何组合物,由此提供与单独可用的或被稀释且与动物的常规饲料混合的动物配给量的其它部分的自由选择,以产生全价饲料。美国饲料控制官员协会(AAFCO)提供了指导,例如该指导包括关于补充剂的讨论,所述补充剂可以以各种形式,包括粉末剂、液体剂、糖浆剂、丸剂、胶囊组合物等。并且,所述宠物食品补充剂可以作为具有部分或全部可消耗组分的用于伴侣动物的玩具的一部分提供。
通过将一种或多种上文列举的能够抑制5-HT3a和/或NK-1受体的化合物与一种或多种上文公开的适用于伴侣动物的化合物混合可容易地形成如上所述的膳食组合物。
为了确定有效剂量,可在待治疗的动物中以不同剂量用所述化合物进行多个完整的交叉研究。基于在显示可感知的特发性呕吐症状的伴侣动物中减轻或消除特发性呕吐的最大能力,选择最佳剂量。在以宠物食品组合物的形式对伴侣动物给药时,上文所述的化合物优选地以0.1ppm至50000ppm、优选1ppm至150ppm的剂量范围给药。在以补充剂的形式给药时,上文所述的植物材料或提取物可优选地以补充剂的0.1重量%至99重量%、优选0.5重量%至5重量%的剂量给药。所述组合物优选是膳食组合物,但也可以是任何其它组合物,其包括但不限于:外用组合物、可注射组合物、鼻用组合物、直肠组合物等。
给药的频率和持续时间可根据动物的病症、所治疗的动物物种、其对治疗的个体反应和所选药物制剂的类型而变化。频率范围可从每月一次至每日六次,优选每周一次至每日四次,且更优选每日一次至每日三次。持续时间的范围可从五日至动物的整个寿命,例如25年。优选的是,持续时间的范围是从一周至15年,更优选从两周至一年,且更优选从一个月至六个月。
其它类型的呕吐或反胃可以与特发性呕吐同期发生。本发明的组合物可包括减少呕吐的其它原因的特征。例如,食品组合物可包括相对于动物个体的口的尺寸较大的食物颗粒,以阻止可能引起反胃的快速进食;或者可以包括减少毛团出现的成分,如蛋白酶、多元醇脂肪酸聚酯、缓泻药等;或者可以包括促进胃肠健康的成分,如益生元(prebiotics)或益生菌(probiotics)。本发明的组合物可包括具有止吐活性的药用药物。
含有膳食组合物的试剂盒
本发明还涵盖一种商业产品,其优选是以试剂盒的形式,所述商业产品包括上文所述的膳食组合物连同提供如何对伴侣动物口服给药或喂食所述膳食组合物的信息的说明书。具体而言,所述说明书可提供关于以下的信息,例如:评价伴侣动物的特发性呕吐病症的严重性;喂食频率;喂食持续时间;喂食方式;和监控所述伴侣动物的特发性呕吐病症以确定何时改变喂食频率和/或喂食持续时间。
适用于运输和售卖本文所公开的膳食组合物的任何标准包装均可用于形成所述试剂盒。所述试剂盒还可包括关于抑制、减轻和消除伴侣动物的特发性呕吐或呕吐的具体的书面效益声明。所述效益声明还可涉及由这种对特发性呕吐或呕吐的预防或治疗所带来的健康效益,如提高体重和能量水平,改善免疫功能和延长寿命。
通过以下实施例说明本发明。然而应理解的是,本发明并不限于这些实施例的具体细节。
实施例
筛选5-HT3a受体抑制剂的试验
各种已知的高通量筛选试验可用于确定材料对5-HT3a受体的抑制作用。
例如,5-HT3a受体是位于中枢神经系统和周围神经系统的配体门控的非选择性阳离子通道。通过诱导钙与钠内流和调动细胞内钙库(calciumstore),以及调整各种神经递质和神经肽如多巴胺、胆囊收缩素、乙酰胆碱、γ-氨基丁酸(GABA)、P物质或血清素自身的释放,活化5-HT3a受体,随后使周围神经元或中枢神经元快速去极化,这导致细胞质的Ca2+和Na+浓度急剧升高。由于5HT3受体的活化跟随钙与钠内流和随后的细胞内钙与钠的快速增加,因此可以容易地使用钙指示剂(例如Fluo-4AM)或钠染料利用荧光成像读板仪(FluorescenceImagePlateReader,FLIPR)分析检测内流Ca2+或Na+信号,以确定5-HT3a受体的激动剂或拮抗剂。
5-HT3aFLIPR分析可具体通过以下步骤进行。首先,在具有5%CO2和90%湿度的哺乳动物细胞培养箱中,使稳定表达h5HT3A受体的HEK-23(人胚肾)细胞在于75cm2的培养瓶内的16-18ml生长培养基中于37℃下生长2-3天。该生长培养基可含有例如补充有10%FBS(胎牛血清)、100μg/ml抗生素/抗真菌剂和150μg/mlG418的DMEM/F12(1:1,英杰(Invitrogen)11039)。然后将细胞培养基转移至50ml试管中,用10mlPBS洗涤细胞。随后,将2ml0.05%胰蛋白酶-EDTA加入以脱附细胞(detachcell),并将上述细胞培养基加回至培养瓶以使胰蛋白酶灭活。下一步,将细胞转移回上述的50ml试管中,将其以850rpm离心3分钟,以去除培养基。然后用生长培养基以每培养瓶细胞1-1.5ml将从离心获得的细胞重悬。随后用20μl的普朗尼克F-127溶解一小瓶Fluo-4AM(钙指示剂,50μg),每培养瓶细胞加入10μlFluo-4AM溶液(1个小瓶Fluo-4AM溶液20μl,正好用于2个培养瓶的细胞)。然后在摇床上轻轻摇动的同时用Fluo-4AM将细胞在室温下染色30分钟,随后加入45ml测定缓冲液[含CaCl2和MgCl2的汉克平衡盐溶液(HBSS)(Invitrogen14025),20mMHEPES,pH7.2]以洗涤一次细胞。再一次以850rpm进行3分钟离心,以去除测定缓冲液。再次将获得细胞团块重悬于测定缓冲液(每培养瓶细胞用18-20ml测定缓冲液)。将90微升的细胞装入96-孔板(50000个细胞/孔),所述96-孔板预装有待测试化合物(10μl的1mM测试材料,测试材料的终浓度将为100μM)。在室温下将板放置于黑暗中15-30分钟,然后转移至FLIPR-384仪器(美谷分子仪器(MolecularDevices))。放置含有6x激动剂(60μM血清素)的母板,所有测试板在加入激动剂后进行读板。最后通过FLIPR程序记录测试板的钙信号。使用Excel计算平均值和标准偏差,并扣除背景(缓冲液)。然后按计算抑制百分比(%)。如果计算得出的抑制百分比大于40%,则认为测试材料对5-HT3a受体具有抑制作用。
或者,可以使用基于细胞的血清素受体分析来筛选5-HT3a受体的抑制剂。通过使用激动剂血清素以及共转染以过表达5-HT3a受体和发光水母素钙敏感报告子(luminescentaequorincalciumsensitivereporter)的细胞,可进行该分析,以鉴定出以高敏感性、可量测性和特异性靶向5-HT3a受体的适合的新型活性物。
水母素(Aequorin)是来源于维多利亚水母(AequoreaVictoria)的光蛋白。最初翻译为脱辅酶蛋白(apo-enzyme),其需要疏水基腔肠素以开始向水母素转化。在结合钙后,通过水母素将腔肠素氧化成腔肠素酰胺(coelenteramide,BFP),导致发射出蓝光并排放CO2。因此,其对于可视化或检测内流Ca+2信号尤其有利。
可用以下步骤进行水母素辅助的血清素受体分析。解冻共表达血清素5HT3a受体和水母素钙传感器的经γ-射线照射的冷冻保藏的人类细胞(HEK293亲本)(珀金-埃尔默(PerkinElmer),目录编号ES-402-AF),并在含Hepes缓冲液、无酚红+10%FBS的无抗生素DMEM/F12(Invitrogen,目录编号11039-021)中培养18-24小时。在培养18-24小时后,通过用其细胞培养基冲洗而轻轻使细胞脱附。用额外的10mL细胞培养基洗涤确保捕获最佳数目的细胞。然后以150xg将细胞离心,计数并在福尔肯(Falcon)离心管中以1x106个细胞/mL重悬于BSA培养基[DMEM/Ham’sF12(含15mMHEPES、L-谷氨酰胺,无酚红)培养基(Invitrogen,目录编号11039-021)+10%无蛋白酶BSA(西格玛奥德里奇(SigmaAldrich),目录编号A9205)于水中,BSA终浓度为0.1%]。以5μM的终浓度将腔肠素加入分析培养基中。由于腔肠素储备溶液是在甲醇中,其得到良好地混合,同时将腔肠素溶液加入细胞悬液中以避免损坏细胞。然后用铝箔包裹10mLFalcon管,并放置在回转轮(约45°角和7rpm)上。随后在约20℃下(温度应保持在25℃以下),将细胞孵育4小时至18小时。在分析当天,在BSA培养基中将细胞稀释至终浓度为2.0x105个细胞/mL。在室温下再将细胞孵育至少1小时。然后准备筛选板。以2x浓度将拮抗剂稀释于上面引用的BSA培养基中,每个孔分配50μl。
将50微升的细胞悬液(对于终浓度1.0x104/孔,为2.0x105/ml)加入拮抗剂孔中,然后在室温下于黑暗中孵育15分钟。在指定时间(attime)仅制备一个板。使用读板器的注射器将50微升的血清素(3xEC80(EC是有效浓度的简称)浓度(30μM)以获得1xEC80(10μM)的终浓度)注射至细胞与拮抗剂的混合物中,记录发射光10s。使用激动剂血清素完成8个点的剂量曲线,以确定对于该系统的EC50。剂量范围为3.9E-7至5E-5[M]。所得EC50确定为1.925E-6±3.715E-6[M]。
图1至图44示出具有高5-HT3a抑制作用的如上所述的化合物的5-HT3a剂量反应曲线。
具体而言,图1示出泛醌-O(CAS号605-94-7)的5-HT3a剂量反应曲线。图2示出白藜芦醇(CAS号501-36-0)的5-HT3a剂量反应曲线。图3示出1,4-苯二酚,2,3-二甲基-(9CI)(CAS号608-43-5)的5-HT3a剂量反应曲线。图4示出岩兰草醇(CAS号89-88-3)的5-HT3a剂量反应曲线。图5示出3,6-二羟黄酮(CAS号92439-20-8)的5-HT3a剂量反应曲线。图6示出香草壬酰胺(CAS号2444-46-4)的5-HT3a剂量反应曲线。图7示出DL-氯化棕榈酰肉碱(CAS号6865-14-1)的5-HT3a剂量反应曲线。图8示出积雪草酸(CAS号464-92-6)的5-HT3a剂量反应曲线。图9示出法呢醛(CAS号19317-11-4)的5-HT3a剂量反应曲线。图10示出诺卡酮(CAS号4674-50-4)的5-HT3a剂量反应曲线。图11示出α-戊基肉桂醇(CAS号101-85-9)的5-HT3a剂量反应曲线。图12示出δ-十二内酯(CAS号713-95-1)的5-HT3a剂量反应曲线。图13示出γ-十二内酯(CAS号2305-05-7)的5-HT3a剂量反应曲线。图14示出α-紫罗兰酮(CAS号127-41-3)的5-HT3a剂量反应曲线。图15示出鹰嘴豆芽素A(CAS号491-80-5)的5-HT3a剂量反应曲线。图16示出δ-十一内酯(CAS号104-67-6)的5-HT3a剂量反应曲线。图17示出δ-十四内酯(CAS号2721-22-4)的5-HT3a剂量反应曲线。图18示出2-(3-苯丙基)吡啶(CAS号2110-18-1)的5-HT3a剂量反应曲线。图19示出1,14-十四烷二醇(CAS号19812-64-7)的5-HT3a剂量反应曲线。图20示出(+)-雪松醇(CAS号77-53-2)的5-HT3a剂量反应曲线。图21示出3-庚基二氢-5-甲基-2(3H)-呋喃酮(CAS号40923-64-6)的5-HT3a剂量反应曲线。图22示出δ-十一内酯(CAS号710-04-3)的5-HT3a剂量反应曲线。图23示出二氢茉莉酮酸甲酯(CAS号24851-98-7)的5-HT3a剂量反应曲线。图24示出乙氧喹(CAS号91-53-2)的5-HT3a剂量反应曲线。图25示出岩芹酸(CAS号593-39-5)的5-HT3a剂量反应曲线。图26示出甲基异丁香酚(CAS号93-16-3)的5-HT3a剂量反应曲线。图27示出香兰基丁醚(CAS号82654-98-6)的5-HT3a剂量反应曲线。图28示出愈疮木油(CAS号8016-23-7)的5-HT3a剂量反应曲线。图29示出藤黄菌素(CAS号491-70-3)的5-HT3a剂量反应曲线。图30示出18-β-甘草次酸(CAS号471-53-4)的5-HT3a剂量反应曲线。图31示出柠檬酸三丁酯(CAS号77-94-1)的5-HT3a剂量反应曲线。图32示出棕榈油酸(CAS号373-49-9)的5-HT3a剂量反应曲线。图33示出红没药醇(CAS号515-69-5)的5-HT3a剂量反应曲线。图34示出姜黄素(CAS号458-37-7)的5-HT3a剂量反应曲线。图35示出胡椒碱(CAS号94-62-2)的5-HT3a剂量反应曲线。图36示出黄酮(CAS号525-82-6)的5-HT3a剂量反应曲线。图37示出薄荷氧基丙二醇(CAS号87061-04-9)的5-HT3a剂量反应曲线。图38示出4-羟基查耳酮(CAS号2657-25-2)的5-HT3a剂量反应曲线。图39示出n-丙基-4-羟基苯甲酸酯(CAS号94-13-3)的5-HT3a剂量反应曲线。图40示出胆钙化醇维生素D3(CAS号67-97-0)的5-HT3a剂量反应曲线。图41示出姜油树脂(CAS号8002-60-6)的5-HT3a剂量反应曲线。图42示出二十碳五烯酸(CAS号10417-94-4)的5-HT3a剂量反应曲线。图43示出核黄素维生素B2(CAS号83-88-5)的5-HT3a剂量反应曲线。图44示出根皮素(CAS号60-82-2)的5-HT3a剂量反应曲线。
筛选NK-1受体抑制剂的试验
各种已知的高通量筛选试验也可用于确定材料对NK-1受体的抑制作用。
一种示例性试验为英杰(Invitrogen)公司的TangoTMG蛋白偶联受体(GPCR)细胞水平测定(cell-basedassay)。首先,在McCoy’s培养基中培养TACR1-blaU2OS细胞(来自Invitrogen)。然后将培养的细胞在DMEM中铺入96-孔板(15125个细胞/孔,以90μL/孔)。在16-24小时后,用测试材料或阳性对照拮抗剂(其为100nM阿瑞匹坦)处理细胞,然后在37℃与5%CO2下孵育30-60分钟。随后,用1nMSAR9P物质激动剂处理细胞,并在37℃与5%CO2下再孵育5小时。从培养箱取出板,并在室温下平衡15分钟。在平衡步骤期间,制备LiveBlazer底物检测溶液(来自Invitrogen)。将6倍的底物混合物加入每个孔,随后在室温下于黑暗中将板孵育2小时。使用“Geneblazer451”方法,通过2通道易美逊(Envision)微板读板器读板,2通道包括蓝色通道(在405处激发和在460处发射)和绿色通道(在405处激发和在535处发射)。
图45-70示出具有高NK-1抑制作用的上文所述的化合物的NK-1剂量反应曲线。
具体而言,图45示出泛醌-O(CAS号605-94-7)的NK-1剂量反应曲线。图46示出白藜芦醇(CAS号501-36-0)的NK-1剂量反应曲线。图47示出甲萘醌(CAS号58-27-5)的NK-1剂量反应曲线。图48示出3,3’-二吲哚甲烷(CAS号1968-05-4)的NK-1剂量反应曲线。图49示出反式,反式-2,4-庚二烯醛(CAS号4313-03-5)的NK-1剂量反应曲线。图50示出反式-2,顺式-6-壬二烯醇(CAS号557-48-2)的NK-1剂量反应曲线。图51示出反式,反式-2,4-壬二烯醛(CAS号5910-87-2)的NK-1剂量反应曲线。图52示出反式-4-甲氧基肉桂醛(CAS号24680-50-0)的NK-1剂量反应曲线。图53示出姜油树脂(CAS号8002-60-6)的NK-1剂量反应曲线。图54示出3,6-二羟黄酮(CAS号92439-20-8)的NK-1剂量反应曲线。图55示出4’-羟基查耳酮(CAS号2657-25-2)的NK-1剂量反应曲线。图56示出DL-氯化棕榈酰肉碱(CAS号6865-14-1)的NK-1剂量反应曲线。图57示出积雪草酸(CAS号464-92-6)的NK-1剂量反应曲线。图58示出2,2’,4’-三羟基查耳酮(CAS号26962-50-5)的NK-1剂量反应曲线。图59示出血卟啉二盐酸盐(CAS号17696-69-4)的NK-1剂量反应曲线。图60示出植物鞘氨醇(CAS号554-62-1)的NK-1剂量反应曲线。图61示出藤黄菌素(CAS号491-70-3)的NK-1剂量反应曲线。图62示出18-β-甘草次酸(CAS号471-53-4)的NK-1剂量反应曲线。图63示出姜黄素(CAS号458-37-7)的NK-1剂量反应曲线。图64示出苯亚甲基丙酮(CAS号122-57-6)的NK-1剂量反应曲线。图65示出染料木黄酮(CAS号446-72-0)的NK-1剂量反应曲线。图66示出芹黄素(CAS号520-36-5)的NK-1剂量反应曲线。图67示出胡椒碱(CAS号94-62-2)的NK-1剂量反应曲线。图68示出查耳酮(CAS号614-47-1)的NK-1剂量反应曲线。图69示出桂皮油(CAS号8015-91-6)的NK-1剂量反应曲线。图70示出二十碳五烯酸(CAS号10417-94-4)的NK-1剂量反应曲线。
包括任何交叉引用的或相关的专利或申请在内的本文所引用的每个文件的全部内容通过引用并入本文,除非明确地排除在外或另有限定。任何文件的引用并不是承认其相对于本文所公开或请求保护的任何发明而言是现有技术,或者承认其单独或与其它任何参考文献任意组合时教导、建议或公开了这样的发明。此外,在本文件中术语的任何含义或定义与通过引用并入的文件中的相同术语的任何含义或定义有矛盾的情况下,应限定为在本文件中指定给该术语的含义或定义。
尽管已示出并描述了本发明的具体实施方式,但对于本领域技术人员而言显而易见的是,在不背离本发明的精神和范围的情况下,可进行各种其它变化和改进。因此,旨在在随附权利要求中涵盖本发明范围内的所有这类变化和改进。
Claims (14)
1.一种用于预防或治疗伴侣动物的特发性呕吐的膳食组合物,所述组合物以对抑制5-羟色胺-3a血清素(5-HT3a)受体和/或神经激肽-1(NK-1)受体有效的量包含一种或多种化合物,其中所述一种或多种化合物选自以下所组成的组中:泛醌-O(CAS号605-94-7)、白藜芦醇(CAS号501-36-0)、1,4-苯二酚,2,3-二甲基-(9CI)(CAS号608-43-5)、岩兰草醇(CAS号89-88-3)、3,6-二羟黄酮(CAS号92439-20-8)、香草壬酰胺(CAS号2444-46-4)、DL-氯化棕榈酰肉碱(CAS号6865-14-1)、积雪草酸(CAS号464-92-6)、法呢醛(CAS号19317-11-4)、诺卡酮(CAS号4674-50-4)、α-戊基肉桂醇(CAS号101-85-9)、δ-十二内酯(CAS号713-95-1)、γ-十二内酯(CAS号2305-05-7)、α-紫罗兰酮(CAS号127-41-3)、鹰嘴豆芽素A(CAS号491-80-5)、δ-十一内酯(CAS号104-67-6)、δ-十四内酯(CAS号2721-22-4)、2-(3-苯丙基)吡啶(CAS号2110-18-1)、1,14-十四烷二醇(CAS号19812-64-7)、(+)-雪松醇(CAS号77-53-2)、3-庚基二氢-5-甲基-2(3H)-呋喃酮(CAS号40923-64-6)、δ-十一内酯(CAS号710-04-3)、二氢茉莉酮酸甲酯(CAS号24851-98-7)、乙氧喹(CAS号91-53-2)、岩芹酸(CAS号593-39-5)、甲基异丁香酚(CAS号93-16-3)、香兰基丁醚(CAS号82654-98-6)、愈疮木油(CAS号8016-23-7)、藤黄菌素(CAS号491-70-3)、18-β-甘草次酸(CAS号471-53-4)、柠檬酸三丁酯(CAS号77-94-1)、棕榈油酸(CAS号373-49-9)、红没药醇(CAS号515-69-5)、姜黄素(CAS号458-37-7)、胡椒碱(CAS号94-62-2)、黄酮(CAS号525-82-6)、薄荷氧基丙二醇(CAS号87061-04-9)、4-羟基查耳酮(CAS号2657-25-2)、N-丙基-4-羟基苯甲酸酯(CAS号94-13-3)、胆钙化醇维生素D3(CAS号67-97-0)、姜油树脂(CAS号8002-60-6)、二十碳五烯酸(CAS号10417-94-4)、核黄素维生素B2(CAS号83-88-5)、根皮素(CAS号60-82-2)、甲萘醌(CAS号58-27-5)、3,3’-二吲哚甲烷(CAS号1968-05-4)、反式,反式-2,4-庚二烯醛(CAS号4313-03-5)、反式-2,顺式-6-壬二烯醇(CAS号557-48-2)、反式,反式-2,4-壬二烯醛(CAS号5910-87-2)、反式-4-甲氧基肉桂醛(CAS号24680-50-0)、4’-羟基查耳酮(CAS号2657-25-2)、2,2’,4’-三羟基查耳酮(CAS号26962-50-5)、血卟啉二盐酸盐(CAS号17696-69-4)、植物鞘氨醇(CAS号554-62-1)、苯亚甲基丙酮(CAS号122-57-6)、染料木黄酮(CAS号446-72-0)、芹黄素(CAS号520-36-5)、查耳酮(CAS号614-47-1)、桂皮油(CAS号8015-91-6),及它们的衍生物,以及它们的组合。
2.如权利要求1所述的膳食组合物,其中所述膳食组合物是包含0.1ppm至75000ppm的所述一种或多种化合物的宠物食品,并且其中所述宠物食品还包括碳水化合物源、蛋白质源和任选的脂肪源。
3.如权利要求1所述的膳食组合物,其中所述组合物是宠物食品补充剂,所述补充剂能够与宠物食品分开或组合地喂给伴侣动物,其中所述宠物食品补充剂包含0.1重量%至99重量%的所述一种或多种化合物。
4.一种用于预防或治疗伴侣动物的特发性呕吐的方法,所述方法包括以下步骤:以对抑制5-羟色胺-3(5-HT3)受体和/或神经激肽-1(NK-1)受体有效的量对所述伴侣动物口服给药一种或多种化合物,其中所述一种或多种化合物选自以下所组成的组中:泛醌-O(CAS号605-94-7)、白藜芦醇(CAS号501-36-0)、1,4-苯二酚,2,3-二甲基-(9CI)(CAS号608-43-5)、岩兰草醇(CAS号89-88-3)、3,6-二羟黄酮(CAS号92439-20-8)、香草壬酰胺(CAS号2444-46-4)、DL-氯化棕榈酰肉碱(CAS号6865-14-1)、积雪草酸(CAS号464-92-6)、法呢醛(CAS号19317-11-4)、诺卡酮(CAS号4674-50-4)、α-戊基肉桂醇(CAS号101-85-9)、δ-十二内酯(CAS号713-95-1)、γ-十二内酯(CAS号2305-05-7)、α-紫罗兰酮(CAS号127-41-3)、鹰嘴豆芽素A(CAS号491-80-5)、香紫苏内酯(CAS号564-20-5)、δ-十一内酯(CAS号104-67-6)、δ-十四内酯(CAS号2721-22-4)、2-(3-苯丙基)吡啶(CAS号2110-18-1)、4'-甲氧基黄铜(CAS号4143-74-2)、(+)-雪松醇(CAS号77-53-2)、3-庚基二氢-5-甲基-2(3H)-呋喃酮(CAS号40923-64-6)、δ-十一内酯(CAS号710-04-3)、二氢茉莉酮酸甲酯(CAS号24851-98-7)、3,3’-二吲哚甲烷(CAS号1968-05-4)、岩芹酸(CAS号593-39-5)、甲基异丁香酚(CAS号93-16-3)、香兰基丁醚(CAS号82654-98-6)、愈疮木油(CAS号8016-23-7)、藤黄菌素(CAS号491-70-3)、根皮素(CAS号60-82-2)、18-β-甘草次酸(CAS号471-53-4)、柠檬酸三丁酯(CAS号77-94-1)、棕榈油酸(CAS号373-49-9)、黄芩甙元(CAS号491-67-8)、胡椒碱(CAS号94-62-2)、黄酮(CAS号525-82-6)、油酸(CAS号112-80-1)、反式,反式-2,4-庚二烯醛(CAS号4313-03-5)、反式-2,顺式-6-壬二烯醇(CAS号557-48-2)、反式,反式-2,4-壬二烯醛(CAS号5910-87-2)、反式-4-甲氧基肉桂醛(CAS号24680-50-0)、β-紫罗兰醇(CAS号22029-76-1)、桦木酸(CAS号472-15-1)、苯亚甲基丙酮(CAS号122-57-6)、染料木黄酮(CAS号446-72-0)、芹黄素(CAS号520-36-5)、4-羟基查耳酮(CAS号2657-25-2)、n-丙基-4-羟基苯甲酸酯(CAS号94-13-3)、及它们的衍生物,以及它们的组合。
5.如权利要求4所述的方法,其中将所述一种或多种化合物作为膳食组合物的一部分口服给药至所述伴侣动物。
6.如权利要求5所述的方法,其中所述膳食组合物是包含0.1ppm至50000ppm的所述一种或多种化合物的宠物食品,并且其中所述宠物食品还包括碳水化合物源、蛋白质源和任选的脂肪源。
7.如权利要求5所述的方法,其中所述膳食组合物是宠物食品补充剂,所述宠物食品补充剂包含0.1重量%至99重量%的所述一种或多种化合物,并且其中所述口服给药的步骤包括将所述宠物食品补充剂与宠物食品分开或组合地喂给所述伴侣动物。
8.如权利要求5所述的方法,其中将所述膳食组合物以每月一次至每日六次的频率口服给药至所述伴侣动物。
9.如权利要求5所述的方法,其中将所述膳食组合物以五日至二十五年的持续时间口服给药至所述伴侣动物。
10.一种用于预防或治疗伴侣动物的特发性呕吐的组合物,所述组合物以对抑制5-羟色胺-3a血清素(5-HT3a)受体和/或神经激肽-1(NK-1)受体有效的量包含一种或多种化合物,其中所述一种或多种化合物选自以下所组成的组中:泛醌-O(CAS号605-94-7)、白藜芦醇(CAS号501-36-0)、1,4-苯二酚,2,3-二甲基-(9CI)(CAS号608-43-5)、岩兰草醇(CAS号89-88-3)、3,6-二羟黄酮(CAS号92439-20-8)、香草壬酰胺(CAS号2444-46-4)、DL-氯化棕榈酰肉碱(CAS号6865-14-1)、积雪草酸(CAS号464-92-6)、法呢醛(CAS号19317-11-4)、诺卡酮(CAS号4674-50-4)、α-戊基肉桂醇(CAS号101-85-9)、δ-十二内酯(CAS号713-95-1)、γ-十二内酯(CAS号2305-05-7)、α-紫罗兰酮(CAS号127-41-3)、鹰嘴豆芽素A(CAS号491-80-5)、δ-十一内酯(CAS号104-67-6)、δ-十四内酯(CAS号2721-22-4)、2-(3-苯丙基)吡啶(CAS号2110-18-1)、1,14-十四烷二醇(CAS号19812-64-7)、(+)-雪松醇(CAS号77-53-2)、3-庚基二氢-5-甲基-2(3H)-呋喃酮(CAS号40923-64-6)、δ-十一内酯(CAS号710-04-3)、二氢茉莉酮酸甲酯(CAS号24851-98-7)、乙氧喹(CAS号91-53-2)、岩芹酸(CAS号593-39-5)、甲基异丁香酚(CAS号93-16-3)、香兰基丁醚(CAS号82654-98-6)、愈疮木油(CAS号8016-23-7)、藤黄菌素(CAS号491-70-3)、18-β-甘草次酸(CAS号471-53-4)、柠檬酸三丁酯(CAS号77-94-1)、棕榈油酸(CAS号373-49-9)、红没药醇(CAS号515-69-5)、姜黄素(CAS号458-37-7)、胡椒碱(CAS号94-62-2)、黄酮(CAS号525-82-6)、薄荷氧基丙二醇(CAS号87061-04-9)、4-羟基查耳酮(CAS号2657-25-2)、N-丙基-4-羟基苯甲酸酯(CAS号94-13-3)、胆钙化醇维生素D3(CAS号67-97-0)、姜油树脂(CAS号8002-60-6)、二十碳五烯酸(CAS号10417-94-4)、核黄素维生素B2(CAS号83-88-5)、根皮素(CAS号60-82-2)、甲萘醌(CAS号58-27-5)、3,3’-二吲哚甲烷(CAS号1968-05-4)、反式,反式-2,4-庚二烯醛(CAS号4313-03-5)、反式-2,顺式-6-壬二烯醇(CAS号557-48-2)、反式,反式-2,4-壬二烯醛(CAS号5910-87-2)、反式-4-甲氧基肉桂醛(CAS号24680-50-0)、4’-羟基查耳酮(CAS号2657-25-2)、2,2’,4’-三羟基查耳酮(CAS号26962-50-5)、血卟啉二盐酸盐(CAS号17696-69-4)、植物鞘氨醇(CAS号554-62-1)、苯亚甲基丙酮(CAS号122-57-6)、染料木黄酮(CAS号446-72-0)、芹黄素(CAS号520-36-5)、查耳酮(CAS号614-47-1)、桂皮油(CAS号8015-91-6),及它们的衍生物,以及它们的组合。
11.一种制备膳食组合物的方法,该方法包括将能够抑制5-羟色胺-3a血清素(5-HT3a)受体和/或神经激肽-1(NK-1)受体的一种或多种化合物与适用于伴侣动物的一种或多种膳食营养物混合的步骤。
12.一种用于预防或治疗哺乳动物的特发性呕吐的组合物,所述组合物以对抑制5-羟色胺-3a血清素(5-HT3a)受体和/或神经激肽-1(NK-1)受体有效的量包含一种或多种化合物,其中所述一种或多种化合物选自以下所组成的组中:泛醌-O(CAS号605-94-7)、白藜芦醇(CAS号501-36-0)、1,4-苯二酚,2,3-二甲基-(9CI)(CAS号608-43-5)、岩兰草醇(CAS号89-88-3)、3,6-二羟黄酮(CAS号92439-20-8)、香草壬酰胺(CAS号2444-46-4)、DL-氯化棕榈酰肉碱(CAS号6865-14-1)、积雪草酸(CAS号464-92-6)、法呢醛(CAS号19317-11-4)、诺卡酮(CAS号4674-50-4)、α-戊基肉桂醇(CAS号101-85-9)、δ-十二内酯(CAS号713-95-1)、γ-十二内酯(CAS号2305-05-7)、α-紫罗兰酮(CAS号127-41-3)、鹰嘴豆芽素A(CAS号491-80-5)、δ-十一内酯(CAS号104-67-6)、δ-十四内酯(CAS号2721-22-4)、2-(3-苯丙基)吡啶(CAS号2110-18-1)、1,14-十四烷二醇(CAS号19812-64-7)、(+)-雪松醇(CAS号77-53-2)、3-庚基二氢-5-甲基-2(3H)-呋喃酮(CAS号40923-64-6)、δ-十一内酯(CAS号710-04-3)、二氢茉莉酮酸甲酯(CAS号24851-98-7)、乙氧喹(CAS号91-53-2)、岩芹酸(CAS号593-39-5)、甲基异丁香酚(CAS号93-16-3)、香兰基丁醚(CAS号82654-98-6)、愈疮木油(CAS号8016-23-7)、藤黄菌素(CAS号491-70-3)、18-β-甘草次酸(CAS号471-53-4)、柠檬酸三丁酯(CAS号77-94-1)、棕榈油酸(CAS号373-49-9)、红没药醇(CAS号515-69-5)、姜黄素(CAS号458-37-7)、胡椒碱(CAS号94-62-2)、黄酮(CAS号525-82-6)、薄荷氧基丙二醇(CAS号87061-04-9)、4-羟基查耳酮(CAS号2657-25-2)、N-丙基-4-羟基苯甲酸酯(CAS号94-13-3)、胆钙化醇维生素D3(CAS号67-97-0)、姜油树脂(CAS号8002-60-6)、二十碳五烯酸(CAS号10417-94-4)、核黄素维生素B2(CAS号83-88-5)、根皮素(CAS号60-82-2)、甲萘醌(CAS号58-27-5)、3,3’-二吲哚甲烷(CAS号1968-05-4)、反式,反式-2,4-庚二烯醛(CAS号4313-03-5)、反式-2,顺式-6-壬二烯醇(CAS号557-48-2)、反式,反式-2,4-壬二烯醛(CAS号5910-87-2)、反式-4-甲氧基肉桂醛(CAS号24680-50-0)、4’-羟基查耳酮(CAS号2657-25-2)、2,2’,4’-三羟基查耳酮(CAS号26962-50-5)、血卟啉二盐酸盐(CAS号17696-69-4)、植物鞘氨醇(CAS号554-62-1)、苯亚甲基丙酮(CAS号122-57-6)、染料木黄酮(CAS号446-72-0)、芹黄素(CAS号520-36-5)、查耳酮(CAS号614-47-1)、桂皮油(CAS号8015-91-6),及它们的衍生物,以及它们的组合。
13.如权利要求12所述的膳食组合物,其中所述组合物是包含0.1ppm至75000ppm的所述一种或多种化合物的食品。
14.如权利要求12所述的膳食组合物,其中所述组合物是补充剂,所述补充剂能够与食品分开或组合地喂给所述哺乳动物,其中所述补充剂包含0.1重量%至99重量%的所述一种或多种化合物。
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CN108002997A (zh) * | 2017-12-15 | 2018-05-08 | 中国医学科学院药用植物研究所海南分所 | 一种具有止呕作用的沉香提取物及其应用 |
CN108002997B (zh) * | 2017-12-15 | 2020-10-23 | 中国医学科学院药用植物研究所海南分所 | 一种具有止呕作用的沉香提取物及其应用 |
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US20140271949A1 (en) | 2014-09-18 |
CN118105365A (zh) | 2024-05-31 |
ES2825064T3 (es) | 2021-05-14 |
JP2016513639A (ja) | 2016-05-16 |
CN105188400B (zh) | 2024-04-05 |
JP6300897B2 (ja) | 2018-03-28 |
RU2015144027A (ru) | 2017-04-26 |
EP2986136B1 (en) | 2020-08-12 |
JP2018076335A (ja) | 2018-05-17 |
AU2019200490B2 (en) | 2021-01-28 |
CA2902827A1 (en) | 2014-09-18 |
US10548935B2 (en) | 2020-02-04 |
AR095483A1 (es) | 2015-10-21 |
CA2902827C (en) | 2022-11-01 |
AU2019200490A1 (en) | 2019-02-14 |
WO2014143539A1 (en) | 2014-09-18 |
AU2014228552A1 (en) | 2015-10-08 |
EP2986136A1 (en) | 2016-02-24 |
RU2715699C2 (ru) | 2020-03-03 |
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