TW201345528A - Pharmaceutical compositions for combination therapy - Google Patents

Abstract

This invention relates to novel pharmaceutical compositions comprising a therapeutically effective combination of a dopaminergic stabilizer known as Pridopidine, and an inhibitor of the vesicular monoamine transporter type 2 (VMAT) known as Tetrabenazine. The pharmaceutical compositions for use according to the invention are contemplated particularly useful for improving the symptomatic therapeutic effects, and for reducing the adverse effects, of Tetrabenazine in the treatment of movement disorders, and in particular movement disorders associated with Huntington's disease, Gilles de la Tourette's syndrome, or tardive dyskinesia.

Description

用於組合療法之醫藥組合物 Pharmaceutical composition for combination therapy

匹多吡啶(Pridopidine)(亦即4-(3-甲磺醯基-苯基)-1-丙基-六氫吡啶)係當前在臨床中經研發用於治療亨廷頓氏病(Huntington's disease)之藥物物質。此化合物首次闡述於WO 01/46145中。 Pridopidine (also known as 4-(3-methylsulfonyl-phenyl)-1-propyl-hexahydropyridine) is currently being developed clinically for the treatment of Huntington's disease. Drug substance. This compound was first described in WO 01/46145.

匹多吡啶係顯示競爭性多巴胺D2受體拮抗作用以及快速解離動力學之多巴胺能穩定劑(Dyhring,2010)。活體內匹多吡啶會增加多巴胺在紋狀體及額皮質中之更新及釋放(Poten,2010；Pettersson 2010)。行為效應包含精神刺激劑誘導之高活動性之拮抗作用(表明抗精神病性質)，但對於自發性運動活動性並無抑制效應(Ponten,2010；Natesan 2006；Nilsson,2004)。 The pipidine is a dopaminergic stabilizer that exhibits competitive dopamine D2 receptor antagonism and rapid dissociation kinetics (Dyhring, 2010). In vivo p-polypyridine increases the renewal and release of dopamine in the striatum and frontal cortex (Poten, 2010; Pettersson 2010). Behavioral effects include a high activity antagonism induced by a psychostimulant (indicating antipsychotic properties) but no inhibitory effect on spontaneous motor activity (Ponten, 2010; Natesan 2006; Nilsson, 2004).

丁苯那嗪(Tetrabenazine)(亦即(SS,RR)-3-異丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氫-吡啶并[2,1-a]異喹啉-2-酮)係經出售用於症狀性治療某些運動病症之藥物物質(FDA Label for XENAZINE(Tetrabenzine)07/06/2011)。丁苯那嗪係2型囊泡單胺轉運體(VMAT)抑制劑，其阻斷單胺神經遞質在腦中之囊泡儲存，由此減少多巴胺、血清素及去甲腎上腺素之突觸釋放(Paleacu,2007)。單胺能神經傳遞之此減少與(例如)多巴胺依賴性功能(包含活動及報酬)之阻抑有關。在治療上使用活動阻抑來改善(例如)亨廷頓氏病、遲發性運動困然及圖雷特病(Tourette's disease)中之非自主運動。然而，丁苯那嗪治療與嚴重副作 用有關。該等副作用包含帕金森氏病(parkinsonism)，亦即僵硬及運動功能缺損、抑鬱及功能能力缺損。 Tetrabenazine (also known as ( SS , RR )-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2] , 1- a ]isoquinolin-2-one) is a drug substance sold for the symptomatic treatment of certain motor disorders (FDA Label for XENAZINE (Tetrabenzine) 07/06/2011). A tetrabenazine-based type 2 vesicular monoamine transporter (VMAT) inhibitor that blocks the storage of vesicles in the brain by monoamine neurotransmitters, thereby reducing synapses in dopamine, serotonin, and norepinephrine Release (Paleacu, 2007). This reduction in monoaminergic neurotransmission is associated with, for example, the inhibition of dopamine-dependent functions, including activity and reward. Activity inhibition is used therapeutically to improve, for example, Huntington's disease, late onset exercise, and involuntary movement in Tourette's disease. However, tetrabenazine treatment is associated with severe side effects. These side effects include Parkinson's disease, which is stiffness and motor impairment, depression, and functional deficits.

非自主運動(例如舞蹈症及運動困然)係作為(例如)亨廷頓氏病之臨床表現之一部分出現，據信其與間接皮質-紋狀體-丘腦路徑中之活動性缺損相關。因此，丁苯那嗪對於該等非自主運動之有益效應係源於降低了間接路徑之中型棘突性神經元上之多巴胺D2受體處的張力，此係因丁苯那嗪引起多巴胺傳遞減少而出現。多巴胺D2受體張力降低使得該等中型棘突性神經元之抑制有所減小，且由此增加了間接路徑之活動性，並改良非自主運動之阻抑。因此，多巴胺D2拮抗劑亦通常用於緩解HD中之舞蹈症(Steward 2001)。 Non-autonomous movements (such as chorea and exercise stagnation) occur as part of the clinical manifestations of, for example, Huntington's disease, which is believed to be associated with active deficits in the indirect cortical-striatum-thalamic pathway. Thus, the beneficial effects of tetrabenazine on these involuntary movements are due to a decrease in the tension at the dopamine D2 receptor in the indirect pathway-type spinous neurons, which is caused by tetrabenazine causing a decrease in dopamine transmission. And appeared. Decreased dopamine D2 receptor tension reduces the inhibition of these mid-type spinous neurons, thereby increasing the mobility of indirect pathways and improving the inhibition of involuntary movement. Therefore, dopamine D2 antagonists are also commonly used to alleviate chorea in HD (Steward 2001).

組合療法Combination therapy

投與兩種藥物來治療給定病狀(例如運動病症)會產生許多潛在問題。兩種藥物之間之活體內相互作用較為複雜。任一單一藥物之效應與其吸收、分配及消除相關。在將兩種藥物引入身體中時，每一藥物可影響另一者之吸收、分配及消除，且由此改變另一者之效應。舉例而言，一種藥物可抑制、激活或誘導在另一藥物之消除之代謝途徑中所涉及酶之產生(Guidance for Industry,1999)。在一實例中，在實驗上已展示GA及干擾素(IFN)之組合投與廢除任一療法之臨床有效性。(Brod 2000)在另一實驗中，已報導潑尼松(prednisone)在組合療法中與IFN-β一起添加拮抗其正調控劑效應。因此，在投與兩種藥物治療同一病狀時，不能預知每一者將補足、不影響抑或干預另一者在人類個體中之治療活性。 There are many potential problems with administering two drugs to treat a given condition, such as a motor condition. The in vivo interaction between the two drugs is more complicated. The effect of any single drug is related to its absorption, distribution, and elimination. When two drugs are introduced into the body, each drug can affect the absorption, distribution, and elimination of the other, and thereby alter the effect of the other. For example, one drug can inhibit, activate, or induce the production of enzymes involved in the metabolic pathway of elimination of another drug (Guidance for Industry, 1999). In one example, the combination of GA and interferon (IFN) has been shown experimentally to abolish the clinical effectiveness of either therapy. (Brod 2000) In another experiment, prednisone has been reported to antagonize its positive modulator effect with IFN-[beta] in combination therapy. Therefore, when two drugs are administered to treat the same condition, it is not foreseen that each will complement, not affect, or interfere with the therapeutic activity of the other in the human individual.

兩種藥物之間之相互作用不僅可影響每一藥物之預期治療活性，且該相互作用亦可增加毒性代謝物之含量(Guidance for Industry,1999)。該相互作用亦可提高或減小每一藥物之副作用。因此，在投與兩種藥物來治療疾病時，不能預知每一藥物之負面副特徵(negative side profile)將發生何種變化。在一實例中，觀測到那他珠單抗(natalizumab)與干擾素β-1a之組合增加意外副作用之風險。(Vollmer,2008；Rudick 2006；Kleinschmidt-DeMasters,2005；Langer-Gould 2005) The interaction between the two drugs not only affects the expected therapeutic activity of each drug, but the interaction also increases the amount of toxic metabolites (Guidance for Industry, 1999). This interaction can also increase or decrease the side effects of each drug. Therefore, when administering two drugs to treat a disease, it is impossible to predict the negative secondary characteristics of each drug (negative Side profile) What will happen. In one example, the combination of natalizumab and interferon beta-1a was observed to increase the risk of unexpected side effects. (Vollmer, 2008; Rudick 2006; Kleinschmidt-DeMasters, 2005; Langer-Gould 2005)

另外，難以準確預測兩種藥物之間之相互作用之效應將何時顯現。舉例而言，藥物之間之代謝相互作用可在初始投與第二藥物後、在兩者已達到穩態濃度後或在該等藥物中之一者中斷後變得顯而易見(Guidance for Industry,1999)。 In addition, it is difficult to accurately predict when the effects of the interaction between the two drugs will appear. For example, metabolic interactions between drugs can become apparent after initial administration of a second drug, after both have reached steady state concentrations, or after one of the drugs is interrupted (Guidance for Industry, 1999) ).

因此，在申請時之目前最佳技術中，兩種藥物、特定而言匹多吡啶及丁苯那嗪之組合療法之效應不可預測，直至可獲得組合研究之結果為止。 Therefore, in the current best technique at the time of application, the effects of combination therapy of the two drugs, in particular, p-polypyridine and tetrabenazine, are unpredictable until the results of the combination study are available.

現已令人吃驚地發現，匹多吡啶能夠逆轉藉由丁苯那嗪引起之行為抑制，同時維持匹多吡啶之主要藥理學效應(亦即多巴胺D2受體阻斷)。該等發現表明，共投與匹多吡啶及丁苯那嗪會改良丁苯那嗪之治療有益效應，亦即進一步緩解非自主運動以及減少不良動作及情感效應。 It has now surprisingly been found that p-polypyridine reverses the behavioral inhibition caused by tetrabenazine while maintaining the primary pharmacological effect of pridopidine (i.e., dopamine D2 receptor blockade). These findings suggest that co-administration of p-polypyridine and tetrabenazine improves the beneficial effects of tetrabenazine, which further attenuates non-autonomous movement and reduces adverse movements and affective effects.

本發明提供治療患有運動病症之個體之方法，其包括向個體週期性投與一含量丁苯那嗪或其醫藥上可接受之鹽及一含量匹多吡啶或其醫藥上可接受之鹽。 The present invention provides a method of treating an individual suffering from a motor disorder comprising periodically administering to the subject a dose of tetrabenazine or a pharmaceutically acceptable salt thereof and a level of p-polypyridine or a pharmaceutically acceptable salt thereof.

本發明亦提供治療患有肥胖症、肥胖症相關病症或對匹多吡啶具心血管副作用之個體之方法，其包括向個體投與一含量匹多吡啶或其醫藥上可接受之鹽及一含量丁苯那嗪或其醫藥上可接受之鹽。 The invention also provides a method of treating an individual suffering from obesity, an obesity-related disorder or a cardiovascular side effect on p-polypyridine, comprising administering to the individual a level of p-polypyridine or a pharmaceutically acceptable salt thereof and a content thereof Tebufenazide or a pharmaceutically acceptable salt thereof.

本發明亦提供減少或預防向個體週期性投與一含量丁苯那嗪或其醫藥上可接受之鹽之一或多種副作用之方法，其包括向個體週期性投與一含量匹多吡啶或其醫藥上可接受之鹽。 The present invention also provides a method of reducing or preventing the periodic administration of one or more side effects of tetrabenazine or a pharmaceutically acceptable salt thereof to an individual, which comprises periodically administering to the individual a level of p-polypyridine or A pharmaceutically acceptable salt.

本發明亦提供一種包裝，其包括： a)第一醫藥組合物，其包括一含量丁苯那嗪或其醫藥上可接受之鹽及醫藥上可接受之載劑；b)第二醫藥組合物，其包括一含量匹多吡啶或其醫藥上可接受之鹽及醫藥上可接受之載劑；及c)使用說明書，其用於指導第一醫藥組合物及第二醫藥組合物一起治療患有運動病症之個體。 The invention also provides a package comprising: a) a first pharmaceutical composition comprising a content of tetrabenazine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising a content of p-polypyridine or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier; and c) instructions for use in directing the first pharmaceutical composition and the second pharmaceutical composition to treat an individual having a motor disorder.

本發明亦提供匹多吡啶或其醫藥上可接受之鹽，其用作丁苯那嗪或其醫藥上可接受之鹽之附加療法或與其組合以用於治療患有運動病症之個體。 The invention also provides a picopolypyridine or a pharmaceutically acceptable salt thereof for use as an additional therapy with or in combination with tetrabenazine or a pharmaceutically acceptable salt thereof for use in treating an individual suffering from a motor disorder.

本發明亦提供一種醫藥組合物，其包括一含量丁苯那嗪或其醫藥上可接受之鹽、一含量匹多吡啶或其醫藥上可接受之鹽及至少一種醫藥上可接受之載劑。 The invention also provides a pharmaceutical composition comprising a content of tetrabenazine or a pharmaceutically acceptable salt thereof, a content of p-polypyridine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

本發明亦提供以下物質之用途：a)一含量丁苯那嗪或其醫藥上可接受之鹽；及b)一含量匹多吡啶或其醫藥上可接受之鹽，其用以製備用於治療患有運動病症之個體之組合，其中同時或同期投與一含量丁苯那嗪或其醫藥上可接受之鹽及一含量匹多吡啶或其醫藥上可接受之鹽。 The invention also provides the use of: a) a content of tetrabenazine or a pharmaceutically acceptable salt thereof; and b) a level of p-polypyridine or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the treatment A combination of individuals having a motor disorder, wherein a dose of tetrabenazine or a pharmaceutically acceptable salt thereof and a level of p-polypyridine or a pharmaceutically acceptable salt thereof are administered simultaneously or concurrently.

本發明亦提供包括一含量丁苯那嗪或其醫藥上可接受之鹽之醫藥組合物，其與一含量匹多吡啶或其醫藥上可接受之鹽組合用於藉由向患有運動病症之個體週期性投與該醫藥組合物及該量之匹多吡啶或其醫藥上可接受之鹽來治療該個體。 The present invention also provides a pharmaceutical composition comprising a content of tetrabenazine or a pharmaceutically acceptable salt thereof, in combination with a content of p-polypyridine or a pharmaceutically acceptable salt thereof for administration to a motor condition The individual is administered the pharmaceutical composition and the amount of the p-polypyridine or a pharmaceutically acceptable salt thereof to treat the subject.

本發明亦提供包括一含量匹多吡啶或其醫藥上可接受之鹽之醫藥組合物，其與一含量丁苯那嗪或其醫藥上可接受之鹽組合用於藉由向患有運動病症之個體週期性投與該醫藥組合物及該量之丁苯那嗪或其醫藥上可接受之鹽來治療該個體。 The present invention also provides a pharmaceutical composition comprising a content of p-polypyridine or a pharmaceutically acceptable salt thereof, in combination with a content of tetrabenazine or a pharmaceutically acceptable salt thereof for administration to a motor disorder The individual is administered the pharmaceutical composition and the amount of tetrabenazine or a pharmaceutically acceptable salt thereof to treat the subject periodically.

本發明亦提供用於治療患有運動病症之個體之丁苯那嗪或其醫藥上可接受之鹽及匹多吡啶或其醫藥上可接受之鹽，其中同時、單獨或依序投與丁苯那嗪或其醫藥上可接受之鹽及匹多吡啶或其醫藥上可接受之鹽。 The present invention also provides a tetrabenazine or a pharmaceutically acceptable salt thereof and a p-polypyridine or a pharmaceutically acceptable salt thereof for use in treating an individual suffering from a motor disorder, wherein butylbenzene is administered simultaneously, separately or sequentially Naazine or a pharmaceutically acceptable salt thereof and p-polypyridine or a pharmaceutically acceptable salt thereof.

本發明亦提供一種產品，其含有同時、單獨或依序用於治療患有運動病症之個體之一含量丁苯那嗪或其醫藥上可接受之鹽及一含量匹多吡啶或其醫藥上可接受之鹽。 The present invention also provides a product comprising, simultaneously, separately or sequentially, for the treatment of tetrabenazine or a pharmaceutically acceptable salt thereof, and a piric acid or a pharmaceutically acceptable salt thereof, in an individual having a motor disorder Accept the salt.

本發明亦提供治療患有肥胖症、肥胖症相關病症或對匹多吡啶具心血管副作用之個體之方法，其包括向個體投與治療有效量匹多吡啶或其醫藥上可接受之鹽及治療有效量丁苯那嗪或其醫藥上可接受之鹽之組合，其中在一起服用時之量可有效治療個體。 The invention also provides a method of treating an individual having obesity, an obesity-related disorder, or a cardiovascular side effect on p-polypyridine, comprising administering to the subject a therapeutically effective amount of p-polypyridine or a pharmaceutically acceptable salt thereof and treatment An effective amount of a combination of tetrabenazine or a pharmaceutically acceptable salt thereof, wherein the amount administered together is effective to treat the individual.

本發明亦提供匹多吡啶或其醫藥上可接受之鹽及丁苯那嗪或其醫藥上可接受之鹽之組合；其用於治療、預防或緩解哺乳動物(包含人類)之肥胖症或肥胖症相關病症且用於治療、預防或緩解其對匹多吡啶具心血管之副作用。 The present invention also provides a combination of p-polypyridine or a pharmaceutically acceptable salt thereof and tetrabenazine or a pharmaceutically acceptable salt thereof for use in the treatment, prevention or amelioration of obesity or obesity in a mammal (including a human) a disease-related condition and is used to treat, prevent or alleviate its cardiovascular side effects on p-polypyridine.

在另一態樣中，本發明提供匹多吡啶或其醫藥上可接受之鹽及丁苯那嗪或其醫藥上可接受之鹽之組合，其用作用於治療、預防或緩解運動病症之藥劑。 In another aspect, the present invention provides a combination of p-polypyridine or a pharmaceutically acceptable salt thereof and tetrabenazine or a pharmaceutically acceptable salt thereof for use as a medicament for the treatment, prevention or amelioration of a motor disorder .

在另一態樣中，本發明提供匹多吡啶或其醫藥上可接受之鹽及丁苯那嗪或其醫藥上可接受之鹽之組合，其用作藥劑。 In another aspect, the invention provides a combination of p-polypyridine or a pharmaceutically acceptable salt thereof and tetrabenazine or a pharmaceutically acceptable salt thereof for use as a medicament.

在另一態樣中，本發明提供匹多吡啶或其醫藥上可接受之鹽及丁苯那嗪或其醫藥上可接受之鹽之組合；其用於治療、預防或緩解哺乳動物(包含人類)之肥胖症或肥胖症相關病症且用於治療、預防或緩解對匹多吡啶具心血管之副作用。 In another aspect, the present invention provides a combination of p-polypyridine or a pharmaceutically acceptable salt thereof and tetrabenazine or a pharmaceutically acceptable salt thereof for use in the treatment, prevention or amelioration of a mammal (including humans) An obesity or obesity-related disorder and for treating, preventing or ameliorating cardiovascular side effects on p-polypyridine.

在另一態樣中，本發明係關於匹多吡啶或其醫藥上可接受之鹽及丁苯那嗪或其醫藥上可接受之鹽之組合之用途；其用以製造用於治 療、預防或緩解哺乳動物(包含人類)之運動病症之藥劑。 In another aspect, the invention relates to the use of a combination of p-polypyridine or a pharmaceutically acceptable salt thereof and tetrabenazine or a pharmaceutically acceptable salt thereof; An agent that treats, prevents, or alleviates a motor condition in a mammal, including a human.

在另一態樣中，本發明提供包括匹多吡啶或其醫藥上可接受之鹽之醫藥組合物，其與包括丁苯那嗪或其醫藥上可接受之鹽之醫藥組合物一起用於組合療法中以治療、預防或緩解運動病症。 In another aspect, the present invention provides a pharmaceutical composition comprising p-polypyridine or a pharmaceutically acceptable salt thereof for use in combination with a pharmaceutical composition comprising tetrabenazine or a pharmaceutically acceptable salt thereof Therapy to treat, prevent or alleviate motor conditions.

在另一態樣中，本發明提供一種醫藥組合物，其包括治療有效量匹多吡啶或其醫藥上可接受之鹽及治療有效量丁苯那嗪或其醫藥上可接受之鹽以及一或多種佐劑、賦形劑、載劑及/或稀釋劑。 In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of p-polypyridine or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of tetrabenazine or a pharmaceutically acceptable salt thereof, and or A variety of adjuvants, excipients, carriers and/or diluents.

在另一態樣中，本發明提供治療、預防或緩解存活動物體(包含人類)之運動病症之方法，該方法包括以下步驟：向有需要之此一存活動物體投與治療有效量匹多吡啶或其醫藥上可接受之鹽與丁苯那嗪或其醫藥上可接受之鹽之組合療法。 In another aspect, the invention provides a method of treating, preventing or ameliorating a motor condition of a living object (including a human), the method comprising the steps of: administering a therapeutically effective amount to the active object in need thereof Combination therapy of pyridine or a pharmaceutically acceptable salt thereof with tetrabenazine or a pharmaceutically acceptable salt thereof.

在另一態樣中，本發明提供若干部分之套組，其包括至少兩個單獨單位劑型(A)及(B)(其中(A)包括匹多吡啶或其醫藥上可接受之鹽；且(B)包括丁苯那嗪或其醫藥上可接受之鹽)及視情況(C)說明書(其用於指導向有需要之患者同時、依序或單獨投與(A)之匹多吡啶及(B)之丁苯那嗪)。 In another aspect, the invention provides a kit of parts comprising at least two separate unit dosage forms (A) and (B) (wherein (A) comprises p-polypyridine or a pharmaceutically acceptable salt thereof; (B) including tetrabenazine or a pharmaceutically acceptable salt thereof, and optionally (C) instructions for directing the simultaneous or sequential administration of (P) picopyridine to a patient in need thereof (B) tetrabenazine).

在另一態樣中，本發明提供一種製造物件，其包括：(A)第一醫藥劑型，包括匹多吡啶或其醫藥上可接受之鹽；及(B)第二醫藥劑型，包括丁苯那嗪或其醫藥上可接受之鹽；其中該物件含有第一醫藥劑型及第二醫藥劑型。 In another aspect, the present invention provides a manufactured article comprising: (A) a first pharmaceutical dosage form comprising picopolypyridine or a pharmaceutically acceptable salt thereof; and (B) a second pharmaceutical dosage form comprising butadiene benzene Naazine or a pharmaceutically acceptable salt thereof; wherein the article comprises a first pharmaceutical dosage form and a second pharmaceutical dosage form.

在另一態樣中，本發明提供治療患有運動病症之個體之方法，其包括向該個體投與治療有效量匹多吡啶或其醫藥上可接受之鹽及治療有效量丁苯那嗪或其醫藥上可接受之鹽之組合，其中在一起服用時之量可有效治療人類患者。 In another aspect, the invention provides a method of treating an individual having a motor disorder, comprising administering to the individual a therapeutically effective amount of p-polypyridine or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of tetrabenazine or A combination of pharmaceutically acceptable salts thereof, which is administered in an amount effective to treat a human patient.

在另一態樣中，本發明提供治療患有肥胖症或肥胖症相關病症或對匹多吡啶具心血管副作用之哺乳動物(包含人類)之方法，其包括向 個體投與治療有效量匹多吡啶或其醫藥上可接受之鹽及治療有效量丁苯那嗪或其醫藥上可接受之鹽之組合，其中在一起服用時之量可有效治療哺乳動物。 In another aspect, the invention provides a method of treating a mammal (including a human) having obesity or obesity-related disorders or having cardiovascular side effects on p-polypyridine, including The individual is administered a therapeutically effective amount of a combination of p-polypyridine or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of tetrabenazine or a pharmaceutically acceptable salt thereof, wherein the amount administered together is effective to treat a mammal.

熟習此項技術者根據下列詳細說明及實例可明瞭本發明之其他目標。 Other objects of the present invention will become apparent to those skilled in the art from the <RTIgt;

藉由參照附圖來進一步闡釋本發明。 The invention is further illustrated by reference to the drawings.

圖1.關於丁苯那嗪之自發性運動活動性(LMA)(以平均對照組值之百分比形式表示)。基於劑量來展示每一記錄時間段之活動性。將動物分成4個不同治療組(n=5)。該等治療組係由媒劑(5.5% v/w葡萄糖)及在三個劑量(0.37 μmol/kg、0.64 μmol/kg及1.1 μmol/kg)下測試之丁苯那嗪組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 1. Spontaneous motor activity (LMA) of tetrabenazine (expressed as a percentage of mean control values). The activity of each recording period is shown based on the dose. Animals were divided into 4 different treatment groups (n=5). The treatment groups consisted of vehicle (5.5% v/w glucose) and tetrabenazine tested at three doses (0.37 μmol/kg, 0.64 μmol/kg and 1.1 μmol/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖2.丁苯那嗪對於紋狀體DOPAC(3,4-二羥基苯基乙酸)之效應。將動物分成4個不同治療組(n=5)。該等治療組係由媒劑(5.5% v/w葡萄糖)及在三個劑量(0.37 μmol/kg、0.64 μmol/kg及1.1 μmol/kg)下測試之丁苯那嗪組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 2. Effect of tetrabenazine on striatum DOPAC (3,4-dihydroxyphenylacetic acid). Animals were divided into 4 different treatment groups (n=5). The treatment groups consisted of vehicle (5.5% v/w glucose) and tetrabenazine tested at three doses (0.37 μmol/kg, 0.64 μmol/kg and 1.1 μmol/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖3.使用丁苯那嗪治療後之Arc基因表現(Arc mRNA含量或Arc，以平均對照組值之百分比形式表現)。基於劑量及區域(紋狀體arc(arcS)或額皮質arc(arcF))來展示表現。將動物分成4個不同治療組(n=5)。該等治療組係由媒劑(5.5% v/w葡萄糖)及在三個劑量(0.37 μmol/kg、0.64 μmol/kg及1.1 μmol/kg)下測試之丁苯那嗪組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 3. Arc gene performance after treatment with tetrabenazine (Arc mRNA content or Arc, expressed as a percentage of the mean control value). Performance is shown based on dose and area (striatum arc(arcS) or frontal cortex arc(arcF)). Animals were divided into 4 different treatment groups (n=5). The treatment groups consisted of vehicle (5.5% v/w glucose) and tetrabenazine tested at three doses (0.37 μmol/kg, 0.64 μmol/kg and 1.1 μmol/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖4.關於匹多吡啶之自發性運動活動性(以平均對照組值之百分 比形式表示)。基於劑量來展示每一記錄時間段之活動性。將動物分成4個不同治療組(n=5)。該等治療組係由媒劑(鹽水，0.9% v/w NaCl)及在三個劑量(11 μmol/kg、33 μmol/kg及100 μmol/kg)下測試之匹多吡啶組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 4. Spontaneous motor activity of p-polypyridine (% of mean control) More than the form). The activity of each recording period is shown based on the dose. Animals were divided into 4 different treatment groups (n=5). The treatment groups consisted of vehicle (saline, 0.9% v/w NaCl) and p-polypyridine tested at three doses (11 μmol/kg, 33 μmol/kg and 100 μmol/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖5.匹多吡啶(NS30016)對於紋狀體DOPAC之效應。將動物分成4個不同治療組(n=5)。該等治療組係由媒劑(鹽水，0.9% v/w NaCl)及在三個劑量(11 μmol/kg、33 μmol/kg及100 μmol/kg)下測試之匹多吡啶組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 5. Effect of picopolypyridine (NS30016) on striatal DOPAC. Animals were divided into 4 different treatment groups (n=5). The treatment groups consisted of vehicle (saline, 0.9% v/w NaCl) and p-polypyridine tested at three doses (11 μmol/kg, 33 μmol/kg and 100 μmol/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖6.使用匹多吡啶治療後之Arc基因表現(以平均對照組值之百分比形式表示)。基於劑量及區域(紋狀體arc(arcS)或額皮質arc(arcF))來展示表現。將動物分成4個不同治療組(n=5)。該等治療組係由媒劑(鹽水，0.9% v/w NaCl)及在三個劑量(11 μmol/kg、33 μmol/kg及100 μmol/kg)下測試之匹多吡啶組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 6. Arc gene performance after treatment with p-polypyridine (expressed as a percentage of mean control values). Performance is shown based on dose and area (striatum arc(arcS) or frontal cortex arc(arcF)). Animals were divided into 4 different treatment groups (n=5). The treatment groups consisted of vehicle (saline, 0.9% v/w NaCl) and p-polypyridine tested at three doses (11 μmol/kg, 33 μmol/kg and 100 μmol/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖7.關於氟哌啶醇(氟哌啶醇)之自發性運動活動性(以平均對照組值之百分比形式表示)。基於劑量來展示每一記錄時間段之活動性。將動物分成4個不同治療組(n=5)。該等治療組係由媒劑(5.5% v/w葡萄糖)及在三個劑量(0.12 μmol/kg、0.37 μmol/kg及1.1 μmol/kg)下測試之氟哌啶醇組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 7. Spontaneous motor activity of haloperidol (haloperidol) expressed as a percentage of the mean control value. The activity of each recording period is shown based on the dose. Animals were divided into 4 different treatment groups (n=5). The treatment groups consisted of vehicle (5.5% v/w glucose) and haloperidol tested at three doses (0.12 μmol/kg, 0.37 μmol/kg and 1.1 μmol/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖8.關於氟哌啶醇之自發性運動活動性(以平均對照組值之百分比形式表示)。將動物分成5個不同治療組(n=4)。該等治療組係由媒劑(5.5% v/w葡萄糖)及在四個劑量(0.04 μmol/kg、0.12 μmol/kg、0.37 μmol/kg及1.1 μmol/kg)下測試之氟哌啶醇組成。在開始記錄運動活動 性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 8. Spontaneous motor activity (in percent of mean control values) for haloperidol. Animals were divided into 5 different treatment groups (n=4). The treatment groups consisted of vehicle (5.5% v/w glucose) and haloperidol tested at four doses (0.04 μmol/kg, 0.12 μmol/kg, 0.37 μmol/kg, and 1.1 μmol/kg). . Start recording sports activities All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before sex.

圖9.匹多吡啶對於紋狀體DOPAC之效應。將動物分成4個不同治療組(n=5)。該等治療組係由媒劑(5.5% v/w葡萄糖)及在三個劑量(0.12 μmol/kg、0.37 μmol/kg及1.1 μmol/kg)下測試之氟哌啶醇組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 9. Effect of picopyridine on striatum DOPAC. Animals were divided into 4 different treatment groups (n=5). The treatment groups consisted of vehicle (5.5% v/w glucose) and haloperidol tested at three doses (0.12 μmol/kg, 0.37 μmol/kg and 1.1 μmol/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖10.使用氟哌啶醇治療後之Arc基因表現(以平均對照組值之百分比形式表示)。基於劑量及區域(紋狀體arc(arcS)或額皮質arc(arcF))來展示表現。將動物分成4個不同治療組(n=5)。該等治療組係由媒劑(5.5% v/w葡萄糖)及在三個劑量(0.12 μmol/kg、0.37 μmol/kg及1.1 μmol/kg)下測試之氟哌啶醇組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 10. Arc gene performance after treatment with haloperidol (expressed as a percentage of the mean control value). Performance is shown based on dose and area (striatum arc(arcS) or frontal cortex arc(arcF)). Animals were divided into 4 different treatment groups (n=5). The treatment groups consisted of vehicle (5.5% v/w glucose) and haloperidol tested at three doses (0.12 μmol/kg, 0.37 μmol/kg and 1.1 μmol/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖11.關於丁苯那嗪+匹多吡啶之自發性運動活動性(以平均對照組值之百分比形式表示)。基於劑量來展示每一記錄時間段之活動性。以以下兩種方式中之一者完成此實驗：(1)「製程BS81」，其中將動物分成4個不同治療組(n=5)，第一組係由1：1媒劑(鹽水(0.9% v/w NaCl)+5.5%葡萄糖以及數滴HAc)組成，第二組係由單一丁苯那嗪劑量(0.64 mg/kg)組成，且第三組及第四組係由在兩個劑量(33 μmol/kg及100 μmol/kg)下測試之匹多吡啶以及一個丁苯那嗪劑量(0.64 mg/kg)組成；或(2)「製程TA284」，其中將動物分成4個不同治療組(n=10)，第一組係由1：1媒劑(鹽水(0.9% v/w NaCl)+5.5%葡萄糖以及數滴HAc)組成，第二組係由單一丁苯那嗪劑量(0.64 mg/kg)組成，且第三組及第四組係由在兩個劑量(33 μmol/kg及100 μmol/kg)下測試之匹多吡啶以及一個丁苯那嗪劑量(0.64 mg/kg)組成。並不自此實驗收集腦組織。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 11. Spontaneous motor activity of tetrabenazine + p-polypyridine (expressed as a percentage of mean control values). The activity of each recording period is shown based on the dose. The experiment was done in one of two ways: (1) "Process BS81", in which the animals were divided into 4 different treatment groups (n=5), and the first group was 1:1 vehicle (saline (0.9) % v/w NaCl) + 5.5% glucose and a few drops of HAc), the second group consisted of a single tetrabenazine dose (0.64 mg/kg), and the third and fourth groups consisted of two doses. (33 μmol/kg and 100 μmol/kg) of p-polypyridine and a dose of tetrabenazine (0.64 mg/kg); or (2) "Process TA284", in which animals were divided into 4 different treatment groups (n=10), the first group consisted of a 1:1 vehicle (saline (0.9% v/w NaCl) + 5.5% glucose and a few drops of HAc), and the second group consisted of a single tetrabenazine dose (0.64). Composition of mg/kg), and the third and fourth groups were tested with p-polypyridine and one tetrabenazine at two doses (33 μmol/kg and 100 μmol/kg) (0.64 mg/kg) composition. Brain tissue was not collected from this experiment. All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖12.匹多吡啶對於丁苯那嗪誘導之紋狀體多巴胺增加之效應。將動物分成4個不同治療組(n=5)。第一組係由1：1媒劑(鹽水(0.9% v/w NaCl)+5.5%葡萄糖以及數滴HAc)組成，第二組係由單一丁苯那嗪劑量(0.64 mg/kg)組成，且第三組及第四組係由在兩個劑量(33 μmol/kg及100 μmol/kg)下測試之匹多吡啶(NS30016)以及一個丁苯那嗪劑量(0.64 mg/kg)組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 12. Effect of picopyridine on tetrabenazine-induced striatal dopamine increase. Animals were divided into 4 different treatment groups (n=5). The first group consisted of a 1:1 vehicle (salt (0.9% v/w NaCl) + 5.5% glucose and a few drops of HAc) and the second group consisted of a single tetrabenazine dose (0.64 mg/kg). The third and fourth groups consisted of p-polypyridine (NS30016) and a tetrabenazine dose (0.64 mg/kg) tested at two doses (33 μmol/kg and 100 μmol/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖13.使用丁苯那嗪+匹多吡啶治療後之Arc基因表現(以平均對照組值之百分比形式表示)。基於劑量及區域(紋狀體arc(arcS)或額皮質arc(arcF))來展示表現。將動物分成4個不同治療組(n=5)。第一組係由1：1媒劑(鹽水(0.9% v/w NaCl)+5.5%葡萄糖以及數滴HAc)組成，第二組係由單一丁苯那嗪劑量(0.64 mg/kg)組成，且第三組及第四組係由在兩個劑量(33 μmol/kg及100 μmol/kg)下測試之匹多吡啶以及一個丁苯那嗪劑量(0.64 mg/kg)組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 13. Arc gene performance after treatment with tetrabenazine + p-polypyridine (expressed as a percentage of mean control values). Performance is shown based on dose and area (striatum arc(arcS) or frontal cortex arc(arcF)). Animals were divided into 4 different treatment groups (n=5). The first group consisted of a 1:1 vehicle (salt (0.9% v/w NaCl) + 5.5% glucose and a few drops of HAc) and the second group consisted of a single tetrabenazine dose (0.64 mg/kg). The third and fourth groups consisted of p-polypyridine tested at two doses (33 μmol/kg and 100 μmol/kg) and one tetrabenazine dose (0.64 mg/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖14.關於丁苯那嗪+氟哌啶醇之自發性運動活動性(以平均對照組值之百分比形式表示)。基於劑量來展示每一記錄時間段之活動性。將動物分成4個不同治療組(n=5)。第一組係由1：1媒劑(鹽水(0.9% v/w NaCl)+5.5%葡萄糖以及數滴HAc)組成，第二組係由單一丁苯那嗪劑量(0.64 mg/kg)組成，且第三組及第四組係由在兩個劑量(0.04 mg/kg及0.12 mg/kg)下測試之氟哌啶醇以及一個丁苯那嗪劑量(0.64 mg/kg)組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 14. Spontaneous motor activity of tetrabenazine + haloperidol (expressed as a percentage of mean control values). The activity of each recording period is shown based on the dose. Animals were divided into 4 different treatment groups (n=5). The first group consisted of a 1:1 vehicle (salt (0.9% v/w NaCl) + 5.5% glucose and a few drops of HAc) and the second group consisted of a single tetrabenazine dose (0.64 mg/kg). The third and fourth groups consisted of haloperidol tested at two doses (0.04 mg/kg and 0.12 mg/kg) and one tetrabenazine dose (0.64 mg/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖15.氟哌啶醇對於丁苯那嗪誘導之紋狀體多巴胺增加之效應。將動物分成4個不同治療組(n=5)。第一組係由1：1媒劑(鹽水(0.9% v/w NaCl)+5.5%葡萄糖以及數滴HAc)組成，第二組係由單一丁苯那 嗪劑量(0.64 mg/kg)組成，且第三組及第四組係由在兩個劑量(0.04 mg/kg及0.12 mg/kg)下測試之氟哌啶醇以及一個丁苯那嗪劑量(0.64 mg/kg)組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 15. Effect of haloperidol on tetrabenazine-induced striatal dopamine increase. Animals were divided into 4 different treatment groups (n=5). The first group consisted of a 1:1 vehicle (salt (0.9% v/w NaCl) + 5.5% glucose and a few drops of HAc), and the second group consisted of a single butylphthalide. The dose of oxazine (0.64 mg/kg), and the third and fourth groups were doses of haloperidol and one tetrabenazine at two doses (0.04 mg/kg and 0.12 mg/kg). Composition of 0.64 mg/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

圖16.使用丁苯那嗪+氟哌啶醇治療後之Arc基因表現(以平均對照組值之百分比形式表示)。基於劑量及區域(紋狀體arc(arcS)或額皮質arc(arcF))來展示表現。將動物分成4個不同治療組(n=5)。第一組係由1：1媒劑(鹽水(0.9% v/w NaCl)+5.5%葡萄糖以及數滴HAc)組成，第二組係由單一丁苯那嗪劑量(0.64 mg/kg)組成，且第三組及第四組係由在兩個劑量(0.04 mg/kg及0.12 mg/kg)下測試之氟哌啶醇以及一個丁苯那嗪劑量(0.64 mg/kg)組成。在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 Figure 16. Arc gene performance after treatment with tetrabenazine + haloperidol (expressed as a percentage of mean control values). Performance is shown based on dose and area (striatum arc(arcS) or frontal cortex arc(arcF)). Animals were divided into 4 different treatment groups (n=5). The first group consisted of a 1:1 vehicle (salt (0.9% v/w NaCl) + 5.5% glucose and a few drops of HAc) and the second group consisted of a single tetrabenazine dose (0.64 mg/kg). The third and fourth groups consisted of haloperidol tested at two doses (0.04 mg/kg and 0.12 mg/kg) and one tetrabenazine dose (0.64 mg/kg). All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

本發明係關於使用匹多吡啶及丁苯那嗪來治療、預防或緩解運動病症之組合療法。 The present invention relates to a combination therapy using p-polypyridine and tetrabenazine to treat, prevent or ameliorate a motor condition.

匹多吡啶在與丁苯那嗪組合給予時之效應表明，首先，匹多吡啶之主要藥理學效應(亦即多巴胺D2受體阻斷)在與丁苯那嗪共投與時仍存在。此可反映為丁苯那嗪治療之大鼠中藉由匹多吡啶誘導之紋狀體DOPAC得以額外增加。考慮到所提出之機制係在紋狀體D2受體處之張力有所減小，根據該機制丁苯那嗪可緩解(例如)亨廷頓氏病、圖雷特病症及遲發性運動困然中之非自主運動，此表明組合丁苯那嗪與匹多吡啶可在該等病症中得到額外臨床益處。 The effect of p-polypyridine in combination with tetrabenazine indicates that, firstly, the main pharmacological effect of p-polypyridine (i.e., dopamine D2 receptor blockade) is still present when co-administered with tetrabenazine. This is reflected in the additional increase in striatum DOPAC induced by p-polypyridine in tetrabenazine-treated rats. Considering that the proposed mechanism is reduced in the tension at the D2 receptor of the striatum, according to this mechanism tetrabenazine can alleviate (for example) Huntington's disease, Tourette's disease and delayed movement. Non-autonomous exercise, which indicates that the combination of tetrabenazine and p-polypyridine provides additional clinical benefit in such conditions.

第二，匹多吡啶逆轉藉由丁苯那嗪引起之行為抑制。此行為抑制係限制丁苯那嗪應用之一些棘手多巴胺相關副作用(尤其係確定之運動副作用(例如帕金森氏病，亦即運動減少)以及可能之情緒低落)之臨床前相關事件。應注意，藉由丁苯那嗪誘導之行為抑制之此逆轉預計 不能自用作多巴胺D2受體處之純拮抗劑的化合物(例如匹多吡啶)獲得，且並未在使用多巴胺D2拮抗劑氟哌啶醇實施之類似研究中觀察到。相反，與氟哌啶醇共投與會進一步減小運動活動性。 Second, p-polypyridine reverses the behavioral inhibition caused by tetrabenazine. This behavioral inhibition limits some of the difficult dopamine-related side effects of tetrabenazine application (especially preclinical related events that determine motor side effects (eg, Parkinson's disease, ie, decreased exercise) and possibly depression). It should be noted that this reversal of behavioral inhibition induced by tetrabenazine is expected Compounds that are not available as pure antagonists at the dopamine D2 receptor (eg, p-polypyridine) were obtained and were not observed in a similar study performed with the dopamine D2 antagonist haloperidol. Conversely, co-administration with haloperidol further reduces exercise activity.

因此，該等臨床前行為數據暗示，匹多吡啶可抵抗丁苯那嗪之不良運動及情感效應。 Therefore, these preclinical behavioral data suggest that pridopridol is resistant to the adverse motor and emotional effects of tetrabenazine.

本發明提供治療患有運動病症之個體之方法，其包括向個體週期性投與一含量丁苯那嗪或其醫藥上可接受之鹽及一含量匹多吡啶或其醫藥上可接受之鹽。 The present invention provides a method of treating an individual suffering from a motor disorder comprising periodically administering to the subject a dose of tetrabenazine or a pharmaceutically acceptable salt thereof and a level of p-polypyridine or a pharmaceutically acceptable salt thereof.

本發明亦提供治療患有肥胖症、肥胖症相關病症或對匹多吡啶具心血管副作用之個體之方法，其包括向個體投與一含量匹多吡啶或其醫藥上可接受之鹽及一含量丁苯那嗪或其醫藥上可接受之鹽。 The invention also provides a method of treating an individual suffering from obesity, an obesity-related disorder or a cardiovascular side effect on p-polypyridine, comprising administering to the individual a level of p-polypyridine or a pharmaceutically acceptable salt thereof and a content thereof Tebufenazide or a pharmaceutically acceptable salt thereof.

在一實施例中，在一起服用時之量可較在以相同量單獨投與每一藥劑時更有效地治療個體。 In one embodiment, the amount administered together may be more effective in treating the individual than when each agent is administered separately in the same amount.

在一實施例中，丁苯那嗪或其醫藥上可接受之鹽之量(在單獨服用時)及匹多吡啶或其醫藥上可接受之鹽之量(在單獨服用時)或每一該量(在單獨服用時)不能有效治療個體。 In one embodiment, the amount of tetrabenazine or a pharmaceutically acceptable salt thereof (when taken alone) and the amount of p-polypyridine or a pharmaceutically acceptable salt thereof (when taken alone) or each The amount (when taken alone) does not effectively treat the individual.

本發明亦提供減少或預防向個體週期性投與一含量丁苯那嗪或其醫藥上可接受之鹽之一或多種副作用之方法，其包括向個體週期性投與一含量匹多吡啶或其醫藥上可接受之鹽。 The present invention also provides a method of reducing or preventing the periodic administration of one or more side effects of tetrabenazine or a pharmaceutically acceptable salt thereof to an individual, which comprises periodically administering to the individual a level of p-polypyridine or A pharmaceutically acceptable salt.

在一實施例中，一或多種副作用係選自抑鬱、自殺傾向、靜坐不能、煩亂不安、躁動、帕金森氏病、鎮靜、嗜睡及吞嚥困難。 In one embodiment, one or more of the side effects are selected from the group consisting of depression, suicidal tendency, sedation, restlessness, agitation, Parkinson's disease, sedation, lethargy, and difficulty swallowing.

在一實施例中，副作用係帕金森氏病。 In one embodiment, the side effect is Parkinson's disease.

在一實施例中，個體患有運動病症。 In one embodiment, the individual has a motor condition.

在一實施例中，經由經口投與來投與一含量丁苯那嗪或其醫藥上可接受之鹽。 In one embodiment, a level of tetrabenazine or a pharmaceutically acceptable salt thereof is administered via oral administration.

在一實施例中，每天投與一含量丁苯那嗪或其醫藥上可接受之 鹽。 In one embodiment, a dose of tetrabenazine or a pharmaceutically acceptable amount thereof is administered daily. salt.

在一實施例中，每天兩次投與一含量丁苯那嗪或其醫藥上可接受之鹽。 In one embodiment, a level of tetrabenazine or a pharmaceutically acceptable salt thereof is administered twice daily.

在一實施例中，每天三次投與一含量丁苯那嗪或其醫藥上可接受之鹽。 In one embodiment, a level of tetrabenazine or a pharmaceutically acceptable salt thereof is administered three times a day.

在一實施例中，丁苯那嗪或其醫藥上可接受之鹽之量為0.05 mg/kg/天至0.20 mg/kg/天。 In one embodiment, the amount of tetrabenazine or a pharmaceutically acceptable salt thereof is from 0.05 mg/kg/day to 0.20 mg/kg/day.

在一實施例中，丁苯那嗪或其醫藥上可接受之鹽之量為5-100 mg/天。 In one embodiment, the amount of tetrabenazine or a pharmaceutically acceptable salt thereof is from 5 to 100 mg/day.

在一實施例中，丁苯那嗪或其醫藥上可接受之鹽之量為12.5 mg/天、25 mg/天、37.5 mg/天、50 mg/天、75 mg/天或100 mg/天。 In one embodiment, the amount of tetrabenazine or a pharmaceutically acceptable salt thereof is 12.5 mg/day, 25 mg/day, 37.5 mg/day, 50 mg/day, 75 mg/day, or 100 mg/day. .

在一實施例中，經由經口投與來投與一含量匹多吡啶或其醫藥上可接受之鹽。 In one embodiment, a level of p-polypyridine or a pharmaceutically acceptable salt thereof is administered via oral administration.

在一實施例中，每天投與一含量匹多吡啶或其醫藥上可接受之鹽。 In one embodiment, one level of p-polypyridine or a pharmaceutically acceptable salt thereof is administered per day.

在一實施例中，每天兩次投與一含量匹多吡啶或其醫藥上可接受之鹽。 In one embodiment, one level of p-polypyridine or a pharmaceutically acceptable salt thereof is administered twice daily.

在一實施例中，匹多吡啶或其醫藥上可接受之鹽之量為1.5 μmol/kg/天至20 μmol/kg/天。 In one embodiment, the amount of the p-polypyridine or a pharmaceutically acceptable salt thereof is from 1.5 μmol/kg/day to 20 μmol/kg/day.

在一實施例中，匹多吡啶或其醫藥上可接受之鹽之量為10-100 mg/天。 In one embodiment, the amount of the p-polypyridine or a pharmaceutically acceptable salt thereof is from 10 to 100 mg/day.

在一實施例中，匹多吡啶或其醫藥上可接受之鹽之量為10 mg/天、20 mg/天、22.5 mg/天、45 mg/天或90 mg/天。 In one embodiment, the amount of the p-polypyridine or a pharmaceutically acceptable salt thereof is 10 mg/day, 20 mg/day, 22.5 mg/day, 45 mg/day, or 90 mg/day.

在一實施例中，運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 In one embodiment, the motor condition is Huntington's disease, Tourette's syndrome, or delayed movement.

在一實施例中，一含量丁苯那嗪或其醫藥上可接受之鹽及一含量 匹多吡啶或其醫藥上可接受之鹽可有效緩解運動病症之症狀。 In one embodiment, a content of tetrabenazine or a pharmaceutically acceptable salt thereof and a content thereof P-polypyridine or a pharmaceutically acceptable salt thereof is effective for alleviating the symptoms of a sports condition.

在一實施例中，症狀係舞蹈症。 In one embodiment, the symptom is chorea.

在一實施例中，在開始投與匹多吡啶或其醫藥上可接受之鹽之前，個體接受丁苯那嗪療法。 In one embodiment, the individual receives tetrabenazine therapy prior to initiating administration of the p-polypyridine or a pharmaceutically acceptable salt thereof.

在一實施例中，同時投與一含量丁苯那嗪或其醫藥上可接受之鹽及一含量匹多吡啶或其醫藥上可接受之鹽。 In one embodiment, a level of tetrabenazine or a pharmaceutically acceptable salt thereof and a level of p-polypyridine or a pharmaceutically acceptable salt thereof are administered simultaneously.

在一實施例中，個體係人類患者。 In one embodiment, the system is a human patient.

本發明亦提供一種包裝，其包括：a)第一醫藥組合物，其包括一含量丁苯那嗪或其醫藥上可接受之鹽及醫藥上可接受之載劑；b)第二醫藥組合物，其包括一含量匹多吡啶或其醫藥上可接受之鹽及醫藥上可接受之載劑；及c)使用說明書，其用於指導第一醫藥組合物及第二醫藥組合物一起治療患有運動病症之個體。 The invention also provides a package comprising: a) a first pharmaceutical composition comprising a content of tetrabenazine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition And a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; and c) instructions for use in instructing the first pharmaceutical composition and the second pharmaceutical composition to treat the same Individuals with motor disorders.

在一實施例中，包裝係用於治療患有運動病症之個體。 In one embodiment, the package is for treating an individual having a motor condition.

在一實施例中，運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 In one embodiment, the motor condition is Huntington's disease, Tourette's syndrome, or delayed movement.

本發明亦提供匹多吡啶或其醫藥上可接受之鹽，其用作丁苯那嗪或其醫藥上可接受之鹽之附加療法或與其組合以用於治療患有運動病症之個體。 The invention also provides a picopolypyridine or a pharmaceutically acceptable salt thereof for use as an additional therapy with or in combination with tetrabenazine or a pharmaceutically acceptable salt thereof for use in treating an individual suffering from a motor disorder.

在一實施例中，運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 In one embodiment, the motor condition is Huntington's disease, Tourette's syndrome, or delayed movement.

本發明亦提供一種醫藥組合物，其包括一含量丁苯那嗪或其醫藥上可接受之鹽、一含量匹多吡啶或其醫藥上可接受之鹽及至少一種醫藥上可接受之載劑。 The invention also provides a pharmaceutical composition comprising a content of tetrabenazine or a pharmaceutically acceptable salt thereof, a content of p-polypyridine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

在一實施例中，丁苯那嗪或其醫藥上可接受之鹽之量為5-100 mg。 In one embodiment, the amount of tetrabenazine or a pharmaceutically acceptable salt thereof is 5-100 Mg.

在一實施例中，丁苯那嗪或其醫藥上可接受之鹽之量為5 mg、6.25 mg、12.5 mg、25 mg、37.5 mg、50 mg、75 mg或100 mg。 In one embodiment, the amount of tetrabenazine or a pharmaceutically acceptable salt thereof is 5 mg, 6.25 mg, 12.5 mg, 25 mg, 37.5 mg, 50 mg, 75 mg or 100 mg.

在一實施例中，匹多吡啶或其醫藥上可接受之鹽之量為10-100 mg。 In one embodiment, the amount of the p-polypyridine or a pharmaceutically acceptable salt thereof is from 10 to 100 mg.

在一實施例中，匹多吡啶或其醫藥上可接受之鹽之量為10 mg、22.5 mg、45 mg或90 mg。 In one embodiment, the amount of the p-polypyridine or a pharmaceutically acceptable salt thereof is 10 mg, 22.5 mg, 45 mg or 90 mg.

在一實施例中，醫藥組合物係用於治療患有運動病症之個體。 In one embodiment, the pharmaceutical composition is for treating an individual having a motor disorder.

在一實施例中，運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 In one embodiment, the motor condition is Huntington's disease, Tourette's syndrome, or delayed movement.

在一實施例中，醫藥組合物係用於治療、預防或緩解個體所患之肥胖症、肥胖症相關病症或對匹多吡啶具心血管副作用。 In one embodiment, the pharmaceutical composition is for treating, preventing or ameliorating an obesity, an obesity-related disorder, or a cardiovascular side effect on p-polypyridine in an individual.

本發明亦提供以下物質之用途： a)一含量丁苯那嗪或其醫藥上可接受之鹽；及 b)一含量匹多吡啶或其醫藥上可接受之鹽， 其用以製備用於治療患有運動病症之個體之組合，其中同時或同期投與一含量丁苯那嗪或其醫藥上可接受之鹽及一含量匹多吡啶或其醫藥上可接受之鹽。 The invention also provides for the use of: a) a content of tetrabenazine or a pharmaceutically acceptable salt thereof; b) a content of p-polypyridine or a pharmaceutically acceptable salt thereof, It is used to prepare a combination for treating an individual suffering from a sports condition, wherein a dose of tetrabenazine or a pharmaceutically acceptable salt thereof and a content of p-polypyridine or a pharmaceutically acceptable salt thereof are administered simultaneously or simultaneously. .

在一實施例中，運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 In one embodiment, the motor condition is Huntington's disease, Tourette's syndrome, or delayed movement.

本發明亦提供包括一含量丁苯那嗪或其醫藥上可接受之鹽之醫藥組合物，其與一含量匹多吡啶或其醫藥上可接受之鹽組合用於藉由向患有運動病症之個體週期性投與該醫藥組合物及該量之匹多吡啶或其醫藥上可接受之鹽來治療該個體。 The present invention also provides a pharmaceutical composition comprising a content of tetrabenazine or a pharmaceutically acceptable salt thereof, in combination with a content of p-polypyridine or a pharmaceutically acceptable salt thereof for administration to a motor condition The individual is administered the pharmaceutical composition and the amount of the p-polypyridine or a pharmaceutically acceptable salt thereof to treat the subject.

本發明亦提供包括一含量匹多吡啶或其醫藥上可接受之鹽之醫藥組合物，其與一含量丁苯那嗪或其醫藥上可接受之鹽組合用於藉由向 患有運動病症之個體週期性投與該醫藥組合物及該量之丁苯那嗪或其醫藥上可接受之鹽來治療該個體。 The present invention also provides a pharmaceutical composition comprising a content of p-polypyridine or a pharmaceutically acceptable salt thereof, in combination with a content of tetrabenazine or a pharmaceutically acceptable salt thereof for use in An individual having a motor disorder periodically administers the pharmaceutical composition and the amount of tetrabenazine or a pharmaceutically acceptable salt thereof to treat the individual.

在一實施例中，運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 In one embodiment, the motor condition is Huntington's disease, Tourette's syndrome, or delayed movement.

本發明亦提供用於治療患有運動病症之個體之丁苯那嗪或其醫藥上可接受之鹽及匹多吡啶或其醫藥上可接受之鹽，其中同時、單獨或依序投與丁苯那嗪或其醫藥上可接受之鹽及匹多吡啶或其醫藥上可接受之鹽。 The present invention also provides a tetrabenazine or a pharmaceutically acceptable salt thereof and a p-polypyridine or a pharmaceutically acceptable salt thereof for use in treating an individual suffering from a motor disorder, wherein butylbenzene is administered simultaneously, separately or sequentially Naazine or a pharmaceutically acceptable salt thereof and p-polypyridine or a pharmaceutically acceptable salt thereof.

在一實施例中，運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 In one embodiment, the motor condition is Huntington's disease, Tourette's syndrome, or delayed movement.

本發明亦提供一種產品，其含有同時、單獨或依序用於治療患有運動病症之個體之一含量丁苯那嗪或其醫藥上可接受之鹽及一含量匹多吡啶或其醫藥上可接受之鹽。 The present invention also provides a product comprising, simultaneously, separately or sequentially, for the treatment of tetrabenazine or a pharmaceutically acceptable salt thereof, and a piric acid or a pharmaceutically acceptable salt thereof, in an individual having a motor disorder Accept the salt.

在一實施例中，運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 In one embodiment, the motor condition is Huntington's disease, Tourette's syndrome, or delayed movement.

本發明亦提供治療患有肥胖症、肥胖症相關病症或對匹多吡啶具心血管副作用之個體之方法，其包括向個體投與治療有效量匹多吡啶或其醫藥上可接受之鹽及治療有效量丁苯那嗪或其醫藥上可接受之鹽之組合，其中在一起投與時之量可有效治療個體。 The invention also provides a method of treating an individual having obesity, an obesity-related disorder, or a cardiovascular side effect on p-polypyridine, comprising administering to the subject a therapeutically effective amount of p-polypyridine or a pharmaceutically acceptable salt thereof and treatment An effective amount of a combination of tetrabenazine or a pharmaceutically acceptable salt thereof, wherein the amount administered together is effective to treat the individual.

在一實施例中，個體係人類患者。 In one embodiment, the system is a human patient.

本發明亦提供匹多吡啶或其醫藥上可接受之鹽及丁苯那嗪或其醫藥上可接受之鹽之組合；其用於治療、預防或緩解哺乳動物(包含人類)之肥胖症或肥胖症相關病症且用於治療、預防或緩解其對匹多吡啶具心血管之副作用。 The present invention also provides a combination of p-polypyridine or a pharmaceutically acceptable salt thereof and tetrabenazine or a pharmaceutically acceptable salt thereof for use in the treatment, prevention or amelioration of obesity or obesity in a mammal (including a human) a disease-related condition and is used to treat, prevent or alleviate its cardiovascular side effects on p-polypyridine.

在另一態樣中，本發明係關於一種組合療法，其中一起投與醫藥有效量匹多吡啶或其醫藥上可接受之鹽與治療有效量丁苯那嗪或其醫 藥上可接受之鹽以用於治療、預防或緩解運動病症。 In another aspect, the invention relates to a combination therapy wherein a pharmaceutically effective amount of p-polypyridine or a pharmaceutically acceptable salt thereof is administered together with a therapeutically effective amount of tetrabenazine or a physician thereof A pharmaceutically acceptable salt for use in the treatment, prevention or alleviation of a motor condition.

在一較佳實施例中，多動運動病症係源於亨廷頓氏病、吉累斯德拉圖雷特症候群(Gilles de la Tourette's syndrome)或遲發性運動困然之無意識多動運動病症，且特定而言係源於亨廷頓氏病之無意識多動運動病症。 In a preferred embodiment, the hyperkinetic motor condition is derived from Huntington's disease, Gilles de la Tourette's syndrome, or an unconscious hyperactive disorder of late onset exercise, and In particular, it is an unconscious hyperactive disorder that originates from Huntington's disease.

根據另一態樣，本發明提供匹多吡啶或其醫藥上可接受之鹽及丁苯那嗪或其醫藥上可接受之鹽之組合，其用作藥劑。 According to another aspect, the present invention provides a combination of p-polypyridine or a pharmaceutically acceptable salt thereof and tetrabenazine or a pharmaceutically acceptable salt thereof for use as a medicament.

在另一態樣中，本發明係關於以下物質之組合之用途： (i)匹多吡啶或其醫藥上可接受之鹽；及 (ii)丁苯那嗪或其醫藥上可接受之鹽； 其用以製造用於治療、預防或緩解哺乳動物(包含人類)之運動病症之藥劑。 In another aspect, the invention is for the use of a combination of: (i) p-polypyridine or a pharmaceutically acceptable salt thereof; (ii) tetrabenazine or a pharmaceutically acceptable salt thereof; It is used to manufacture an agent for treating, preventing or ameliorating a motor condition in a mammal, including a human.

在另一態樣中，本發明提供包括匹多吡啶或其醫藥上可接受之鹽之醫藥組合物，其與丁苯那嗪或其醫藥上可接受之鹽一起用於組合療法中來治療、預防或緩解多動運動病症。 In another aspect, the present invention provides a pharmaceutical composition comprising p-polypyridine or a pharmaceutically acceptable salt thereof for use in combination therapy with tetrabenazine or a pharmaceutically acceptable salt thereof, Prevent or alleviate hyperactive exercise disorders.

在另一態樣中，本發明提供治療、預防或緩解存活動物體之多動運動病症之方法，該方法包括以下步驟：向有需要之動物體投與治療有效量匹多吡啶或其醫藥上可接受之鹽與丁苯那嗪或其醫藥上可接受之鹽之組合療法。 In another aspect, the invention provides a method of treating, preventing or ameliorating a hyperkinetic condition of a living subject, the method comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of p-polypyridine or a medicinal thereof Combination therapy of an acceptable salt with tetrabenazine or a pharmaceutically acceptable salt thereof.

在另一態樣中，本發明提供一種醫藥組合物，其包括治療有效量匹多吡啶或其醫藥上可接受之鹽及治療有效量丁苯那嗪或其醫藥上可接受之鹽。 In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of p-polypyridine or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of tetrabenazine or a pharmaceutically acceptable salt thereof.

在另一態樣中，本發明提供若干部分之套組，其包括至少兩個單獨單位劑型(A)及(B)(其中(A)包括匹多吡啶或其醫藥上可接受之鹽；且(B)包括丁苯那嗪或其醫藥上可接受之鹽)及視情況(C)說明書(其用於指導向有需要之患者同時、依序或單獨投與(A)之匹多吡啶及(B)之 丁苯那嗪)。 In another aspect, the invention provides a kit of parts comprising at least two separate unit dosage forms (A) and (B) (wherein (A) comprises p-polypyridine or a pharmaceutically acceptable salt thereof; (B) including tetrabenazine or a pharmaceutically acceptable salt thereof, and optionally (C) instructions for directing the simultaneous or sequential administration of (P) picopyridine to a patient in need thereof (B) Tetrabenazine).

在另一態樣中，本發明提供一種製造物件，其包括：(A)第一醫藥劑型，包括匹多吡啶或其醫藥上可接受之鹽；及(B)第二醫藥劑型，包括丁苯那嗪或其醫藥上可接受之鹽；其中該物件含有第一醫藥劑型及第二醫藥劑型。 In another aspect, the present invention provides a manufactured article comprising: (A) a first pharmaceutical dosage form comprising picopolypyridine or a pharmaceutically acceptable salt thereof; and (B) a second pharmaceutical dosage form comprising butadiene benzene Naazine or a pharmaceutically acceptable salt thereof; wherein the article comprises a first pharmaceutical dosage form and a second pharmaceutical dosage form.

在另一態樣中，本發明提供治療患有運動病症之個體之方法，其包括向該個體投與治療有效量匹多吡啶或其醫藥上可接受之鹽及治療有效量丁苯那嗪或其醫藥上可接受之鹽之組合，其中在一起服用時之量可有效治療人類患者。 In another aspect, the invention provides a method of treating an individual having a motor disorder, comprising administering to the individual a therapeutically effective amount of p-polypyridine or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of tetrabenazine or A combination of pharmaceutically acceptable salts thereof, which is administered in an amount effective to treat a human patient.

在一實施例中，運動病症係源於亨廷頓氏病、吉累斯德拉圖雷特症候群或遲發性運動困然之無意識多動運動病症。 In one embodiment, the motor condition is derived from Huntington's disease, Gires De La Tourette syndrome, or an unconscious hyperactive motor condition in which delayed motion is impaired.

在一實施例中，運動病症係源於亨廷頓氏病之無意識多動運動病症。 In one embodiment, the motor condition is derived from an unconscious hyperkinetic condition of Huntington's disease.

在另一態樣中，本發明提供治療患有肥胖症或肥胖症相關病症或對匹多吡啶具心血管副作用之哺乳動物(包含人類)之方法，其包括向個體投與治療有效量匹多吡啶或其醫藥上可接受之鹽及治療有效量丁苯那嗪或其醫藥上可接受之鹽之組合，其中在一起服用時之量可有效治療哺乳動物。 In another aspect, the invention provides a method of treating a mammal (including a human) having an obesity or obesity-related disorder or having a cardiovascular side effect on p-polypyridine, comprising administering to the individual a therapeutically effective amount of A combination of pyridine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of tetrabenazine or a pharmaceutically acceptable salt thereof, wherein the amount administered together is effective to treat a mammal.

在一實施例中，經口投與治療有效量匹多吡啶或其醫藥上可接受之鹽及治療有效量丁苯那嗪或其醫藥上可接受之鹽。 In one embodiment, a therapeutically effective amount of p-polypyridine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of tetrabenazine or a pharmaceutically acceptable salt thereof are administered orally.

在一實施例中，經靜脈內投與治療有效量匹多吡啶或其醫藥上可接受之鹽及治療有效量丁苯那嗪或其醫藥上可接受之鹽。 In one embodiment, a therapeutically effective amount of p-polypyridine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of tetrabenazine or a pharmaceutically acceptable salt thereof are administered intravenously.

在一實施例中，藉由使藥物直接滲透穿過角質層來投與治療有效量匹多吡啶或其醫藥上可接受之鹽及治療有效量丁苯那嗪或其醫藥上可接受之鹽。 In one embodiment, a therapeutically effective amount of p-polypyridine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of tetrabenazine or a pharmaceutically acceptable salt thereof is administered by allowing the drug to permeate directly through the stratum corneum.

可以依序方式或藉由單獨投與同時施加含有匹多吡啶之藥劑與丁 苯那嗪。較佳地，與丁苯那嗪同時給予匹多吡啶。 The agent containing the p-polypyridine can be administered simultaneously or separately by administering the same Benazin. Preferably, the p-polypyridine is administered concurrently with tetrabenazine.

當前，據信，可以在每天約0.01-1000 mg API範圍內、更佳在每天約1-500 mg API範圍內、甚至更佳在每天約10-200 mg API範圍內之治療有效量使用匹多吡啶(與丁苯那嗪共投與)。 Currently, it is believed that it is possible to use a therapeutically effective amount in the range of about 0.01-1000 mg API per day, more preferably in the range of about 1-500 mg API per day, or even better in the range of about 10-200 mg API per day. Pyridine (co-administered with tetrabenazine).

當前，據信，可以在每天約0.01-1000 mg API範圍內、更佳在每天約1-500 mg API範圍內、甚至更佳在每天約10-200 mg API範圍內之治療有效量使用丁苯那嗪(與匹多吡啶共投與)。 Currently, it is believed that butylbenzene can be used in a therapeutically effective amount in the range of about 0.01-1000 mg API per day, more preferably in the range of about 1-500 mg API per day, or even better in the range of about 10-200 mg API per day. Naazine (co-administered with p-polypyridine).

可藉由任一習用途徑共投與匹多吡啶及丁苯那嗪。在一較佳實施例中，經口、經靜脈內、經血管內、經腹膜腔內、經皮下、經肌內、以吸入方式、局部、藉由貼劑或藉由栓劑投與匹多吡啶及丁苯那嗪。 Picopolypyridine and tetrabenazine can be co-administered by any conventional route. In a preferred embodiment, the peptide is administered orally, intravenously, intravascularly, intraperitoneally, subcutaneously, intramuscularly, by inhalation, topically, by patch or by suppository. And tetrabenazine.

在更佳實施例中，經口(p.o.)投與匹多吡啶及丁苯那嗪。 In a more preferred embodiment, the p-polypyridine and tetrabenazine are administered orally (p.o.).

在另一更佳實施例中，經靜脈內(i.v.)投與匹多吡啶及丁苯那嗪。 In another more preferred embodiment, p-polypyridine and tetrabenazine are administered intravenously (i.v.).

在另一實施例中，藉由皮下(s.c.)注射投與匹多吡啶及丁苯那嗪。 In another embodiment, the p-polypyridine and tetrabenazine are administered by subcutaneous (s.c.) injection.

本文所闡述實施例中之兩者或更多者之任一組合皆視為屬於本發明範圍內。 Combinations of two or more of the embodiments set forth herein are considered to be within the scope of the invention.

醫藥上可接受之鹽Pharmaceutically acceptable salt

用於本發明之活性化合物可以任一適於預期投與之形式提供。適宜形式包含本發明化合物之醫藥上(亦即生理學上)可接受之鹽及前藥(predrug或prodrug)形式。 The active compounds used in the present invention may be provided in any form suitable for the intended administration. Suitable forms include the pharmaceutically (i.e., physiologically) acceptable salts and prodrugs (predrug or prodrug) forms of the compounds of the invention.

醫藥上可接受之加成鹽之實例包含但不限於無毒無機及有機酸加成鹽，例如鹽酸鹽、氫溴酸鹽、硝酸鹽、高氯酸鹽、磷酸鹽、硫酸鹽、甲酸鹽、乙酸鹽、阿康酸鹽、抗壞血酸鹽、苯磺酸鹽、苯甲酸鹽、肉桂酸鹽、檸檬酸鹽、恩貝酸鹽、庚酸鹽、富馬酸鹽、麩胺酸鹽、羥乙酸鹽、乳酸鹽、馬來酸鹽、丙二酸鹽、扁桃酸鹽、甲磺酸 鹽、萘-2-磺酸鹽、鄰苯二甲酸鹽、水楊酸鹽、山梨酸鹽、硬脂酸鹽、琥珀酸鹽、酒石酸鹽、對甲苯磺酸鹽及諸如此類。可藉由業內熟知及闡述之程序形成該等鹽。 Examples of pharmaceutically acceptable addition salts include, but are not limited to, non-toxic inorganic and organic acid addition salts such as hydrochlorides, hydrobromides, nitrates, perchlorates, phosphates, sulfates, formates , acetate, aconsate, ascorbate, besylate, benzoate, cinnamate, citrate, enbeate, heptanoate, fumarate, glutamate, hydroxy Acetate, lactate, maleate, malonate, mandelate, methanesulfonic acid Salt, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, p-toluenesulfonate and the like. The salts can be formed by procedures well known and described in the art.

醫藥組合物Pharmaceutical composition

儘管用於本發明之化合物可以原始化合物形式投與，但較佳地視情況以生理學上可接受之鹽形式、以與一或多種佐劑、賦形劑、載劑、緩衝劑、稀釋劑及/或其他常見醫藥輔助劑之醫藥組合物形式引入活性成份。 Although the compounds used in the present invention may be administered as the original compound, it is preferably in the form of a physiologically acceptable salt, in combination with one or more adjuvants, excipients, carriers, buffers, diluents. And/or other pharmaceutical ingredients in the form of a pharmaceutical composition to introduce the active ingredient.

在一較佳實施例中，本發明提供一種醫藥組合物，其包括活性化合物或其醫藥上可接受之鹽或衍生物以及為此之一或多種醫藥上可接受之載劑及視情況業內已知及使用之其他治療性及/或預防性成份。載劑必須在與調配物之其他成份相容且對其接受者無害之意義上「可接受」。 In a preferred embodiment, the present invention provides a pharmaceutical composition comprising an active compound or a pharmaceutically acceptable salt or derivative thereof, and one or more pharmaceutically acceptable carriers for this purpose and, as the case may be, Know other therapeutic and/or prophylactic ingredients used. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.

可藉由適用於期望療法之任一便利途徑投與本發明之醫藥組合物。較佳投與途徑包含經口投與(特定而言以錠劑、膠囊、糖衣錠、粉末或液體形式)及非經腸投與(特定而言係經皮、皮下、肌內或靜脈內注射)。熟習此項技術者可藉由使用適用於期望調配物之標準方法及習用技術來製造本發明之醫藥組合物。在期望時，可採用適於持續釋放活性成份之組合物。 The pharmaceutical compositions of the present invention can be administered by any convenient route suitable for the desired therapy. Preferred routes of administration include oral administration (specifically in the form of lozenges, capsules, dragees, powders or liquids) and parenteral administration (specifically transdermal, subcutaneous, intramuscular or intravenous) . Those skilled in the art can make pharmaceutical compositions of the present invention by using standard methods and conventional techniques that are suitable for the desired formulation. When desired, a composition suitable for sustained release of the active ingredient may be employed.

關於調配及投與技術之其他細節可參見Remington’s Pharmaceutical Sciences之最新版本(Maack Publishing公司，Easton,PA)。 Further details on blending and administration techniques can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing, Inc., Easton, PA).

每一活性成份之實際劑量取決於所治療疾病之性質及嚴重程度、確切投與模式、投與形式且由醫師確定，且可根據本發明特定情況中之劑量滴定加以變化以產生期望治療效應。然而，下文之用於化合物及抗肥胖症化合物之劑量可視為適宜。 The actual dosage of each active ingredient will depend on the nature and severity of the condition being treated, the exact mode of administration, the form of administration, and will be determined by the physician, and may be varied according to the dosage titrations in the particular circumstances of the invention to produce the desired therapeutic effect. However, the dosages below for the compound and the anti-obesity compound may be considered suitable.

以API(活性醫藥成份)形式來測定化合物之劑量，亦即以游離鹼形式計算。 The dose of the compound is determined in the form of an API (active pharmaceutical ingredient), i.e., in the form of the free base.

在每天約0.1-2 mg API、較佳地每天約0.25-1 mg API範圍內、尤其每天0.25 mg、0.5 mg或1.0 mg API之日劑量適用於治療性治療。可每天以一個或若干個劑量(例如兩個)投與化合物之日劑量。在一實施例中，以一個劑量投與日劑量。 A daily dose of about 0.1-2 mg API per day, preferably about 0.25-1 mg API per day, especially 0.25 mg, 0.5 mg or 1.0 mg API per day, is suitable for therapeutic treatment. The daily dose of the compound can be administered in one or several doses (e.g., two) per day. In one embodiment, the daily dose is administered in one dose.

端視實際化合物，本發明中抗肥胖症化合物之日劑量預計在約0.1-500 mg活性成份範圍內。更具體日劑量間隔可在約0.1-2 mg、約1-10 mg、約10-50 mg、約25-100 mg、約50-200 mg及約100-500 mg範圍內。可每天以一個或若干個劑量(例如兩個)投與抗肥胖症化合物之日劑量。在一實施例中，以一個劑量投與日劑量。 Depending on the actual compound, the daily dosage of the anti-obesity compound of the present invention is expected to be in the range of from about 0.1 to 500 mg of active ingredient. More specifically, the daily dosage interval can range from about 0.1 to 2 mg, from about 1 to 10 mg, from about 10 to 50 mg, from about 25 to 100 mg, from about 50 to 200 mg, and from about 100 to 500 mg. The daily dose of the anti-obesity compound can be administered in one or several doses (e.g., two) per day. In one embodiment, the daily dose is administered in one dose.

如本文中所使用，有效達成一定目標之量中之「有效」意指如下組份量：在以本揭示內容之方式使用時，其足以得到指示治療反應，並無過度不良副作用(例如毒性、刺激或過敏反應)，且與合理利益/風險比相稱。例如，有效運動病症之量。具體有效量將隨諸如以下因素而有所變化：所治療特定病狀、患者身體狀況、所治療哺乳動物之類型、治療持續時間、並行療法(若存在)之性質及所採用具體調配物以及化合物或其衍生物之結構。 As used herein, "effective" in an amount effective to achieve a certain objective means the amount of the component: when used in the manner of the present disclosure, is sufficient to indicate a therapeutic response without excessive adverse side effects (eg, toxicity, irritation) Or an allergic reaction) and is commensurate with the reasonable benefit/risk ratio. For example, the amount of an effective motor condition. The specific effective amount will vary depending on factors such as the particular condition being treated, the condition of the patient, the type of mammal being treated, the duration of treatment, the nature of the concurrent therapy (if present), and the particular formulation and compound employed. Or the structure of its derivatives.

如本文中所使用，「治療」(treat或treating)涵蓋(例如)誘導病症及/或疾病之抑制、消退或停滯。如本文中所使用，「抑制」個體之疾病進展或疾病併發症意指預防或降低個體之疾病進展及/或疾病併發症。 As used herein, "treat or treating" encompasses, for example, the induction, regression or arrest of a condition and/or disease. As used herein, "inhibiting" an individual's disease progression or disease complication means preventing or reducing disease progression and/or disease complications in an individual.

如本文中所使用，「組合」意指藉由同時或同期投與用於療法中之試劑之集合體。同時投與係指投與匹多吡啶及丁苯那嗪之混合物(無論真混合物、懸浮液、乳液抑或其他物理組合)。在此情形下，該組合可係在即將投與之前組合之匹多吡啶及丁苯那嗪之混合物或單獨 容器。同期投與係指同時或在足夠接近之時間單獨投與匹多吡啶及丁苯那嗪，其中觀察到協同活性或相對於單獨匹多吡啶或丁苯那嗪之活性之加和活性或大於該加和活性。 As used herein, "combination" means the administration of a collection of agents for use in therapy by simultaneous or concurrent administration. Simultaneous administration refers to the administration of a mixture of p-polypyridine and tetrabenazine (whether true mixture, suspension, emulsion or other physical combination). In this case, the combination may be a mixture of p-polypyridine and tetrabenazine or a combination of them before being administered. container. Simultaneous administration refers to the simultaneous administration of p-polypyridine and tetrabenazine at the same time or at a time close enough, wherein synergistic activity or additive activity relative to the activity of p-polypyridine or tetrabenazine alone is observed or greater than Addition activity.

如本文中所使用，「DOPAC」係3,4-二羥基苯基乙酸。 As used herein, "DOPAC" is 3,4-dihydroxyphenylacetic acid.

如本文中所使用，「LMA」係運動活動性。 As used herein, "LMA" is athletic activity.

如本文中所使用，「TBZ」係丁苯那嗪。 As used herein, "TBZ" is tetrabenazine.

若干部分之醫藥套組Several parts of the medical kit

根據本發明，亦提供若干部分(包括至少兩個單獨單位劑型(A)及(B))之套組，其中(A)包括匹多吡啶或其醫藥上可接受之鹽；及(B)包括丁苯那嗪或其醫藥上可接受之鹽；及視情況(C)說明書，其用於指導向有需要之患者同時、依序或單獨投與(A)之匹多吡啶及(B)之丁苯那嗪。 According to the present invention, there are also provided a kit of parts comprising at least two separate unit dosage forms (A) and (B), wherein (A) comprises p-polypyridine or a pharmaceutically acceptable salt thereof; and (B) comprises Butalazine or a pharmaceutically acceptable salt thereof; and, as the case may be, (C) instructions for directing simultaneous, sequential or separate administration of (A) p-polypyridine and (B) to a patient in need thereof Tebuconazine.

可較佳地以適於連同另一物質一起投與之形式提供用於本發明之匹多吡啶及用於本發明之丁苯那嗪。此意欲包含以下情形：其中兩種調配物中之一者或另一者可在投與另一組份之前、之後及/或同時投與(視情況重複投與)。 The p-polypyridine useful in the present invention and the tetrabenazine used in the present invention may preferably be provided in a form suitable for administration together with another substance. This is intended to include situations in which one or the other of the two formulations can be administered before, after, and/or at the same time as the other component (as the case may be repeated).

另外，可以組合形式或單獨或單獨及依序投與用於本發明之匹多吡啶及用於本發明之丁苯那嗪，其中依序投與在時間上較為接近或在時間上較為遠離。特定而言，此可包含在足夠接近之時間投與(視情況重複投與)兩種調配物以使患者在相關病狀之治療過程中獲得有益效應，該有益效應大於在相同治療過程中在不存在其他調配物下單獨投與(視情況重複投與)兩種調配物中之任一者之情形。組合是否在特定病狀之治療過程中提供關於該特定病狀之較大有益效應之確定取決於所治療或預防的病狀，但通常可由熟習此項技術者來確定。 Alternatively, the p-polypyridine used in the present invention and the tetrabenazine used in the present invention may be administered in combination or separately or separately and sequentially, wherein the sequential administration is relatively close in time or relatively distant in time. In particular, this may involve administering (as the case may be repeated) two formulations at a time close enough to allow the patient to obtain a beneficial effect in the course of treatment of the relevant condition, which benefit is greater than during the same treatment There is no case of either of the two formulations administered separately (as the case may be repeated) under other formulations. The determination of whether a combination provides a greater beneficial effect on a particular condition during the course of treatment of a particular condition depends on the condition being treated or prevented, but is generally determined by those skilled in the art.

在此上下文中使用時，術語「同時投與」(administered simultaneously及administered at the same time as)包含彼此在48小時(例如24小時)內投與匹多吡啶及丁苯那嗪之個別劑量。 When used in this context, the term "simultaneous administration" (administered) The simultaneous and administered at the same time as) comprises individual doses of p-polypyridine and tetrabenazine administered within 48 hours (e.g., 24 hours).

使兩種組份彼此混合包含以下情形：可以單獨調配物(亦即彼此獨立)提供組份(A)及(B)，隨後使其彼此一起用於組合療法中；或以「組合封包」之單獨組份一起封裝及呈現以彼此一起用於組合療法中。 Mixing the two components with each other includes the case where the components (A) and (B) can be provided separately (i.e., independently of each other), and then used together in combination therapy; or in a "combination package" The individual components are packaged and presented together for use in combination therapy with each other.

根據本發明，亦提供一種製造物件，其包括：(A)第一醫藥劑型，包括匹多吡啶或其醫藥上可接受之鹽；及(B)第二醫藥劑型，包括丁苯那嗪或其醫藥上可接受之鹽；其中該物件含有第一醫藥劑型及第二醫藥劑型。 According to the present invention, there is also provided a manufactured article comprising: (A) a first pharmaceutical dosage form comprising picopolypyridine or a pharmaceutically acceptable salt thereof; and (B) a second pharmaceutical dosage form comprising tetrabenazine or a pharmaceutically acceptable salt; wherein the article comprises a first pharmaceutical dosage form and a second pharmaceutical dosage form.

治療方法treatment method

在另一態樣中，本發明提供治療、預防或緩解存活動物體(包含人類)之多動運動病症之方法，該方法包括以下步驟：向有需要之此一存活動物體投與治療有效量匹多吡啶或其醫藥上可接受之鹽與丁苯那嗪或其醫藥上可接受之鹽之組合療法。 In another aspect, the invention provides a method of treating, preventing or ameliorating a hyperkinetic condition of a living subject (including a human), the method comprising the steps of: administering a therapeutically effective amount to the active subject in need thereof Combination therapy of p-polypyridine or a pharmaceutically acceptable salt thereof with tetrabenazine or a pharmaceutically acceptable salt thereof.

特定而言，多動運動病症可為源於亨廷頓氏病、吉累斯德拉圖雷特症候群或遲發性運動困然之無意識運動病症。 In particular, the hyperactive disorder can be an unconscious motor disorder that is caused by Huntington's disease, Gires De La Tourette syndrome, or late onset exercise.

在一較佳實施例中，多動運動病症係源於亨廷頓氏病之無意識運動病症。 In a preferred embodiment, the hyperkinetic motor condition is derived from an unconscious motor disorder of Huntington's disease.

實例導論Introduction to examples

運動功能係由連接具有皮質下結構(包含基底神經節及丘腦)之大腦皮質之複雜迴路控制。此迴路內之一個主要路徑係所謂的「間接路徑」，其經由表現多巴胺D2型受體之紋狀體GABA-ergic中型棘突性神經元群體形成連接皮質、紋狀體及丘腦之閉合反饋環路。此路徑用作活動之負性調控劑，且對於活動過度之阻抑而言較為重要。多巴胺藉由抑制性多巴胺D2受體調整間接路徑，其中該等受體處多巴胺張力 之增加可減小間接路徑之活動性，且由此減小阻抑活動之能力。另一方面，減小多巴胺張力會增加與較強活動阻抑有關之間接路徑之活動性。 Motor function is controlled by a complex circuit that connects the cerebral cortex with subcortical structures including the basal ganglia and the thalamus. One of the major pathways in this loop is the so-called "indirect pathway", which forms a closed feedback loop that connects the cortex, striatum, and thalamus via a population of striatal GABA-ergic medium spine processes that exhibit dopamine D2 receptors. road. This pathway serves as a negative regulator of activity and is important for the inhibition of hyperactivity. Dopamine modulates the indirect pathway by inhibitory dopamine D2 receptors, where dopamine tension is present at these receptors This increase reduces the activity of the indirect path and thereby reduces the ability to suppress activity. On the other hand, reducing dopamine tension increases the mobility of the pathway associated with stronger activity suppression.

另一涉及運動控制之重要皮質-紋狀體-丘腦路徑係所謂的「直接路徑」，其經由表現多巴胺D1型受體之紋狀體GABA-ergic中型棘突性神經元形成閉合正性反饋環路。直接路徑係運動功能之正性調整劑，其涉及隨意活動之選擇及促成。在D1型受體處發揮作用之多巴胺刺激直接路徑中之紋狀體GABA-ergic神經元，由此增強活動。相反，減小該等D1受體處之多巴胺張力會減小實施隨意活動之能力。 Another important cortical-striatum-thalamic pathway system involved in motor control is the so-called "direct path", which forms a closed positive feedback loop via the striatum GABA-ergic medium spine-like neurons that exhibit dopamine D1 receptors. road. The direct path is a positive modifier of the motor function, which involves the selection and facilitation of random activities. Dopamine, which acts at the D1 receptor, stimulates the striatum GABA-ergic neurons in the direct pathway, thereby enhancing activity. Conversely, reducing the dopamine tension at these D1 receptors reduces the ability to perform random activities.

源自丁苯那嗪治療之多巴胺傳遞普遍減少亦減少其他多巴胺依賴性功能。特定而言，直接路徑(具有表現多巴胺D1受體之紋狀體神經元)之多巴胺張力亦有所減小，從而使直接路徑減弱並由此減小實施隨意活動之能力。另外，藉由丁苯那嗪誘導之多巴胺空乏很可能損害多巴胺依賴性動機及報酬，此可假設為丁苯那嗪之促抑鬱不良效應之基礎。 The general reduction in dopamine transmission from tetrabenazine treatment also reduces other dopamine-dependent functions. In particular, the direct path (having striatal neurons that exhibit dopamine D1 receptors) also reduces dopamine tension, thereby attenuating the direct path and thereby reducing the ability to perform voluntary activities. In addition, dopamine deficiency induced by tetrabenazine is likely to impair dopamine-dependent motivation and reward, which can be assumed to be the basis for the adverse effects of tetrabenazine on depression.

考慮到匹多吡啶係多巴胺D2受體之純拮抗劑且並無激動劑活性，故預計與僅使用丁苯那嗪治療相比，匹多吡啶及丁苯那嗪之治療組合會進一步減小多巴胺D2受體處之張力，且由此進一步減小整體運動活動性。 Considering the pure antagonist of the p-polypyridine-based dopamine D2 receptor and no agonist activity, it is expected that the combination of p-polypyridine and tetrabenazine will further reduce dopamine compared to the treatment with tetrabenazine alone. The tension at the D2 receptor, and thus further reduces overall motor activity.

實例Instance

參照下列實例進一步闡釋本發明，該等實例並不意欲以任一方式限制所主張之本發明之範圍。 The invention is further illustrated by the following examples, which are not intended to limit the scope of the claimed invention in any way.

下文實例研究匹多吡啶與丁苯那嗪之間關於運動活動性之相互作用。亦測定多巴胺及DOPAC之紋狀體含量。丁苯那嗪減小多巴胺之組織含量，此係抑制VMAT之直接後果。兩種化合物在活體內皆以劑量依賴性方式增加紋狀體DOPAC含量，此反映了多巴胺D2受體處之 張力有所降低(Ponten)。另外，在額皮質及紋狀體中量測對於立即早期基因Arc(活動調節細胞骨架關聯蛋白/活動調節基因3.1)之表現之效應。Arc基因表現係反映突觸活動性之生物標記物(Steward,2001；Kawashima 2009)。亦使用丁苯那嗪及多巴胺D2拮抗劑氟哌啶醇實施相互作用實驗以比較匹多吡啶效應與經典多巴胺D2受體拮抗劑之彼等效應。 The following example investigates the interaction between picopyridine and tetrabenazine on motor activity. The striatum content of dopamine and DOPAC was also determined. Tetrabenazine reduces the tissue content of dopamine, which inhibits the direct consequences of VMAT. Both compounds increased striatal DOPAC levels in a dose-dependent manner in vivo, reflecting a decrease in the tension at the dopamine D2 receptor (Ponten). In addition, the effects on the expression of the immediate early gene Arc (activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1) were measured in the frontal cortex and striatum. Arc gene expression is a biomarker that reflects synaptic activity (Steward, 2001; Kawashima 2009). Interaction experiments were also performed using tetrabenazine and the dopamine D2 antagonist haloperidol to compare the effects of the pipidine effect with the classical dopamine D2 receptor antagonist.

1)丁苯那嗪對於運動活動性、紋狀體DOPAC及Arc之效應1) Effect of tetrabenazine on motor activity, striatum DOPAC and Arc

以0.37 mg/kg、0.64 mg/kg及1.1 mg/kg經皮下給予丁苯那嗪。在投藥之後60分鐘記錄LMA。然後將大鼠處死且收集腦。腦組織分析包含紋狀體中之DOPAC及額皮質及紋狀體中之Arc mRNA。 Tebuconazine was administered subcutaneously at 0.37 mg/kg, 0.64 mg/kg, and 1.1 mg/kg. LMA was recorded 60 minutes after administration. The rats were then sacrificed and the brains were collected. Brain tissue analysis included DOPAC in the striatum and Arc mRNA in the frontal cortex and striatum.

丁苯那嗪會減小運動活動性。(圖1)。丁苯那嗪以劑量依賴性方式抑制自發性運動活動性。在考慮記錄之完整一小時時，1.1 mg/kg丁苯那嗪劑量組顯示顯著減小至媒劑對照組平均值之40%(P<0.01)。在初始15 min期間，看到1.1 mg/kg及0.37 mg/kg丁苯那嗪劑量組顯著減小(P<0.05)，而對於投藥後之15-60分鐘時段而言，在0.64 mg/kg及1.1 mg/kg下觀察到顯著效應(P<0.05)。運動活動性減小反映了藉由抑制VMAT2引起之多巴胺傳遞降低。 Terfenazazine reduces exercise activity. (figure 1). Tebuconazine inhibits spontaneous motor activity in a dose-dependent manner. At the one hour of complete recording, the 1.1 mg/kg tetrabenazine dose group showed a significant reduction to 40% of the vehicle control mean (P < 0.01). During the initial 15 min period, the doses of 1.1 mg/kg and 0.37 mg/kg tetrabenazine were significantly reduced (P<0.05), while for the 15-60 minute period after administration, at 0.64 mg/kg. Significant effects were observed at 1.1 mg/kg (P < 0.05). The decrease in exercise activity reflects a decrease in dopamine transmission caused by inhibition of VMAT2.

丁苯那嗪以劑量依賴性方式增加紋狀體DOPAC，且在所測試之所有劑量下皆具有統計學顯著效應。DOPAC增加係多巴胺D2受體處之張力減小之神經元標記物，該張力減小係由於使用丁苯那嗪治療之大鼠中多巴胺傳遞有所降低。參見表1及圖2。 Tebuconazine increased striatal DOPAC in a dose-dependent manner and had statistically significant effects at all doses tested. DOPAC increases the neuronal marker of reduced tension at the dopamine D2 receptor, which is reduced by the transmission of dopamine in rats treated with tetrabenazine. See Table 1 and Figure 2.

紋狀體及皮質中之Arc：丁苯那嗪增加紋狀體Arc且減少額皮質Arc。丁苯那嗪以劑量依賴性方式增加紋狀體中之Arc mRNA，其在所測試最高劑量(1.1 mg/kg)下達到媒劑對照組平均值之147%(P<0.01)。在額皮質中，在1.1 mg/kg之丁苯那嗪劑量下，觀察到Arc mRNA顯著減少至媒劑對照組平均值之66%(P<0.05)。在0.64 mg/kg之丁苯那嗪 劑量下，額皮質mRNA往往會減少(對照組平均值之83%，p=0.14)。參見圖3。紋狀體中之Arc增加最可能係由於多巴胺D2受體處之張力減小。額皮質中之Arc減少很可能與皮質中之多巴胺傳遞有所降低從而減小多巴胺D1受體處之張力相關。 Arc in the striatum and cortex: tetrabenazine increases the striatum Arc and reduces the frontal cortex Arc. Tebufenazine increased Arc mRNA in the striatum in a dose-dependent manner, reaching a maximum of 147% (P < 0.01) of the media control group at the highest dose tested (1.1 mg/kg). In the frontal cortex, a significant reduction in Arc mRNA to 66% of the media control group was observed at a dose of 1.1 mg/kg of tetrabenazine (P < 0.05). Tetrabenazine at 0.64 mg/kg At the dose, the amount of mRNA in the frontal cortex tends to decrease (83% of the mean of the control group, p=0.14). See Figure 3. The increase in Arc in the striatum is most likely due to the reduced tension at the dopamine D2 receptor. The decrease in Arc in the frontal cortex is likely to be associated with a decrease in dopamine transmission in the cortex and a decrease in the tension at the dopamine D1 receptor.

2)匹多吡啶對於運動活動性、紋狀體DOPAC及Arc之效應2) Effect of p-polypyridine on exercise activity, striatum DOPAC and Arc

以11 μmol/kg、33 μmol/kg及100 μmol/kg經皮下給予匹多吡啶。匹多吡啶顯示對於自發性運動活動性並無抑制效應。在中間劑量33 μmol/kg下於完整60分鐘記錄時段中，觀察到運動活動性略有增加。參見圖4。在檢驗記錄之完整一小時時，觀察到33 μmol/kg匹多吡啶劑量組之運動活動性顯著增加至媒劑對照組平均值之138%(P<0.05)。在初始15 min期間，看到在11 μmol/kg匹多吡啶劑量組中顯著增加(P<0.05)，而對於投藥後之15-60分鐘時段而言，並未觀察到顯著效應。 Picopolypyridine was administered subcutaneously at 11 μmol/kg, 33 μmol/kg, and 100 μmol/kg. P-polypyridine showed no inhibitory effect on spontaneous motor activity. A slight increase in motor activity was observed during the full 60 minute recording period at an intermediate dose of 33 μmol/kg. See Figure 4. At the end of the test record, the exercise activity of the 33 μmol/kg pipidine dose group was significantly increased to 138% of the media control group mean (P < 0.05). During the initial 15 min period, a significant increase was seen in the 11 μmol/kg pipidine dose group (P < 0.05), while no significant effect was observed for the 15-60 min period after administration.

匹多吡啶以劑量依賴性方式增加紋狀體DOPAC，且在所測試之所有劑量下皆具有統計學顯著效應。DOPAC增加係多巴胺D2受體處之張力減小之神經元標記物，該張力減小係由於藉由匹多吡啶所產生之多巴胺D2受體拮抗作用。參見圖5及表1。 P-polypyridine increased striatal DOPAC in a dose-dependent manner and had statistically significant effects at all doses tested. DOPAC increases the neuronal marker of reduced tension at the dopamine D2 receptor due to dopamine D2 receptor antagonism produced by picopolypyridine. See Figure 5 and Table 1.

匹多吡啶以劑量依賴性方式增加紋狀體及皮質arc基因表現，從而在所測試之最高劑量下達到統計學顯著性。匹多吡啶以劑量依賴性方式增加額皮質中之Arc mRNA含量，在33 μmol/kg及100 μmol/kg之劑量下分別最高達到媒劑對照組平均值之149%(p<0.01)及222%(p<0.001)(圖6)。匹多吡啶以劑量依賴性方式增加紋狀體中之Arc mRNA含量。與相關對照組平均值相比，含量達到168%及253%(對於分別為33 μmol/kg及100 μmol/kg之兩種匹多吡啶劑量，p<0.01)。(圖6)。紋狀體中之Arc增加最可能係由於多巴胺D2受體處之張力減小。額皮質中之Arc增加很可能與皮質中之多巴胺傳遞有所增加從而增加 多巴胺D1受體處之張力相關。 P-polypyridine increased the striatum and cortical arc gene expression in a dose-dependent manner, achieving statistical significance at the highest dose tested. P-polypyridine increased the amount of Arc mRNA in the frontal cortex in a dose-dependent manner, reaching a maximum of 149% ( p <0.01) and 222% of the media control group at 33 μmol/kg and 100 μmol/kg, respectively. ( p < 0.001) (Fig. 6). P-polypyridine increases the amount of Arc mRNA in the striatum in a dose-dependent manner. Compared with the mean of the relevant control group, the content reached 168% and 253% ( p <0.01 for the two p -polypyridine doses of 33 μmol/kg and 100 μmol/kg, respectively). (Figure 6). The increase in Arc in the striatum is most likely due to the reduced tension at the dopamine D2 receptor. The increase in Arc in the frontal cortex is likely to be associated with increased dopamine transmission in the cortex and increased tension at the dopamine D1 receptor.

3)氟哌啶醇對於運動活動性、紋狀體DOPAC及Arc之效應3) Effect of haloperidol on exercise activity, striatum DOPAC and Arc

以0.12 mg/kg、0.37 mg/kg及1.1 mg/kg經皮下給予氟哌啶醇(參見圖7)。在評價較低劑量下之效應之額外實驗中，給予0.04 mg、0.12 mg、0.37 mg及1.1 mg(參見圖8)。氟哌啶醇顯示對於自發性運動活動性之劑量依賴性抑制效應。在0.12 mg/kg及更高劑量下觀察到統計學顯著效應，但在所測試之最低劑量0.04 mg/kg下並未觀察到。 Haloperidol was administered subcutaneously at 0.12 mg/kg, 0.37 mg/kg, and 1.1 mg/kg (see Figure 7). In an additional experiment evaluating the effect at lower doses, 0.04 mg, 0.12 mg, 0.37 mg, and 1.1 mg were administered (see Figure 8). Haloperidol shows a dose-dependent inhibitory effect on spontaneous motor activity. A statistically significant effect was observed at doses of 0.12 mg/kg and higher, but was not observed at the lowest dose tested at 0.04 mg/kg.

更具體而言，在考慮記錄之完整一小時時，0.37 mg/kg及1.1 mg/kg氟哌啶醇劑量組顯示顯著減小至媒劑對照組平均值之約35%(P<0.05)。在初始15 min期間，看到0.37 mg/kg及1.1 mg/kg氟哌啶醇劑量組顯著減小(P<0.05)，而對於投藥後之15-60分鐘時段而言，觀察到僅1.1 mg/kg劑量組具有顯著效應(P<0.05)。 More specifically, the 0.37 mg/kg and 1.1 mg/kg haloperidol dose groups showed a significant reduction to about 35% of the mean of the vehicle control group (P < 0.05) when considering the complete one hour of recording. During the initial 15 min period, a significant reduction was observed in the 0.37 mg/kg and 1.1 mg/kg haloperidol dose groups (P < 0.05), while only 1.1 mg was observed for the 15-60 minute period after administration. The /kg dose group had a significant effect (P < 0.05).

氟哌啶醇以劑量依賴性方式增加紋狀體DOPAC，且在所測試之所有劑量下皆具有統計學顯著效應。DOPAC增加係多巴胺D2受體處之張力減小之神經元標記物，該張力減小係由於多巴胺D2受體拮抗作用。參見表1及圖9。 Haloperidol increased striatal DOPAC in a dose-dependent manner and had statistically significant effects at all doses tested. DOPAC increases the neuronal marker of reduced tension at the dopamine D2 receptor due to dopamine D2 receptor antagonism. See Table 1 and Figure 9.

氟哌啶醇以劑量依賴性方式增加紋狀體中之Arc mRNA，在0.12 mg/kg、0.37 mg/kg及1.1 mg/kg劑量下分別達到媒劑對照組平均值之262%(P<0.01)、331%(P<0.001)、409%(P<0.01)。紋狀體中之Arc增加最可能係由於多巴胺D2受體處之張力減小。氟哌啶醇對於皮質Arc基因表現並無顯著效應。參見圖10。 Haloperidol increased the Arc mRNA in the striatum in a dose-dependent manner, reaching 262% of the mean of the vehicle control group at doses of 0.12 mg/kg, 0.37 mg/kg, and 1.1 mg/kg, respectively (P<0.01). ), 331% (P < 0.001), and 409% (P < 0.01). The increase in Arc in the striatum is most likely due to the reduced tension at the dopamine D2 receptor. Haloperidol has no significant effect on the performance of the cortical Arc gene. See Figure 10.

數據係展示為DOPAC含量之平均值±SEM，此係以對照組平均值之百分比形式表示。 Data are presented as mean ± SEM of DOPAC content, expressed as a percentage of the mean of the control group.

C，媒劑對照組；DOPAC，3,4-二羥基苯基乙酸；TC，丁苯那嗪對照組 C, vehicle control group; DOPAC, 3,4-dihydroxyphenylacetic acid; TC, tetrabenazine control group

相對於媒劑對照組，*p<0.05；**p<0.01***；相對於丁苯那嗪對照組，p<0.001；^† p<0.05；^†† p<0.01；^††† p<0.001。 Relative to the vehicle control group, * p <0.05; ** p <0.01 ***; with respect to the tetrabenazine ^{group, p <0.001; † p <} 0.05; †† p <0.01; ††† p < 0.001.

總而言之，儘管所有三種抗多巴胺能化合物皆產生增加之紋狀體DOPAC及增加之紋狀體arc基因表現，且兩種效應最可能與多巴胺D2 受體處之張力降低相關，但匹多吡啶之獨特之處在於其並不抑制運動活動性。匹多吡啶不同於氟哌啶醇或丁苯那嗪之另一特徵在於，其增加皮質Arc基因表現。 In conclusion, although all three anti-dopaminergic compounds produced increased striatal DOPAC and increased striatum arc gene performance, and the two effects most likely with dopamine D2 The decrease in tension at the receptor is related, but piopyridine is unique in that it does not inhibit motor activity. Another feature of picopolypyridine differs from haloperidol or tetrabenazine in that it increases cortical Arc gene expression.

組合實驗Combined experiment

為測試多巴胺D2拮抗劑在投與部分地多巴胺空乏之動物時之效應，以對紋狀體dopac及運動活動性產生次極大但顯著效應之劑量組合氟哌啶醇及匹多吡啶與丁苯那嗪。 To test the effect of dopamine D2 antagonists in the administration of partially dopamine deficient animals, haloperidol and pipidine were combined with buprenorphine at doses that produced submaximal but significant effects on striatum dopac and motor activity. Oxazine.

4)匹多吡啶對於丁苯那嗪誘導之運動活動性減小、紋狀體多巴胺增加及Arc之效應4) Picopolypyridine reduces the motor activity induced by tetrabenazine, the increase of striatal dopamine and the effect of Arc

在使用匹多吡啶及丁苯那嗪之相互作用實驗中，給予33 μmol/kg及100 μmol/kg匹多吡啶與0.64 mg/kg丁苯那嗪之組合。參見圖11。運動記錄顯示，匹多吡啶逆轉藉由丁苯那嗪誘導之行為抑制。然而，對於紋狀體DOPAC之效應具有加和性，亦即共投與匹多吡啶會進一步增加紋狀體DOPAC。 In the interaction experiment using p-polypyridine and tetrabenazine, a combination of 33 μmol/kg and 100 μmol/kg of p-polypyridine and 0.64 mg/kg of tetrabenazine was administered. See Figure 11. Exercise records showed that p-polypyridine reversed the behavioral inhibition induced by tetrabenazine. However, the effect on the striatum DOPAC is additive, ie co-administration with p-polypyridine further increases striatum DOPAC.

對於運動抑制而言，對於記錄之完整一小時(P<0.001)以及0-15 min時段(P<0.01)及15-60 min時段(P<0.01)而言，丁苯那嗪對照組與媒劑治療對照相比發生顯著降低。對於記錄之完整一小時而言，在33 μmol/kg及100 μmol/kg劑量組中，匹多吡啶逆轉藉由丁苯那嗪誘導之運動抑制，其分別達到丁苯那嗪對照平均值之135%(P<0.05)及137%(P<0.01)。對於匹多吡啶之100 μmol/kg劑量組而言，在0-15 min以及15-60 min時段期間，此逆轉效應達到顯著性。此暗示在向單胺空乏動物中添加匹多吡啶時，紋狀體D2受體處之張力得以進一步減小。參見圖11。 For exercise inhibition, for the complete one hour (P < 0.001) and 0-15 min period (P < 0.01) and 15-60 min period (P < 0.01), the tetrabenazine control group and the medium There was a significant decrease in the agent treatment compared to the control. For the complete one hour of recording, in the 33 μmol/kg and 100 μmol/kg dose groups, p-polypyridine reversed the inhibition of exercise induced by tetrabenazine, which reached 135 of the tetrabenazine control mean, respectively. % (P < 0.05) and 137% (P < 0.01). For the 100 μmol/kg dose group of p-polypyridine, this reversal effect was significant during the 0-15 min and 15-60 min periods. This suggests that the tension at the striatum D2 receptor is further reduced when padopyridine is added to monoamine-poor animals. See Figure 11.

在組合0.64 mg/kg丁苯那嗪與33 μmol/kg或100 μmol/kg匹多吡啶之相互作用實驗中，看到與媒劑治療對照組相比丁苯那嗪誘導紋狀體DOPAC含量顯著增加(p<0.01；表1)。匹多吡啶進一步增加紋狀體中 之DOPAC含量，其在100 μmol/kg劑量下達到丁苯那嗪對照組平均值之155%(p<0.01)。參見表1及圖12。 In the interaction experiment of combining 0.64 mg/kg tetrabenazine with 33 μmol/kg or 100 μmol/kg p-polypyridine, it was found that tetrabenazine induced striatal DOPAC content was significantly higher than vehicle-treated control group. Increased (p<0.01; Table 1). P-polypyridine further increases striatum The DOPAC content reached 155% (p < 0.01) of the mean of the tetrabenazine standard at a dose of 100 μmol/kg. See Table 1 and Figure 12.

同樣，紋狀體Arc表現因添加匹多吡啶而進一步增加。與之相比，匹多吡啶抵抗藉由丁苯那嗪誘導之Arc減少。 Similarly, the striatum Arc is further increased by the addition of p-polypyridine. In contrast, picopyridine resistance is reduced by tetrabenazine-induced Arc.

匹多吡啶逆轉藉由丁苯那嗪誘導之額皮質Arc減少，如圖13中所展示。更具體而言，在相互作用實驗中所使用之0.64 mg/kg劑量下，丁苯那嗪對於紋狀體Arc mRNA並無顯著效應。在與丁苯那嗪共投與時，匹多吡啶以劑量依賴性方式增加紋狀體Arc，在33 μmol/kg及100 μmol/kg劑量之匹多吡啶下，分別達到丁苯那嗪對照組平均值之144%(P<0.05)及207%(P<0.01)。 Picopolypyridine reverses the reduction of the frontal cortex Arc induced by tetrabenazine, as shown in Figure 13. More specifically, tetrabenazine had no significant effect on striatal Arc mRNA at the dose of 0.64 mg/kg used in the interaction experiments. When co-administered with tetrabenazine, p-polypyridine increased striatal Arc in a dose-dependent manner, reaching the tetrabenazin control group at 33 μmol/kg and 100 μmol/kg dose of p-polypyridine, respectively. The mean was 144% (P < 0.05) and 207% (P < 0.01).

丁苯那嗪誘導額皮質Arc mRNA顯著減少(P<0.05)，此與在使用丁苯那嗪之劑量反應實驗中所觀察到之0.64 mg/kg劑量下之額皮質Arc mRNA減少趨勢一致(圖3)。匹多吡啶以劑量依賴性方式逆轉藉由丁苯那嗪誘導之額皮質Arc mRNA減少。在33 μmol/kg及100 μmol/kg匹多吡啶下，Arc mRNA分別增加至丁苯那嗪對照組平均值之125%(P<0.05)及193%(P<0.05) Tetrabenazine induced a significant decrease in Arc mRNA in the frontal cortex (P<0.05), which is consistent with the decrease in Arc mRNA expression in the frontal cortex at a dose of 0.64 mg/kg observed in a dose-response experiment with tetrabenazine. 3). P-polypyridine reversed the reduction of Arc mRNA in the frontal cortex induced by tetrabenazine in a dose-dependent manner. At 33 μmol/kg and 100 μmol/kg p-polypyridine, Arc mRNA increased to 125% (P<0.05) and 193% (P<0.05), respectively, in the control group of tetrabenazine.

5)氟哌啶醇對於丁苯那嗪誘導之運動活動性減小、紋狀體多巴胺增加及Arc之效應5) The effect of haloperidol on the activity of tetrabenazine-induced exercise, the increase of striatal dopamine and the effect of Arc

在使用氟哌啶醇及丁苯那嗪之相互作用實驗中，給予0.04 mg/kg及0.12 mg/kg氟哌啶醇與0.64 mg/kg丁苯那嗪之組合。 In the interaction experiment using haloperidol and tetrabenazine, a combination of 0.04 mg/kg and 0.12 mg/kg haloperidol and 0.64 mg/kg tetrabenazine was administered.

運動記錄展示，氟哌啶醇進一步減小使用丁苯那嗪治療之動物中之運動活動性。更具體而言，完整一小時中之運動記錄顯示，在0.04 mg/kg及0.12 mg/kg劑量下，氟哌啶醇分別將使用丁苯那嗪治療之大鼠中之運動活動性顯著(P<0.01)減小至丁苯那嗪對照組平均值之51%及41%。對於記錄之最初15 min而言，在0.04 mg/kg(P<0.01)及0.12 mg/kg(P<0.05)劑量下，此減小效應較為顯著，而對於15-60 min時段 而言，僅0.12 mg/kg劑量之減小較為顯著(P<0.05)。參見圖14。 The exercise record showed that haloperidol further reduced exercise activity in animals treated with tetrabenazine. More specifically, the exercise record for the entire hour showed that haloperidol was significantly more active in rats treated with tetrabenazine at doses of 0.04 mg/kg and 0.12 mg/kg (P <0.01) was reduced to 51% and 41% of the mean value of the tetrabenazine standard. For the first 15 min of the recording, the reduction effect was significant at 0.04 mg/kg (P<0.01) and 0.12 mg/kg (P<0.05) doses, while for the 15-60 min period In all cases, the decrease of the dose of only 0.12 mg/kg was significant (P < 0.05). See Figure 14.

對於紋狀體DOPAC之效應具有加和性，亦即共投與氟哌啶醇與丁苯那嗪使得紋狀體DOPAC額外增加。在組合0.64 mg/kg丁苯那嗪與0.04 mg/kg或0.12 mg/kg氟哌啶醇之相互作用實驗中，與媒劑治療對照組相比，丁苯那嗪誘導紋狀體DOPAC含量顯著增加(p<0.001；表1)。氟哌啶醇進一步增加紋狀體中之DOPAC含量，在0.04 mg/kg及0.12 mg/kg劑量下分別達到丁苯那嗪對照組平均值之187%及218%(對於兩個劑量而言，p<0.001)。參見表1及圖15。 The effect on the striatum DOPAC is additive, that is, co-administration of haloperidol and tetrabenazine increases the striatum DOPAC. In the interaction experiment of a combination of 0.64 mg/kg tetrabenazine and 0.04 mg/kg or 0.12 mg/kg haloperidol, tetrabenazine induced striatal DOPAC levels significantly compared with the vehicle-treated control group. Increased ( p <0.001; Table 1). Haloperidol further increased DOPAC content in the striatum, reaching 187% and 218% of the mean of the tetrabenazine standard at 0.04 mg/kg and 0.12 mg/kg, respectively (for both doses, p <0.001). See Table 1 and Figure 15.

在與丁苯那嗪共治療之大鼠中，氟哌啶醇對於皮質Arc基因表現並無顯著效應。氟哌啶醇進一步增加丁苯那嗪治療動物中之紋狀體Arc(圖16)。在相互作用實驗中所使用之0.64 mg/kg劑量下，丁苯那嗪對於紋狀體Arc mRNA並無顯著效應。在與丁苯那嗪共投與時，氟哌啶醇以劑量依賴性方式增加紋狀體Arc，在0.04 mg/kg及0.12 mg/kg劑量之氟哌啶醇下分別達到丁苯那嗪對照組平均值之272%(P<0.001)及400%(P<0.001)。 In rats co-treated with tetrabenazine, haloperidol had no significant effect on cortical Arc gene performance. Haloperidol further increases the striatum Arc in the treated tetrabenazine (Fig. 16). At a dose of 0.64 mg/kg used in the interaction experiments, tetrabenazine had no significant effect on striatal Arc mRNA. When co-administered with tetrabenazine, haloperidol increased striatum Arc in a dose-dependent manner, reaching tetrabenazine at 0.04 mg/kg and 0.12 mg/kg dose of haloperidol, respectively. The mean of the group was 272% (P < 0.001) and 400% (P < 0.001).

丁苯那嗪往往會降低額皮質Arc mRNA(P=0.08)，此與使用丁苯那嗪之劑量反應實驗中所觀察到之0.64 mg/kg劑量下額皮質Arc mRNA降低趨勢(圖3)及在使用匹多吡啶及丁苯那嗪之相互作用實驗中所觀察到之顯著降低(圖13)一致。氟哌啶醇對於丁苯那嗪治療動物中之額皮質Arc mRNA並無顯著效應。 Tebuconazine tends to reduce Arc mRNA in the frontal cortex (P=0.08), which is associated with a decrease in Arc mRNA in the frontal cortex at a dose of 0.64 mg/kg observed in a dose-response experiment with tetrabenazine (Figure 3). Significant reductions (Figure 13) were observed in the interaction experiments using p-polypyridine and tetrabenazine. Haloperidol has no significant effect on the frontal cortex Arc mRNA in tetrabenazine-treated animals.

測試方法testing method

使用下列測試評估用於本發明之化合物。 The compounds used in the present invention were evaluated using the following tests.

動物animal

使用來自B&K Scanbur(Sollentuna,Sweden)(IBBS58)、Charles River(Köln,Germany)(KR104、BS31)或Taconic(Ejby,Denmark)(BS85、BS81、KR219、TA284)之雄性斯普拉-道來氏(Sprague- Dawley)大鼠。在到達時，大鼠重160-180g。在進行運動及組織神經化學研究時，大鼠重220-260g。以每籠5隻動物圈養該等動物且06：00與18：00之間通光。所有實驗皆係根據瑞典動物保護立法(Swedish animal protection legislation)且在哥德堡地方動物倫理委員會(local Animal Ethics Committee in Gothenburg)之批准下來實施。 Male Sprague-Dawleys from B&K Scanbur (Sollentuna, Sweden) (IBBS58), Charles River (Köln, Germany) (KR104, BS31) or Taconic (Ejby, Denmark) (BS85, BS81, KR219, TA284) (Sprague- Dawley) Rat. Upon arrival, the rats weighed 160-180 g. Rats weighed 220-260 g during exercise and tissue neurochemistry studies. The animals were housed in 5 animals per cage and were lighted between 06:00 and 18:00. All experiments were carried out in accordance with Swedish animal protection legislation and approved by the local animal Ethics Committee in Gothenburg.

投藥Dosing

IBBS58：將動物分成4個不同治療組(n=5)。該等治療組係由媒劑(鹽水；0.9% v/w NaCl)及在三個劑量(11 μmol/kg、33 μmol/kg及100 μmol/kg)下測試之ACR16組成。 IBBS58: Animals were divided into 4 different treatment groups (n=5). The treatment groups consisted of vehicle (saline; 0.9% v/w NaCl) and ACR16 tested at three doses (11 μmol/kg, 33 μmol/kg and 100 μmol/kg).

BS31：將動物分成4個不同治療組(n=5)。該等治療組係由媒劑(5.5% v/w葡萄糖)及在三個劑量(0.12 μmol/kg、0.37 μmol/kg及1.1 μmol/kg)下測試之氟哌啶醇組成。 BS31: Animals were divided into 4 different treatment groups (n=5). The treatment groups consisted of vehicle (5.5% v/w glucose) and haloperidol tested at three doses (0.12 μmol/kg, 0.37 μmol/kg and 1.1 μmol/kg).

KR104：將動物分成5個不同治療組(n=4)。該等治療組係由媒劑(5.5% v/w葡萄糖)及在4個劑量(0.04 μmol/kg、0.12 μmol/kg、0.37 μmol/kg及1.1 μmol/kg)下測試之氟哌啶醇組成。 KR104: Animals were divided into 5 different treatment groups (n=4). The treatment groups consisted of vehicle (5.5% v/w glucose) and haloperidol tested at 4 doses (0.04 μmol/kg, 0.12 μmol/kg, 0.37 μmol/kg, and 1.1 μmol/kg). .

KR219：將動物分成4個不同治療組(n=5)。該等治療組係由媒劑(5.5% v/w葡萄糖)及在三個劑量(0.37 μmol/kg、0.64 μmol/kg及1.1 μmol/kg)下測試之丁苯那嗪組成。 KR219: Animals were divided into 4 different treatment groups (n=5). The treatment groups consisted of vehicle (5.5% v/w glucose) and tetrabenazine tested at three doses (0.37 μmol/kg, 0.64 μmol/kg and 1.1 μmol/kg).

BS81：將動物分成4個不同治療組(n=5)。第一組係由1：1媒劑(鹽水(0.9% v/w NaCl)+5.5%葡萄糖以及數滴HAc)組成，第二組係由單一丁苯那嗪劑量(0.64 mg/kg)組成，且第三組及第四組係由在兩個劑量(33 μmol/kg及100 μmol/kg)下測試之NS30016以及一個丁苯那嗪劑量(0.64 mg/kg)組成。 BS81: Animals were divided into 4 different treatment groups (n=5). The first group consisted of a 1:1 vehicle (salt (0.9% v/w NaCl) + 5.5% glucose and a few drops of HAc) and the second group consisted of a single tetrabenazine dose (0.64 mg/kg). The third and fourth groups consisted of NS30016 tested at two doses (33 μmol/kg and 100 μmol/kg) and one tetrabenazine dose (0.64 mg/kg).

TA284：將動物分成4個不同治療組(n=10)。第一組係由1：1媒劑(鹽水(0.9% v/w NaCl)+5.5%葡萄糖以及數滴HAc)組成，第二組係由單一丁苯那嗪劑量(0.64 mg/kg)組成，且第三組及第四組係由在兩個 劑量(33及100 μmol/kg)下測試之NS30016以及一個丁苯那嗪劑量(0.64 mg/kg)組成。並不自此實驗收集腦組織。 TA284: Animals were divided into 4 different treatment groups (n=10). The first group consisted of a 1:1 vehicle (salt (0.9% v/w NaCl) + 5.5% glucose and a few drops of HAc) and the second group consisted of a single tetrabenazine dose (0.64 mg/kg). And the third and fourth groups are in two NS30016 tested at a dose (33 and 100 μmol/kg) and a dose of tetrabenazine (0.64 mg/kg). Brain tissue was not collected from this experiment.

BS85：將動物分成4個不同治療組(n=5)。第一組係由1：1媒劑(鹽水(0.9% v/w NaCl)+5.5%葡萄糖以及數滴HAc)組成，第二組係由單一丁苯那嗪劑量(0.64 mg/kg)組成，且第三組及第四組係由在兩個劑量(0.04 mg/kg及0.12 mg/kg)下測試之氟哌啶醇以及一個丁苯那嗪劑量(0.64 mg/kg)組成。 BS85: Animals were divided into 4 different treatment groups (n=5). The first group consisted of a 1:1 vehicle (salt (0.9% v/w NaCl) + 5.5% glucose and a few drops of HAc) and the second group consisted of a single tetrabenazine dose (0.64 mg/kg). The third and fourth groups consisted of haloperidol tested at two doses (0.04 mg/kg and 0.12 mg/kg) and one tetrabenazine dose (0.64 mg/kg).

在開始記錄運動活動性之前4分鐘，以5 ml/kg之體積經皮下注射所有化合物。 All compounds were injected subcutaneously in a volume of 5 ml/kg 4 minutes before the start of recording of motor activity.

活體內測試：行為In vivo testing: behavior

使用8個Digiscan活動監測器(RXYZM(16)TAO,Omnitech Electronics,Columbus,OH,USA)量測行為活動，該等Digiscan活動監測器與Omnitech Digiscan分析儀及配備有數位介面板之Apple Macintosh電腦(NB DIO-24,National Instruments,USA)連接。每一活動監測器係由配備有光電感測器之方形金屬框組成。在量測行為活動期間，將大鼠放置於具有粗糙黑色底板之透明丙烯酸聚合物籠(WxLxH,41×41×30 cm)中，繼而將該透明丙烯酸聚合物籠置於活動監測器中。每一活動監測器皆配備有三列紅外光電感測器，每一列係由16個感測器組成。將兩列置於籠底板之前面及側面且呈90度角度，且將第三列置於底板上方10 cm處以量測垂直活動。光電感測器係間隔2.5 cm。每一活動監測器皆裝配至含有弱場燈及風扇之相同聲光衰減盒(WxLxH-55×55×45)中。 Behavioral activities were measured using eight Digiscan activity monitors (RXYZM (16) TAO, Omnitech Electronics, Columbus, OH, USA), the Digiscan activity monitor and the Omnitech Digiscan analyzer and an Apple Macintosh computer equipped with a digital panel ( NB DIO-24, National Instruments, USA). Each activity monitor consists of a square metal frame equipped with a photo-electrical sensor. During the measurement of behavioral activities, rats were placed in a clear acrylic polymer cage (WxLxH, 41 x 41 x 30 cm) with a rough black bottom plate, which was then placed in an activity monitor. Each activity monitor is equipped with three columns of infrared photo-sensing sensors, each consisting of 16 sensors. Two columns were placed at the front and side of the cage floor at an angle of 90 degrees, and the third column was placed 10 cm above the floor to measure vertical movement. The photoinductor is spaced 2.5 cm apart. Each activity monitor is assembled into the same acousto-optic attenuation box (WxLxH-55 x 55 x 45) containing weak field lamps and fans.

使用物件導向程式設計(LabVIEW^TM,National instruments,Austin,TX,USA)書寫電腦軟體。 Using object-oriented programming ^{(LabVIEW TM, National instruments, Austin} , TX, USA) writing computer software.

以25 Hz之採樣頻率記錄來自每一活動監測器之行為數據(其代表動物在每一時間之位置(重力及垂直活動之水平中心))，且使用慣用之 書寫LABView^TM應用進行收集。儲存來自每一記錄期之數據並針對所行進之距離進行分析。每一行為記錄期持續60分鐘，其始於在注射測試化合物之後大約4分鐘。將結果呈現為計數/60分鐘、計數/45分鐘或計數/15分鐘(以任意長度單位表示)。使用司徒登氏t測試(Student’s t-test)針對對照組實施統計學比較。 At a sampling frequency of 25 Hz recorded behavioral data from each activity monitor it (which represents the position of each animal at the time (horizontal center of gravity and vertical activity)), and using the usual application written LABView ^TM collected. The data from each recording period is stored and analyzed for the distance traveled. Each behavioral recording period lasted 60 minutes, starting approximately 4 minutes after injection of the test compound. The results are presented as counts / 60 minutes, counts / 45 minutes or counts / 15 minutes (expressed in arbitrary length units). Statistical comparisons were performed against the control group using the Student's t-test.

活體內測試：神經化學In vivo testing: neurochemistry

在行為活動期之後，立即將大鼠斬首，且快速取出其腦並置於冰冷培養皿中。 Immediately after the behavioral activity period, the rats were decapitated and their brains were quickly removed and placed in ice-cold petri dishes.

將腦解剖分成紋狀體、邊緣區域(含有依核(核心及外殼)、扁桃腺、大部分嗅結節及腹側蒼白球)、額皮質及海馬迴。將組織試樣立即冷凍並儲存於-80℃下，直至使用高氯酸(PCA)(0.1M)、乙二胺四乙酸(EDTA)(5.37 mM)、谷胱甘肽(GSH)(0.65 mM)及作為內部標準之α-甲基-多巴胺(0.25 μM)將其均質化為止。使用數位超音波儀(Branson數位超音波儀250-D)均質化紋狀體及邊緣區域之組織。使用Ultra Turrax T25均質器均質化皮質組織。在10,000 rpm及+4℃下，將所有試樣離心10分鐘。在Munktell濾紙(5.5 cm，1F品質)中過濾皮質組織。藉由HPLC分離及電化學檢測(HPLC/EC)分析組織洗脫物中單胺遞質物質(去甲腎上腺素(NA)、多巴胺(DA)、5-羥基色胺(5-HT))以及其胺代謝物(去甲變腎上腺素(NM)、3-甲氧基酪胺(3-MT))及酸代謝物(3,4-二羥基苯基丙胺酸(DOPAC)、5-羥基吲哚乙酸(5-HIAA)、高香草酸(HVA))之組織濃度(ng/g組織)。每三個月一次製備原液標準(DA、NA、5-HT、3-MT、DOPAC、HVA、HIAA，500μg/ml)及內部標準(AMDA，500μg/ml)。將5-HT及5HIAA溶於milliQ水中。將DA、NA、DOPAC、NM、3-MT及HVA溶於0.01 M HCl中。將5-HT、5-HIAA、NM及HVA保持於冰箱中；將DA、DOPAC、NA及3-MT保持於冷凍庫中。每天製備用於分析之標準溶液，其含有稀釋於均質化溶 液中之0.05 μg/ml濃度之標準品。 The brain is dissected into the striatum, the marginal zone (containing the nucleus (core and outer shell), the tonsils, most of the olfactory nodules and the ventral pallidus), the frontal cortex and the hippocampus. Tissue samples were immediately frozen and stored at -80 °C until perchloric acid (PCA) (0.1 M), ethylenediaminetetraacetic acid (EDTA) (5.37 mM), glutathione (GSH) (0.65 mM) And homogenization of α-methyl-dopamine (0.25 μM) as an internal standard. The tissue of the striatum and marginal regions was homogenized using a digital ultrasonic instrument (Branson Digital Ultrasonic Instrument 250-D). The cortical tissue was homogenized using an Ultra Turrax T25 homogenizer. All samples were centrifuged for 10 minutes at 10,000 rpm and +4 °C. Cortical tissue was filtered in Munktell filter paper (5.5 cm, 1F quality). Analysis of monoamine neurotransmitters (norepinephrine (NA), dopamine (DA), 5-hydroxytryptamine (5-HT)) in tissue eluate by HPLC separation and electrochemical detection (HPLC/EC) Its amine metabolites (nor-adrenalin (NM), 3-methoxytyramine (3-MT)) and acid metabolites (3,4-dihydroxyphenylalanine (DOPAC), 5-hydroxyindole) Tissue concentration of indole acetic acid (5-HIAA), high vanillic acid (HVA) (ng/g tissue). Stock standards (DA, NA, 5-HT, 3-MT, DOPAC, HVA, HIAA, 500 μg/ml) and internal standards (AMDA, 500 μg/ml) were prepared every three months. 5-HT and 5HIAA were dissolved in milliQ water. DA, NA, DOPAC, NM, 3-MT and HVA were dissolved in 0.01 M HCl. 5-HT, 5-HIAA, NM, and HVA were kept in the refrigerator; DA, DOPAC, NA, and 3-MT were kept in a freezer. Prepare a standard solution for analysis every day, which contains diluted in homogenized solution A standard of 0.05 μg/ml concentration in the solution.

分析方法係基於兩個專用於胺或酸之層析分離。兩個層析系統共享具有10埠閥之共用自動注入器及兩個試樣環路以用於在兩個系統中同時注入。兩個系統皆配備有反相管柱(Luna C18(2),dp 3 μm,50×2 mm i.d.,Phenomenex)且在玻璃碳電極(MF-1000,Bioanalytical Systems公司)上於兩個電勢下進行電化學檢測。使管柱流出物通過T形聯接到達檢測單元或廢物出口。藉由兩個電磁閥來達成此過程，該等電磁閥封鎖廢物或檢測器出口。藉由防止層析前沿到達檢測器來達成較佳檢測條件。用於酸系統之水性流動相(0.4 ml/min)含有14 mM檸檬酸、10 mM檸檬酸鈉、15%(v/v)MeOH及0.1 mM EDTA。相對於Ag/AgCl參考之檢測電勢為0.45 V及0.60V。用於胺系統之水性離子配對流動相(0.5 ml/min)含有5 mM檸檬酸、10 mM檸檬酸鈉、9%(v/v)MeOH、10.5%(v/v)MeCN、0.45 mM癸烷磺酸及0.1 mM EDTA。相對於Ag/AgCl參考之檢測電勢為0.45 V及0.65 V。 The analytical method is based on two chromatographic separations specific to amines or acids. The two chromatography systems share a common automatic injector with 10 埠 valves and two sample loops for simultaneous injection in both systems. Both systems were equipped with reversed-phase columns (Luna C18 (2), dp 3 μm, 50 × 2 mm id, Phenomenex) and were run at two potentials on a glassy carbon electrode (MF-1000, Bioanalytical Systems). Electrochemical detection. The column effluent is passed through a T-joint to the detection unit or waste outlet. This process is achieved by two solenoid valves that block the waste or detector outlet. Better detection conditions are achieved by preventing the chromatographic front from reaching the detector. The aqueous mobile phase (0.4 ml/min) used in the acid system contained 14 mM citric acid, 10 mM sodium citrate, 15% (v/v) MeOH and 0.1 mM EDTA. The detection potential relative to the Ag/AgCl reference is 0.45 V and 0.60 V. Aqueous ion-paired mobile phase (0.5 ml/min) for the amine system contains 5 mM citric acid, 10 mM sodium citrate, 9% (v/v) MeOH, 10.5% (v/v) MeCN, 0.45 mM decane Sulfonic acid and 0.1 mM EDTA. The detection potential relative to the Ag/AgCl reference is 0.45 V and 0.65 V.

PCRPCR

將下列方法用於圖3、圖13及圖16中所展示之數據：藉由異硫氰酸胍方法製備總RNA(Chomczynski,1987)。將RNA沈澱物溶於MQ水中且儲存於-80℃下。藉由NanoDrop ND-1000以分光光度方式測定試樣濃度。在隨機試樣中使用Experion(Bio-Rad)量測r-RNA之品質指標計數及完整性計數。 The following method was used for the data shown in Figures 3, 13 and 16: Total RNA was prepared by the guanidinium isothiocyanate method (Chomczynski, 1987). The RNA pellet was dissolved in MQ water and stored at -80 °C. The sample concentration was measured spectrophotometrically by NanoDrop ND-1000. Experion (Bio-Rad) was used to measure the quality index and integrity count of r-RNA in random samples.

藉由使用SuperScript III套組(Invitrogen)實施兩步驟逆轉錄。使用5 μl 2×RT反應混合物、1 μl RT酶混合物逆轉錄1 μg總RNA，使用經DEPC處理之水將體積調節至10 μl。添加1 U大腸桿菌(E.coli)RNase H。將cDNA稀釋40倍且儲存於-20℃下。 Two-step reverse transcription was performed by using the SuperScript III kit (Invitrogen). 1 μg of total RNA was reverse transcribed using 5 μl of 2×RT reaction mixture, 1 μl of RT enzyme mixture, and the volume was adjusted to 10 μl using DEPC-treated water. Add 1 U E. coli RNase H. The cDNA was diluted 40-fold and stored at -20 °C.

以三重PCR反應將三個序列(一個所關注基因及兩個參考基因)一起擴增。即時PCR量測：在20 μl含有10 μl Quanta緩衝液、3.5 μl MQ、0.15 μM每一引物及0.1 μM每一探針之反應混合物中擴增5 μl cDNA反應液。在CFX96(Biorad)上使用用於所有基因之下列設置量測即時PCR：在95℃下預培育3 min，隨後在95℃下進行40個15s變性循環，退火且在60℃下延伸1分鐘。 The three sequences (one gene of interest and two reference genes) were amplified together in a triple PCR reaction. Real-time PCR measurement: 10 μl of Quanta buffer, 3.5 μl in 20 μl 5 μl of cDNA reaction solution was amplified in MQ, 0.15 μM of each primer and 0.1 μM of each probe reaction mixture. Real-time PCR was performed on CFX96 (Biorad) using the following settings for all genes: pre-incubation at 95 °C for 3 min followed by 40 15s denaturation cycles at 95 °C, annealing and extension at 60 °C for 1 minute.

參考基因係HPRT及親環素。 The reference gene line HPRT and cyclophilin.

對於arc量測而言，引物及探針序列如下： For arc measurements, the primer and probe sequences are as follows:

活動調節基因(Arc)(登錄編號：U19866)Activity regulatory gene (Arc) (registration number: U19866)

有義：5’-GGA GTT CAA GAA GGA GTT TC-3’ Righteousness: 5’-GGA GTT CAA GAA GGA GTT TC-3’

反義：5’-CCA CAT ACA GTG TCT GGT A-3’ Antisense: 5'-CCA CAT ACA GTG TCT GGT A-3’

探針：CCG CTT ACG CCA GAG GAA CT Probe: CCG CTT ACG CCA GAG GAA CT

染料：5'FAM Dyes: 5'FAM

猝滅劑：3'BHQ1 Quencher: 3'BHQ1

產物大小：149 Product size: 149

次黃嘌呤磷酸核糖轉移酶(HPRT)(登錄編號：AF001282)Hypoxanthine phosphoribosyltransferase (HPRT) (accession number: AF001282)

有義：5’-AGG GAT TTG AAT CAT GTT TG-3’ Righteousness: 5’-AGG GAT TTG AAT CAT GTT TG-3’

反義：5’-CTG CTA GTT CTT TAC TGG C-3’ Antisense: 5'-CTG CTA GTT CTT TAC TGG C-3’

探針：TGT AGA TTC AAC TTG CCG CTG TC Probe: TGT AGA TTC AAC TTG CCG CTG TC

染料：5'HEX Dyestuff: 5'HEX

猝滅劑：3'BHQ1 Quencher: 3'BHQ1

產物大小：121 Product size: 121

親環素A(登錄編號：M19533)Cyclophilin A (registration number: M19533)

有義：5’-CTG GAC CAA ACA CAA ATG-3’ Righteousness: 5’-CTG GAC CAA ACA CAA ATG-3’

反義：5’-ATG CCT TCT TTC ACC TTC-3’ Antisense: 5'-ATG CCT TCT TTC ACC TTC-3’

探針：TTG CCA TCC AGC CAC TCA GT Probe: TTG CCA TCC AGC CAC TCA GT

染料：5'Texas red Dyestuff: 5'Texas red

猝滅劑：3'BHQ2 Quencher: 3'BHQ2

產物大小：100 Product size: 100

藉由瓊脂糖凝膠電泳(2%)證實正確PCR產物。使用來自Qiagen之PCR純化套組(Valencia,CA,USA)純化PCR產物。在德國之MWG處對所有基因進行測序。使用兩種參考基因HPRT及親環素A將所關注基因之量正規化。 The correct PCR product was confirmed by agarose gel electrophoresis (2%). The PCR product was purified using a PCR purification kit from Qiagen (Valencia, CA, USA). All genes were sequenced at MWG in Germany. The two reference genes HPRT and cyclophilin A were used to normalize the amount of the gene of interest.

對於圖6中所展示之數據而言，如下所述來實施逆轉錄及PCR： 藉由使用ThermoScript套組(Invitrogen)實施逆轉錄。使用25 pmol寡核苷酸(dT)、62.5 ng無規六聚體、7.5U Thermoscript RT、10U RNaseOut、2μl 5×cDNA合成緩衝液、1mM dNTP、0.05 M DTT逆轉錄1μg總RNA，使用經DEPC處理之水將體積調節至10 μl。然後將cDNA稀釋40倍且儲存於-20℃下。 For the data shown in Figure 6, reverse transcription and PCR were performed as follows: Reverse transcription was performed by using a ThermoScript kit (Invitrogen). Reverse transcription of 1 μg total RNA using 25 pmol oligonucleotide (dT), 62.5 ng random hexamer, 7.5 U Thermoscript RT, 10 U RNaseOut, 2 μl 5× cDNA synthesis buffer, 1 mM dNTP, 0.05 M DTT, using DEPC The treated water was adjusted to a volume of 10 μl. The cDNA was then diluted 40-fold and stored at -20 °C.

即時單重PCR量測：在25 μl含有1×pcr緩衝液、0.2 mM dNTP、3.7 mM MgCl2、0.15 mM SYBR green、0.4 μM引物及1 U Taq聚合酶之反應混合物中擴增0.7 μl cDNA反應液。在Icycler(Biorad)上使用用於所有基因之下列設置量測即時PCR：在95℃下預培育60s，隨後在95℃下進行40個20s變性循環，在56℃下退火20 s且在72℃下延伸30 s。 Immediate single-plex PCR assay: Amplification of 0.7 μl cDNA reaction solution in 25 μl reaction mixture containing 1×pcr buffer, 0.2 mM dNTP, 3.7 mM MgCl2, 0.15 mM SYBR green, 0.4 μM primer and 1 U Taq polymerase . Real-time PCR was performed on Icycler (Biorad) using the following settings for all genes: pre-incubation at 95 ° C for 60 s, followed by 40 20 s denaturation cycles at 95 ° C, annealing at 56 ° C for 20 s and at 72 ° C Extend for 30 s.

Arc mRNA之分析：丁苯那嗪、匹多吡啶及氟哌啶醇之劑量-反應及相互作用研究Analysis of Arc mRNA: Dose-Reaction and Interaction Studies of Tetrabenazine, Pipidine and Haloperidol

藉由異硫氰酸胍方法製備總RNA(Schaefer,1984)。將RNA沈澱物溶於超純水中且儲存於-80℃下。使用NanoDrop ND-1000(Thermo Scientific,Waltham,Massachusetts,USA)以分光光度方式測定RNA濃度。使用Experion電泳系統(Bio-Rad實驗室，Hercules,California,USA)測定隨機試樣中核糖體RNA之品質指標計數及完整性計數。使用SuperScript III套組或ThermoScript套組(二者皆來自Life Technologies Europe BV,Stockholm,Sweden)實施逆轉錄。對於丁苯那 嗪劑量-反應及相互作用研究而言，使用5 μl 2×RT反應混合物及1 μl RT酶混合物(SuperScript III套組)逆轉錄1 μg RNA；對於使用匹多吡啶及氟哌啶醇之研究而言，使用ThermoScript套組利用25 pmol寡核苷酸(dT)、62.5 ng無規六聚體、7.5 U ThermoScript逆轉錄酶、10 U RNaseOut、2 μl 5×cDNA合成緩衝液、1 mM dNTP及0.05 M二硫蘇糖醇逆轉錄1 μg RNA。在所有研究中，使用經焦碳酸二乙酯處理之水將cDNA體積調節至10 μl。添加大腸桿菌RNase H(1 U)，然後將cDNA稀釋40倍且儲存於-20℃下。 Total RNA was prepared by the guanidinium isothiocyanate method (Schaefer, 1984). The RNA pellet was dissolved in ultrapure water and stored at -80 °C. RNA concentration was determined spectrophotometrically using a NanoDrop ND-1000 (Thermo Scientific, Waltham, Massachusetts, USA). The quality index and integrity counts of ribosomal RNA in random samples were determined using an Experion electrophoresis system (Bio-Rad Laboratories, Hercules, California, USA). Reverse transcription was performed using a SuperScript III kit or a ThermoScript kit (both from Life Technologies Europe BV, Stockholm, Sweden). For tetrabenone For the dose-response and interaction studies, 5 μl of 2×RT reaction mixture and 1 μl of RT enzyme mix (SuperScript III kit) were used to reverse-transcribe 1 μg of RNA; for the study using p-polypyridine and haloperidol Using the ThermoScript kit with 25 pmol of oligonucleotide (dT), 62.5 ng of random hexamer, 7.5 U of ThermoScript reverse transcriptase, 10 U of RNaseOut, 2 μl of 5× cDNA synthesis buffer, 1 mM dNTP and 0.05 M dithiothreitol reverse transcribes 1 μg of RNA. In all studies, the volume of cDNA was adjusted to 10 μl using water treated with diethylpyrocarbonate. E. coli RNase H (1 U) was added, and then the cDNA was diluted 40-fold and stored at -20 °C.

藉由即時PCR以三重反應(丁苯那嗪研究)或三個單重反應(使用匹多吡啶及氟哌啶醇之研究)擴增Arc及兩種參考基因次黃嘌呤鳥嘌呤磷酸核糖轉移酶(HPRT)及親環素A之cDNA。對於三重即時PCR而言，在20 μl含有10 μl Quanta緩衝液(Quanta BioSciences公司，Gaithersburg,Maryland,USA)、3.5 μl超純水、0.15 μM每一引物及0.1 μM每一探針(所使用之引物及探針序列詳述於表3中)之反應混合物中擴增5 μl cDNA。在CFX96系統(Bio-Rad實驗室，Hercules,California,USA)下使用用於所有基因之下列設置來檢測三重即時PCR產物：在95℃下預培育3分鐘，隨後在95℃下進行40個15秒變性循環，退火且在60℃下延伸1分鐘。對於單重即時PCR量測而言，在25 μl含有1×PCR緩衝液、0.2 mM dNTP、3.7 mM MgCl₂、0.15 mM SYBR Green、0.4 μM引物(表2)及1 U Taq聚合酶之反應混合物中擴增0.7 μl cDNA。使用Icycler檢測系統(Bio-Rad實驗室，Hercules,California,USA)，利用用於所有基因之下列設置：在95℃下預培育60秒，隨後在95℃下進行40個20秒變性循環，在56℃下退火20秒且在72℃下延伸30秒。藉由瓊脂糖凝膠電泳(2%)證實正確大小之PCR產物；然後使用來自Qiagen之PCR純化套組(Valencia,CA,USA)純化產物。在MWG Biotech(Ebersberg,Germany)處對所有基因進行測序。藉由每一基因之標準曲 線將Arc mRNA量正規化至兩種參考基因之彼等量，該標準曲線係使用純化PCR產物之6個連續4倍稀釋液所構建。 Amplification of Arc and two reference genes, hypoxanthine guanine phosphoribosyltransferase by triple-reaction (tetrabenazine study) or three single-reactions (research using p-polypyridine and haloperidol) by real-time PCR ( HPRT ) and cDNA of cyclophilin A. For triple-on-time PCR, 20 μl contains 10 μl of Quanta buffer (Quanta BioSciences, Gaithersburg, Maryland, USA), 3.5 μl of ultrapure water, 0.15 μM of each primer, and 0.1 μM of each probe (used The primers and probe sequences are detailed in the reaction mixture of Table 3) and 5 μl of cDNA was amplified. The triple-instant PCR product was tested under the CFX96 system (Bio-Rad Laboratories, Hercules, California, USA) using the following settings for all genes: pre-incubation at 95 °C for 3 minutes followed by 40 at 95 °C. The second denaturation cycle, annealed and extended at 60 ° C for 1 minute. For single-use real-time PCR measurements, 25 μl of reaction mixture containing 1× PCR buffer, 0.2 mM dNTP, 3.7 mM MgCl ₂ , 0.15 mM SYBR Green, 0.4 μM primer (Table 2) and 1 U Taq polymerase Amplification of 0.7 μl cDNA was performed. The Icycler detection system (Bio-Rad Laboratories, Hercules, California, USA) was used, using the following settings for all genes: pre-incubation at 95 ° C for 60 seconds, followed by 40 20 second denaturation cycles at 95 ° C, Annealed at 56 ° C for 20 seconds and at 72 ° C for 30 seconds. The correct size PCR product was confirmed by agarose gel electrophoresis (2%); the product was then purified using a PCR purification kit from Qiagen (Valencia, CA, USA). All genes were sequenced at MWG Biotech (Ebersberg, Germany). The amount of Arc mRNA was normalized to the equivalent of the two reference genes by a standard curve for each gene constructed using 6 consecutive 4-fold dilutions of the purified PCR product.

引物： Primer: 次黃嘌呤磷酸核糖轉移酶(HPRT)(登錄編號：AF001282)Hypoxanthine phosphoribosyltransferase (HPRT) (accession number: AF001282)

有義：5’-GGC CAG ACT TGT TGG ATT TG-3’ Righteousness: 5’-GGC CAG ACT TGT TGG ATT TG-3’

反義：5’-CCG CTG TCT TTT AGG CTT TG-3’ Antisense: 5'-CCG CTG TCT TTT AGG CTT TG-3’

親環素A(登錄編號：M19533)Cyclophilin A (registration number: M19533)

有義：5’-GTC TCT TTT CGC CGC TTG CT-3’ Righteousness: 5’-GTC TCT TTT CGC CGC TTG CT-3’

反義：5’-TCT GCT GTC TTT GGA ACT TTG TCT G-3’ Antisense: 5'-TCT GCT GTC TTT GGA ACT TTG TCT G-3’

活動調節基因(Arc)(登錄編號：U19866)Activity regulatory gene (Arc) (registration number: U19866)

有義：5’-GTC CCA GAT CCA GAA CCA CA-3’ Righteousness: 5’-GTC CCA GAT CCA GAA CCA CA-3’

反義：5’-CCT CCT CAG CGT CCA CAT AC-3’ Antisense: 5’-CCT CCT CAG CGT CCA CAT AC-3’

藉由每一基因之標準曲線量化初始DNA量，該標準曲線係使用純化PCR產物之6個連續4倍稀釋液所構建。 The initial amount of DNA was quantified by a standard curve for each gene constructed using 6 consecutive 4-fold dilutions of purified PCR products.

對於圖10中所展示之數據而言，應用與圖6中之數據相同之方法，只是在MyIQ熱循環儀(Biorad)上運行PCR。 For the data shown in Figure 10, the same method as the data in Figure 6 was applied except that the PCR was run on a MyIQ Thermal Cycler (Biorad).

實例論述：Example discussion:

匹多吡啶顯示可逆轉藉由丁苯那嗪誘導之行為抑制。氟哌啶醇並不擁有此效應，其會降低丁苯那嗪治療動物中之運動活動性。相互作用實驗進一步展示，在與丁苯那嗪共投與時，匹多吡啶及氟哌啶醇保留其特徵性神經化學效應，亦即增加紋狀體DOPAC。同樣，在與丁苯那嗪之相互作用實驗中維持藉由匹多吡啶及氟哌啶醇誘導之紋狀體Arc mRNA含量之伴隨增加。 P-polypyridine showed reversible inhibition of behavior induced by tetrabenazine. Haloperidol does not possess this effect, which reduces the motor activity in tetrabenazine-treated animals. The interaction experiments further demonstrated that p-polypyridine and haloperidol retained their characteristic neurochemical effects when co-administered with tetrabenazine, ie, increased striatal DOPAC. Similarly, the concomitant increase in striatal Arc mRNA content induced by p-polypyridine and haloperidol was maintained in the interaction experiment with tetrabenazine.

除運動抑鬱及紋狀體DOPAC含量增加外，丁苯那嗪使得紋狀體多巴胺含量產生劑量依賴性降低，此並不受匹多吡啶或氟哌啶醇之投與影響。另外，丁苯那嗪使得額皮質Arc mRNA含量產生劑量依賴性 增加。匹多吡啶以劑量依賴性方式抵抗此效應，但氟哌啶醇並非如此。 In addition to exercise depression and increased striatum DOPAC content, tetrabenazine caused a dose-dependent decrease in striatal dopamine content, which was not affected by the administration of pipidine or haloperidol. In addition, tetrabenazine caused a dose-dependent dose of Arc mRNA in the frontal cortex. increase. P-polypyridine resists this effect in a dose-dependent manner, but not with haloperidol.

匹多吡啶抵抗藉由丁苯那嗪誘導之行為抑鬱。與先前數據一致，丁苯那嗪及氟哌啶醇皆顯著抑制自發性運動活動性(Satou 2001,Schaefer 1984)，而匹多吡啶并不顯示該等效應。對於大鼠中自發性運動活動性之此抑制效應缺乏係匹多吡啶之特徵性藥理學性質之一部分(Ponten 2010)。 Pidadopyridine resists depression induced by tetrabenazine. Consistent with previous data, both tetrabenazine and haloperidol significantly inhibited spontaneous motor activity (Satou 2001, Schaefer 1984), whereas p-polypyridine did not exhibit these effects. This inhibitory effect on spontaneous motor activity in rats lacks one of the characteristic pharmacological properties of pipyridin (Ponten 2010).

對於相互作用實驗而言，選擇使得運動活動性產生中等減小之丁苯那嗪劑量，從而能夠在與其他測試化合物共投與時檢測進一步抑制以及行為激活。匹多吡啶顯著地且以劑量依賴性方式抵抗藉由丁苯那嗪誘導之運動活動性降低，此係先前未知之情形。匹多吡啶之此運動刺激效應類似於匹多吡啶能夠增加適用性大鼠、活動減退性大鼠中之運動活動性。該效應具有劑量依賴性(亦即在所測試之最高劑量下更為明顯)，且出現於與有效地(例如)拮抗d-***(d-amphetamine)誘導之高活動性基本相同之劑量範圍中。另外，活體內雷氯必利(raclopride)替換研究表明在該等劑量下具有顯著DA D2受體結合。與之相比，如對於多巴胺D2拮抗劑所期望，氟哌啶醇並不顯示該等效應，且減小丁苯那嗪治療大鼠以及初始大鼠中之運動活動性。 For interaction experiments, a dose of tetrabenazine that resulted in moderately reduced motor activity was selected to enable detection of further inhibition and behavioral activation when co-administered with other test compounds. P-polypyridine resists the decrease in motor activity induced by tetrabenazine in a significant and dose-dependent manner, a previously unknown situation. This motor stimulatory effect of p-polypyridine is similar to that of p-polypyridine, which can increase the mobility of activity in a rat, hypoactive rat. This effect is dose dependent (i.e., more pronounced at the highest dose tested) and occurs in a dose range that is substantially identical to, for example, antagonizing the high activity induced by d-amphetamine. . In addition, in vivo raclopride replacement studies have shown significant DA D2 receptor binding at these doses. In contrast, haloperidol did not exhibit these effects as expected for dopamine D2 antagonists, and reduced motor activity in tetrabenazine-treated rats as well as in the initial rats.

在與丁苯那嗪共投與時，匹多吡啶對於多巴胺D2受體亦存在藥理學效應。神經化學分析顯示，所測試之所有三種化合物皆使得紋狀體DOPAC產生劑量依賴性增加，在最高施加劑量下達到對照含量之約250-300%，此與先前結果一致。紋狀體DOPAC增加係多巴胺D2拮抗劑以及通常在中樞多巴胺D2受體處產生減小張力之化合物(包含具有低固有活性之部分激動劑及單胺消耗性藥物)之共有特徵(Jordan,2004；Roffler-Tarlov 1971)。在紋狀體DOPAC中所看到之增加由此代表所測試每一化合物之核心藥理學效應。在相互作用實驗中，在與丁 苯那嗪共投與時，氟哌啶醇及匹多吡啶皆使得紋狀體DOPAC產生額外增加。此強烈表明匹多吡啶及氟哌啶醇之主要效應仍存在於部分性單胺空乏大鼠中。另外，儘管實際上在共投與時匹多吡啶逆轉丁苯那嗪之運動阻抑效應，但所誘導之多巴胺組織含量降低(作為丁苯那嗪之標誌效應)未受匹多吡啶影響，從而表明匹多吡啶并不廢除丁苯那嗪之藥理學效應。 Picopolypyridine also has a pharmacological effect on the dopamine D2 receptor when co-administered with tetrabenazine. Neurochemical analysis showed that all three compounds tested resulted in a dose-dependent increase in striatum DOPAC, reaching approximately 250-300% of the control content at the highest applied dose, which is consistent with previous results. The striatal DOPAC increase is a common feature of dopamine D2 antagonists and compounds that typically produce reduced tension at the central dopamine D2 receptor (including partial agonists with low intrinsic activity and monoamine depleting drugs) (Jordan, 2004; Roffler-Tarlov 1971). The increase seen in the striatum DOPAC thus represents the core pharmacological effect of each compound tested. In the interaction experiment, in the Ding Both haloperidol and p-polypyridine caused an additional increase in striatal DOPAC when penbenazine was co-administered. This strongly suggests that the major effects of pipidine and haloperidol are still present in partially monoamine-deficient rats. In addition, despite the fact that in the co-administered pipidine reverses the motor inhibitory effect of tetrabenazine, the induced dopamine tissue content (as a hallmark effect of tetrabenazine) is not affected by the picopyridine. It is indicated that pridolidine does not abolish the pharmacological effects of tetrabenazine.

總而言之，在所有研究中皆存在所有三種化合物對於DOPAC以及多巴胺含量之典型神經化學效應，從而表明每一化合物對於多巴胺能傳遞之核心效應得以保留。 In summary, the typical neurochemical effects of all three compounds on DOPAC and dopamine content were present in all studies, indicating that the core effect of each compound on dopaminergic transmission was retained.

匹多吡啶共治療使得皮質中之Arc mRNA增加可幫助闡釋丁苯那嗪誘導之運動抑鬱之逆轉。作為尤其用於區分匹多吡啶及氟哌啶醇之其他相關生物標記物，在額皮質及紋狀體中量測Arc mRNA。Arc係與突觸激活及NMDA受體信號傳導有關之早期基因，且先前已報導其在紋狀體中因應若干多巴胺D2拮抗劑以及多巴胺能穩定劑而增加。然而，先前並無關於丁苯那嗪對於Arc基因表現之效應之報導。如實例中所顯示，丁苯那嗪誘導紋狀體Arc顯著增加。儘管效應大小略小於匹多吡啶及氟哌啶醇，但此效應可與丁苯那嗪治療動物中亦存在之紋狀體多巴胺傳遞減小相關。如同DOPAC之情形，丁苯那嗪及匹多吡啶在初始大鼠中皆對於紋狀體Arc產生類似效應(如同丁苯那嗪治療大鼠)。 Co-polypyridyl treatment increases the increase in Arc mRNA in the cortex to help elucidate the reversal of tetrabenazine-induced exercise depression. As an especially relevant biomarker for distinguishing between p-polypyridine and haloperidol, Arc mRNA was measured in the frontal cortex and striatum. Arc is an early gene involved in synaptic activation and NMDA receptor signaling and has previously been reported to increase in the striatum in response to several dopamine D2 antagonists and dopaminergic stabilizers. However, there have been no previous reports of the effects of tetrabenazine on the performance of the Arc gene. As shown in the examples, tetrabenazine induced a significant increase in striatum Arc. Although the effect size was slightly less than that of p-polypyridine and haloperidol, this effect was associated with a reduction in striatum dopamine transmission that was also present in tetrabenazine-treated animals. As in the case of DOPAC, tetrabenazine and p-polypyridine produced similar effects on striatal Arc in the initial rats (as in tetrabenazine-treated rats).

在額皮質中，丁苯那嗪以劑量依賴性方式減小Arc基因表現，且在用於相互作用實驗之劑量下及高於該劑量下具有顯著效應。匹多吡啶及氟哌啶醇之劑量反應研究顯示，匹多吡啶使得額皮質Arc基因表現發生劑量依賴性增加，但氟哌啶醇並無效應。匹多吡啶增加額皮質Arc基因表現之能力在丁苯那嗪治療大鼠中亦顯而易見。因此，區分匹多吡啶與氟哌啶醇及其他經典多巴胺D2拮抗劑之此藥理學效應在 部分性單胺空乏時得以維持。可以想像，其代表可有助於匹多吡啶抵抗丁苯那嗪治療大鼠中之行為抑制之能力之一定皮質突觸激活程度。作為此解釋之證據，匹多吡啶已展示可增加額皮質中自發性活性椎體細胞之放電。 In the frontal cortex, tetrabenazine reduced the Arc gene performance in a dose-dependent manner and had a significant effect at doses above and above the dose used in the interaction experiments. Dosimetric studies of p-polypyridine and haloperidol showed that p-polypyridine caused a dose-dependent increase in the Arc's expression in the frontal cortex, but haloperidol had no effect. The ability of p-polypyridine to increase the expression of the Arc's Arc gene was also evident in tetrabenazine-treated rats. Therefore, the pharmacological effect of distinguishing pipidide from haloperidol and other classical dopamine D2 antagonists is Partial monoamines are maintained when they are deficient. It is conceivable that it represents a certain degree of cortical synaptic activation that can contribute to the ability of pridopridol to resist the inhibition of behavior in tetrabenazine. As evidence for this explanation, p-polypyridine has been shown to increase the discharge of spontaneously active vertebral cells in the frontal cortex.

儘管實例明確表明匹多吡啶之效應在共投與匹多吡啶與丁苯那嗪時得以保留，匹多吡啶及丁苯那嗪之組合並不產生任何不良效應徵兆。與之相比，組合氟哌啶醇及丁苯那嗪會產生明顯行為抑鬱，此表明在人類中使用此一組合具有過度抗多巴胺能運動副作用之風險，此與當前關於向患有亨廷頓氏病之患者共投與丁苯那嗪及精神安定藥之警告建議一致。 Although the examples clearly show that the effect of p-polypyridine is retained when co-administered with p-polypyridine and tetrabenazine, the combination of p-polypyridine and tetrabenazine does not produce any signs of adverse effects. In contrast, combination of haloperidol and tetrabenazine produced significant behavioral depression, suggesting that the use of this combination in humans carries the risk of excessive anti-dopaminergic side effects, which is currently associated with having Huntington's disease The patients were co-injected with the warning recommendations for tetrabenazine and neuroleptics.

紋狀體中之多巴胺含量之匯總Summary of dopamine content in the striatum

在表1中給出不同治療對於紋狀體組織多巴胺含量之效應。丁苯那嗪誘導紋狀體多巴胺之劑量依賴性減小。在相互作用實驗中所使用之劑量(0.64 mg/kg)下，在所實施之所有研究中，丁苯那嗪顯著減小紋狀體多巴胺，達到媒劑對照組平均值之大約50%。在所測試之最高劑量下，匹多吡啶及氟哌啶醇皆使得紋狀體多巴胺產生較小降低。在相互作用實驗中，丁苯那嗪對於紋狀體多巴胺之效應基本上不受與匹多吡啶或氟哌啶醇之共治療影響。 The effect of different treatments on dopamine content in striatal tissue is given in Table 1. Tebuconazine induced a dose-dependent decrease in striatal dopamine. At all doses (0.64 mg/kg) used in the interaction experiments, tetrabenazine significantly reduced striatal dopamine in all studies performed, reaching approximately 50% of the mean of the vehicle control group. At the highest dose tested, both picopolypyridine and haloperidol produced a small decrease in striatal dopamine production. In the interaction experiments, the effect of tetrabenazine on striatal dopamine was essentially unaffected by co-treatment with piopolypyridine or haloperidol.

總而言之，匹多吡啶逆轉藉由單胺消耗性化合物丁苯那嗪誘導之行為抑制，同時保留匹多吡啶之與多巴胺D2受體拮抗作用相關之核心神經化學效應。因此，在除丁苯那嗪外投與匹多吡啶時，匹多吡啶緩解丁苯那嗪之運動抑鬱效應，但紋狀體多巴胺D2受體處之張力會進一步減小。匹多吡啶亦逆轉藉由丁苯那嗪誘導之額皮質Arc基因表現降低。在試驗意義上，此反映了激活皮質神經元活性可有助於部分性單胺空乏之活動減退性大鼠中匹多吡啶之運動刺激效應。 In conclusion, p-polypyridine reverses the behavioral inhibition induced by the monoamine-depleting compound tetrabenazine, while preserving the core neurochemical effects of pipidine associated with dopamine D2 receptor antagonism. Therefore, in the case of administration of p-polypyridyl in addition to tetrabenazine, p-polypyridine attenuates the motor depression effect of tetrabenazine, but the tension at the striatal dopamine D2 receptor is further reduced. P-polypyridine also reversed the decrease in Arc gene expression in the frontal cortex induced by tetrabenazine. In the experimental sense, this reflects the motor stimulatory effect of pyridinopyridine in attenuated rats with activated cortical neuron activity that contributes to partial monoamine deficiency.

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FDA Label for XENAZINE (Tetrabenzine) 07/06/2011 FDA Label for XENAZINE (Tetrabenzine) 07/06/2011

Claims (49)

一種治療患有運動病症之個體之方法，其包括向該個體週期性投與一含量之丁苯那嗪(Tetrabenazine)或其醫藥上可接受之鹽及一含量之匹多吡啶(Pridopidine)或其醫藥上可接受之鹽。 A method of treating an individual having a motor disorder, comprising periodically administering to the individual a level of tetraprabenazine or a pharmaceutically acceptable salt thereof and a level of Pridopidine or A pharmaceutically acceptable salt. 一種治療患有肥胖症、肥胖症相關病症或對匹多吡啶具心血管副作用之個體之方法，其包括向該個體投與一含量之匹多吡啶或其醫藥上可接受之鹽及一含量丁苯那嗪或其醫藥上可接受之鹽。 A method of treating an individual suffering from obesity, an obesity-related disorder, or a cardiovascular side effect on p-polypyridine, comprising administering to the individual a level of p-polypyridine or a pharmaceutically acceptable salt thereof and a diced amount Benazidine or a pharmaceutically acceptable salt thereof. 如請求項1至2中任一項之方法，其中該等含量當一起投與時較每一藥劑以相同量單獨投與時更能有效地治療該個體。 The method of any one of claims 1 to 2, wherein the levels are more effective in treating the individual when administered together than when each agent is administered separately in the same amount. 如請求項1至3中任一項之方法，其中單獨投與該含量之丁苯那嗪或其醫藥上可接受之鹽時、及單獨投與該含量之匹多吡啶或其醫藥上可接受之鹽時，或單獨投與每一該含量時不能有效地治療該個體。 The method of any one of claims 1 to 3, wherein the content of the tetrabenazine or the pharmaceutically acceptable salt thereof is administered alone or separately, or the pharmaceutically acceptable amount thereof is pharmaceutically acceptable The individual is not effectively treated when the salt is administered or when each of the levels is administered alone. 一種減少或預防向個體週期性投與一含量之丁苯那嗪或其醫藥上可接受之鹽之一或多種副作用之方法，其包括向該個體週期性投與一含量之匹多吡啶或其醫藥上可接受之鹽。 A method for reducing or preventing the periodic administration of a content of one or more side effects of tetrabenazine or a pharmaceutically acceptable salt thereof to an individual, comprising periodically administering to the individual a level of p-polypyridine or A pharmaceutically acceptable salt. 如請求項5之方法，其中該一或多種副作用係選自抑鬱、自殺傾向、靜坐不能、煩亂不安、躁動、帕金森氏病、鎮靜狀態、嗜睡及吞嚥困難。 The method of claim 5, wherein the one or more side effects are selected from the group consisting of depression, suicidal tendency, sedation, restlessness, agitation, Parkinson's disease, sedation, lethargy, and difficulty swallowing. 如請求項6之方法，其中該副作用係帕金森氏病。 The method of claim 6, wherein the side effect is Parkinson's disease. 如請求項5至7中任一項之方法，其中該個體患有運動病症。 The method of any one of claims 5 to 7, wherein the individual has a motor disorder. 如請求項1至8中任一項之方法，其中該含量之丁苯那嗪或其醫藥上可接受之鹽係以經口投藥方式投與。 The method of any one of claims 1 to 8, wherein the content of tetrabenazine or a pharmaceutically acceptable salt thereof is administered orally. 如請求項1至9中任一項之方法，該含量之丁苯那嗪或其醫藥上 可接受之鹽係每日投與。 The method of any one of claims 1 to 9, the content of tetrabenazine or its medicinal Acceptable salts are administered daily. 如請求項1至9中任一項之方法，其中該含量之丁苯那嗪或其醫藥上可接受之鹽係每日投與兩次。 The method of any one of claims 1 to 9, wherein the content of tetrabenazine or a pharmaceutically acceptable salt thereof is administered twice daily. 如請求項1至9中任一項之方法，其中該含量之丁苯那嗪或其醫藥上可接受之鹽係每日投與三次。 The method of any one of claims 1 to 9, wherein the content of tetrabenazine or a pharmaceutically acceptable salt thereof is administered three times a day. 如請求項1至12中任一項之方法，其中該丁苯那嗪或其醫藥上可接受之鹽之含量為每日0.05 mg/kg至每日0.20 mg/kg。 The method of any one of claims 1 to 12, wherein the content of the tetrabenazine or a pharmaceutically acceptable salt thereof is from 0.05 mg/kg per day to 0.20 mg/kg per day. 如請求項1至12中任一項之方法，其中該丁苯那嗪或其醫藥上可接受之鹽之含量為5 mg/天至100 mg/天。 The method of any one of claims 1 to 12, wherein the content of the tetrabenazine or a pharmaceutically acceptable salt thereof is from 5 mg/day to 100 mg/day. 如請求項14之方法，其中該丁苯那嗪或其醫藥上可接受之鹽之含量為12.5 mg/天、25 mg/天、37.5 mg/天、50 mg/天、75 mg/天或100 mg/天。 The method of claim 14, wherein the content of the tetrabenazine or a pharmaceutically acceptable salt thereof is 12.5 mg/day, 25 mg/day, 37.5 mg/day, 50 mg/day, 75 mg/day or 100. Mg/day. 如請求項1至15中任一項之方法，其中該含量之匹多吡啶或其醫藥上可接受之鹽係以經口投藥方法投與。 The method of any one of claims 1 to 15, wherein the amount of the p-polypyridine or a pharmaceutically acceptable salt thereof is administered by an oral administration method. 如請求項1至16中任一項之方法，其中該含量之匹多吡啶或其醫藥上可接受之鹽係每日投與。 The method of any one of claims 1 to 16, wherein the amount of the p-polypyridine or a pharmaceutically acceptable salt thereof is administered daily. 如請求項1至16中任一項之方法，其中該含量之匹多吡啶或其醫藥上可接受之鹽係每日投與兩次。 The method of any one of claims 1 to 16, wherein the amount of the p-polypyridine or a pharmaceutically acceptable salt thereof is administered twice daily. 如請求項1至18中任一項之方法，其中該匹多吡啶或其醫藥上可接受之鹽之含量為每日1.5 μmol/kg至每日20 μmol/kg。 The method of any one of claims 1 to 18, wherein the content of the p-polypyridine or a pharmaceutically acceptable salt thereof is from 1.5 μmol/kg per day to 20 μmol/kg per day. 如請求項1至18中任一項之方法，其中該匹多吡啶或其醫藥上可接受之鹽之含量為10 mg/天至100 mg/天。 The method of any one of claims 1 to 18, wherein the content of the p-polypyridine or a pharmaceutically acceptable salt thereof is from 10 mg/day to 100 mg/day. 如請求項20之方法，其中該匹多吡啶或其醫藥上可接受之鹽之含量為10 mg/天、20 mg/天、22.5 mg/天、45 mg/天或90 mg/天。 The method of claim 20, wherein the content of the picopolypyridine or a pharmaceutically acceptable salt thereof is 10 mg/day, 20 mg/day, 22.5 mg/day, 45 mg/day or 90 mg/day. 如請求項1、3、4或8至21中任一項之方法，其中該運動病症係亨廷頓氏病(Huntington’s disease)、圖雷特症候群(Tourette’s syndrome)或遲發性運動困然。 The method of any one of claims 1, 3, 4 or 8 to 21, wherein the motor disorder is Huntington&apos;s disease, Tourette&apos;s Syndrome) or delayed movement is sleepy. 如請求項1、3、4或8至22中任一項之方法，其中該含量之丁苯那嗪或其醫藥上可接受之鹽及該含量之匹多吡啶或其醫藥上可接受之鹽可有效緩解該運動病症之症狀。 The method of any one of claims 1, 3, 4 or 8 to 22, wherein the content of tetrabenazine or a pharmaceutically acceptable salt thereof and the amount of the p-polypyridine or a pharmaceutically acceptable salt thereof It can effectively alleviate the symptoms of this sports condition. 如請求項23之方法，其中該症狀係舞蹈症。 The method of claim 23, wherein the symptom is chorea. 如請求項1至24中任一項之方法，其中該個體在開始投與匹多吡啶或其醫藥上可接受之鹽之前先接受丁苯那嗪療法。 The method of any one of claims 1 to 24, wherein the individual receives the tetrabenazine treatment prior to initiating administration of the p-polypyridine or a pharmaceutically acceptable salt thereof. 如請求項1至25中任一項之方法，其中該含量之丁苯那嗪或其醫藥上可接受之鹽及該含量之匹多吡啶或其醫藥上可接受之鹽係同時投與。 The method of any one of claims 1 to 25, wherein the content of tetrabenazine or a pharmaceutically acceptable salt thereof and the amount of the pridopol or a pharmaceutically acceptable salt thereof are simultaneously administered. 如請求項1至26中任一項之方法，其中該個體係人類患者。 The method of any one of claims 1 to 26, wherein the system is a human patient. 一種包裝，其包括：a)第一醫藥組合物，其包括一含量之丁苯那嗪或其醫藥上可接受之鹽及醫藥上可接受之載劑；b)第二醫藥組合物，其包括一含量之匹多吡啶或其醫藥上可接受之鹽及醫藥上可接受之載劑；及c)使用說明書，其用於指導該第一醫藥組合物及該第二醫藥組合物一起治療患有運動病症之個體。 A package comprising: a) a first pharmaceutical composition comprising a content of tetrabenazine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising a content of p-polypyridine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; and c) instructions for use in directing treatment of the first pharmaceutical composition and the second pharmaceutical composition together Individuals with motor disorders. 如請求項28之包裝，其用於治療患有運動病症之個體。 A package according to claim 28 for use in treating an individual having a motor disorder. 如請求項28至29中任一項之包裝，其中該運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 The package of any one of claims 28 to 29, wherein the motor condition is Huntington's disease, Tourette's syndrome or delayed movement. 一種匹多吡啶或其醫藥上可接受之鹽，其用作丁苯那嗪或其醫藥上可接受之鹽之附加療法或與其組合以用於治療患有運動病症之個體。 A p-polypyridine or a pharmaceutically acceptable salt thereof for use as an additional therapy with or in combination with tetrabenazine or a pharmaceutically acceptable salt thereof for use in treating an individual suffering from a motor disorder. 用於如請求項31之匹多吡啶或其醫藥上可接受之鹽，其中該運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 A p-polypyridine or a pharmaceutically acceptable salt thereof according to claim 31, wherein the motor disorder is Huntington's disease, Tourette's syndrome or delayed movement. 一種醫藥組合物，其包括一含量之丁苯那嗪或其醫藥上可接受之鹽、一含量之匹多吡啶或其醫藥上可接受之鹽及至少一種醫藥上可接受之載劑。 A pharmaceutical composition comprising a content of tetrabenazine or a pharmaceutically acceptable salt thereof, a level of p-polypyridine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 如請求項33之醫藥組合物，其中該丁苯那嗪或其醫藥上可接受之鹽之含量為5 mg至100 mg。 The pharmaceutical composition according to claim 33, wherein the tetrabenazine or a pharmaceutically acceptable salt thereof is contained in an amount of from 5 mg to 100 mg. 如請求項34之醫藥組合物，其中該丁苯那嗪或其醫藥上可接受之鹽之含量為5 mg、6.25 mg、12.5 mg、25 mg、37.5 mg、50 mg、75 mg或100 mg。 The pharmaceutical composition according to claim 34, wherein the content of the tetrabenazine or a pharmaceutically acceptable salt thereof is 5 mg, 6.25 mg, 12.5 mg, 25 mg, 37.5 mg, 50 mg, 75 mg or 100 mg. 如請求項32至35中任一項之醫藥組合物，其中該匹多吡啶或其醫藥上可接受之鹽之含量為10 mg至100 mg。 The pharmaceutical composition according to any one of claims 32 to 35, wherein the p-polypyridine or a pharmaceutically acceptable salt thereof is contained in an amount of 10 mg to 100 mg. 如請求項36之醫藥組合物，其中該匹多吡啶或其醫藥上可接受之鹽之含量為10 mg、22.5 mg、45 mg或90 mg。 The pharmaceutical composition according to claim 36, wherein the content of the polypyridyl or a pharmaceutically acceptable salt thereof is 10 mg, 22.5 mg, 45 mg or 90 mg. 如請求項33至37中任一項之醫藥組合物，其用於治療患有運動病症之個體。 A pharmaceutical composition according to any one of claims 33 to 37 for use in treating an individual having a motor disorder. 如請求項38之醫藥組合物，其中該運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 The pharmaceutical composition of claim 38, wherein the motor disorder is Huntington's disease, Tourette's syndrome or delayed movement. 如請求項33至37中任一項之醫藥組合物，其用於治療、預防或緩解罹患肥胖症、肥胖症相關病症或對匹多吡啶具心血管副作用之個體。 The pharmaceutical composition according to any one of claims 33 to 37 for use in the treatment, prevention or alleviation of an individual suffering from obesity, an obesity-related disorder or a cardiovascular side effect on p-polypyridine. 一種下列各項之用途，a)一含量之丁苯那嗪或其醫藥上可接受之鹽及b)一含量之匹多吡啶或其醫藥上可接受之鹽，其用以製備用於治療患有運動病症之個體之組合，其中該含量之丁苯那嗪或其醫藥上可接受之鹽及該含量之匹多吡啶或其醫藥上可接受之鹽係同時或同時期地投與。 Use of one of the following, a) a content of tetrabenazine or a pharmaceutically acceptable salt thereof and b) a level of p-polypyridine or a pharmaceutically acceptable salt thereof for use in the treatment of a patient A combination of individuals having a motor disorder, wherein the content of tetrabenazine or a pharmaceutically acceptable salt thereof and the amount of the pridopol or a pharmaceutically acceptable salt thereof are administered simultaneously or simultaneously. 如請求項41之用途，其中該運動病症係亨廷頓氏病、圖雷特症 候群或遲發性運動困然。 The use of claim 41, wherein the motor condition is Huntington's disease, Tourette's disease Hours or late-onset exercise is in jeopardy. 一種包括一含量之丁苯那嗪或其醫藥上可接受之鹽之醫藥組合物，其與一含量之匹多吡啶或其醫藥上可接受之鹽組合用於藉由向患有運動病症之個體週期性投與該醫藥組合物及該含量之匹多吡啶或其醫藥上可接受之鹽來治療該個體。 A pharmaceutical composition comprising a content of tetrabenazine or a pharmaceutically acceptable salt thereof, in combination with a level of p-polypyridine or a pharmaceutically acceptable salt thereof for use in an individual having a motor disorder The pharmaceutical composition and the amount of the p-polypyridine or a pharmaceutically acceptable salt thereof are administered periodically to treat the individual. 一種包括一含量之匹多吡啶或其醫藥上可接受之鹽之醫藥組合物，其與一含量之丁苯那嗪或其醫藥上可接受之鹽組合用於藉由向患有運動病症之個體週期性投與該醫藥組合物及該含量之丁苯那嗪或其醫藥上可接受之鹽來治療該個體。 A pharmaceutical composition comprising a content of p-polypyridine or a pharmaceutically acceptable salt thereof, in combination with a content of tetrabenazine or a pharmaceutically acceptable salt thereof for use in an individual having a motor disorder The pharmaceutical composition and the amount of tetrabenazine or a pharmaceutically acceptable salt thereof are administered periodically to treat the individual. 如請求項43至44中任一項之醫藥組合物，其中該運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 The pharmaceutical composition according to any one of claims 43 to 44, wherein the motor disorder is Huntington's disease, Tourette's syndrome or delayed movement. 一種丁苯那嗪或其醫藥上可接受之鹽及匹多吡啶或其醫藥上可接受之鹽，其用於治療患有運動病症之個體，其中該丁苯那嗪或其醫藥上可接受之鹽及該匹多吡啶或其醫藥上可接受之鹽係同時、單獨或依序投與。 A tetrabenazine or a pharmaceutically acceptable salt thereof and a p-polypyridine or a pharmaceutically acceptable salt thereof for use in treating an individual suffering from a motor disorder, wherein the tetrabenazine or a pharmaceutically acceptable substance thereof The salt and the polypyridyl or a pharmaceutically acceptable salt thereof are administered simultaneously, separately or sequentially. 如請求項46之丁苯那嗪或其醫藥上可接受之鹽及匹多吡啶或其醫藥上可接受之鹽，其中該運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 The tetrabenazine or a pharmaceutically acceptable salt thereof and the p-polypyridine or a pharmaceutically acceptable salt thereof, wherein the exercise disorder is Huntington's disease, Tourette's syndrome or delayed movement . 一種產品，其含有一含量之丁苯那嗪或其醫藥上可接受之鹽及一含量之匹多吡啶或其醫藥上可接受之鹽用以同時、單獨或依序用於治療患有運動病症之個體。 A product comprising a content of tetrabenazine or a pharmaceutically acceptable salt thereof and a level of p-polypyridine or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use in the treatment of a motor disorder Individual. 如請求項48之產品，其中該運動病症係亨廷頓氏病、圖雷特症候群或遲發性運動困然。 The product of claim 48, wherein the motor condition is Huntington's disease, Tourette's syndrome, or delayed movement.