200920358 九、發明說明： 【發明所屬之技術領域】 本發明係關於治療憂鬱症之方法，其包含向患者投予 治療有效量之加波沙朵（gaboxadol),其中該患者體内— 或多種發炎標記之含量增加或異常。本發明亦係關於治療 壓力介導之憂鬱症之方法，其包含向患者投予治療有效量 之加波沙朵，其中該患者體内一或多種發炎標記之含量增 加或異常。本發明亦係關於一種治療憂鬱症或改善一或多 種憂鬱症狀之方法，其包含向患者投予治療有效量之加波 沙朵，其中一或多種憂鬱症狀之臨床表現為一般醫學病況 之生理效應。此外，本發明亦係關於一種測試化合物在治 療憂鬱症或減少憂鬱症狀中之治療效用之方法，其包含在 向患者投予該化合物之前量測來自該患者之樣本中一或多 種發炎標S己之量，且在向該患者投予該化合物之後與來自 同一患者之樣本中一或多種發炎標記之量比較。 發明背景 【先前技術】 選擇性血清素再吸收抑制劑（selective serotonin reuptake inhibitor，下文稱為SSRI )已成為治療憂鬱症、某 些形式之焦慮症及社交恐懼症之首選治療劑，因為其相較 於傳統三環抗憂鬱劑有效、良好耐受且具有有利安全性概 況。 然而’對憂鬱症及焦慮症之臨床研究表明對sSRI無反 應之比例相當大’高達30%。抗憂鬱治療中通常被忽視之 200920358 另一因素為順應性’此對患者繼續藥物治療之動機具有相 當深遠之影響。 曰益增多之證據表明發炎與憂鬱症之間存在關聯性。 例如已發現一些憂鬱患者具有較高含量之發炎標記，諸如 前發炎細胞因子（proinflammatory cytokine )、急性期蛋白 質（acute Phase P⑽ein )、趨化因子（chem〇kine )及細胞 . 黏附分子（eeUular adhesion molecule)。此外，已發現在 高達50%患者中，治療性投予細胞因子干擾素_α導致憂鬱 症。可促成憂鬱症之壓力（諸如過去情感經歷）亦可藉由 對交感神經及副交感神經系統路徑之影響來促進發炎反應 (Raison 等人，2006, Trends in Immunology，第 27 卷，第 1 期，24-31)。此外，由醫學疾病或由克服疾病或與其有關之 藥物治療所引起的生理壓力，在許多狀況下導致憂#症或 憂鬱症狀。生理壓力亦與較高含量之發炎標記（諸如前發 炎細胞因子、急性期蛋白質、趨化因子及細胞黏附分子） 有關。 上述共同表明，對發炎標記增加的逆轉可能治療具有 增加之發炎標記之患者體内的憂鬱症，尤其壓力介導之憂 鬱症或壓力介導之憂鬱症狀。 加波λ/木（4,5,6,7-四氫異噁唑并[5,4_c]吡啶_3_醇） 1ΤΗΙΡ)，作為—種選擇性突料GABAa促效冑，描述於 2洲專利第〇000338號及歐洲專利第〇84〇6〇1號中，且先 前已顯示治療睡眠障礙之巨大潛力。加波沙朵具有以下通 200920358200920358 IX. Description of the Invention: [Technical Field] The present invention relates to a method for treating depression comprising administering to a patient a therapeutically effective amount of gaboxadol, wherein the patient has one or more inflammatory markers The content is increased or abnormal. The invention is also directed to a method of treating stress mediated depression comprising administering to a patient a therapeutically effective amount of gaboxadol wherein the amount of one or more inflammatory markers in the patient is increased or abnormal. The invention also relates to a method of treating depression or ameliorating one or more symptoms of depression comprising administering to a patient a therapeutically effective amount of gaboxadol, wherein one or more of the clinical manifestations of depression symptoms are physiological effects of a general medical condition. Furthermore, the present invention is also directed to a method of treating a compound for treating a depression or reducing the symptoms of depression, comprising measuring one or more inflammatory markers in a sample from the patient prior to administering the compound to the patient. The amount and the amount of one or more inflammatory markers in a sample from the same patient after administration of the compound to the patient. BACKGROUND OF THE INVENTION [Prior Art] Selective serotonin reuptake inhibitor (hereinafter referred to as SSRI) has become the preferred therapeutic agent for the treatment of depression, some forms of anxiety and social phobia, as it compares It is effective, well tolerated and has a favorable safety profile for traditional tricyclic antidepressants. However, clinical studies of depression and anxiety have shown that the proportion of non-response to sSRI is quite large, up to 30%. Another factor that is often overlooked in antidepressant treatment is 200920358. Another factor is compliance', which has a profound impact on patients' motivation to continue medication. Evidence of increased benefit indicates a link between inflammation and depression. For example, some depressed patients have been found to have high levels of inflammatory markers, such as proinflammatory cytokine, acute phase P(10)ein, chem〇kine, and cells. eeUular adhesion molecule ). In addition, therapeutically administered cytokine interferon-α has been found to cause depression in up to 50% of patients. Stress that can contribute to depression (such as past emotional experiences) can also promote inflammatory responses by affecting the sympathetic and parasympathetic nervous system pathways (Raison et al., 2006, Trends in Immunology, Vol. 27, No. 1, 24 -31). In addition, physiological stress caused by medical diseases or by overcoming diseases or drug treatments associated therewith, in many cases, causes anxiety or depression symptoms. Physiological stress is also associated with higher levels of inflammatory markers such as pro-inflammatory cytokines, acute phase proteins, chemokines, and cell adhesion molecules. The above indicates that an increased reversal of inflammatory markers may treat depression in patients with increased inflammatory markers, especially stress-mediated depression or stress-mediated depression. Addition of λ/wood (4,5,6,7-tetrahydroisoxazo[5,4_c]pyridine-3-ol) 1ΤΗΙΡ), as a selective excipient GABAa agonist, described in 2 continent patents No. 000338 and European Patent No. 84〇6〇1, and have previously shown great potential for treating sleep disorders. Gaposadu has the following pass 200920358
加波沙朵可使用此項技術中熟知 如歐洲專利第0000338號中所揭示。 之方法製備 。例如， 则讓揭示加波沙朵作為單—療法或 其他藥物之組合療法治療憂鬱症之用 ‘、·-Gaboxadol can be used as is well known in the art, as disclosed in European Patent No. 0000,338. Method of preparation. For example, let gaboxadol be disclosed as a combination therapy for monotherapy or other drugs for the treatment of depression ‘,·-
„ 必 坪s之加波沙I 可/、用於治療憂鬱症之血清素再吸收抑制劑（諸如，依： 普蘭（escitalopram))組合。本揭示案因此廣泛描述加: 沙朵作為單一療法或與其他藥物組合治療憂鬱症之用途。 然而，在憂鬱症中存在多種副適應症（subindication) 諸如壓力介導之憂鬱症，其中發炎標記增加或異常。 相較於參考值具有增加之發炎標記或具有異常含量之 發炎標記的憂鬱患者，在某些狀況下可能難以以一些抗憂 鬱化合物治療。造成此困難之一個原因可能為，以抗憂鬱 化合物治療此等患者不能使增加或異常含量之發炎標記正 常化。 因此’需要用於患有憂鬱症（諸如，壓力介導之憂鬱 症）之患者的新穎治療’其中相較於參考值而言，該患者 體内之一或多種發炎標記之含量增加或一或多種發炎標記 之含量異常。 現已發現在憂鬱症模型中，動物體内之發炎標記藉由 使動物暴露於壓力環境而增加，且此發炎標記增加藉由向 200920358 有壓力之動物投予加波沙朵而被逆轉。 【發明内容】 本發明之一態樣係關於治療憂鬱症之方法，其包含向 患者投予治療有效量之加波沙朵，其中該患者體内一或多 種發炎標記之含量增加或異常。 本發明之另一態樣係關於治療壓力介導之憂鬱症之方 法，其包含向患者投予治療有效量之加波沙朵，其中—或 多種發炎標記之含量增加或異常。 本發明之另一態樣係關於一種治療憂鬱症或改善—或 多種憂鬱症狀之方法，其包含向患者投予治療有效量之加 波沙朵’其中一或多種憂鬱症狀之臨床表現為一般醫學病 況之生理效應。 本發明之另一態樣係關於一種測試化合物在治療憂營 症或減少憂鬱症狀中之治療效用之方法，其包含在向患者 投予該化合物之前量測來自該患者之樣本中一或多種發炎 標記之量，且在向該患者投予該化合物之後與來自同一患 者之樣本中一或多種發炎標記之量比較。 本發明之另一態樣係關於治療憂鬱症之方法，其包含 以下步驟： a •測义來自患者之樣本中一或多種發炎標記之量，且將 該量與該—或多種發炎標記之參考值比較； 人汰若該一或多種發炎標記之量相較於該等參考值為異 系’則向該患者投予治療有效量之加波沙朵。 本發明之另一態樣係關於加波沙朵之用途，其係用於 200920358 製備用以治療患有憂鬱症之患者的醫藥組合物，其中該串 者體内一或多種發炎標記之含量增加或異常。 本發明之另一悲樣係關於加波沙朵之用途，其係用於 製備用以治療患有壓力介導之憂鬱症之患者的醫藥組合 物，其中該患者體内一或多種發炎標記之含量增加或異常。 本發明之另一態樣係關於加波沙朵之用途，其係用於 製備用以治療患有憂鬱症之患者或改善患者的一或多種憂 鬱症狀之醫藥組合物，其中一或多種憂鬱症狀之臨床表現 為一般醫學病況之生理效應。 本發明之另一態樣係關於加波沙朵之用途，其係用於 治療患有憂鬱症之患者的方法中，其中該患者體内一或多 種發炎標記之含量增加或異常。 本發明之另一態樣係關於加波沙朵之用途，其係用於 治療患有壓力介導之憂鬱症之患者的方法中，其中該患者 體内一或多種發炎標記之含量增加或異常。 本發明之另一態樣係關於加波沙朵，其係用於治療患 有憂繫症之患者或改善患者的一或多種憂鬱症狀之方法 一般醫學病況之 中，其中一或多種憂鬱症狀之臨床表現為 生理效應。 【實施方式】 發明之敘述 在WO2004U2786中，加波沙朵先前已被證實在動物 模型中具有抗憂鬱作用。在新穎實驗系列中，吾人研究了 加波沙朵在憂鬱症之動物模型中對發炎榡記的影響。此動 10 200920358 物模型使用慢性溫和不可預測之壓力（chr〇nic mild unpredictive stress )在動物中誘導快感缺乏狀態（anhed〇nic state)，此狀態可由治療活性抗憂鬱劑逆轉。令人驚奇地， 加波沙朵獨立給藥能夠使多數慢性溫和壓力誘導之細胞因 子合量的變化逆轉，表明在壓力有關病況下的強消炎作 用。此作用僅在細胞因子含量不同於對照動物之動物體内 出現，且因此為發炎系統變化的後果且非一般作用（ effect)。加波沙朵因此能夠特異性地使發炎標記，諸如具 有異常細胞因子含量之動物體内的細胞因子含量正常化。 因為若干與壓力有關之疾病以細胞因子含量的較大改變作 為潛伏病況之一部分，所以本發明者提議加波沙朵在此等 特定病況中將具有優於當前治療的治療優勢，當前治療一 般不影響細胞因子含量。設想細胞因子含量正常化以預測 增加之反應率、增加之功效水準及降低之緩解率。 定義 術語「壓力介導之憂鬱柠 Qdf . ^ ^ 震臀足」有時亦稱為壓力誘導之憂 鬱症，係指由患者之過去情感經歷及/或生理壓力（諸如醫 學疾病或與醫學疾病有關之藥物治療）引起的憂鬱症，其 中一或多種發炎標記增加或異常。 術語「來自患者之樣本」係沪Α ώ虫& η Α 」係私來自患者之生物樣本， 且意欲包括自患者分離之组織 、職•細胞、生物體液（諸如血 次及其分離物）以及存於患者 百體内之組織、細胞及體液。 如本文所用，術語「患者仫 ,, 」係扣任何哺乳動物。待以 加波沙朵治療之患者（諸如人類） 貝J貫際上可為人類群體之 200920358„ 坪 s 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 The use of other drug combinations for the treatment of depression. However, there are various subindications in depression such as stress-mediated depression, in which the inflammatory markers are increased or abnormal. Compared with the reference value, there is an increased inflammatory mark or has Depressed patients with abnormal levels of inflammatory markers may be difficult to treat with some antidepressant compounds under certain conditions. One reason for this difficulty may be that treatment with antidepressant compounds does not result in increased or abnormal levels of inflammatory markers. Therefore, 'requires novel treatment for patients suffering from depression (such as stress-mediated depression), where the content of one or more inflammatory markers in the patient is increased or compared to the reference value Abnormal content of one or more inflammatory markers. It has been found that in the depression model, the inflammatory markers in animals are Exposure of the animal to a stressful environment increases, and this increase in inflammatory markers is reversed by administering gaboxadol to a stressed animal in 200920358. [Invention] One aspect of the present invention relates to a method of treating depression. A method comprising administering to a patient a therapeutically effective amount of gaboxadol, wherein the amount of one or more inflammatory markers in the patient is increased or abnormal. Another aspect of the invention is a method of treating stress-mediated depression comprising Therapeutic effective amount of gaboxadol is administered to the patient, wherein the content of the inflammatory marker is increased or abnormal. Another aspect of the invention relates to a method of treating depression or ameliorating - or a plurality of depression symptoms, comprising The patient is administered a therapeutically effective amount of gaboxadol's clinical manifestation of one or more of the symptoms of depression as a physiological effect of a general medical condition. Another aspect of the invention relates to a test compound for treating sorrow or reducing depression symptoms A method of therapeutic utility comprising measuring one or more of a sample from the patient prior to administering the compound to the patient The amount of inflammation is labeled and compared to the amount of one or more inflammatory markers in a sample from the same patient after administration of the compound to the patient. Another aspect of the invention relates to a method of treating depression comprising the following steps : a • Measure the amount of one or more inflammatory markers in the sample from the patient and compare the amount to the reference value of the one or more inflammatory markers; if the amount of the one or more inflammatory markers is compared to such The reference value is heterologous' then the patient is administered a therapeutically effective amount of gaboxadol. Another aspect of the invention relates to the use of gaboxadol for the treatment of patients suffering from depression in 200920358. A pharmaceutical composition wherein the content of one or more inflammatory markers in the string is increased or abnormal. Another sorrow of the present invention relates to the use of gaboxadol for the preparation of a medicament for the treatment of stress-mediated A pharmaceutical composition for a patient suffering from depression, wherein the amount of one or more inflammatory markers in the patient is increased or abnormal. Another aspect of the invention relates to the use of gaboxadol for the preparation of a pharmaceutical composition for treating a patient suffering from depression or for ameliorating one or more symptoms of depression in a patient, wherein one or more symptoms of depression Clinical manifestations are the physiological effects of general medical conditions. Another aspect of the invention relates to the use of gaboxadol for the treatment of a patient suffering from depression, wherein the amount of one or more inflammatory markers in the patient is increased or abnormal. Another aspect of the invention relates to the use of gaboxadol for the treatment of a patient suffering from stress-mediated depression, wherein the patient has an increased or abnormal level of one or more inflammatory markers. Another aspect of the present invention relates to gaboxadol, which is a method for treating a patient suffering from a worry or ameliorating one or more symptoms of depression in a general medical condition, wherein one or more clinical symptoms of depression It manifests as a physiological effect. [Embodiment] Description of the Invention In WO2004U2786, gaboxadol has previously been shown to have an antidepressant effect in animal models. In the novel experimental series, we studied the effect of gaboxadol on inflammatory melancholia in an animal model of depression. This model uses a chronically unpredictive stress (chr〇nic mild unpredictive stress) to induce an anhed〇nic state in an animal that can be reversed by a therapeutically active antidepressant. Surprisingly, independent administration of gaboxadol reversed most of the changes in cytokine induced by chronic mild stress, indicating a strong anti-inflammatory effect in stress-related conditions. This effect occurs only in animals with cytokine levels different from those of control animals, and is therefore a consequence of changes in the inflammatory system and is not a general effect. Gaboxadol is therefore capable of specifically normalizing inflammatory markers, such as cytokine levels in animals with abnormal cytokine levels. Since several stress-related diseases are part of a latent condition with a large change in cytokine content, the inventors propose that gaboxadol will have a therapeutic advantage over current treatments in such specific conditions, and current treatment generally does not affect Cytokine content. It is envisaged that the cytokine content is normalized to predict an increased response rate, an increased level of efficacy, and a reduced rate of remission. Defining the term "pressure-mediated melancholic lime Qdf. ^ ^ shock-hip foot" is sometimes referred to as stress-induced depression, which refers to past emotional experiences and/or physiological stress (such as medical illness or medical disease) The drug is caused by depression, in which one or more inflammatory markers are increased or abnormal. The term "sample from a patient" is a biological sample from a patient, and is intended to include tissue, cells, biological fluids (such as blood and its isolates) isolated from the patient. And tissues, cells and body fluids stored in the body of the patient. As used herein, the term "patient 仫 , , " is used to bind any mammal. Patients treated with gaboxadol (such as humans) can be used as human groups in 200920358
B 任何個體（男性或女性），其可分為兒童、成人或老人。 此等患者群體中之任_者係關於本發明之具體實例。在一 八體實例+自體為老年人類。在__具體實例中，個體未 罹患睡眠障礙或睡眠病況。 如本文所用，術語Γ治療有效量」係指在向患者投予 時足以產生有效反應（亦即，研究者、獸醫、醫生或臨床 醫生所探尋之組織、系統、動物或人類的生物或醫學反應) 之化合物或醫藥組合物的量/劑量。「治療有效量」將尤其 視疾病及其嚴重程度，待治療之患者的年齡、體重、身體 狀況及反應性而改變。此外，若本發明化合物與一或多種 化合物組合，則「治療有效量」可改變，在該狀況下，給 定化合物之量可能降低（諸如次有效量（sub_effective amount) ) ° 如本文所用，術語「治療」係指防止或延遲疾病或病 況之臨床,症狀在可能受該疾病或病況折冑以患該疾病或 病況，但尚未經歷或表現該疾病或病況之臨床或次臨床症 狀的患者體内出現。「治療」亦係指抑制疾病或病況，亦 即延遲或減慢其發展或其至少一種臨床或次臨床症狀。「治 療」此外係指減輕疾病或病況，亦即引起疾病或病況或其 至少一種臨床或次臨床症狀衰退。對待治療之患者的益處 為統计學顯著的或至少為患者及/或醫師可察覺到的。儘管 如此，預防性及治療性治療仍為本發明之兩個單獨具禮實 例。 如本文所用，術語「醫藥學上可接受」係指「一般認 12 200920358 為安全」之分子實體及組合物 —例如在向人類投予時為B Any individual (male or female) that can be divided into children, adults or the elderly. Any of these patient groups are specific examples of the invention. In the eight-body instance + self-aged for the elderly. In the __ specific example, the individual does not suffer from sleep disorders or sleep conditions. As used herein, the term "therapeutically effective amount" means a biological or medical response sufficient to produce an effective response when administered to a patient (ie, a tissue, system, animal or human being sought by a researcher, veterinarian, doctor or clinician). The amount/dosage of the compound or pharmaceutical composition. The "therapeutically effective amount" will vary depending on the disease and its severity, the age, weight, physical condition and reactivity of the patient to be treated. Furthermore, a "therapeutically effective amount" may vary if a compound of the invention is combined with one or more compounds, in which case the amount of a given compound may be reduced (such as a sub-effective amount) ° as used herein, the term "Treatment" means the clinical prevention or delay of a disease or condition in which a patient is suffering from a disease or condition that is afflicted with the disease or condition but has not experienced or manifested clinical or subclinical symptoms of the disease or condition. appear. "Treatment" also refers to the inhibition of a disease or condition, that is, delaying or slowing its progression or at least one of its clinical or subclinical symptoms. "Treatment" also refers to alleviating a disease or condition, i.e., causing a disease or condition or a decline in at least one of its clinical or subclinical symptoms. The benefit to the patient being treated is statistically significant or at least detectable by the patient and/or physician. Despite this, prophylactic and therapeutic treatments are still two separate examples of the invention. As used herein, the term "pharmaceutically acceptable" means a molecular entity and composition "generally recognized 12 200920358 is safe" - for example, when administered to humans
胃部不適（gastric upset)及其類似者）。 “乂不艮反應（諸如 。在另一具體實例 中，此術語係指由聯邦之管理機構或州政府核准的或美國 藥典或另一一般公認藥典所列的用於動物，且尤其人類之 分子實體及組合物。 醫師可判定一或多種發炎標記之含量是否增加或異 常。此判定係基於醫師的聽診且可基於與參考值的比較， 諸如來自健康個體的參考值^在一些狀況下，發炎標記含 量之模式決定發炎標記含量是否異常。在醫師判斷中通常 亦考慮以下因素，諸如相關環境，包括待治療之病況、患 者的年齡、體重、性別、遺傳背景及種族。在本發明之一 個具體實例中，若發炎標記與例如來自健康個體的參考值 相差超過1%，或超過5%，或超過1〇% ,或超過15%，或 超過20%，或超過25%，或超過3〇%，或超過35%，或超 過40%，或超過45%，或超過50°/。，或超過55°/。，或超過 60% ’或超過65% ’或超過70% ’或超過75% ,或超過8〇%， 或超過85%，或超過90%，或超過95❶/。，或超過1〇〇❶/◦，或 超過1 50°/❶，則該發炎標記增加或異常。 可根據本發明治療之病症根據已確立且已接受之分類 已知’該等分類可在各種來源中發現。舉例而言，目前， 《精神疾病診斷與統計手冊》（Diagnostic and StatisticalGastric upset and the like). "In case of a specific example, this term refers to a molecule approved by the federal regulatory agency or state government or listed in the US Pharmacopoeia or another generally recognized pharmacopoeia for use in animals, and especially humans. Entities and compositions. The physician can determine whether the content of one or more inflammatory markers is increased or abnormal. This determination is based on the auscultation of the physician and can be based on comparisons with reference values, such as reference values from healthy individuals, in some cases, inflammation The mode of labeling content determines whether the inflammatory labeling content is abnormal. The following factors are generally considered in the judgment of the physician, such as the relevant environment, including the condition to be treated, the age, weight, sex, genetic background and ethnicity of the patient. In the example, if the inflammatory marker differs from, for example, a reference value from a healthy individual by more than 1%, or more than 5%, or more than 1%, or more than 15%, or more than 20%, or more than 25%, or more than 3% , or more than 35%, or more than 40%, or more than 45%, or more than 50 ° /., or more than 55 ° /., or more than 60% 'or more than 65% ' or more than 70% ' More than 75%, or more than 8%, or more than 85%, or more than 90%, or more than 95 ❶ /, or more than 1 〇〇❶ / ◦, or more than 1 50 ° / ❶, the inflammatory mark is increased or abnormal The conditions that can be treated according to the invention are known from established and accepted classifications. 'The classifications can be found in a variety of sources. For example, currently, Diagnostic and Statistical
Manual of Mental Disorders) (DSM-IVtm) (2000，華盛頓特 £ 美國心理協會（American Psychiatric Association， 13 200920358Manual of Mental Disorders) (DSM-IVtm) (2000, Washington, USA £ American Psychiatric Association, 13 200920358
Washington，D.C·))之第4版提供用於識別本文所述之許多 病症的診斷工具。同樣，國際疾病分類第十版（Internati〇nalThe fourth edition of Washington, D.C.)) provides diagnostic tools for identifying many of the conditions described herein. Similarly, the tenth edition of the International Classification of Diseases (Internati〇nal
Classification of Diseases, Tenth Revision) (ICD-10)提供本 文所述之許多病症的分類。熟習此項技術者將認識到存在 本文所述之病症的替代命名法、疾病分類學及分類系統， 包括DMS-IV及ICD-10中所述之彼等，且術語學及分類系 統隨醫學科學之進步而發展。此外，科學文獻亦給出關於 病症之疋義’例如 Rydmark 等人，Bi〇i〇gicai Psychiatry， 2006, 00, 867-8 73 中描述了 過勞症（burn-out)。 在本說明書全文中，「加波沙朵」意欲包括化合物之 任何形式，諸如游離鹼（兩性離子）、醫藥學上可接受之 鹽（例如醫藥學上可接受之酸加成鹽）、鹼或鹽之水合物 或溶劑合物以及無水物，亦及非晶形式或結晶形式。 在另一具體實例中，加波沙朵選自兩性離子，通常為 其水合物，儘管無水物亦合適。合適具體實例為兩性離子 早水合物。 在另一具體實例中，加波沙朵選自酸加成鹽，通常為 醫藥學上可接受之酸加成鹽。合適具體實例為有機酸加成 鹽，諸如順丁烯二酸加成鹽、反丁烯二酸加成鹽、苯甲酸 加成鹽、抗壞血酸加成鹽、丁二酸加成鹽、草酸加成鹽、 雙亞曱基水楊酸加成鹽、曱烷磺酸加成鹽、乙烷二磺酸加 成鹽、乙酸加成鹽、丙酸加成鹽、酒石酸加成鹽、水揚酸 加成鹽、檸檬酸加成鹽、葡萄糖酸加成鹽、乳酸加成鹽、 蘋果酸加成鹽、扁桃酸加成鹽、肉桂酸加成鹽、檸康酸加 200920358 m 成鹽、天冬胺酸加成鹽、硬脂酸加成鹽、棕櫊酸加成鹽、 衣康酸加成鹽、乙醇酸加成鹽、對胺基苯甲酸加成鹽、麩 胺酸加成鹽、苯磺酸加成鹽或茶鹼乙酸加成鹽以及8-鹵基 舍驗（例如8 -漠-茶驗）乙酸加成鹽中之任一者。另一合適 具體實例為無機酸加成鹽，諸如鹽酸加成鹽、氫溴酸加成 鹽、硫酸加成鹽、胺磺酸加成鹽、磷酸加成鹽或硝酸加成 鹽中之任一者。 在另一具體實例中，加波沙朵為鹽酸鹽、氫溴酸鹽或 兩性離子單水合物形式。 在另一具體實例中’加波沙朵為結晶，諸如結晶鹽酸 鹽、結晶氫溴酸鹽或結晶兩性離子單水合物。 可藉由在惰性溶劑中以酸處理加波沙朵，隨後藉由已 知方法沈澱、分離及視情況再結晶，且若需要則藉由濕式 或乾式研磨或另一便利方法使結晶產物微粉化，或自溶劑 乳化過程製備微粒，來獲得本發明之酸加成鹽。合適方法 (例如）描述於歐洲專利第〇〇〇〇338號中。 鹽的沈澱通常在惰性溶劑，例如惰性極性溶劑，諸如 醇（例如，乙醇、2·丙醇及正丙醇）中進行，但亦可使用水 或水與惰性溶劑之混合物。 在本發明之另一具體實例中，發炎標記或細胞因子選 :包含以下者之群：脂蛋白元A1 (APolipGpr〇tein Ap〇 1) 、/3 2 微球蛋白（Beta_2 Micr〇gl〇bulin)、凝聚素 (ClUSterin)、C 反應蛋白（C Reactive protein，CRp)、 、*蛋白酶抑制子_C ( Cystatin_c )、嗜酸性粒細胞趨化因子 15 200920358 — (Eotaxin)、因子VII (Factor VII)、纖維母細胞生長因 子-9 ( Fibroblast Growth Factor-9，FGF-9 )、顆粒球趨化蛋 白-2 ( Granulocyte Chemotactic Protein-2，GCP-2 )、生長 激素（Growth Hormone)、免疫球蛋白 A (Immunoglobulin A，IgA)、介白素-10 (Interleukin-10，lL-l〇)、介白素 冷（IL-1 /3 )、介白素-2 ( IL-2)、介白素·4 ( IL_4)、介 白素-5( IL-5 )、胰島素（Insulin)、可誘導性蛋白_1〇( Inducible Protein-10，IP-10 )、瘦素（Leptin )、白血病抑制因子 (Leukemia Inhibitory Factor，LIF )、巨噬細胞產生之趨化 因子（Macrophage-Derived Chemokine，MDC )、巨嗤細胞 發炎蛋白-1 α ( Macrophage Inflammatory Protein-1 alpha， MIP-1 a)、巨噬細胞發炎蛋白-1/5( MIP-1冷）、巨噬細 胞發炎蛋白-1 Τ ( MIP-1 r )、巨噬細胞發炎蛋白-2( MIP-2 )、 巨噬細胞發炎蛋白-3 /3 ( MIP-3 /3)、髓過氧化物酶 (Myeloperoxidase，MPO)、肌紅蛋白（Myoglobin)、嗜 中性球明勝酶相關脂籠蛋白 （neutrophil gelatinase-associated lipocalin ， NGAL ) (月旨窥蛋白-2 (Lipocalin-2 ))、制瘤素 M ( Oncostatin M，OSM )、骨 橋蛋白（Osteopontin )、血清殺粉樣蛋白p ( Serum Amyloid P 5 SAP )、幹細胞因子（Stem Cell Factor，SCF ) 、jk 清 楚胺酸-草乙酸轉胺酶（Serum Glutamic-Oxaloacetic Transaminase ’ SGOT )、1型金屬蛋白酶之組織抑制子（Tissue Inhibitor of Metalloproteinase Type-1，TIMP-1)、組織因 子（Tissue Factor )、血小板生成素（Thrombopoietin，TPO ) 16 200920358 0 及血官内皮細胞生長因子（Vascuiar End〇thelial cell Growth Factor，VEGF ) 〇 在本發明之另一具體實例中，加波沙朵之治療有效量 在每天1 mg至20 mg加波沙朵，諸如每天5 mg至15 mg 加波沙朵之範圍内。 在本發明之另一具體實例中，加波沙朵係作為口服劑 型投予。 在本發明之另一具體實例中，加波沙朵為固體口服劑 型’諸如錠劑或膠囊，或液體口服劑型。 在本發明之另一具體實例中，加波沙朵為結晶。 在本發明之另一具體實例中，患者為人類。 在本發明之另一具體實例中，該患者被另外投予治療 有效量之依地普蘭或其醫藥學上可接受之鹽。在另一具體 實例中，依地普蘭之醫藥學上可接受之鹽為依地普蘭之草 酸鹽、HC1鹽或HBr鹽。 在本發明之另一具體實例中，待治療患者體内的一或 多種發炎標記之含量增加或異常。 在本發明之另一具體實例中，該壓力介導之憂營症係 由與工作有關之憂鬱症、過勞、慢性疲勞症候群、創傷後 壓力症（Post traumatic stress disorder，PTSD )、衰竭性疲 勞（exhaustion fatigue )、衰竭性憂鬱症或急性壓力症（acute stress disorder，ASD)引起。 在本發明之另一具體實例中’該壓力係由（諸如離 婚）、自然災害、貧困、人際關係衝突、喪親 '應付醫學 17 200920358 疾病或失業之過去情感經歷引起。 在本發明之另一具體實例中，該壓力為生理壓力，諸 如醫學疾病或與醫學疾病有關之藥物治療。 在本發明之另一具體實例中，該醫學疾病為多發性硬 化症；中風；甲狀腺功能低下（hypothyroidism );糖尿病， 諸如1型或2型糖尿病；心臟病，諸如急性心肌梗塞或心 絞痛；癌症；HIV感染或愛滋病（AIDS );神經性病症， 諸如腦血管病症、帕金森氏症（Parkinson’s Disease);創 傷性腦損傷；中風，諸如涉及背外側額葉皮質（dorsal lateral frontal cortex )之左大腦半球中風；慢性疲勞症候群；纖維 肌痛症（fibromyalgia );神經分泌異常（neur〇crine abnormalities)，諸如皮質醇（cortis〇i)及/或促皮質素釋 放激素（corticotropin-releasing hormone)分泌增加；接受 細胞因子’諸如干擾素-α及/或介白素_2之患者；創傷後壓 力症（PTSD );過勞；與工作有關之憂鬱症；衰竭性疲勞； I"又性疼痛病況；血脂異常（dySiipidemia );輕鬱症 (dysthymia );發炎疾病；衰竭性憂鬱症或急性壓力症 (ASD)。 在本發明之另一具體實例中，該一般醫學病況為多發 性硬化症；中風；甲狀腺功能低下；糖尿病，諸如丨型或2 型糖尿病；心臟病’諸如急性心肌梗塞或心絞痛；癌症； HIV感染或aIDS ;神經性病症，諸如腦血管病症、帕金森 氏症，創傷性腦損傷；中風，諸如涉及背外側額葉皮質之 左大腦半球中風，慢性疲勞症候群；纖維肌痛症；神經分 18 200920358 泌異常，諸如皮質酵及/或促皮質素釋放激素分泌增加；接 受細胞因子’諸如干擾素-α及/或介白素_2之患者；創傷後 壓力症（PTSD );過勞；與工作有關之憂鬱症；衰竭性疲 勞；慢性疼痛病況；血脂異常；輕鬱症；發炎<疾病；衰竭 性憂鬱症或急性壓力症（ASD )。 在本發明之另一具體實例中，待測試治療效用之化合 物選自抗憂鬱化合物，諸如SSRI、SNRI或由政府機構（諸 如，FDA核准用於該用途的其他抗憂鬱化合物。在本發明 之另一具體實例中，此化合物為加波沙朵。 在本發明之另一具體實例中，醫藥组合物包含1 mg至 2〇 mg，諸如5 mg至15 mg加波沙朵。在本發明之另一具 體實例中，醫藥組合物為口服劑型。在本發明之另一具體 實例中，醫藥組合物為固體口服劑型，諸如錠劑或膠囊， 或液體口服劑型。在本發明之另一具體實例中，醫藥組合 物另外包含依地普蘭或其醫藥學上可接受之鹽。在本發明 之另-具體實例中，依地普蘭之醫藥學上可接受之鹽為依 地普蘭之草酸鹽、HC1鹽或HBr鹽。 在本發明之一具體實例中，加波沙朵係用於維持療法 (maintenance therapy ) 〇 調配物 加波沙朵可作為口服劑型，諸如固體口服劑型，通常 錠劑或膠囊，或作為液體口服劑型投予。加波沙朵可以速 釋（immediate release)劑型或控釋（c〇ntr〇Ued 代卜牡“） 劑型或緩釋（sustained release )劑型投予。根據一具體實 200920358 例，劑型以低於睡眠誘導量之量提供加波沙朵之控釋或、緩 釋。加波沙朵可以每天約〇. 1至約150 mg ’每天約0.2至約 100 mg，每天約0.5至約50 mg，每天約0.1至約5〇 mg， 每天約1至約15 mg或每天約2至約5 mg之量，以含有活 性成份的單位劑型，諸如錠劑或膠囊，便利地經口投予。 通常’醫藥組合物包含約〇·5 mg至約20 mg，諸如約〇 5 mg，約 1 mg，約 1.5 mg，约 2 mg，約 2.5 mg ,約 3 mg， 約 3.5 mg，約 4 mg，約 4.5 mg，約 5 mg，約 5.5 mg，約 6 mg，約 6.5 mg，約 7 mg，約 7.5 mg，約 8 mg，約 8.5 約 9 mg，約 9.5 mg ,約 1〇 mg，約 10.5 mg，約 u mg，約 11.5 mg，約 12 mg，約 12·5 mg，約 13 mg，約 13.5 mg， 約 14 mg，約 14.5 mg，約 15 mg，約 15_5 mg，約 i6 mg， 約 16·5 mg，約 17 mg，約 17.5 mg，約 18 mg，約 18.5 %， 約19 mg，約19 5 mg或約2〇 mg的加波沙朵。加波沙朵之 里係基於游離鹼（兩性離子）形式計算。 在—具體實例中，加波沙朵係使用約丨mg至約2〇 之劑里每日一次投予（例如，早晨或下午）。在另-具體 實例中，加波沙朵係使用非睡眠誘導濃度之加波沙朵（例 以低劑量每天投予2·3次）或使用此項技術中已知的習 約^法製備之修飾釋放調配物（使得每24小時向個體投予 予。=約5〇 mg加波沙杀）以更持久且持續釋放的方式投 另-具體實例中，加波沙杂係以低於睡眠誘導量之 重守又予。 根據本發明，加波沙朵或其醫藥學上可接受之鹽可以 20 200920358 任何合適方式（例如，經口 ^ ^ 7 次非經腸）投予，且其可以適 於該投予之任何形式提供 將如+ 飞故供例如為錠劑、膠囊、散劑、糖 漿劑或用於注射之泼七人 耵之冷液或分散液形式。在另一具體實例 中支且根據本發明之㈣，加波沙朵為❹作錠劑或膠囊 用於注射之料液、溶液或分散液的形式投予的固體 醫藥實體形式。此外’加波沙朵可與醫藥學上可接受之載 劑，諸如佐劑及/或稀釋劑一起投予。 用於製備固體或液體醫藥製劑之方法為此項技術中所 Remington: The Science and Practice ofClassification of Diseases, Tenth Revision) (ICD-10) provides a breakdown of many of the conditions described herein. Those skilled in the art will recognize that there are alternative nomenclature, disease taxonomy, and classification systems for the disorders described herein, including those described in DMS-IV and ICD-10, and the terminology and classification system along with the medical sciences. Progress and development. In addition, the scientific literature also gives a description of the meaning of the disease. For example, Rydmark et al., Bi〇i〇gicai Psychiatry, 2006, 00, 867-8 73 describe burn-out. Throughout the specification, "gaboxadol" is intended to include any form of the compound, such as a free base (zwitterion), a pharmaceutically acceptable salt (eg, a pharmaceutically acceptable acid addition salt), a base or a salt. Hydrates or solvates and anhydrates, as well as amorphous or crystalline forms. In another embodiment, gaboxadol is selected from the group consisting of zwitterions, usually hydrates thereof, although anhydrate is also suitable. A suitable specific example is a zwitterionic early hydrate. In another embodiment, gaboxadol is selected from the group consisting of acid addition salts, typically pharmaceutically acceptable acid addition salts. Suitable specific examples are organic acid addition salts such as maleic acid addition salts, fumaric acid addition salts, benzoic acid addition salts, ascorbic acid addition salts, succinic acid addition salts, oxalic acid addition salts Salt, bis-indenyl salicylic acid addition salt, decane sulfonic acid addition salt, ethane disulfonic acid addition salt, acetic acid addition salt, propionic acid addition salt, tartaric acid addition salt, salicylic acid addition Salt formation, citric acid addition salt, gluconic acid addition salt, lactic acid addition salt, malic acid addition salt, mandelic acid addition salt, cinnamic acid addition salt, citraconic acid plus 200920358 m salt, aspartame Acid addition salt, stearic acid addition salt, palmitic acid addition salt, itaconic acid addition salt, glycolic acid addition salt, p-aminobenzoic acid addition salt, glutamic acid addition salt, benzenesulfonate An acid addition salt or a theophylline acetic acid addition salt and an 8-halo group test (for example, an 8-iso-tea test) acetic acid addition salt. Another suitable specific example is a mineral acid addition salt such as a hydrochloric acid addition salt, a hydrobromic acid addition salt, a sulfuric acid addition salt, an amine sulfonic acid addition salt, a phosphoric acid addition salt or a nitric acid addition salt. By. In another embodiment, gaboxadol is in the form of a hydrochloride, hydrobromide or zwitterionic monohydrate. In another embodiment, gaboxadol is crystalline, such as crystalline hydrochloride, crystalline hydrobromide or crystalline zwitterionic monohydrate. The gaboxadol can be treated with an acid in an inert solvent, followed by precipitation, separation and, where appropriate, recrystallization by known methods, and if desired, micronization of the crystalline product by wet or dry milling or another convenient method. The microparticles are prepared from a solvent emulsification process to obtain the acid addition salt of the present invention. A suitable method (for example) is described in European Patent No. 338. The precipitation of the salt is usually carried out in an inert solvent such as an inert polar solvent such as an alcohol (e.g., ethanol, 2. propanol and n-propanol), but water or a mixture of water and an inert solvent may also be used. In another embodiment of the invention, the inflammatory marker or cytokine is selected from the group consisting of lipoprotein A1 (APolipGpr〇tein Ap〇1) and /3 2 microglobulin (Beta_2 Micr〇gl〇bulin) , ClUSterin, C Reactive protein (CRp), , * protease inhibitor _C ( Cystatin_c ), eosinophil chemokine 15 200920358 — (Eotaxin), Factor VII (Factor VII), Fibroblast Growth Factor-9 (FGF-9), Granulocyte Chemotactic Protein-2 (GCP-2), Growth Hormone, Immunoglobulin A ( Immunoglobulin A, IgA), Interleukin-10 (lL-l〇), Interleukin Cold (IL-1 /3), Interleukin-2 (IL-2), Interleukin-4 (IL_4), interleukin-5 (IL-5), insulin (Insulin), inducible protein-1 (IP-10), leptin (Leptin), leukemia inhibitor (Leukemia Inhibitory) Factor, LIF), macrophage-Derived Chemokine (MDC), giant cell cell hair Macrophage Inflammatory Protein-1 alpha (MIP-1 a), macrophage inflammatory protein-1/5 (MIP-1 cold), macrophage inflammatory protein-1 Τ (MIP-1 r ), Macrophage Inflammatory Protein-2 (MIP-2), Macrophage Inflammatory Protein-3 /3 (MIP-3 /3), Myeloperoxidase (MPO), Myoglobin, Myopia Neutrophil gelatinase-associated lipocalin (NGAL) (Lipocalin-2), Oncostatin M (OSM), Osteopontin, Serum Amyloid P 5 SAP, Stem Cell Factor (SCF), jk, Serum Glutamic-Oxaloacetic Transaminase (SGOT), Tissue of Type 1 Metalloproteinase Tissue Inhibitor of Metalloproteinase Type-1 (TIMP-1), Tissue Factor, Thrombopoietin (TPO) 16 200920358 0 and Vascuiar End〇thelial Cell Growth Factor (Vascuiar End〇thelial Cell Growth Factor, VEGF) 〇 in this hair In another embodiment the therapeutically effective amount of gaboxadol per day at 1 mg to 20 mg of gaboxadol, gaboxadol such as the range of 5 mg to 15 mg per day. In another embodiment of the invention, gaboxadol is administered as an oral dosage form. In another embodiment of the invention, gaboxadol is a solid oral dosage form such as a lozenge or capsule, or a liquid oral dosage form. In another embodiment of the invention, gaboxadol is crystalline. In another embodiment of the invention, the patient is a human. In another embodiment of the invention, the patient is additionally administered a therapeutically effective amount of escitalopram or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutically acceptable salt of escitalopram is an edetate, HCl salt or HBr salt. In another embodiment of the invention, the amount of one or more inflammatory markers in the patient to be treated is increased or abnormal. In another embodiment of the present invention, the stress-mediated depression is caused by work-related depression, overwork, chronic fatigue syndrome, post traumatic stress disorder (PTSD), and exhaustive fatigue. (exhaustion fatigue), failure depression or acute stress disorder (ASD). In another embodiment of the invention, the stress is caused by a past emotional experience (such as divorce), natural disasters, poverty, interpersonal conflicts, bereavement, and illness or unemployment. In another embodiment of the invention, the pressure is a physiological stress, such as a medical condition or a medical treatment associated with a medical condition. In another embodiment of the invention, the medical condition is multiple sclerosis; stroke; hypothyroidism; diabetes, such as type 1 or type 2 diabetes; heart disease, such as acute myocardial infarction or angina; cancer; HIV infection or AIDS (AIDS); neurological disorders such as cerebrovascular disorders, Parkinson's Disease; traumatic brain injury; stroke, such as the left cerebral hemisphere involving the dorsal lateral frontal cortex Stroke; chronic fatigue syndrome; fibromyalgia; neurosecretion (neur〇crine abnormalities), such as cortisol (cortis〇i) and / or corticotropin-releasing hormone secretion increased; Cytokines such as patients with interferon-α and/or interleukin-2; post-traumatic stress disorder (PTSD); overwork; work-related depression; exhaustive fatigue; I"sexual pain conditions; dyslipidemia (dySiipidemia); dysthymia; inflammatory disease; depressive depression or acute stress disorder (ASD). In another embodiment of the invention, the general medical condition is multiple sclerosis; stroke; hypothyroidism; diabetes, such as sputum or type 2 diabetes; heart disease such as acute myocardial infarction or angina; cancer; Or aIDS; neurological disorders, such as cerebrovascular disease, Parkinson's disease, traumatic brain injury; stroke, such as left cerebral hemisphere stroke involving the dorsolateral frontal cortex, chronic fatigue syndrome; fibromyalgia; nerves 18 200920358 Abnormal secretions, such as increased secretion of corticulin and/or corticotropin-releasing hormone; patients receiving cytokines such as interferon-α and/or interleukin-2; post-traumatic stress disorder (PTSD); overwork; Related depression; exhaustive fatigue; chronic pain conditions; dyslipidemia; mild depression; inflammation <disease; failure depression or acute stress disorder (ASD). In another embodiment of the invention, the compound to be tested for therapeutic utility is selected from the group consisting of antidepressants, such as SSRI, SNRI, or other antidepressant compounds approved by government agencies such as the FDA for use in this application. In a specific embodiment, the compound is gaboxadol. In another embodiment of the invention, the pharmaceutical composition comprises from 1 mg to 2 mg, such as from 5 mg to 15 mg gaboxadol. Another specific embodiment of the invention In an embodiment, the pharmaceutical composition is an oral dosage form. In another embodiment of the invention, the pharmaceutical composition is a solid oral dosage form, such as a lozenge or capsule, or a liquid oral dosage form. In another embodiment of the invention, the pharmaceutical The composition additionally comprises escitalopram or a pharmaceutically acceptable salt thereof. In another embodiment of the invention, the pharmaceutically acceptable salt of escitalopram is edetranol oxalate, HCl salt or HBr salt. In one embodiment of the invention, gaboxadol is used in maintenance therapy. The bismuth formulation plus poloxadol can be used as an oral dosage form, such as a solid oral dosage form. It is usually administered as a lozenge or capsule, or as a liquid oral dosage form. Gaporafil can be administered as an immediate release dosage form or as a controlled release (c〇ntr〇Ued 代卜) or sustained release dosage form. According to a specific example of 200920358, the dosage form provides controlled release or sustained release of gaboxadol in an amount lower than the amount of sleep induction. Gaborsadol can be about 1 to about 150 mg per day, about 0.2 to about 100 mg per day. , from about 0.5 to about 50 mg per day, from about 0.1 to about 5 mg per day, from about 1 to about 15 mg per day or from about 2 to about 5 mg per day, in unit dosage form containing the active ingredient, such as a lozenge or capsule, Conveniently administered orally. Typically the 'pharmaceutical composition comprises from about 5 mg to about 20 mg, such as about 5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 about 9 mg, about 9.5 mg, about 1 〇 mg, about 10.5 mg, about u mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, About 14.5 mg, about 15 mg, about 15_5 mg, about i6 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5%, about 19 mg, about 19 5 mg or about 2 〇 Mg of gaboxa. The gaboxadol is calculated based on the free base (zwitter ion) form. In a specific embodiment, gaboxadol is administered once daily (e.g., morning or afternoon) using an agent of from about mg to about 2 Torr. In another embodiment, gaboxadol is administered with a non-sleep-inducing concentration of gaboxadol (e.g., 2 times a day at a low dose) or modified release using a conventional method known in the art. The formulation (so that it is administered to the individual every 24 hours. = about 5 mg of gamma) is administered in a more persistent and sustained release manner - in the specific example, the gazapine is lower than the sleep-inducing amount. Give. According to the present invention, gaboxadol or a pharmaceutically acceptable salt thereof can be administered in any suitable manner (e.g., parenteral), and can be provided in any form suitable for the administration. For example, it can be used as a cold liquid or dispersion for tablets, capsules, powders, syrups or tablets for injection. In another embodiment, and in accordance with (4) of the present invention, gaboxadol is a solid pharmaceutical entity in the form of a solution, solution or dispersion for injection. In addition, gaboxadol can be administered with a pharmaceutically acceptable carrier such as an adjuvant and/or a diluent. A method for preparing a solid or liquid pharmaceutical preparation is in the art Remington: The Science and Practice of
Pharmacy，第 21 版，Lippincott Williams & Wilkins (2005)。因此，可藉由使活性成份與一般載劑（諸如佐劑及 /或稀釋劑）混合’且隨後在製錠機中壓實混合物而製備錠 劑。佐劑及/或稀釋劑的非限制實例包括：玉米澱粉、乳糖、 滑石、硬脂酸鎂、明膠、乳糖、膠及其類似物。亦可使用 其他佐劑或添加劑，諸如著色劑、芳香劑及防腐劑，其限 制條件為其與活性成份相容。本發明之醫藥組合物因此通 常包含有效量之加波沙朵及醫藥學上可接受之載劑。 加波沙朵之合適調配描述於wo 02/094225中。不以任 何方式限制本發明，希望本專利申請案之態樣或具體實例 中之任一者適用於本文所述之藥物或醫藥組合物。舉例而 5 ’標題為「加波沙朵顆粒製劑（Granular Preparations ofPharmacy, 21st ed., Lippincott Williams & Wilkins (2005). Thus, a tablet can be prepared by mixing the active ingredient with a conventional carrier such as an adjuvant and/or a diluent, and then compacting the mixture in a tablet machine. Non-limiting examples of adjuvants and/or diluents include: corn starch, lactose, talc, magnesium stearate, gelatin, lactose, gums, and the like. Other adjuvants or additives may also be used, such as coloring agents, fragrances, and preservatives, which are limited in their compatibility with the active ingredient. The pharmaceutical compositions of the present invention thus typically comprise an effective amount of gaboxadol and a pharmaceutically acceptable carrier. A suitable blend of gaboxadol is described in wo 02/094225. The invention is not limited in any way, and it is intended that any of the aspects or specific examples of the present patent application apply to the pharmaceutical or pharmaceutical compositions described herein. For example, 5 ‘title is “Granular Preparations of Granular Preparations of
Gaboxadol)」之WO 02/094225係關於特定熔融製粒法（melt granulation )’其尤其適用於調配酸加成鹽，但本發明不以 任何方式侷限於該調配。 21 200920358 蕖理試驗 使用大鼠體内之慢性溫和壓力模型進行以下試驗以評 估加波沙朵對與壓力有關之生物化學改變的潛在影響 (Jayatissa MN, Bisgaard C, Tingstrom A, Papp M, Wiborg O. Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression. Neuropsychopharmacology· 2006 年 11 月；31(1 1):2395-404 )° 壓力模型中研究之動物體内誘導的生物化學改變導致發炎 介體/標記增加。 在本研究結束時，收集末期血清樣本用於標記分析， 以評估具有或不具有藥物之狀況下壓力對約60個血液標記 之含量的影響。先前公開之數據表明，慢性溫和壓力介導 許多血漿蛋白質的表現。加波沙朵及依地普蘭對此反應的 差異調節可指示不同作用機制且可為臨床功效之替代預示 者(predictor)。 實驗程序 動物 在最後一次藥物注射24小時後的白天（09:00 - 17:00) 期間，在未致暈（stunning )之狀況下自尾部抽取血清樣本。 將血液收集入含有用於血清製備之促凝固劑及凝膠的BD 真空採血管（BD vacutainer )中，顛倒5次且保持於冰上直 至在4°C下在3000 rpm下離心分離10分鐘。將血清傾析出 來，置於冰上，且在當天結束時儲存於-80°C下。動物治療 組如下（參見表1 ): 22 200920358 動物組 治療編碼 壓力條件 藥物治療或行為 CMS-VEH 慢性溫和壓力 媒劑 CMS-ECT 慢性溫和壓力 依地普蘭 CMS-GBX-5 mg/kg 慢性溫和壓力 加波沙朵 CMS-GBX-10 mg/kg 慢性溫和壓力 加波沙朵 CMS-RES 慢性溫和壓力 抵抗性 NS-VEH 無壓力 媒劑 NS-ECT 無壓力 依地普蘭 NS-GBX 無壓力 加波沙朵 表1.動物組 分析 隨後之血清樣本分析顯示以下結果（參見表2) 23 200920358 嶄蜗ffi-^'ΑΙ ( Apo A1) /5-2薛钨蜗处 #5據命蜗Ilh(calbindin) '0Sc^li蜗φηκρ) 滓蜗!^隳菩寺J-f-C Ξ 屮 VII 難孫#la赛忤-s:s屮-9 (FGF-9) 缴铮與盎4(τ蜗卧-2 (GCP-2) ^^鍊^ 释浑4浑8-裳雄8| α (Glutathione S-Transferase alpha > GST- α ) GST-M/z 沙狰钨^ΦΑ (IgA) ->φ_-10 (IL-10) 冷φ_-11 (IL-11) ->φ__18 (IL-18)WO 02/094225 to Gaboxadol) is particularly suitable for formulating acid addition salts with respect to specific melt granulations, but the invention is not limited in any way to this formulation. 21 200920358 The limulus test uses the chronic mild stress model in rats to perform the following experiments to assess the potential effects of gaboxadol on stress-related biochemical changes (Jayatissa MN, Bisgaard C, Tingstrom A, Papp M, Wiborg O. Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression. Neuropsychopharmacology· November 2006; 31(1 1): 2395-404)° Biochemical changes induced in animals studied in the stress model Inflammatory mediator/marker increased. At the end of the study, the final serum samples were collected for marker analysis to assess the effect of pressure on the content of about 60 blood markers with or without the drug. Previously published data indicate that chronic mild stress mediates the performance of many plasma proteins. The differential adjustment of gaboxadol and edephrine to this response may indicate different mechanisms of action and may be an alternative predictor of clinical efficacy. Experimental procedure Animals During the day after the last drug injection 24 hours (09:00 - 17:00), serum samples were taken from the tail without stunning. Blood was collected into a BD vacuum tube (BD vacutainer) containing a coagulant and gel for serum preparation, inverted 5 times and kept on ice until centrifugation at 3000 rpm for 10 minutes at 4 °C. The serum was decanted, placed on ice, and stored at -80 °C at the end of the day. The animal treatment group was as follows (see Table 1): 22 200920358 Animal group treatment coded pressure condition drug treatment or behavior CMS-VEH chronic mild pressure medium CMS-ECT chronic mild pressure edephrine CMS-GBX-5 mg/kg chronic mild pressure Gaposadu CMS-GBX-10 mg/kg Chronic mild pressure plus Posada CMS-RES Chronic mild pressure resistance NS-VEH No pressure medium NS-ECT No pressure ED-Puls NS-GBX No pressure plus Posada Table 1 Animal group analysis Subsequent analysis of serum samples showed the following results (see Table 2) 23 200920358 崭 f ffi-^'ΑΙ (Apo A1) /5-2 Xue tungsten worms #5 according to the life worm Ilh (calbindin) '0Sc^ Li φφηκρ) 滓 !!^隳菩寺JfC Ξ 屮VII 难孙#la赛忤-s:s屮-9 (FGF-9) 铮 铮 and Ang 4 (τ 蜗卧-2 (GCP-2) ^ ^链^ 释浑4浑8-长雄8| α (Glutathione S-Transferase alpha > GST- α ) GST-M/z 沙狰tungsten ^ΦΑ (IgA) ->φ_-10 (IL-10) Cold φ_-11 (IL-11) -> φ__18 (IL-18)
ug/mL ug/mL ng/mL ug/mL ug/mL ng/mL pg/mL ng/mL ng/mL ng/mL ng/mL ng/mL ng/mL ug/mL pg/mL Og/mL ng/mL 7.10 27800 129.00 0.07 S500 §500 005100 P300 PM L66 700 -S·麻 6.83 22800 S5.00 0.14^ 1 1440.00 121P00 P95 0.23 5.67 7.30 5.91 24S0 128.00 007 P59 P19 7OS7 1140.00 116500 8.20 GWX ^51 6.5私 31700 166.00 1060.00 1300.00 0.90 P21 1.300 8.40 MSC5 Bg/kg 480 4500 0.40 11 1130.00 717.00 52.00 0,400 L70 P200 1200 P89 2080.00 5.70 360.00 16S0 0.53 5.80 5900 P12 14600 11 95600 165S0 007 2.40 0.31 2300 P40soo 7_60私一 1.00 98.00 P85 1190.00 έο 362.00 0.43Ug/mL ug/mL ng/mL ug/mL ug/mL ng/mL pg/mL ng/mL ng/mL ng/mL ng/mL ng/mL ng/mL ug/mL pg/mL Og/mL ng/ mL 7.10 27800 129.00 0.07 S500 §500 005100 P300 PM L66 700 -S· hemp 6.83 22800 S5.00 0.14^ 1 1440.00 121P00 P95 0.23 5.67 7.30 5.91 24S0 128.00 007 P59 P19 7OS7 1140.00 116500 8.20 GWX ^51 6.5 Private 31700 166.00 1060.00 1300.00 0.90 P21 1.300 8.40 MSC5 Bg/kg 480 4500 0.40 11 1130.00 717.00 52.00 0,400 L70 P200 1200 P89 2080.00 5.70 360.00 16S0 0.53 5.80 5900 P12 14600 11 95600 165S0 007 2.40 0.31 2300 P40soo 7_60 Private One 1.00 98.00 P85 1190.00 έο 362.00 0.43
6.20 3800 58.00 150.00 69600 1072.00 0,30 1.70 0.29 3.S 潍薄 ΙΙΛ GBXS Bg/kg 袖l·^拽 200920358 256.20 3800 58.00 150.00 69600 1072.00 0,30 1.70 0.29 3.S 潍 ΙΙΛ GBXS Bg/kg sleeve l·^拽 200920358 25
->π>ίψ-1 α (IL-lft) pg/mL ->φ^-1·εο(Ιί-1·&)) ng/mL ->φ_-2 (IL-2) pg/mL ->D>^-4 (IL-4) pg/mL ->nh:l:-5 (IL-5 ) ng/mL ->B>_-7 (IL-7) ng/mL s_UIU/mL 4灘，蜗Φ-10 (IP-10) pg/mL βφng/mL 13>.01.激^堂13+( LIF ) pg/mL ^eit^^^s+pymphotactin) - Pg/mL +3翁^^^π^^φ-ι pg/mL (Monocyte Chemoattractant Protein-了 MCP-1 ) 相翁t·赛盎n=蜗 Φ-3 (MCP-3) pg/mL 郝翁贫赛蘀o=蜗Φ-5 (MCP-5) pg/mL E.^?^^^.$_j^la^ng/mL (Macrophage-Colony Stimulating Factor > M-CSF ) E.疵貧赛_^籮o^s 屮(MDC) pg/mL 冲螓贫赛皞泠蜗φ-ια (MIP-ια ) ng/mL 冲豳f赛皞辞嘟10--1/3 (ΜΙΡ-lys) pg/mL 抑豳?赛雄於蜗^-一 7 (MIP-1 7 ) ng/mL ^修，?^^^^11>-2 ( MIP-2 ) pg/mL E.^'r&^jl^m'-s'cbCMIP-s'tb) ng/mL 潔族1^10=1^81 (Mpo)_ng/mL 116.00 209.00 17300 244.00 6.42 13.10 7.95ΠΙΛΟ 005 0.11 008os 89.40 53000κίροοοso 813.00 875.00 865.00 566.00 0.76 65700 0.73 65500 P77 885.00 P87 94100 1095.00 S95.00 1185.00 1500.00 0.11 S.90 86.70 3_2私 36.60 41.80 P22 12.20 186.00 117 70.50 73.70 0.16 000000 138.00 2.59 53.90 53.80 22.30 38.80 31.30 24.65 46.70 29.60 8.12 13.80 11.30 15.40 38.80 51.70 P22 11.30 一宏.00 2.S 67.20 68.00 0·13 12000 Pol 1600 0.21 21.75 6S.00 0.26 S7.00 0.02 1500 P3私 13.70 39.85 Ρ12 12700 Pol ISO 0.22 29.70 533.00 196000 1610.00 1400.00 65300 Ρ75 703.00 0.75 65S0 P72 1065.00 1025.00 1020.00 0.53 3300 0·26 震 9.40 3100 0.9私 49.00 2.00 P65 46.00 0.51 00私 3.S 36.00 0.27 93.00 7200 P56 22.00 0.24^ 0.06 14.50 41.00 1.35 6700 63.00 >2.和缈穿0>瘠聆 A^mJ^s 屮 S-S-麻。 弇^蜗2>ng/mL NGAL (龉齡啣I!>-2) ng/mL ♦Jly^M (OSM) ng/mL 碑薄蜗I!>ng/mL 5sii^iE f Tt 赛>鋅今»'θ屮 (Regulation Upon Activation,I>Jormal T-Cell pg/mL Expressed and Secreted > RANTES )-ώ.^捧寒萍^D>p (SAP) ug/mL ^1-^0^( SCF ) pg/mL Tbit雜港踝-姑0»漭#翁嚴(SGOT) ug/mL Q—.c ng/mL 淨第s^ng/mL 銪澈癌^®屮-a (Tumor Necrosis Factor-alpha > TNF- a ) ng/mL J&.、J'^^^it(Tpo) ng/mL .1&-峨1-^翁^^^-1 ( VCAM-1 ) ng/mL b 蝴2^1-赛阼洳回屮(VEGF) pg/mL 菌ι^Α1^1^νΞι^( von Willebrand Factor ;WF )_ng/3T. 134.00 299.00 5500 142.00 381.00 8S0 147.00 361.00 81.00 sbo 409.00 56.00 sbo 12.55 P16 009 008 m.oo 15.30 P27 0.28 0.13 133.00 14.85 P21 0.16 0.10 17800 16.95 0.31 0.22 P15 188.00 39L00 396.00 310.00 P21 P12 0_17 0.22 24L00 39.20 6.16 0.37 006 2.55 130.00 330.00soo 198.00 50.80 6.M 0.77 003 16700 31100 24300 12.85 11.25 408.00ps 21.95 35600 sbo pll 岑90 509.00 520.00 P15 19.10soo 1P60 45.00 11_30 00.53 0.2私 006 445 11900soo 7800 200920358 數據 收集各動物之各因子濃度的數值。 結果及結論 上述樂理試驗顯示慢性溫和壓力相較 ， 顯著改變許多血渣恭ώ祕 對… s蛋白払記。在CMS治療後未顯示行為及 應之大鼠（CMS-RFS如、_ι * 組）相較於無壓力對照，未顯示此筹 血清蛋白標記的顧^ 顯者上調。本發明者發現以加波沙朵治瘰 將壓力誘導之血法q , β杯屺改變顯著逆轉為無壓力對照中所發 現之含量。 因此’發明者自前述測試及結果發現，慢性溫和壓力 顯著改變一組血清標年 ,°己蛋白的表現，且以加波沙朵（但未 使用依地普蘭）使此作用部分或完全逆轉表明加波沙朵藉 由減：發炎介體來影響與壓力有關之生物化學改變。因 單獨、σ藥之加波沙朵能夠逆轉或部分逆轉多數由慢性 溫和壓力料的發炎參數之改變。相反，依地普蘭在多數 此專改變中無活性。 因此’加；皮沙朵可用於有效治療壓力介導之憂營症， ”中此等發炎參數中之一或多者牽涉於憂鬱症進程之中。 本說明書中所引用且論述之所有非專利參考案、專利 士專利中請案皆以引用的方式全部併人本文中且引用程度 就像其各自以引用的方式個別併入一 無 明 說 單 簡 式 圖 27 200920358 【主要元件符號說明】 無 28->π>ίψ-1 α (IL-lft) pg/mL ->φ^-1·εο(Ιί-1·&)) ng/mL ->φ_-2 (IL-2) pg /mL ->D>^-4 (IL-4) pg/mL ->nh:l:-5 (IL-5 ) ng/mL ->B>_-7 (IL-7) ng/ mL s_UIU/mL 4 beach, worm Φ-10 (IP-10) pg/mL βφng/mL 13>.01. 激^堂13+( LIF ) pg/mL ^eit^^^s+pymphotactin) - Pg/ mL +3 Weng ^^^π^^φ-ι pg/mL (Monocyte Chemoattractant Protein-MCP-1) Xiang Weng t·赛昂n= 蜗Φ-3 (MCP-3) pg/mL Hao Weng萚o= worm Φ-5 (MCP-5) pg/mL E.^?^^^.$_j^la^ng/mL (Macrophage-Colony Stimulating Factor > M-CSF) E. Poor game _^箩o^s 屮(MDC) pg/mL 螓 螓 皞泠 φ φ-ια (MIP-ια ) ng/mL 冲豳f赛皞辞10--1/3 (ΜΙΡ-lys) pg/mL豳 豳? Sai Xiong in the worm ^-7 (MIP-1 7) ng / mL ^ repair, ^ ^ ^ ^ ^ 11 > -2 ( MIP-2 ) pg / mL E. ^ 'r & ^ jl ^ m '-s'cbCMIP-s'tb) ng/mL Clean 1^10=1^81 (Mpo)_ng/mL 116.00 209.00 17300 244.00 6.42 13.10 7.95ΠΙΛΟ 005 0.11 008os 89.40 53000κίροοοso 813.00 875.00 865.00 566.00 0.76 65700 0.73 65500 P77 885.00 P87 94100 1095.00 S95.00 1185.00 1500.00 0.11 S.90 86.70 3_2 Private 36.60 41.80 P22 12.20 186.00 117 70.50 73.70 0.16 000000 138.00 2.59 53.90 53.80 22.30 38.80 31.30 24.65 46.70 29.60 8.12 13.80 11.30 15.40 38.80 51.70 P22 11.30 One macro.00 2.S 67.20 68.00 0·13 12000 Pol 1600 0.21 21.75 6S.00 0.26 S7.00 0.02 1500 P3 Private 13.70 39.85 Ρ12 12700 Pol ISO 0.22 29.70 533.00 196000 1610.00 1400.00 65300 Ρ75 703.00 0.75 65S0 P72 1065.00 1025.00 1020.00 0.53 3300 0·26 Shock 9.40 3100 0.9 Private 49.00 2.00 P65 46.00 0.51 00 Private 3.S 36.00 0.27 93.00 7200 P56 22.00 0.24^ 0.06 14.50 41.00 1.35 6700 63.00 >2. and 缈 wear 0> 瘠 A A^mJ^s 屮 SS-麻.弇^ 蜗 2>ng/mL NGAL (龉 age I!>-2) ng/mL ♦Jly^M (OSM) ng/mL Stele worm I!>ng/mL 5sii^iE f Tt Race> Zinc current»'θ屮(Regulation Upon Activation, I>Jormal T-Cell pg/mL Expressed and Secreted > RANTES )-ώ.^持寒萍^D>p (SAP) ug/mL ^1-^0 ^( SCF ) pg/mL Tbit 杂港踝-姑0»漭#翁严(SGOT) ug/mL Q—.c ng/mL net s^ng/mL 铕Cell cancer^®屮-a (Tumor Necrosis Factor-alpha > TNF- a ) ng/mL J&., J'^^^it(Tpo) ng/mL .1&-峨1-^ Weng^^^-1 ( VCAM-1 ) ng/mL b 蝶2^1-赛阼洳回屮 (VEGF) pg/mL ι^Α1^1^νΞι^( von Willebrand Factor ;WF )_ng/3T. 134.00 299.00 5500 142.00 381.00 8S0 147.00 361.00 81.00 sbo 409.00 56.00 sbo 12.55 P16 009 008 m.oo 15.30 P27 0.28 0.13 133.00 14.85 P21 0.16 0.10 17800 16.95 0.31 0.22 P15 188.00 39L00 396.00 310.00 P21 P12 0_17 0.22 24L00 39.20 6.16 0.37 006 2.55 130.00 330.00soo 198.00 50.80 6.M 0.77 003 16700 31100 24300 12.85 11.25 408.00ps 21.95 35600 sbo pll 岑90 509.00 520.00 P15 19.10soo 1P60 45.00 11_30 00.53 0.2 private 006 445 11900soo 7800 200920358 Data Collect the values of the concentration of each factor in each animal. RESULTS AND CONCLUSIONS The above-mentioned music theory showed that compared with chronic mild pressure, many blood slags were significantly changed to ... s protein 払. Rats that did not show behavior and response after CMS treatment (CMS-RFS, _ι * group) did not show up-regulation of this serum protein marker compared to the no-pressure control. The inventors have found that the treatment of gaboxadol significantly reverses the pressure-induced blood method q, β cup 屺 change to the content found in the no-pressure control. Therefore, the inventors have found from the above tests and the results that chronic mild stress significantly changes the performance of a group of serum markers, °H protein, and the partial or complete reversal of this effect by gaboxadol (but without the use of escitalopride) indicates that the wave is added. Sando affects the biochemical changes associated with stress by reducing the inflamed mediator. Because of the serotonin alone, gaboxadol can reverse or partially reverse most of the inflammatory parameters of chronic mild stressors. In contrast, escitalopram is inactive in most of these changes. Therefore, 'plus; Pisado can be used to effectively treat stress-mediated depression," one or more of these inflammatory parameters are involved in the progression of depression. All non-patents cited and discussed in this specification The references in the reference patents and the patents in the patents are all quoted in the text and the degree of citation is as if they were individually incorporated by reference. A single ambiguous statement is simple. Figure 27 200920358 [Main component symbol description] No 28
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| TW097129977ATW200920358A (en) | 2007-08-13 | 2008-08-07 | Method of treating stress-mediated depression |
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