TW202135788A - 氯胺酮用於治療惡病質之用途 - Google Patents
氯胺酮用於治療惡病質之用途 Download PDFInfo
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Abstract
本發明係揭露一種氯胺酮用於製備改善惡病質之藥物之用途,該藥物係給予接受5-FU治療之患者;其中氯胺酮之劑量至少約為5-FU之劑量之60%。特定而言,本發明之藥物可提高生存率以及改善惡病質所引起的體重降低。
Description
本發明係關於氯胺酮用於治療惡病質之用途;特定而言,氯胺酮係用於接受5-FU治療所導致的惡病質。
5-氟尿嘧啶(5-FU)用於癌症治療已有將近50多年的歷史,可用於治療多種癌症。雖其治療癌症功效頗佳,但亦產生大量之副作用,例如噁心、嘔吐、腹瀉、黏膜發炎、頭痛、肌肉無力、掉髮、心肌梗塞、或肺炎等。因此服用5-FU對於癌症患者而言是極大負擔。
惡病質(又稱惡病體質)係由於疾病所產生的複合性代謝症候群,症候群中的代謝不良和神經性厭食症往往造成患者異常虛弱,主要症狀包括肌肉耗損以及體重下降等。其他症狀例如白蛋白、血紅素降低,發炎因子(如,介素白-6(IL-6)、反應蛋白(CRP))上升等。惡病質之肌肉耗損病徵無法單純藉由供給營養而回復,即便增加進食量或提高營養之攝取,也無法預防或停止病患體重的持續下降。
目前的治療方法僅能透過治療導致惡病質的疾病(例如癌症)來舒緩症狀,但往往成效不佳且難以痊癒,通常透過肌肉活動、給予刺激食慾或降低噁心感之藥物、直接投予營養藥劑、或其他支持性療法來緩和惡病質之惡化。因此,本領域亟需研發一種可有效改善惡病質之症候群之藥物或方法,使癌症患者的生存率可以提高。
為解決前述問題並達成發明之目的,本發明之一實施態樣係提供一種氯胺酮用於製備改善惡病質之藥物之用途,其中該藥物係給予接受5-FU治療之患者。
於本發明之一實施例,其中氯胺酮之人體劑量為每周1-100 mg/60 kg。
於本發明之一實施例,其中該藥物係用於非腸胃道給藥。
於本發明之一實施例,其中該藥物係用於改善因惡病質引起之體重降低。
於本發明之一實施例,其中該藥物係用於提高存活率。
本發明之另一實施態樣係提供一種治療癌症之醫藥組合物,包括:5-FU、氯胺酮、和一醫藥上可接受之載劑;其中氯胺酮之人體劑量為每周1-100 mg/60 kg。
本發明之另一實施態樣係提供一種氯胺酮和5-FU之醫藥組合物用於製備治療癌症之藥物之用途。
於本發明之一實施例,其中氯胺酮之人體劑量為每周1-100 mg/60 kg。
於本發明之一實施例,其中該藥物係用於非腸胃道給藥。
於本發明之一實施例,其中氯胺酮和5-FU係同時或分別給予患者。
以下參照實施例說明本發明,以明確闡釋本發明之技術內容、特徵、和功效。通過特定實施例的說明,習知技術者可進一步明瞭本發明採取的技術手段和功效,以達成前述發明目的。另,本說明書所公開的技術可為習知技術者理解並且實施,在不悖離發明概念之前提下,任何變更或改良均可被請求項所涵蓋。
本說明書及請求項中所述之所有技術性及科學用語,除非另有所定義,皆為本發明所屬技術領域具有通常知識者可知曉之定義。其中若為單數用語「一」、「一個」、「該」、或其近似用語,除非另有說明,皆可指涉多於一個對象。本說明書使用之「或」、「以及」、「和」,除非另有說明,皆指涉「或/和」。此外,用語「包含」、「包括」皆非有所限制之開放式連接詞。前述定義僅說明用語定義之指涉而不應解釋為對發明標的之限制。除非另有說明,本發明所用之材料皆市售易於取得。
5-氟尿嘧啶(fluorouracil,本說明書簡稱5-FU)係一種嘧啶類似物,主要用於治療腫瘤。目前認為5-FU之作用方式係透過抑制胸苷酸合酶(Thymidylate synthase)之功能,進一步阻礙DNA之合成。
5-FU之副作用包括嚴重脫水、骨髓抑制、腸炎、口腔潰瘍、皮炎、心絞痛以及心肌梗死、急性腎功能不全、間質性肺炎、肝功能損害、黃疸、腹瀉等等。5-FU也可導致急性的中樞神經系統損傷(白質腦病),以及中樞神經系統的退化。
氯胺酮(Ketamine,IUPAC:(R, S)-2-(2-氯苯基)-2-甲基胺-環己-1-酮((R, S)-2-(2-chlorophenyl)-2-methylamino-cyclohexan-1-one)),又稱K他命,係一種非競爭性NMDA受體拮抗劑,自60年代起廣泛地使用於麻醉、止痛、和鎮靜等用途。氯胺酮係藉由肝臟細胞色素(cytochrome)P450而代謝,以及與包括NMDA在內多種受體結合,形成麻醉之效果。
氯胺酮可抑制麩胺酸(中樞神經系統之神經傳導物質)所誘發的NMDA受體活化,亦可抑制突觸前神經元釋放麩胺酸並增強抑制性神經傳導物質:GABA之作用。
於本說明書,「氯胺酮」可指涉外消旋(racemic)或鏡相異構富集(enantiomerically enriched)(例如鏡相異構純粹(enantiomerically pure))之形式。於一實施例,本發明所述之氯胺酮係外消旋氯胺酮。於另一實施例,本發明所述之氯胺酮係鏡相異構富集氯胺酮。於一特定實施例,本發明所述之氯胺酮係S
-鏡相異構物或R
-鏡相異構物。
於本說明書,藥物之劑量係定義為每公斤體重給予之藥物重量,例如:每公斤體重給予之藥物克數(g/ kg)或每公斤體重給予之藥物毫克數(mg/kg)。
本說明書用語「約」或「近似」等詞指涉習知技術者理解的可接受偏差程度,其可在一定程度上根據文中的使用而變化。一般而言,例如,「約」或「近似」可指引用值附近±10%、±5%、或±3%範圍的數值。
本說明書用語「治療」、「改善」、或其近似用語,係包含以治療或預防之方式緩和、減輕、或改善至少一項疾病症狀或生理狀況、預防新增之症狀、抑制疾病或生理狀況、阻止或減緩疾病發展、造成疾病或生理狀況之復原、減緩因疾病造成的生理狀況、停止疾病症狀或生理狀況。
本說明書用語「惡病質」(又稱惡病體質)指涉因持續性體重嚴重流失、厭食、無力、貧血及蛋白質、脂肪和醣類代謝異常所造成的症候群。臨床上把惡病質定義為一種以厭食、貧血、體重減輕為主要症狀的綜合症。惡病質可發生於多種病況,包括腫瘤、化療、厭食症、嚴重創傷、腸胃吸收功能不良、體重下降、貧血、肥胖症及嚴重的敗血症,其中以腫瘤誘發的惡病質最為常見,稱為腫瘤惡病質。
本發明之醫藥組合物可用於治療個體之惡病質。具體而言,本發明之醫藥組合物可施用於具有產生惡病質風險或感受惡病質相關病徵之個體,以避免惡病質之發生或改善或延緩惡病質之進展。
本說明書用語「有效量(effective amount)」或「治療(therapeutically)有效量」,係指涉化合物或藥物之一足夠量,可於患者服藥後減輕一或多項疾病症狀或生理狀況;其結果為降低和/或緩和徵象(sign)、症狀(symptom)、或病因,或為其他生理系統之有意圖之改變。舉例而言,治療之「有效量」係包含一本發明提供化合物之可於臨床上顯著降低疾病症狀之劑量。
依據本發明,治療有效量依據疾病嚴重程度、患者年齡、患者健康狀態、癌症潛在風險、或其他因素而改變。
依據本發明,本說明書所述之組合物以及其他藥劑成分不必以同一醫藥組合物給藥;因不同的物理和化學特性,可以不同途徑給藥。
本說明書用語「組合物」或「醫藥組合物」指涉至少一種藥物及其他載劑之混和,該載劑包含但不限於:安定劑、稀釋劑、分散劑、懸浮劑、增厚劑、或賦形劑、或上述之組合。
本說明書用語「醫藥上可接受」指涉化合物、組合物、和/或劑型於合理的醫療判斷範圍中,適合用於與服藥者(如人類)組織接觸,並且無過量之毒性、刺激、過敏反應、或其他問題或併發症,以及具有相當合理之利益/風險比。各載劑必須在與其他配方成分相容之前提上,方為「可接受」。
本說明書用語「載劑(carrier)」,係指涉不具毒性之化合物或藥劑,其具有協助細胞或組織吸收藥物之功能。
適當賦形劑之例示包括但不限於:乳糖、右旋糖、蔗糖、山梨糖、甘露糖、澱粉、阿拉伯膠、磷酸鈣、褐藻酸鹽、黃蓍樹膠、明膠、矽酸鈣、微晶纖維素、聚乙烯吡咯啶酮、纖維素、滅菌水、糖漿和甲基纖維素。
組合物可另外包括潤滑劑,例如,滑石粉、硬脂酸鎂和礦物油;濕潤劑;乳化和懸浮劑;保存劑,例如,羥基苯甲酸甲酯和丙酯;甜味劑;以及調味劑。
依據本發明,本發明之藥物可應用於多種給藥技術,包括但不限於靜脈注射、口服、非消化道給藥、眼部給藥、肺部給藥、或局部給藥、或上述給藥途徑之組合。
依據本發明,本發明之藥物係用於腹腔注射。
依據本發明,醫藥組合物的形式可為錠劑、藥丸、粉末、糖錠、藥包、藥片、酏劑、懸浮液、乳劑、溶劑、糖漿、軟和硬明膠膠囊、栓劑、滅菌注射液和包裝粉末。
本發明係提供一種治療5-FU引起之惡病質之方法,包括:給予患者一治療有效量之氯胺酮,其中該患者係接受5-FU之治療。
本發明另提供一種氯胺酮用於製備改善惡病質之藥物之用途,其中該藥物係給予接受5-FU治療之患者。
於一較佳實施例,該藥物係用於改善因惡病質引起之體重降低。
於一較佳實施例,該藥物係用於提高存活率。
本發明另提供一種治療癌症之方法,包括:給予患者一治療有效量之醫藥組合物,其中該醫藥組合物包括:5-FU、氯胺酮、和一醫藥上可接受之載劑。
於一較佳實施例,該癌症包括但不限於:肛門癌、乳癌、大腸直腸癌、口咽癌、胃癌、胰臟癌、皮膚癌、或頭頸癌。
於一較佳實施例,其中該氯胺酮和該5-FU係同時或分別給予患者。
本發明另提供一種治療癌症之醫藥組合物,包括:5-FU、氯胺酮、和一醫藥上可接受之載劑。
於一較佳實施例,該醫藥組合物之氯胺酮之劑量至少約為5-FU之劑量之60%。
於一較佳實施例,氯胺酮之人體劑量為每周1-100mg/60kg。
於一更佳實施例,氯胺酮之人體劑量為每周1-50 mg/60kg。
於一較佳實施例,氯胺酮之人體劑量為每周約25mg/60kg。
抗腫瘤藥物卡培他濱(Capecitabine)經口服吸收後在組織內被轉化成5-FU從而發揮抗腫瘤的作用。因此於一特定實施例,該5-FU可以卡培他濱之形式給予患者。
去甲基氯胺酮(norketamine,IUPAC:(R,S)-2-(2-氯苯基)-2-(胺)環己酮((R,S)-2-(2-chlorophenyl)-2-(amino)cyclohexanone))係氯胺酮去甲基後之代謝產物,並相較於氯胺酮具有較低且較緩生效之活性。
因此,於一特定實施例,該氯胺酮可以去甲基氯胺酮之形式給予患者。於本說明書,「去甲基氯胺酮」可指涉外消旋或鏡相異構富集(例如純粹鏡相異構)之形式。
實施例
材料與方法
6至12週大的小鼠(取自國家實驗動物中心)個別飼養於溫控房,其飼養條件為12小時光照/12小時黑暗之循環,溫度為24±1℃。
將小鼠區分為4組,每組4隻。
將5-FU配製為小鼠每公斤50毫克(50 mg/kg)之劑量,每日於腹腔內(i.p.)注射一次並連續注射3日。
另將氯胺酮(Ketamine)配置為15 mg/kg或30 mg/kg之劑量,並於5-FU之最後一劑注射後24小時注射於小鼠腹腔(i.p.)。
使用食鹽水作為5-FU和氯胺酮之載劑以及控制組。
上述注射完成後,觀察小鼠存活率、體重、和進食量。
實驗結果
本實施例之實驗結果揭示於表1至表3。
可由結果得知,全部組別之小鼠均接受50 mg/kg之5-FU腹腔注射,但於注射5-FU後第17日,注射50 mg/kg之5-FU以及15 mg/kg之氯胺酮之組別僅存25%之存活率。但於50 mg/kg之5-FU以及30 mg/kg之氯胺酮之組別仍有100%之存活率。
其次,關於進食量,控制組攝取235.2 克(g)之食物(標準差:4.0)。注射5-FU之組別攝取189.6 g之食物(標準差:7.5)。而給予 5-FU和氯胺酮之二組別攝取量相近,氯胺酮15 mg/kg之組別攝取 215.0 g之食物(標準差:8.3);氯胺酮30 mg/kg之組別攝取 219.1 g之食物(標準差:5.7)。
再者,關於體重變化,注射50 mg/kg之5-FU以及15 mg/kg之氯胺酮之組別之小鼠平均體重下降19.9%,與僅注射5-FU之組別之小鼠下降幅度相近。相對地,於50 mg/kg之5-FU以及30 mg/kg之氯胺酮之組別,體重僅下降7.5%,與控制組(下降0.2%)較為接近。
表1 試驗結束時最後觀察值推估(Last Observation Carried Forward,LOCF)群體之小鼠體重
s.d.: 標準差(Standard deviation)
治療 | 體重 (g) 平均值 (s.d.)/ 中位數 | 進食量 (g) 平均值 (s.d.) | 飲水量 (ml) 平均值 (s.d.) | 存活率 (%) |
控制組 | 21.1 (0.7) 21.0 | 235.2(4.0) | 200.19(3.0) | 100 |
5-FU (50 mg/kg) | 17.6 (2.7) 16.4 | 189.6(7.5) | 149.6(3.3) | 25 |
5-FU (50 mg/kg) +氯胺酮(15 mg/kg) | 17.6 (4.0) 17.1 | 215.1(8.3) | 140.3(3.9) | 25 |
5-FU (50 mg/kg) +氯胺酮(30 mg/kg) | 20.5 (2.9) 21.2 | 219.0(5.7) | 188.8(3.0) | 100 |
表2 試驗結束時LOCF群體之小鼠體重變化量
治療 | 自基準起算之體重變化 (g) 平均值 (s.d.)/ 中位數 | 攝食量 (g) 平均值 (s.d.) | 存活率 (%) |
控制組 | -0.0 (0.5)/ 0.1 | 235.2(4.0) | 100 |
5-FU (50 mg/kg) | -4.4 (3.1)/ -5.7 | 189.6(7.5) | 25 |
5-FU (50 mg/kg) +氯胺酮(15 mg/kg) | -4.3 (3.6)/ -4.6 | 215.1(8.3) | 25 |
5-FU (50 mg/kg) +氯胺酮(30 mg/kg) | -1.6 (2.4)/ -1.1 | 219.0(5.7) | 100 |
表3 試驗結束時LOCF群體之小鼠體重變化百分比
治療 | 自基準起算之體重變化率 (%) 平均值 (s.d.)/ 中位數 | 攝食量 (g) 平均值 (s.d.) | 存活率 (%) |
控制組 | -0.2 (2.5)/ 0.5 | 235.2(4.0) | 100 |
5-FU (50 mg/kg) | -19.9 (13.8)/ -25.6 | 189.6(7.5) | 25 |
5-FU (50 mg/kg) +氯胺酮(15 mg/kg) | -19.9 (16.5)/ -21.3 | 215.1(8.3) | 25 |
5-FU (50 mg/kg) +氯胺酮(30 mg/kg) | -7.5 (11.1)/ -4.9 | 219.0(5.7) | 100 |
依據本申請案揭露之內容,可於動物實驗得知注射5-FU後可能引起體重降低、攝食和飲水量降低、以及存活率降低等惡病質之症狀及併發症,而共同給予氯胺酮可改善上述症狀。因此,習知技術者可依據本說明書得知,氯胺酮可用於改善或治療5-FU所引起的惡病質。
於本說明書實施例揭示之內容,本發明所屬領域具有通常知識者可明顯得知前述實施例僅為例示而非限制;本發明所屬技術領域具有通常知識者可藉由諸多變換、替換而實施,並不與本發明之技術特徵有所差異。依據說明書實施例,本發明可有多種變換仍無礙於實施。本說明書提供之請求項界定本發明之範圍,該範圍涵蓋前述方法與結構及與其相等之創作。
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Claims (10)
- 一種氯胺酮用於製備改善惡病質之藥物之用途,其中該藥物係給予接受5-FU治療之患者。
- 如請求項1所述之用途,其中氯胺酮之人體劑量為每周1-100 mg/60 kg。
- 如請求項1所述之用途,其中該藥物係用於非腸胃道給藥。
- 如請求項1所述之用途,其中該藥物係用於改善因惡病質引起之體重降低。
- 如請求項1所述之用途,其中該藥物係用於提高存活率。
- 一種治療癌症之醫藥組合物,包括:5-FU、氯胺酮、和一醫藥上可接受之載劑;其中氯胺酮之人體劑量為每周1-100 mg/60 kg。
- 一種氯胺酮和5-FU之醫藥組合物用於製備治療癌症之藥物之用途。
- 如請求項7所述之用途,其中氯胺酮之人體劑量為每周1-100 mg/60 kg。
- 如請求項7所述之用途,其中該藥物係用於非腸胃道給藥。
- 如請求項7所述之用途,其中氯胺酮和5-FU係同時或分別給予患者。
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