TW201615221A - 炎症用藥臨床新應用 - Google Patents
炎症用藥臨床新應用 Download PDFInfo
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- TW201615221A TW201615221A TW104134952A TW104134952A TW201615221A TW 201615221 A TW201615221 A TW 201615221A TW 104134952 A TW104134952 A TW 104134952A TW 104134952 A TW104134952 A TW 104134952A TW 201615221 A TW201615221 A TW 201615221A
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Abstract
本發明提供多種炎症用藥的新臨床之應用。該多種炎症用藥皆是經過衛生署通過核准上市的炎症用藥。本發明提供多種炎症用藥有效的抑制不同類型的癌細胞。
Description
本發明係為多種炎症用藥的新適應症之應用,尤其該多種藥物為通過臨床實驗且具有抑制多種癌症之用途。
癌症長期高居全球死因之首,且罹患癌症人數更是逐年攀升,因此治療癌症儼然成為重要的課題。癌症的治療可區分為手術治療、放射線治療、化學治療及標靶治療。
一般來說,癌症藥物治療無論是化學治療或標靶治療,目的多是讓癌細胞無法複製、分裂,來阻斷腫瘤的蔓延擴張。在臨床治療選擇上,通常會結合一到數種化療藥物以及標靶治療,希望能藉由不同機制來殺死癌細胞以提高治療效果,但事實上,還是常遇到患者對於治療藥物的反應不佳。進一步,許多癌細胞相繼產生抗藥性,使藥物的使用成效大幅降低,最終導致癌症治療失敗。
炎症反應、炎性反應,俗稱發炎,指生物組織受到外傷、出血、或病原感染等刺激,激發的生理反應。其中包括了紅
腫、發熱、疼痛等症狀。炎性反應是先天免疫系統為移除有害刺激或病源體及促進修復的保護措施,並非如後天免疫系統般針對特定病源體。炎性反應並非等同於感染,即使很多時發炎是因感染而發生,發炎是生物體對病源體之反應之一。通常情况下,炎症是有益的,是人体的自动的防御反应,但是有的时候,炎症可以引起人体自身免疫系統的過敏,進而攻击自身的組織及細胞、如類風濕性關節炎和紅班狼瘡症等免疫系統過敏病症,免疫系統過敏所生成的COX-2及Interleukin-1 alpha使到軟骨組織疼痛及發炎。長期發炎可引起一系列疾病,如花粉症、牙周炎、動脈粥樣硬化、類風濕性關節炎,甚至癌症(如膽囊癌),因此炎性反應在正常情況下受生物體緊密監控。炎性反應可分為急性炎症和慢性炎症。急性炎症是生物體應該有害刺激的初步反應,更多的血漿和白血球(特別是粒細胞)從血液移往受損組織。一連串的生化反應進行傳播並熟成進一步的炎性反應,當中牽涉局部的血管系統,免疫系統及受損組織內的各個細胞。慢性炎症引致發炎部位的細胞類型改變,組織的毀滅與修復同時進行。
應用藥物包含:1.抗生素,如果是由感染引起的感染性炎症,可以使用一般人所说的“消炎药”或注射「消炎針」,实际上指的是抗生素,其實是殺死或抑制細菌的繁殖,而使感染引起的發
炎減少。2.抗發炎劑,如果不是由感染引起的炎症,医学上对于抑制炎症反应,用的是非類固醇抗發炎劑或類固醇。本發明所使用之檢測藥物,為抗發炎劑。
發明人依據長年的研究經驗,人類的癌症細胞常常有與正常細胞具有不同的表現性狀,型態上的差異或是作用機轉的變化或許也有可能被視為一種外來的侵入者,而每一種癌症細胞所在的位置不同,變異的狀態又與所處的環境有關,因此,第一個提出使用炎症用藥抑制癌症細胞的發明概念並且進行實驗。
相對的,在這些已經使用數十年炎症用藥,是早已被FDA所認可的用藥,具有大量藥物機轉及人體研究成果資料,因此,若應用在癌症方面,這項新發展會更省時、減少成本,也能和其他治療方式結合來提高效果。目前尚未有任何研究針對本發明所使用之藥物,進行癌症治療研究。
儘管如此,藥物開發依然是重要的醫學議題,必須經過繁複的臨床前試驗才能進入臨床試驗,根據統計,平均每一萬個新藥約只有五個能夠進入第一期臨床試驗。此外,除了藥物本身是否能大量製造的難題外,還需克服藥物安全性、病人篩選、試用劑量等問題,即便藥物已經通過FDA的核准並上市,亦有可能因上市後於人體發現不良反應而強制下架回收,由此可見藥物開發具有
一定的困難程度。
為解決上述的問題,本發明係針對通過臨床實驗的多種藥物進行新適應症的研發,而達到老藥新用的目標。
經過實驗設計結果顯示炎症用藥對正常細胞沒有或僅有微小的毒性,但至於炎症用藥在正常細胞與腫瘤細胞之間是否具有選擇性的影響,還待更多的研究釐清,而且並非所有的炎症用藥在相同的條件下均能有效的抑制腫瘤細胞,需要有許多的問題進行克服。
名詞定義
炎症用藥依據藥物的結構可以分為二大類,包含類固醇類及非類固醇性消炎劑。
類固醇又稱「腎上腺皮質素」,是存在人體內正常情況下的分泌的賀爾蒙,除了控制身體的養份代謝如:葡萄糖、脂肪、蛋白質、電解質的平衡、影響免疫系統外,在特殊的情況下還會大量分泌,讓身體可以應付一些緊急的需要,所以又屬於「壓力性賀爾蒙」的一種。既然是人體自然產生的物質,理論上它就不可能是對身體有害的「毒藥」,之所以讓大眾聞聲色變,完全是因為過去被濫用的後果。類固醇是一種強力的抗發炎劑,可以減輕骨破壞性疼
痛、及神經或脊髓受擠壓引起的疼痛。此外,還能提高情緒、增加食慾,所以對疼痛整體性改善都有幫助。舉凡因為發炎或自體免疫(也是一種發炎)而導致的疾病,例如氣喘、類風濕性關節炎、紅斑性狼瘡、重症肌無力...等,類固醇都可以扮演著救命仙丹的角色。
非類固醇性消炎劑(NSAIDS)具有顯著的鎮痛、消炎及解熱作用。主要治療風濕性關節炎、骨關節炎、經痛、牙痛、一般疼痛緩解以及神經痛、腰背痛、上呼吸道感染、手術及外傷的消炎止痛。由於人體腸胃系統有一套保護自己胃壁不會被胃酸侵蝕的系統,此一系統依賴前列腺素的調節,而前列腺素的產生由環氧化酵素(cyclo-oxygenase),簡字為Cox來催化。而非類固醇消炎止痛藥物會抑制Cox的作用,減少前列腺素的產生,使胃壁上的胃黏液屏壁變薄,容易被胃酸侵蝕而形成潰瘍。最近發現Cox有兩種,在胃內的是Cox1而與發炎有關的是Cox2。理論上,若發現止痛藥物只抑制Cox2而不影響Cox1就不會有胃腸不適,且可望達到消炎止痛的目的。新一代Cox2抑制劑,既有止痛消炎的作用,也不會抑制Cox1保護腸胃的功能而減少副作用了。
本發明所使用之藥物包含:
1. Nepafenac治療白內障手術後疼痛及發炎之含0.1% nepafenac眼藥,屬於[非類固醇抗炎的專門用藥],具特定作用,
來快速穿透眼睛組織,藉此將治療效果最佳化,並改善病人手術後結果
2. CELEBREX 200MG,是一種[非類固醇消炎藥],它在動物摸式中具有抗發炎,止痛及解熱的活性,一般認為,本品作機轉乃是抑制前列線素(prostaglandin)之合成,主要經由抑制環氧酶-2(cyclooxygenase-2COX-2):在治尞劑量下,本品並不會抑制環氧醇-1(COX-1)同功,所以本品不會影響COX-1對冑黏膜保護以及維持血小皮凝血作用的功能。緩解骨關節炎之症狀與徵兆,緩解成人類風濕性關節炎之症狀與徵兆,及減少家族性腺瘤息肉症(FAP)病患之息肉數目。本品主要經由肝臟細胞色素P450 2C9代謝。
3. Adapalene(1)本品類似維生素A酸(Tretinoin),可結合特定維生素A酸細胞核受體(Retinoic acid nuclear receptors);但和維生素A酸(Tretinoin)不同的是,本品不會和細胞質受體結合蛋白(Cytosolic receptor binding proteins)相結合。(2)本品可抑制人類多形核白血球之趨化反應及化學動力學反應,同時也可抑制花生四烯酸(Arachidonic Acid)脂肪氧化(Lipoxidation)的方式,抑制其形成發炎前驅媒介物。也就是說本品可改變粉刺的細胞媒介發炎成份,局部使用本品可使上皮毛囊細胞化正常。Adaplaene是一種維生素A類化合物,於活體試驗及體外試驗發炎反應中皆顯示其具有抗發炎性。
Adapalene本質上對氧氣及光線呈現穩定。Adapalene類似維生素A酸(Tretinoin),可結合特定維生素A酸細胞核受體(Retinoic acid nuclear receptors);但和維生素A酸(Tretinoin)不同的是,Adapalene不會和細胞質受體結合蛋白(Cytosolic receptor binding proteins)相結合。Adapalene在Rhino小鼠試驗模式施用於皮膚時,具有分解粉刺的性質,且對異常的表皮角質化,分化過程有療效。而表皮異常角質化,分化即為促成尋常痤瘡(acne vulgaris)的病理因素。因此推測Adapalene的作用模式係使毛囊上皮細胞分化正常而導致微細粉刺的生成減少。Adapalene在標準抗發炎檢定分析中皆比參考品維生素A酸類優異,此分析包括體外試驗及活體試驗,就機轉方面而言,Adapalene可抑制人類多形核白血球之趨化反應及化學動力學反應,同時也可抑制花生四烯酸(Arachidonic Acid)脂肪氧化(Lipoxidation)的方式,抑制其形成發炎前驅媒介物此一代謝作用。此種情況即顯示粉刺的細胞媒介發炎成分可被Adapalene改變。對人類病人進行研究也提供了臨床證據,證實施用Adapalene於皮膚可有效減少粉刺之發炎成分(即丘疹和膿胞顯著減少)。Adapalene經由人類皮膚之吸收量低;臨床試驗中,長時間經皮膚用藥於大面積粉刺皮膚後採用0.15ng.mL-1之靈敏度分析,結果並未發現任何可測量的血漿Adapalene濃度。在投予放射線標示之[14C]-Adapalene於
大鼠(IV,IP,口服及經皮膚吸收)、兔(IV,口服及經皮膚吸收)、犬(IV及口服)後,放射性則分佈於數種組織中,最高濃度出現於肝、脾、腎上腺及卵巢;動物體內代謝已被證實主要係經O-去甲基化(O-Demethylation)、羥基化(Hydroxylation)及共軛接合反應(Conjugation),排泄主要係經由膽汁途徑。動物研究中,施用Adapalene於兔皮膚長達6個月時間及小鼠皮膚長達2年時間,皆對Adapalene的忍受性良好。全部動物以口服投藥的實驗中,發現的主要毒性症狀係為類似維生素A過量症候群,包括了骨質溶解,鹼性磷酸酵素增高及略為貧血。口服大劑量Adapalene對動物並未造成神經、心血管或呼吸方面的不良影響;Adapalene不具致突變性。於小鼠皮膚劑量0.6、2及6mg.kg-1.d-1和大鼠口服劑量0.15、0.5及1.5mg.kg-1.d-1已完成Adapalene的終生使用研究,唯一有意義的發現是,接受Adapalene 1.5mg.kg-1.d-1劑量的雄大鼠,腎上腺髓質的良性嗜鉻細胞瘤統計上顯著增加。但此種改變被視為與經皮膚使用Adapalene無關
4. Febuxostat(Uloric),非嘌呤類(non-purine)的黃嘌呤氧化酶抑制劑(xanthine oxidase inhibitor)。〔黃嘌呤氧化酶主要是將次黃嘌呤(hypoxanthine)轉換成黃嘌呤(xanthine),進一步再轉換成尿酸(uric acid)〕。藉由抑制黃嘌呤氧化酶而達到降低尿酸的
作用。Feburic是一種黃嘌呤氧化酶抑制劑,可降低血清尿酸達到治療作用。在治療濃度時不會抑制參與在嘌呤、嘧碇的合成與代謝過程中其他酵素作用。可治療慢性痛風患者的高尿酸血症:Febuxostat通過尿苷雙磷酸葡萄糖醛酸基轉移酶包括UGT1A1、UGT1A3、UGT1A9和UGT2B7的共軛結合作用,以及通過細胞色素P450(CYP)包括CYP1A2、2C8和2C9和非P450酵素的氧化作用被廣泛地代謝。Febuxostat是由肝和腎路徑排除。
5. Tazarotene(Avage),是維生素A酸類的前驅藥物,局部使用tazarotene可遮斷誘生小鼠表皮鳥胺酸脫羧酵素ornithine decarboxylase,ODC)活性,此與細胞的增生與增殖有關。tazarotene可阻遏MRP8的表現,MRP8是一種發炎標記,高濃度存在於乾癬患者的表皮。用於人類角質細胞培養,tazarotene可抑制角化包囊(cornified envelope)的形成,角化包囊的積聚構成乾癬鱗片的一種成分。tazarotene可抑制錢鼠皮膚角質細胞的堆積,且於培養的人類角質細胞可抑制交聯包囊(cross-linked envelope)的形成。Tazarotene是類視黃質前驅藥物,tazarotene經由動物及人體內快速脫酯化反應,而轉化其活性形式,亦即tazarotene均一羧酸(AGN 190299),AGN 190299(Tazarotenic acid)結合屬於視黃酸接受器(RAR)家族的全部三個成員:RARα、RARβ及RARγ,但對RARβ及RARγ表現出
相對選擇性,可修改基因表現,
6. Ibuprofen(Advil),是一種丙酸的衍生物,經由作用於末梢神經產生止痛作用。就藥理學來說,Ibuprofen提供鎮痛、消炎及解熱三種功效。與市售常見止痛藥成分(acetaminophen)不同,Ibuprofen可以抑制“前列腺素”的產生,直接作用於疼痛部位,還多了具有消炎作用功能。本品為NSAID具有腸胃道傷害副作用,但與高劑量比較,低劑量安舒疼止痛錠較溫和,也比較不刺激胃。
7. Ketoprofen(Actron),非類固醇類止痛及抗發炎,抑制前列線素產生。
8. Triamcinolone(Aristocort),為類固醇荷爾蒙,具有抗炎症作用,加入口腔專用基劑,目的在以溼潤創傷面,使藥劑能有效的潤治傷處,本劑另有特點具優異粘著性,在口腔內抑制唾液的流出,故對於口腔內之各種炎症及患能發揮迅速之治療效果。
9. Methoxsalen(Oxsoralen),是天然存在的光活性物質,源自於繖形科植物Ammimajus的種子,它是屬於Psoralens補骨脂或furocoumarins呋喃香豆素類的成員。化學式是9-methoxy-7H-furo[3,2-g][1]-benzopyran-7-one。藥理作用:皮膚的光線感受性增強,特別是長波長紫外線(320-42Onm)的感受性增加。患者照射紫外線,皮膚角質層肥厚,皮膚發炎反應露光部位melatonin
沉著。一旦色素再沉著,就不需重複治療,可維持8~14年。
10. Psoralens補骨脂是誘變劑,西柚中的一種化學成分香豆素(furanocoumarins)會抑制人體中一種化解藥物的酵素,從而使過量的藥物成分透過消化系統被人體吸收。
11. Strontium ranelate(Protelos),停經後婦女骨質疏鬆症之治療,以降低脊椎骨折與髖骨骨折的風險。在骨組織培養中增加骨質形成,並且在骨細胞培養中,增加造骨細胞先驅物(osteoblast precusor)複製及膠質合成。降低破骨細胞(osteoclast)分化及再吸收之活性。在不同的非臨床試驗模式中已對strontium ranelate之活性進行過研究。特別是在完整的大鼠中,strontium ranelate會增加骨小梁(trabecular)骨質量、骨小梁(trabeculae)數量及厚度;而改善骨骼強度。在接受治療的動物與人的骨組織中,strontium主要被吸附到磷灰石結晶表面,而且有些取代新形成骨質中磷灰石結晶內的鈣。在使用三年後,骨組織中每100個鈣約含有1個strontium,在動物實驗(猴子)中最多每10個鈣便有一個被strontium取代。但並不會因此改變骨結晶性質。於第三期臨床試驗中,每日以strontium ranelate 2g治療長達60個月後所取得的骼嵴(iliac crest)骨切片中,未發現到對骨品質或礦質化有害的影響。strontium在骨中分佈及其高於鈣的X光吸收之性質,使得以骨密度測量儀(DXA)測得之骨
質密度值(BMD)比實際值高出約50%。因此使用Protos®治療期間,BMD的增加應根據上述因素加以校正。在第三期臨床試驗中已說明Protos®抗骨折的療效,以Protos®治療,所測得的平均BMD值比基準點(baseline)增加,在腰椎每年增加將近4%,在股骨頸(femoral neck)每年增加約2%,在不同臨床試驗中在3年後分別達到13~15%及5~6%。於第三期臨床試驗中,相較於安慰劑組,strontium ranelate組從第3個月到最長3年,其骨質形成的生化標記(骨特異性的alkaline phosphatase及第一型procollagen C端propeptide)增加,而骨質再吸收的生化標記(血清C-telopeptide及尿液N-telopeptide交互連結)降低。經過strontium ranelate的藥理作用之後,會觀察到血鈣濃度及血中副甲狀腺(PTH)濃度降低,血中磷濃度及alkaline phosphatase活性增加,並沒有觀察到臨床症狀。臨床療效:骨質疏鬆症定義為脊椎骨或髖骨的BMD值比正常年輕族群平均值低2.5倍標準差或更低。有許多危險因子和停經後骨質疏鬆症有相關,包括低骨量、低骨密度(BMD)、提早停經、抽菸史或骨質疏鬆症家族史。骨質疏鬆症臨床上的後續結果是骨折。骨折的風險會隨著危險因子數增加而增加。對於停經後骨質疏鬆症之治療:抗骨折研究計畫是由兩個安慰劑對照的第三期臨床試驗組成:SOTI試驗及TROPOS試驗。SOTI涵括1,649位確定患有骨質疏
鬆症(腰椎的BMD值低且曾有脊椎骨折)的停經婦女,其平均年齡為70歲。TROPOS涵括5,091位患有骨質疏鬆症的停經婦女(股骨頸(femoral neck)BMD值低且一半以上有一般性骨折),其平均年齡為77歲。SOTI和TROPOS在收案時總共收入1,556位超過80歲的患者(占總受試者人數的23.1%)。在這兩個臨床試驗中除了試驗藥物之外(每日strontium ranelate 2g或安慰劑),受試者並接受適當的鈣與維生素D補充。於SOTI試驗中,經過3年後,Protos®會使新脊椎骨折相對危險性降低達41%(表一)。此效果從第一年已達顯著性。對於在基準點已患有多重骨折的婦女,也顯示出類似的效果。關於臨床上的脊椎骨折(定義為與背痛相關骨折以及/或身高減少至少1公分者),其相對危險性降低約38%。相較於安慰劑組,Protos®也使身高減少至少1公分的受試者數目減少。相較於安慰劑組,以QUALIOST特定尺度所作的生活品質評估以及SF-36一般尺度的總體健康認知分數都指出Protos®的益處。於TROPOS試驗中確認了Protos®降低新脊椎骨折危險性的療效,包括在基準點時沒有脆弱骨折的骨質疏鬆症患者。
12. Gallamine triethiodide(Flaxedil)加拉碘銨,(三碘季銨酚gallamine tricthiodide,flexedil)是含有三個季銨基團的人工合成的非除極化型肌松藥。(非去極化肌肉鬆弛劑)肌鬆作用和筒箭毒
堿相似,但無阻斷神經節和釋放組胺的作用,卻有較強的阿托品樣作用,能明顯解除迷走神經的張力,使心率加快,血壓輕度升高,心輸出量增加。靜脈給藥大部分經腎排出。重症肌無力、心動過速、高血壓及腎功能不全者忌用。三碘季銨酚為非去極化型肌松藥,是筒箭毒堿的第一個合成代用品,肌肉鬆弛作用與筒箭毒堿相似但較弱。持續效能隨用量而異,小劑量時比氯化筒箭毒堿為短,肌松的效能有限;大劑量時可使呼吸暫停,但肌張力並未完全消失。三碘季銨酚的肌肉鬆弛作用能為新斯的明所對抗。其可釋放組胺,對心肌功能無直接影響。常用劑量的神經節阻斷作用不明顯,但能抑制迷走神經節的衝動傳導,並有阿托品樣作用。非去極化型肌松藥又稱競爭型肌松藥。小劑量時與Ach競爭性結合N2膽鹼受體,藥物無內在活性,但使Aeh對受體的激動作用減弱或被取消,肌肉鬆弛。大劑量時,也干擾神經末梢Ach的流動性。本類藥物的阻斷作用可被膽鹼酯酶抑制劑(如新斯的明)拮抗。
13. Quinapril HCl(Accupril),ACCUPRIL®(Quinapril hydrochloride)是Quinapril的鹽酸鹽,而Quinapril是Quinaprilat的乙酯,為一種不含硫氫基(SH group)之血管收縮素轉化酵素(Angiotensin-Converting Enzyme)抑制劑。Quinapril hydrochloride之化學簡式為C25H30N2O5˙HCl,化學式為3S-[2[R*(R*)],
3R*]]-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxoprophl]-1,2,3,4-etrahydro-3-isoquinolinecarboxylic acid,monohydrochloride。Quinapril hydrochloride是一種白色至灰白色的非結晶粉末,易溶於水。每錠含Quinapril 10毫克或20毫克,口服投予。非活性成分包括candelilla蠟、crospovidone、明膠、乳糖、碳酸鎂、硬脂酸鎂、合成紅氧化鐵、及二氧化鈦。臨床藥理學:作用機轉Quinapril口服後迅速去酯化成Quinaprilat(為Quinapeil主要的代謝物)。Quinaprilat在人體及動物體內,為一強效的血管收縮素轉化酵素(ACE)抑制劑。ACE為一種胜類的二胜酵素(peptidyl dipeptidase),它可使血管收縮素I(angiotensin I)轉化成強力的血管收縮素-血管收縮素II(angiotensin II)。Quinapril對高血壓及充血性心衰竭(CHF)的影響,主要是來自於抑制循環及組織內的血管收縮素轉化酵素,進而減少血管收縮素II的形成所致。Quinapril可抑制靜脈注射血管收縮素I所引起的血壓升高,但是對於身體對血管收縮素II、正腎上腺素(norepinephrine)或腎上腺素(epinephrine)的反應並無影響。血管收縮素II也會刺激腎上腺皮質分泌醛固酮(aldosterone),進而促進腎臟的鈉離子與水分再吸收。Quinapril會減少醛固酮的分泌,使血鉀濃度小幅升高。在對照性高血壓試驗中,單獨使用ACCUPRIL®治療可使血鉀濃度平均升高0.07毫莫耳/公升(請參閱
注意事項)。消除血管收縮素II對腎素(renin)分泌的負迴饋作用,可導致血漿腎素活性(PRA)增加。Quinapril的主要降血壓作用機轉被認為是經由腎素-血管收縮素-醛固酮系統,但是對於低腎素高血壓患者,Quinapril仍具有降血壓作用。經由研究証實,ACCUPRIL單一療法對各人種均可有效降低其血壓,然而對黑色人種(通常腎素含量較低)的效果比非黑色人種差。ACE亦即“Kininase II”,可分解強力的血管舒張胜類bradykinin;bradykinin濃度升高是否在Quinapril的療效上扮演某種角色,仍待釐清。
14. Beclomethasone dipropionate,為一種強效局部作用之抗發炎劑,局部使用時可有效地抑制肥大細胞的細胞膜被分解,因而抑制發炎介質的釋出,緩解之氣管發炎的現象,改善肺部功能。為達到藥效,Beclomet Easyhaler需規則性地使用:藥品的最大療效於使用數日後就會出現。所有吸入型皮質類固醇,均可能產生全身性效應,尤其是長期使用高劑量。因此,務必定期檢查患者,並將吸入型皮質類固醇降低至足以有效控制氣喘的最低劑量。長期使用高劑量吸入型皮質類固醇來治療患者,可能造成腎上腺功能抑制與急性腎上腺危象(adrenal crisis)。以吸入方式投予beclomethasone dipropionate建議劑量時,在肺內具有糖皮質素的抗發炎作用,能減輕氣喘的症狀與惡化程度,副作用少於全身性投予
皮質類固醇。
15. olsalazine sodium本品為水楊酸類藥物,通過偶氮鍵連接兩分子5-氨基水楊酸,到達結腸部位後其偶氮橋在細菌作用下斷裂,分解為二分子5-氨基水楊酸並作用於結腸炎症粘膜,抑制前列腺素合成,抑制炎症介質白三烯的形成,降低腸壁細胞膜的通透性減輕腸粘膜水腫。
16. AzodisatSodium,Cl14130,Disodiumazobis,Dipentum,常用其鈉鹽,白色或類白色結晶性粉末,熔點>300℃。本品以活性成分5-氨基水楊酸替代柳氮磺胺吡啶中無活性的磺胺吡啶,即通過偶氮鍵連接兩分子5-氨基水楊酸,提高了療效,降低了不良反應發生率。5-氨基水楊酸是治療潰瘍性結腸炎的有效成份,但口服5-氨基水楊酸後在小腸被吸收,乙醯化後隨尿排出,不能到達結腸部位。本品在胃及小腸中不被吸收也不分解,到達結腸部位後其偶氮橋在細菌作用下斷裂,分解為二分子5-氨基水楊酸並作用於結腸炎症粘膜,抑制前列腺素合成,抑制炎症介質白三烯的形成,降低腸壁細胞膜的通透性,減輕腸粘膜水腫。本品原形很少被吸收,其分解產物5-氨基水楊酸在結腸部位的濃度大於血清中藥物濃度1000倍。潰瘍性結腸炎患者口服治療量(每日1~4g)後,本品和5-氨基水楊酸在管腔內的濃度分別為0.04~0.14g/L和0.8~3.5g/L。人口
服15mg/kg後,tmax為1~2小時,Cmax為2~4mg/L,24小時後仍有少量藥物存留在血液中。口服劑量的99%到達結腸,全身吸收很少。本品分佈容積低,僅6.2±1.5L,蛋白結合率高。輕度至嚴重活動性潰瘍性結腸炎患者每日口服本品1~3g,療程3個月,54%~66%患者臨床症狀獲得改善,28%患者病情獲緩解。活動性潰瘍性結腸炎患者(包括對柳氮磺胺吡啶過敏和不能耐受的病人)每日口服本品0.75~4g達6個月至2年,臨床總改善率相似(58%~65%)。病情緩解後繼續服藥可維持療效。63%~88%的患者經6~24個月治療,病情繼續獲得緩解。用於治療急、慢性潰瘍性結腸炎與節段性回腸炎,並用於緩解期的長期維持治療。
17. tetrahydrozoline hydrochloride用於治療眼睛疲勞、刺激性過敏、眼睛過敏、結膜炎、結膜充血。
18. Sertraline HCl,用於治療憂鬱症。本品為一作用強具有高度專一性的神經傳導物質serotornin(5HT)再回收抑制劑,試驗顯示其有加強5-HT作用的效果,其對於norepinephrine和dopamin等其他神經傳導物質的影響很低。在正常健康受試者的對照試驗,顯示本品無鎮靜作用且不影響精神運動性的表現,由於本品的選擇性高,因此不會使catecholaminergics活性增強,且對於muscarinic(cholinergic),seroionergic,dopaminergic,adrenergic,
histaminergic,GABA,benzodiazepine等接受器無親合性。和其他三環抗憂鬱劑不同,治療後病人體重並不會增加,有些病人的體重反而減輕。本藥上未發現有任何身體上或精神上的依賴性。
19. triamterene脫浮腫膠囊所含成分Triamterene為美國S.K.F.科學家Wieblhans於1961年首先發明之Pteridine系利尿劑,本品不但副作用少,而且對鉀之排泄很少,此點為所有利尿劑稀有之特殊優越作用,臨床實驗方面1961年美國Crosley氏Laragh氏德國Harken氏Kriick氏以及1962年英國Donnely氏更確證本品在利尿方面之卓越效果故本品必將成為醫藥界所期待之利尿降壓劑。
20. Carprofen,動物最常用的非類固醇類止痛劑。1997年出廠輝瑞藥廠的Rimadyl(carprofen)也可以用來以減輕短期術後疼痛,炎症,和後葉面噴施,絕育腫脹,和其它程序。卡布洛芬通過抑制減少炎症,COX-2和炎症的其他來源的前列腺素。這是針對保護,因為它不干擾的COX-1的活性
21. Benzydamine Hydrochloride,為一抗炎止痛劑,其化學結構為非類固醇,並與其他的非固醇類抗炎藥性質不同,是一鹼類而非酸類。動物實驗顯示使用全身性的benzydamine可有效的治療發炎引起的疼痛及水腫,亦可抑制肉芽腫的生成。在局部的治療濃度下,benzydamine具有局部麻醉作用。大鼠口服benzydamine
達劑量100mg/kg,並未造成胃黏膜潰瘍。Benzydamine對發炎性的疼痛其止痛效果較非發炎性的疼痛為佳,和aspirin類似藥品相同,benzydamine亦具有解熱作用,貓靜脈注射benzydamine,會短暫抑制其周邊反射反應。Benzydamine抗發炎的作用基轉與刺激腦下腺一腎上腺軸無關,其與其他的非固醇類抗炎藥相同,在某些情況下benzydamine的作用方式為抑制前列腺素的合成,但其特性尚未完全闡明。穩定細胞膜亦為作用轉機之一。
22. Auranofin典型或肯定的活動性類風濕性關節炎患者。服用一種或多種非甾體類抗炎藥物效果不顯著或無法耐受的,可接受金諾芬治療。金諾芬不能消除已出現的骨關節破壞,但有可能阻止或減緩關節的進一步損害。由於金諾芬起效慢,平均為3個月,有遲至5~6個月者,所以在服用金諾芬的同時宜加服非甾體抗炎藥(NSAID),以便在金諾芬發揮作用前減輕病人類風濕關節炎引起的疼痛。其能抑制DNA合成。
本發明提供一種一種製備抑制癌症之醫藥組合物之方法,其中該醫藥組合物係選自一抗發炎藥物所組成群組之藥物。
本發明一實施例中,其中該抗發炎藥物係選自一類固醇抗發炎藥物、一非類固醇抗發炎藥物。
本發明一實施例中,其中該類固醇抗發炎藥物係選
自Triamcinolone(Aristocort)、Beclomethasone dipropionate。
本發明一實施例中,其中該非類固醇抗發炎藥物係選自維生素A類化合物,其中該維生素A類化合物係包括Adapalene。
本發明一實施例中,其中該非類固醇抗發炎藥物係選自維生素A之前驅物,其中該維生素A之前驅物係包括Tazarotene(Avage)。
本發明一實施例中,其中該非類固醇抗發炎藥物係選自黃嘌呤氧化酶抑制劑,其中該黃嘌呤氧化酶抑制劑係包括Febuxostat(Uloric)。
本發明一實施例中,其中該非類固醇抗發炎藥物係選自丙酸之衍生物,其中該丙酸之衍生物係包括Ibuprofen(Advil)。
本發明一實施例中,其中該非類固醇抗發炎藥物係選自植物種子之光活性物質,其中該植物種子之光活性物質係包括Methoxsalen(Oxsoralen)
本發明一實施例中,其中該非類固醇抗發炎藥物係選自骨骼疾病治療劑,其中該骨骼疾病治療劑係包括Strontium ranelate(Protelos)。
本發明一實施例中,其中該非類固醇抗發炎藥物係選自去極化肌肉鬆弛劑,其中該去極化肌肉鬆弛劑係包括Gallamine
triethiodide(Flaxedil)
如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自血管收縮素轉化酶抑制劑,其中該血管收縮素轉化酶抑制劑係包括Quinapril HCl(Accupril)。
本發明一實施例中,其中該非類固醇抗發炎藥物係選自Imidazole類衍生物,其中該Imidazole類衍生物係包括tetrahydrozoline hydrochloride。
本發明一實施例中,其中該類固醇抗發炎藥物係選自血清素回收抑制劑,其中該血清素回收抑制劑係包括Sertraline HCl。
本發明一實施例中,其中該非類固醇抗發炎藥物係選自利尿降壓劑,其中該利尿降壓劑係包括triamterene。
本發明一實施例中,其中該非類固醇抗發炎藥物係選自乙酸之衍生物,其中該乙酸之衍生物係包括Amfenac Sodium(monohydrate)。
本發明一實施例中,其中該非類固醇抗發炎藥物係選自抗微生物製劑,其中該抗微生物製劑係包括Chloroquine Phosphate。
本發明一實施例中,其中該非類固醇抗發炎藥物係
選自DNA合成抑制劑,其中該DNA合成抑制劑係包括Auranofin。
本發明一實施例中,其中該類固醇抗發炎藥物更包括Nepafenac、CELEBREX、Ketoprofen(Actron)、olsalazine sodium、Carprofen、Benzydamine Hydrochloride。
本發明一實施例中,其中該癌症係選自由肺癌、腸道癌、大腸直腸癌、攝護腺癌、膀胱癌、子宮頸癌、乳癌及皮膚癌所組成之群組。
本發明一實施例中,其中該藥物的有效劑量濃度為20mg/kg/day。
現今癌症藥物費用動輒上萬至數百萬元,若未來更進一步證實炎症用藥對腫瘤的療效,對於無法負擔昂貴治療的患者們,這些便宜而歷史悠久的藥物,會是帶來健康的新希望。
第一圖顯示本發明炎症用藥應用於抑制癌細胞分析結果。
建立細胞株
請參考表一,將不同癌症類型的細胞株進行繼代培養,計算細胞數目後,回種2x106細胞數,然後加入培養該細胞株之培養液補至體積為10ml,繼續培養2-3天。之後將細胞計數,並分裝至96孔盤,其中每孔的細胞數目固定為3000顆,且體積為100ul。
細胞存活分析方法
將96孔盤中原有的培養液吸掉,每孔加入濃度10um、體積100ul的市售藥物,放置72小時後,每孔再加入100ul已稀釋的WST-1試劑,該稀釋比例為培養液與WST-1原液的體積比為9:1,最後每個孔盤的總體積為200ul,然後將96孔盤放置於37度30~90分鐘,利用elisa reader於OD450偵測吸光值,並計算各癌症細胞株之存活率。
炎症用藥應用於抑制癌細胞分析結果
炎症用藥依據藥物的結構可以分為類固醇抗發炎藥物、非類固醇抗發炎藥物。
實驗結果明顯的顯示有許多的炎症用藥並無法有效
的抑制癌症的細胞的生長(表二)。
而相對的各種的炎症用藥分子對於各種癌症細胞的抑制效果也不盡相同(圖一),經過發明人實驗結果,證實炎症用藥藥物Nepafenac AuranofinCelecoxib、Adapalene、Febuxostat(Uloric)、Tazarotene(Avage)、Ibuprofen(Advil)、Ketoprofen(Actron)、Triamcinolone(Aristocort)、Methoxsalen(Oxsoralen)、Strontium ranelate(Protelos)、Gallamine triethiodide(Flaxedil)、Quinapril HCl(Accupril)、Beclomethasone dipropionate、olsalazine sodium、tetrahydrozoline hydrochloride、Sertraline HCl、triamterene、
Carprofen、Amfenac Sodium(monohydrate)、Chloroquine Phosphate、Benzydamine Hydrochloride等藥物對於不同的癌症細胞有明顯的抑制效果。(表三)
Leflunomide對肺癌,胃癌,皮膚癌,膀胱癌有抑制效果;Nepafenac對肺癌,胃癌,前列腺癌,皮膚癌,乳癌有抑制效果;Celecoxib對肺癌,胃癌,前列腺癌,皮膚癌,膀胱癌,乳癌有抑制效果;Adapalene對肺癌,胃癌,直腸癌,前列腺癌,膀胱癌,乳癌,血癌有抑制效果;Cetirizine Dihydrochloride對肺癌,直腸癌有抑制效果;Etodolac(Lodine)對肺癌,皮膚癌有抑制效果;Loratadine對肺癌,胃癌,直腸癌,皮膚癌,有抑制效果;Pizotifen malate對肺癌,胃癌,皮膚癌有抑制效果;Rolipram對肺癌,胃癌,皮膚癌有抑制效果;Betamethasone(Celestone)對肺癌,胃癌有抑制效果;Ibuprofen Lysine(NeoProfen)對肺癌,胃癌有抑制效果;Febuxostat(Uloric)對肺癌,胃癌,膀胱癌,乳癌有抑制效果;Tazarotene(Avage)對肺癌,胃癌,皮膚癌,膀胱癌,乳癌有抑制效果;Sulfasalazine(Azulfidine)對肺癌,胃癌,膀胱癌有抑制效果;Naproxen(Aleve)對胃癌膀胱癌,乳癌有抑制效果;Triamcinolone Acetonide對胃癌,乳癌有抑制效果;
Zafirlukast(Accolate)對胃癌,乳癌有抑制效果;Ibuprofen(Advil)對肺癌,胃癌,膀胱癌,乳癌有抑制效果;Ketoprofen(Actron)對肺癌,胃癌,結腸癌,前列腺癌,膀胱癌,乳癌有抑制效果;Mesalamine(Lialda)對肺癌,胃癌有抑制效果;Desonide對胃癌,乳癌有抑制效果;Piroxicam(Feldene)對肺癌,胃癌有抑制效果;Indomethacin(Indocid,Indocin)對肺癌,乳癌有抑制效果;Meloxicam(Mobic)對皮膚癌,乳癌有抑制效果;Suprofen(Profenal)對皮膚癌,乳癌有抑制效果;Fenoprofen calcium對肺癌,胃癌,乳癌有抑制效果;Cimetidine(Tagamet)對胃癌抑制效果;Triamcinolone(Aristocort)對肺癌,胃癌,結腸癌,前列腺癌,皮膚癌,膀胱癌,乳癌有抑制效果;Methoxsalen(Oxsoralen)對肺癌,胃癌,結腸癌,前列腺癌,皮膚癌,乳癌有抑制效果;Mometasone furoate對肺癌有抑制效果;Fluticasone propionate(Flonase,Veramyst)對肺癌有抑制效果;Maraviroc對肺癌有抑制效果;Epalrestat對肺癌,乳癌有抑制效果;
Dyclonine HCl對肺癌,結腸癌,前列腺癌,乳癌有抑制效果;Lornoxicam(Xefo)對肺癌,結腸癌,前列腺癌,乳癌有抑制效果;Strontium ranelate(Protelos)對肺癌,胃癌,結腸癌,前列腺癌,皮膚癌,乳癌有抑制效果;Vinpocetine(Cavinton)對胃癌有抑制效果;Gallamine triethiodide(Flaxedil)對胃癌,肝癌,直腸癌,結腸癌,前列腺癌,皮膚癌,膀胱癌有抑制效果;Tobramycin對膀胱癌有抑制效果;Quinapril HCl(Accupril)對肺癌,胃癌,結腸癌,前列腺癌,乳癌有抑制效果;Ethisterone對肺癌有抑制效果;Zaltoprofen對皮膚癌有抑制效果;Rimonabant(SR141716)對胃癌,皮膚癌有抑制效果;PMSF(Phenylmethylsulfonyl Fluoride)對胃癌有抑制效果;Cinepazide maleate對肺癌,胃癌有抑制效果;(R)-baclofen對肺癌,胃癌,前列腺癌,皮膚癌有抑制效果;Beclomethasone dipropionate對肺癌,胃癌,皮膚癌,前列腺癌有抑制效果;
Betahistine 2HCl對肺癌直腸癌,皮膚癌有抑制效果;Catharanthine對前列腺癌,血癌有抑制效果;Sodium Monofluorophosphate對前列腺癌有抑制效果;Cyclamic acid對肺癌,胃癌,前列腺癌,皮膚癌有抑制效果;olsalazine sodium對胃癌,肝癌,結腸癌,皮膚癌,前列腺癌,皮膚癌有抑制效果;tetrahydrozoline hydrochloride對肺癌,胃癌,肝癌,直腸癌,結腸癌,前列腺癌,皮膚癌,膀胱癌有抑制效果;Sertraline HCl對胃癌,直腸癌,結腸癌,前列腺癌,皮膚癌,膀胱癌有抑制效果;triamterene對肺癌,胃癌,直腸癌,結腸癌,前列腺癌,皮膚癌有抑制效果;Halobetasol Propionate對前列腺癌,皮膚癌,膀胱癌有抑制效果;Fenspiride HCl對胃癌有抑制效果;Carprofen對肺癌,直腸癌,結腸癌,前列腺癌,膀胱癌,乳癌有抑制效果;Amfenac Sodium(monohydrate)對肺癌,胃癌,直腸癌,前列腺癌,皮膚癌,乳癌,血癌有抑制效果;Chloroquine Phosphate對肺癌,胃癌,結腸癌,前列腺癌,皮膚癌,膀胱癌,乳癌有抑制效果;
Benzydamine Hydrochloride對肺癌,胃癌,直腸癌,結腸癌,前列腺癌,皮膚癌,膀胱癌,乳癌有抑制效果;Sasapyrine對結腸癌有抑制效果;Fluorometholone Acetate對肺癌,乳癌有抑制效果;Oxaprozin對肺癌有抑制效果;Auranofin對肺癌,胃癌,肝癌,結腸癌,前列腺癌,皮膚癌,膀胱癌,乳癌,血癌有抑制效果;Glafenine HCl對肝癌,皮膚癌,膀胱癌有抑制效果;Dichlorisone Acetate對肺癌,皮膚癌,乳癌有抑制效果;Isoxicam對肺癌,胃癌,膀胱癌,乳癌有抑制效果;Nifenazone對肺癌,,皮膚癌,膀胱癌,乳癌有抑制效果;對肺癌,胃癌,肝癌,直腸癌,結腸癌,前列腺癌,皮膚癌,膀胱癌,乳癌,血癌有抑制效果;
重複性實驗
依據表三所示結果,針對對癌症細胞株有效之藥物進行重覆性實驗,其結果如表四所示。
表四、具抑制癌症細胞株之炎症用藥
上列詳細說明係針對本發明之一可行實施例之具體說明,惟該實施例並非用以限制本發明之專利範圍,凡未脫離本發明技藝精神所為之等效實施或變更,均應包含於本發明之專利範圍中。
Claims (19)
- 一種製備抑制癌症之醫藥組合物之方法,其中該醫藥組合物係選自一抗發炎藥物所組成群組之藥物。
- 如申請專利範圍第1項所述之方法,其中該抗發炎藥物係選自一類固醇抗發炎藥物、一非類固醇抗發炎藥物。
- 如申請專利範圍第2項所述之方法,其中該類固醇抗發炎藥物係選自Triamcinolone(Aristocort)、Beclomethasone dipropionate。
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自維生素A類化合物,其中該維生素A類化合物係包括Adapalene。
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自維生素A之前驅物,其中該維生素A之前驅物係包括Tazarotene(Avage)。
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自黃嘌呤氧化酶抑制劑,其中該黃嘌呤氧化酶抑制劑係包括Febuxostat(Uloric)。
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自丙酸之衍生物,其中該丙酸之衍生物係包括Ibuprofen(Advil)。
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自植物種子之光活性物質,其中該植物種子之光活性物質係包括Methoxsalen(Oxsoralen)
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自骨骼疾病治療劑,其中該骨骼疾病治療劑係包括Strontium ranelate(Protelos)。
- 如申請專利範圍第2所述之方法,其中該非類固醇抗發炎藥物係選自去極化肌肉鬆弛劑,其中該去極化肌肉鬆弛劑係包括Gallamine triethiodide(Flaxedil)
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自血管收縮素轉化酶抑制劑,其中該血管收縮素轉化酶抑制劑係包括Quinapril HCl(Accupril)。
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自Imidazole類衍生物,其中該Imidazole類衍生物係包括tetrahydrozoline hydrochloride。
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自血清素回收抑制劑,其中該血清素回收抑制劑係包括Sertraline HCl。
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自利尿降壓劑,其中該利尿降壓劑係包括triamterene。
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自乙酸之衍生物,其中該乙酸之衍生物係包括Amfenac Sodium(monohydrate)。
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自抗微生物製劑,其中該抗微生物製劑係包括Chloroquine Phosphate。
- 如申請專利範圍第2項所述之方法,其中該非類固醇抗發炎藥物係選自DNA合成抑制劑,其中該DNA合成抑制劑係包括Auranofin。
- 如申請專利範圍第2項所述之方法,其中非類固醇抗發炎藥物更包括Nepafenac、CELEBREX、Ketoprofen(Actron)、olsalazine sodium、Carprofen、Benzydamine Hydrochloride。
- 如申請專利範圍第1項所述之方法,其中該癌症係選自由肺癌、腸道癌、大腸直腸癌、攝護腺癌、膀胱癌、子宮頸癌、乳癌及皮膚癌所組成之群組。
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TW104134933A TWI652060B (zh) | 2014-10-24 | 2015-10-23 | 阿折地平藥物應用於癌症治療 |
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TW104134942A TW201615195A (zh) | 2014-10-24 | 2015-10-23 | 阿那格雷藥物應用於癌症治療 |
TW104134965A TW201615226A (zh) | 2014-10-24 | 2015-10-23 | 代謝性疾病藥物臨床新應用 |
TW104134944A TW201615219A (zh) | 2014-10-24 | 2015-10-23 | 呼吸系統疾病用藥臨床新應用 |
TW104134956A TW201615196A (zh) | 2014-10-24 | 2015-10-23 | 山喜多藥物應用於癌症治療 |
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TW104134960A TW201615191A (zh) | 2014-10-24 | 2015-10-23 | 氨氯地平藥物應用於癌症治療 |
TW104134928A TW201615197A (zh) | 2014-10-24 | 2015-10-23 | 蘋果酸丙氯陪拉辛錠藥物應用於癌症治療 |
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TW104134950A TWI663969B (zh) | 2014-10-24 | 2015-10-23 | 莫諾苯宗藥物應用於癌症治療 |
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WO2016062278A1 (zh) * | 2014-10-24 | 2016-04-28 | 朗齐生物医学股份有限公司 | 内分泌疾病用药在制备抑制癌症的医药组合物中的应用 |
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