TWI463977B - 用於激活自然殺手細胞之茄紅素及白藜蘆醇複合物 - Google Patents
用於激活自然殺手細胞之茄紅素及白藜蘆醇複合物 Download PDFInfo
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Description
本專利揭示由一個類胡蘿蔔素和一個萜類化合物組成的複合物。該複合物中的類胡蘿蔔素特指茄紅素，萜類化合物特指白藜蘆醇。這兩個化合物以適當的比例混合後，作為膳食補充劑攝入到哺乳動物體內後經過代謝，發生協同作用提升自然殺手(NK)細胞活性，進而幫助機體抵抗腫瘤。
在我們於2009年5月14日提出申請的專利(編號No.SG 200903301-0)中，我們揭示了一個以茄紅素和白藜蘆醇為成分的配方，這兩個化合物按適當的比例進行混合後擁有抑制腫瘤生長的協同效應。但在該專利申請的時間點，抗腫瘤的協同作用的機理並不清楚。
哺乳動物體內的天然免疫由NK細胞承擔。NK細胞是一類大顆粒型淋巴球(LGL)，負責監視體內發生癌變的細胞，受病原體感染的細胞，和移植器官這樣的外來物。作為第一線的天然免疫，NK細胞不需要抗原來進行啟動，它先是找出因病原體或細胞癌變而發生變化的細胞，然後通過釋放穿孔素(perforin)、顆粒溶解酶(granzyme)等對細胞有毒的物質來殺死靶細胞。
由於NK細胞所擁有的強大的細胞裂解活性和無需預先活化的特性，NK細胞的細胞毒活性必須受到嚴格的調控，由一個專門的“扣扳機”的生化機制來控制。參與這個“扣扳機”的分子包括雙鏈RNA、細胞因子、Fc受體、以及其他相關因子的受體等。腫瘤的發病率業已證明與NK
細胞的數量和活性成反比。
在本專利申請之前，已有的啟動NK細胞活性之生化信號相關的專利有以下。美國專利US-4,883,662(Stout)揭示了應用生物物質來刺激腫瘤患者增殖NK細胞的方法，是通過將一株免疫抑制性的病毒注射到動物體內，再從動物上回收並分離動物體應對病毒而產生的物質，然後再注射到腫瘤患者血液中。
美國專利US-5,728,378(Hellstrand)描述了由α干擾素(IFN-α)和組織胺(histamine)、血清素(seretonin)構成的組合，可以用來提升單核細胞中的NK細胞的活性。該製備可以局部使用或系統性給藥用於腫瘤患者和受病毒感染的患者。該製品中的各成分之間有協同作用，組織胺和血清素的作用是抑制單核細胞的活動以有利於α干擾素活化NK細胞。
上述專利的一個後續美國專利US-6,063,373(Hellstrand)，揭示了一種由NK細胞啟動劑和細胞內過氧化氫抑制劑組成的組合，啟動單核細胞中的NK細胞的活性。其中NK啟動劑選自以下細胞因數中的一個：間白素-1(IL-1)、間白素-2(IL-2)、間白素-12(IL-12)、間白素-15(IL-15)、α-干擾素(IFN-α)、β-干擾素(IFN-β)、或γ-干擾素(IFN-γ)。NK細胞的啟動劑也可以是類黃酮，包括flavone-8 acetic acid(FAA)和xanthenone-4 acetic acid(XAA)。而細胞內過氧化氫抑制劑則選自組織胺、過氧化氫受體拮抗劑或血清素。
以植物來源的成分為組分通過提高NK活性(包括促進NK細胞增殖或提高NK細胞活性)來有效治療腫瘤或病
毒感染的膳食補充劑相關的專利並不多見。在歐洲專利EP-1,243,274(Lu Kung-Ming)中描述了用乳酸菌或酵母進行發酵處理後的大豆水抽提物擁有導致細胞凋亡的活性。在美國專利出版US 2002/010149(Yagita)描述了香菇(Lentinus edodes)的菌絲體可以誘導間白素-12(IL-12)的產生進而活化NK細胞。在PCT專利出版WO 2007/131767(Goral-Czyk)揭示了由茄紅素和染料木黃酮來治療攝護腺癌，其中提到可以添加白藜蘆醇用於輔助，但是沒有提出對NK細胞活性的影響。
1. Mein J.R., Lian F., Wang X.D., “Biological activity of lycopene metabolites: Implications for cancer prevention”, Nutr. Rev. 2008; 66(12):667 -83.
2. Giovannucci E., “Tomatoes, tomato-based products, lycopene, and cancer: Review of the epidemiologic literature”, Journal of the National Cancer Institute 1999; 91: 317-331.
3. Gann P.H., Ma J., Giovannucci E., Willett W., Sacks F.M., Hennekens C.H., Stampfer M.J., “Lower prostate cancer risk in men with elevated plasma lycopene levels: Results of a prospective analysis”, Cancer Res. 1999 Mar 15; 59(6):1225-30.
4. Ruhl R., et al. “Carotenoids and their metabolites are naturally occurring activators of gene expression via the pregnane X receptor”, Eur. J. Nutr. 2004; 43:336-343.
5. Lindshield B.L.,et al. “Lycopenoids: are lycopene metabolites bioactive？” Arch. Biochem. Biophys. 2007;
458(2):136-40.
6. Mossine V.V., et al. “Interaction of tomato lycopene and ketosamine against rat prostate tumorigenesis” Cancer Res. 2008; 68:4384-4391.
7. Venkateswaran V., et al. “A combination of micronutrients is beneficial in reducing the incidence of prostate cancer and increasing survival in the lady transgenic model”, Cancer Prev. Res. 2009; 2:473-483.
8. Arichi H, et al. “Effects of stilbene components of the roots of Polygonum cuspidatum” Chem. Pharm. Bull. 1982; 30: 1766-1770.
9. Kimura, Y., Okuda, H., and Arichi, S., “Effects of stilbenes, on arachidonate metabolism in leukocytes”, Biochim. Biophys. Acta 1985; 834: 275-278.
10. Gao X, et al. “Immunomodulatory activity of resveratrol: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production”, Biochem. Pharmacol. 2001; 62: 1299-1308.
11．Tsai S.H., et al. “Suppression of nitric oxide synthase and the down-regulation of the activation of NF-kB in macrophages by resveratrol”, Br. J. Pharmacol. 1999; 126: 673-680.
12. Falchetti R., et al. “Effects of resveratrol on human immune cell function”, Life Sci. 2001; 70: 81-96.
13. Heynekamp J.J., et al. “Substituted trans-stilbenes, including analogues of the natural product resveratrol, inhibit
the human tumor necrosis factor alpha-induced activation of transcription factor nuclear factor KappaB”, J. Med. Chem. 2006; 49: 7182-7189.
14. Andlauer W, et al. “Assessment of resveratrol bioavailability in the perfused small intestine of the rat”, Drugs Exp. Clin. Res. 2000; 26: 47-55.
15. De Santi, C. et al. “Sulphation of resveratrol, a natural product present in grapes and wine, in the human liver and duodenum”, Xenobiotica, 2000; 30: 609-17.
16. Vitrac X., et al. “Distribution of 14C-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration”, Life Sci. 2003; 72: 2219-2233.
17. Shannon Reagan-Shaw, et al., “Dose translation from animal to human studies revisited, The FASEB Journal, 2007; 22: 659-661.
18. Zhang H, & Huang W. “Fusion proteins of Hsp70 with tumor-associated antigen acting as a potent tumor vaccine and the C-terminal peptide-binding domain of Hsp70 being essential in inducing antigen-independent anti-tumor response in vivo” Cell Stress & Chaperones, 2006; 11(3): 216-226.
根據我們持續深入的研究結果，一些來自植物的化合物攝入體內後經代謝後會通過提升NK細胞的免疫監視活性而顯示抗腫瘤功效。我們建立的植物化合物的配方，可以在實驗哺乳動物中有效提升NK細胞的數量和活性。在
本專利中，“NK細胞活性的提升”定義為NK細胞的增殖和細胞裂解活性增加之綜合。而專利的重點則是發現兩個化合物的同時攝入與單獨攝入任何其中之一的化合物相比，會有加乘效應。
廣義而言，我們的複合物由一個類胡蘿蔔素化合物和一個萜類化合物組成，當攝入具有治療效果的劑量後經過吸收和代謝，可以提升包括NK細胞在內的大顆粒淋巴細胞的活性。狹義而言，本專利中特指複合物由具有治療效果的劑量的茄紅素和白藜蘆醇組成，起到提升NK細胞活性的作用。
本發明的第一部分，是申請專利範圍第2項中所敘的由茄紅素和白藜蘆醇組成的複合物，通過包括增加NK細胞在淋巴細胞中之比例的方式提升NK細胞活性。NK細胞活性的提升還包括提供激發NK細胞擁有細胞毒活性的生物化學信號；或增加每個NK細胞對雙鏈RNA、細胞因子、抗體的Fc受體、以及其他相關的配體受體分子的應答能力。這樣得到提升的NK細胞的細胞毒性活性有延續效應。
本發明的第二部分，聲明在複合茄紅素與白藜蘆醇形成配方時，合適的茄紅素對白藜蘆醇的莫耳比範圍為1：10到10：1，更合適的莫耳比範圍為1：1到3：1，最佳莫耳比為3：1。換算成重量比，則合適的茄紅素對白藜蘆醇的重量比為1：4到25：1，更合適的重量比為2½：1 to 7½：1，最佳重量比為7½：1。該複合物可以做成製劑用於製藥、膳食補充劑或食品等用途。當茄紅素與白藜蘆醇的重量比為2½：1時，合適的劑量則為每20克實驗動物體重攝取3.5mg，這個劑量相當於一個典型人每天攝取400mg到1000mg即可有效
提升NK細胞活性。
本發明的第三部分，茄紅素和白藜蘆醇的複合物以口服製劑為優選劑型，但也可以不製成複合物而以單獨化合物的形式先後分開口服。而這兩個化合物攝入體內通過代謝後形成的可以啟動NK細胞活性的代謝產物，前藥或其他有治療作用的中間產物，也屬於本專利的保護範圍。
我們廣義定義了一種由一個類胡蘿蔔素和一個萜類化合物組成的混成物，口服攝入後經過代謝可以幫助提高包括NK細胞在內的大顆粒型淋巴球的活性。作為具體的混合物，其中的類胡蘿蔔素為茄紅素，萜類化合物為白藜蘆醇。
茄紅素是可以被人體吸收並積蓄的六種類胡蘿蔔素化合物中的一種[Ref.1：Mein(2008)]。它主要分佈在睾丸、攝護腺、肝臟和小腸等組織。茄紅素是地球上最強的抗氧化劑，分別是β-胡蘿蔔素和維生素E的3.2倍和100倍。
此前的研究已經證明茄紅素有諸多促進健康的功能，包括抗衰老、促進免疫、減少心血管疾病、抗腫瘤等。臨床研究表明，茄紅素對抑制腫瘤生長，預防轉移很有效，特別是胰腺癌、肺癌和胃腸道癌[Ref.2：Giovannucci(1999)；Ref.3：Gann(1999)]。由於其多彩的益生作用，茄紅素被譽為是21世紀的健康之星，而且得到越來越廣泛的認同。在發達國家，包括美國、西歐國家、日本和以色列，大量的人力物力投入到茄紅素相關的藥品、膳食補充品、食品和化妝品的研發之中。
在人體小腸中，可以觀察到茄紅素可以與脂肪及膽酸一起在黏膜細胞表面形成微囊後得到吸收。天然的茄紅素一般呈全反式結構。胃酸可以將部分全反式茄紅素轉化成各類順式異構體，從而變得更容易被吸收。在人體中大約可以找到15-18種順式異構體，這些異構體可能跟茄紅素的不同功能有關係。茄紅素的強抗氧化功能，並不能解釋其抗腫瘤功效，也不能解釋預防心血管疾病的功效。最近，茄紅素的代謝產物可能會像維生素A那樣參與眾多基因的表達調控。在已知的代謝產物中，有5,6-dihydroxy-5’,6’-dihydrolycopene,2,6-cyclolycopene-1,5-diol A & B,apo-10’-lycopenoic acid,acycloretinoic acid,apo-8’-lycopenal,apo-10’-lycopenal,apo-12’-lycopenal和and apo-14’lycopenal等[Ref.4：Ruhl(2004)；Ref.5：Lindshield,(2007)；Ref.1：Mein(2008)]。
由於不管體內還是體外實驗，所使用的茄紅素的濃度要遠遠超過人體中的濃度，這暗示在人體中可能有其他的協助作用。2008年，終於出現了這樣的報導，描述為茄紅素發揮最佳的抗腫瘤效果，需要有其他因子的參與[Ref.6：Mossine(2008)；Ref.7：Venkateswaran(2009)]。
白藜蘆醇是一個萜類化合物，其含量最豐富的有葡萄皮、花生、鳳梨和虎杖等植物。白藜蘆醇是一個抗氧化劑，能降低血黏度，抑制血小板凝聚，促進血管舒張，因此可以幫助血液迴圈。白藜蘆醇也能降血脂[Ref.8：Arichi(1982)]，因此可以幫助預防動脈粥樣硬化和心肌梗塞等疾病。白藜蘆醇也有抗腫瘤功效，是一個天然的雌激素替代
物。白藜蘆醇的其他保健功能還有抗衰老、降低低密度脂蛋白(LDL)的氧化、抗炎症和抗過敏。白藜蘆醇還被用來治療急性肝炎，絕經綜合症，風濕性關節炎，骨頭和肌肉疼痛，支氣管炎和高膽固醇症，高血脂症，高膽紅素症等。
白藜蘆醇還被認識到可以調節免疫體系[Ref.9：Kimura(1985)；Ref.10：Gao(2001)]它抑制前炎症因子的合成與分泌，抑制I型和II型環化氧化酶(cyclooxygenase)的活性，抑制淋巴細胞增殖，促進細胞毒性T細胞的活化，刺激細胞因子的分泌等。最重要的是，白藜蘆醇可以抑制包括NF-κB在內的轉錄因子的活性，因此很可能其抗腫瘤活性是通過調節免疫體系來實現的[Ref.11：Tsai(1999)；Ref.12：Falchetti(2001)；Ref.13：Heynekamp(2006)]。
即便是攝入了大量的白藜蘆醇，保留完整結構的白藜蘆醇在人體中的含量很低[Ref.14：Andlauer(2000)；Ref.15：De Santi(2000)]，遠遠低於在體外試驗中殺死腫瘤細胞的濃度。然後，其抗腫瘤活性又是實實在在在一系列的動物實驗上可以得到確認[Ref.16：Vitrac X(2003)]，因此有人提出白藜蘆醇的抗腫瘤活性是通過其代謝產物在人體或小鼠上實現。我們做了一系列的實驗，以下是我們做實驗的的方法和步驟。
NK細胞的分離：NK細胞從Balb/c小鼠的脾臟分離。每組小鼠在餵食茄紅素/白藜蘆醇後的第七天殺死，摘取脾臟，在75%酒精中浸泡5分鐘，在100目的細胞篩子上小心碾碎，用RPMI-1640培養基沖洗細胞篩後收集濾過的培
養基，放置在淋巴細胞分離液上2000rpm離心25分鐘，收集白色的淋巴細胞層，用無血清的RPMI-1640培養基洗滌二次，懸浮後轉移到6孔培養皿(或35mm直徑培養皿)中備用。這樣製備的淋巴細胞含10~20%的NK細胞，可用於NK細胞活性測定。[Ref.18：Zhang(2006)]。
B16黑色素瘤細胞的分離：在C57小鼠上接種B16黑色素瘤細胞，待腫瘤長大後摘取，在Hank’s培養基中浸泡30分鐘。除去脂肪組織和壞死組織後，將腫瘤切成小塊，以含0.1%II型膠原蛋白酶的RPMI-1640培養基在4℃處理12小時。消化處理後的腫瘤組織在100目的細胞篩上小心碾碎濾過，收集濾液在100%的Ficoll溶液上離心分離得到單個的腫瘤細胞。
NK細胞的活性測定：從小鼠脾臟分離到的NK細胞與從黑色素瘤上分離到的B16單個細胞，以25：1，50：1和100：1的不同比例進行混合，在37℃放置5小時後，取100ul培養基進行乳酸脫氫酶(LDH)活性的測定，以此作為NK細胞的細胞裂解活性。細胞裂解毒性由以下公式進行計算。
其中ODEx：B16靶細胞和NK細胞共培養後測得的光密度值；ODE.SP：NK細胞培養來源的光密度值；ODT.SP：B16靶細胞培養來源的光密度值；
ODTmax：以1%的NP40將細胞100%裂解後的光密度值。
在本實驗中小鼠被分成4組，每組6隻。第一組為對照組，餵生理鹽水；第二組每天每隻餵2mg茄紅素；第三組每天每隻餵4mg白藜蘆醇；第四組每天餵6mg的紅白金丹(注：紅白金丹為謝氏生技的一個註冊產品，茄紅素與白藜蘆醇的重量比為1：2)。各組小鼠在餵食1週後殺死，按照上述方法測定脾臟來源淋巴細胞中的NK細胞的活性。單獨餵食了茄紅素或白藜蘆醇的小組的NK細胞活性，與餵食生理鹽水的相比較，只有微弱的增加，統計學上不明顯。但是餵食了紅白金丹的小組其NK細胞活性卻有了>100%的提升，而且統計上有意義(P<0.01)。
茄紅素和白藜蘆醇對NK細胞活性的提升作用在圖1的矩形圖中得到客觀且清楚的比較。顯然，NK細胞活性的提升，是茄紅素和白藜蘆醇的協同作用的結果。作為對照組，對應20：1，50：1和100：1的效應細胞/靶細胞比(E：T)的活性測定體系中，沒有餵食任何植物化合物的動物組的NK細胞活性分別為10，20和40%，而同時餵食了茄紅素和白藜蘆醇的實驗組的NK細胞活性分別為20，40和80%。
從圖1的實驗結果我們可以看到，在任何一個E：T比例中餵食了茄紅素和白藜蘆醇的混合物的細胞裂解活性都增加了2倍左右。而且，餵食混合物的細胞裂解活性比單獨餵食茄紅素或者白藜蘆醇的小鼠的也要高出一倍。這個現象明確告訴我們茄紅素和白藜蘆醇可以協同作用啟動淋巴細胞中抗體非依賴性NK細胞的細胞毒活性。
本實驗意在確定提升NK細胞活性的茄紅素與白藜蘆醇的最佳比例。5組小鼠(每組6隻)分別每天餵食3.5mg不同比例的茄紅素和白藜蘆醇。5天後殺死小鼠，測定NK細胞的細胞裂解活性，結果列在表1和圖2中。
根據圖2，當茄紅素與白藜蘆醇的莫耳比為3：1或重量比為7.5：1時(見組4)，NK細胞的活性得到了最大的提升，在E：T=50：1的條件下測得其細胞裂解率為63%。
茄紅素與白藜蘆醇混合物對NK細胞活性提升的劑量效應。各組小鼠每天餵食不同劑量的茄紅素與白藜蘆醇的混合物(重量比2.5：1)，第5天殺死後以E：T=50：1的條件測定NK細胞的細胞毒活性。如圖3所示，NK細胞活性的提升，與餵食的茄紅素與白藜蘆醇的混合物之間存在劑量效應關係。對於茄紅素與白藜蘆醇的重量比為2.5：1的混合物而言，要達到最大NK細胞活性提升的最低劑量為每天
3.5mg。
需要注意的是，如何以最少餵食劑量得到活的NK細胞活性最大提升效率是與混合比有關。但是當不計成本而過量攝入時，不同混合比的混合物都能獲得最大的NK細胞活性提升率。當圖2中的各個不同混合比的混合物增加到三倍的劑量(即每天每隻鼠餵食9mg)是，結果如圖4所示，基本上NK細胞活性都得到最大的提升效果。似乎茄紅素和白藜蘆醇各自存在一個提升最大NK細胞活性的最低劑量。
重量比為2.5：1的茄紅素與白藜蘆醇的混合物對NK細胞活性提升作用的時間效應。小鼠每天餵給3.5mg的混合物，在不同的天數後測定其NK細胞的活性水準。
如圖5所示，小鼠NK細胞活性從第三天可是提升，到第五天上升到大概為第一天的2.5倍，這個上升的幅度只要餵食茄紅素與白藜蘆醇的混合物就可以一直維持下去(本實驗只觀察了第5天到第14天的情況)。
從這些實驗結果來看，很明顯茄紅素和白藜蘆醇以適當的比例混合就能發生協同作用，達到所期待的NK細胞活性的提升，並維持所需要的時間。對於一個熟悉這兩個植物化合物的專業人員而言，完全有能力根據這兩個化合物的原材料的純度、晶體顆粒大小、工業純化的進展以及最後產品的狀態等因素而進行比例調整。
另外，上述實例展示的都是在小鼠上的資料，但是可以根據體表面積(BSA)的概念從齧齒類動物的使用劑量來推算人體使用劑量。根據BSA的概念，經驗上人體使用
劑量(mg/kg)為小鼠的1/25到1/50，文獻報導的理論計算值為1/12[文獻17：Reagan-Shaw(2007)]。根據圖3，為得到最大的NK細胞活性的提高，重量比2.5：1(茄紅素：白藜蘆醇)的混合物的攝入量為3.5mg/天/鼠。一隻小鼠的體重為20g，因此小鼠上的劑量可以換算成3.5×50=175mg/kg。那麼對於一個75公斤的成人，其使用劑量就可以進行計算：經驗值，(75×175)÷(25~50)=262.5~525mg；理論值為，(75×175)÷12=1094mg。
依據前面所述的產品紅白金丹，每粒膠囊內含淨重為200mg的茄紅素與白藜蘆醇的混合物，如果每天口服2~5粒膠囊，這相當於每天服用400~1000mg。
一位53歲腦血管瘤患者的個案報告。該患者因經常昏厥而在2008年8月接受腦部核磁共振(MRI)檢查，發現直徑2cm的血管瘤。她從2008年10月起每天服用4~5粒紅白金丹(每粒膠囊含65mg茄紅素和135mg白藜蘆醇，茄紅素與白藜蘆醇的莫耳比為1：5)，2009年2月接受了腦部的CT掃描。
一位42歲女性患者的個案報告。此患者於2007年診斷為胸腺癌，曾接受一系列的手術、放射治療，但是胸腺癌於2009年1月診斷出發生了復發。她於2009年2月開始每天口服5粒紅白金丹膠囊(每粒內含65mg茄紅素，
135mg白藜蘆醇，茄紅素與白藜蘆醇的莫耳比為1：5)。2009年5月18日患者再度接受了CT檢查，發現復發的腫瘤已經完全消失。
64歲男性患者的個案報告。該病人於2007年底被診斷為非小細胞肺癌。肺部腫瘤病灶以及周邊發生轉移的淋巴結通過手術除去，病人還接受了化療。2009年5月因為頭部感覺不適進行核磁共振(MRI)檢查，結果發現兩個轉移病灶，大的直徑2.0cm。他於2009年6月初開始每天口服3-4粒紅白金丹(每粒膠囊內含65mg茄紅素和135mg白藜蘆醇，茄紅素與白藜蘆醇的莫耳比為1：5)。他分別在7月7日和10日10日進行了兩次腦部MRI檢查，結果表明腦部的腫瘤在持續縮小。
上述茄紅素和白藜蘆醇的比例是根據小鼠上得到的實驗資料所提出。這個結果可以拓寬到人體，並可因多樣性和抗性而做修改。上述配方或組合的功效同樣可以用一次攝入這兩種植物化合物來達到。這些改進、轉換或選擇性改進，將被認為與我們的發明相等，因此屬於下列申請專利範圍的範疇之內。
附圖以及說明，是為了幫助更好理解本發明的內容，為本發明提供具有示範性但並非局限性的範例。
圖1的條線圖中展示了對照組，單獨攝入用茄紅素組，單獨攝入白藜蘆醇組，以及同時攝入茄紅素和白藜蘆醇組的小鼠之NK細胞活性。
圖2的條線圖確定了最大程度提高NK細胞活性時茄紅素與白藜蘆醇的最佳比例。
圖3為攝入了不同劑量的茄紅素與白藜蘆醇複合物(重量比為2.5：1)時小鼠的NK細胞活性。
圖4為攝入了圖2中的各種不同比例之複合物的三倍劑量時的小鼠NK細胞活性變化。
圖5為每天攝入2.5mg茄紅素加1mg白藜蘆醇的小鼠的NK細胞活性隨時間的變化。
Claims (11)
- 一種複合物在製備用於提升自然殺手(NK)細胞的活性之藥物的用途，該複合物係至少由一茄紅素和一白藜蘆醇組成，其中該茄紅素和該白藜蘆醇的合適莫耳比範圍在1：10到10：1，其中該複合物所提升的NK細胞活性係NK細胞比例的增加。
- 如申請專利範圍第1項所述之用途，其中該茄紅素和該白藜蘆醇的莫耳比為1：1到1：3。
- 如申請專利範圍第1項所述之用途，其中該茄紅素和該白藜蘆醇的莫耳比為3：1。
- 如申請專利範圍第1項所述之用途，其中該茄紅素和該白藜蘆醇的合適重量比範圍在1：4到25：1。
- 如申請專利範圍第4項所述之用途，其中該茄紅素和該白藜蘆醇的重量比範圍在2½：1到7½：12。
- 如申請專利範圍第4項所述之用途，其中該茄紅素和該白藜蘆醇的重量比在7½：1。
- 如申請專利範圍第1項所述之用途，其中該複合物製備成藥用、膳食補充劑用或食品用產品。
- 如申請專利範圍第7項所述之用途，其中該複合物以每次每20克哺乳動物體重3.5mg的劑量提供給哺乳動物。
- 如申請專利範圍第7項所述之用途，其中該複合物提供給一個成人的劑量為每次400mg到1000mg。
- 如申請專利範圍第7項所述之用途，其中該複合物為口服劑型。
- 如申請專利範圍第1項所述之用途，其中該茄紅素和該白藜蘆醇可用以下任何一種方式攝取： 同一種製劑包括兩種化合物；或者兩種化合物各自形成製劑同時服用。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4883662A (en) | 1984-04-10 | 1989-11-28 | Clinical Biotechnologies, Inc. | Method of increasing natural killer cell population of cancer patients |
| US6063373A (en) | 1989-09-19 | 2000-05-16 | Maxim Pharmaceuticals, Inc. | Enhanced activation of NK cells using an NK cell activator and a hydrogen peroxide scavenger or inhibitor |
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| CN100379425C (zh) * | 2002-02-21 | 2008-04-09 | 北京龙兴科技股份有限公司 | 一种改善骨质疏松的组合物 |
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| KR20080068850A (ko) * | 2005-10-14 | 2008-07-24 | 디에스엠 아이피 어셋츠 비.브이. | 레스베라트롤을 포함하는 기능성식품 조성물의 신규한 용도 |
| CN101442995A (zh) | 2006-05-15 | 2009-05-27 | 帝斯曼知识产权资产管理有限公司 | 新型的抗前列腺癌活性剂 |
| WO2008006581A2 (en) * | 2006-07-14 | 2008-01-17 | Dsm Ip Assets B.V. | Compositions and use thereof for the treatment, co-treatment or prevention of imflammatory disorders |
| US7794758B2 (en) * | 2007-04-05 | 2010-09-14 | Pmc Formulas, Inc. | Compounds and methods for promoting cellular health and treatment of cancer |
| SG166688A1 (en) * | 2009-05-14 | 2010-12-29 | Hsiehs Biotech Singapore Pte Ltd | Lycopene and resveratrol dietary supplement |
-
2010
- 2010-01-27 SG SG201000589-0A patent/SG166716A1/en unknown
- 2010-04-13 JP JP2012510781A patent/JP5755640B2/ja active Active
- 2010-04-13 CN CN2010800316502A patent/CN102481267A/zh active Pending
- 2010-04-13 WO PCT/SG2010/000147 patent/WO2010132024A1/en active Application Filing
- 2010-04-13 US US13/320,480 patent/US8802732B2/en active Active
- 2010-04-13 EP EP10775171.1A patent/EP2429509B1/en active Active
- 2010-04-13 SG SG2011084001A patent/SG176071A1/en unknown
- 2010-04-13 DK DK10775171.1T patent/DK2429509T3/en active
- 2010-04-13 KR KR1020117028681A patent/KR101715139B1/ko active IP Right Grant
- 2010-05-14 TW TW099115487A patent/TWI463977B/zh active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003068202A1 (en) * | 2002-02-15 | 2003-08-21 | Dsm Ip Assets B.V. | Compositions comprising lycopene for the treatment and prevention of angiogenesis associated pathologies |
| EP1825850A1 (en) * | 2006-02-24 | 2007-08-29 | DSMIP Assets B.V. | Use of resveratrol and derivatives thereof for promoting the wellness state in mammals |
Non-Patent Citations (1)
| Title |
|---|
| Rose M.G. et al.,"T-Cell Large Granular Lymphocyte Leukemia and Related Disorders", The Oncologist June 2004 vol.9 no.3 247-258 * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20120060942A (ko) | 2012-06-12 |
| DK2429509T3 (en) | 2016-10-24 |
| SG176071A1 (en) | 2011-12-29 |
| JP5755640B2 (ja) | 2015-07-29 |
| CN102481267A (zh) | 2012-05-30 |
| TW201100070A (en) | 2011-01-01 |
| WO2010132024A1 (en) | 2010-11-18 |
| JP2012526807A (ja) | 2012-11-01 |
| KR101715139B1 (ko) | 2017-03-10 |
| EP2429509B1 (en) | 2016-09-07 |
| US8802732B2 (en) | 2014-08-12 |
| US20120136061A1 (en) | 2012-05-31 |
| SG166716A1 (en) | 2010-12-29 |
| EP2429509A1 (en) | 2012-03-21 |
| EP2429509A4 (en) | 2013-06-26 |
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