TWI293562B - Enhancers for enhancing the antibiotic activities of antibiotics and uses thereof in combination with antibiotics - Google Patents

Description

1293562 (sulfonamide)和甲氧辛啶(tirmethoprim); (4)干擾DNA合成，例如：利福平（rifampin)、甲确峻 (metronidazole)、喳啉（quinoline)和諾波黴素 (novobiocin) 〇 5 (5)干擾細胞膜功能，例如：多黏菌素B (polymyxin B) 和短桿菌素(gramicidin)。 抗生素的種類繁多，而不論藥理作用為何，抗生素療 法的最終目的皆是促使感染性病原（infectious pathogens)的 死亡。但是，近年來於臨床治療上發現，接受抗生素療法 10 的個體可能會出現潛在的危險性。有逐漸增加的來自於活 體外、動物與臨床研究的證據頒不·抗生素媒介的生物活 性細胞壁組份(衍生自革蘭氏陽性細菌、革蘭氏陰性細菌或 黴菌的有機物質）的釋放，可能與快速的臨床惡化有關(Ρ·Μ. Lepper et al (2002), Intensive Care Med., 28:824-833) ° 15 革蘭氏陰性細菌敗血症(gram-negative bacterial sepsis) 目前在臨床上仍是一常見的、威脅生命的疾病。發展出敗 血症相關的併發症之病人的預後(prognosis)很差，而與敗血 症相關的併發症包含：急性呼吸窘迫症候群（acute respiratory distress syndrome，ARDS)、瀰漫性血管内血液凝 20 固症（disseminated intravascular coagulation, DIC)、系統性 血管陷落（systemic vascular collapse)、多重器官衰竭 (multiorgan failure)等。在患有敗血症與ARDS的病人和實驗 動物之間的一個共同發現是：内皮損傷（endothelial injury) 和/或功能障礙(dysfunction)。 6 1293562 種革闌氏陰性細囷外膜的組份，亦即脂多釀(LPS)或 内毒素(endotoxin)，重大地牽涉到與這些疾病狀態有關聯的 内皮細胞的知傷和/或功能障礙之發病（pathogenesis)。LPS 疋一種而度性前發炎分子(proinflammatory factor)，它會引 5發一廣泛群列的内皮性反應，包括··細胞激素、附著分子 與組織因子的向上調控（upregulation)。除了活化作用之 外，LPS會誘發本質為細胞凋亡（ap0pt0Sis)的内皮細胞死亡 (D.D. Bannerman and S.E. Goldblum (2003), Am J Physiol CeZ/ MoZ 284 (6): L899-914)。 10 從分子病理學的角度來探討：何以在抗生素成功地殺 滅病菌後，某些病患依然會出現多重器官衰竭症候群呢？ 當革蘭氏陰性病菌侵入一個體體内時，將誘使免疫系統的 活化，此時由於受到免疫系統的攻擊或抗生素的投藥將引 起病菌的大量死亡，接而從死亡的細菌外表面釋出LPS。這 15 些LPS隨後會和LPS結合蛋白（LPS-binding protein，LBP)結 合並分解成單體(monomers)。之後，該等單體與免疫細胞 表面的把關受器（Toll-like receptors, TLR)辅助分子CD 14、 MD2結合，而由此所形成的複合物會結合並活化TLR。被 活化的TLR接而激活下游的細胞質訊號傳遞鏈(cytoplasmic 20 signal transduction cascade)，而導致自由的核因子-凡 B (nuclear factor-/c B，NF-/c B)的釋出 外 α/· (2⑽力，/· Am· 旋如⑺/·，7U2S9-99)，並增加發炎因子 的基因轉錄作用，該等發炎因子包括：腫瘤壞死因子 (tumor necrosis factor- a , TNF- α)、介白素-1 万 1293562 (interleukin-1 β , IL-1 β )(Γ. Shogi et aly Magnes Res., 2003 June，16(2):lll-9·，H· Oono et al·，Magnes Res·，2002 Dec” 75(Ά··753-(50)以及可誘發的氧化氮合成酶(inducible nitric oxide synthase，iNOS)等（Ρ·Μ· d d· (2002)，如上述 5 (supra); D.D. Bannerman and S. E. Goldblum (2003), 士口上 述）。 當被釋出至細胞外後，這些發炎因子會活化嗜中性白 血球(neutrophils)，而這些被活化的嗜中性白血球進而製造 •出諸如超氧化物自由基(superoxide free radicals)等的活性 10 氧物質（reactive oxygen species, ROS)，用以殺滅湧入的細 菌。但是，這些ROS同樣地會攻擊位於血管内壁上的内皮 細胞，並導致這些内皮細胞產生細胞凋亡（apoptosis)。當處 於氧化壓力（oxidative stress)及細胞凋亡的狀況下時，内皮 細胞也會在其細胞内產生ROS。這些ROS又會活化NF-/c B 15 途徑並啟動發炎因子[包括黏附分子(adhesion molecules)、 TNF與IL-8等等]的基因表現。這一連串的正性迴饋反應1293562 (sulfonamide) and methoxyxylidine (tirmethoprim); (4) Interfering with DNA synthesis, for example: rifampin, metronidazole, quinoline, and novobiocin 5 (5) Interfering with cell membrane functions, such as polymyxin B and gramicidin. There are many types of antibiotics, and regardless of the pharmacological effects, the ultimate goal of antibiotic therapy is to promote the death of infectious pathogens. However, in recent years, it has been found in clinical treatment that individuals who receive antibiotic therapy 10 may be potentially dangerous. There is an increasing amount of evidence from in vitro, animal and clinical studies that release the bioactive cell wall component of an antibiotic vector (an organic substance derived from Gram-positive bacteria, Gram-negative bacteria or mold), possibly Associated with rapid clinical deterioration (Ρ·Μ. Lepper et al (2002), Intensive Care Med., 28:824-833) ° 15 Gram-negative bacterial sepsis is still clinically A common, life-threatening disease. The prognosis of patients with sepsis-related complications is poor, and the complications associated with sepsis include: acute respiratory distress syndrome (ARDS), diffuse intravascular hemocoagulation (disseminated) Intravascular coagulation, DIC), systemic vascular collapse, multiorgan failure, and the like. A common finding between patients with sepsis and ARDS and experimental animals is: endothelial injury and/or dysfunction. 6 1293562 The composition of the outer membrane of the sputum negative sputum, also known as lipopolysaccharide (LPS) or endotoxin, is significantly involved in the know-how and/or function of endothelial cells associated with these disease states. Pathogenesis. LPS is a proinflammatory factor that induces a broad array of endothelium reactions, including upregulation of cytokines, attachment molecules, and tissue factors. In addition to activation, LPS induces endothelial cell death in the form of apoptosis (ap0pt0Sis) (D. D. Bannerman and S. E. Goldblum (2003), Am J Physiol CeZ/MoZ 284 (6): L899-914). 10 From the perspective of molecular pathology: Why do some patients still experience multiple organ failure syndrome after antibiotics successfully kill the bacteria? When a Gram-negative pathogen invades a body, it will induce activation of the immune system. At this time, due to attack by the immune system or administration of antibiotics, a large number of bacteria will be killed, and then released from the outer surface of the dead bacteria. LPS. These 15 LPSs are then combined with LPS-binding protein (LBP) to decompose into monomers. Thereafter, the monomers bind to the Toll-like receptors (TLR) accessory molecules CD 14, MD2 on the surface of the immune cells, and the resulting complex binds to and activates the TLR. The activated TLR activates the downstream cytoplasmic 20 signal transduction cascade, resulting in the release of free nuclear factor-B (nuclear factor-/c B, NF-/c B). (2(10) force, /· Am· 旋 (7) / ·, 7U2S9-99), and increase the transcription of inflammatory factors, including tumor necrosis factor-a (TNF-α),素素-1万1293562 (interleukin-1 β , IL-1 β ) (Γ. Shogi et aly Magnes Res., 2003 June, 16(2): lll-9·, H·Oono et al·, Magnes Res· , 2002 Dec" 75 (Ά··753-(50) and inducible nitric oxide synthase (iNOS), etc. (Ρ·Μ·dd· (2002), as mentioned above 5 (supra); DD Bannerman and SE Goldblum (2003), Shikou above). When released to the outside of the cell, these inflammatory factors activate neutrophils, and these activated neutrophils become manufactured. Reactive oxygen species (ROS), such as superoxide free radicals, To kill the influx of bacteria. However, these ROS also attack endothelial cells located on the inner wall of blood vessels and cause apoptosis in these endothelial cells. When they are in oxidative stress and apoptosis Under conditions, endothelial cells also produce ROS in their cells, which in turn activate the NF-/c B 15 pathway and initiate genes for inflammatory factors [including adhesion molecules, TNF and IL-8, etc.] Performance. This series of positive feedback responses

I (positive feedback reactions)將使得血管内皮受到大量損 傷，並裸露出其下的組織而引發瀰漫性血管内血液凝固 症。若此種傷害超過病患身體所能忍受的閾值時，將引起 20 發炎反應持續地進行正性迴饋路線，最後導致多重器官衰 竭症候群的產生，而造成病患的預後不佳或死亡（/>.从 Lepper et al. (2002),如上述；ΖλΖλ am/ S·五· (2003),如上述）。 由上述可瞭解到，抗生素療法的缺點在於其殺滅病菌 8 1293562 之後會促成大量的菌體殘骸遺留，進而於接受抗生素療法 的個體體内誘發過度發炎反應的產生。過度發炎反應可能 的作用機轉為：（1) NF-/CB途禋的活化；（2)自由基的大量 產生（Ζλ/λ 5⑽狀nmm⑽以· Go7伽麵力如上述）〇 、 5 為解決上述問題，有許多研究嘗試尋找或合成新抗生 素。無疑地’這將是艱辛且耗時的工作，不但所費不貲， 且可能緩不濟急。 各種不同的佐劑治療方式曾被仔細地分析過，包括使 用標準的靜脈内免疫球蛋白或内毒素核心專一性抗體 10 (endotoxin core-specific antibody)、細胞激素(cytokine)、細 胞激素受體拮抗劑（cytokine receptor antagonist)或免疫調 節劑(immuno-modulator)來進行的治療。儘管近年來以皮質 類固醇(corticosteroid)與活化蛋白 C (activated protein C)所 進行的隨機多中心試驗(randomised multicentre trial)被證 15 實較有希望，但是到目前為止，這些佐劑治療方式的效果 是令人大為失望的（尸·M. d (20(92),如上述）。 • 因此，到目前為止，尚未找到一種可以搭配抗生素療 . 法並且可以降低在抗生素療法之後可能出現的不利副作用 之成功方法。 2 0 【考务明内】 發明概要 於是，本發明希望可以找到一藥物來搭配抗生素療 法，俾以在達到殺菌目的之時，不必擔心菌體殘骸會對接 受抗生素療法的個體造成二次傷害。 9 1293562 在第三方焉，太 .^, 努明提供一種由一如上所述的用以增 進抗生素的抗 人…^’ 的增進劑與一抗生素所構成的組合用 於製造一醫樂品的 Α ^ 用攻’其中當該醫藥品當被投藥給一個 體時，會展現出要 ^ ^ αη ^ 早獨投藥該抗生素為高的抗生活性。 本發明的上述 及其他目的、特徵及優點，在參照以 下詳細說明與較伴告# 土灵靶例後，將變得明顯。 【實施令武】I (positive feedback reactions) will cause extensive damage to the vascular endothelium and expose the underlying tissue to cause diffuse intravascular coagulation. If the damage exceeds the threshold that the patient can tolerate, it will cause 20 inflammatory reactions to continue the positive feedback route, and finally lead to the generation of multiple organ failure syndrome, resulting in poor prognosis or death (/&gt ;. from Lepper et al. (2002), as described above; ΖλΖλ am/ S·5· (2003), as described above). As can be seen from the above, the disadvantage of antibiotic therapy is that it kills bacteria 8 1293562 and promotes the retention of a large number of bacterial residues, thereby inducing excessive inflammatory reaction in individuals receiving antibiotic therapy. The possible effects of excessive inflammatory reaction are: (1) activation of NF-/CB pathway; (2) mass production of free radicals (Ζλ/λ 5(10)-like nmm(10) with · Go7 gamma force as described above), 5 To solve the above problems, there are many studies trying to find or synthesize new antibiotics. Undoubtedly, this will be a difficult and time-consuming task, not only costly, but also may not be alleviated. Various adjuvant treatments have been carefully analyzed, including the use of standard intravenous immunoglobulin or endotoxin core-specific antibodies, cytokine, and cytokine receptor antagonism. Treatment with a cytokine receptor antagonist or an immuno-modulator. Although the recent trial of randomized multicentre trials with corticosteroids and activated protein C has been promising, the effects of these adjuvant treatments have so far been achieved. It is very disappointing (Kn. M. d (20 (92), as mentioned above).) Therefore, so far, no antibiotic treatment has been found and can reduce the adverse side effects that may occur after antibiotic therapy. The successful method. 2 0 [Examination of the examination] Summary of the invention Therefore, the present invention hopes to find a drug to be combined with antibiotic therapy, so that when the purpose of sterilization is achieved, there is no need to worry that the bacteria residue will cause the individual receiving antibiotic therapy. Secondary injury. 9 1293562 In a third party, .,^, Numming provides a combination of a booster and an antibiotic that is used to promote antibiotics as described above for the manufacture of a medical doctor. The product of the music is used to attack the body. When the drug is administered to a body, it will show that it is necessary to ^ ^ αη ^ Prime to a high antibiotic activity. The above and other objects, features and advantages of the present invention, described in detail in reference to the rear compared with the target Advertisement # earthen embodiment, will become apparent.] [Wu embodiment Order

較佳實施例之詳細說明 一般而言，薪雜 4梁的研發有幾種方式，包括··（1)隨機篩 10選；（2)現有藥物的处構# 1ν、α構修改；以及(3)老藥新用。目前製藥 界業者在新藥研發上大多傾向於採用「針對現有藥物的結 構來作修改」以及「老藥新用」這兩種方式，因所需投入 的成本較低且回收較快。申請人則是綜合上述三種研發方 式’以一邏輯思考的方法來迅速找出能符合本發明所欲達 15 成目的之藥物。 欲尋找一新藥，最佳的方法莫過於電腦輔助藥物設計 (Computer Aided Drug Design, CADD)，它已成為現代藥物 研究與開發的一個重要方法和工具。將電腦輔助藥物設 計，特別是電腦輔助組合化學庫設計，加入新藥研究的循 20 環能縮短新藥研究的週期、節省研究與開發費用，以及提 高新藥篩選的命中率。透過採用分子對接、構效關係、分 子類藥性、多樣性、虛擬篩選等方法，進行電腦輔助藥物 設計，可以提供可合成的、成為藥物機率高的化合物。 在本發明中，為了成功地尋找出一藥物來搭配抗生素 12DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT In general, there are several ways to develop a salary of 4 beams, including (1) random screening 10; (2) existing drug composition #1ν, α structural modification; 3) New use of old drugs. At present, the pharmaceutical industry tends to adopt the two methods of “modification for existing drugs” and “new drugs for new drugs” in the research and development of new drugs, because the required input costs are lower and the recovery is faster. The Applicant combines the above three research and development methods to quickly find a drug that meets the goals of the present invention in a logical way. The best way to find a new drug is Computer Aided Drug Design (CADD), which has become an important method and tool for modern drug research and development. The design of computer-aided drugs, especially the computer-assisted combinatorial chemistry library, and the addition of new drug research can shorten the cycle of new drug research, save research and development costs, and increase the hit rate of new drug screening. By using molecular docking, structure-activity relationships, molecular medicinal properties, diversity, and virtual screening, computer-aided drug design can provide compounds that can be synthesized and become highly drug-producing. In the present invention, in order to successfully find a drug to match antibiotics 12

1293562 (cannabidiol)、辣椒素（capsaicin)、鼠尾草驗(carnosol)、母 菊莫（chamazulene)、大黃紛（chrysophanol)、薑黃素 (curcumin)、大豆黃酮（daidzein)、去曱基油撖欖苦素 (demethyloleuropein)、二丙稀基硫化物（diallyl sulfide)、二 5 十二碳六稀酸（docosahexaenoic acid，DHA)、依布石西 (ebselen)、鞣花酸(ellagic acid)、大黃素(emodin)、丁香紛 (eugenol)、金雀異黃酮（genistein)、銀杏素(ginkgetin)、銀 杏苦内酯（ginkgolide)、甘草酸(glycyrrhizic acid)、厚樸酉分 (honokiol)、氫化胡椒紛（hydrochavicol)、貫葉金絲桃素 10 (hyperforin)、金絲桃素（hypericin)、異鼠李素 (isorhamnetin)、山柰驗(kaempferol)、胡黃連醇（kutkiol)、 胡黃連甾醇（kutkisterol)、胡黃連（kutkoside)、枯烧酮C (kuwanon C)、木鏈苦(ligstroside)、甘草根萃取精華 (liquiritin)、葉黃素(lutein)、木犀草素(luteolin)、茄紅素 15 (lycopene)、桑根皮素(morusin)、齊墩果酸(oleanolic acid)、 油橄欖苦素（oleuropein)、芍藥酮（paeoniflorigenone)、芍藥 苷（paeoniflorin)、丹皮酚(paeonol)、丹皮酚原（paeonolide)、 人參炔醇(panaxynol)、胡黃蓮苦甲(picroside I)、.原人參三 醇（protopanaxatriol)、獬皮酮（quercetin)、白藜蘆醇 20 (resveratrol)、大黃酸(rhein)、迷迭香酸(rosmarinic acid)、 芸香（蘆丁）[rutoside (rutin)]及其衍生物、s-烯丙基半胱胺酸 (s-allyl cysteine)、桑根酮 D (sanggenon D)、東莨菪素 (scopoletin)、紫草素(shikonin)、薑烤酚(shogaol)、水飛薊 賓（silybin)、阿魏酸鈉（sodium ferulate)、精胺(spermine)、 14 1293562 休克展現了保護的功用，其藉由改善存活狀況並且降低以 LPS的攻毒所引起的内毒素休克症狀(例如··昏睡、腹瀉以 及淚汪汪的眼睛）。薑黃素會抑制來自血管的嗜中性白血球 的移行與浸潤至位於血管下方的肝臟組織，因而抑制對於 5 身體組織的損傷 〇β· jB. (2003)， 19(1):91-96)。1293562 (cannabidiol), capsaicin, carnosol, chamazulene, chrysophanol, curcumin, daidzein, deuterated base oil Demethyloleuropein, diallyl sulfide, docosahexaenoic acid (DHA), ebselen, ellagic acid, rhubarb Emodin, eugenol, genistein, ginkgetin, ginkgolide, glycyrrhizic acid, hnokiol, hydrogenated pepper Hydrochavicol, hyperforin, hypericin, isorhamnetin, kaempferol, kutkiol, kutkisterol , kutkoside, kuwanon C, ligstroside, liquiritin, lutein, luteolin, lycopene 15 ( Lycopene), morusin, oleanolic acid (o Leanolic acid), oleuropein, paeoniflorigenone, paeoniflorin, paeonol, paeonolide, panaxynol, picoside I), protopanaxatriol, quercetin, resveratrol, rhein, rosmarinic acid, musk (rutin) [ Rutoside (rutin)] and its derivatives, s-allyl cysteine, sanggenone D, scopoletin, shikonin, ginger Shogaol, silybin, sodium ferulate, spermine, 14 1293562 shock demonstrates the protective function by improving survival and reducing LPS attack Endotoxin shock symptoms caused by poison (eg, drowsiness, diarrhea, and tearful eyes). Curcumin inhibits the migration and infiltration of neutrophils from blood vessels to liver tissue located under the blood vessels, thereby inhibiting damage to body tissues. 〇β· jB. (2003), 19(1): 91-96).

Shishodia等人的研究顯示出··人類非小細胞肺癌細胞 之經由香煙的煙所誘導的NF-/c B活化與NF-/c B所調控的 > 基因表現，可以經由I zc B 〇：激酶而被薑黃素所抑制 10 Shishodia et al，(2003)，Carcinogenesis，24(7):1269-1279) 〇Studies by Shishodia et al. have shown that NF-/c B activation induced by cigarettes in human non-small cell lung cancer cells and NF-/c B-regulated gene expression can be via I zc B 〇: Kinase is inhibited by curcumin 10 Shishodia et al, (2003), Carcinogenesis, 24(7): 1269-1279)

Das和Das的研究顯示出：在生理或藥理濃度下，薑黃 素為一強力的單氧抑制劑（single oxygen quencher)(KC. Das and C.K· Das (2002)，Biochem Biophys Res Commum， 295(1):62-66) 〇 15 Manikandan等人的研究顯示出··薑黃素可保護大鼠心 > 肌不受局部缺血的損傷，並且該保護功效係起因於它的抗 氧化性質’以及它對於黃嗓呤脫氫酶/黃令氧化酶轉化與 所生成的超氧陰離子生產的抑制效用（尸·々⑽d从Studies by Das and Das have shown that curcumin is a strong oxygen quencher at physiological or pharmacological concentrations (KC. Das and CK· Das (2002), Biochem Biophys Res Commum, 295 (1). ): 62-66) 〇15 Manikandan et al.'s research shows that curcumin protects the rat's heart from muscle damage, and that the protective effect is due to its antioxidant properties' and its Inhibition effect on the transformation of xanthine dehydrogenase/yellow oxidase and the production of superoxide anion produced (corpse 々(10)d from

Int J Biochem Cell Biol，2004 Oct·，36(10):1967-80)。 20 Ν· Chainani~Wu的研究顯示出：在6個人體試驗中，薑 黃素展現出安全性並且具有抗發炎活性。它可以透過抑制 一些參與發炎作用的不同分子來發揮它的抗發炎活性 Chainani-Wu，J Altern Complement Med，2003 Feb·， 9(1):161-8) 〇 16 1293562 (amikacin)、女痏j撤素（apramycin)、阿貝卡星（arbekacin)、 黃黴素（bambermycins)、丁苷菌素（butirosin)、地貝卡星 (dibekacin)、雙氫鏈黴素（dihydrostreptomycin)、福提黴素 (fortimicin)、健大撤素(gentamicin)、異帕米星(isepamicin)、 5 康納Μ素(kanamycin)、小諾米星(micronomicin)、新黴素 (neomycin)、奈替米星（netilmicin)、巴龍黴素 (paromomycin)、核糖黴素（ribostamycin)、西索米星 (sisomicin)、觀徽素(spectinomycin)、鍵徽素(streptomycin)、 •妥布黴素(tobramycin)、丙大觀黴素(trospectomycin);氯黴 10 素類抗生素（amphenicols)，例如疊氮氣黴素 (azidamfenicol)、氣黴素(chloramphenicol)、氟甲磺氯黴素 (florfenicol)、甲磺氯黴素(thiamphenicol);安莎黴素類抗生 素（ansamycins)，例如利福米特（rifamide)、利福平 (rifampin)、利福黴素 SV (rifamycin sv)、利福噴汀 15 (rifapentine)、利福昔明（rifaximin) ; /3 ·内醯胺 (beta-lactam)，包含：碳頭孢稀類抗生素(carbacephem)，例 如氣碳頭孢（loracarbef);碳醯胺基類抗生素 (carbapenems)，必安培南（biapenem)、亞胺培南 (imipenem)、美羅培南（meropenem)、帕尼培南（panipenem); 20 頭孢菌素抗生素（cephalosporins)，例如西華克樂 (cefaclor)、安泛黴素(cefadroxil)、世大黴素(cefamandole)、 西華治辛（cefatrizine)、頭孢美唾（cefazedone)、西華樂林 (cefazolin)、頭孢卡品 i旨（cefcapene pivoxil)、頭孢克定 (cefclidin)、頭孢地尼（cefdinir)、頭孢托倫(cefditoren)、頭 18Int J Biochem Cell Biol, 2004 Oct., 36(10): 1967-80). 20 Chain·Chalin~Wu's study showed that curcumin showed safety and anti-inflammatory activity in 6 human tests. It exerts its anti-inflammatory activity by inhibiting some of the different molecules involved in inflammation. Chainani-Wu, J Altern Complement Med, 2003 Feb·, 9(1): 161-8) 〇16 1293562 (amikacin), son-in-law j Apramycin, arbekacin, bambermycins, butirosin, dibekacin, dihydrostreptomycin, fuzimycin (fortimicin), gentamicin, isepamicin, 5 kanamycin, micronomicin, neomycin, netilmicin ), paromomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, gamma Trospectomycin; ampicillin, such as azimadfenicol, chloramphenicol, florfenicol, thiamphenicol Ansamycins, such as rifamitide (rifamide), rifampin, rifamycin sv, rifapentine, rifaximin; /3 · beta-lactam, Including: carbacephem, such as loracarbef; carbapenems, biapenem, imipenem, meropenem, Panipenem; 20 cephalosporins, such as cefaclor, cefadroxil, cefmandole, cefatrizine, Cefazedone, cefazolin, cefcapene pivoxil, cefclidin, cefdinir, cefditoren, head 18

1293562 抱°比月亏（cefepime)、頭孢他美（cefetamet)、希復欣 (cefixime)、頭孢地秦(cef〇dizime)、頭孢尼西（cefonicid)、 頭孢酮（cefoperazone)、頭孢氨甲苯唑(ceforanide)、西弗士 林（cefotaxime)、頭孢替安（cefotiam)、頭孢唑蘭 5 (cefozopran)、頭孢咪唑（cefpimizole)、頭孢匹胺 (cefpiramide)、頭孢匹羅（cefpirome)、頭孢泊肟酯 (cefpodoxime proxetil)、頭孢丙烯(cefprozil)、頭孢氧甲環 氨（cefroxadine)、西蘇羅錠（cefsul〇din)、頭孢塔齊定 (ceftazidime)、頭孢特侖(cefteram)、頭孢去甲唑(ceftezole)、 10 頭孢布坦（ceftibuten)、頭孢嗤（ceftizoxime)、頭孢曲松 (ceftriaxone)、頭孢呋肟（cefuroxime)、頭孢唑南 (cefuzonam)、頭孢乙氰鈉（cephacetrile sodium)、頭孢氨苄 (cephalexin)、頭孢來星（cephaloglycin)、頭孢利素 I (cephaloridine)、頭孢子黴素（cephalosporin)、頭胞菌素 15 (cephalothin)、頭孢匹林納（cephapirin sodium)、西華定 (cephradine);頭黴素類抗生素(cephamycins)，例如頭孢拉 宗鈉（cefbuperazone)、頭孢替坦(cefotetan)、頭孢甲氧黴素 (cefoxitin);單環胺基類抗生素(monobactams)，例如氨曲 南（aztreonam)、卡蘆莫南納（carumonam)、替吉莫南 20 (tigemonam);氧頭孢烯類抗生素(oxacephems)，例如t;氧 頭孢(flomoxef)、拉氧頭抱(moxalactam);青黴素類抗生素 (penicillins)，例如氮卓西林（amdinocillin)、阿莫西林 (amoxicillin)、氨苄西林(ampicillin)、阿帕西林(apalcillin)、 阿扑西林（aspoxicillin)、阿度西林（azidocillin)、阿洛西林 191293562 抱°比月失 (cefepime), cefetamet (cefetamet), cefixime, cefedidizime, cefonicid, cefoperazone, cefotaxazole (ceforanide), cefotaxime, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime Ester (cefpodoxime proxetil), cefprozil, cefroxadine, cefsul〇din, ceftazidime, ceftelam, cefotaxazole (ceftezole), 10 ceftibuten, ceftizoxime, ceftrixone, cefuroxime, cefuzonam, cephacetrile sodium, cephalexin (cephalexin), cephaloglycin, cephaloridine, cephalosporin, cephalothin, cephapirin sodium, cepacidine Phradine); cephamycins, such as cefbuperazone, cefotetan, cefoperitin; monobactams, such as ammonia Aztreonam, carumonam, tigemonam; oxacephems, such as t; flomoxef, moxalactam; penicillin Antibiotics (penicillins), such as amdinocillin, amoxicillin, ampicillin, apalcillin, apoxicillin, azidocillin, alo Xilin 19

1293562 (oleandomycin)、普利黴素（primycin)、羅他黴素 (rokitamycin)、嗇薇黴素（rosaramicin)、羅紅黴素 (roxithromycin)、史黴素（SpiramyCin)、醋竹桃黴素 (troleandomycin);多肽類抗生素(polypeptides)，例如安福 5 黴素（amphomycin)、枯草菌素（bacitracin)、卷曲黴素 (capreomycin)、黏桿菌素(c〇iistin)、安來黴素(eriraniycin)、 恩維黴素(enviomycin)、鐮孢真菌素(fusafungine)、短捍菌 肽S (gramicidin S)、米卡黴素（mikamycin)、多黏菌素3 (polymyxin B)、普那黴素（pristinamycin)、瑞斯托黴素 10 (ristocetin)、替考拉寧（teicoplanin)、硫鏈絲菌狀 (thiostrepton)、結核放線菌素(tuberactinomycin)、短桿菌路 肽（tyrocidine)、短桿菌肽（tyrothricin)、萬古黴素 (vancomycin)、紫黴素(viomycin)、純黴素(virginiamycin); 四環素類抗生素（tetracyclines)，例如阿旅環素 15 (apicycline)、金黴素（chlortetracycline)、氣莫環素 (clomocycline)、地美環素(demeclocycline)、脫氧經四環徵 素（doxycycline)、脈曱環素（guamecycline)、賴甲環素 (lymecycline)、甲氯環素（meclocycline)、美他環素 (methacycline)、米諾環素（minocycline)、土黴素 20 (oxytetracycline)、青派環素（penimepicycline)、匹旅環素 (pipacycline)、勞利環素（rolitetracycline)、山環素 (sancycline)、四環素(tetracycline);以及其他，例如環絲胺 酸(cycloserine)、莫匹羅星(mupirocin); 2·合成的抗菌藥(synthetic antibacterials): 211293562 (oleandomycin), primycin, rokitamycin, rosaramicin, roxithromycin, spiramyCin, oleandomycin Troleandomycin); polypeptide antibiotics such as amphomycin, bacitracin, capreomycin, c〇iistin, eiraniycin, Enviomycin, fusafungine, gramicidin S, mikamycin, polymyxin B, pristinamycin Pristinamycin), ristocetin 10, teicoplanin, thiostrepton, tuberactinomycin, tyrocidine, gramicidin Tyrothricin), vancomycin, viomycin, virginiamycin; tetracyclines, such as apicycline, chlortetracycline, gas Clomocycline, dimetridin (dem Eclocycline), deoxytetracycline (doxycycline), guamecycline, lymecycline, meclocycline, methacycline, minocycline , oxytetracycline, penimepicycline, pipacycline, rolitetracycline, sancycline, tetracycline; and others, such as a ring Cyclosine, mupirocin; 2. synthetic antibacterials: 21

1293562 2,4-二氨基。密。定類抗菌藥（2,4-siaminopyrimidines)，例 如漠莫普林(brodimoprim)、四氧普林(tetroxoprim)、三甲氧 苄氨17密咬(trimethoprim);硝基吱喃類(nitrofurans)，例如咬 喃他 i同(furaltadone)、吱唾氣銨(furazolium chloride)、石肖0夫 5 拉定（nifuradene)、石肖吱太爾（nifuratel)、石肖吱復林 (nifurfoline)、瑣 °夫 σ比醇（nifurpirinol)、石肖吱拉唤 (nifurprazine)、硝吱妥因醇(nifurtoinol);奎諾酮類及其類 似物（quinolones and analogs)，例如西諾沙星（cinoxacin)、 環丙殺星（ciprofloxacin)、克林沙星(clinafloxacin)、二氟沙 10 星(difloxacin)、依諾沙星(enoxacin)、氟羅沙星(fleroxacin)、 氟甲喧(flumequine)、格帕沙星（grepafloxacin)、洛梅沙星 (lomefloxacin)、米洛沙星（miloxacin)、那氣沙星 (nadifloxacin)、那利得酸（nalidixic acid)、諾氣沙星 (norfloxacin)、氧氟沙星（ofloxacin)、歐索林酸（oxolinic 15 acid)、帕珠沙星(pazufloxacin)、培敗沙星(pefloxacin)、°比 口辰酸(pipemidic acid)、吨洛米酸(piromidic acid)、羅梭沙星 (rosoxacin)、蘆氟沙星（rufloxacin)、司帕沙星 (sparfloxacin)、替馬沙星（temafloxacin)、托氟i 沙星 (tosufloxacin)、曲氟沙星(trovafloxacin)；磺胺類 20 (sulfonamides)，例如苄石黃胺（benzylsulfamide)、氯胺 B (chloramine-B)、氣胺-T (chloramine-T)、雙氣胺 T (dichloramine T)、磺胺米隆（mafenide)、謹丙石黃胺 (noprylsulfamide)、酜石黃醋胺（phthalylsulfacetamide)、敝石黃 胺 °塞哇 （phthalylsulfathiazole)、 柳氮石黃。密口定 221293562 2,4-Diamino. dense. 2,4-siaminopyrimidines, such as brodimoprim, tetroxoprim, trimethoprim, nitrofurans, for example It is furtaltadone, furazolium chloride, nishawadene, nifuratel, nifurfoline, and nifufoline. Nifurpirinol, nifurprazine, nifurtoinol, quinolones and analogs, such as cinoxacin, cyclopropene Ciprofloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin, flumequine, grepafloxacin ), lomefloxacin, miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, Oxolinic 15 acid, pazufloxacin, peffloxacin (pef Loxacin), ° pipemidic acid, piromidic acid, rosoxacin, rufloxacin, sparfloxacin, temafloxacin (temafloxacin), tosufloxacin, trovafloxacin; sulfonamides, such as benzylsulfamide, chloramine-B, amiamine-T (chloramine-T), dichloramine T, mafenide, noprylsulfamide, phthalylsulfacetamide, phthalylsulfathiazole , sulphate yellow.密口定 22

1293562 (salazosulfadimidine) 、 玻 拍 石黃 胺 °塞 口坐 (succinylsulfathiazole)、磺胺苯龜（sulfabenzamide)、石黃胺醋 醯(sulfacetamide)、績胺氣達唤(sulfachlorpyridazine)、石黃胺 柯定（sulfachrysoidine)、石黃胺西、;丁 (sulfacytine)、石黃胺 口密咬 5 (sulfadiazine)、績胺戊稀(sulfadicramide)、石黃胺二甲氧口密°定 (sulfadimethoxine)、石黃胺多辛（sulfadoxine)、石黃胺乙二口坐 (sulfaethidole)、磺胺月米（sulfaguanidine)、石黃胺二曱口亞σ坐月米 (sulfaguanol)、磺胺林（sulfalene)、績胺洛西酸（sulfaloxic acid)、磺胺甲喊σ定（sulfamerazine)、磺胺甲氧嘴唆 10 (sulfameter)、磺胺二甲。密°定(sulfamethazine)、磺胺甲二口坐 (sulfamethizole)、石黃胺甲 ϋ惡嗤(sulfamethoxazole)、石黃胺甲氧 口秦(81^&11161：]10\；^5^(1&21116)、石黃胺美曲（8111£&11^1：1>〇16)、磺胺 米柯定(sulfamidochrysoidine)、石黃胺σ惡峻(sulfamoxole)、氨 苯磺胺（sulfanilamide)、績胺脲(sulfanilylurea)、石黃胺石肖苯 15 (sulfanitran)、磺胺苯 °比。坐（sulfaphenazole)、磺胺普羅林 (sulfaproxyline)、石黃胺 σ比唤（sulfapyrazine)、石黃胺吼口定 (sulfapyridine)、磺胺異嗟。坐(sulfasomizole)、磺胺均三 口秦 (sulfasymazine)、石黃胺。塞。坐(sulfathiazole)、石黃胺硫脲 (sulfathiourea)、磺胺托拉米（sulfatolamide)、石黃胺索 〇密口定 20 (sulfisomidine)、石黃胺異 σ惡嗤（sulfisoxazole)；石風類 (sulfones)，例如醋氨苯颯（acedapsone)、gf地石風 (acediasulfone)、石黃胺苯石風鈉（acetosulfone sodium)、氨苯礙 (dapsone)、地百裡石風（diathymosulfone)、葡萄糖氨苯颯納 (glucosulfone sodium)、苯丙石風（solasulfone)、破 j白氨苯石風 23 1293562 (succisulfone)、對氨基苯磺酸(suifanilic acid)、亞錯氨苯石風 納（sulfoxone sodium);以及其他的抗菌藥，例如氣福克紛 (clofoctol)、海克西定(hexedine)、烏洛托品（methenamine)、 硝羥喹啉(nitroxoline)、牛磺羅定(taur〇Udine)。 5 較佳地，該抗生素是選自於下列所構成的群組：万-内 醯胺，例如青黴素、頭胞菌素；單-内醯胺，例如派拉西林、 亞胺培南、萬古黴素、枯草菌素；克林達黴素、林可黴素、 氯黴素、四環黴素、健大黴素、磺胺、甲氧苄啶、利福平、 > 甲硝唑、嗖啉、諾波黴素、多黏菌素B和短桿菌素，以及此 10 等抗生素的組合。 在本發明的-個較佳具體例中，該抗生素是派拉西 林。在本發明的另一較佳具體例中’該抗生素是亞胺培南。 依據本發明的藥學組成物可利用熟習此藝者所詳知的 技術被製造成一合適的藥學形式以供非經腸道地或口服地 15投藥，這包括’但不限於，注射品（injecti〇n)[例如，無菌的 水溶液或分散體]、無菌的粉末、錠劑、片劑、丸劑、膠囊 以及類似之物。而在本發明的藥學組成物的製造上，可二 將該抗生素與該增進劑混合或分別製成一適於投藥的藥物 組份而後包裝成適於投藥的劑型。 , 20車交佳地’依據本發明的藥學組成物可被製造成適於注 射用的形式，該藥學組成物可包含生理上可接受之益菌水 性或是非水性的溶液、分散劑、懸浮液或是乳狀液，以及 供用於復原成無菌注射溶液或是分散劑的無菌粉末。在此 適合之水性以及非水性之载劑、稀釋劑、溶劑或是載體的 24 1293562 實例，包括水、乙醇、丙稀乙二醇、聚乙稀乙二醇、甘油、 橄挽油以及此等_似物），以及諸如乙基油酸鹽的注射用 有機酯類。 如此處所用的，“治療有效量，，此術語係指當一依據本 5發明的樂學組成物被投予—需要該藥學組成物來治療的個 體時足以提供所欲達致之治療功效且不會對該個體的 身二器官或組織產生非所欲的嚴重危害的用量。該治療有 效量會視不同的因素而變化，該等因素包括，例如，病症 之義，要被治療的個體之體重、年齡、身體狀況以及反 10應’藥物的投藥途控等。此一治療有效量可為熟習此項技 4标人士來決定。 依據本發明的藥學組成物可呈單一劑量或是分成數個 劑$的形式而被非經腸道地或口服地投藥，且該抗生素輿 该增進劑這兩種藥物組份可被同時地或分開地投藥。依據 15本發明的藥學組成物之投藥劑量與投藥次數會視下列因素 而變化：要被治療的疾病之嚴重性，投藥途徑，以及要被 治療的個體之體重、年齡、身體狀況與反應 。例如，依據 本發明的藥學組成物的每次投藥劑量通常可預估該增進劑 的投樂劑量範圍為5 mg/Kg體重至4000 mg/Kg體重，較佳為 20 50 mWKg體重至1500 mg/Kg體重，而該抗生素的投藥劑量 fe圍可按照醫藥界對該抗生素所設定的投藥劑量範圍或是 低些。 本發明將就下面實施例來作進一步說明，但應瞭解的 疋’該等實施例僅為例示說明之用，而不應被解釋為本發 25 1293562 Β·實驗方法： 1·活體外感受性試驗(/f2 vitro susceptibility testing)： 感受性試驗係依據由國家委員會臨床實驗室標準 (National Committee for Clinical Laboratory Standards)所概 5 述的微肉湯稀釋方法(microbroth dilution method)操作程序 來進行。最小抑制濃度(Minimum Inhibitory Concentration， MIC)為可觀察到的生長情形被抑制的最低濃度。 2.動物試驗： > 動物試驗是採用革蘭氏-陰性敗血症動物模式（參照&乂 10 Parker and P. E. Watkins (2001), British J of Surgery, 88(1): 22-30)來進行。 大腸桿菌（五· ATCC 25922被培養於腦心浸出肉湯 (brain-heart infusion broth)中。當細菌達到對數生長期（l〇g phase of growth)時，以1000 g來離心菌液歷時15分鐘。丟棄 15 上清液，並將沉澱的菌體重新懸浮於注射用生理食鹽水中。 全部的大鼠（5組，各組包含20隻大鼠）以腹膜内注射戊1293562 (salazosulfadimidine), succinylsulfathiazole, succinylsulfathiazole, sulfabenzamide, sulfacetamide, sulfachlorpyridazine, sulfachrysoidine ), sulphate, sulfacytine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulphate Sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanol, sulfalene, dextrozine Sulfaxic acid), sulfamerazine, sulfameter, sulfamethazine. Sulfamethazine, sulfamethizole, sulfamethoxazole, sulfamethoxazole (81^&11161:]10\;^5^(1&; 21116), scutellaria mellifera (8111 £ & 11 1:1 gt; 〇 16), sulfamidochrysoidine, sulfamoxole, sulfanilamide, performance Sulfanilylurea, sulfanitran, sulfabenzene ratio, sulfaphenazole, sulfaproxyline, sulfapyrazine, sulphate (sulfapyridine), sulfamethoxazole, sulfasomizole, sulfasymazine, sulfasymazine, sulphate, sulfathiazole, sulfathiourea, sulfatolamide, stone Sulfomoxidine, sulfisoxazole, sulfones, such as acetapedone, acediasulfone Acetosulfone sodium, dapsone, diathymo Sulfone), glucosulfone sodium, solasulfone, succisulfone 23, succisulfone, suifanilic acid, smectite Sulfone sodium; and other antibacterial agents, such as clofoctol, hexedine, methenamine, nitroxoline, tauroplatin ( Taur〇Udine). 5 Preferably, the antibiotic is selected from the group consisting of valino-lactam, such as penicillin, cephalosporin; mono-indoleamine, such as piracetam, imine Peinan, vancomycin, subtilin; clindamycin, lincomycin, chloramphenicol, tetracycline, gentamicin, sulfonamide, trimethoprim, rifampicin, > Nitrazole, porphyrin, nopamycin, polymyxin B and brevisin, and a combination of these 10 antibiotics. In a preferred embodiment of the invention, the antibiotic is piracetam. In another preferred embodiment of the invention, the antibiotic is imipenem. The pharmaceutical composition according to the present invention can be manufactured into a suitable pharmaceutical form for parenteral or oral administration by a technique well known to those skilled in the art, including, but not limited to, injectables (injecti〇). n) [for example, sterile aqueous solutions or dispersions], sterile powders, lozenges, tablets, pills, capsules and the like. In the manufacture of the pharmaceutical composition of the present invention, the antibiotic may be mixed with the enhancer or separately prepared into a pharmaceutical composition suitable for administration and then packaged into a dosage form suitable for administration. The pharmaceutical composition according to the present invention may be manufactured in a form suitable for injection, and the pharmaceutical composition may comprise a physiologically acceptable aqueous or non-aqueous solution, dispersant, suspension Or an emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Examples of 24 1293562 suitable for aqueous and non-aqueous vehicles, diluents, solvents or carriers, including water, ethanol, propylene glycol, polyethylene glycol, glycerin, olive oil, and the like _like), and organic esters for injection such as ethyl oleate. As used herein, "therapeutically effective amount," refers to an individual that is required to be treated when the composition of the invention is administered in accordance with the invention, and is sufficient to provide the desired therapeutic effect and An amount that does not cause an undesired serious harm to the individual's body organs or tissues. The therapeutically effective amount will vary depending on various factors, including, for example, the meaning of the condition, the individual to be treated Body weight, age, physical condition, and anti-drug administration, etc. This therapeutically effective amount can be determined by those skilled in the art. The pharmaceutical composition according to the present invention can be in a single dose or divided into several numbers. The drug is administered parenterally or orally, and the two drug components of the antibiotic and the enhancer can be administered simultaneously or separately. According to the dosage of the pharmaceutical composition of the present invention The number of administrations will vary depending on factors such as the severity of the condition to be treated, the route of administration, and the weight, age, physical condition and response of the individual to be treated. For example, The dosage of the pharmaceutical composition of the present invention can generally be estimated to be in the range of 5 mg/kg to 4000 mg/kg body weight, preferably 20 50 mWKg body weight to 1500 mg/kg body weight. The dosage of the antibiotic may be lower or lower according to the dosage range set by the pharmaceutical industry for the antibiotic. The present invention will be further illustrated by the following examples, but it should be understood that the examples are only For illustrative purposes, it should not be interpreted as this issue. 25 1293562 实验·Experimental methods: 1. In vitro susceptibility testing: The susceptibility test is based on the National Committee for Clinical Standards (National Committee for Clinical Laboratory Standards) The microbroth dilution method is used to perform the procedure. The Minimum Inhibitory Concentration (MIC) is the lowest concentration at which the observed growth condition is suppressed. : > Animal testing is based on the Gram-negative sepsis animal model (see & 乂 10 Parker and PE Watkins (2001), British J of Surgery, 88(1): 22-30). E. coli (5 · ATCC 25922 is cultured in brain-heart infusion broth. When the bacteria reach logarithmic growth phase (l〇 For g phase of growth, the bacteria solution was centrifuged at 1000 g for 15 minutes. The 15 supernatant was discarded, and the precipitated cells were resuspended in physiological saline for injection. All rats (5 groups, each group containing 20 rats) were injected intraperitoneally with pentyl

I 巴比妥納（sodium pentobarbital)(35 mg/kg體重）的方式予以 麻醉。每隻大鼠的腹部被剃毛並以碘消毒作準備。每隻大 鼠被施予配於生理食鹽水1 mL内的含有2xl〇1G CFU的大腸 20 桿菌（五· co/ί) ATCC 25922之腹膜内接種物。緊接在細菌攻 毒之後，各組大鼠如表1所示分別接受含有下列物質的等張 氣化鈉溶液之腹膜内注射：注射用生理食鹽水0.5 mL/kg+ 撖欖油（0.5 mL/kg)(對照組）；派拉西林（120 mg/kg，配於0.5 mL/kg注射用生理食鹽水内）+撖欖油（0.5 mL/kg);亞胺培南 27 1293562 (20 mg/kg in 0·5 mL/kg注射用生理食鹽水）+橄欖油（〇·5 mL/kg);派拉西林（120 mg/kg，配於〇·5 mL/kg注射甩生理 食鹽水内）+薑黃素[70 mg/kg，配於橄欖油（0.5 mL/kg)内]; 以及亞胺培南（20 mg/kg，配於0.5 mL/kg注射用生理食鹽水 5 内）+薑黃素[70 mg/kg，配於橄欖油（0.5 mL/kg)内]。之後， 將大鼠置回動物室，待其甦醒後，給予正常飲食，並觀察 大鼠的存活情形歷時5天。 表1.動物試驗組別 組別 大腸桿菌菌液 藥物 輔助藥物 A 對照組 2xl010 CFU/mL 注射用生理 食鹽水 橄欖油 B 派拉西林 2xl010 CFU/mL 派拉西林 120 mg/kg 撖欖油 C 亞胺培南 2xl010 CFU/mL 亞胺培南 20mg/kg 橄欖油 D 派拉西林+薑黃素 2xl010 CFU/mL 派拉西林 120 ms/ks 撖欖油+薑黃素（70 m 〇 !\c q ^ E 亞胺培南+薑黃素 2xl010 CFU/mL 亞胺培南 20 mg/kg 橄欖油+薑黃素（70 mg/kg) C•結果：I was anesthetized in the form of sodium pentobarbital (35 mg/kg body weight). The abdomen of each rat was shaved and prepared with iodine disinfection. Each rat was administered an intraperitoneal inoculum containing 2xl of G1G CFU of 20 strain of Escherichia coli (five co/ί) ATCC 25922 in 1 mL of physiological saline. Immediately after the bacterial challenge, each group of rats received an intraperitoneal injection of an isotonic sodium solution containing the following substances as shown in Table 1: physiological saline for injection 0.5 mL/kg + eucalyptus oil (0.5 mL/ Kg) (control group); Pelagisin (120 mg/kg in 0.5 mL/kg saline solution for injection) + eucalyptus oil (0.5 mL/kg); Imipenem 27 1293562 (20 mg/ Kg in 0·5 mL/kg saline for injection) + olive oil (〇·5 mL/kg); Pelagisin (120 mg/kg, in 甩·5 mL/kg injection 甩 physiological saline) +curcumin [70 mg/kg in olive oil (0.5 mL/kg)]; and imipenem (20 mg/kg in 0.5 mL/kg saline for injection) 5 + curcumin [70 mg/kg in olive oil (0.5 mL/kg)]. Thereafter, the rats were returned to the animal room, and after they were awakened, a normal diet was administered, and the survival of the rats was observed for 5 days. Table 1. Animal test group Escherichia coli bacterial drug adjuvant drug A Control group 2xl010 CFU/mL Injection saline, olive oil B Pelagisin 2xl010 CFU/mL Pelagisin 120 mg/kg 撖油油 C亚Amipenem 2xl010 CFU/mL Imipenem 20mg/kg Olive oil D Pelagillin + Curcumin 2xl010 CFU/mL Pelagicin 120 ms/ks Eucalyptus oil + Curcumin (70 m 〇!\cq ^ E Asia Amipenem + curcumin 2xl010 CFU/mL Imipenem 20 mg/kg Olive oil + curcumin (70 mg/kg) C•Results:

15 活體外感受性試驗： 在此試驗中，MIC被作為觀察抑制大腸桿菌（五·⑺⑺細 月匕生長的最低抗生素濃度，並用以作為動物實驗時，抗生 素的使用及參考劑量。 對於依據彳放肉湯稀釋方法，大腸桿菌C〇h) ATCC 25922 派^所試驗的兩種抗生素具有不_感受性··亞胺培南與 ^西林之MIC分別為0·11 mg/L和0.24 mg/L。 •大腸桿菌-誘發的腹膜炎： 久&被腹膜内，主射以大腸桿⑽）ATCC 25922後， 的大鼠在5天後的存活情形如表2所示，其中存活數據 28 1293562 係使用logrank試驗來作比較。 表2.大鼠在被腹膜内注射以大腸桿菌（£. co/ί) ATCC 25922後 的存活情形15 In vitro susceptibility test: In this test, MIC was used as the lowest antibiotic concentration for observing the growth of E. coli (5·(7)(7), and used as an antibiotic in animal experiments and reference dose. The method of diluting the soup, Escherichia coli C〇h) ATCC 25922 The two antibiotics tested were non-susceptive. The MICs of imipenem and cillin were 0.11 mg/L and 0.24 mg/L, respectively. • E. coli-induced peritonitis: After a long time & intraperitoneal, main shot with the large intestine rod (10) ATCC 25922, the survival of the rats after 5 days is shown in Table 2, where survival data 28 1293562 is using logrank Test to compare. Table 2. Survival of rats after intraperitoneal injection of E. coli (£. co/ί) ATCC 25922

組別 大腸桿菌攻 治療方式 致死率 毒劑量(CFU) 死亡數目/總數 存活％ A 2 X 1010 橄欖油（對照組） 20/20 0% B 2 X 1010 派拉西林 3/20** 85% C 2 X 1010 亞胺培南 4/20** 80% D 2 X 1010 派拉西林+薑黃素 1/2〇**## 95% E 2 X 1010 亞胺培南+薑黃素 1/20**## 95% :相對於對照組，ρ<〇·〇5 〇 5 ## :相對於使用抗生素本身的組別，ρ<0.05。 表2清楚顯示，相較於單獨使用抗生素，薑黃素和抗生 素的組合使用確實可以提高大鼠的存活率。再者，所用的試 劑並未顯現出任何毒性。事實上，沒有任何一隻大鼠出現 有藥物相關的不利影響（例如，局部發炎的症狀、食慾衰 10 退、體重減輕、嘔吐、腹瀉、發燒和行為改變）之臨床證據。 被引述於本案發明說明書中之所有文獻資料以其整體 被併入本案作為參考資料。若有所衝突時，本發明的詳細 說明（包含界定在内）將佔上風。 雖然本發明已參考上述特定的具體例被描述，明顯地 15 在不背離本發明的範圍和精神下，可以作出很多的修改和 變化。因此意欲的是，本發明僅受如隨文檢附的申請專利 範圍所示者的> 艮制。 L圖式簡單說明】 (無圖） 20 【主要元件符號說明】 (無） 29Group E. coli treatment method Mortality toxic dose (CFU) Number of deaths / total survival % A 2 X 1010 Olive oil (control group) 20/20 0% B 2 X 1010 Paracilin 3/20** 85% C 2 X 1010 Imipenem 4/20** 80% D 2 X 1010 Pelagillin + Curcumin 1/2〇**## 95% E 2 X 1010 Imipenem + Curcumin 1/20** ## 95% : ρ<〇·〇5 〇5 ## : Relative to the control group, ρ < 0.05. Table 2 clearly shows that the combined use of curcumin and antibiotics does increase the survival rate of rats compared to the use of antibiotics alone. Furthermore, the reagents used did not show any toxicity. In fact, none of the rats had clinical evidence of adverse drug-related effects (eg, symptoms of local inflammation, loss of appetite, weight loss, vomiting, diarrhea, fever, and behavioral changes). All documents cited in the specification of the present invention are incorporated herein by reference in their entirety. In the event of a conflict, the detailed description of the invention (including definitions) will prevail. While the invention has been described with reference to the specific embodiments of the invention, it is understood that many modifications and changes can be made without departing from the scope and spirit of the invention. It is therefore intended that the present invention be limited only by the "" Simple description of L pattern] (No picture) 20 [Description of main component symbols] (None) 29

Claims (1)

1293562 十、申請專利範圍： [ϋ: 第094108197號專利申請案申請專利範圍修正本1293562 X. Patent application scope: [ϋ: Amendment of patent application scope for patent application No. 094108197 55 1515 20 修正日期：96年10月 一種具有增進的抗生活性的藥學組成物，其包含有薑黃 素作為增進劑以及一抗生素，其中該抗生素是選自於下 列所構成的群組： ⑴胺基配醣體類抗生素(aminoglycosides)，例如阿米卡 星（amikacin)、安痢黴素（apramycin)、阿貝卡星 (arbekacin)、黃黴素（bambermycins)、丁 苷菌素 (butirosin)、地貝卡星（dibekacin)、雙氫鏈黴素 (dihydrostreptomycin)、福提黴素（fortimicin)、健大 Μ素(gentamicin)、異帕米星(isepamicin)、康納黴素 (kanamycin)、小諾米星（micronomicin)、新黴素 (neomycin)、奈替米星（netilmicin)、巴龍黴素 (paromomycin)、核糖黴素(ribostamycin)、西索米星 (sisomicin)、觀黴素（spectinomycin)、鏈黴素 (streptomycin)、妥布黴素(tobramycin)、丙大觀黴素 (trospectomycin);氣黴素類抗生素（amphenicols)， 例如疊氮氯黴素（azidamfenicol)、氯黴素 (chloramphenicol)、氟甲磺氣黴素(florfenicol)、甲磺 氯黴素（thiamphenicol);安莎黴素類抗生素 (ansamycins)，例如利福米特（rifamide)、利福平 (rifampin)、利福黴素SV (rifamycin sv)、利福喷汀 (rifapentine)、利福昔明（rifaximin) ; /5 内醮胺 1 1293562 520 Amendment date: October 1986 A pharmaceutical composition with enhanced anti-life, comprising curcumin as a promoter and an antibiotic, wherein the antibiotic is selected from the group consisting of: (1) Amine-based glycoside Antibiotics (aminoglycosides), such as amikacin, apramycin, arbekacin, bambermycins, butirosin, dibeka Dibekacin, dihydrostreptomycin, fortimicin, gentamicin, isepamicin, kanamycin, small nomiline (micronomicin), neomycin, netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin, chain Streptomycin, tobramycin, trospectomycin; amphenicols, such as azidamfenicol, chloramphenicol, fluorocarbon Fumfenicol , thiamphenicol; ansamycin antibiotics (ansamycins), such as rifamide, rifampin, rifamycin sv, rifapentine (rifapentine), rifaximin; /5 indoleamine 1 1293562 5 (beta-lactam)，包含：碳頭孢烯類抗生素 (carbacephem)，例如氯碳頭孢(loracarbef);碳酿胺 基類抗生素(carbapenems)，必安培南（biapenem)、亞 胺培南（imipenem)、美羅培南（meropenem)、帕尼培 南（panipenem);頭孢菌素抗生素（cephalosporins)， 例如西華克樂（cefaclor)、安泛黴素(cefadroxil)、世 大黴素（cefamandole)、西華治辛（cefatrizine)、頭孢 美唾(cefazedone)、西華樂林(cefazolin)、頭孢卡品醋 (cefcapenepivoxil)、頭孢克定（cefclidin)、頭孢地尼 10 15 20 (cefdinir)、頭孢托倫（cefditoren)、頭孢 σ比將 (cefepime)、頭孢他美（cefetamet)、希復欣 (cefixime)、頭孢地秦（cefodizime)、頭孢尼西 (cefonicid)、頭孢酮（cefoperazone)、頭孢氨甲苯峻 (ceforanide)、西弗士林（cefotaxime)、頭孢替安 (cefotiam)、頭孢唾蘭（cefozopran)、頭孢哺嗤 (cefpimizole)、頭孢匹胺（cefpiramide)、頭孢匹羅 (^€口卜〇1116)、頭孢泊月亏醋（。6€0〇(1〇\111^卩1<〇\61^1)、頭 孢丙烯(cefprozil)、頭孢氧甲環氨(cefroxadine)、西 蘇羅鍵(cefsulodin)、頭孢塔齊定(ceftazidime)、頭孢 特侖(cefteram)、頭孢去甲唾（ceftezole)、頭孢布坦 (ceftibuten)、頭孢嗤（ceftizoxime)、頭孢曲松 (ceftriaxone)、頭孢0夫將（cefuroxime)、頭孢 ϋ坐南 (cefuzonam)、頭孢乙氰納（cephacetrile sodium)、頭 孢氨苄（cephalexin)、頭孢來星(cephaloglycin)、頭孢 2 1293562(beta-lactam), comprising: carbapenphem, such as loracarbef; carbaeneems, biapenem, imipenem, Meropenem, panipenem; cephalosporins, such as cefaclor, cefadoxil, cefmandole, xihuazhi Cefatrizine, cefazedone, cefazolin, cefcapenepivoxil, cefclidin, cefdinir 10 15 20 (cefdinir), cefditoren (cefditoren) ), cefepime ratio (cefepime), cefetamet (cefetamet), cefixime, cefodizime, cefonicid, cefoperazone, cefotaxon (ceforanide) ), cefotaxime, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome (^€ 口1〇1116), Cefpox month vinegar (.6 €0〇(1〇\111^卩1<〇\61^1), cefprozil, cefroxadine, cefsulodin, ceftazidime, cefote Cefteram, ceftezole, ceftibuten, ceftizoxime, ceftrixone, cefuroxime, cefozonam, cephalosporin Cephacetrile sodium, cephalexin, cephaloglycin, cephalosporin 2 1293562 10 15 20 利素I (cephaloridine)、頭孢子黴素(cephalosporin)、 頭胞菌素（cephalothin)、頭孢匹林鈉（cephapirin sodium)、西華定（cephradine);頭黴素類抗生素 (cephamycins)，例如頭孢拉宗鈉（cefbuperazone)、頭 孢替坦(cefotetan)、頭孢甲氧黴素（cef0Xitin);單環 胺基類抗生素（monobactams)，例如氨曲南 (aztreonam)、卡蘆莫南鈉（carumonam)、替吉莫南 (tigemonam);氧頭孢浠類抗生素(oxacephems)，例 如氟氧頭孢(flomoxef)、拉氧頭孢(moxalactam);青 黴素類抗生素（penicillins)，例如氮卓西林 (amdinocillin)、阿莫西林（amoxicillin)、氨节西林 (ampicillin)、阿帕西林（apalcillin)、阿扑西林 (aspoxicillin)、阿度西林（azidocillin)、阿洛西林 (azlocillin)、巴氨西林(bacampicillin)、苄青黴素鈉 (benzylpenicillin sodium)、魏苄西林(carbenicillin)、 卡茚西林(carindacillin)、氯甲西林(clometocillin)、 氯峻西林(cloxacillin)、環已西林(cyclacillin)、雙氯 西林(dicloxacillin)、依匹西林(epicillin)、芬貝西林 (fenbenicillin)、氟氣西林（floxacillin)、喜大西林 (hetacillin)、侖氨西林（lenampicillin)、美坦西林 (metampicillin)、甲氧西林納(methicillin sodium)、美 洛西林（mezlocillin)、乙氧萘青黴素鈉（nafcillin sodium)、奥煞西林（oxacillin)、培那西林 (penamecillin)、青黴素G (penicillin G)、青黴素N 3 129356210 15 20 cephaloridine, cephalosporin, cephalothin, cephapirin sodium, cephradine; cephamycins For example, cefbuperazone, cefotetan, cefoxin (cef0Xitin); monocyclic amines (such as aztreonam, carumalam sodium) Carumonam), tigemonam; oxacephems, such as flomoxef, moxalactam; penicillins, such as amdinocillin, Amoxicillin, ampicillin, apalcillin, apiccillin, aspiricillin, azidocillin, azlocillin, bacampicillin, benzyl Benzpenicillin sodium, carbenicillin, carindacillin, clometacillin, cloxacillin, cyclacillin Dicloxacillin, epicurilin, fenbenicillin, floxacillin, hetacillin, lenampicillin, metampicillin, armor Methillillin sodium, mezlocillin, nafcillin sodium, oxacillin, penamecillin, penicillin G, penicillin N 3 1293562 10 15 20 (penicillin N)、青黴素〇 (penicillin Ο)、青黴素V (penicillin V)、青旅環素(penimepicycline)、非奈西 林釺（phenethicillin potassium)、派拉西林 (piperacillin)、匹氨青黴素(pivampicillin)、丙匹西林 (propicillin)、喹那西林（quinacillin)、石黃苄西林 (sulbenicillin)、舒他西林（sultamicillin)、酞氨西林 (talampicillin)、替莫西林（temocillin)、替卡西林 (ticarcillin);其他的抗生素，例如利替培南 (ritipenem);林可胺類抗生素(lincosamides)，克林達 黴素（clindamycin)、林可黴素（lincomycin);巨環類 抗生素抗生素（macrolides)，例如阿奇黴素 (azithromycin)、卡波黴素（carbomycin)、克拉黴素 (clarithromycin)、地紅黴素（dirithromycin)、紅黴素 (erythromycin)、交沙黴素（josamycin)、白黴素 (leucomycin)、麥迪黴素(midecamycin)、美歐卡黴素 (miokamycin)、竹才北黴素(oleandomycin)、普利黴素 (primycin)、羅他黴素（rokitamycin)、薔薇黴素 (rosaramicin)、羅紅黴素（roxithromycin)、史黴素 (spiramycin)、醋竹桃黴素(troleandomycin);多肽類 抗生素（polypeptides)，例如安福黴素 (amphomycin)、枯草菌素（bacitracin)、卷曲黴素 (capreomycin)、黏桿菌素（colistin)、安來黴素 (enramycin)、恩維黴素（enviomycin)、鐮孢真菌素 (fusafungine)、短桿菌素（gramicidin)、短桿菌肽 s 4 1293562 510 15 20 (penicillin N), penicillin 〇, penicillin V, penimepicycline, phenethicillin potassium, piperacillin, penicillin Pivampicillin), propicillin, quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin, ticarcillin Ticarcillin); other antibiotics such as ritipenem; lincosamides, clindamycin, lincomycin; macrocyclic antibiotics (macrolides) For example, azithromycin, carbomycin, clarithromycin, dihithromycin, erythromycin, josamycin, leucomycin ), midecamycin, miokamycin, oleandomycin, primycin, rokitamycin, rose Rosaramicin, roxithromycin, spiramycin, troleandomycin; peptide antibiotics such as amphomycin, bacitracin ), capreomycin, colistin, enramycin, enviomycin, fusafungine, gramicidin, Brevibacterium Peptide s 4 1293562 5 10 1510 15 20 (gramicidin S)、米卡黴素(mikamycin)、多黏菌素B (polymyxin B)、普那黴素(pristinamycin)、瑞斯托黴 素(ristocetin)、替考拉寧(teicoplanin)、硫鏈絲菌肽 (thiostrepton)、結核放線菌素(tuberactinomycin)、短 桿菌酪肽(tyrocidine)、短桿菌肽(tyrothricin)、萬古 黴素（vancomycin)、紫黴素（viomydn)、純黴素 (virginiamycin);四環素類抗生素(tetracyclines)，例 如阿娘環素（apicycline)、金黴素（chlortetracycline)、 氯莫環素（clomocycline)、 地美環素 (demeclocycline)、脫氧經四環黴素（doxycycline)、脈 甲環素（guamecycline)、賴甲環素（lymecycline)、甲 氯環素(meclocycline)、美他環素(methacycline)、米 諾環素(minocycline)、土黴素（oxytetracycline)、青口辰 環素(penimepicycline)、匹旅環素(pipacycline)、勞 利環素(rolitetracycline)、山環素（sancycline)、四環 素(tetracycline);以及環絲胺酸(cycloserine)、莫匹 羅星(mupirocin); (ii) 2,4_二氨基喂。定類抗菌藥（2,4-siaminopyrimidines)， 例如演莫普林（brodimoprim)、四氧普林 (tetroxoprim)、三甲氧苄氨口密唆(trimethoprim);石肖基 α夫喃類(nitrofurans)，例如吱喃他酮(furaltadone)、吱 ϋ坐氣鈹（furazolium chloride)、硝咬拉定 (nifuradene)、硝吱太爾（nifuratel)、硝咬復林 (nifurfoline)、石肖 °夫 ϋ比醇（nifurpirinol)、石肖吱拉唤 5 129356220 (gramicidin S), mikamycin, polymyxin B, pristinamycin, ristocetin, teicoplanin, sulfur Thiostreprex, tuberactinomycin, tyrocidine, tyrothricin, vancomycin, viomydn, virginiamycin ); tetracyclines, such as apicycline, chlortetracycline, clomocycline, demeclocycline, deoxycycline , guamecycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, Qingkouchen (penimepicycline), pipacycline, rolitetracycline, sancycline, tetracycline; and cycloserine, mupirocin; (ii) 2,4_diaminofeed2,4-siaminopyrimidines, such as brodimoprim, tetroxoprim, trimethoprim, nitrofurans, for example Furantazine (furaltadone), furazolium chloride, nifuradene, nifuratel, nifurfoline, and stone sulphate Nifurpirinol), 石肖吱 calling 5 1293562 10 15 (nifurprazine)、硝吱妥因醇（nifurtoinol);奎諾酮類 及其類似物（quinolones and analogs)，例如西諾沙星 (cinoxacin)、環丙殺星（ciprofloxacin)、克林沙星 (clinafloxacin)、二氟沙星（difloxacin)、依諾沙星 (enoxacin)、氟羅沙星（fleroxacin)、氟甲啥 (flumequine)、格帕沙星（grepafloxacin)、洛梅沙星 (lomefloxacin)、米洛沙星（miloxacin)、那氟沙星 (nadifloxacin)、那利得酸(nalidixic acid)、諾氟沙星 (norfloxacin)、氧氟沙星（ofloxacin)、歐索林酸 (oxolinic acid)、帕珠沙星(pazufloxacin)、培氟沙星 (pefloxacin)、°比 口辰酸（pipemidic acid)、°比洛米酸 (piromidic acid)、羅梭沙星(rosoxacin)、蘆氟沙星 (rufloxacin)、司帕沙星（sparfloxacin)、替馬沙星 (temafloxacin)、托氟沙星(tosufloxacin)、曲氟沙星 (trovafloxacin);績胺類（sulfonamides)，例如石黃胺 (sulfonamide)、苄石黃胺（benzylsulfamide)、氯胺 B (chloramine-B)、氣胺·Τ (chloramine-T)、雙氯胺 T (dichloramine T)、績胺米隆(mafenide)、諾丙石黃胺 (noprylsulfamide) 、 酞 磺 醋 胺 20 (phthalylsulfacetamide) 、 酜 磺 胺 噻 口坐 (phthalylsulfathiazole) 、 柳 氮 磺 口密 口定 (salazosulfadimidine) 、 琥珀 石黃 胺 噻 口坐 (succinylsulfathiazole)、石黃胺苯醯(sulfabenzamide)、 石黃胺醋醯（sulfacetamide)、績胺氯達唤 6 129356210 15 (nifurprazine), nifurtoinol; quinolones and analogs, such as cinoxacin, ciprofloxacin, clinfloxacin ), difloxacin, enoxacin, fleroxacin, flumequine, grepafloxacin, lomefloxacin, rice Miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic acid, pazu Pazufloxacin, pefloxacin, pipemidic acid, piromidic acid, rosoxacin, rufloxacin, Sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin, sulfonamides, such as sulfonamide, benzite Benzylsulfamide, chloramine-B, chloramine- T), dichloramine T, mafenide, noprylsulfamide, phthalylsulfacetamide, phthalylsulfathiazole, sulfasalazine Salazosulfadimidine, succinylsulfathiazole, sulfabenzamide, sulfacetamide, chlorhexidine 6 1293562 10 15 20 (sulfachlorpyridazine)、績胺柯定(sulfachrysoidine)、 績胺西汀（sulfacytine)、石黃胺喊唆(sulfadiazine)、石黃 胺戊烯（sulfadicramide)、石黃胺二甲氧。密咬 (sulfadimethoxine)、石黃胺多辛（sulfadoxine)、石黃胺乙 :°^(sulfaethidole)、績胺脉（sulfaguanidine)、績胺二 甲口亞唑脒（sulfaguanol)、石黃胺林(sulfalene)、石黃胺洛 西酸(sulfaloxic acid)、石黃胺甲 口密唆(sulfamerazine)、 石黃胺甲氧喊σ定（sulfameter)、石黃胺二甲喊唆 (sulfamethazine)、石黃胺甲二唾(sulfamethizole)、石黃胺 曱°惡唾（sulfamethoxazole)、石黃胺甲氧唤 (sulfamethoxypyridazine)、石黃胺美曲（sulfametrole)、 石黃胺米柯定（sulfamidochrysoidine)、石黃胺°惡°坐 (sulfamoxole)、氨苯石黃胺（sulfanilamide)、績胺脲 (sulfanilylurea)、石黃胺石肖苯(sulfanitran)、確胺苯°比吐 (sulfaphenazole)、石黃胺普羅林(sulfaproxyline)、石黃胺 口比嗪(sulfapyrazine)、石黃胺π比咬(sulfapyridine)、石黃胺 異 °塞峻(sulfasomizole)、 績胺均三口秦 (sulfasymazine)、石黃胺 ^^(sulfathiazole)、石黃胺硫脲 (sulfathiourea)、石黃胺托拉米（sulfatolamide)、績胺索 口密口定(sulfisomidine)、績胺異^^(sulfisoxazole);石風 類（sulfones)，例如醋氨苯颯（acedapsone)、醋地石風 (acediasulfone)、石黃胺苯颯鈉（acetosulfone sodium)、 氨苯颯(dapsone)、地百裡礙(diathymosulfone)、葡萄 糖氨苯颯納（glucosulfone sodium)、苯丙石風 7 (solasulfone)、琥珀氨苯颯(succisulfone)、對氨基苯 石黃酸（sulfanilic acid)、亞磺氨苯石風納（sulfoxone sodium);以及氣福克紛（clofoctol)、海克西定 (hexedine)、烏洛托品（methenamine)、琐經唾琳 (nitroxoline)、牛續羅定(taurolidine);以及 (iii)甲氧爷口定(tirmethoprim)、甲墙口坐(metronidazole)、口奎 琳(quinoline)、諾波黴素(novobiocin);以及此等抗 生素的組合。 如申請專利範圍第1項的藥學組成物，其中該抗生素是 派拉西林。 如申請專利範圍第1項的藥學組成物，其中該抗生素是 亞胺培南。 如申請專利範圍第1項的藥學組成物，其被製成呈一適 於非經腸道投藥的形式。 如申請專利範圍第1項的藥學組成物，其被製成呈一適 於口服的形式。 一種由薑黃素與一抗生素所構成的組合用於製造一醫 藥品的用途，其中當該醫藥品當被投藥給一個體時，會 展現出要比單獨投藥該抗生素為高的抗生活性，以及其 中該抗生素是選自於下列所構成的群組： ⑴胺基配醣體類抗生素(aminoglycosides)，例如阿米卡 星（amikacin)、安病黴素（apramycin)、阿貝卡星 (arbekacin)、黃黴素（bambermycins)、丁 芽菌素 (butirosin)、地貝卡星（dibekacin)、雙氣鍵徽素 129356210 15 20 (sulfachlorpyridazine), sulfachrysoidine, sulfacytine, sulfadiazine, sulfadicramide, and diamine. Sulfadimethoxine, sulfadoxine, sulphate B: °^ (sulfaethidole), sulfaguanidine, sulfaguanol, sulphate Sulfalene), sulfaloxic acid, sulfamerazine, sulfameter, sulfamethazine, feldspar Sulfamethizole, sulfamethoxazole, sulfamethoxypyridazine, sulfametrole, sulfamidochrysoidine, feldspar Amine sulfamoxole, sulfanilamide, sulfanilylurea, sulfanitran, sulfaphenazole, sulphate prolin (sulfaproxyline), sulfapyrazine, sulfapyridine, sulfasomizole, sulfasymazine, sulphate (^) Sulfathiazole), sulfathiourea, sulphate Sulfatolamide, sulfisomidine, sulfisoxazole; sulfones, such as acedapsone, acediasulfone, stone Acetosulfone sodium, dapsone, diathymosulfone, glucosulfone sodium, solasulfone, succisulfone ), sulfanilic acid, sulfoxone sodium; and clofoctol, hexedine, methenamine, Trinitroxine, taurolidine; and (iii) tirmethoprim, metronidazole, quinoline, novobiocin ); and a combination of such antibiotics. A pharmaceutical composition according to claim 1, wherein the antibiotic is piracetam. The pharmaceutical composition of claim 1, wherein the antibiotic is imipenem. A pharmaceutical composition according to claim 1 of the patent application, which is formulated in a form suitable for parenteral administration. The pharmaceutical composition of claim 1 of the patent application is formulated in a form suitable for oral administration. A use of a combination of curcumin and an antibiotic for the manufacture of a pharmaceutical product, wherein when the pharmaceutical product is administered to a body, it exhibits a higher resistance to life than the administration of the antibiotic alone, and The antibiotic is selected from the group consisting of: (1) aminoglycosides, such as amikacin, apramycin, arbekacin, Bambermycins, butirosin, dibekacin, double gas bond 1293356 10 15 20 (dihydrostreptomycin)、福提黴素（fortimicin)、健大 黴素(gentamicin)、異帕米星(isepamicin)、康納黴素 (kanamycin)、小諾米星（micronomicin)、新黴素 (neomycin)、奈替米星（netilmicin)、巴龍黴素 (paromomycin)、核糖黴素(ribostamycin)、西索米星 (sisomicin)、觀黴素（spectinomycin)、鏈黴素 (streptomycin)、妥布黴素(tobramycin)、丙大觀黴素 (trospectomycin);氣黴素類抗生素（amphenicols)， 例如疊氮氯黴素（azidamfenicol)、氯黴素 (chloramphenicol)、氟甲磺氯黴素(florfenicol)、甲磺 氯黴素（thiamphenicol);安莎黴素類抗生素 (ansamycins)，例如利福米特（rifamide)、利福平 (rifampin)、利福黴素SV (rifamycin sv)、利福喷汀 (rifapentine)、利福昔明（rifaximin) ; /3 -内醯胺 (beta-lactam)， 包含：碳頭孢烯類抗生素 (carbacephem)，例如氣碳頭孢(loracarbef);礙醯胺 基類抗生素(carbapenems)，必安培南（biapenem)、亞 胺培南（imipenem)、美羅培南（meropenem)、帕尼培 南（panipenem);頭孢菌素抗生素（cephalosporins)， 例如西華克樂（cefaclor)、安泛黴素（cefadroxil)、世 大黴素（cefamandole)、西華治辛（cefatrizine)、頭孢 美口坐(cefazedone)、西華樂林(cefazolin)、頭孢卡品酷 (cefcapenepivoxil)、頭孢克定(cefclidin)、頭孢地尼 (cefdinir)、頭孢托倫（cefditoren)、頭孢 π比將 9 129356210 15 20 (dihydrostreptomycin), fortimicin, gentamicin, isepamicin, kanamycin, micronomicin, neomycin (neomycin), netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, Tobramycin, trospectomycin; amphenicols, such as azidamfenicol, chloramphenicol, florfenicol , thiamphenicol; ansamycin antibiotics (ansamycins), such as rifamide, rifampin, rifamycin sv, rifapentine (rifapentine), rifaximin; /3 -beta-lactam, including: carbapenem antibiotics (carbacephem), such as carbocene (loracarbef); Carbapenems), biapenem, imipenem , meropenem (meropenem), panipenem; cephalosporins, such as cefaclor, cefadroxil, cefamandole, xihua Cefatrizine, cefazedone, cefazolin, cefcapenepivoxil, cefclidin, cefdinir, cefditoren , cephalosporin π ratio will be 9 1293562 10 15 20 (cefepime)、頭孢他美（cefetamet)、希復欣 (cefixime)、頭孢地秦（cefodizime)、頭孢尼西 (cefonicid)、頭孢嗣（cefoperazone)、頭孢氨甲苯唾 (ceforanide)、西弗士林（cefotaxime)、頭孢替安 (cefotiam)、頭孢唾蘭（cefozopran)、頭孢口米唾 (cefpimizole)、頭孢匹胺（cefpiramide)、頭孢匹羅 (cefpirome)、頭孢泊將酯（cefpodoxime proxetil)、頭 孢丙稀（cefprozil)、頭孢氧甲環氨(cefroxadine)、西 蘇羅錠(cefsulodin)、頭孢塔齊定(ceftazidime)、頭孢 特命(cefteram)、頭孢去甲唑（ceftezole)、頭孢布坦 (ceftibuten)、頭孢唾（ceftizoxime)、頭孢曲松 (ceftriaxone)、頭孢吱將（cefuroxime)、頭孢嗤南 (cefuzonam)、頭孢乙氰鈉（cephacetrile sodium)、頭 孢氨 T(cephalexin)、頭孢來星(cephaloglycin)、頭孢 利素I (cephaloridine)、頭孢子黴素(cephalosporin)、 頭胞菌素（cephalothin)、頭孢匹林鈉（cephapirin sodium)、西華定（cephradine);頭黴素類抗生素 (cephamycins) ’ 例如頭孢拉宗鈉（Cefbuperazone)、頭 孢替坦(cefotetan)、頭孢甲氧黴素(Cef〇xitin);單環 胺基類抗生素（monobactams)，例如氨曲南 (aztreonam)、卡蘆莫南鈉（Carumonam)、替吉莫南 (tigemonam);氧頭孢烯類抗生素(oxacephems)，例 如氟氧頭孢（flomoxef)、拉氧頭孢(moxalactam);青 黴素類抗生素（penicillins)，例如氮卓西林 10 乜9356210 15 20 (cefepime), cefetamet, cefixime, cefodizime, cefonicid, cefoperazone, ceforanide, cefo Cefotaxime, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime proxetil ), cefprozil, cefroxadine, cefsulodin, ceftazidime, ceftelam, ceftezole, cefotaxime Ceftibuten, ceftizoxime, ceftrixone, cefuroxime, cefuzonam, cephacetrile sodium, cephalexin, cephalosporin Cephalolycin, cephaloridine, cephalosporin, cephalothin, cephapirin sodium, cephradine; cephalosporin Antibiotics (cephamycins) such as Cefbuperazone, cefotetan, cef〇xitin, monobactams, such as aztreonam, Carumonam, tigemonam; oxacephems, such as flomoxef, moxalactam; penicillins, such as nitrogen Zhuo Xilin 10 乜93562 10 15 20 (amdinocillin)、阿莫西林（amoxicillin)、氨苄西林 (ampicillin)、阿帕西林（apalcillin)、阿扑西林 (aspoxicillin)、阿度西林（azidocillin)、阿洛西林 (azlocillin)、巴氨西林(bacampicillin)、苄青黴素納 (benzylpenicillin sodium)、魏苄西林(carbenicillin)、 卡茚西林(carindacillin)、氯甲西林(clometocillin)、 氯口坐西林(cloxacillin)、環已西林(cyclacillin)、雙氯 西林(dicloxacillin)、依匹西林(epicillin)、芬貝西林 (fenbenicillin)、氟氣西林（floxacillin)、喜大西林 (hetacillin)、侖氨西林（lenampicillin)、美坦西林 (metampicillin)、甲氧西林納(methicillin sodium)、美 洛西林（mezlocillin)、 乙氧萘青黴素鈉（nafcillin sodium)、奥煞西林（oxacillin)、培那西林 (penamecillin)、青黴素G (penicillin G)、青黴素N (penicillin N)、青黴素Ο (penicillin 0)、青黴素V (penicillin V)、青旅環素(penimepicycline)、非奈西 林卸（phenethicillin potassium)、派拉西林 (piperacillin)、匹氨青黴素(pivampicillin)、丙匹西林 (propicillin)、喧那西林（quinacillin)、石黃苄西林 (sulbenicillin)、舒他西林（sultamicillin)、酜氨西林 (talampicillin)、替莫西林（temocillin)、替卡西林 (ticarcillin);其他的抗生素，例如利替培南 (ritipenem);林可胺類抗生素(lincosamides)，克林達 黴素（clindamycin)、林可黴素(lincomycin);巨環類 11 1)93562 10 15 20 抗生素抗生素（macrolides)，例如阿奇黴素 (azithromycin)、卡波黴素（carbomycin)、克拉黴素 (clarithromycin)、地紅黴素（dirithromycin)、紅黴素 (erythromycin)、交沙黴素（josamycin)、白黴素 (leucomycin)、麥迪黴素(midecamycin)、美歐卡黴素 (miokamycin)、竹桃徽素(oleandomycin)、普利徽素 (primycin)、羅他黴素（rokitamycin)、薔薇黴素 (rosaramicin)、羅紅黴:素（roxithromycin)、史黴素 (spiramycin)、醋竹桃黴素(troleandomycin);多肽類 抗生素（polypeptides)，例如安福黴素 (amphomycin)、枯草菌素（bacitracin)、卷曲黴素 (capreomycin)、黏桿菌素（colistin)、安來黴素 (enramycin)、恩維黴素（enviomycin)、鐮孢真菌素 (fusafungine)、短桿菌素、短桿菌肽 S (gramicidin S)、米卡黴素(mikamycin)、多黏菌素B (polymyxin B)、普那黴素（pristinamycin)、瑞斯托黴素 (ristocetin)、替考拉寧（teicoplanin)、硫鏈絲菌肽 (thiostrepton)、結核放線菌素(tuberactinomycin)、短 桿菌酪肽(tyrocidine)、短桿菌肽(tyrothricin)、萬古 黴素（vancomycin)、紫黴素（viomycin)、純黴素 (virginiamycin);四環素類抗生素(tetracyclines)，例 如阿旅環素（apicycline)、金黴素（chlortetracycline)、 氣莫環素（clomocycline)、 地美環素 (demeclocycline)、脫氧羥四環黴素（doxycycline)、胍 12 129356210 15 20 (amdinocillin), amoxicillin, ampicillin, apalcillin, apoxicillin, azidocillin, azlocillin, baamine Baccamicillin, benzylpenicillin sodium, carbenicillin, carindacillin, clometacillin, cloxacillin, cyclacillin, double Dicoxacillin, epicurilin, fenbenicillin, floxacillin, hetacillin, lenampicillin, metampicillin, methoxy Methillillin sodium, mezlocillin, nafcillin sodium, oxacillin, penamecillin, penicillin G, penicillin N ), penicillin (penicillin 0), penicillin V (penicillin V), penetin (cyclimepicycline), phenethicillin potassium (phenethicillin potassium) Piperacillin, pivampicillin, propicillin, quinacillin, sulbenicillin, sultamicillin, talampicillin, Temocillin, ticarcillin; other antibiotics such as ritipenem; lincosamides, clindamycin, lincomycin Lincomycin); macrocyclic class 11 1) 93562 10 15 20 antibiotic antibiotics (macrolides), such as azithromycin (azithromycin), carbomycin, clarithromycin, dihithromycin, red mold Erythromycin, josamycin, leucomycin, midecamycin, miokamycin, oleandomycin, primycin ), rokitamycin, rosaramicin, roxithromycin, spiramycin, troleandomycin; peptide antibiotic (polypepti) Des), for example, amphomycin, bacitracin, capreomycin, colistin, enramycin, enviomycin, Fusarium Fusafungine, gramicidin, gramicidin S, mikamycin, polymyxin B, pristinamycin, ristocetin Ristocetin, teicoplanin, thiostrepton, tuberactinomycin, tyrocidine, tyrothricin, vancomycin ), viomycin, virginiamycin; tetracyclines, such as apicycline, chlortetracycline, clomocycline, and dexamethasone Demeclocycline, deoxycycline, 胍12 1293562 10 1510 15 20 甲環素(guamecycline)、賴甲環素(lymecycline)、甲 氣環素(meclocycline)、美他環素(methacycline)、米 諾環素(minocycline)、土黴素(oxytetracycline)、青口底 環素(penimepicycline)、匹旅環素(pipacycline)、勞 利環素(rolitetracycline)、山環素(sancycline)、四環 素(tetracycline);以及環絲胺酸(cycloserine)、莫匹 羅星(mupirocin); (ii) 2,4·二氨基口密咬類抗菌藥（2,4-siaminopyrimidines)， 例如溴莫普林（brodimoprim)、四氧普林 (tetroxoprim)、三曱氧苄氨嘧口定(trimethoprim);硝基 吱喃類(nitrofurans)，例如吱喃他酮(furaltadone)、吱 口坐氯銨（furazolium chloride)、硝’ σ夫拉定 (nifuradene)、硝’吱太爾（nifuratel)、硕吱復林 (nifurfoline)、硝吱 °比醇（nifurpirinol)、硝吱拉嗓 (nifurprazine)、硝吱妥因醇（nifurtoinol);奎諾酮類 及其類似物（quinolones and analogs)，例如西諾沙星 (cinoxacin)、環丙殺星（ciprofloxacin)、克林沙星 (clinafloxacin)、二氟沙星（difloxacin)、依諾沙星 (enoxacin)、氟羅沙星（fleroxacin)、氟甲啥 (flumequine)、格帕沙星（grepafloxacin)、洛梅沙星 (lomefloxacin)、米洛沙星（miloxacin)、那氟沙星 (nadifloxacin)、那利得酸(nalidixic acid)、諾氟沙星 (norfloxacin)、氧氟沙星（ofloxacin)、歐索林酸 (oxolinic acid)、帕珠沙星(pazufloxacin)、培氟沙星 13 ,129356220 guanein (guamecycline), lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, qingkou cyclin (penimepicycline), pipacycline, rolitetracycline, sancycline, tetracycline; and cycloserine, mupirocin; Ii) 2,4-diaminopyrimidines, such as brodimoprim, tetroxoprim, trimethoprim Nitrofurans, such as furantazine (furaltadone), furazolium chloride, nifuradene, nifuratel, sorghum Nifurfoline, nifurpirinol, nifurprazine, nifurtoinol, quinolones and analogs, such as Sinora Cinoxacin, ciprofloxacin, clinfloxac In), difloxacin, enoxacin, fleroxacin, flumequine, grepafloxacin, lomefloxacin, Miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin, oxolinic acid, pa Bezufloxacin, pefloxacin 13, 1293562 10 15 20 (pefloxacin)、吡哌酸（pipemidic acid)、°比洛米酸 (piromidic acid)、羅梭沙星(r〇s〇xacin)、蘆氟沙星 (rufloxacin)、司帕沙星（sparfloxacin)、替馬沙星 (temafloxacin)、托氟沙星（tosufloxacin)、曲氟沙星 (trovafloxacin);石黃胺類（sulfonamides)，例如績胺、 苄石黃胺(benzylsulfamide)、氯胺B (chloramine-B)、氯 胺-T (chloramine-T)、雙氯胺T (dichloramine T)、石黃 胺米隆(mafenide)、諾丙石黃胺（noprylsulfamide)、S太 石黃醋胺（phthalylsulfacetamide)、酞石黃胺嗟嗤 (phthalylsulfathiazole)、 柳 氮 石黃。密。定 (salazosulfadimidine) 、 琥 ί白石黃 胺 °塞 唾 (succinylsulfathiazole)、石黃胺苯醯（sulfabenzamide)、 石黃胺醋醯（sulfacetamide)、石黃胺氣達唤 (sulfachlorpyridazine)、石黃胺柯定（sulfachrysoidine)、 石黃胺西、汀（sulfacytine)、續胺σ密咬（sulfadiazine)、石黃 胺戊烯（sulfadicramide)、石黃胺二甲氧。密。定 (sulfadimethoxine)、石黃胺多辛（sulfadoxine)、石黃胺乙 二唾(sulfaethidole)、石黃胺脉（sulfaguanidine)、石黃胺二 甲17亞嗤脒（sulfaguanol)、石黃胺林(sulfalene)、石黃胺洛 西酸(sulfaloxic acid)、石黃胺曱癌唆(sulfamerazine)、 石黃胺甲氧°密11 定（sulfameter)、石黃胺二甲喊咬 (sulfamethazine)、石黃胺甲二0坐(sulfamethizole)、石黃胺 甲0惡σ坐（sulfamethoxazole)、石黃胺甲氧嗪 (sulfamethoxypyridazine)、石黃胺美曲（sulfametrole)、 14 螫乜93562 510 15 20 (pefloxacin), pipemidic acid, piromidic acid, r〇s〇xacin, rufloxacin, sparfloxacin Sparfloxacin), temafloxacin, tosufloxacin, trovafloxacin, sulfonamides, such as chloramine, benzylsulfamide, chloramine B (chloramine-B), chloramine-T, dichloramine T, mafenide, noprylsulfamide, S-tallow acetamide Phthalylsulfacetamide, phthalylsulfathiazole, sulfoxide. dense. (salazosulfadimidine), succinylsulfathiazole, sulfabenzamide, sulfacetamide, sulfachlorpyridazine, sulphate (sulfachrysoidine), sulphate, sulfacytine, sulfadiazine, sulfadicramide, and diamine. dense. Sulfadimethoxine, sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanol, sulphate Sulfalene), sulfaloxic acid, sulfamerazine, sulfameter, sulfamethazine, feldspar Sulfamethizole, sulfamethoxazole, sulfamethoxypyridazine, sulfametrole, 14 螫乜93562 5 石黃胺米柯定（sulfamidochrysoidine)、石黃胺°惡嗤 (sulfamoxole)、氨苯石黃胺（sulfanilamide)、石黃胺脲 (sulfanilylurea)、石黃胺确苯(sulfanitran)、石黃胺苯11 比口坐 (sulfaphenazole)、石黃胺普羅林(sulfaproxyline)、石黃胺 口比唤(sulfapyrazine)、續胺11比唆(sulfapyridine)、石黃胺 異嗟嗤（sulfasomizole)、 磺胺均三口秦 (sulfasymazine)、石黃胺σ塞嗤(sulfathiazole)、石黃胺硫脲 (sulfathiourea)、石黃胺托拉米（sulfatolamide)、石黃胺索 口密口定(sulfisomidine)、石黃胺異〇惡口坐(sulfisoxazole);石風 10 15Sulfadamine sulfamidochrysoidine, sulfamoxole, sulfanilamide, sulfanilylurea, sulfanitran, sulphate 11 sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine, sulfasomizole, sulfonamide (sulfasymazine), sulfathiazole, sulfathiourea, sulfatolamide, sulfisomidine, sulphate Sulphurxazole; stone wind 10 15 20 類（sulfones)，例如醋氨苯颯（acedapsone)、醋地颯 (acediasulfone)、石黃胺苯颯鈉（acetosulfone sodium)、 氨苯颯(dapsone)、地百裡石風(diathymosulfone)、葡萄 糖氨苯颯納（glucosulfone sodium)、苯丙颯 (solasulfone)、琥拍氨苯石風(succisulfone)、對氨基苯 磺酸（sulfanilic acid)、亞石黃氨苯礙鈉（sulfoxone sodium);以及氯福克酚（dofbctol)、海克西定 (hexedine)、烏洛托品（methenamine)、硝經嗜琳 (nitroxoline)、牛石黃羅定（taurolidine);以及 (iii)甲氧苄啶、甲硝唑、喳啉、諾波黴素；以及此等抗 生素的組合。 7·如申请專利範圍第6項的用途，其中該抗生素是派拉西 林。 8·如申請專利範圍第6項的用途，其中該抗生素是亞胺培 南0 15 ,¢293562 ▼ 9.如申請專利範圍第6項的用途，其中該醫藥品呈一適於 ' 非經腸道投藥的形式。 10.如申請專利範圍第6項的用途，其中該醫藥品呈一適於 口服的形式。20 sulfones, such as acedapsone, acediasulfone, acetosulfone sodium, dapsone, diathymosulfone, glucose Glucosulfone sodium, solasulfone, succisulfone, sulfanilic acid, sulfoxone sodium; and chlorine Dofbctol, hexedine, methenamine, nitroxoline, taurolidine; and (iii) trimethoprim, metronidazole , porphyrin, nopamycin; and combinations of such antibiotics. 7. The use of claim 6 in the scope of patent application, wherein the antibiotic is paracelillin. 8. The use of the scope of claim 6 wherein the antibiotic is imipenem 0 15 , ¢ 293562 ▼ 9. The use of the scope of claim 6 wherein the pharmaceutical product is suitable for a parenteral The form of the drug. 10. The use of claim 6 wherein the pharmaceutical product is in a form suitable for oral administration. 1616