布格呋喃是中國醫(yī)學(xué)科學(xué)院藥物研究所和北京協(xié)和制藥二廠合作研制開發(fā)的1.1類化學(xué)新藥，擬用于治療廣泛性焦慮癥（generalized anxiety disorder）。
Buagafuran is a kind of Class 1.1 new chemical drug, developed under the cooperation of Pharmaceutical Research Institute of Chinese Academy of Medical Sciences and No.2 Pharmaceutical Plant of Beijing Union Medical College, intended to treat the generalized anxiety disorder.
 
布格呋喃是名貴中藥沉香提取物沉香呋喃的衍生物。《本草綱目》記載：沉香有清人神，益氣合神等作用。70年代初，中國醫(yī)學(xué)科學(xué)院藥物研究所即已觀察到沉香精油具有一定的鎮(zhèn)靜催眠作用，因此對沉香呋喃天然化合物進(jìn)行了立體選擇性合成和結(jié)構(gòu)改造，合成了一系列新的衍生物，經(jīng)過藥效學(xué)和毒理學(xué)篩選，發(fā)現(xiàn)布格呋喃具有顯著的抗焦慮活性，毒副作用較低，無依賴性和耐受性。
Buagafuran is the derivative of Agarofuran (an extract of aloe wood, a precious traditional Chinese medicine). In “Compendium of Materia Medica”, it records that agilawood can restore consciousness, be benefit to Qi, etc. In early 1970s, Pharmaceutical Research Institute of Chinese Academy of Medical Sciences has already found that the essential oil of agilawood had a certain sedative and hypnotic effect, so the natural compounds of Agarofuran have been stereo-selectively synthesized and structurally transformed to form a series of new derivatives, after the screening of drug efficiency and toxicology, it found that buagafuran had significant anxiolytic activity, with lower side effects, without dependence and tolerance.
 
藥效試驗顯示，布格呋喃具有穩(wěn)定的抗焦慮作用。其抗焦慮強度接近安定。在12種焦慮模型中, 布格呋喃均有量-效相關(guān)的抗焦慮作用，其抗焦慮譜與安定相同而明顯寬于丁螺環(huán)酮。且重復(fù)給藥時，布格呋喃的抗焦慮作用不發(fā)生耐受性（且有逐漸增強的趨勢），也沒有停藥反應(yīng)。在單獨給藥時，布格呋喃只有鎮(zhèn)靜效應(yīng)，無論多大劑量和給藥途徑，都沒有催眠作用。布格呋喃也無肌松與肌協(xié)調(diào)損傷作用；對學(xué)習(xí)、記憶損傷不明顯；無木僵效應(yīng)；對痛疼無抑制作用。
The pharmacodynamic trial showed that the buagafuran had stable anxiolytic effect. Its anxiolytic strength was close to Diazepam. In the twelve kinds of anxiety model, the buagafuran had the anxiolytic effect related with dosage-efficiency, and its anti-anxiety spectrum was same as that of Diazepam, and wider that than that of Buspirone. If repeatedly administrated, the anxiolytic effect of buagafuran didn’t have tolerance (in gradually increasing trend) or withdrawal reaction. If independently administrated, the buagafuran only had sedative effect, no matter how much dosage and what the route of administration, there was no hypnotic effects. Buagafuran also cannot relax muscle or damage the muscle coordination; the damage to learning and memory was not obvious; no stupor effect; no inhibition to pain.
 
在急毒試驗中，布格呋喃5 g/kg 不會引起動物死亡，也無共濟失調(diào)或其它感覺-運動的明顯毒性效應(yīng)。因此，布格呋喃中樞神經(jīng)系統(tǒng)毒性、副作用低于丁螺環(huán)酮。安全性藥理研究結(jié)果顯示布格呋喃治療劑量范圍內(nèi)對犬心電圖、血壓、心率、及呼吸無異常影響。Beagle犬口服給予布格呋喃9個月的無明顯毒副反應(yīng)劑量為5 mg/kg，15mg/kg和50mg/kg劑量組除血清ALP水平升高外，體重、進(jìn)食量、心電圖、神經(jīng)活動狀況、尿生化、血液學(xué)、以及其它血清生化指標(biāo)等均未見明顯變化。布格呋喃對動物生殖力對仔代無明顯影響，亦無遺傳毒性。依賴性實驗顯示實驗動物對布格呋喃不產(chǎn)生生理依賴性和精神依賴性。
In acute toxicity test, 5g/kg buagafuran cannot cause death of animal, nor ataxia or other obvious toxic effects of sensory-motor. Therefore, the central nervous system toxicity and side effects of buagafuran are lower than these of buspirone. The results of safety pharmacology study showed that it could not affect the ECG, blood pressure, heart rate, and respiratory of dog in the therapeutic dosage range of buagafuran. After Beagle dogs were oral administrated buagafuran for 9 months, the dosage without significant toxic side effects was 5 mg/kg, while in the dosage group of15mg/kg and 50mg/kg there was no significant changes in body weight, food intake, ECG, status of neural activities, urine biochemistry, hematology, and other serum biochemical parameters except the serum ALP level was increased. Buagafuran has no significant impact on the reproductive capacity and offspring of animal, and it also has no genotoxicity. In the dependence experiment, it showed that the experimental animals didn’t generate physical dependence or psychological dependence to buagafuran.
 
大鼠和犬藥代動力學(xué)研究顯示布格呋喃吸收較快，口服后5~10min血漿中既可檢測到原形藥物，10-40min血藥濃度達(dá)峰，各組織均有分布，經(jīng)過尿、糞排泄出體外，大鼠和人血漿蛋白結(jié)合率為97%。
In the pharmacokinetic studies of rat and dog, it showed that buagafuran was absorbed quickly, after oral administration for 5 ~ 10min the unchanged drug could be detected in plasma, and 10-40min later the plasma concentration would be up to peak, distributed in every tissue, excreted outside via urine and feces, the binding rate of rat and human plasma protein was 97%.
 
布格呋喃現(xiàn)已完成Ⅰ期臨床研究，包括單次給藥和多次給藥的健康人體耐受性試驗、單次給藥和多次給藥的健康人體藥代動力學(xué)研究以及食物對藥代動力學(xué)影響的研究。人體耐受性研究證實本品在15~90mg劑量范圍內(nèi)單次和多次給藥的人體耐受性良好。
Buagafuran has completed Phase I clinical studies, including the tolerance test of single-dose and multiple dose administration to healthy human, the pharmacokinetic study of single-dose and multiple dose administration to healthy human, and the study about the influence of food on pharmacokinetics. The human tolerance study confirmed that the human tolerance was good in single-dose and multiple dose administration in the dosage range of 15 to 90mg of this product.
 
人體藥代動力學(xué)實驗結(jié)果顯示：中國健康受試者單次、多次空腹及進(jìn)食后口服30~120mg布格呋喃安全性和耐受性良好。中國健康男性受試者單次口服布格呋喃膠囊30mg，60mg或120mg后，吸收較為迅速，總體暴露量和最高瞬時暴露水平都隨著劑量的增加而升高，但與劑量并不成比例關(guān)系，藥物消除隨劑量增加而減慢。進(jìn)食對單次口服60mg布格呋喃膠囊的系統(tǒng)暴露水平有影響：達(dá)峰時間延長，血漿峰濃度下降，曲線下面積增加。單次和每日兩次連續(xù)口服布格呋喃膠囊60mg或120mg后，布格呋喃被快速吸收，并在每日兩次重復(fù)口服后不久達(dá)穩(wěn)態(tài)。與單劑的藥代動力學(xué)參數(shù)相比，重復(fù)給藥后的暴露量有中度蓄積。120mg組的布格呋喃清除率低于60mg組。
The human pharmacokinetics experimental results showed: Chinese healthy subjects orally administrated 30 to 120mg buagafuran in single and multiple times after fasting or eating, the security and tolerance were good. After the Chinese healthy male subjects single orally administrated 30mg, 60mg or 120mg buagafuran capsules, the absorption was relative fast, and the overall exposure and maximum instantaneous exposure levels were increased with the increase of dosage, but not proportional to dosage, and the drug elimination was slowed down with the increase of dosage. Eating would affect the system exposure level of 60mg buagafuran capsule in single oral administration: time to reach peak was prolonged, the peak plasma concentration was decreased, and the area under the curve was increased. After oral administration of 60mg or 120mg buagafuran capsules in single time and two consecutive times a day, buagafuran was rapidly absorbed; after two repeated oral administration a day it would be in steady state shortly. Compared with the pharmacokinetic parameters of single dose, the exposure had moderate accumulation after repeated dosage. In 120mg group, the elimination rate of buagafuran was less than that of 60 mg group.
 
布格呋喃Ⅰ期臨床研究報告已提交CDE，正在申報Ⅱ期臨床試驗。
Buagafuran Phase I clinical study report has been submitted to CDE under the application for Phase II clinical trial.
 
應(yīng)用領(lǐng)域：抗焦慮癥
Application field: anti-anxiety disorder
 
藥理毒理特點：抗焦慮作用穩(wěn)定，其抗焦慮強度接近安定，其中樞神經(jīng)系統(tǒng)毒性、副作用低于丁螺環(huán)酮，無依賴性和耐受性。
Pharmacological and toxicological features: stable anxiolytic effect, its anxiolytic strength is close to Diazepam, and its central nervous system toxicity, side effects were lower than these of buspirone; it has no dependence or tolerance.
 
創(chuàng)新點和優(yōu)勢：與現(xiàn)有抗焦慮藥物結(jié)構(gòu)不同；重復(fù)給藥時，布格呋喃的抗焦慮作用不發(fā)生耐受性（且有逐漸增強的趨勢），也沒有停藥反應(yīng)。在單獨給藥時，布格呋喃只有鎮(zhèn)靜效應(yīng)，無論多大劑量和給藥途徑，都沒有催眠作用。布格呋喃也無肌松與肌協(xié)調(diào)損傷作用；對學(xué)習(xí)、記憶損傷不明顯；無木僵效應(yīng)；對痛疼無抑制作用。
Innovations and advantages: its structure is different from the existing anti-anxiety drugs. In repeated administration, the anxiolytic effect of buagafuran does not have any tolerance have tolerance (in gradually increasing trend) or withdrawal reactions. In single administration, buagafuran only has sedative effect, no matter how much dose and what route of administration, there will be no hypnotic effects. Buagafuran also cannot relax muscle or damage the muscle coordination; the damage to learning and memory is not obvious; no stupor effect; no inhibition to pain.
 
開發(fā)階段：完成Ⅰ期臨床試驗，30~120mg范圍內(nèi)安全性和耐受性良好，確定了健康人體藥代動力學(xué)參數(shù)。2012年4月申報開展Ⅱ期臨床試驗（CXHB1200054、CXHB1200055），目前正在CDE審評。
Development stage: Phase I clinical trial was completed, safety and tolerability were good in the range of 30 to 120mg; the healthy human pharmacokinetic parameters were confirmed. In April 2012, it reported to carry out Phase II clinical trials (CXHB1200054 CXHB1200055), now it is reviewed by CDE.
 
 
天麻芐醇酯苷原料藥及片劑（獲得Ⅰ期臨床試驗批件）
Tianma benzyl alcohol ester glycosides bulk drug and tablets (Obtained the approval of Phase I clinical trials)
 
一、藥品基本信息：
    通用名稱：天麻芐醇酯苷片
化學(xué)結(jié)構(gòu)：本品主要有效成分為天麻芐醇酯苷化合物，主要含有：派立辛、派立辛B、派立辛C，其中派立辛占提取物的45%以上，
I. Basic information of drug:
Common name: Tianma benzyl alcohol ester glycosides tablet
Chemical structure: The main active ingredient of this product is Tianma benzyl alcohol ester glycoside, mainly containing: pa fabulousrishin, pa fabulousrishin B, pa fabulousrishin C, of which pa fabulousrishin is accounted for more than 45% of the extract,
 
 派立辛pa fabulousrishin
適應(yīng)癥：血管性癡呆
劑型及規(guī)格：薄膜衣片，100mg/片（每片含天麻芐醇酯苷14mg）
注冊類別：中藥5類
Indications: vascular dementia
Formulation and specification: film-coated tablets, 100 mg/tablet (each tablet contains 14 mg Tianma benzyl alcohol ester glycosides)
Registration category: Category 5, traditional Chinese medicine
 
二、藥理、毒理研究：
經(jīng)藥理學(xué)試驗證明，各劑量組可以不同程度地提高擬血管性癡呆模型大鼠學(xué)習(xí)記憶能力，減輕模型大鼠的神經(jīng)病理損傷。其可能的作用環(huán)節(jié)包括：①有效誘導(dǎo)腦損傷修復(fù)過程中神經(jīng)元生長相關(guān)蛋白的合成，抑制星形膠質(zhì)細(xì)胞的過度增殖, 促進(jìn)腦缺血損傷后神經(jīng)元突起再生。②調(diào)控退化的谷氨酸神經(jīng)元的突觸活性，重建腦內(nèi)Glu/GABA學(xué)習(xí)記憶調(diào)節(jié)系統(tǒng)穩(wěn)態(tài)③改善腦內(nèi)膽堿能系統(tǒng)的功能④抗脂質(zhì)過氧化，激活抗自由基氧化酶SOD活性,加快腦組織自由基的清除速率,減少自由基代謝產(chǎn)物MDA的堆積。
II. Pharmacological, toxicological studies:
Pharmacological test has proved that the learning and memory capabilities of simulative vascular dementia rat model could be improved in different degrees in each dosage group, reducing the neuropathic injury of rat model. The possible active links included: ① to effectively induce the synthesis of neuron growth-related protein during the repair of cerebral injury, to inhibit the excessive proliferation of astrocytes, to promote the neurite regeneration after cerebral ischemic injury. ② to regulate and control the postsynaptic activity of degraded glutamate neurons, to reconstruct the steady state of Glu/GABA learning and memory-conditioning system in brain ③ to improve the functions of cholinergic system in brain ④ anti-lipid peroxidation, to activate the activity of anti-free radical oxidation enzyme SOD, to accelerate the elimination rate of free radicals in brain, to reduce accumulation of MDA, the product from metabolism of free radicals.
 
經(jīng)GLP試驗室安全性評價，本品在小鼠急性毒性研究中無法測得LD50，其口服最大給藥量達(dá)49.28g/kg，大鼠及Beagle犬長期毒性研究未發(fā)現(xiàn)毒性作用。
According to GLP laboratory safety evaluation, this product cannot be detected LD50 in the acute toxicity study of mice, and the max dosage of oral administration was up to 49.28g/kg, and there was no toxic effects in long-term toxicity studies of rats and Beagle dogs.
 
三、創(chuàng)新點及優(yōu)勢：
1．本產(chǎn)品申請4項中國發(fā)明專利，1項PCT專利，其中2項專利已授權(quán)。
2．天麻是傳統(tǒng)中藥，已經(jīng)廣泛栽培，不存在資源問題，可以為將來的生產(chǎn)提供充分的保障。
3．天麻芐醇酯苷有效部位包含三個有效單體，總含量超過80％。主成分化學(xué)結(jié)構(gòu)明確，質(zhì)量可控，化學(xué)性質(zhì)穩(wěn)定，且制備過程不需使用特殊裝置，非常有利于臨床口服劑型的制備，方便老年癡呆患者的長期用藥。
4．藥效學(xué)研究顯示，起效劑量僅為1.6mg/kg，與7mg/kg陽性對照藥尼麥角林片作用相當(dāng)；在預(yù)試驗當(dāng)中，其作用與市場公認(rèn)的老年癡呆治療藥物鹽酸多奈哌齊（5mg/kg）作用相當(dāng)，且療效好于300 mg/kg腦復(fù)康，顯示其具有極佳的開發(fā)潛力和應(yīng)用前景。
5．天麻屬于國家規(guī)定的可用于保健食品的物質(zhì)之一，其安全性得到公認(rèn)。本有效部位在小鼠急性毒性研究中測不出LD₅₀，其口服最大給藥量為49.28g/kg，經(jīng)大鼠、犬長期毒性試驗，本有效部位無毒性作用，具有極高的安全性。
6．作用機制新穎，藥理研究表明，該有效部位可以增強動物腦內(nèi)膽堿乙酰化酶的活性，從而促進(jìn)乙酰膽堿的合成，因此很有可能對膽堿酯酶抑制劑無效的較嚴(yán)重的老年癡呆患者起作用，優(yōu)于目前歐美等國家批準(zhǔn)上市的治療老年性癡呆的藥物，市場應(yīng)用前景非常好。
7．本項目獲得國家“十一五”、“十二五”新藥創(chuàng)制重大專項支持。
III. Innovations and advantages:
1. This product is applied for four patents of China, one PCT patent, of which two patents have been authorized.
2. Tianma is a traditional Chinese medicine, has been widely cultivated, there is no problem about resources, can provide adequate protection for future production.
3. The effective part of Tianma benzyl alcohol ester glycosides includes three active monomers, and the total content is more than 80%. For the main components, the chemical structure is clear, the quality is controllable, and the chemical properties are stable, and it’s no need to use special devices during preparation, which is very conducive to the preparation of clinical oral agent and convenient for the long-term medication of patients with senile dementia.
4. Pharmacodynamic study showed that the onset dosage was 1.6mg/kg only, which was equal to 7mg/kg Nicergoline (the positive control drug); In the pre-test, its effect was equal to donepezil hydrochloride (5mg/kg), which is the drug for senile dementia proven in the market, and its efficiency was better than 300 mg/kg piracetam, so it has excellent potential for development and application prospects.
5. Tianma is one of substances that can be used in health food prescribed by State, and its safety has been recognized. The effective parts cannot be detected LD50 in the acute toxicity study of mice, and the max dosage of oral administration was up to 49.28g/kg, and there was no toxic effects in long-term toxicity studies of rats and dogs, so it has a very high security.
6. The working mechanism is novel. The pharmacological study showed that the effective part can enhance the activity of choline acetylase in animal’s brain, thereby promoting the synthesis of acetylcholine, so it’s likely to have effects in patients with senile dementia who fail to respond the cholinesterase inhibitors, and better than the existing drugs for senile dementia in the market approved by Europe and the United States, so its market prospect is very good.
7. The project won supports from new drugs creation and production major projects from the national “Eleventh Five-Year”, “Twelfth Five-Year” plan.
 
四、項目進(jìn)展
天麻芐醇酯苷及片2010年12月向SFDA提交臨床申請。2012年12月獲得《藥物臨床試驗批件》臨床批件并轉(zhuǎn)讓北京協(xié)和制藥二廠。
IV. Progress of the project
Tianma benzyl alcohol ester glycosides tablets have submitted clinical application to the SFDA in December 2010. The clinical approvals of Clinical trials of drug approval documents was obtained in December 2012, and then transferred to NO.2 Pharmaceutical Plant of Beijing Union Medical College.
 
 
抗腫瘤及抗腫瘤轉(zhuǎn)移雙功能藥物候選物MTC-220（臨床前研究）
 MTC-220, candidate for drugs with anti-tumor and anti-metastatic dual functions (pre-clinical study)
 
腫瘤轉(zhuǎn)移是腫瘤患者的主要臨床致死原因，占腫瘤死亡人數(shù)的83%。最新研究表明，腫瘤的炎癥微環(huán)境與惡性腫瘤的侵襲與轉(zhuǎn)移直接相關(guān)，改變這種微環(huán)境可以阻止腫瘤轉(zhuǎn)移。本課題是將免疫調(diào)節(jié)劑胞壁酰二肽（MDP）衍生物與紫杉醇以適當(dāng)形式共綴，在保持紫杉醇抗腫瘤活性的同時，還可通過調(diào)節(jié)腫瘤微環(huán)境而產(chǎn)生抗腫瘤轉(zhuǎn)移作用。
The tumor metastasis is the main clinical cause of death in patients with cancer, accounting for 83% of cancer deaths. The latest research showed that the inflammatory microenvironment of tumor was directly related with the invasion and metastasis of malignant tumors, to change such microenvironment might prevent tumor metastasis. In this topic, it is to conjugate the derivatives of muramyl dipeptide (MDP) (an immunomodulating agent) and paclitaxel in an appropriate form; it cannot only keep the antitumor activity of paclitaxel but also generate the anti-metastatic effect by regulating tumor microenvironment.
 
系統(tǒng)研究顯示，紫杉醇與MDP簡化物的共綴物MTC-220是一個新穎、有效、安全的雙功能抗腫瘤候選藥物，不僅在動物體內(nèi)高效抗腫瘤，而且通過減少髓樣抑制細(xì)胞（MDSCs）以及調(diào)節(jié)腫瘤微環(huán)境的細(xì)胞因子水平（TNF-a等）顯著地抑制惡性腫瘤的轉(zhuǎn)移。MTC-220在體外可對60株人癌細(xì)胞具有與紫杉醇相類似的抗腫瘤譜；在裸鼠體內(nèi)可顯著抑制多種原發(fā)瘤的生長；在BALB/c小鼠和C57Bl/6小鼠可分別顯著抑制高轉(zhuǎn)移性乳腺癌和肺癌的轉(zhuǎn)移；小鼠尾靜脈注射MTC-220最大耐受劑量（138.2mg/kg）遠(yuǎn)大于紫杉醇靜脈給藥的半數(shù)致死量（25mg/kg）。MTC-220理化性質(zhì)得以改善，其制劑可避免使用致敏性的環(huán)氧乙烯蓖麻油，為實現(xiàn)低劑量多次靜脈注射給藥以提高抗腫瘤及抗腫瘤轉(zhuǎn)移效果提供了基本依據(jù)。所有實驗結(jié)果均顯示：MTC-220極有望開發(fā)為新穎的抗腫瘤及抗腫瘤轉(zhuǎn)移的雙功能藥物。
The systematic research showed that the conjugates MTC-220 of paclitaxel and simplified matter of MDP was a novel, effective and safe dual-function anti-tumor drug candidate, it’s not only able to efficiently prevent tumor in vivo, but also significantly suppress the metastasis of malignant tumors via reducing suppressor cells (MDSCs) and adjusting the levels of cytokines (TNF-a, etc.) of the tumor microenvironment. The anti-tumor spectrum of MTC-220 to 60 strains of human cancer cells in vitro was similar with that of paclitaxel; it could significantly inhibit the growth of primary tumor in nude mice; for BALB/c mice and C57Bl/6 mice, it could respectively significantly inhibit the metastasis of highly metastatic breast cancer and lung cancer; the max tolerated dosage (138.2mg/kg) of MTC-220 in intravenous injection for mice was much more than the median lethal dose (25mg/kg) of paclitaxel in intravenous administration. The physical and chemical properties of MTC-220 were improved, the preparations were avoided the use of allergenic ethylene castor oil, providing the fundamental basis for improving the anti-tumor and anti-metastatic effects via low-dosage multiple intravenous administrations. All experimental results showed that: MTC-220 was highly expected to be developed as a novel anti-tumor and anti-metastatic dual-function drug.
 
目前，國內(nèi)外無類似報道及藥物上市，原創(chuàng)性強。MTC-220及其系列化合物具有我國自主知識產(chǎn)權(quán)，發(fā)明專利201180007150.X已進(jìn)入實審階段，共綴物制備工藝專利已獲得受理號201210361925.X。
At present, no similar reports or drugs in the market in China, its originality is powerful. MTC-220 and its family of compounds have China's own intellectual property rights, and the invention patent 201180007150.X has been under the review stage, the conjugate preparation technology patent has obtained the accepted number, 201210361925.X.
 
課題與參加單位北京協(xié)和制藥二廠共同組織、并依據(jù)SFDA 抗腫瘤藥物非臨床研究技術(shù)指導(dǎo)原則全面開展并完成MTC-220原料藥和制劑的臨床前藥學(xué)、藥理毒理研究。本研究為國家“重大新藥創(chuàng)制”十二五科技重大專項“創(chuàng)新藥物研究開發(fā)之新藥臨床前研究”基金資助課題（編號：2011ZX09102-001-01）。
With the organization of No.2 Pharmaceutical Plant of Beijing Union Medical College, in accordance with the non-clinical studies technical guidance for anti-tumor drugs of the SFDA, comprehensively carried out and completed the pre-clinical pharmacy, pharmacology and toxicology studies for MTC-220 bulk drugs and preparations. This study is the national “Key new drugs creation and production” Twelfth Five Years major science and technology projects “Innovative drug research and development - New drugs clinical research” funded project (Number: 2011ZX09102-001-01).
 
1．MTC-220 原料藥的合成工藝研究
根據(jù)新藥注冊技術(shù)要求，制備了MTC-220精制品，通過紅外光譜、紫外光譜、質(zhì)譜、核磁共振等方法進(jìn)行了系統(tǒng)結(jié)構(gòu)解析和確證。目前，已完成MTC-220原料藥中試生產(chǎn)工藝研究，合成了5批中試規(guī)模MTC-220原料藥（~200克/批），累積生產(chǎn)原料藥超過1000克。
1. Synthesis technology of MTC-220 bulk drug
In accordance with the technical requirements for registration of new drugs, MTC-220 refined products were prepared, and the system structure was analyzed and confirmed by IR spectrometry, UV spectrometry, mass spectrometry, nuclear magnetic resonance and other methods. Now, the medium trial production technology research for MTC-220 bulk drugs has been completed, five batches of medium scale MTC-220 bulk drugs (~ 200 g/batch) were synthesized, and the cumulative bulk drugs were produced over 1000 g.
 
2．MTC-220原料藥的質(zhì)量控制研究
對MTC-220原料藥的含量、有關(guān)物質(zhì)及殘留溶劑分析方法進(jìn)行了線性、精密度、檢測限、專屬性等系統(tǒng)方法學(xué)考察，初步制定了MTC-220原料藥質(zhì)量標(biāo)準(zhǔn)。目前已完成3批中試規(guī)模原料藥的質(zhì)量控制標(biāo)準(zhǔn)的研究工作。
2. MTC-220 bulk drugs quality control research
For the content, related substances and residual solvent of MTC-220 bulk drugs, it used the linearity, precision, detection limit, proprietary and other systematic methods to scientifically investigate, primarily developing the quality standards for MTC-220 bulk drugs. Now, the researches of QC standards for three batches of pilot bulk drugs were completed.
 
3．MTC-220制劑的處方及優(yōu)化
系統(tǒng)考察了液體制劑中注射液四種劑型的可行性，其中，普通注射液/輸液、無菌分裝注射用粉針、亞微乳注射液不具有可行性；環(huán)糊精包合物因國內(nèi)外臨床應(yīng)用安全性前景不明朗，暫未進(jìn)行深入研究。最終確定凍干粉針具有可行性，并完成了凍干粉針的處方優(yōu)化。目前正開展對MTC-220凍干粉針的中試放大研究及質(zhì)量研究工作。
3. Prescription and optimization of MTC-220 preparation 
The feasibility of four dosage forms of injection liquid preparation was systematically studied, of which, the ordinary injection/infusion, sterile packing powder for injection, submicron emulsion for injection are not feasible; due to the unclear security prospects in the clinical application at home and abroad, cyclodextrin inclusion complex is not planned in depth study. Ultimately the feasibility of freeze-dried powder was determined, and the formulation of freeze-dried powder was optimized. Now, the medium pilot enlarged research and quality research of MTC-220 freeze-dried powder is being carried out.
 
4．MTC-220制劑的藥物代謝動力學(xué)研究
建立MTC-220體內(nèi)LC/MS分析方法，完成了大鼠腹腔及靜脈注射MTC-220制劑后血漿藥代學(xué)動力特征研究。
4. MTC-220 preparation pharmacokinetic studies
MTC-220 in vivo LC/MS analysis method was built, and the plasma pharmacokinetic characteristic study after intraperitoneal and intravenous injection of MTC-220 to rats was completed.
 
5．MTC-220 制劑的主要藥效學(xué)研究
建立了小鼠4T1乳腺癌自發(fā)轉(zhuǎn)移模型，并對MTC-220制劑抗腫瘤生長及抗腫瘤轉(zhuǎn)移的作用進(jìn)行了評價，結(jié)果可見小鼠腹腔注射MTC-220可顯著抑制腫瘤生長及肺表面轉(zhuǎn)移結(jié)節(jié)數(shù)，與對照組相比具有統(tǒng)計學(xué)意義。
5. Main pharmacodynamic study of MTC-220 preparation 
Mice 4T1 breast cancer spontaneous metastasis model was established, and the role of MTC-220 in anti-tumor growth and anti-metastasis was evaluated, the results showed that the mice via intraperitoneal injection MTC-220 could significantly inhibit tumor growth and the number of metastasis nodules on lung surface, compared with control group there was statistic significance.
 
6．MTC-220 制劑的初步安全性評價（非GLP試驗結(jié)果）
完成了小鼠單次腹腔注射及靜脈注射MTC-220制劑的急性毒性試驗，Bliss法計算小鼠單次腹腔注射MTC-220的LD₅₀及95%可信限為283.8 (263.3 -306.0) mg/kg； 小鼠單次靜脈注射MTC-220的LD₅₀及95%可信限為187.1 (168.9 -207.1) mg /kg。
小鼠單次腹腔注射MTC-220的最大耐受劑量為204.8mg/kg；小鼠單次靜脈注射MTC-220的最大耐受劑量為138.2mg/kg。
    目前正在制備MTC-220中試制劑樣品，準(zhǔn)備進(jìn)行GLP實驗室的安全性評價。
6. Preliminary safety evaluation of MTC-220 formulations (non-GLP Test Results)
The acute toxicity test of single intraperitoneal injection and intravenous MTC-220 preparation to mice was completed. With Bliss method, LD50 in single intraperitoneal injection of MTC-220 to mice and 95% confidence limit was 283.8 (263.3 -306.0) mg/kg; LD50 in single intravenous injection of MTC-220 to mice and 95% confidence limit was 187.1 (168.9 -207.1) mg / kg.
 
The maximum tolerated dosage in single intraperitoneal injection of MTC-220 to mice was 204.8mg/kg; the maximum tolerated dosage in single intravenous injection of MTC-220 to mice was 138.2mg/kg.
 
Now, MTC-220 medium pilot samples are being prepared for GLP laboratory safety evaluation.
 
 
圓錐繡球總香豆素苷HP（臨床前研究）
Cone hydrangea coumarin glycoside HP (Pre-clinical studies)
 
圓錐繡球總香豆素苷（簡稱HP）是中國醫(yī)學(xué)科學(xué)院藥物研究所和北京協(xié)和制藥二廠聯(lián)合研制開發(fā)的5類天然藥物，擬用于治療糖尿病腎病和高血壓腎病。
Cone hydrangea coumarin glycoside (HP) is a Class 5 natural medicine, jointly researched and developed by Pharmaceutical Research Institute of Chinese Academy of Medical Sciences and No.2 Pharmaceutical Plant of Beijing Union Medical College, intended to treat diabetic nephropathy and hypertensive nephropathy.
 
圓錐繡球總香豆素苷是利用現(xiàn)代制藥工藝手段從中藥圓錐繡球中制備提取的有效部位，主要成分為以茵芋苷為代表的香豆素苷類化合物，其中茵芋苷含量超過50%。圓錐繡球在我國的天然資源豐富，主要藥用部位為該植物的莖枝，有效成分含量高，生產(chǎn)工藝簡單，適合于工業(yè)化生產(chǎn)，生產(chǎn)成本低。
Cone hydrangea coumarin glycoside is the effective part extracted from cone hydrangea (a traditional Chinese medicine) via modern pharmaceutical technological means, mainly composed of coumarin glycosides compounds (skimmianine glycoside is the representative), of which skimmianine glycoside is more than 50%. Cone hydrangea is rich in natural resources in China, the main medicinal parts of this plant are stems, the content of active ingredient is higher, the production technology is simple, so it’s suitable for industrial production, and the production costs are lower.
 
藥效學(xué)研究顯示：圓錐繡球總香豆素苷具有明確的腎功能保護(hù)作用，對順鉑所致小鼠急性腎功能不全、5/6腎切除大鼠慢性腎功能不全模型、鏈脲霉素誘發(fā)Wistar、SD大鼠糖尿病腎病模型及遺傳性高血壓大鼠腎病模型均顯示療效顯著，效應(yīng)強度與氯沙坦相當(dāng)。進(jìn)一步的作用機制研究顯示，圓錐繡球總香豆素苷通過降低血管緊張素Ⅱ（AⅡ）和抑制轉(zhuǎn)化生長因子b1（TGF-b1）的產(chǎn)生而保護(hù)腎功能，抑制腎纖維化發(fā)生。
The pharmacodynamic study showed that: cone hydrangea coumarin glycoside had clear renal protective effects, and it showed significant effects in the mice with cisplatin-induced acute renal failure, the rats model of chronic renal insufficiency with 5/6 nephrectomy, the model of streptozotocin-induced Wistar, SD rat model of diabetic nephropathy and the rat model of hereditary hypertensive nephropathy, its efficacy was equal to Losartan. The further action mechanism study showed that, cone hydrangea coumarin glycosides could protect renal function  and prevent the renal fibrosis via reducing the angiotensin II (A II) and inhibiting the generation of transforming growth factor b1 (TGF-b1).
 
急毒研究顯示：大鼠、小鼠對圓錐繡球總香豆素苷的最大耐受量均為5g/kg；一般藥理學(xué)研究顯示圓錐繡球總香豆素苷對實驗動物的呼吸、心血管及精神神經(jīng)系統(tǒng)無明顯影響；生殖毒性、遺傳毒性研究及在國家藥物安全評價中心完成的犬270天長毒研究結(jié)果均提示該藥安全性好，不影響動物的機體功能和組織結(jié)構(gòu)。
The acute toxicity study showed that: the maximum tolerated dosage of rat and mice to cone hydrangea coumarin glycoside was 5g/kg; the general pharmacology study showed that cone hydrangea coumarin glycoside would not significantly affect the breathing, cardiovascular or nervous system of experimental animals; In the reproductive toxicity, genetic toxicity studies, and the long-term toxicity study of 270 days for dogs completed in the National Drug Safety Evaluation Center, it indicated that the safety of this drug was good, it would not affect the animal's body functions or organizational structure.
 
目前圓錐繡球的有效成分茵芋苷治療腎功能不全的用途發(fā)明專利（專利號：ZL200310100220.3），以及圓錐繡球有效部位治療腎功能不全的用途和制備方法專利（專利號：ZL 20041034068.8）均已獲得授權(quán)。
該藥預(yù)計將于2014年申報臨床試驗。
Now, the purpose invention patent of skimmianine glycoside (the effective ingredients of cone hydrangea) for the treatment of renal insufficiency (Patent No.: ZL200310100220.3), and the purpose and preparation method patent of skimmianine glycoside (the effective ingredients of cone hydrangea) for the treatment of renal insufficiency (No.: ZL 20,041,034,068.8,) have been authorized.
The drug is expected to report clinical trials in 2014.
 
應(yīng)用領(lǐng)域：糖尿病腎病、高血壓腎病
Application fields: diabetic nephropathy, hypertensive nephropathy
 
藥理毒理特點：治療糖尿病腎病和高血壓腎病效果與血管緊張素II受體抑制劑（ARB）相當(dāng)，作用機制新穎，安全性好。
Pharmacological and toxicological features: the therapeutic effects to diabetic nephropathy and hypertensive nephropathy are equal to the effect of angiotensin II receptor blockers (ARB), and the action mechanism is novel and the safety is good.
 
 

茶芎治療缺血性腦卒中和缺血性癡呆的有效部位（臨床前研究）
Effective parts of Chao Xiong in the treatment of ischemic stroke and ischemic dementia (Pre-clinical study) 
 
茶芎揮發(fā)油有效部位是中國醫(yī)學(xué)科學(xué)院藥物研究所開發(fā)的5類中藥，擬用于治療缺血性腦卒中和缺血性癡呆。
The effective parts of volatile oil of Cha Xiong is Class 5 traditional Chinese medicine, developed by the Chinese Academy of Medical Sciences, intended to use in the treatment of ischemic stroke and ischemic dementia.
 
茶芎系傘形科藁本屬植物，在江西已有悠久的栽培和藥用歷史，臨床上與川芎混用，具有活血行氣、祛風(fēng)止痛等功效。文獻(xiàn)記載茶芎有活血行氣、祛風(fēng)止痛等功效，被列入《江西省藥材標(biāo)準(zhǔn)》。
Cha Xiong is a plant of Apiaceae Ligusticum species, has a long history of cultivation and medication in Jiangxi Province, and it is mixed with Rhizoma in clinical, for promoting blood circulation and removing Qi, dispelling the wind and relieving pains and other effects. It is documented that Cha Xiong could promote blood circulation and remove Qi, dispel the wind and relieve pains and so on, which was included in Herbs Standard of Jiangxi Province.
 
中國醫(yī)學(xué)科學(xué)院藥物研究所和北京協(xié)和制藥二廠采用現(xiàn)代天然藥物處理方法將采自江西的茶芎藥材制備成為揮發(fā)油。茶芎揮發(fā)油中主要化學(xué)成分為苯酞類化合物，文獻(xiàn)報道苯酞類化合物具有抗血栓作用，能改善局部腦缺血引起的記憶障礙，改善腦缺血區(qū)血流，對神經(jīng)細(xì)胞損傷有保護(hù)作用，并具有抗氧自由基作用。其代表化合物正丁基苯酞有較強的抗腦缺血損傷和抗血小板作用，同時具有抗血管性癡呆和老年性癡呆的作用，經(jīng)臨床試驗證實療效確切，目前已上市銷售。
Chinese Academy of Medical Sciences and No.2 Pharmaceutical Plant of Beijing Union Medical College adopted the modern treatment methods for natural medicine to prepare Cha Xiong herbs (from Jiangxi) to be volatile oil. Main chemical components in the volatile oil of Cha Xiong were phthalide compounds, and it’s reported in the literature that phthalide compounds had antithrombotic effect, and could improve memory impairment caused by focal cerebral ischemia and improve the blood flow in cerebral ischemia area, so it could protect nerve cells from damage and the role of anti-oxygen free radicals. N-butyl phthalide, its representative compounds, not only has powerful effects on anti-cerebral ischemic injury and anti-platelet, but also has the effects on anti-vascular dementia and Alzheimer's disease, and its efficacy was confirmed by clinical trials, now it has been marketed for sale.
 
藥效學(xué)研究顯示，茶芎揮發(fā)油對過氧化氫、谷氨酸所致的大鼠原代培養(yǎng)神經(jīng)細(xì)胞具有明顯的保護(hù)作用；對大鼠大腦中動脈阻塞模型可以顯著減小實驗動物的腦梗死體積；具有顯著的拮抗谷氨酸神經(jīng)毒性和抗電驚厥等作用。茶芎揮發(fā)油兼具目前市場上的治療缺血性腦卒中的兩類藥物包括改善腦血流類藥物和腦神經(jīng)保護(hù)劑的優(yōu)點，多靶點阻斷缺血性腦卒中的病理環(huán)節(jié)，改善缺血腦組織血流，改善損傷神經(jīng)細(xì)胞功能，不增加腦出血風(fēng)險。
The pharmacodynamic study showed that the volatile oil of Cha Xiong could significantly protect the hydrogen peroxide, glutamate-induced primary cultured neurons of rats; could significantly reduce the volume of cerebral infarction of the experimental animals in the rat model with cerebral artery occlusion; and had significant antagonism to glutamate neurotoxicity and anti-electrofit. The volatile oil of Cha Xiong has the advantages of two types of drugs for the treatment of ischemic stroke (including drugs for improving cerebral blood flow and cerebral neuroprotective agent), to block the pathological aspects of ischemic stroke in multi-target, to improve the cerebral blood flow in ischemic area, to improve the functions of damaged nerve cells, without increase the risk of cerebral hemorrhage.
 
茶芎揮發(fā)油灌胃給藥的LD₅₀為5.3138±0.0325ml/kg，可信限范圍為4.5925~ 6.1595ml/kg。
The volatile oil of Cha Xiong was administrated LD50 to 5.3138 ± 0.0325ml/kg in gavage, and the confidence limit range was from 4.5925 to 6.1595ml/kg.
 
經(jīng)過前期嚴(yán)格的藥效學(xué)和急毒研究篩選，茶芎揮發(fā)油提取物工藝已經(jīng)確定，進(jìn)入正式開發(fā)階段。采用現(xiàn)代制藥工藝，有效部位茶芎揮發(fā)油提取物中的苯酞類化合物相對含量達(dá)到90%以上，有效部位的成分鑒定已經(jīng)完成。建立了質(zhì)量標(biāo)準(zhǔn)，已完成2種成分的標(biāo)準(zhǔn)物質(zhì)合成，藥效學(xué)研究證實了本品的腦神經(jīng)保護(hù)作用和改善局部缺血區(qū)血流供應(yīng)的作用。
預(yù)計2014年末申報臨床研究。
After the rigorous pharmacodynamic and acute toxicity screening in early stage, the extraction technology for the volatile oil of Cha Xiong has been ascertained, now it is in the formal stage of development. With the use of modern pharmaceutical technology, the relative content of phthalide compounds in the volatile oil extracts from the effective parts of Cha Xiong was more than 90%, and the identification for the composition of effective part has been completed. The quality standard was established, and the standard materials of two components have been synthesized. The pharmacodynamic study confirmed the cerebral neuroprotective effects and the improving effects on the blood supply in ischemic area of this product.
It is expected to report for clinical research in the end of 2014.
 
 
 
S1P₁受體激動劑（臨床前研究）
S1P1 Receptor Agonist (Preclinical study)
 
S1P₁受體（Sphingosine-1-Phosphate Receptor，5個亞型S1P1~5）激動劑是新型免疫抑制劑，通過誘導(dǎo)外周循環(huán)系統(tǒng)中的淋巴細(xì)胞回到淋巴結(jié)，即“歸巢”，降低外周循環(huán)中的淋巴細(xì)胞數(shù)量而達(dá)到治療自身免疫性疾病的目的。該類藥物既不影響粒細(xì)胞和單核細(xì)胞活性，也不損害淋巴細(xì)胞和造血系統(tǒng)，并且淋巴細(xì)胞對外界抗原的記憶仍然保存，與傳統(tǒng)免疫抑制藥物相比，對自身免疫系統(tǒng)毒性較小。該類藥物的代表是Fingolimod（FTY720），由諾華制藥公司開發(fā)，已于2010年9月上市，用于多發(fā)硬化癥治療。但是臨床應(yīng)用中發(fā)現(xiàn)，F(xiàn)TY720有致患者心動過緩的不良反應(yīng)，與其同時激動S1P₃受體有關(guān)。因此，開發(fā)選擇性更高的S1P₁受體激動劑成為開發(fā)治療自身免疫性疾病藥物的方向。
S1P1 receptor (Sphingosine-1-Phosphate Receptor, five subtypes: S1P1-5) agonist is a kind of novel immunosuppressant, through the induction of lymphocytes returning from the peripheral circulatory system to the lymph nodes (i.e., “homing”), to reduce the quantity of lymphocytes in peripheral circulation, it can achieve the purpose of treating autoimmune diseases. Such drugs will not affect neither the activity of granulocyte and monocyte or damage the lymphocytes and hematopoietic system, and the antigens of lymphocyte to the external memory will be still stored, compared with conventional immune suppressing drugs, it has less toxicity to the autoimmune system. The representative of these drugs is Fingolimod (FTY720), developed by Novartis Pharma, was marketed in September 2010, for the treatment of multiple sclerosis. In the clinical applications, it found that FTY720 might induce adverse reactions of bradycardia in patients, which was related with exciting S1P3 receptor. Therefore, the development of more selective S1P1 receptor agonist may be the direction for the development of drugs for treating autoimmune diseases.
 
中國醫(yī)學(xué)科學(xué)院藥物研究開展了系統(tǒng)的S1P₁選擇性激動劑研究，對200余個新化合物的體內(nèi)外活性評價發(fā)現(xiàn)多個化合物具有選擇性S1P₁受體激動作用，降低外周血淋巴細(xì)胞的活性與FTY720相當(dāng)或略強，但無心動過緩副作用。與目前國際上正在進(jìn)行臨床或臨床前研究的新型S1P₁受體激動劑作用強度相當(dāng)。已申請國內(nèi)、國際化合物專利保護(hù)。
The Pharmaceutical Research Institute of Chinese Academy of Medical Sciences carried out the systematic researches in S1P1 selective agonist, found that many compounds had the effects of selective S1P1 receptor agonist in the activity evaluation of 200 new compounds in vitro and in vivo, the efficiency to reduce the activity of peripheral blood lymphocyte was equal to or better than that of FTY720, without side effect of bradycardia. The strength was equal to that of new S1P1 receptor agonist which was ongoing clinical or pre-clinical research in international society. It has been applied for domestic and international compound patent protection.
 
通過體外對S1P₁和S1P₃受體的選擇性試驗、正常大鼠體內(nèi)減低淋巴細(xì)胞作用強度試驗、對大鼠心率的影響試驗，以及在大鼠體內(nèi)的初步藥代特性研究，結(jié)合化學(xué)合成工藝難度分析，確定化合物IMMH001、IMMH002能有效降低外周血淋巴細(xì)胞活性而對心率影響較小。
With the selectivity test of S1P1 and S1P3 receptor in vitro, the strength test of reducing lymphocytes in normal rats, the heart rate test of rats, and the preliminary pharmacokinetic characteristics research of rats in vivo, together with the difficulty analysis of chemical synthesis, it was determined that the compound IMMH001, IMMH002 could effectively reduce the activity of peripheral blood lymphocyte with less effects on heart rate.
 
初步藥效學(xué)篩選試驗顯示，兩種化合物分別對類風(fēng)濕性關(guān)節(jié)炎模型和銀屑病模型具有較好的療效。
The preliminary pharmacodynamic screening test showed that the two compounds had a good therapeutic effect on the model of rheumatoid arthritis and psoriasis.
 
藥代動力學(xué)研究顯示，IMMH001口服生物利用度為20.2%，IMMH002口服生物利用度為48.6%；IMMH001體內(nèi)消除半衰期較短，為4-7h，IMMH002半衰期較長，達(dá)20-26h；兩種化合物在人、猴、鼠肝微粒體中較為穩(wěn)定，對CYP2E1有輕度抑制作用，各原形藥及其磷酸化產(chǎn)物對其他CYPs活性均無明顯影響，兩種化合物及其磷酸化產(chǎn)物（10mM）體外與大鼠、犬、猴及人血漿蛋白高度結(jié)合（90-99.64％），且無明顯種屬差異。
The pharmacokinetic study showed that the oral bioavailability of IMMH001 was 20.2%, and the oral bioavailability of IMMH002 was 48.6%; the elimination half-life of IMMH001 was shorter in the body, which was 4-7h; and the half-life of IMMH002 was longer, which was 20-26h; the two compounds were relatively stable in liver microsomes of human, monkey and rat, and it could slightly inhibit CYP2E1, each prototype drug and its phosphorylated products had no significant affects on the activity of other CYPs. The two compounds and its phosphorylated products (10mM) were highly bound (90-99.64%) with plasma protein of rat, dog, monkey and human in vitro, and there was no obvious species differences.
 
初步安全性評價顯示，正常昆明小鼠一次性灌胃給予IMMH001和IMMH002各500mg/kg（n=4, 雌雄各半），連續(xù)觀察14天，無明顯不良癥狀，動物體重增加�；�合物遺傳毒性（微生物回復(fù)突變試驗）的檢測，提示IMMH001和IMMH002及其相應(yīng)的磷酸化產(chǎn)物的Ames試驗結(jié)果均為陰性。IMMH001和IMMH002對心臟hERG鉀電流抑制作用的IC₅₀（μM）分別為6.57和8.07，而IMMH001-P和IMMH002-P對hERG鉀電流抑制作用的IC₅₀均大于100μM。
The preliminary safety evaluation showed that, normal Kunming mice were respectively administrated 500mg/kg IMMH001 and IMMH002 in one gavage (n = 4, male and female for half), observed for 14 consecutive days, no significant adverse symptoms, animal body weight was increased. Compound genotoxicity (microbial reverse mutation assay) detection suggested that the test results of IMMH001 and IMMH002 and their corresponding phosphorylation products Ames were negative. IC50 (μM) of IMMH001 and IMMH002 to the inhibition of cardiac hERG potassium current was 6.57 and 8.07, respectively; and IC50 (μM) of IMMH001-P and IMMH002 of-P to the inhibition of hERG potassium current were greater than 100μM.
 
上述結(jié)果提示，IMMH001和IMMH002均具有較好的理化性質(zhì)和藥代特性，各有其特點，顯示了進(jìn)一步開發(fā)的前景。
預(yù)計2014年末申報臨床研究。
The above results suggested that IMMH001 and IMMH002 had better physicochemical properties and pharmacokinetic characteristics, and each had its own characteristics, showing the prospects for further development.
It is expected to report for clinical research in the end of 2014.
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