布格呋喃是中国医学科学院药物研究所和北京协和制药二厂合作研制开发的1.1类化学新药，拟用于治疗广泛性焦虑症（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.
 
布格呋喃是名贵中药沉香提取物沉香呋喃的衍生物。《本草纲目》记载：沉香有清人神，益气合神等作用。70年代初，中国医学科学院药物研究所即已观察到沉香精油具有一定的镇静催眠作用，因此对沉香呋喃天然化合物进行了立体选择性合成和结构改造，合成了一系列新的衍生物，经过药效学和毒理学筛选，发现布格呋喃具有显著的抗焦虑活性，毒副作用较低，无依赖性和耐受性。
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.
 
药效试验显示，布格呋喃具有稳定的抗焦虑作用。其抗焦虑强度接近安定。在12种焦虑模型中, 布格呋喃均有量-效相关的抗焦虑作用，其抗焦虑谱与安定相同而明显宽于丁螺环酮。且重复给药时，布格呋喃的抗焦虑作用不发生耐受性（且有逐渐增强的趋势），也没有停药反应。在单独给药时，布格呋喃只有镇静效应，无论多大剂量和给药途径，都没有催眠作用。布格呋喃也无肌松与肌协调损伤作用；对学习、记忆损伤不明显；无木僵效应；对痛疼无抑制作用。
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.
 
在急毒试验中，布格呋喃5 g/kg 不会引起动物死亡，也无共济失调或其它感觉-运动的明显毒性效应。因此，布格呋喃中枢神经系统毒性、副作用低于丁螺环酮。安全性药理研究结果显示布格呋喃治疗剂量范围内对犬心电图、血压、心率、及呼吸无异常影响。Beagle犬口服给予布格呋喃9个月的无明显毒副反应剂量为5 mg/kg，15mg/kg和50mg/kg剂量组除血清ALP水平升高外，体重、进食量、心电图、神经活动状况、尿生化、血液学、以及其它血清生化指标等均未见明显变化。布格呋喃对动物生殖力对仔代无明显影响，亦无遗传毒性。依赖性实验显示实验动物对布格呋喃不产生生理依赖性和精神依赖性。
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.
 
大鼠和犬药代动力学研究显示布格呋喃吸收较快，口服后5~10min血浆中既可检测到原形药物，10-40min血药浓度达峰，各组织均有分布，经过尿、粪排泄出体外，大鼠和人血浆蛋白结合率为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%.
 
布格呋喃现已完成Ⅰ期临床研究，包括单次给药和多次给药的健康人体耐受性试验、单次给药和多次给药的健康人体药代动力学研究以及食物对药代动力学影响的研究。人体耐受性研究证实本品在15~90mg剂量范围内单次和多次给药的人体耐受性良好。
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.
 
人体药代动力学实验结果显示：中国健康受试者单次、多次空腹及进食后口服30~120mg布格呋喃安全性和耐受性良好。中国健康男性受试者单次口服布格呋喃胶囊30mg，60mg或120mg后，吸收较为迅速，总体暴露量和最高瞬时暴露水平都随着剂量的增加而升高，但与剂量并不成比例关系，药物消除随剂量增加而减慢。进食对单次口服60mg布格呋喃胶囊的系统暴露水平有影响：达峰时间延长，血浆峰浓度下降，曲线下面积增加。单次和每日两次连续口服布格呋喃胶囊60mg或120mg后，布格呋喃被快速吸收，并在每日两次重复口服后不久达稳态。与单剂的药代动力学参数相比，重复给药后的暴露量有中度蓄积。120mg组的布格呋喃清除率低于60mg组。
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期临床研究报告已提交CDE，正在申报Ⅱ期临床试验。
Buagafuran Phase I clinical study report has been submitted to CDE under the application for Phase II clinical trial.
 
应用领域：抗焦虑症
Application field: anti-anxiety disorder
 
药理毒理特点：抗焦虑作用稳定，其抗焦虑强度接近安定，其中枢神经系统毒性、副作用低于丁螺环酮，无依赖性和耐受性。
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.
 
创新点和优势：与现有抗焦虑药物结构不同；重复给药时，布格呋喃的抗焦虑作用不发生耐受性（且有逐渐增强的趋势），也没有停药反应。在单独给药时，布格呋喃只有镇静效应，无论多大剂量和给药途径，都没有催眠作用。布格呋喃也无肌松与肌协调损伤作用；对学习、记忆损伤不明显；无木僵效应；对痛疼无抑制作用。
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.
 
开发阶段：完成Ⅰ期临床试验，30~120mg范围内安全性和耐受性良好，确定了健康人体药代动力学参数。2012年4月申报开展Ⅱ期临床试验（CXHB1200054、CXHB1200055），目前正在CDE审评。
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.
 
 
天麻苄醇酯苷原料药及片剂（获得Ⅰ期临床试验批件）
Tianma benzyl alcohol ester glycosides bulk drug and tablets (Obtained the approval of Phase I clinical trials)
 
一、药品基本信息：
    通用名称：天麻苄醇酯苷片
化学结构：本品主要有效成分为天麻苄醇酯苷化合物，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
适应症：血管性痴呆
剂型及规格：薄膜衣片，100mg/片（每片含天麻苄醇酯苷14mg）
注册类别：中药5类
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、药理、毒理研究：
经药理学试验证明，各剂量组可以不同程度地提高拟血管性痴呆模型大鼠学习记忆能力，减轻模型大鼠的神经病理损伤。其可能的作用环节包括：①有效诱导脑损伤修复过程中神经元生长相关蛋白的合成，抑制星形胶质细胞的过度增殖, 促进脑缺血损伤后神经元突起再生。②调控退化的谷氨酸神经元的突触活性，重建脑内Glu/GABA学习记忆调节系统稳态③改善脑内胆碱能系统的功能④抗脂质过氧化，激活抗自由基氧化酶SOD活性,加快脑组织自由基的清除速率,减少自由基代谢产物MDA的堆积。
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.
 
经GLP试验室安全性评价，本品在小鼠急性毒性研究中无法测得LD50，其口服最大给药量达49.28g/kg，大鼠及Beagle犬长期毒性研究未发现毒性作用。
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、创新点及优势：
1．本产品申请4项中国发明专利，1项PCT专利，其中2项专利已授权。
2．天麻是传统中药，已经广泛栽培，不存在资源问题，可以为将来的生产提供充分的保障。
3．天麻苄醇酯苷有效部位包含三个有效单体，总含量超过80％。主成分化学结构明确，质量可控，化学性质稳定，且制备过程不需使用特殊装置，非常有利于临床口服剂型的制备，方便老年痴呆患者的长期用药。
4．药效学研究显示，起效剂量仅为1.6mg/kg，与7mg/kg阳性对照药尼麦角林片作用相当；在预试验当中，其作用与市场公认的老年痴呆治疗药物盐酸多奈哌齐（5mg/kg）作用相当，且疗效好于300 mg/kg脑复康，显示其具有极佳的开发潜力和应用前景。
5．天麻属于国家规定的可用于保健食品的物质之一，其安全性得到公认。本有效部位在小鼠急性毒性研究中测不出LD₅₀，其口服最大给药量为49.28g/kg，经大鼠、犬长期毒性试验，本有效部位无毒性作用，具有极高的安全性。
6．作用机制新颖，药理研究表明，该有效部位可以增强动物脑内胆碱乙酰化酶的活性，从而促进乙酰胆碱的合成，因此很有可能对胆碱酯酶抑制剂无效的较严重的老年痴呆患者起作用，优于目前欧美等国家批准上市的治疗老年性痴呆的药物，市场应用前景非常好。
7．本项目获得国家“十一五”、“十二五”新药创制重大专项支持。
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、项目进展
天麻苄醇酯苷及片2010年12月向SFDA提交临床申请。2012年12月获得《药物临床试验批件》临床批件并转让北京协和制药二厂。
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.
 
 
抗肿瘤及抗肿瘤转移双功能药物候选物MTC-220（临床前研究）
 MTC-220, candidate for drugs with anti-tumor and anti-metastatic dual functions (pre-clinical study)
 
肿瘤转移是肿瘤患者的主要临床致死原因，占肿瘤死亡人数的83%。最新研究表明，肿瘤的炎症微环境与恶性肿瘤的侵袭与转移直接相关，改变这种微环境可以阻止肿瘤转移。本课题是将免疫调节剂胞壁酰二肽（MDP）衍生物与紫杉醇以适当形式共缀，在保持紫杉醇抗肿瘤活性的同时，还可通过调节肿瘤微环境而产生抗肿瘤转移作用。
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.
 
系统研究显示，紫杉醇与MDP简化物的共缀物MTC-220是一个新颖、有效、安全的双功能抗肿瘤候选药物，不仅在动物体内高效抗肿瘤，而且通过减少髓样抑制细胞（MDSCs）以及调节肿瘤微环境的细胞因子水平（TNF-a等）显著地抑制恶性肿瘤的转移。MTC-220在体外可对60株人癌细胞具有与紫杉醇相类似的抗肿瘤谱；在裸鼠体内可显著抑制多种原发瘤的生长；在BALB/c小鼠和C57Bl/6小鼠可分别显著抑制高转移性乳腺癌和肺癌的转移；小鼠尾静脉注射MTC-220最大耐受剂量（138.2mg/kg）远大于紫杉醇静脉给药的半数致死量（25mg/kg）。MTC-220理化性质得以改善，其制剂可避免使用致敏性的环氧乙烯蓖麻油，为实现低剂量多次静脉注射给药以提高抗肿瘤及抗肿瘤转移效果提供了基本依据。所有实验结果均显示：MTC-220极有望开发为新颖的抗肿瘤及抗肿瘤转移的双功能药物。
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，国内外无类似报道及药物上市，原创性强。MTC-220及其系列化合物具有我国自主知识产权，发明专利201180007150.X已进入实审阶段，共缀物制备工艺专利已获得受理号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.
 
课题与参加单位北京协和制药二厂共同组织、并依据SFDA 抗肿瘤药物非临床研究技术指导原则全面开展并完成MTC-220原料药和制剂的临床前药学、药理毒理研究。本研究为国家“重大新药创制”十二五科技重大专项“创新药物研究开发之新药临床前研究”基金资助课题（编号：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 原料药的合成工艺研究
根据新药注册技术要求，制备了MTC-220精制品，通过红外光谱、紫外光谱、质谱、核磁共振等方法进行了系统结构解析和确证。目前，已完成MTC-220原料药中试生产工艺研究，合成了5批中试规模MTC-220原料药（~200克/批），累积生产原料药超过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原料药的质量控制研究
对MTC-220原料药的含量、有关物质及残留溶剂分析方法进行了线性、精密度、检测限、专属性等系统方法学考察，初步制定了MTC-220原料药质量标准。目前已完成3批中试规模原料药的质量控制标准的研究工作。
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制剂的处方及优化
系统考察了液体制剂中注射液四种剂型的可行性，其中，普通注射液/输液、无菌分装注射用粉针、亚微乳注射液不具有可行性；环糊精包合物因国内外临床应用安全性前景不明朗，暂未进行深入研究。最终确定冻干粉针具有可行性，并完成了冻干粉针的处方优化。目前正开展对MTC-220冻干粉针的中试放大研究及质量研究工作。
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制剂的药物代谢动力学研究
建立MTC-220体内LC/MS分析方法，完成了大鼠腹腔及静脉注射MTC-220制剂后血浆药代学动力特征研究。
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 制剂的主要药效学研究
建立了小鼠4T1乳腺癌自发转移模型，并对MTC-220制剂抗肿瘤生长及抗肿瘤转移的作用进行了评价，结果可见小鼠腹腔注射MTC-220可显著抑制肿瘤生长及肺表面转移结节数，与对照组相比具有统计学意义。
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 制剂的初步安全性评价（非GLP试验结果）
完成了小鼠单次腹腔注射及静脉注射MTC-220制剂的急性毒性试验，Bliss法计算小鼠单次腹腔注射MTC-220的LD₅₀及95%可信限为283.8 (263.3 -306.0) mg/kg； 小鼠单次静脉注射MTC-220的LD₅₀及95%可信限为187.1 (168.9 -207.1) mg /kg。
小鼠单次腹腔注射MTC-220的最大耐受剂量为204.8mg/kg；小鼠单次静脉注射MTC-220的最大耐受剂量为138.2mg/kg。
    目前正在制备MTC-220中试制剂样品，准备进行GLP实验室的安全性评价。
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.
 
 
圆锥绣球总香豆素苷HP（临床前研究）
Cone hydrangea coumarin glycoside HP (Pre-clinical studies)
 
圆锥绣球总香豆素苷（简称HP）是中国医学科学院药物研究所和北京协和制药二厂联合研制开发的5类天然药物，拟用于治疗糖尿病肾病和高血压肾病。
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.
 
圆锥绣球总香豆素苷是利用现代制药工艺手段从中药圆锥绣球中制备提取的有效部位，主要成分为以茵芋苷为代表的香豆素苷类化合物，其中茵芋苷含量超过50%。圆锥绣球在我国的天然资源丰富，主要药用部位为该植物的茎枝，有效成分含量高，生产工艺简单，适合于工业化生产，生产成本低。
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.
 
药效学研究显示：圆锥绣球总香豆素苷具有明确的肾功能保护作用，对顺铂所致小鼠急性肾功能不全、5/6肾切除大鼠慢性肾功能不全模型、链脲霉素诱发Wistar、SD大鼠糖尿病肾病模型及遗传性高血压大鼠肾病模型均显示疗效显著，效应强度与氯沙坦相当。进一步的作用机制研究显示，圆锥绣球总香豆素苷通过降低血管紧张素Ⅱ（AⅡ）和抑制转化生长因子b1（TGF-b1）的产生而保护肾功能，抑制肾纤维化发生。
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).
 
急毒研究显示：大鼠、小鼠对圆锥绣球总香豆素苷的最大耐受量均为5g/kg；一般药理学研究显示圆锥绣球总香豆素苷对实验动物的呼吸、心血管及精神神经系统无明显影响；生殖毒性、遗传毒性研究及在国家药物安全评价中心完成的犬270天长毒研究结果均提示该药安全性好，不影响动物的机体功能和组织结构。
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.
 
目前圆锥绣球的有效成分茵芋苷治疗肾功能不全的用途发明专利（专利号：ZL200310100220.3），以及圆锥绣球有效部位治疗肾功能不全的用途和制备方法专利（专利号：ZL 20041034068.8）均已获得授权。
该药预计将于2014年申报临床试验。
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.
 
应用领域：糖尿病肾病、高血压肾病
Application fields: diabetic nephropathy, hypertensive nephropathy
 
药理毒理特点：治疗糖尿病肾病和高血压肾病效果与血管紧张素II受体抑制剂（ARB）相当，作用机制新颖，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.
 
 

茶芎治疗缺血性脑卒中和缺血性痴呆的有效部位（临床前研究）
Effective parts of Chao Xiong in the treatment of ischemic stroke and ischemic dementia (Pre-clinical study) 
 
茶芎挥发油有效部位是中国医学科学院药物研究所开发的5类中药，拟用于治疗缺血性脑卒中和缺血性痴呆。
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.
 
茶芎系伞形科藁本属植物，在江西已有悠久的栽培和药用历史，临床上与川芎混用，具有活血行气、祛风止痛等功效。文献记载茶芎有活血行气、祛风止痛等功效，被列入《江西省药材标准》。
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.
 
中国医学科学院药物研究所和北京协和制药二厂采用现代天然药物处理方法将采自江西的茶芎药材制备成为挥发油。茶芎挥发油中主要化学成分为苯酞类化合物，文献报道苯酞类化合物具有抗血栓作用，能改善局部脑缺血引起的记忆障碍，改善脑缺血区血流，对神经细胞损伤有保护作用，并具有抗氧自由基作用。其代表化合物正丁基苯酞有较强的抗脑缺血损伤和抗血小板作用，同时具有抗血管性痴呆和老年性痴呆的作用，经临床试验证实疗效确切，目前已上市销售。
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.
 
药效学研究显示，茶芎挥发油对过氧化氢、谷氨酸所致的大鼠原代培养神经细胞具有明显的保护作用；对大鼠大脑中动脉阻塞模型可以显著减小实验动物的脑梗死体积；具有显著的拮抗谷氨酸神经毒性和抗电惊厥等作用。茶芎挥发油兼具目前市场上的治疗缺血性脑卒中的两类药物包括改善脑血流类药物和脑神经保护剂的优点，多靶点阻断缺血性脑卒中的病理环节，改善缺血脑组织血流，改善损伤神经细胞功能，不增加脑出血风险。
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.
 
茶芎挥发油灌胃给药的LD₅₀为5.3138±0.0325ml/kg，可信限范围为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.
 
经过前期严格的药效学和急毒研究筛选，茶芎挥发油提取物工艺已经确定，进入正式开发阶段。采用现代制药工艺，有效部位茶芎挥发油提取物中的苯酞类化合物相对含量达到90%以上，有效部位的成分鉴定已经完成。建立了质量标准，已完成2种成分的标准物质合成，药效学研究证实了本品的脑神经保护作用和改善局部缺血区血流供应的作用。
预计2014年末申报临床研究。
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受体激动剂（临床前研究）
S1P1 Receptor Agonist (Preclinical study)
 
S1P₁受体（Sphingosine-1-Phosphate Receptor，5个亚型S1P1~5）激动剂是新型免疫抑制剂，通过诱导外周循环系统中的淋巴细胞回到淋巴结，即“归巢”，降低外周循环中的淋巴细胞数量而达到治疗自身免疫性疾病的目的。该类药物既不影响粒细胞和单核细胞活性，也不损害淋巴细胞和造血系统，并且淋巴细胞对外界抗原的记忆仍然保存，与传统免疫抑制药物相比，对自身免疫系统毒性较小。该类药物的代表是Fingolimod（FTY720），由诺华制药公司开发，已于2010年9月上市，用于多发硬化症治疗。但是临床应用中发现，FTY720有致患者心动过缓的不良反应，与其同时激动S1P₃受体有关。因此，开发选择性更高的S1P₁受体激动剂成为开发治疗自身免疫性疾病药物的方向。
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.
 
中国医学科学院药物研究开展了系统的S1P₁选择性激动剂研究，对200余个新化合物的体内外活性评价发现多个化合物具有选择性S1P₁受体激动作用，降低外周血淋巴细胞的活性与FTY720相当或略强，但无心动过缓副作用。与目前国际上正在进行临床或临床前研究的新型S1P₁受体激动剂作用强度相当。已申请国内、国际化合物专利保护。
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.
 
通过体外对S1P₁和S1P₃受体的选择性试验、正常大鼠体内减低淋巴细胞作用强度试验、对大鼠心率的影响试验，以及在大鼠体内的初步药代特性研究，结合化学合成工艺难度分析，确定化合物IMMH001、IMMH002能有效降低外周血淋巴细胞活性而对心率影响较小。
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.
 
初步药效学筛选试验显示，两种化合物分别对类风湿性关节炎模型和银屑病模型具有较好的疗效。
The preliminary pharmacodynamic screening test showed that the two compounds had a good therapeutic effect on the model of rheumatoid arthritis and psoriasis.
 
药代动力学研究显示，IMMH001口服生物利用度为20.2%，IMMH002口服生物利用度为48.6%；IMMH001体内消除半衰期较短，为4-7h，IMMH002半衰期较长，达20-26h；两种化合物在人、猴、鼠肝微粒体中较为稳定，对CYP2E1有轻度抑制作用，各原形药及其磷酸化产物对其他CYPs活性均无明显影响，两种化合物及其磷酸化产物（10mM）体外与大鼠、犬、猴及人血浆蛋白高度结合（90-99.64％），且无明显种属差异。
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.
 
初步安全性评价显示，正常昆明小鼠一次性灌胃给予IMMH001和IMMH002各500mg/kg（n=4, 雌雄各半），连续观察14天，无明显不良症状，动物体重增加。化合物遗传毒性（微生物回复突变试验）的检测，提示IMMH001和IMMH002及其相应的磷酸化产物的Ames试验结果均为阴性。IMMH001和IMMH002对心脏hERG钾电流抑制作用的IC₅₀（μM）分别为6.57和8.07，而IMMH001-P和IMMH002-P对hERG钾电流抑制作用的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.
 
上述结果提示，IMMH001和IMMH002均具有较好的理化性质和药代特性，各有其特点，显示了进一步开发的前景。
预计2014年末申报临床研究。
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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