Difficulties,opportunitiesand away forward for China

【迈克尔·司拜丁:博士，IUPHAR秘书长，法国司拜丁研究所所长；主要研究方向：药理学，药物研发，认知的脑回路，应激与精神病学及疾病、免疫和炎症的影响。】

【谢里·文莱特：博士，英国罗伯特戈登大学教授，天然产物研究中心主任；主要研究方向：应用广泛的细胞、体外和体内心血管疾病模型探讨心血管病理学中正常生理机制的改变，特别是对饮食影响的反应。】

【瓦拉瑞·西里可斯：博士，IUPHAR天然药物药理分委会副主席，法国斯特拉斯堡大学教授；主要研究方向：心血管药理学，特别是在健康和疾病状态下，如高血压、糖尿病和生理性衰老中，内皮调控血管内稳态的关键作用。】

Natural products(NPs)have always been rich sources of drugs,but there is also a great need for evidence-based medicine as NPs can also have side-effects.Therefore,therapeutic benefit must also be proven unless agents are nutraceu⁃ticals,food additives or foods.In Europe and USA,centuries of use of TCM for certain diseases must be reinforced by clinical evidence approved by regulatory authorities in the relevant countries.The world is split in healthcare and in therapies between NPs,traditional medicines,and new chemical entities.NPs need evidence-based medicine,both preclinically for their pharmacoki⁃netics,chemical structures,pharmacological drug targets,approved clinical effects for widespread acceptation.How?【天然产物是药物研发的丰富来源，但由于天然产物的副作用，循证医学研究是必要的。因此除非是保健品、食品添加剂或食物，其他药物的疗效必须被证明。在欧洲和美国，尽管中药治疗疾病已经应用了几个世纪，仍然必须得到相关国家监管部门批准的临床证据的支持。有关利用天然产物、传统药物还是新化合物进行医疗保健和治疗疾病这个问题，全球还未达成共识。天然产物需要循证医学的支持，包括临床前药代动力学、化学结构、药物作用靶标及经过验证的临床疗效等，才能被广为接受。但是应该怎样做呢？】

Perhaps,by using the same way as IUPHAR structured modern pharmacology using its Nomen⁃clature Committee(NC-IUPHAR),creating expert subcommittees and having six-monthly meetings with published reviews in high impact journals with clear recommendations would achieve the desired outcome.NC-IUPHAR has now＞100 committees of 860 experts,125 expert reviews which have an h-index of 80 and has authoritative databases on all drug targets(www.guidetophar⁃macology.org and the new www.guidetoimmuno⁃pharmacology.org).The IUPHAR Natural Products Database Committee could expand its scope and membership to become a worldwide instrument for the promotion of evidence-based medicine for natural products and TCM.【可能借鉴IUPHAR应用命名委员会（NC-IUPHAR）构建现代药理学的方法，建立专家分委会，每6个月召开高影响因子杂志发表的综述的会议，并给出明确的建议，有望获得预期效果。NC-IUPHAR有100多个委员会，860名专家，125个专业综述，h因子达到80，还有权威的药物靶点数据库（www.guidetopharmacology.org和www.guidetoimmunopharmacology.org）。IUPHAR天然产物数据库委员会应该扩大其范围和成员，成为促进天然产物和传统中药循证医学发展的世界性工具。】

1 Difficulties（难点）

Because of recent events，some early studies performed in China must be validated.Furthermore,animal studies may not always be predictive.Many western medicines are single substances and complex mixtures may be viewed with a certain suspicion,because of the difficulty of maintaining quality and reproducibility,and also because certain of the ingredients may be harmful to sensitive individuals,and it is not easy to ascertain which substances apport benefit.In the past,contami⁃nation with insecticides,herbicides or heavy metals was also a genuine difficulty with some traditional products produced in developing countries,but that has been improved.One difficulty in Europe and the US,which is rarely mentioned,is public appreciation of traditional medicine concerning the environmental impact,and clear separation of traditional medicine from the inclusion of items from animals and fish which are environmentally threatened.【因为近年发生的一些事件，中国的一些早期研究必须要验证。此外，动物研究并不总是具有预测性。许多西药是单一物质，而因为复杂的混合物很难保持质量和重现性，其某些成分对敏感个体有害，以及确定混合物中有益物质的困难，所以总是对复杂的混合物持有怀疑。过去，杀虫剂、除草剂和重金属污染也是发展中国家一些传统产品生产的真正难题，但是这种状况已经好转。在欧洲和美国较少提及的一个难题是公众对传统药物对环境影响的认识，及把传统药物与列入受环境威胁的动物和鱼类等明确区分开。】

Another difficulty for research on NPs is the non-standardised application of the Nagoya protocol.The difficulty is that scientists wishing to use NPs must use due diligence before starting experiments.Nations are very rapidly defining restrictive laws on use of genetic material,which includes NPs,but which are made by politicians and lawyers with little knowledge of the pharmacological impli⁃cations of their propositions,and where the term"biodiversity"is a"passe-partout".Thus it is very difficult to be compliant throughout the world.This is a particular difficulty for patents to be globally compliant for all countries with a single Patent Cooperation Treaty(PCT).【另一个天然产物研究的难点在于《名古屋议定书》的非标准化应用。困难在于，想要应用天然产物的科学家在开始试验前必须付出很多努力。各国正在迅速制定关于遗传资源，包括天然产物使用的限制性法律。这些法律是由政客和律师制定的，但是他们对药理学含义知之甚少。“生物多样性”这个术语是一把“万能钥匙”，因此很难在世界范围内做到遵纪守法。特别是世界各国仅用专利合作条约（PCT）来保持专利全球兼容性是非常困难的。】

2 Opportunities（机遇）

However,clinical testing gives opportunities to extend clinical studies to other indications,and to enrich Chinese science with Western tech⁃nology-and vice versa!【然而，临床试验为扩展临床适应证，用西方的技术丰富中国的科学，提供了机遇，反之亦然。】

However,the FDA has only approved herbal mixtures as drugs for rare/orphan indications:green tea extracts for genital warts;FulyzaqR(now MytesiR)for diarrhoea in HIV/AIDs.Thus,proven efficacy in orphan diseases may be a key way for developing herbal mixtures/traditional medicines.It may be easier to develop TCM for such indications with simple and clear clinical endpoints rather than going for major markets such as Alzheimer disease,where so many drugs have failed.Furthermore,some modern technological advances allow a new vision of NPs and TCM which may create a cultural and scientific revolution.In this respect，biosynthesis of NPs,or of mixtures,may be a useful way forward by introducing biosynthetic genes into bacteria and yeast to produce the relevant substances.Metabolomics can also define the substances in complex mixtures and deconvolute screening programs on new targets.【到目前为止，FDA仅批准了植物混合物作为药物治疗罕见病或孤儿病，如绿茶提取物治疗尖锐湿疣，FulyzaqR（MytesiR）治疗艾滋病腹泻。因而，证实治疗孤儿病的有效性可能是开发植物混合物或传统药物的关键方法。针对类似有简单明确临床终点的疾病开发传统中药可能更容易，而不是针对如阿尔茨海默病等疾病的主要市场，在此领域许多药物都失败了。此外，现代技术的进步为天然产物和传统中药的研究提供了新的视角，可能引发科学和文化的革命。在这方面，通过将生物合成基因导入细菌和酵母产生相关物质，生物合成天然产物或混合物可能是有用的方法。代谢组学也能够定义复杂混合物中的物质，并对新靶点进行反卷积筛选。】

Food products are also important.Professor SCHINI-KERTH showed the key importance of food and nutritional-derived products to protect the cardiovascular system and,hence,to retard the development of ageing-related major cardio⁃vascular diseases,the leading cause of death worldwide.Adherence to the mediterranean diet characterized by the daily intake of polyphenolrich fruits and vegetables,cereals and a moderate consumption of red wine,a weekly intake of fish,white meat and eggs,and a monthly intake of red meat was associated with a 9%reduction in mortality from cardiovascular diseases and a 6%in the incidence of or mortality from cancer.Regular consumption of red wine resulted also in a 36%reduction of the relative risk of cardiovascular diseases.The health benefit of these dietary products has been related to their high content of polyphenols.Experimental studies using a red wine extract(Vin de Corbières;2.9 g·L-1of poly⁃phenols)indicated that red wine polyphenols,a mixture of more than 800 compounds including flavanols,anthocyanins and phenolic acids,are potent stimulators of the endothelial formation of vasoprotective factors including nitric oxide and endothelium-dependent hyperpolarization.Similar effects were also observed in response to grape skin polyphenols and a grape juice indicating that the bioactive compounds originate from the fruit.Moreover,a superior vasoprotective effect was observed with juices and purees from aronia,blackcurrant,blueberry,cranberry and lingonberry compared to grape juice.The potential of nutri⁃tional-derived polyphenols to protect the cardio⁃vascular system is also indicated by the fact that intake of red wine polyphenols prevented angio⁃tensin II-induced endothelial dysfunction in an experi⁃mental model of hypertension,and improved flowmediated vasodilatation in humans.Thus,poly⁃phenol-rich natural products appear to be an inter⁃esting approach to protect the cardiovascular system.In this respect,the difference between Food-Dietary and Supplement-Drug is important.The dietary supplement category is limited to oral route of administration;if skin application,then it is regu⁃lated as a cosmetic.The FDA has recently published guidelines for"New Dietary Ingredi⁃ents"(NDIs).These are not yet implemented,but the intent is that companies introducing dietary supplement products containing an ingredient that was not marketed in the US prior to Oct 15,1994,must provide NDI notification to the FDA prior to marketing,with the basis for reasonable expectation of safety.【食物也是药物的重要来源。衰老相关的心血管疾病是世界范围内的主要死因，SCHINI-KERTH教授展示了食物和营养衍生产品在保护心血管系统而延缓衰老相关心血管疾病发展上的重要性。坚持地中海式饮食，包括每天食用富含多酚的水果、蔬菜、谷物和饮用适量红酒，每周吃鱼、白肉和鸡蛋，每月食用红肉，可使心血管疾病死亡率降低9%，癌症发病率或死亡率降低6%。经常饮用红酒可使患心血管疾病的相对风险降低36%。这些食品对健康有益与其富含多酚有关。对红酒提取物（科比埃酒，含多酚2.9 g·L-1）的实验研究显示，红酒多酚是含有包括黄烷醇、花青素、酚酸等800余种化合物的混合物，是一氧化氮和内皮依赖性超极化等内皮血管保护因子形成的强力刺激剂。在葡萄皮多酚和葡萄汁上也观察到了相似的结果，表明具有生物活性的化合物来源于葡萄果实。而且，与葡萄汁相比，野樱莓、黑加仑、蓝莓、红莓和林果莓的果汁和果泥血管保护效果更好。摄入红酒多酚可阻止高血压实验模型血管紧张素Ⅱ诱发的内皮功能紊乱，也可改善人的血管扩张，这些都表明营养衍生的多酚具有保护心血管系统的潜力。因此，富含多酚的天然产物是一种保护心血管系统的有趣方法。从这方面来看，将食物、膳食补充剂和药物进行区分是重要的。膳食补充剂仅限于口服途径，如果应用于皮肤，则被作为化妆品管理。美国食品药品管理局最近发布了新膳食成分（New Dietary Ingredients′，NDI）指南。虽然尚未实施，但它的目的是如果膳食补充剂采用的成分1994年10月15日前未在美国上市，公司必须在市场推广之前向FDA提供NDI通知，并以合理的安全预期为依据。】

3 A way forward for China（中国的前进方向）

We were impressed by the move of the Chinese Government to invest heavily in innovative phar⁃maceutical research,with the aim of increasing innovation and making China a key player in the global Pharma"space".China has a rich history in the use of TCMs and following our visit to the Jiangsu Kanion Pharmaceutical Company in Lianyun⁃gang we were highly impressed by the strides being made to isolate and manufacture to a high quality TCMs for use in traditional medicine.This is clearly a highly innovative business,as judged by the large number of patents generated and the focus on quality control.However,for China to make a serious impact in the global pharma market with their TCM preparations,there is a need to address the key regulatory requirements that are already imposed upon western medi⁃cines.These include providing solid scientific evidence of the mechanism of action by which the TCMs exert their therapeutic effects,followed by well designed clinical trials to provide sound indica⁃tion of clinical benefit.【中国政府大力投资创新药物研究的举措给我们留下了深刻的印象，旨在加大创新力度，使中国成为全球制药“空间”的重要力量。中国在应用传统中药方面有悠久的历史，在参观连云港江苏康缘药业有限公司后，我们对从传统中药中分离和制造高品质中药取得的长足进步深表赞叹。从获得的大量专利和对质量控制的关注可以看出，康缘药业有限公司是一个高度创新的企业。然而，中国想要通过中药在全球制药市场产生重大影响，需要解决西药现有的关键监管要求，包括为中药疗效作用机制提供坚实的科学依据，并设计完善的临床试验，为临床使用提供合理的提示。】

The documentation detailing the Lianyungang Talent Policy provided very interesting reading and demonstrated a keen desire to encourage and support innovation and entrepreneurship within the academic community,with the inten⁃tion of bringing their expertise into local SME′s.The financial support is highly commendable and should serve as a good incentive to academic/business partnership working.However,perhaps there is an additional opportunity to increase the number of companies by encouraging academics to take their innovative ideas and discoveries and "spin out"companies from within the University base.To support this skills develop⁃ment,rather than financial incentive,could be the key whereby training in creating a business plan,identifying market needetcwould assist academicsinthetransformationfrom being"business facilitators"to"business creators".【连云港人才政策非常详细，可读性极佳，体现了学术界鼓励和支持创新和创业精神的强烈愿望，目的是把人才的专业知识输入当地的中小企业。财政支持值得称道，激励了学术/商业合作。此外，鼓励大学采纳公司的创新观点和发明，在大学基地内拆分公司也是增加公司数量的机会。支持技能的发展，而不是经济激励，可能是至关重要的，培训制定商业计划、确定市场需求将有助于学者从“为企业服务”转变为“创建企业”。】