Lecture 9 TCM Herbs in Traditionally Defined Properties Y. Z Lecture 9 TCM Herbs in Traditionally Defined Properties Y.Z. Chen Department of Pharmacy National University of Singapore Tel: 65-6616-6877; Email: phacyz@nus.edu.sg ; Web: http://bidd.nus.edu.sg Content TCM herbs in traditionally defined properties Digitization of TCM herbs in traditionally defined properties Classification methods for identifying TCM recipes TCM herb pairs TCM combination therapy

TCM herbs in traditionally defined properties Herb Property 1. Four Characters （四性） 2. Five Taste （五味） 3. Meridian （归经） 4. Lifting, lowering, floating and sinking （升降浮沉） 华盛顿大学研究员奥哈拉指出，天然草药其实同样含有化学物质，假使不熟悉药性而随意与西药混合服用，可能会发生中毒现象，甚至死亡。   　　一名服用“贫血药”的病人，五年来一直情况稳定，但后来同时服用人参后，病情恶化。医生也不知道这一现象的真正原因，经过检查发现是人参稀释血液功能，使病情出现变化。 　　除人参外，大蒜和银杏也同样有轻稀释血液功能，故必须小心服用。 　　能治哮喘的麻黄素，对于心脏病及高血压病也有潜在危险。而天然减肥药中一般都含麻黄，使服用者在不知不觉中患了高血压。 急性中毒患者也有轻重之分，一般早期出现恶心呕吐、腹痛腹泻等消化道症状，以及呼吸频率、心率的改变，重者则出现烦躁不安、谵语、氏迷、休克等症状。 2

TCM herbs in traditionally defined properties 1. Four Characters 四性 (Qi) ( The temperature Characteristic ) Clinic Practicing Treating cold syndrome with hot-natured drugs (or heating the cold). Treating heat syndrome with cold-natured drugs ( or cooling the heat) Identify the “Real cold syndrome with fake heat syndromes” or “Real heat syndromes with fake cold syndromes” According to the development of disease to choose proper herbs Treating both heat & cold symptoms with both cold & hot natured drugs Cold & Cool Hot & Warm Even TCM treatment Clear Heat; Cool the heat toxin in Blood; Clear Empty Heat; Phlegm-heat; Promote defecating; Promote urination; Nourish Yin; Calm down liver wind; Warm the internal cold; Expel the external cold; Tonify the Yang Qi; Warm up the meridian; Rescue the exhausted Yang; Could be widely used; Herb Shi Gao; Jin Yin Hua; Qin Hao; Gua Lou; Da Huang; Shen Di; Ling Yang Jiao Gang Jiang; Gui Zhi; Ma Huang; Fu Zi; Du Huo; Rou Gui; Gan Cao; 对于寒热格拒的复杂病症，当采用寒热并用，反佐之法。张介宾云：“反佐者，谓药同于病而顺其性也。则以热治寒，而寒拒热，则反佐以寒而入之；以寒治热，而热拒寒，则反佐以热而入之。张仲景：白通加猪胆汁汤，治阴寒内盛，虚阳被逼于上，阳欲上散，阴欲下脱，阴阳寒热格拒的戴阳证。干姜，附子回阳通脉，佐入猪胆汁并用佐治之法， 3

TCM herbs in traditionally defined properties 2. Five Taste 五味 Spicy Sweet Bitter Sour Salty Function Disperse Tonifying Down bearing Astringing Softening Moderating Moving Moistening Draining Contra- Indication All types of Def. Dampness Pregnant women Any condition of excess: Damp or Stagnation Fluid accumulat-ion Exterior Wind Prolapse Diarrhea, Profuse urine Damp Sp. Def. , Blood Def. , Yin def. Loose stools 华盛顿大学研究员奥哈拉指出，天然草药其实同样含有化学物质，假使不熟悉药性而随意与西药混合服用，可能会发生中毒现象，甚至死亡。   　　一名服用“贫血药”的病人，五年来一直情况稳定，但后来同时服用人参后，病情恶化。医生也不知道这一现象的真正原因，经过检查发现是人参稀释血液功能，使病情出现变化。 　　除人参外，大蒜和银杏也同样有轻稀释血液功能，故必须小心服用。 　　能治哮喘的麻黄素，对于心脏病及高血压病也有潜在危险。而天然减肥药中一般都含麻黄，使服用者在不知不觉中患了高血压。 急性中毒患者也有轻重之分，一般早期出现恶心呕吐、腹痛腹泻等消化道症状，以及呼吸频率、心率的改变，重者则出现烦躁不安、谵语、氏迷、休克等症状。 4

TCM herbs in traditionally defined properties 3. Meridian 归经 Herb agents target specific channels within the body to effect a change in that channel Clear heat from heart: irritability, restlessness, insomnia The herb which enter the small intestine are cold to treat damp heat urinary problem or expel water through intestine Transform damp and treat wind damp, phlegm, diarrhea or toxic swelling 华盛顿大学研究员奥哈拉指出，天然草药其实同样含有化学物质，假使不熟悉药性而随意与西药混合服用，可能会发生中毒现象，甚至死亡。   　　一名服用“贫血药”的病人，五年来一直情况稳定，但后来同时服用人参后，病情恶化。医生也不知道这一现象的真正原因，经过检查发现是人参稀释血液功能，使病情出现变化。 　　除人参外，大蒜和银杏也同样有轻稀释血液功能，故必须小心服用。 　　能治哮喘的麻黄素，对于心脏病及高血压病也有潜在危险。而天然减肥药中一般都含麻黄，使服用者在不知不觉中患了高血压。 急性中毒患者也有轻重之分，一般早期出现恶心呕吐、腹痛腹泻等消化道症状，以及呼吸频率、心率的改变，重者则出现烦躁不安、谵语、氏迷、休克等症状。 5

TCM herbs in traditionally defined properties Many herbs which enter the stomach channel clear heat, especially toxic heat All herbs in the surface releasing categories enter lung channels Treat damp heat diarrhea or intestinal abscess Tonify Yin, Yang or essence; Clear empty heat in kidney; or help drain damp

TCM herbs in traditionally defined properties Treat jaundice or to guide the herb to the shao yang energetic level Treat wind syndromes like inchy skin, bloody diarrhea, or tremors, drain liver fire, relieve liver Qi stagnation, or treat eye problem due to heat Treat edema; Drain damp heat from the lower burner;

TCM herbs in traditionally defined properties 4. lifting, lowering, floating and sinking 升降浮沉 Varying disease often appear to bear a tendency to move upward, downward, towards the exterior or the interior. Corresponding to the above, the direction of actions of medicinal herbs on human body also have the lifting, lowering, floating and sinking distinction lifting Lowering Floating Sinking The direction of herbal actions is toward the upper parts, which are indicated for a disease in a lower and deeper parts They function toward the lower parts and possess the action of descending adverse Qi and are indicated for the disease due to adverse ascending of pathogenic factors Floating herbs function toward the upper and outward parts, generally exert the effects of sweating and dispersing and are indicated for the disease in the upper and superficial parts Sinking herbs function toward the lower and inward parts, have the effects of lowering the adverse flow of Qi and relaxing bowels and are indicated for the disease in the lower and interior Huang Qi + Sheng Ma: Dai Zhe Shi; Cheng Xiang; Shi Jue Ming MaHuang; Zi Su; Fang Feng; Du Huo Da Huang; Mu Tong Prolapse disease Cough, dizziness, vomiting Exterior cold Constipation; dysuria 8

TCM herbs in traditionally defined properties

TCM herbs in traditionally defined properties

Digitization of TCM herbs in traditionally defined properties

Digitization of TCM herbs in traditionally defined properties

Digitization of TCM herbs in traditionally defined properties

Digitization of TCM herbs in traditionally defined properties

Geometric Picture of Digital Representation Feature vectors: Descriptor Feature vector Positive examples Negative examples A=(1, 1, 1) B=(0, 1, 1) C=(1, 1, 1) D=(0, 1, 1) E=(0, 0, 0) F=(1, 0, 1)

Geometric Picture of Digital Representation Feature vectors in input space: Z Input space X Y B A E F Feature vector A=(1, 1, 1) B=(0, 1, 1) C=(1, 1, 1) D=(0, 1, 1) E=(0, 0, 0) F=(1, 0, 1)

Classification methods for identifying TCM recipes kNN method

Classification methods for identifying TCM recipes Support Vector Machines (SVM) method

Classification methods for identifying TCM recipes Support Vector Machines (SVM) method

Classification methods for identifying TCM recipes

Classification methods for identifying TCM recipes

Compatibility of TCM Herb Pairs 1. Mutual reinforcement （相须） 2. Mutual assistance （相使 ） 3. Mutual restraint or detoxication（相畏 or相杀） 4. Mutual Antagonism （相恶） 5. Mutual Incompatibility （相反） 华盛顿大学研究员奥哈拉指出，天然草药其实同样含有化学物质，假使不熟悉药性而随意与西药混合服用，可能会发生中毒现象，甚至死亡。   　　一名服用“贫血药”的病人，五年来一直情况稳定，但后来同时服用人参后，病情恶化。医生也不知道这一现象的真正原因，经过检查发现是人参稀释血液功能，使病情出现变化。 　　除人参外，大蒜和银杏也同样有轻稀释血液功能，故必须小心服用。 　　能治哮喘的麻黄素，对于心脏病及高血压病也有潜在危险。而天然减肥药中一般都含麻黄，使服用者在不知不觉中患了高血压。 急性中毒患者也有轻重之分，一般早期出现恶心呕吐、腹痛腹泻等消化道症状，以及呼吸频率、心率的改变，重者则出现烦躁不安、谵语、氏迷、休克等症状。 22

TCM Herb Pairs 1. Mutual reinforcement （相须） That is, two or more ingredients with similar properties and effects are used in combination to reinforce each other’s action Mutual reinforcement Effects & Action Da Huang + Mang Xiao Purgating action Tao Ren + Hong Hua Invigorating the blood Zhi Mu + Huang Bai Clear deficient fever Ru Xiang + Mo Yao Fu Zi + Gan Jiang Warm up the Yang Qi Quan Xie +Wu Gong Stop muscle Spasm 药对是中药复方配伍的最简单、最基本和最常见的形式，其配伍符合中医“七情和合”理论和组合原则，具备复方的基本主治功能和疗效，可以通过揭示药对配伍规 律阐明复方配伍的科学性。梁日欣等研究了血府逐瘀汤中川芎和赤芍合用及川芎、赤芍单用对高脂血症大鼠降脂、抗氧化及对血管内皮细胞功能的影响，结果表明： 两药合用及单用均明显降低血清胆固醇、甘油三酯和低密度脂蛋白水平。揭示在降脂作用方面，两药没有协同作用。但是两药合用能降低血清MDA水平性，增加NO释放。这提示两药在抗氧化及保护血管内皮细胞功能方面，产生协同作用。 配伍还可发挥增效减毒效应。如对四逆汤配伍规律研究发现，附子虽有一定的强心作用，但并不强，配以强心作用并不强的干姜后，能明显增强心肌收缩力，扩张冠脉，这与“相须”之论是一致的。而且，二药配伍后附子的毒性大大降低。说明附子为方中主药，它和干姜配伍即有君臣关系，干姜在方中能助附子增效，又有佐制作用，包括辅佐及制约附子之毒性。 23

TCM Herb Pairs 2. Mutual assistance （相使 ） That is, Chinese medicinal herbs that are not certainly similar but have some relationship in the aspect of medicinal properties and actions are used in combination, in which one herb is taken as the dominate factor and the others as its assistants to raise its therapeutic effects. Dominate herb Assistant herbs Effects & Action Huang Qi Fang Ji Promote water circulation & permeating the dampness Huang Lian Mu Xiang Stop diarrhea & abdomen pain Da Huang Huang Qin Clear damp-heat 24

3. Mutual restraint or detoxification（相畏or相杀） TCM Herb Pairs 3. Mutual restraint or detoxification（相畏or相杀） That is, mutual restraining effect of different medicines to weaken or neutralize each other’s harmfulness, such as toxicity or side-effects. Mutual restraint Ban Xia; Dan Nan Xing Sheng Jiang Ren Sheng Wu Ling Zhi Fu Zi Gan Jiang Gan Cao

Shi Xiang Fan Hun San ( 十香反魂散 ) TCM Herb Pairs Mutual Antagonism (相恶) The ability of two substances to minimize or neutralize each other’s positive effects Ba Dou Qian Niu Zi Gan Yin Wan ( 感应丸 ) Ding Xiang Yu Jin Shi Xiang Fan Hun San ( 十香反魂散 ) Chuan Wu & Cao Wu Xi Jiao Da Huo Luo Wan ( 大活络丸 ) Ren Shen Wu Ling Zhi Rou Gui Chi Shi Zhi *Liu Huang *Pu Xiao *Shui Yin *Pi Shuang *Lang Du *Mi Tuo Shen *Ya Xiao *San Leng 《神農本草經‧序例》指出“勿用相惡、相反者”，“若有毒宜制，可用相畏、相殺者爾，勿合用也”。自宋代以后，將“相畏”關系也列為配伍禁忌，与“相惡”混淆不清。因此，“十九畏”的概念，与“配伍”一節中所談的“七情”之一的“相畏”，涵義并不相同。 　　“十九畏”和“十八反”諸藥，有一部分同實際應用有些出入，歷代醫家也有所論及，引古方為据，証明某些藥物仍然可以合用。如感應丸中的巴豆与牽牛同 用；甘遂半夏湯以甘草同甘遂并列；散腫潰堅湯、海藻玉壺湯等均合用甘草和海藻；十香返魂丹是將丁香、郁金同用；大活絡丹烏頭与犀角同用等等。現代這方面的 研究工作做得不多，有些實驗研究初步表明，如甘草、甘遂兩种藥合用時，毒性的大小主要取決于甘草的用量比例，甘草的劑量若相等或大于甘遂，毒性較大；又如 貝母和半夏分別与烏頭配伍，未見明顯的增強毒性。而細辛配伍藜蘆，則可導致實驗動物中毒死亡。由于對“十九畏”和“十八反”的研究，還有待進一步作較深入 的實驗和觀察，并研究其机理，因此，目前應采取慎重態度。一般說來，對于其中一些藥物，若無充分根据和應用經驗，仍須避免盲目配合應用。 \ 复方芦荟胶囊，脾胃虚寒者、大便偏稀的人就不适合用，因为服用这个药会通大便.大便原本很稀的人就不适合使用。 26

TCM Herb Pairs Mutual Incompatibility (相反) Cause side effects or toxicity if use together Gan Cao Gan Sui Da Ji Yuan Hua Hai Zao Dosage: Gan Cao>= Gan Sui Wu Tou ( Fu Zi ) Ban Xia Gua Lou Bei Mu Bai Ji Bai Lian Bei Mu or Ban Xia + Fu Zi ( No evidence support it ) Li Lu Ren Shen Dang Shen Dan Shen Xuan Shen Sha Shen Ku Shen Xi Xin Bai Shao Xi Xin + Li Lu: cause animal death in the lab 《神農本草經‧序例》指出“勿用相惡、相反者”，“若有毒宜制，可用相畏、相殺者爾，勿合用也”。自宋代以后，將“相畏”關系也列為配伍禁忌，与“相惡”混淆不清。因此，“十九畏”的概念，与“配伍”一節中所談的“七情”之一的“相畏”，涵義并不相同。 　　“十九畏”和“十八反”諸藥，有一部分同實際應用有些出入，歷代醫家也有所論及，引古方為据，証明某些藥物仍然可以合用。如感應丸中的巴豆与牽牛同 用；甘遂半夏湯以甘草同甘遂并列；散腫潰堅湯、海藻玉壺湯等均合用甘草和海藻；十香返魂丹是將丁香、郁金同用；大活絡丹烏頭与犀角同用等等。現代這方面的 研究工作做得不多，有些實驗研究初步表明，如甘草、甘遂兩种藥合用時，毒性的大小主要取決于甘草的用量比例，甘草的劑量若相等或大于甘遂，毒性較大；又如 貝母和半夏分別与烏頭配伍，未見明顯的增強毒性。而細辛配伍藜蘆，則可導致實驗動物中毒死亡。由于對“十九畏”和“十八反”的研究，還有待進一步作較深入 的實驗和觀察，并研究其机理，因此，目前應采取慎重態度。一般說來，對于其中一些藥物，若無充分根据和應用經驗，仍須避免盲目配合應用。 \ 复方芦荟胶囊，脾胃虚寒者、大便偏稀的人就不适合用，因为服用这个药会通大便.大便原本很稀的人就不适合使用。 27

TCM Herb Pairs

TCM Herb Pairs Method Training Set Testing Set Testing Method Herb-Pair Accuracy Non-Herb-Pair Accuracy PNN 360 39 10-fold CV 87.9% 91.6% kNN 72.1% 97.1% SVM 78.1% 97.6%

TCM Herb Pairs TCM herbal ingredient pairs displaying pharmacokinetic synergism By inhibiting the actions of the drug efflux transporters, resulting in an accumulation of the TCM herbal ingredients and thus a potentiation of their effects in the target cells. An example is the combination of genistein (from Semen Sojae Praeparata, Oleum Glycines, Radix Sophorae Japoniae, Flos Sophorae, Fructus Sophorae, Folium Sophorae Japoniae, Semen Glycines Max, Caulis Spatholobi, Radix Sophorae Tonkinensis) and paclitaxel (from Taxus Chinensis)

TCM Herb Pairs Mechanism of synergistic actions of paclitaxel and genistein

TCM Herb Pairs TCM herbal ingredient pairs displaying pharmacokinetic synergism By modulating its metabolism, resulting in an accumulation of the TCM herbal ingredient and thus a potentiation of their effects in the target cells. An example is the combination of TCM herbal ingredient pair comprising of caffeine (from Radix Camellia Sinensis, Folium Camelliae Sinensis, Fructus Camellia Sinensis, Folium Ilicis Cornutae, Cortex Firmianae Plantanifoliae, Radix Firmianae Plantanifoliae, Flos Firmianae Plantanifoliae, Folium Firmianae Plantanifoliae, Semen Firmianae) and apigenin (from Herba Lagotidis, Flos Campsis, Herba Artemisiae Anomalae, Herba Ephedrae, Flos Buddlejae, Herba Artemisiae Anomalae, Flos Genkwa, Radix seu Cortex Daphnes Genkwae, Radix Campsis Grandiflorae)

TCM Herb Pairs Mechanism of synergistic actions of caffeine and apigenin

TCM herbal ingredient pairs displaying pharmacodynamic synergism TCM Herb Pairs TCM herbal ingredient pairs displaying pharmacodynamic synergism The combination of eugenol (from Fructus Artemisiae Argyi, Folium Artemisiae Argyi, Caulis Perillae Frutescentis, Folium Perillae Frutescentis, Dianthus Superbus, Fructus Perillae Preparata, Alpinia Galangae, Flos Caryophylli, Radix Syzygii Aromatic, Liquor Destillata Caryophylli, Cortex Syzygii Aromatic, Ramulus Syzygii Aromatic, Fructus Galangae, Pericarpium Zanthoxyli, Flos Lonicerae, Herba Asari) and low concentration of quercetin (from Herba Patriniae Scabiosaefoliae, Herba Patriniae, Radix Bupleuri, Herba Euphorbiae Humifusae, Radix Lamiophlomidis Rotatae, Rhizoma Alpiniae Officinarum, Herba Hyperici, Herba Lagotidis, Cannabis Sativa L.,

TCM herbal ingredient pairs displaying pharmacodynamic synergism TCM Herb Pairs TCM herbal ingredient pairs displaying pharmacodynamic synergism Radix Astragali, Fructus Ligustri Lucidi, Herba Artemisiae Annuae, Radix Artemiiae Annua, Semen Artemisiae, Herba Taxilli, Fructus Quisqualis, Radix Quisqualis Indica, Herba Pyrolae Chinensis, Herba Ephedrae) exerts an anti-allergic and anti-inflammatory effect that alleviates allergic rhinitis, which is congruous to the therapeutic effect of the TCM herbal pair, Herba Asari and Herba Ephedrae, containing eugenol and quercetin respectively. This TCM herbal pair has been used to treat allergic rhinitis. The similarity in therapeutic effect of the TCM herbal ingredient pair and the TCM herbal pair can be a sign of possible synergism between the ingredients in the TCM herbal ingredient pair.

TCM Herb Pairs Mechanism of synergistic actions of eugenol and quercetin (low concentration)

TCM Combination Therapy Case study 1: Antidepressant activity of St. John’s Wort St. John’s Wort (SJW) is an extract from the plant Hypericum perforatum L. Numerous clinical trials have shown that SJW had significant antidepressant efficacy and lower side effects than standard antidepressants. In many countries, it has been widely used for the treatment of mild to moderate forms of depression. SJW has been included in the pharmacopoeias of Germany and the US. The main active ingredients of SJW are hyperforin (HP), hypericin (HY), pseudohypericin (PH), amentoflavone (AF), and several flavonoids (FL)

TCM Combination Therapy Case study 1: Antidepressant activity of St. John’s Wort

TCM Combination Therapy Case study 1: Antidepressant activity of St. John’s Wort

TCM Combination Therapy Case study 2: The effect of Realgar-Indigo naturalis formula (RIF) on acute promyelocytic leukemia (APL) TCM formula RIF has been used in China to treat APL since 1980s. RIF consists of four herbs, realgar, Indigo naturalis, Salvia miltiorrhiza, and Radix pseudostellariae. In TCM theory, multiple agents contained in one formula must work synergistically. Realgar is regarded as the principal component of the formula RIF, and the other three are adjuvant components to assist the effect of realgar. The main active compounds of realgar, Indigo naturalis and Salvia miltiorrhiza are tetraarsenic tetrasulfide (As4S4, A), indirubin (I) and tanshinone IIA (T), respectively.

TCM Combination Therapy Case study 2: The effect of Realgar-Indigo naturalis formula (RIF) on acute promyelocytic leukemia (APL) A) Protein interaction network. (B) Protein-pathway association network.

TCM Combination Therapy Case study 2: The effect of Realgar-Indigo naturalis formula (RIF) on acute promyelocytic leukemia (APL)

TCM Combination Therapy Comparison with combination therapy in Western medicine

TCM Combination Therapy Comparison with combination therapy in Western medicine

TCM Combination Therapy Comparison with combination therapy in Western medicine

TCM Combination Therapy Comparison with combination therapy in Western medicine

Acknowledgement Current Group Members: Former Members: Computer-Aided Drug Design: CY Ung, XH Ma, XH Liu, Pankaj Kumar, F Zhu, X Liu, J Jia Protein Function, Interaction, Network: HL Zhang, CY Ung, XH Ma, F Zhu, WK Teo, Z Shi Databases and Servers: J Jia Medicinal Herb: CY Ung, Pankaj Kumar, Cao Jinyi(undergraduate students) Microarray and biomarkers: J Jia, ZQ Tang Former Members: PhD: ZW Cao (Prof SCBIT, Tongji U), ZL Ji (Assoc Prof Xiamen U), X Chen (Assoc Prof Zhejiang U), CW Yap (Assist Prof NUS), LY Han (Postdoc NIH), CJ Zheng (Postdoc NIH), HH Lin (Postdoc Harvard ), J Cui (Postdoc U Georgia), H Li (Postdoc Einstein College Med) Research Fellow/Assistant: ZR Li (Assoc Prof SiChuan U), Y Xue (Prof SiChuan U), W Liu (Assoc Prof DUT), D Mi (Assoc Prof DUT), CZ Cai (Prof ChongQing U), DG Zhi (Postdoc, Berkeley), MSc: Y.J. Guo (Postdoc NIH), L.Z. Sun (RA, U Tenn.), J. F. Wang (MSU), L.X. Yao (Columbia), S Ong (Washington U), H Zhou (local company), B Xie (local company) BSc: W.K. Yeo (IMCB, Novartis)