Qi et al. Chin Med (2019) 14:57 https://doi.org/10.1186/s13020-019-0277-2 Chinese Medicine REVIEW Open Access Huang-Lian Jie-Du decoction: a review on phytochemical, pharmacological and pharmacokinetic investigations Yiyu Qi1,2,3, Qichun Zhang1,2,3,4* and Huaxu Zhu1,2,3* Abstract Huang-Lian Jie-Du decoction (HLJDD), a famous traditional Chinese prescription constituted by Rhizoma Coptidis, Radix Scutellariae, Cortex Phellodendri and Fructus Gradeniae, has notable characteristics of dissipating heat and detoxi- fcation, interfering with tumors, hepatic diseases, metabolic disorders, infammatory or allergic processes, cerebral diseases and microbial infections. Based on the wide clinical applications, accumulating investigations about HLJDD focused on several aspects: (1) chemical analysis to explore the underlying substrates responsible for the therapeutic efects; (2) further determination of pharmacological actions and the possible mechanisms of the whole prescrip- tion and of those representative ingredients to provide scientifc evidence for traditional clinical applications and to demonstrate the intriguing molecular targets for specifc pathological processes; (3) pharmacokinetic feature studies of single or all components of HLJDD to reveal the chemical basis and synergistic actions contributing to the pharma- cological and clinically therapeutic efects. In this review, we summarized the main achievements of phytochemical, pharmacological and pharmacokinetic profles of HLJDD and its herbal or pharmacologically active chemicals, as well as our understanding which further reveals the signifcance of HLJDD clinically. Keywords: Huang-Lian Jie-Du decoction, Traditional Chinese medicine, Phytochemical, Parmacological, Pharmacokinetic Background exuberant heat, which is transformed from the process Herbal formula, the most popular therapeutic approach of external pathogens entering the internal organs. Te of traditional Chinese medicine (TCM), was recorded in heat is in the form of an elevation in the body tempera- ancient medical literature with fxed herbal components, ture above normal or a subjective feeling of feverishness. defnite curative efects, and acceptable adverse efects [1]. Detoxicating indicates the measure to reduce the viru- Huang-Lian Jie-Du decoction (HLJDD) (Oren- lence and neutralize the toxicity of pathogens. Here, heat gedoku-to in Japanese and Hwangryun-Hae-Dok-Tang and poison are the forms of pathogens in Chinese medi- in Korean), a well-known classic TCM formula, was frst cines. HLJDD shows the ability to dispel the heat and described in Wang Tao’s treatise “Wai Tai Mi Yao” in the poison and relieve the associated syndromes. Tis ability Tang dynasty (752 A.D.). It has been a representative pre- is achieved by four common crude herbs, Rhizoma Cop- scription for heat-clearing and detoxicating. Heat-clear- tidis (RC) (Coptis chinensis Franch, Huang Lian), Radix ing is to ameliorate the interior pattern or syndromes of Scutellariae (RS) (Scutellaria baicalensis Georgi, Huang Qin), Cortex Phellodendri (CP) (Phellodendron amurense *Correspondence: [email protected]; [email protected] Rupr., Huang Bo), and Fructus Gradeniae (FG) (Gardenia 1 Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources jasminoides Ellis, Zhi Zi) in a ratio of 3:2:2:3. According Industrialization, Nanjing University of Chinese Medicine, Nanjing, China to the strict principle of “sovereign, minister, assistant Full list of author information is available at the end of the article © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the origi- nal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Qi et al. Chin Med (2019) 14:57 Page 2 of 22 and courier” [2], which was developed from “Huangdi’s has acquired the permission of Chinese State Food and Internal Classic” to enhance the efectiveness of Chinese Drug Administration to market (drug approval number medicinal herbs and to reduce toxics or side efects by Z20025356) [11]. Te appearance and processing technol- combining various kinds of herbs, RC is the sovereign ogy of Huang-Lian Jie-Du concentrated pill are shown in medicine with the action of purging the fre from the Fig. 1. In other Asian countries, HLJDD was approved for heart and middle energizer. RS acts as the ministerial palliative cares and atopic dermatitis treatment by Min- medicine, removing the heat from the lungs and elimi- istry of Health, Labour and Welfare of Japan and Korean nating the fre from the upper energizer. CP purges the Food and Drug Administration [12, 13]. Furthermore, fre from lower energizer as the assistant medicine. FG HLJDD has been manufactured as a powdered, freeze- purges the triple energizers and delivers the heat back to dried water extract by Tsumura Co, Ltd in Japan [9]. its origin as the courier medicine [3]. Te whole formula More and more clinical application cases have prompted is carefully designed and precise in formation. Xu et al. people to explore the potential pharmacological efects manufactured four HLJDD variants by leaving one herb and possible molecular mechanisms of HLJDD by mod- out each time and found that the integral formula exhib- ern pharmacology and molecular biotechnology. Modern ited the strongest therapeutic efects in the cecal ligation pharmacological studies indicate that HLJDD exhibits and puncture rats among the four variants [4]. Te pre- therapeutic actions in various pathological aspects, such cise and rigorous herbal combination is believed to be as hyperlipidemia [14], tumor [6, 15, 16], arthritis [17–19], advantageous over single reagent since that various com- sepsis [20–22], cardiac damage [23], liver injury [24, 25], ponents can hit multiple targets simultaneously and per- kidney disease [26], cerebral ischemia [27–29], type 2 dia- form synergistic therapeutic actions [5]. Moreover, due betes mellitus (T2DM) [30, 31], Alzheimer’s disease (AD) to the lack of TCM theories such as the theoretical mech- [32–34], fungal infection [35] and infammation [36]. In anisms of diseases, researches on decomposed recipes of the meantime, with the deepening of researches and the Chinese herbal compounds fnd it difcult to reveal the continuous development of technology, more and more complex interactions between couplet medicines. chemical compositions of HLJDD have been discovered. Based on the clinical practice and inheritance of nearly Te efects of drugs are based on their chemical com- a 1000 years as well as the integration of Chinese and position. Tis mainstream view holds that the diferent Western medicine, the clinical application of HLJDD has pharmacological efects and clinical applications of drugs gradually expanded from the diseases and symptoms of depend on the tissue distribution and concentration of TCM to the diseases of Western medicine, and its use has their active ingredients. Terefore, pharmacokinetics (PK) also expanded to other countries besides China. With the should be adopted to interpret the active substance basis remarkable therapeutic efects on removing excess heat of HLJDD. PK has the characteristics of holistic, compre- and fre toxins, HLJDD plays an important role in the reso- hensive and dynamic, which is similar to the holistic con- lution of delirium, internal heat-related mania, insomnia, cept and dialectical treatment of TCM. Although there irritability, dry mouth and throat, heat-induced blood are numerous researches with positive results on HLJDD, omitting, skin spots, and sore furuncle, according to Medi- most of them were only performed with a fraction of the cal Secretes of an Ofcial. Tis formula is also used to treat total compounds. Hence, it is necessary for us to sum up heat-pathogen-induced pyrostagnant rhinorrhagia, car- these past researches which are signifcant in guilding fur- buncle, and jaundice as summarized by Prescriptions for ther researches of HLJDD. In this review, we summarized Emerent Ref. [6]. At present, HLJDD has been widely used the phytochemical, pharmacological and pharmacokinetic in the clinical practices to treat infammation, hyperten- investigations that have been conducted in recent years. sion, gastrointestinal disorders, liver and cerebrovascular diseases [7]. In a clinical study, the addition of HLJDD to Phytochemical investigation of HLJDD yokukan-san (Japanese traditional herbal prescription) Te components of TCM formulas are complex, but not exhibited the same efcacy as aripiprazole (antipsychot- all of them have pharmacological activities. Terefore, it ics) in controlling aggressiveness of an Alzheimer’s type is of great signifcance to