Chapter 1 Introductory Chapter : Future Prospect of Licorice , Popular Crude Drug and Food Sweetener

Drugs are classified into “over‐the‐counter (OTC) drugs” that are sold in drug stores and “medicinal (or ethical) drugs” that are prescribed by doctors [1] (Figure 1). “Herbal drug materials” and “Kampo (Japanese Traditional Medicines)” belong to OTC drugs, whereas new drugs and generics belong to the medicinal drugs. In contrast to Western medicines that recognize the drug as single compounds, Kampo medicines are a mixture of more than two components of herbal extracts. Pharmacopeia 17th edition accommodates a total of 323 herbal medicines (33 Kampo medicine + 290 herbal drug materials/formulations). Licorice is a crude drug prescribed in various herbal formulas in traditional Japanese and Chinese medicines and also used worldwide as a food natural sweetener. The origin of licorice was the root or stolon of Glycyrrhiza uralensis or G. glabra (Legminosae) [1]. Licorice con‐ tains three orders higher amounts of glycyrrhizin, as compared with other components [2].


Difference of Kampo medicine and Western medicine
To select the best Kampo medicine, the patient's condition will be first checked by the criteria of yin-yang and xu-shi categorization (activity and physical fitness) and then narrowed down by the life force, blood and colorless bodily fluids, (if necessary) followed by the five viscera theory and the pulse, tongue and belly (Figure 2). As compared with Western medicine, Kampo medicine is more empirical (rather than scientific), comprehensive (rather than analytical), global (rather than local) and personal (rather than general) and normalizes the patient's condition (rather than removing the cause of disease).
During the business sorting work in 2009, the then Japanese regime proposed the exemption of insurance against Kampo medicines, fomentations and mouth washes, claiming that Kampo medicine is evidence less and it can be obtained very easily by anybody. However, the patients, herbalists and medical personnel moved against this proposal by means of collecting approximately one million signatures and made the proposal withdrawn. Now, in Japan, approximately 150 Kampo medicines and 200 herbal drugs used as decoctions are covered by health insurance. Among the 900 physicians who worked in the core cancer treatment hospitals, 92.4% reported having prescribed Kampo medications [3]. Nationwide, random-sampled and population-weighted telephone survey demonstrated that respondents who had used at least one complementary and alternative medicine (CAM) therapy (76.0%) were greater than those who had used orthodox Western medicine (65.6%) and that the expenditure for CAM was nearly half that of orthodox Western medicine [4]. The most common CAM practice was Kampo, which corresponded to 96.1% of CAM-practicing doctors [5]. However, it still remains to be clarified why the Kampo medicines exert beneficial effects on our body.

Application of Kampo medicines
Kampo medicines have been used to improve the symptoms of various diseases (Table 1). Bakumondoto, Hochuekkito and Kiyoshihaiyu, which contains licorice, have been reported to improve the symptoms of chronic obstructive pulmonary disease (COPD) [6,7]. Daikenchuto (that contains hydroxy-α-sanshool and 6-shogaol as major ingredients) improved the intestinal motor paralysis and Crohn's disease, by increasing the RAMP (receptor activity-modifying membrane protein) 1, 2, 3, mobilizing the CGRP (calcitonin gene-related peptide) and AMD (adrenomedullin) and inhibiting the expression of pro-inflammatory cytokines (TNF-α, IFN-γ) [8]. Rikkunshito recovered the meal uptake by increasing the plasma des-acyl ghrelin level, suggesting its possible application to dyspepsia [9].
Old people experience the decline of body strength and vital function, the continuous languor, the loss of appetite and the fatigability. This kind of aging-associated characteristics cannot be remedied by Western medicines, but more easily alleviated by treating with co-agents such as Hochuekkito and Juzentaihoto. However, licorice present therein may induce hypokalemia (hypertension, edema, feeling of weakness, convulsions paralysis of the extremities, arrhythmia) [10]. Shosaikoto, which also contains licorice, is known to induce interstitial pneumonia (fever, dry cough, exertional dyspnea) [11]. The use of herbal medicines is increasing all over the world and when a patient with such risk factors is prescribed an herbal medicine containing licorice, careful follow-up is required. The patient's symptoms should be carefully monitored and if no improvement in symptoms is observed, continuous treatment should be avoided.

Application to oral diseases
Oral cares are important to maintain the normal oral functions and prevent oral diseases. Recent report suggests an association between oral health and the risk of lacunar infarction [12]. Tooth-blushing and myofunctional therapy stimulate the secretion of saliva [13,14]. Mouthrinsing with aqueous biocompatible 2-methacryloyloxyethyl phosphorylcholine (MPC)-polymer inhibited the increase in oral bacterial numbers, especially of S. mutans [15]. The inhibition of bacterial adherence and biofilm development may prevent the aspiration pneumonia and the periodontitis [16].

Future direction
We sometimes experience that purification of active ingredients leads to significant loss of the biological activity. Furthermore, the amount of ingredients is different from one batch to another depending on where they are harvested. Therefore, it is essential to reconstruct the best sets of active ingredients for the standardization of the contents. First step to accomplish this is to investigate the relationship between the biological activity of structurally related compounds and chemical descriptors, using quantitative structure-activity relationship (QSAR) analysis. Once the best 3D structure is predicted, such compounds should be quickly synthesized to confirm its biological activity. This process is repeated until the satisfactory results are obtained. The next step is to determine the best combination of ingredients (Figure 3).
The relative potency of ingredients may depend on the type of target cells. For example, licorice flavonoids showed potent anti-HSV activity, while they were inactive against HIV infection [29]. During isolation of active ingredients, some aggregations between ingredients may happen [30]. Accumulation and analysis of such data are crucial to manufacture the best Kampo medicine.
Using QASR analysis, we recently found that anti-HSV activity of 19 flavonoids including 10 licorice flavonoids correlated well with six chemical descriptors that represent polarizability (MATS5p, GATS5p), ionization potential (GATS5i), number of ring systems (NRS), atomic number (J_Dz(Z)) and mass (J_Dz(m) (p < 0.0001). This result suggests that the physicochemical properties, rather than the category of compound, are important factors in determining the anti-HSV activity [29]. The possibility that their target site may be common is under investigation.
It is expected that in the future, alternative therapy with Kampo medicines will be versioned up, in synchronization with the improvement in the personalized medicine based on the gene information.