*Edited by Thomas Heinbockel and Balwant Singh Gendeh*

Our sense of smell is of critical importance in our daily lives and it contributes to our personal wellbeing and safety as well as communication with others. However, it is only when disease or injury impairs its function that we appreciate the relevance of this sensory modality. During the past three decades, research of the olfactory sense has seen an ever-growing interest in this exciting field of study. This book provides the reader with an overview of the latest developments in sino-nasal and olfactory system disorders and focuses on the most important evidence-based developments in this area. This book addresses disorders, dysfunctions, diseases, and syndromes of the olfactory system ranging from molecular, cellular, and systems to cognitive and behavioral topics. Individual chapters center around recent advances in specific areas of chemosensory pathological conditions, while other chapters focus on technological developments to study the function and dysfunction of the olfactory pathways.

ISBN 978-1-83880-950-8

Sino-Nasal and Olfactory System Disorders

Published in London, UK © 2020 IntechOpen © Hank Grebe / iStock


The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine Clinics

*Ji Yeon Ryu, Jung Youn Park, Angela Dongmin Sung and Soo Hyun Sung*

### **Abstract**

A cross-sectional study has been conducted to detect the facts about the use of traditional herbal medicines (THMs) in South Korea. The questionnaire has been adopted from the 2017 National Survey for the usage of traditional Korean medicine (TKM) and consumption of THMs. A total number of 1346 participants have been involved in this study. Results showed that the non-decoction types of herbal medicines, which are mostly used for therapeutic purposes (89.0%), and the decoction types of herbal medicines were not only used for the purpose of treatment of diseases (62.5%) but also health improvement purposes (21.9%). Results presented that decoction types of THMs are used for musculoskeletal diseases (56.0%), digestive diseases (21.3%), and respiratory diseases (6.3%), whereas the non-decoction types of THMs are commonly used in musculoskeletal diseases (55.6%), respiratory diseases (20.5%), and digestive diseases (18.1%). Future studies are highly recommended to detect more details about the medical use of THMs in South Korea.

**Keywords:** medicinal herb, herbal medicine, traditional Korean medicine, traditional herbal medicine, medical use of herbal medicine

### **1. Introduction**

#### **1.1 Herbal medicine**

Traditional herbal medicines (THMs) are the most popular and preferred forms of traditional medicines (TMs) [1–3]. The World Health Organization (WHO) estimated that 80% of the population in developing countries rely on traditional herbs for their primary health care [4]. Compared with the developed countries, in the United States of America (USA), 19% of the population uses THMs for their treatment [5].

THMs have gained an increasing popularity in the last two decades in the industrialized countries [6–8]. The Europe market for THMs is estimated to be valued at \$5.18 billion in 2016 [9]. The American botanical council reported that the sales of THMs in the USA reached a total of \$7.45 billion in 2016 [10]. Thus, the global THM market is expected to grow and reach \$129.68 billion by 2023 [11].

TMs, such as traditional Chinese medicines (TCMs), Ayurveda, Kampo, traditional Korean medicines (TKMs), and Unani, have used herbal medicines for hundreds or even thousands of years worldwide [6, 12–15]. Before Western medicine was introduced, TMs, especially herbal medicines, were used for preventing and treating diseases in many nations [16]. The use of THMs is well established, and it is widely known to be safe and effective [17].

TM practitioners in Asian countries, such as China, South Korea, and Taiwan, practice TM treatment in medical clinics as doctors defined by law [18, 19]. South Korea has the highest percentage (15.26%) of TM doctors in medical clinics in East Asia, followed by China (12.63%) and the Taiwan region (9.69%) [18].

#### **1.2 Traditional herbal medicines in Korea**

Koreans have traditionally used herbs for treatment and prevention of diseases. In 1894, Je Ma Lee, a TKM doctor, established the theory of Sasang constitutional medicine (SCM), which is a unique TKM form [14, 20]. Based on the SCM theory, humans are categorized into four constitution types: Taeyangyin (Greater Yang type), Tae-eumin (Greater Yin type), Soyangyin (Lesser Yang type), and Soeumin (Lesser Yin type) [14, 20]. SCM has classified therapeutic THMs according to the four constitutions because THMs that respond to the characteristics of four constitutions are different [14, 20].

In South Korea, TKM is legally institutionalized and covered by national insurance [18]. Since 1987 herbal extracts based on good manufacturing practice (GMP) are covered by health insurance, but the decoction type of traditional herbal medicines (THMs) which is combined with two or more medicinal herbs is still not insured yet [18]. In addition, as a member of the WHO Pharmacovigilance, Korea is monitoring adverse drug reactions, including THMs [21].

#### *1.2.1 Medicinal use of herbs in traditional Korean medicine clinics*

The Korean Ministry of Food and Drug Safety (MFDS) introduced the Good Manufacturing Practice for herbs (hGMP) in 2012 and made it mandatory in 2015 [22]. Thus, medicinal herbs must be manufactured by the hGMP facilities that are licensed by the Korean MFDS [22].

Standards for commonly used herbal materials and preparations are included in the "Korean Pharmacopoeia (KP)" and "Korean Herbal Pharmacopoeia (KHP)" [23]. As of 2019, there are 601 kinds of herbal materials called medicinal herbs listed in the "Korean Pharmacopeia" and "Korean Herbal Pharmacopoeia" [24, 25]. The amount of hazardous substances (e.g., heavy metals, pesticides, aflatoxins, sulfur dioxide, and benzopyrene) in herbal materials is restricted by the "Regulations on Limits and Test Methods for Residues and Contaminants in Herbal Medicines" [26].

According to the Korea medical law, TKM clinics should utilize medicinal herbs certified by the Korean MFDS [22]. Since 2015, TKM clinics have been using THMs composed of medicinal herbs for treating diseases and promoting health.

THMs are the second most commonly used treatment in South Korea, mainly utilized as a combination of two or more medicinal herbs [27, 28]. In addition, they are used in various forms, such as a decoction, powder, tablet, soft extract, paste, and pill [27].

In previous studies related to Korean THMs, Fan [23] reviewed the role of MFDS in THM management: pre-market approval, post-market inspection, and management of the product quality system. Choi [29] reported that THMs are

**113**

**Table 1.**

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine…*

standardized, regulated, and quality controlled by MFDS guidelines such as KP and KHP. Park [18] investigated the TKM system and summarized development of TM system, policy, education system, medical insurance coverage, and herbal drug monitoring system. Yarnell [30] introduced herbal medicine market and modern-

To the best of our knowledge, this is the first study aims to *shed* some *light on* the overall status of THM usage in South Korea (TKM clinics). The objective of this research was to examine the medical use of THMs, particularly mixtures of THMs, in South Korea, a country with an extensive knowledge and experience in THM use

The cross-sectional study design has been used to address the research goals.

The population of the study included TKM doctors who worked at the TKM

All TKM doctors who used to prescribe THMs and provide their consent form

① Musculoskeletal disease ② Neurological disease ③ Cerebrovascular disease ④ Cardiovascular disease ⑤ Cancer ⑥ Endocrine disease ⑦ Digestive disease ⑧ Respiratory disease ⑨ Mental disease ⑩ Obstetrics and

① Musculoskeletal disease ② Neurological disease ③ Cerebrovascular disease ④ Cardiovascular disease ⑤ Cancer ⑥ Endocrine disease ⑦ Digestive disease ⑧ Respiratory disease ⑨ Mental disease ⑩ Obstetrics and

gynecology disease ⑪ Urogenital disease ⑫ Skin disease ⑬ Disease in eyes and ears ⑭ Others (2) Which disease prescribed non-decoction types of THMs the most when treating the disease?

gynecology disease ⑪ Urogenital disease ⑫ Skin disease ⑬ Disease in eyes and ears ⑭ Others

1.Which disease prescribed decoction types of THMs the most when treating the disease? 2.Which disease prescribed non-decoction types of THMs the most when treating the disease?

2. What is the prescription purpose rate when prescribing herbal medicines? (total 100%)

3. Which disease prescribed herbal medicine the most when treating the disease? (1) Which disease prescribed decoction types of THMs the most when treating the disease?

4. Which disease prescribed herbal medicine the most when treating the disease?

*DOI: http://dx.doi.org/10.5772/intechopen.88714*

ized decoction device of TKM hospitals.

for preventing and treating diseases.

clinics. Inclusion and exclusion criteria are as follows:

1. How many prescription cases are being used in the practice? (1) Decoction types of THMs: \_\_\_\_\_\_\_\_\_\_\_\_\_\_ cases (2) Non-decoction types of THMs: \_\_\_\_\_\_\_\_\_\_\_\_\_\_ cases

**2. Methods**

**2.1 Study design**

**2.2 Study population**

*2.2.1 Inclusion criteria*

have been included.

(1) Diseases treatment \_\_\_\_\_\_\_\_\_% (2) Health improvement \_\_\_\_\_\_\_\_\_%

(3) Beauty \_\_\_\_\_\_\_\_\_% (4) Traffic accident \_\_\_\_\_\_\_\_\_% (5) Others \_\_\_\_\_\_\_\_\_%

*TKM: Traditional Korean medicine THM: Traditional herbal medicine*

*Questionnaire on THM prescriptions of TKM doctors.*

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine… DOI: http://dx.doi.org/10.5772/intechopen.88714*

standardized, regulated, and quality controlled by MFDS guidelines such as KP and KHP. Park [18] investigated the TKM system and summarized development of TM system, policy, education system, medical insurance coverage, and herbal drug monitoring system. Yarnell [30] introduced herbal medicine market and modernized decoction device of TKM hospitals.

To the best of our knowledge, this is the first study aims to *shed* some *light on* the overall status of THM usage in South Korea (TKM clinics). The objective of this research was to examine the medical use of THMs, particularly mixtures of THMs, in South Korea, a country with an extensive knowledge and experience in THM use for preventing and treating diseases.

### **2. Methods**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

it is widely known to be safe and effective [17].

**1.2 Traditional herbal medicines in Korea**

monitoring adverse drug reactions, including THMs [21].

*1.2.1 Medicinal use of herbs in traditional Korean medicine clinics*

tutions are different [14, 20].

licensed by the Korean MFDS [22].

Medicines" [26].

and pill [27].

TMs, such as traditional Chinese medicines (TCMs), Ayurveda, Kampo, traditional Korean medicines (TKMs), and Unani, have used herbal medicines for hundreds or even thousands of years worldwide [6, 12–15]. Before Western medicine was introduced, TMs, especially herbal medicines, were used for preventing and treating diseases in many nations [16]. The use of THMs is well established, and

TM practitioners in Asian countries, such as China, South Korea, and Taiwan, practice TM treatment in medical clinics as doctors defined by law [18, 19]. South Korea has the highest percentage (15.26%) of TM doctors in medical clinics in East

Koreans have traditionally used herbs for treatment and prevention of diseases. In 1894, Je Ma Lee, a TKM doctor, established the theory of Sasang constitutional medicine (SCM), which is a unique TKM form [14, 20]. Based on the SCM theory, humans are categorized into four constitution types: Taeyangyin (Greater Yang type), Tae-eumin (Greater Yin type), Soyangyin (Lesser Yang type), and Soeumin (Lesser Yin type) [14, 20]. SCM has classified therapeutic THMs according to the four constitutions because THMs that respond to the characteristics of four consti-

In South Korea, TKM is legally institutionalized and covered by national insurance [18]. Since 1987 herbal extracts based on good manufacturing practice (GMP) are covered by health insurance, but the decoction type of traditional herbal medicines (THMs) which is combined with two or more medicinal herbs is still not insured yet [18]. In addition, as a member of the WHO Pharmacovigilance, Korea is

The Korean Ministry of Food and Drug Safety (MFDS) introduced the Good Manufacturing Practice for herbs (hGMP) in 2012 and made it mandatory in 2015 [22]. Thus, medicinal herbs must be manufactured by the hGMP facilities that are

Standards for commonly used herbal materials and preparations are included in the "Korean Pharmacopoeia (KP)" and "Korean Herbal Pharmacopoeia (KHP)" [23]. As of 2019, there are 601 kinds of herbal materials called medicinal herbs listed in the "Korean Pharmacopeia" and "Korean Herbal Pharmacopoeia" [24, 25]. The amount of hazardous substances (e.g., heavy metals, pesticides, aflatoxins, sulfur dioxide, and benzopyrene) in herbal materials is restricted by the "Regulations on Limits and Test Methods for Residues and Contaminants in Herbal

According to the Korea medical law, TKM clinics should utilize medicinal herbs certified by the Korean MFDS [22]. Since 2015, TKM clinics have been using THMs

THMs are the second most commonly used treatment in South Korea, mainly utilized as a combination of two or more medicinal herbs [27, 28]. In addition, they are used in various forms, such as a decoction, powder, tablet, soft extract, paste,

In previous studies related to Korean THMs, Fan [23] reviewed the role of MFDS in THM management: pre-market approval, post-market inspection, and management of the product quality system. Choi [29] reported that THMs are

composed of medicinal herbs for treating diseases and promoting health.

Asia, followed by China (12.63%) and the Taiwan region (9.69%) [18].

**112**

#### **2.1 Study design**

The cross-sectional study design has been used to address the research goals.

#### **2.2 Study population**

The population of the study included TKM doctors who worked at the TKM clinics. Inclusion and exclusion criteria are as follows:

#### *2.2.1 Inclusion criteria*

All TKM doctors who used to prescribe THMs and provide their consent form have been included.

2.Which disease prescribed non-decoction types of THMs the most when treating the disease?

*TKM: Traditional Korean medicine THM: Traditional herbal medicine*

#### **Table 1.**

*Questionnaire on THM prescriptions of TKM doctors.*

### **2.3 Sample selection**

The survey group of THM consumption included individuals who worked at TKM clinics, hospitals (TKM, long-term care, and general hospitals), traditional herbal medicine pharmacies, and community pharmacies. In the study, 1354 TKM doctors working in TKM clinics were included. Among them, 1346 respondents were selected for the final analysis, excluding 8 who said they do not prescribe THMs.

### **2.4 Questionnaire**

The questionnaire adopted and used in this study has been developed by the Korea Ministry of Health and Welfare (MHW), and the National Statistics of Korea reviewed and approved the questionnaire [27]. The 10-page structured questionnaire contained questions on the use, experience, treatment, management status, preference form, number of prescriptions, prescription purpose, frequently prescribed THMs for treatment, ways to purchase herbs, reasons for difficulty in purchase herbs, and plans to expand the use of THMs [27].

There are four sections used in the analysis: the number of THM prescriptions per year, prescription purpose when prescribing THMs, diseases treated with THMs, and THMs used for the disease [27]. The used questionnaire is shown in **Table 1**.

### **2.5 Data analysis**

Descriptive statistics (mean and proportions) were used to describe the characteristics of the representatives of TKM clinics in the sample. Cross-analysis was used to determine the relationships between the high frequency of disease and prescription. All data analyses were performed using SPSS software (version 21.0 for Windows; IBM cop., Armonk, United States).

### **3. Results**

### **3.1 Basic characteristics of participant TKM doctors**

A total number of 1346 TKM doctors participated in this study, 1204 were men (89.5%) and 142 were women (10.5%). Most of them (73.5%) aged between 41 and 60. Out of the 1346 clinics, 779 (57.9%) were located in the capital area, while the rest 567 (42.1%) were located in the noncapital area. Majority of the participants 882 (65.5%) were with less than 20 years of clinical experience, 417 (31.0%) were with 21–38 years of treatment experience, and 47 (3.5%) of them were with 39–56 years of experience, as shown in **Table 2**.

### **3.2 Types of THMs prescribed in TKM clinics**

### *3.2.1 Dispensing of decoction types of THMs*

Results showed that 1346 of the TKM doctors prescribed an average of 590.4 ± 1105.5 decoction types of THMs/year, and the prescription distribution was as follows: 378 (28.1%) had ≤200 cases, 428 (31.8%) had 201–400 cases, 256 (19.0%) had 401–600 cases, and 284 (21.1%) had ≥601 cases (**Table 3**).

**115**

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine…*

**Factors** *N* **(%)**

Male 1204 (89.5) Female 142 (10.5)

30–40 191 (14.2) 41–50 550 (40.8) 51–60 440 (32.7) ≥61 165 (12.3)

Capital area 779 (57.9) Chungcheong Province 122 (9.1) Gyeongsang Province 287 (21.3) Jeolla Province 158 (11.7)

≤20 882 (65.5) 21–38 417 (31.0) 39–56 47 (3.5)

**Prescription frequency** *N* **(%) Mean ± SD** ≤200 378 (28.1) 590.4 ± 1105.5

*DOI: http://dx.doi.org/10.5772/intechopen.88714*

Gender

Age (years)

Place of work

Clinical experience

**Table 2.**

**Table 3.**

*TKM: Traditional Korean medicine*

*THM: Traditional herbal medicine TKM: Traditional Korean medicine*

*Demographics of participating TKM doctors.*

*3.2.2 Dispensing of non-decoction types of THMs*

*Decoction types of THMs prescribed in TKM clinics.*

201–400 428 (31.8) 401–600 256 (19.0) ≥601 284 (21.1)

*3.3.1 Purpose of prescribed decoction types of THMs*

(59.4%) had ≥601 cases (**Table 4**).

**3.3 Purpose of prescribed THMs**

Out of the total 1346 respondents, 1070 TKM doctors prescribed non-decoction types of THMs. The average of prescription cases was 1775.9 ± 2349.1 non-decoction types of THMs/year, and prescription distribution was as follows: 222 (20.7%) had ≤200 cases, 120 (11.2%) had 201–400 cases, 92 (8.6%) had 401–600 cases, and 636

Decoction types of THMs have been prescribed in the TKM clinics for various reasons: disease treatment (62.5%), health promotion (21.9%), traffic accidents

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine… DOI: http://dx.doi.org/10.5772/intechopen.88714*

#### **Table 2.**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

purchase herbs, and plans to expand the use of THMs [27].

for Windows; IBM cop., Armonk, United States).

**3.1 Basic characteristics of participant TKM doctors**

39–56 years of experience, as shown in **Table 2**.

**3.2 Types of THMs prescribed in TKM clinics**

*3.2.1 Dispensing of decoction types of THMs*

The survey group of THM consumption included individuals who worked at TKM clinics, hospitals (TKM, long-term care, and general hospitals), traditional herbal medicine pharmacies, and community pharmacies. In the study, 1354 TKM doctors working in TKM clinics were included. Among them, 1346 respondents were selected for the final analysis, excluding 8 who said they do not prescribe

The questionnaire adopted and used in this study has been developed by the Korea Ministry of Health and Welfare (MHW), and the National Statistics of Korea reviewed and approved the questionnaire [27]. The 10-page structured questionnaire contained questions on the use, experience, treatment, management status, preference form, number of prescriptions, prescription purpose, frequently prescribed THMs for treatment, ways to purchase herbs, reasons for difficulty in

There are four sections used in the analysis: the number of THM prescriptions

Descriptive statistics (mean and proportions) were used to describe the characteristics of the representatives of TKM clinics in the sample. Cross-analysis was used to determine the relationships between the high frequency of disease and prescription. All data analyses were performed using SPSS software (version 21.0

A total number of 1346 TKM doctors participated in this study, 1204 were men (89.5%) and 142 were women (10.5%). Most of them (73.5%) aged between 41 and 60. Out of the 1346 clinics, 779 (57.9%) were located in the capital area, while the rest 567 (42.1%) were located in the noncapital area. Majority of the participants 882 (65.5%) were with less than 20 years of clinical experience, 417 (31.0%) were with 21–38 years of treatment experience, and 47 (3.5%) of them were with

Results showed that 1346 of the TKM doctors prescribed an average of 590.4 ± 1105.5 decoction types of THMs/year, and the prescription distribution was as follows: 378 (28.1%) had ≤200 cases, 428 (31.8%) had 201–400 cases, 256

(19.0%) had 401–600 cases, and 284 (21.1%) had ≥601 cases (**Table 3**).

per year, prescription purpose when prescribing THMs, diseases treated with THMs, and THMs used for the disease [27]. The used questionnaire is shown in

**2.3 Sample selection**

**2.4 Questionnaire**

THMs.

**Table 1**.

**3. Results**

**2.5 Data analysis**

**114**

*Demographics of participating TKM doctors.*

#### **Table 3.**

*Decoction types of THMs prescribed in TKM clinics.*

### *3.2.2 Dispensing of non-decoction types of THMs*

Out of the total 1346 respondents, 1070 TKM doctors prescribed non-decoction types of THMs. The average of prescription cases was 1775.9 ± 2349.1 non-decoction types of THMs/year, and prescription distribution was as follows: 222 (20.7%) had ≤200 cases, 120 (11.2%) had 201–400 cases, 92 (8.6%) had 401–600 cases, and 636 (59.4%) had ≥601 cases (**Table 4**).

### **3.3 Purpose of prescribed THMs**

#### *3.3.1 Purpose of prescribed decoction types of THMs*

Decoction types of THMs have been prescribed in the TKM clinics for various reasons: disease treatment (62.5%), health promotion (21.9%), traffic accidents

#### **Table 4.**

*Non-decoction types of THMs prescribed in TKM clinics.*

(8.6%), beauty (5.9%), and others (1.1%). It was found that most TKM clinics prescribe decoction of Korean medicine herbs for treatment of diseases, as shown in **Table 5**.

### *3.3.2 Purpose of prescribed non-decoction types of THMs*

Same as above, non-decoction types of THMs have been prescribed for several reasons: disease treatment (89.0%), health promotion (6.0%), car accidents (2.8%), beauty (1.4%), and others (0.9%), as shown in **Table 6**.

#### **3.4 Disease proportions and THMs prescribing pattern**

#### *3.4.1 Decoction types of THMs*

The decoction types of THMs were prescribed for patients suffering from musculoskeletal diseases (56.0%), digestive diseases (21.3%), respiratory diseases (6.3%), and obstetrics and gynecology disease (4.2%).

Results showed that decoction types of THMs frequently used for musculoskeletal diseases were Ojeoksan (22.5%), Bojungikgitang (10.3%), and Sipjeondaebotang (7.5%); for digestive diseases were Bojungikgitang (12.5%), Sipjeondaebotang (8.8%), and Ojeoksan (8.8%); for respiratory diseases were Bojungikgitang (9.9%), Socheongryongtang (9.9%), Sipjeondaebotang (8.6%), and Ojeoksan (8.6%); for obstetrics and gynecology diseases were Jogyeongjongogtang (11.1%), Ojeoksan (9.3%), and Bojungikgitang (7.4%); for skin diseases (*n* = 38) were Ojeoksan (10.5%) and Bojungikgitang (7.9%); for neurological diseases were Ojeoksan (16.7%), Galgeuntang (8.3%), and Yukmijihwangtang (8.3%); for cerebrovascular diseases were Ojeoksan (18.8%), Ganghwangyupungtang (12.5%), and Sipjeondaebotang (9.4%); for mental diseases were Gamiondamtang (11.5%), Kwibitang (7.7%), Bunsimgieum (7.7%), and Ojeoksan (7.7%); for cardiovascular diseases was Gamiondamtang (30.0%); for endocrine diseases was Sipjeondaebotang (25.0%); for urogenital diseases were Ssanghwatang (33.3%), Ojeoksan (33.3%), and Yukmijihwangtang (33.3%); for diseases in eyes and ears was Ojeoksan (100.0%); and for cancer was Banhasasimtang (100.0%), as shown in **Table 7**.

#### *3.4.2 Non-decoction types of THMs*

The non-decoction types of THMs were prescribed for patients suffering from musculoskeletal diseases (55.6%), respiratory diseases (20.5%), and digestive diseases (18.1%).

**117**

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine…*

**Prescription purpose Mean ± SD** Disease treatment 62.5 ± 24.7 Health improvement 21.9 ± 19.6 Traffic accidents 8.6 ± 12.5 Beauty 5.9 ± 12.5 Others 1.1 ± 4.6

**Purpose of prescription Mean ± SD** Disease treatment 89.0 ± 19.3 Health improvement 6.0 ± 13.3 Beauty 2.8 ± 6.5 Traffic accidents 1.4 ± 9.1 Others 0.9 ± 5.1

**Types of diseases Top 3 used THMs** *N* **(%)** Musculoskeletal disease (*n* = 716) Ojeoksan (五積散) 161 (22.5)

Digestive disease (*n* = 272) Bojungikgitang (補中益氣湯) 34 (12.5)

Obstetrics and gynecology disease (*n* = 54) Jogyeongjongogtang (調經種玉湯) 6 (11.1)

Skin disease (*n* = 38) Ojeoksan (五積散) 4 (10.5)

Neurological disease (*n* = 36) Ojeoksan (五積散) 6 (16.7)

Cerebrovascular disease (*n* = 32) Ojeoksan (五積散) 6 (18.8)

Respiratory disease (*n* = 81) Bojungikgitang (補中益氣湯)

Bojungikgitang (補中益氣湯) 74 (10.3) Sipjeondaebotang (十全大補湯) 54 (7.5)

Ojeoksan (五積散) 5 (9.3) Bojungikgitang (補中益氣湯) 4 (7.4)

Bojungikgitang (補中益氣湯) 3 (7.9)

Ganghwangyupungtang (羌活愈風湯) 4 (12.5) Sipjeondaebotang (十全大補湯) 3 (9.4)

24 (8.8)

8 (9.9)

7 (8.6)

2 (5.3)

3 (8.3)

Sipjeondaebotang (十全大補湯) Ojeoksan (五積散)

Socheongryongtang (小靑龍湯)

Sipjeondaebotang (十全大補湯) Ojeoksan (五積散)

Dangguisusan (當歸鬚散) Wolbitang (越婢湯) Hwangryunhaedoktang (黃蓮解毒湯)

Galgeuntang (葛根湯) Yukmijihwangtang (六味地黃湯)

*DOI: http://dx.doi.org/10.5772/intechopen.88714*

*THM: Traditional herbal medicine*

*THM: Traditional herbal medicine*

*Purpose of prescribed non-decoction types of THMs.*

*Purpose of prescribed decoction types of THMs.*

**Table 5.**

**Table 6.**

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine… DOI: http://dx.doi.org/10.5772/intechopen.88714*

#### **Table 5.**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

201–400 120 (11.2) 401–600 92 (8.6) ≥601 636 (59.4)

*Non-decoction types of THMs prescribed in TKM clinics.*

*3.3.2 Purpose of prescribed non-decoction types of THMs*

(8.6%), beauty (5.9%), and others (1.1%). It was found that most TKM clinics prescribe decoction of Korean medicine herbs for treatment of diseases, as shown in

**Prescription frequency** *N* **(%) Mean ± SD** ≤200 222 (20.7) 1775.9 ± 2349.1

reasons: disease treatment (89.0%), health promotion (6.0%), car accidents

The decoction types of THMs were prescribed for patients suffering from musculoskeletal diseases (56.0%), digestive diseases (21.3%), respiratory diseases

Results showed that decoction types of THMs frequently used for musculoskeletal diseases were Ojeoksan (22.5%), Bojungikgitang (10.3%), and Sipjeondaebotang (7.5%); for digestive diseases were Bojungikgitang (12.5%), Sipjeondaebotang (8.8%), and Ojeoksan (8.8%); for respiratory diseases were Bojungikgitang (9.9%), Socheongryongtang (9.9%), Sipjeondaebotang (8.6%), and Ojeoksan (8.6%); for obstetrics and gynecology diseases were Jogyeongjongogtang (11.1%), Ojeoksan (9.3%), and Bojungikgitang (7.4%); for skin diseases (*n* = 38) were Ojeoksan (10.5%) and Bojungikgitang (7.9%); for neurological diseases were Ojeoksan (16.7%), Galgeuntang (8.3%), and Yukmijihwangtang (8.3%); for cerebrovascular diseases were Ojeoksan (18.8%), Ganghwangyupungtang (12.5%), and Sipjeondaebotang (9.4%); for mental diseases were Gamiondamtang (11.5%), Kwibitang (7.7%), Bunsimgieum (7.7%), and Ojeoksan (7.7%); for cardiovascular diseases was Gamiondamtang (30.0%); for endocrine diseases was Sipjeondaebotang (25.0%); for urogenital diseases were Ssanghwatang (33.3%), Ojeoksan (33.3%), and Yukmijihwangtang (33.3%); for diseases in eyes and ears was Ojeoksan (100.0%); and for cancer was Banhasasimtang (100.0%), as shown

The non-decoction types of THMs were prescribed for patients suffering from musculoskeletal diseases (55.6%), respiratory diseases (20.5%), and digestive

(2.8%), beauty (1.4%), and others (0.9%), as shown in **Table 6**.

**3.4 Disease proportions and THMs prescribing pattern**

(6.3%), and obstetrics and gynecology disease (4.2%).

*3.4.1 Decoction types of THMs*

*THM: Traditional herbal medicine TKM: Traditional Korean medicine*

Same as above, non-decoction types of THMs have been prescribed for several

**116**

in **Table 7**.

diseases (18.1%).

*3.4.2 Non-decoction types of THMs*

**Table 5**.

**Table 4.**

*Purpose of prescribed decoction types of THMs.*

#### **Table 6.**

*Purpose of prescribed non-decoction types of THMs.*

#### **Table 7.**

*Disease proportions and pattern of prescribed decoction types of THMs.*

**119**

**Table 8.**

*THM: Traditional herbal medicine*

*Disease proportions and pattern of prescribed non-decoction types of THMs.*

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine…*

**Types of diseases Top 3 used THMs** *N* **(%)** Cerebrovascular disease (*n* = 11) Ojeoksan (五積散) 3 (27.3)

Cardiovascular disease (*n* = 9) Banhabackchulchunmatang (半夏白朮天麻湯) 2 (22.2)

Skin disease (*n* = 5) Gamisoyosan (加味逍遙散) 1 (20.0)

Mental disease (*n* = 5) Ojeoksan (五積散) 2 (40.0)

Urogenital disease (*n* = 3) Ojeoksan (五積散) 2 (66.7)

Endocrine disease (*n* = 2) Gumiganghwaltang (九味羌活湯) 1 (50.0)

Disease in eyes and ears (*n* = 1) Ojeoksan (五積散) 1 (100.0) Cancer (*n* = 1) Gunghatang (芎夏湯) 1 (100.0)

Yeongyopaedoksan (蓮翹敗毒散) 2 (18.2) Gunghatang (芎夏湯) 1 (9.1)

Gumiganghwaltang (九味羌活湯) 1 (11.1)

Ojeoksan (五積散) 2 (25.0) Gamisoyosan (加味逍遙散) 1 (12.5)

Gamisoyosan (加味逍遙散) 1 (20.0)

Pyeongwisan (平胃散) 1 (33.3)

Bojungikgi-tang (補中益氣湯) Socheongryongtang (小靑龍湯) Ijintang (二陳湯) Jaeumganghwatang (滋陰降火湯) Pyeongwisan (平胃散)

Gunghatang (芎夏湯) Bojungikgitang (補中益氣湯) Sosihotang (小柴胡湯) Ijungtang (理中湯) Ijintang (二陳湯) Pyeongwisan (平胃散)

Gunghatang (芎夏湯) Bulhwangeumjeonggisan (不換金正氣散) Samsoeum (蔘蘇飮) Ijintang (二陳湯) Pyeongwisan (平胃散)

> Gunghatang (芎夏湯) Ojeoksan (五積散) Insampaedoksan (人蔘敗毒散) Pyeongwisan (平胃散)

Gumiganghwaltang (九味羌活湯) Daecheongnyongtang (大靑龍湯)

Pyeongwisan (平胃散)

*DOI: http://dx.doi.org/10.5772/intechopen.88714*

Obstetrics and gynecology disease

(*n* = 8)

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine… DOI: http://dx.doi.org/10.5772/intechopen.88714*

#### **Table 8.**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

**Types of diseases Top 3 used THMs** *N* **(%)** Mental disease (*n* = 26) Gamiondamtang (加味溫膽湯) 3 (11.5)

Cardiovascular disease (*n* = 10) Gamiondamtang (加味溫膽湯) 3 (30.0)

Endocrine disease (*n* = 8) Sipjeondaebotang (十全大補湯) 2 (25.0)

Disease in eyes and ears (*n* = 1) Ojeoksan (五積散) 1 (100.0) Cancer (*n* = 1) Banhasasimtang (半夏瀉心湯) 1 (100.0)

**Types of diseases Top 3 used THMs** *N* **(%)** Musculoskeletal disease (*n* = 591) Ojeoksan (五積散) 216 (36.5)

Respiratory disease (*n* = 218) Ojeoksan (五積散) 35 (16.1)

Digestive disease (*n* = 192) Pyeongwisan (平胃散) 38 (19.8)

Neurological disease (*n* = 16) Socheongryongtang (小靑龍湯) 3 (18.8)

Urogenital disease (*n* = 3) Ssanghwatang (雙和湯)

*Disease proportions and pattern of prescribed decoction types of THMs.*

*THM: Traditional herbal medicine*

**Table 7.**

Kwibitang (歸脾湯) Bunsimgieum (分心氣飮) Ojeoksan (五積散)

Ganghwangyupungtang (羌活愈風湯) Bojungikgitang (補中益氣湯) Sipjeondaebotang (十全大補湯) Ojeoksan (五積散) Yukmijihwangtang (六味地黃湯) Insamnyangyeongtang (人蔘養榮湯) Galgeuntang (葛根湯)

Gwakhyangjunggisan (藿香正氣散) Banhasasimtang (半夏瀉心湯) Bangpungtongseongsan (防風通聖散) Yukgunjatang (六君子湯) Yukmijihwangtang (六味地黃湯) Palmultang (八物湯)

Ojeoksan (五積散) Yukmijihwangtang (六味地黃湯)

Gunghatang (芎夏湯) 92 (15.6) Ijintang (二陳湯) 45 (7.6)

Samsoeum (蔘蘇飮) 30 (13.8)

Ojeoksan (五積散) 37 (19.3)

Galgeuntang (葛根湯) 2 (12.5)

Hyangsapyungwisan (香砂平胃散) 21 (10.9)

Socheongryongtang (小靑龍湯)

Ojeoksan (五積散) Gumiganghwaltang (九味羌活湯) Samsoeum (蔘蘇飮) Pyeongwisan (平胃散)

2 (7.7)

1 (10.0)

1 (12.5)

1 (33.3)

**118**

*Disease proportions and pattern of prescribed non-decoction types of THMs.*

Results showed that decoction types of THMs frequently used for musculoskeletal diseases were Ojeoksan (36.5%), Gunghatang (15.6%), and Ijintang (7.6%); for respiratory diseases were Ojeoksan (16.1%), Samsoeum (13.8%), and Socheongryongtang (13.8%); for digestive diseases were Pyeongwisan (19.8%), Ojeoksan (19.3%), and Hyangsapyungwisan (10.9%); for neurological diseases was Socheongryongtang (18.8%); for cerebrovascular diseases were Ojeoksan (27.3%) and Yeongyopaedoksan (18.2%); for cardiovascular diseases was Banhabackchulchunmatang (22.2%); for obstetrics and gynecology diseases was Ojeoksan (25.0%); for skin diseases were Gamisoyosan (20.0%), Gunghatang (20.0%), Ojeoksan (20.0%), Insampaedoksan (20.0%), and Pyeongwisan (20.0%); for mental diseases was Ojeoksan (40.0%); for urogenital diseases were Ojeoksan (66.7%) and Pyeongwisan (33.3%); for endocrine diseases were Gumiganghwaltang (50.0%) and Pyeongwisan (50.0%); for diseases in eyes and ears was Ojeoksan (100.0%); and for cancer (*n* = 1) was Gunghatang (100.0%), as shown in **Table 8**.

### **4. Discussion**

This study investigated the use of THMs in TKM clinics in South Korea.

Results showed that average prescription cases of 590.4 ± 1105.5 decoction types of THMs and 1775.9 ± 2349.1 non-decoction types of THMs had been prescribed by doctors per year in the TKM clinics. According to the Korean national survey [27], the use of decoction types of THMs was 54.8%, and non-decoction types of THMs with the exception of insurance herbal extracts was 45.2% [27].

The reason for the preference for decoction types of THMs in South Korea is that the traditional way to boil herbs is familiar to the people, and it is possible to prescribe customized prescription according to the symptoms of the patients [31]. Non-decoction types of THMs such as granule, pill, tablet, soft extract, paste, and powder are convenient to store and carry because it is smaller in size than the decoction types of THMs [27]. In the case of the same prescription, the non-decoction types of THMs found to be cheaper than decoction types of THMs, so that patients may prefer non-decoction types of THMs for economic reason [27].

According to the 2017 national survey, Koreans responded that decoction types of THMs were too expensive (44.3%) and required health insurance coverage with a top priority (55.2%) [27]. This point will be solved soon since the Korean MHW has a plan to conduct a pilot program for insurance coverage expansion to the THMs in the latter half of 2019 [32].

The Korean MHW has a plan to conduct a pilot program for insurance coverage expansion to the THMs in the latter half of 2019 [32]. This point will make decoction types of THMs more affordable; this is mainly because the decoction type is found to be more potent and used in a wide range than the non-decoction type. As mentioned by Yoo and Son [33], unlike the non-decoction types of THMs, which were mostly used for therapeutic purposes (89.0%), the decoction types of THMs were not only used for the purpose of treatment of diseases (62.5%) but also for health improvement purposes (21.9%). THMs, especially decoction types of THMs, have played an important role in the prevention of diseases and health promotion in people in South Korea [33]. It is related to the viewpoint of TKM, which improves the vitality by correcting the imbalance of the human body, and the traditional way of boiling herbs reflects this [33].

In respiratory diseases, non-decoction types of THMs (20.5%) were more frequently prescribed than decoction types of THMs (6.3%). It is important to take the medication early during a cold, because of the need to combat the virus. It relieves

**121**

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine…*

symptoms such as cough, nasal congestion, and rhinorrhea [34]. The decoction types of THMs require about 1 day of preparation time because it takes time to boil the mixed herbs. In the case of non-decoction types of THMs, it is presumed that it is used in respiratory diseases such as cold, because it can be prepared in advance, or ready-made products (pharmaceutical products) can be prescribed immediately. Koreans suffer from digestive diseases due to the preference of spicy and salty Foods, and frequent use of antibiotics [35, 36]. In general, decoction types of THMs are used for treating digestive diseases [27]. The reason for using decoction types of THMs for treating digestive diseases is related to drug manufacturing method and patient's digestive condition [37]. As a result of that, decoction types of THMs seem

There are several limitations in this study. First, some data were limited or deficient due to their limited sources, and the information may be biased despite our efforts to obtain objective data. Since this study was particularly purposed to identify the prescription of THMs for each disease, there is a limitation to the

Second, we could not analyze the results of the use of all Korean THMs because the questionnaire was designed specifically for decoction types of THMs. In addition, we could not assess the utilization status of different THM forms (e.g., granule, pill, tablet, soft extract, paste, and powder) and their target diseases, except for the decoction types of THMs. The dosage has an important influence on the treatment [38]. In order to examine the whole use and status of dosage forms of THMs,

Third, we investigated the disease categories, not the specific diseases that THMs were prescribed for. In the 2020 national survey, the questionnaire needs to be cor-

Our study, based on a national survey of TKM doctors, presented the overall status of medical use of THMs in South Korea. However, the 2017 national survey was conducted separately for decoction and non-decoction types of THMs. Therefore, we could not assess the whole status of THM usage and therapeutic effects of each THM formulation. In future survey, we hope to be able to assess the details of medi-

This work was supported by the Policy Support Project for the Development of

Traditional Korean Medicine funded by the Ministry of Health and Welfare.

to be more preferable and suitable for digestive diseases [27, 37].

the questionnaire needs to be revised in a future survey.

rected so that the respondents can reply in regard to specific diseases.

*DOI: http://dx.doi.org/10.5772/intechopen.88714*

analysis by excluding "other" diseases.

**5. Conclusions**

cal use of THMs in South Korea.

**Acknowledgements**

**Conflict of interest**

**Abbreviations**

The authors declare no conflict of interest.

THM Traditional herbal medicine TM Traditional medicine

#### *The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine… DOI: http://dx.doi.org/10.5772/intechopen.88714*

symptoms such as cough, nasal congestion, and rhinorrhea [34]. The decoction types of THMs require about 1 day of preparation time because it takes time to boil the mixed herbs. In the case of non-decoction types of THMs, it is presumed that it is used in respiratory diseases such as cold, because it can be prepared in advance, or ready-made products (pharmaceutical products) can be prescribed immediately.

Koreans suffer from digestive diseases due to the preference of spicy and salty Foods, and frequent use of antibiotics [35, 36]. In general, decoction types of THMs are used for treating digestive diseases [27]. The reason for using decoction types of THMs for treating digestive diseases is related to drug manufacturing method and patient's digestive condition [37]. As a result of that, decoction types of THMs seem to be more preferable and suitable for digestive diseases [27, 37].

There are several limitations in this study. First, some data were limited or deficient due to their limited sources, and the information may be biased despite our efforts to obtain objective data. Since this study was particularly purposed to identify the prescription of THMs for each disease, there is a limitation to the analysis by excluding "other" diseases.

Second, we could not analyze the results of the use of all Korean THMs because the questionnaire was designed specifically for decoction types of THMs. In addition, we could not assess the utilization status of different THM forms (e.g., granule, pill, tablet, soft extract, paste, and powder) and their target diseases, except for the decoction types of THMs. The dosage has an important influence on the treatment [38]. In order to examine the whole use and status of dosage forms of THMs, the questionnaire needs to be revised in a future survey.

Third, we investigated the disease categories, not the specific diseases that THMs were prescribed for. In the 2020 national survey, the questionnaire needs to be corrected so that the respondents can reply in regard to specific diseases.

### **5. Conclusions**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

shown in **Table 8**.

**4. Discussion**

the latter half of 2019 [32].

of boiling herbs reflects this [33].

Results showed that decoction types of THMs frequently used for musculoskeletal diseases were Ojeoksan (36.5%), Gunghatang (15.6%), and Ijintang (7.6%); for respiratory diseases were Ojeoksan (16.1%), Samsoeum (13.8%), and Socheongryongtang (13.8%); for digestive diseases were Pyeongwisan (19.8%), Ojeoksan (19.3%), and Hyangsapyungwisan (10.9%); for neurological diseases was Socheongryongtang (18.8%); for cerebrovascular diseases were Ojeoksan (27.3%) and Yeongyopaedoksan (18.2%); for cardiovascular diseases was Banhabackchulchunmatang (22.2%); for obstetrics and gynecology diseases was Ojeoksan (25.0%); for skin diseases were Gamisoyosan (20.0%), Gunghatang

(20.0%), Ojeoksan (20.0%), Insampaedoksan (20.0%), and Pyeongwisan (20.0%); for mental diseases was Ojeoksan (40.0%); for urogenital diseases were Ojeoksan (66.7%) and Pyeongwisan (33.3%); for endocrine diseases were Gumiganghwaltang (50.0%) and Pyeongwisan (50.0%); for diseases in eyes and ears was Ojeoksan (100.0%); and for cancer (*n* = 1) was Gunghatang (100.0%), as

This study investigated the use of THMs in TKM clinics in South Korea.

with the exception of insurance herbal extracts was 45.2% [27].

may prefer non-decoction types of THMs for economic reason [27].

Results showed that average prescription cases of 590.4 ± 1105.5 decoction types of THMs and 1775.9 ± 2349.1 non-decoction types of THMs had been prescribed by doctors per year in the TKM clinics. According to the Korean national survey [27], the use of decoction types of THMs was 54.8%, and non-decoction types of THMs

The reason for the preference for decoction types of THMs in South Korea is that the traditional way to boil herbs is familiar to the people, and it is possible to prescribe customized prescription according to the symptoms of the patients [31]. Non-decoction types of THMs such as granule, pill, tablet, soft extract, paste, and powder are convenient to store and carry because it is smaller in size than the decoction types of THMs [27]. In the case of the same prescription, the non-decoction types of THMs found to be cheaper than decoction types of THMs, so that patients

According to the 2017 national survey, Koreans responded that decoction types of THMs were too expensive (44.3%) and required health insurance coverage with a top priority (55.2%) [27]. This point will be solved soon since the Korean MHW has a plan to conduct a pilot program for insurance coverage expansion to the THMs in

The Korean MHW has a plan to conduct a pilot program for insurance coverage expansion to the THMs in the latter half of 2019 [32]. This point will make decoction types of THMs more affordable; this is mainly because the decoction type is found to be more potent and used in a wide range than the non-decoction type. As mentioned by Yoo and Son [33], unlike the non-decoction types of THMs, which were mostly used for therapeutic purposes (89.0%), the decoction types of THMs were not only used for the purpose of treatment of diseases (62.5%) but also for health improvement purposes (21.9%). THMs, especially decoction types of THMs, have played an important role in the prevention of diseases and health promotion in people in South Korea [33]. It is related to the viewpoint of TKM, which improves the vitality by correcting the imbalance of the human body, and the traditional way

In respiratory diseases, non-decoction types of THMs (20.5%) were more frequently prescribed than decoction types of THMs (6.3%). It is important to take the medication early during a cold, because of the need to combat the virus. It relieves

**120**

Our study, based on a national survey of TKM doctors, presented the overall status of medical use of THMs in South Korea. However, the 2017 national survey was conducted separately for decoction and non-decoction types of THMs. Therefore, we could not assess the whole status of THM usage and therapeutic effects of each THM formulation. In future survey, we hope to be able to assess the details of medical use of THMs in South Korea.

### **Acknowledgements**

This work was supported by the Policy Support Project for the Development of Traditional Korean Medicine funded by the Ministry of Health and Welfare.

### **Conflict of interest**

The authors declare no conflict of interest.

#### **Abbreviations**

### **Author details**

Ji Yeon Ryu1 , Jung Youn Park<sup>2</sup> , Angela Dongmin Sung1 and Soo Hyun Sung1 \*

1 National Institute of Korean Medicine Development, Seoul, South Korea

2 Yuhan University, Bucheon, South Korea

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**123**

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine…*

2018

2018

2017;**115**:56-65

molecules21050559

10.1155/2014/739895

molecules181214670

10.1136/ewjm.175.2.125

& Alternative Medicine. 2017;**9**:317. DOI: 10.15406/ijcam.2017.09.00317

[9] Research and Markets. Europe Spice and Herb Extracts Market—Segmented by Type, Application, and Geography— Growth, Trends and Forecasts (2018- 2023). Dublin: Research and Markets;

[10] Smith T, Kawa K, Eckl V, Morton C, Stredney R. Herbal supplement sales in US increase 7.7% in 2016. Herbal Gram.

[11] Market Research Future. Herbal Medicine Market Research Report— Forecast to 2023. Maharashtra:

WantStats Research and Media Pvt. Ltd;

[12] Yuan H, Ma Q, Ye L, Piao G. The traditional medicine and modern medicine from natural products. Molecules. 2016;**21**:E559. DOI: 10.3390/

[13] Pan SY, Litscher G, Chan K, Yu ZL,

Chen HQ, Ko KM. Traditional medicines in the world: Where to go next? Evidence-based Complementary and Alternative Medicine. 2014;**2014**:739895. DOI:

[14] Kumar H, Song SY, More SV, Kang SM, Kim BW, Choi DK.

and herbal formulations for cognitive impairment. Molecules. 2013;**18**:14670-14693. DOI: 10.3390/

Traditional Korean East Asian medicine

[15] Vickers A, Zollman C, Lee R. Herbal medicine. The Western Journal of Medicine. 2001;**175**:125-128. DOI:

[16] Na-Bangchang K, Karbwang J. Traditional herbal medicine for the control of tropical diseases. Tropical

*DOI: http://dx.doi.org/10.5772/intechopen.88714*

[1] Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. National Health Statistics Reports. 2008;**10**:1-23. DOI: 10.1016/j.sigm.2004.07.003

[2] Thomas K, Coleman P. Use of complementary or alternative medicine in a general population in Great Britain. Results from the national omnibus survey. Journal of Public Health.

2004;**26**:152-167. DOI: 10.1093/pubmed/

[3] Eardley S, Bishop FL, Prescott P, Cardini F, Brinkhaus B, Santos-Rey K, et al. A systematic literature review of complementary and alternative medicine prevalence in EU. Forschende Komplementärmedizin. 2012;**19**:18-28.

[4] World Health Organization. Health of Indigenous Peoples. Geneva: World Health Organization; 2007. p. 1132

[5] Gardiner P, Graham R, Legedza ATR, Ahn AC, Eisenberg DM, Phillips RS. Factors associated with herbal therapy use by adults in the United States. Alternative Therapies in Health and

[6] Msomi NZ, Simelane MBC. Herbal Medicine. London: IntechOpen; 2018. pp. 215-227. DOI: 10.5772/

[7] Ekor M. The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety. Frontiers in Pharmacology.

[8] Wegener T. Patterns and trends in the use of herbal products, herbal medicine

International Journal of Complementary

and herbal medicinal products.

DOI: 10.1159/000342708

Medicine. 2007;**13**:22-29

2013;**4**:177. DOI: 10.3389/

intechopen.72816

fphar.2013.00177

**References**

fdh139

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine… DOI: http://dx.doi.org/10.5772/intechopen.88714*

### **References**

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

TKM Traditional Korean medicine MFDS Ministry of Food and Drug Safety MHW Ministry of Health and Welfare

**122**

**Author details**

, Jung Youn Park<sup>2</sup>

2 Yuhan University, Bucheon, South Korea

provided the original work is properly cited.

\*Address all correspondence to<EMAIL_ADDRESS>
, Angela Dongmin Sung1

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 National Institute of Korean Medicine Development, Seoul, South Korea

and Soo Hyun Sung1

\*

Ji Yeon Ryu1

[1] Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. National Health Statistics Reports. 2008;**10**:1-23. DOI: 10.1016/j.sigm.2004.07.003

[2] Thomas K, Coleman P. Use of complementary or alternative medicine in a general population in Great Britain. Results from the national omnibus survey. Journal of Public Health. 2004;**26**:152-167. DOI: 10.1093/pubmed/ fdh139

[3] Eardley S, Bishop FL, Prescott P, Cardini F, Brinkhaus B, Santos-Rey K, et al. A systematic literature review of complementary and alternative medicine prevalence in EU. Forschende Komplementärmedizin. 2012;**19**:18-28. DOI: 10.1159/000342708

[4] World Health Organization. Health of Indigenous Peoples. Geneva: World Health Organization; 2007. p. 1132

[5] Gardiner P, Graham R, Legedza ATR, Ahn AC, Eisenberg DM, Phillips RS. Factors associated with herbal therapy use by adults in the United States. Alternative Therapies in Health and Medicine. 2007;**13**:22-29

[6] Msomi NZ, Simelane MBC. Herbal Medicine. London: IntechOpen; 2018. pp. 215-227. DOI: 10.5772/ intechopen.72816

[7] Ekor M. The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety. Frontiers in Pharmacology. 2013;**4**:177. DOI: 10.3389/ fphar.2013.00177

[8] Wegener T. Patterns and trends in the use of herbal products, herbal medicine and herbal medicinal products. International Journal of Complementary & Alternative Medicine. 2017;**9**:317. DOI: 10.15406/ijcam.2017.09.00317

[9] Research and Markets. Europe Spice and Herb Extracts Market—Segmented by Type, Application, and Geography— Growth, Trends and Forecasts (2018- 2023). Dublin: Research and Markets; 2018

[10] Smith T, Kawa K, Eckl V, Morton C, Stredney R. Herbal supplement sales in US increase 7.7% in 2016. Herbal Gram. 2017;**115**:56-65

[11] Market Research Future. Herbal Medicine Market Research Report— Forecast to 2023. Maharashtra: WantStats Research and Media Pvt. Ltd; 2018

[12] Yuan H, Ma Q, Ye L, Piao G. The traditional medicine and modern medicine from natural products. Molecules. 2016;**21**:E559. DOI: 10.3390/ molecules21050559

[13] Pan SY, Litscher G, Chan K, Yu ZL, Chen HQ, Ko KM. Traditional medicines in the world: Where to go next? Evidence-based Complementary and Alternative Medicine. 2014;**2014**:739895. DOI: 10.1155/2014/739895

[14] Kumar H, Song SY, More SV, Kang SM, Kim BW, Choi DK. Traditional Korean East Asian medicine and herbal formulations for cognitive impairment. Molecules. 2013;**18**:14670-14693. DOI: 10.3390/ molecules181214670

[15] Vickers A, Zollman C, Lee R. Herbal medicine. The Western Journal of Medicine. 2001;**175**:125-128. DOI: 10.1136/ewjm.175.2.125

[16] Na-Bangchang K, Karbwang J. Traditional herbal medicine for the control of tropical diseases. Tropical Medicine and Health. 2013;**42**:3-13. DOI: 10.2149/tmh.2014-S01

[17] Li Y, Zhu X, Bensussan A, Li P, Moylan E, Delaney G, et al. Herbal medicine for hot flushed induced by endocrine therapy in women with breast cancer: A systematic review and meta-analysis. Evidence-based Complementary and Alternative Medicine. 2016;**2016**:1327251. DOI: 10.1155/2016/1327251

[18] Park HL, Lee HS, Shin BC, Liu JP, Shang Q, Yamashita H, et al. Traditional medicine in China, Korea, and Japan: A brief introduction and comparison. Evidence-based Complementary and Alternative Medicine. 2012;**2012**:429103. DOI: 10.1155/2012/429103

[19] Cheung F. TCM: Made in China. Nature. 2011;**480**:S82-S83. DOI: 10.1038/480S82a

[20] Kim JY, Pham DD. Sasang constitutional medicine as a holistic tailored medicine. Evidence-based Complementary and Alternative Medicine. 2009;**6**:11-19. DOI: 10.1093/ ecam/nep100

[21] Kang DY, Ahn KM, Kang HR, Cho SH. Past, present, and future of pharmacovigilance in Korea. Asia Pacific Allergy. 2017;**7**:173-178. DOI: 10.5415/apallergy.2<IP_ADDRESS>

[22] Korea Ministry of Food and Drug Safety. 2016 Ministry of Food and Drug Safety White Paper. Osang: Ministry of Food and Drug Safety; 2015

[23] Fan TP, Deal G, Koo HL, Rees D, Sun H, Chen S, et al. Future development of global regulations of Chinese herbal products. Journal of Ethnopharmacology. 2012;**140**:568-586. DOI: 10.1016/j.jep.2012.02.029

[24] National Law Information Center. Korean Pharmacopoeia [Internet]. 2019. Available from: http://www.

law.go.kr/LSW/admRulInfoP. do?admRulSeq=2100000176764

[25] National Law Information Center. Korean Herbal Pharmacopoeia [Internet]. 2019. Available from: http:// www.law.go.kr/LSW/admRulInfoP. do?admRulSeq=2100000176201

[26] Lee YJ, Park CG. A Study on the Collection of Oriental Herbal Medicine and the Production of Standardized Items. Osong: Ministry of Food and Drug Safety; 2015. Available from: http://www.ndsl.kr/ndsl/commons/util/ ndslOriginalView.do?dbt=TRKO&cn= TRKO201600010697&rn=&url=&page Code=PG18

[27] Ministry of Health and Welfare, National Development Institute of Korean Medicine, Gallup Korea. 2017 Years National Survey for Usage and Consumption of Traditional Herbal Medicine. Seoul: National Development Institute of Korean Medicine; 2018. Available from: http://www.koms. or.kr/board/researchReport/view. do?post\_no=43&menu\_no=21

[28] Kwon SH, Heo SH, Kim DS, Kang SH, Woo JM. Changes in trust and the use of Korean medicine in South Korea: A comparison of surveys in 2011 and 2014. BMC Complementary and Alternative Medicine. 2017;**17**:463. DOI: 10.1186/s12906-017-1969-8

[29] Choi DW, Kim JH, Cho SY, Kim DH, Chang SY. Regulation and quality control of herbal drugs in Korea. Toxicology. 2002;**181-182**:581-586. DOI: 10.1016/S0300-483X(02)00487-0

[30] Yarnell E, Abascal K. Herbal medicine in Korea "alternative" is mainstream. Alternative and Complementary Therapies. 2004;**10**:161-166. DOI: 10.1089/1076280041138298

[31] Pusan National University. A Study on Establishment of

**125**

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine…*

*DOI: http://dx.doi.org/10.5772/intechopen.88714*

Foundation for Strengthening the Health Insurance Coverage of Herbal Medicine(Decoction). Wonju: National

Health Insurance Service; 2018. Available from: http://www.alio.go.kr/

Welfare. National Health Insurance Comprehensive Plan (2019-2023). Sejong: Ministry of Health and Welfare; 2019. Available from: http:// www.mohw.go.kr/react/al/sal0301vw. jsp?PAR\_MENU\_ID=04&MENU\_ ID=0403&CONT\_SEQ=349272

[33] Yoo SR, Son CG. Survey analysis of 101 subjects using herbal medicine with deer antler. Journal of Korean Medicine. 2008;**29**:41-46. Available from: https://www.jkom.org/journal/

[34] Simasek M, Blandino DA. Treatment of the common cold. American Family

[35] Jung HK, Jang BH, Kim YH, Park JY, Park SY, Nam MH, et al. Health care costs of digestive diseases in Korea. The Korean Journal of Gastroenterology. 2011;**58**:323-331. DOI: 10.4166/

[36] Kim BN. Overview of antibiotic use in Korea. Infection & Chemotherapy. 2012;**44**:250-262. DOI: 10.3947/

Standardization of Drug Processing in Traditional Korean Medicine. Sejong: Ministry of Health and Welfare; 2001

[38] Yang XY, Shi GX, Li QQ, Zhang ZH, Wu A, Liu CZ. Characterization of Deqi sensation and acupuncture effect. Evidence-based Complementary and Alternative Medicine. 2013;**2013**:319734.

view.php?number=3465

Physician. 2007;**75**:515-520

kjg.2<IP_ADDRESS>3

ic.2<IP_ADDRESS>

[37] Kim HC. Study on the

DOI: 10.1155/2013/319734

popSusiViewB1040.do

[32] Ministry of Health and

*The Utilization of Traditional Herbal Medicine for Treatment in Traditional Korean Medicine… DOI: http://dx.doi.org/10.5772/intechopen.88714*

Foundation for Strengthening the Health Insurance Coverage of Herbal Medicine(Decoction). Wonju: National Health Insurance Service; 2018. Available from: http://www.alio.go.kr/ popSusiViewB1040.do

*Medicinal Plants - Use in Prevention and Treatment of Diseases*

law.go.kr/LSW/admRulInfoP. do?admRulSeq=2100000176764

[25] National Law Information Center. Korean Herbal Pharmacopoeia

[Internet]. 2019. Available from: http:// www.law.go.kr/LSW/admRulInfoP. do?admRulSeq=2100000176201

[26] Lee YJ, Park CG. A Study on the Collection of Oriental Herbal Medicine and the Production of Standardized Items. Osong: Ministry of Food and Drug Safety; 2015. Available from: http://www.ndsl.kr/ndsl/commons/util/ ndslOriginalView.do?dbt=TRKO&cn= TRKO201600010697&rn=&url=&page

[27] Ministry of Health and Welfare, National Development Institute of Korean Medicine, Gallup Korea. 2017 Years National Survey for Usage and Consumption of Traditional Herbal Medicine. Seoul: National Development Institute of Korean Medicine; 2018. Available from: http://www.koms. or.kr/board/researchReport/view. do?post\_no=43&menu\_no=21

[28] Kwon SH, Heo SH, Kim DS,

10.1186/s12906-017-1969-8

[30] Yarnell E, Abascal K. Herbal medicine in Korea "alternative" is mainstream. Alternative and Complementary Therapies. 2004;**10**:161-166. DOI: 10.1089/1076280041138298

[31] Pusan National University. A Study on Establishment of

Kang SH, Woo JM. Changes in trust and the use of Korean medicine in South Korea: A comparison of surveys in 2011 and 2014. BMC Complementary and Alternative Medicine. 2017;**17**:463. DOI:

[29] Choi DW, Kim JH, Cho SY, Kim DH, Chang SY. Regulation and quality control of herbal drugs in Korea. Toxicology. 2002;**181-182**:581-586. DOI: 10.1016/S0300-483X(02)00487-0

Code=PG18

Medicine and Health. 2013;**42**:3-13.

[17] Li Y, Zhu X, Bensussan A, Li P, Moylan E, Delaney G, et al. Herbal medicine for hot flushed induced by endocrine therapy in women with breast cancer: A systematic review and meta-analysis. Evidence-based Complementary and Alternative Medicine. 2016;**2016**:1327251. DOI:

[18] Park HL, Lee HS, Shin BC, Liu JP, Shang Q, Yamashita H, et al. Traditional medicine in China, Korea, and Japan: A brief introduction and comparison. Evidence-based Complementary and Alternative Medicine. 2012;**2012**:429103.

[19] Cheung F. TCM: Made in China. Nature. 2011;**480**:S82-S83. DOI:

[20] Kim JY, Pham DD. Sasang constitutional medicine as a holistic tailored medicine. Evidence-based Complementary and Alternative Medicine. 2009;**6**:11-19. DOI: 10.1093/

[21] Kang DY, Ahn KM, Kang HR, Cho SH. Past, present, and future of pharmacovigilance in Korea. Asia Pacific Allergy. 2017;**7**:173-178. DOI: 10.5415/apallergy.2<IP_ADDRESS>

[22] Korea Ministry of Food and Drug Safety. 2016 Ministry of Food and Drug Safety White Paper. Osang: Ministry of

[23] Fan TP, Deal G, Koo HL, Rees D,

development of global regulations of Chinese herbal products. Journal of Ethnopharmacology. 2012;**140**:568-586.

[24] National Law Information Center. Korean Pharmacopoeia [Internet]. 2019. Available from: http://www.

Food and Drug Safety; 2015

Sun H, Chen S, et al. Future

DOI: 10.1016/j.jep.2012.02.029

DOI: 10.2149/tmh.2014-S01

10.1155/2016/1327251

DOI: 10.1155/2012/429103

10.1038/480S82a

ecam/nep100

**124**

[32] Ministry of Health and Welfare. National Health Insurance Comprehensive Plan (2019-2023). Sejong: Ministry of Health and Welfare; 2019. Available from: http:// www.mohw.go.kr/react/al/sal0301vw. jsp?PAR\_MENU\_ID=04&MENU\_ ID=0403&CONT\_SEQ=349272

[33] Yoo SR, Son CG. Survey analysis of 101 subjects using herbal medicine with deer antler. Journal of Korean Medicine. 2008;**29**:41-46. Available from: https://www.jkom.org/journal/ view.php?number=3465

[34] Simasek M, Blandino DA. Treatment of the common cold. American Family Physician. 2007;**75**:515-520

[35] Jung HK, Jang BH, Kim YH, Park JY, Park SY, Nam MH, et al. Health care costs of digestive diseases in Korea. The Korean Journal of Gastroenterology. 2011;**58**:323-331. DOI: 10.4166/ kjg.2<IP_ADDRESS>3

[36] Kim BN. Overview of antibiotic use in Korea. Infection & Chemotherapy. 2012;**44**:250-262. DOI: 10.3947/ ic.2<IP_ADDRESS>

[37] Kim HC. Study on the Standardization of Drug Processing in Traditional Korean Medicine. Sejong: Ministry of Health and Welfare; 2001

[38] Yang XY, Shi GX, Li QQ, Zhang ZH, Wu A, Liu CZ. Characterization of Deqi sensation and acupuncture effect. Evidence-based Complementary and Alternative Medicine. 2013;**2013**:319734. DOI: 10.1155/2013/319734

**127**

**Chapter 8**

R.M.Sm

**Abstract**

health.

Zingiberaceae

**1. Introduction**

plan future studies.

Pharmacological Activities and

*Etlingera pavieana* (Pierre ex Gagnep) R.M.Sm. (Zingiberaceae family) is commonly found in Southeast Asia. The rhizome of the plant is used as a spice and folk medicine in southeastern Thailand and Cambodia. The extracts, essential oil, and compounds from *E. pavieana* were found to possess a variety of pharmacological activities like anti-inflammatory, antioxidant, antiatherogenic, and antimicrobial effects. Furthermore, phytochemical studies have reported the presence of various chemical constituents, the main being phenylpropanoids such as *trans*-4-methoxycinnamaldehyde (MCD) and 4-methoxycinnamyl *p*-coumarate (MCC). Therefore, *E. pavieana* seems to be a potential source of natural products for treatment of various diseases and promotion of good

**Keywords:** *Etlingera pavieana*, pharmacological activity, phytochemical constituents,

Plant-based nutraceuticals or functional foods have gained attention due to their

health promotion and safety in comparison to synthetic food ingredients [1, 2]. Presently, worldwide researchers have focus on scientific evaluation of medicinal plants to detect their pharmacological activities. Zingiberaceae family is distributed worldwide and comprises approximately 52 genera and 1587 species [3]. It is about 300 species belonging to 26 genera found in Thailand [4]. The plants in this family are the natural sources for traditional medicine, foods, spice, and other ethnobotanical uses [4]. *Etlingera pavieana* (Pierre ex Gagnep) R.M.Sm. is a member of the Zingiberaceae family and a medicinal plant of southeastern Thailand [5]. Several *in vitro* and *in vivo* pharmacological experiments and phytochemistry studies of *E. pavieana* have been reported. This chapter has presented comprehensive information about morphological characteristics, traditional uses, pharmacology activities, and phytochemical constituents of *E. pavieana*, which provide the data to

Phytochemicals of *Etlingera*

*pavieana* (Pierre ex Gagnep)

*Klaokwan Srisook and Ekaruth Srisook*

### **Chapter 8**


**1.5.2 Imaging**

The echocardiography or abdominal ultrasound is the most commonly applied diagnostic method to confirm clinical suspicion of TE or to screen babies for clinically silent disease. (Roy et al, 2002) comparing echocardiographic investigations with venograms and reported a sensitivity of 21-43% and specificities ranging from 76-94%. This study concluded that venography is required to accurately diagnose UVC related TE in neonates.

#### **1.5.3 Laboratory**

Initial laboratory work-up in a neonate in whom thrombosis is suspected should include a full blood count as well as a coagulation screening with determination of prothrombin time, thrombin time and activated partial thromboplastin time.

 Conversely, negative Ddimers are relatively accurate in ruling out thrombosis in most patients, including neonates.

In almost all neonates, platelet numbers decrease after birth. However, a sudden and severe drop in platelet counts should alert the intensivist. The thrombocytopenia remains one of the most sensistive indicators for micro- (in the setting of sepsis) or macro-circulatory thrombosis (Veldman, 2008).

Also it has been recommended that infants who are diagnosed with clinically significant VTE should undergo testing for inherited and acquired thrombophilic traits. (Beardsley, 2007).

#### **1.6 Management**

There are no published randomized controlled trials (RCTs) and no large cohort studies that report on the outcomes of different treatment modalities in the management of neonatal Pathophysiology and Clinical Aspects of 40 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

the first week of life and it is likely that a number of these :events initially develop antenatally. (Monagle et al., 2008; Veldman, 2008). Presenting symptoms and clinical findings are different in neonates and older patients and are influenced by the extent and rapidity of thrombus formation. Neonates usually have a flank mass, hematuria, proteinuria, thrombocytopenia and nonfunction of the involved kidney. (Nathan et al., 2003). Approximately 25% of cases are bilateral and 52-60% are reported to have evidence of extension into the inferior vena caval (IVC). (Monagle et al., 2008). Overall survival following neonatal RVT is generally favorable. Four small cohort studies with variable follow-up reported 81-100% of neonates survived. Clinical sequelae included chronic renal

Thombosis of the inferior vena cava can present with signs resembling obstruction of the renal vein (hematuria and retroperitoneal mass); however, these will occur bilaterally when the inferior vena cava is affected. In addition, the lower limbs may be edematous and, if blood flow is susbstantially impared, the child may be in respiratory distress and may have

Signs of impared liver function, hepatomegaly and splenomegaly should raise the suspicion of portal vein thrombosis (PVT); however, only about 10% of children with PVT develop

The echocardiography or abdominal ultrasound is the most commonly applied diagnostic method to confirm clinical suspicion of TE or to screen babies for clinically silent disease. (Roy et al, 2002) comparing echocardiographic investigations with venograms and reported a sensitivity of 21-43% and specificities ranging from 76-94%.  Conversely, negative Ddimers are relatively accurate in ruling out thrombosis in most patients, including neonates. In almost all neonates, platelet numbers decrease after birth. However, a sudden and severe drop in platelet counts should alert the intensivist. The thrombocytopenia remains one of the most sensistive indicators for micro- (in the setting of sepsis) or macro-circulatory

Also it has been recommended that infants who are diagnosed with clinically significant VTE should undergo testing for inherited and acquired thrombophilic traits. (Beardsley, 2007).

There are no published randomized controlled trials (RCTs) and no large cohort studies that report on the outcomes of different treatment modalities in the management of neonatal

venography is required to accurately diagnose UVC related TE in neonates.

thrombin time and activated partial thromboplastin time.

impairment and hypertension. (Monagle et al., 2008)

high blood pressure. (Veldman, 2008)

acute clinical symptoms (Veldman, 2008).

**1.5.2 Imaging**

**1.5.3 Laboratory**

thrombosis (Veldman, 2008).

**1.6 Management**

VTE. Valuable and comprehensive evidence-based clinical practice guidelines have been developed by the American College of Chest Physicians (ACCP) on antithrombotic therapy in neonates and children (Monagle et al, 2008). Their recommendations are necessarily based on extrapolation of principles of therapy from adult guidelines, limited clinical information from registries, individual case studies and knowledge of current common clinical practice.

The following is the summary of the recommendations of the ACCP 2008 on Anticoagulation and Trombolytic Therapy for neonates with VTE: We suggest that central venous lines (CVL) or UVCs associated with confirmed thrombosis be removed, if possible, after 3 to 5 days of anticoagulation (Grade 2C).It is a weak recommendation. We suggest either initial anticoagulation, or supportive care with radiologic monitoring (Grade 2C); however, we recommend subsequent anticoagulation if extension of the thrombosis occurs during supportive care (Grade 1B). It is a strong recommendation. We suggest anticoagulation should be with either of the following: (1) LMWH given bid and adjusted to achieve an anti-FXa level of 0.5–1.0 U/mL: or (2) UFH for 3 to 5 days adjusted to achieve an anti-FXa of 0.35 to 0.7 U/mL or a corresponding APTT range, followed by LMWH. We suggest a total duration of anticoagulation of between 6 weeks and 3 months (Grade 2C). We suggest that if either a CVL or a UVC is still in place on completion of therapeutic anticoagulation, a prophylactic dose of LMWH be given to prevent recurrent VTE until such time as the CVL or UVC is removed (Grade 2C). We recommend against thrombolytic therapy for neonatal VTE unless major vessel occlusion is causing critical compromise of organs or limbs (Grade 1B). We suggest that if thrombolysis is required the clinician use tPA and supplement with plasminogen fresh frozen plasma) prior to commencing therapy (Grade 2C). For neonates or children with unilateral renal vein thrombosis (RVT) in the absence of renal impairment or extension into the inferior vena cava, we suggest supportive care with monitoring of the RVT for extension or anticoagulation with UFH/LMWH or LMWH in therapeutic doses; we suggest continuation for 3 months (Grade 2C). For unilateral RVT that extends into the inferior vena cava, we suggest anticoagulation with UFH/LMWH or LMWH for 3 months (Grade 2C). For bilateral RVT with various degrees of renal failure, we suggest anticoagulation with UFH and initial thrombolytic therapy with TPA, followed by anticoagulation with UFH/LMWH (Grade 2C).Remark: LMWH therapy requires careful monitoring in the presence of significant renal impairment.


**2. Framework of** *Cancer Evo-Dev*

The synergetic effects of genetic predisposition and environmental factors contribute to the imbalance of the immune system, resulting in the activation and maintenance of non-resolving inflammation, that functions as the microenvironment for the *Cancer Evo-Dev*. Activated inflammatory signaling pathways can trans-activate the expression of nucleic acid editing enzymes, such as the human apolipoprotein B mRNA-editing enzyme catalytic polypeptides (APOBECs) family, thus promoting viral and somatic mutations. Viral mutants facilitate the malignant transformation of normal cells. Most mutant cells are eliminated under the selective pressure of the inflammatory microenvironment, while a small proportion of mutated cells survive. These survived mutant clones evolve to tumor-initiating cells by altering the original cell signal patterns, promoting epithelial-mesenchymal transition (EMT), or reprogramming the metabolic patterns, etc. Some established cancer markers, such as α-fetoprotein (AFP) and carcinoembryonic antigen (CEA), are usually expressed at the embryonic stage, silenced after birth, and re-expressed in cancer patients. These pieces of evidence imply that the process of *Cancer Evo-Dev* can be characterized as "backward evolution" and "retro-differentiation".

*Hepatitis B Virus (HBV) - Induced Hepatocarcinogenesis, a Founding Framework of Cancer… DOI: http://dx.doi.org/10.5772/intechopen.99838*

## **3. Chronic inflammation is indispensable for HBV-HCC evolution**

As a defense mechanism responding to exogenous infection and injury, acute inflammation is beneficial to humans. However, chronic inflammation, also termed non-resolving inflammation is essential for carcinogenesis. The weak immunity, HBV mutation, and HBV genotype contribute to the chronicity of inflammation. During the development of HBV-induced HCC evolution, non-resolving inflammation is evident. By relieving hepatic inflammation, antiviral therapy can significantly lower the risks of HCC occurrence and postoperative recurrence [15, 16]. Interestingly, the risk of HCC is still significantly higher in the complete responder group of oral-administered antiviral therapy, compared with the subjects with inactive chronic hepatitis B (CHB) [17]. The active inflammation on chronic infection background also indicated postoperative recurrence [18, 19]. The close association between chronic inflammation and the risk of HCC can be explained from the perspective of *Cancer Evo-Dev*. Cancer evolution is based on two conditions: the continuous acquisition of somatic mutations and natural selection acting on the resultant phenotypic diversity [20]. These two conditions were fulfilled by HBV infection-induced chronic inflammation, that induces mutagenic factors such as APOBECs and provides selection pressure.

#### **3.1 Chronicity of HBV infection and hepatic inflammation**

The oncogenic capability of HBV is closely related to its capacity to induce and maintain chronic inflammation. The chronicity of HBV infection is dependent on 3 aspects: infection occasion, HBV genotypes, and genetic predisposition of the key immune molecules. HBV infection in early childhood is generally believed to be one of the major causes of chronic HBV infection in adulthood. The perinatal infection occurred in 8.7% and 84.2% of infants born to hepatitis B e-antigen (HBeAg) positive mothers who did and did not receive immunoprophylaxis, respectively. The infection rates were 0.4% and 6.7% for infants born to HBeAg-negative mothers and HBeAg-positive mothers, respectively. Furthermore, the chronicity of HBV infection acquired perinatally was 28.2% and 64.5% for infants born to HBeAgnegative mothers and HBeAg-positive mothers, respectively [21]. This vulnerability of infants may due to the immaturity of the immune system. Although perinatal HBV infection is an important cause of chronic HBV infection, the chronic transformation of acute hepatitis B is the predominant cause of chronic HBV infection in adults. In China, 8.5% of patients with acute hepatitis B develop into chronic HBV infection 6 months after acute infection [22]. The HBV genotype and genetic predisposition of immune molecules contribute to this transformation.

According to sequence divergence of 8% in the whole viral genome, HBV can be classified into eight genotypes (A to H) [23]. Variant genotypes are distributed unevenly around the world, and the predominant one in mainland China is genotype C (68.3%), followed by genotype B (25.5%) [24]. Under selection pressure from the inflammatory microenvironment, the fates of different HBV genotypes are distinct. Genotype B HBV is prone to causing acute infection, whereas genotype C HBV is associated with chronic infection and contributes independently to the development of HCC [22, 25, 26].

The genetic predisposition of immune molecules is the third major cause of chronic HBV infection. The single nucleotide polymorphisms (SNPs) in the loci encoding human leukocyte antigen class II (HLA-II) are significantly associated with vaccine response as well as the risk of CHB, HBV-induced liver cirrhosis, and HBV-HCC [27–32]. Interestingly, the allele frequencies of SNPs affecting the expression of HLA-DP and HLA-DQ are variant in different human races. The polymorphic genotypes that are more frequent in the Han Chinese than in European populations are significantly associated with the increased risk of chronicity of HBV infection as well as the immune selection of HBV mutations related to end-stage liver diseases [21]. These data suggest that the Han Chinese are inherently more apt to progress into chronic infection once exposed to HBV infection than Europeans. This might be partly responsible for the fact that chronic HBV infection, HBV-induced liver cirrhosis, and HBV-HCC are more frequent in Chinese than in European populations. The genetic polymorphisms of HLA-II may facilitate the progression of CHB into HCC through predisposing immune imbalance and maintain HBV infection. Due to the chronicity of inflammation, the mutagenic force that serves as antiviral immunity is prone to injury the human genome, thus induce *Cancer Evo-Dev.*

#### **3.2 HBV promote the generation of inflammatory mutations**

The APOBECs are powerful endogenous mutagenic factors that can catalyze irreversible cytidine and deoxycytidine deamination to convert bases from cytosine to uracil, creating a cytosine-to-uracil mismatch in minus-strand and reversetranscript G-to-A (guanosine-to-adenosine) transitions in plus-stranded DNA. APOBEC3s play important roles in the innate immune system [7]. Mutagenesis mediated by APOBEC3s can increase the viral mutation load to a level that exceeds the threshold for viral viability. Accordingly, APOBEC3s can similarly increase the number of somatic mutations to a threshold that exceeds the host's repair ability and starts the *Cancer Evo-Dev*. Three mechanisms prevent the induction of somatic mutations by the APOBEC3s family. First, APOBEC3s rarely express in normal tissues, and short-term activation of APOBEC3s is beneficial for eliminating pathogens. Second, the cytidine deaminase activity of APOBEC3s is applied almost exclusively to single-stranded nucleotides, in which mutagenesis is 200–300 times more efficient than it is in double-stranded DNA. Third, the uracil-induced mutagenesis of APOBEC3s is counteracted by uracil–DNA glycosylase (UNG), that plays an important role in the base-excision repair mechanism [7, 33]. However, genetic susceptibility, viral mutations, and an unbalanced immune system interact with each other to prevent the absolute elimination of HBV, resulting in chronic inflammation accompanied with APOBEC3s expression. During the HBV-induced malignant transformation, inflammatory signaling pathways including interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) and tumor necrosis factor α (TNF-α)/ nuclear factor kappa B (NF-κB) are activated, which up-regulate the expression of APOBEC3s [7]. Among the members of APOBEC3s, APOBEC3B was identified as the major subtype responsible for the APOBECsignature somatic mutations in multiple cancers [34]. The mutagenic effect of inflammatory factors on the HBV genome depends on the degree of the damage to the APOBEC3B–UNG balance. IL-6 can increase the expression of APOBEC3B and decrease the expression of UNG. The functional polymorphisms located in the *APOBEC3B* promoter (rs2267401-G) and *UNG* enhancer (rs3890995-C) predispose the IL-6 induced APOBEC3B-UNG imbalance and increase the risk of HCC [35].

#### **3.3 HBV affects the selection pressure of the inflammatory microenvironment**

In an inflammatory microenvironment, continuous necrosis and proliferation can help to accumulate somatic mutations, and tumor-initiating cell clones with strong viability are selected. HBV replication directly reflects the selective stress and influences the evolution of HCC. It has been revealed by various studies that HBV DNA load increases the risk of HCC in CHB patients [25, 36]. A high level of HBV DNA load either in serum or liver tissue predicts poor postoperative prognosis *Hepatitis B Virus (HBV) - Induced Hepatocarcinogenesis, a Founding Framework of Cancer… DOI: http://dx.doi.org/10.5772/intechopen.99838*

in HCC [37]. Meanwhile, HBV in turn affecting the selective pressure of the inflammatory microenvironment. The innate immune and adaptive immune against HBV are both participate in the selection of malignant cells. During the chronic infection of HBV, APOBEC3B is stimulated and reduces the occupancy of H3K27me3 on the promoter of CC-chemokine ligand 2 (CCL2). By this mechanism, APOBEC3B upregulates the CCL2 to enhance the recruitment of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). TAMs and MDSCs suppress the function of CD8<sup>+</sup> T cells and are associated with a poor prognosis of HCC [38]. HBV can transmit into natural killer (NK) cells through exosomes, thereby inducing the disfunction of NK cells, which promotes the HCC evolution [39, 40]. HBV also induced the exhaustion of HBV-specific CD8+ T cells through impairing the mitochondrial functions, including electron transport, membrane transport, and the transcription of mitochondrial DNA [41]. The glucose metabolism of T cells is reprogramed by HBV, which leads to increased lactate production and decreased migration of T cells [42]. During chronic infection, HBV promotes the recruitment of regulatory T cells (Tregs) through activating the growth factor-beta (TGF-β)/ miR-34a/ CC-motif chemokine ligand 22 (CCL22) axis [43]. The increased Tregs suppress HCC antigen-specific immune responses and HBV antigen-specific immune response at the same time [44]. Thus, the HBV that survives the survival competition can in turn affect the inflammatory microenvironment.

### **4. Roles of HBV mutation during the process of HCC evolution**

During HBV-induced hepatocarcinogenesis, viruses also experience the process of evolution. Viral evolution serves as a valuable clue to investigate the mechanism underlying the HBV-HCC [45]. The generation and accumulation of HBV mutations abide by the Darwinian model: mutation-selection–adaptation. In the inflammatory microenvironment, most HBV mutants are eliminated by the antiviral immune response. Only a tiny fraction of mutant viruses that facilitate the regeneration of hepatocytes can survive and gradually develop into the HCC-promoting clones.

#### **4.1 The generation of HBV mutation**

Two major mechanisms are responsible for the generation of HBV mutation. The first pattern is the replicative errors. During viral replication, the partially doublestranded HBV DNA is generated from an intermediate RNA through the reverse transcription activity of the viral polymerase. Due to lack of proofreading capacity, the HBV genome has a higher mutation rate than other DNA viruses, which is in the range of 1.5 × 10−5 to 5 × 10−5 nucleotide substitutions per site per year, which can increase after HBeAg seroconversion [46]. The second viral mutation pattern is induced by host cytidine deaminases [7]. The APOBEC family has a dual effect on HBV: reduction of HBV and induction of HBV mutations [47]. The expression levels of APOBEC3s are positively correlated with the quasispecies complexity of HBV [48]. The genetic polymorphisms predisposing the IL-6 induced APOBEC3B-UNG imbalance significantly promote the generation of HCC related HBV mutations [35]. Although many HBV genome fragments, including the Enhancer II (EnhII) / basal core promoter (BCP)/ precore region and the S region, are generally sensitive to editing by members of APOBEC3 [49–53], the sequence encoding HBV X protein (HBx) is more vulnerable. APOBEC3 prefers the HBx region as its editing target and generates carboxylic acid–terminal truncated HBx (Ct-HBx). Although most HBV mutations are random, the directional evolution of HBV occurs under the selective pressures of chronic inflammation. In the immune tolerance phase of

chronic infection, the immune pressure is weak, and most of the individual viruses are wild-type. Immune pressure increases with the progression of chronic inflammation, which facilitates the gradual occurrence of viral mutations, especially in HBeAg-negative individuals [54, 55]. HCC-related HBV mutations are selected by the immune microenvironment before the occurrence of HCC and can be used as predictive markers. Single-nucleotide polymorphisms of the inflammatory signaling pathway genes, including STAT3, NF-κB, HLA-DP, and HLA-DQ have been demonstrated to maintain the chronic infection and to facilitate the selection of HCC-related HBV mutations that contribute to the risk of liver cancer [32, 56, 57]. However, those viral mutants that affect the pre-cancer hepatocytes are less infectious to normal liver cells, which leads to a process of "dead-end" evolution.

#### **4.2 The "dead-end" evolution of HBV**

Hepatitis B virus belongs to the Hepadnaviridae family and is evolutionarily conservative in the long-term evolution of species [58]. However, the evolution of the HBV genome is evident in infected individuals during chronic infection. Previous research by our group established the wild-type HBV sequences of HBV subgenotypes B2 and C2, based on the whole HBV genome sequenced using 1000 asymptomatic carriers of the HBV surface antigen from community-based epidemiologic surveys. Based on the wild-type HBV sequences, HCC-related mutations and their development patterns were subsequently identified. We also observed that HBV mutations posing a significant HCC risk are located mainly within the BCP and preS regions [59–61]. During the HBV-induced carcinogenic "trilogy" (chronic hepatitis, liver cirrhosis, HCC), the species and frequencies of those mutations often accumulate consecutively and can be used to predict the occurrence and development of liver cirrhosis and HCC [15, 32, 56, 62]. Retrospective and prospective cohort studies have both identified a combination of HBV mutations (C1653T, A1762T/G1764A, and T1753V) that have significant predictive value [32, 63, 64]. Among them, the A1762T/G1764A mutation usually appears in the early stage; other mutations, including T1753V, C1653T, preS deletion, are evident only in a late stage of the evolution [65]. Reaction to chronic HBV infection (characterized by the immune response–induced hepatocyte injury and release of transaminase) is usually accompanied by HBeAg seroconversion and an increase in HBV mutations, indicating the selective effect of immune cells on viral mutants. The deficiency of CD8+ T cell epitopes is one of the main features of HBV mutations. The mutant virus with a low density of CD8+ T cells epitopes can evade immune eradication [66, 67]. The proportion of mutant preS/S region is higher in patients with occult HBV infection than in CHB patients [67, 68]. Therefore, CD+ 8 T cell is essential for the immune selection of HCC-related HBV mutants.

Hepatitis B virus acquired during infancy or early childhood, or at the early infection stage in adults, is usually the wild type [15, 32, 56]. During the chronic inflammation process, especially after an HBeAg shift from HBeAg-positive to HBeAg-negative, mutant HBV subgroups gradually increase. Although the HCCrelated HBV mutants are present in fetal cord blood, neonatal infection is usually caused by wild-type HBV rather than by mutant subgroups. At 1–15 years in HBV-infected children, the frequencies of HCC-related mutations increase with increasing age. However, compared with their mothers, who have been exposed to chronic infection for at least about 25 years, the children have fewer HCC-related HBV mutations [65]. The foregoing results are based on analyses of serum HBV. In individuals with chronic HBV infection, most all HBV is synthesized in hepatocytes and released into the circulation at a pace of up to 1011 viral particles daily [69]. The immune microenvironment of circulation, tumor tissue, and tumor-adjacent

*Hepatitis B Virus (HBV) - Induced Hepatocarcinogenesis, a Founding Framework of Cancer… DOI: http://dx.doi.org/10.5772/intechopen.99838*

liver tissue are all necessary for the HBV evolution [48]. Interestingly, HBV evolves more advanced in the sera than in the tumors of HCC patients. The evolutionary similarity between the sera-derived HBV strains and adjacent tissue-derived ones is significantly stronger than that between sera-derived HBV strains and tumorderived ones [48]. Although tumor-adjacent tissues are pathologically categorized as "normal," they are typical precancerous lesions and have already entered the middle stage of the cancer evolutionary process. The HCCs that relapse more than 2 years after resection are considered to be recurrent HCC and not a result of the initial HCC cell diffusion into remnant liver tissue [18]. The species and frequencies of certain HBV mutations in adjacent tissues are distinct in the different populations. Together with immune markers and expression levels of inflammatory genes, they can therefore be used to predict prognosis in HCC patients receiving curative surgery. For example, HBV mutations in the EnhII/BCP/PreC region, such as A1762T/G1764A, can serve as predictive markers for survival and recurrence [18], indicating that HBV evolution in adjacent tissues continues until the patient dies. Antiviral therapy can block HBV evolution in adjacent tissues by easing inflammation and notably prolongs survival in HCC patients [15].

Taken together, the Hepadnaviridae family members are highly conservative across species [65]. Wild-type HBV has the advantage of infecting hepatocytes, facilitating viral spread from one individual to another, and contributing to the maintenance of its viral species. The HCC-related mutants can cause malignant transformation but have lost the advantage of person-to-person infection. Those mutants are therefore usually eliminated at the death of the carriers, which is termed "dead-end" evolution.

#### **4.3 High-risk HBV mutations promote the** *Cancer Evo-Dev*

During hepatocarcinogenesis, high-risk HBV mutations are selected by the immune microenvironment. Because of overlapping open reading frames, HBV mutations altering the genes necessary for viral replication are unlikely transferred into their progeny viruses. Natural selection ensures only the fittest survive to pass their genes on to the next generation. Thus, the random natural mutations are therefore constrained to special regions of the HBV genome, especially in the fragment of HBx gene and large envelope protein gene fragment (preS1/preS2/S). These HBV mutations that survive the selective pressure can promote the evolution of HCC, which is supported by many pieces of evidence from epidemiology studies and mechanism studies.

Previous longitudinal studies, especially cohort studies, support that combo HBV mutations including A1762T/G1764A, C1653T, and T1753V in HBx gene in sera can predict the occurrence of HCC [64, 70]. The mutations in the HBV preS fragment, including the preS deletion, accumulate during the process of inflammation-HCC transformation, which is significantly associated with increased risk of HCC [62, 71, 72]. Epidemiological evidence identified the interaction effect between HBV mutations and genetic polymorphisms of immune molecules. For the population with the infection of genotype B HBV, the SNPs of HLA-DP, including rs3077 (T allele), rs2281388 (T allele), rs3135021 (G allele), and rs9277535 (G allele) can promote the HBV persistence and are associated with a higher prevalence of HBV mutation increasing HCC risk. Moreover, the effects of HBV mutations on HCC risk are selectively significant in subjects with these HLA-DP SNPs that promote HBV persistence [32]. For the population with the infection of genotype C HBV, the HLA-DQ SNP, rs9275319 (GG genotype), is significantly associated with an increased prevalence of preS1 start codon mutation, an HCCrisk mutation [63]. The SNPs of STAT3 SNPs appear to promote HCC evolution

in the host with HBV mutations [56]. The interaction effect of STAT3 rs1053004 with T1674C/G and the interaction effect of STAT3 rs4796793 with preS2 start codon mutation are both significantly associated with an increased HCC risk. The T allele of rs223406 impairs the promoter activity of NFKBIA, a key molecule of the NF-κB signaling pathway. The interaction of rs223406 T allele with A1762T/ G1764A is significantly associated with an increased risk of HCC [57]. The genetic polymorphisms predisposing the imbalance of APOBEC3B and UNG increase the risk of HCC through through facilitate the generation of APOBEC3B-signature HBV mutations. Furthermore, the positive rate of APOBEC-signature HBV mutations consecutively increased from asymptomatic HBsAg carrier (ASC) to HCC in HBV-infected subjects [35]. This line of evidence highlights the important role of HBV mutation in the process of HCC evolution.

Experimental evidence also confirms that HBV mutation can endow the hepatocytes with a survival advantage. The HBx with A1762T/G1764A–based combo mutations can upregulate the expression of S-phase kinase-associated protein 2 (SKP2) by activating E2F1, a transcription factor, downregulate cell cycle inhibitors, and facilitate the ubiquitin-mediated proteasomal degradation of p21, thereby enhancing the proliferation of HCC cells [73, 74]. Moreover, HBx with A1762T/G1764A–based combo mutations also enhance the cell migration through activating the Wnt/βcatenin signaling pathway [75]. Ct-HBx mutation can promote cell metastasis and invasiveness by activating the C-Jun/matrix metalloproteinase protein 10 signaling pathway [15, 76]. The HBx gene with K130M/V131I mutations enhances HCC evolution by activating the arachidonic acid metabolism and the hypoxia-inducible factor-1a [77, 78]. Besides the mutated HBx gene, the mutated preS1, preS2, and S regions also notably facilitate carcinogenesis [18, 61]. The preS2 region with F141L can significantly downregulate the expression of the p53 pathway and upregulate the expression of cyclin-dependent kinase 4 and cyclin A, thereby promoting proliferation and colony-forming rates [79]. The accumulation of mutant envelop protein in the endoplasmic reticulum (ER) leads to the activation of ER stress signaling pathway [80]. ER stress promotes HCC evolution through generating reactive oxygen species (ROS), inducing oxidative DNA damage, and ultimately increasing genomic instability [81, 82]. Although HBV mutation plays important role in hepatocarcinogenesis, somatic mutation of the human genome is the direct cause of cell evolution.


**3.1.5 Pulmonary malformations (n=3)**

The pH and the pO2, and likewise the bicarbonate concentration of the UVB, are lower in a fetus presenting a major cystic adenomatoid malformation of the left lung, type 2, with the start of hydrops and hydramnios.

In the case of type 1 adenomatoid malformation, the biological balance is normal.

The third clinical case (pulmonary hypoplasia with amniotic band syndrome) is associated with acidosis (pH of 7.20) with hypercapnia (pCO2 of 7.22 kPa); at birth, the infant presented generalised cyanosis and acute respiratory distress.