Kampo (Traditional Japanese Herbal) Formulae for Treatment of Stomatitis and Oral Mucositis

Stomatitis is occasionally multiple, recurrent, and refractory. Currently, mucositis induced by chemotherapy and radiation therapy in patients with cancer has become a significant clinical problem. Effective treatments have not been established and the treatment of numerous cases remains a challenge for physicians. Traditional Japanese herbal medicines termed Kampo formulae (i.e., Hangeshashinto, Orengedokuto, Inchinkoto, Orento, Byakkokaninjinto, Juzentaihoto, Hochuekkito, and Shosaikoto) are used for treating various types of stomatitis and mucositis. Its use has been based on the Kampo medical theories—empirical rules established over thousands of years. However, recently, clinical and basic research studies investigating these formulae have been conducted to obtain scientific evidence. Clinical studies investigating efficacies of Shosaikoto and Orento for the treatment of cryptogenic stomatitis and acute aphthous stomatitis and those investigating the effects of Hangeshashinto, Orengedokuto, and Juzentaihoto on chemotherapy- or radiotherapy-induced mucositis have been conducted. The Kampo formulae comprise several crude drugs, whose mechanisms of action are gradually being clarified. Most of these drugs that are used for the treatment of stomatitis possess anti-inflammatory, analgesic, and antioxidative properties. In this review, we introduce the clinical applications and summarize the available evidence on the Kampo formulae for the treatment of stomatitis and oral mucositis.


Introduction
Stomatitis is a sore and often recurrent inflammatory condition of the oral mucosa, characterized by various symptoms such as the presence of vesicles, erosions, aphthae, and ulcerations. Stomatitis is caused by various factors such as viral, fungal, and bacterial infections, allergic reactions, loose-fitting dental prosthetics, and systemic diseases. Occasionally, stomatitis is multiple, recurrent, and refractory. Currently, mucositis induced by chemotherapy and radiation therapy in patients with cancer has become a significant clinical problem [1]. The pain associated with mucositis often affects a patient's functional status and quality of life.
Kampo formula, a traditional Japanese herbal medicine, has its root in ancient Chinese medicine, and the antecedent form of medicine was introduced to Japan between the 5th and 6th century. It was developed into an individual form of medicine adapting the constitutions of the Japanese people. Kampo formulae have been reported to be effective for the treatment of stomatitis and mucositis [2,3]. The objective of this review was to introduce the clinical applications and summarize the available evidence on the Kampo formulae for the treatment of these two conditions.
In addition, Cinnamomi Cortex, Scutellariae Radix, Glycyrrhizae Radix, Astragali Radix, Coptidis Rhizoma, and Phellodendri Cortex inhibit several bacterial infections. Moreover, Cinnamomi Cortex, Scutellariae Radix, and Anemarrhenae Rhizome exert antifungal effects. Furthermore, Scutellariae Radix and Glycyrrhizae Radix have been shown to inhibit viral infections [8].  [4]. The trends in the use of the Kampo formulae at hospitals and faculties of oral surgery of dental/medical universities in Japan were surveyed. A total of 55 hospitals participated in the survey and rated the frequency of Kampo formulae use via a scale from 0 to 3. This graphic summarizes the results of rating.  [4]. The trends in the use of the Kampo formulae at hospitals and faculties of oral surgery of dental/medical universities in Japan were surveyed. A total of 55 hospitals participated in the survey and rated the frequency of Kampo formulae use via a scale from 0 to 3. This graphic summarizes the results of rating. Regarding the antioxidative effects of these formulae, only herbs that Dragland, et al. [7] assessed are described. In addition, Cinnamomi Cortex, Scutellariae Radix, Glycyrrhizae Radix, Astragali Radix, Coptidis Rhizoma, and Phellodendri Cortex inhibit several bacterial infections. Moreover, Cinnamomi Cortex, Scutellariae Radix, and Anemarrhenae Rhizome exert antifungal effects. Furthermore, Scutellariae Radix and Glycyrrhizae Radix have been shown to inhibit viral infections [8].
In Kampo medicine, the approach to the treatment of stomatitis differs depending on the nature of the symptoms (i.e., acute or chronic). Furthermore, the most appropriate treatment is determined according to the presence of oral and general symptoms. The effectiveness of each Kampo formula according to the pathognomonic symptoms of patients is shown in Table 2. In the acute type, formulae exerting cooling effects (i.e., HST, ORT, OGT, BNT, SST, and ICT) are used. In the chronic type, formulae such as HIS, JTT, and HET are used [3]. The JTT and HET supply energy in patients with symptoms of tiredness, fatigue, or lowered/suppressed immunity [9,10]. The oral cavity is a part of the digestive system; thus, digestive symptoms are important selection criteria for the Kampo formulae. The HST, ORT, OGT, SST, ICT, HIS, JTT, and HET are applied for the treatment of gastrointestinal diseases and symptoms by the national health insurance in Japan.

Clinical Studies
Use of the Kampo formulae has been based on the Kampo medical theories-empirical rules established over thousands of years. In recent years, clinical and basic research studies investigating the Kampo formulae have been performed to obtain scientific evidence.
For our literature review, PubMed (National Center for Biotechnology Information, Bethesda, MD, USA) and ICHUSHI (Japan Medical Abstracts Society, Tokyo, Japan) were used to identify relevant evidence. Reports of clinical studies (randomized controlled trials, case-control studies, and case series studies) identified through this search are summarized in Table 3.
Ogino, et al. [11] showed that the efficacy of SSK administered to patients with cryptogenic stomatitis accompanied by pain (n = 10) was 80%. SSK was particularly effective against symptoms such as erosion and redness. Oka [12] investigated the effect of ORT in patients with acute aphthous stomatitis (n = 39). The numbers of days until the resolution of pain (2.6 days) and complete cure (6.3 days) were reduced in patients treated with ORT compared with those observed in patients treated with a steroid ointment (pain: 7.5 days; cure: 12.3 days).
Currently, there are effective treatment options for chemotherapy-or radiotherapy-induced stomatitis. HST exerts a preventive effect against these types of stomatitis. Yuki, et al. [13] administered OGT for the treatment of chemotherapy-induced stomatitis and diarrhea in patients with acute myeloblastic or lymphoblastic leukemia (n = 40). The incidence of stomatitis in ORG-treated patients (n = 14) was significantly lower compared with that reported in those who received a gargle consisting of allopurinol, sodium gualenate, and povidone-iodine (n = 25) (27.9% vs. 71.6%, respectively; p < 0.0001). Moreover, the incidence of diarrhea was significantly lower (9.3% vs. 31.7%, respectively; p < 0.005). HST has been administered for the treatment of chemotherapy-induced mucositis in patients with various types of cancers, such as colorectal [14][15][16][17], gastric [16][17][18], and renal cancers [19]. In all studies, HST extract granules (TJ-14; Tsumura, Tokyo, Japan) were dissolved in drinking water and subjects rinsed their oral cavity with the solution thrice daily. Kono, et al. [14] reported that 92.8% of patients (13/14 patients) with chemotherapy-induced oral mucositis (COM) during treatment with mFOLFOX6 or FOLFIRI for metastasis of advanced colorectal cancer showed significant improvement following a 1-week topical application of HST. Moreover, a significantly decreased mean Common Terminology Criteria for Adverse Events grade was reported in patients treated with HST (p = 0.0012). Aoyama, et al. [18] conducted a double-blinded, placebo-controlled, randomized study of HST for the treatment of COM in patients with gastric cancer (n = 91). Although treatment with HST did not reduce the incidence of grade ≥ 2 COM, a trend toward the reduction of the risk of grade 1 COM by HST was observed during the screening cycle. Matsuda, et al. [15] also conducted a double-blinded, randomized study investigating the effect of HST against mucositis induced by infusional fluorinated-pyrimidine-based colorectal cancer chemotherapy (n = 93). Although the incidence of grade ≥ 2 mucositis was lower in patients treated with HST than in those treated with placebo, the difference was not statistically significant (48.8% vs. 57.4%, respectively; p = 0.41). The median duration of grade ≥ 2 mucositis was 5.5 days versus 10.5 days, respectively (p = 0.018). Nishikawa, et al. [17] demonstrated similar results in patients with gastric and colorectal cancer (n = 181), with a median time to improvement from grade ≥ 2 to grade < 1 COM of 8 days versus 15 days in the HST and placebo groups, respectively (p = 0.072). Yoshida, et al. [16] and Ohoka, et al. [19] also administered HST to patients with various types of cancer, demonstrating significant decreases in the Common Terminology Criteria for Adverse Events (v4.0) grades. The findings of these studies suggested that HST may be effective for the treatment of chemotherapy-or radiotherapy-induced stomatitis.
A previous study investigated the administration of JTT for the treatment of radiation-induced stomatitis in patients with oral cancer, in whom oral ingestion was not possible (n = 15) [20]. The mean period during which oral ingestion was not possible in these patients showed a reducing trend (i.e., 17.9 ± 7.1 days vs. 26.0 ± 11.6 days in the JTT-treated (n = 8) and non-treated (n = 7) groups, respectively (p < 0.121)). The clinical use of HST for the treatment of radiation-induced stomatitis has also been reported [21,22]. sunitinib-induced oral mucositis (OM) in patients with metastatic renal cancer (n = 22) > HST-gargling (n = 12) and non-gargling (n = 10) groups The gargling with HST significantly improved OM grade and eating status (Global self assessment) (p = 0.002). The mean period that patients could not ingest orally was 17.9 ± 7.1 days in the JTT-treated group, while that in the non-treated group was 26.0 ± 11.6 day (p = 0.121).

Basic Studies of HST
Stomatitis and oral mucositis are induced by various factors, such as infection, inflammation, concomitant oxidative stress, suppressed immunity, depressed function of the digestive tract, malnutrition, psychological stress, and physical stress. Regarding chemotherapy-and radiotherapy-induced mucositis, these treatments induce DNA and non-DNA damage that results in injury of basal epithelial, submucosal, and endothelial cells. In response to this damage, oxidative stress results in the formation of ROS. The presence of ROS damages cell membranes, induces proinflammatory cytokines such as tumor necrosis factor-α, prostaglandin (PG) E 2 , interleukin-6, and interleukin-1β, and upregulates cyclooxygenase (COX)-2 in submucosal fibroblasts and endothelial cells leading to mucosal ulceration [23,24]. Furthermore, chemotherapy and radiotherapy reduce immunity, facilitating the development of infectious diseases [25].
Hitomi, et al. [26] conducted in-vivo studies evaluating the analgesic effects of HST using an oral ulcer rat model treated with acetic acid. The topical application of HST in ulcerative oral mucosa suppressed mechanical pain hypersensitivity without exerting effects on healthy mucosa. Moreover, Kamide, et al. [27] assessed the effectiveness of HST for the prevention of radiation-induced mucositis using a hamster model. Administration of HST significantly reduced the severity of mucositis. The percentage of severe mucositis (score ≥ 3) was 100% and 16.7% in the untreated and HST groups, respectively. Moreover, HST inhibited the infiltration of neutrophils and expression of COX-2 in irradiated mucosa.
Regarding its anti-inflammatory effect, HST inhibited the production of PGE 2 and suppressed the expression of COX-2 protein. In vitro studies show that Scutellariae Radix, Glycyrrhizae Radix, Zingiberis Rhizoma Processum, and Coptidis Rhizoma are involved in these effects [35][36][37][38]. As stated earlier in this review, Hitomi, et al. reported the analgesic action of HST [26] and subsequently found through in vitro and in vivo studies that blockage of Na + channels by components of Zingiberis Rhizoma Processum ([6]-gingerol and ([6]-shogaol) play an essential role in HST-associated analgesia. Moreover, the Ginseng Radix extract demonstrated an acceleration of substance permeability into the tissue of the oral ulcer and enhanced the analgesic action of Zingiberis Rhizoma Processum [39]. Baicalein-an active constituent of Scutellariae Radix-alleviated mechanical allodynia in rats with cancer-induced bone pain [40]. Glycyrrhizin-an active constituent of Glycyrrhizae Radix-ameliorated inflammatory pain by inhibiting the microglial activation-mediated inflammatory response in mice with inflammatory pain [41]. HST induces its analgesic effect through the synergistic actions of certain crude drugs. Therefore, HST exerts a combination of antioxidative, anti-inflammatory, immunostimulatory, and analgesic effects. Moreover, HST is able to control the symptoms and simultaneously eliminate the underlying causes of the condition (Figure 2). anti-inflammatory, immunostimulatory, and analgesic effects. Moreover, HST is able to control the symptoms and simultaneously eliminate the underlying causes of the condition (Figure 2).

Figure 2.
The effects of Hangeshashinto (HST) and the crude drugs on chemotherapy-and radiotherapy-induced mucositis. HST exerts antioxidative, anti-inflammatory, immunostimulatory, and analgesic effects. Moreover, HST is able to control the symptoms and simultaneously eliminate the underlying causes of the condition. PGE2; prostaglandin E2. COX-2; cyclooxygenase-2.

Conclusions
In general, western medicines such as steroid ointments, nonsteroidal anti-inflammatory drugs, and antiviral and antifungal drugs are applied for stomatitis and oral mucositis according to the causes and symptoms. In contrast to western medicines which generally include a single component, the Kampo formulae contain multiple components and their effects are exerted through complex mechanisms of action. Use of the Kampo formulae may be an alternative treatment option for patients who failed to respond to conventional therapies. In addition, the concomitant use of Kampo formulae with western medicines may be useful. Kobayashi [42] reported effective cases in which the concomitant use of HST with steroid ointment was applied. In this review, we introduced the clinical applications and summarized the available evidence of the Kampo formulae for the treatment of stomatitis and oral mucositis. Despite the availability of clinical reports, the evidence (except for that related to treatment with HST) is limited. Future clinical and basic research studies are warranted to further investigate the effectiveness on the Kampo formulae against these conditions.  Acknowledgments: The authors would like to thank Shigemasa Kubo for his valuable assistance during the preparation of this manuscript and Enago (www.enago.jp) for English language review.

Conflicts of Interest:
The authors declare no conflict of interest.

BKN
Byakkokaninjinto COM chemotherapy-induced oral mucositis COX cyclooxygenase HET Hochuekkito HST Hangeshashinto Figure 2. The effects of Hangeshashinto (HST) and the crude drugs on chemotherapy-and radiotherapy-induced mucositis. HST exerts antioxidative, anti-inflammatory, immunostimulatory, and analgesic effects. Moreover, HST is able to control the symptoms and simultaneously eliminate the underlying causes of the condition. PGE 2 ; prostaglandin E 2 . COX-2; cyclooxygenase-2.

Conclusions
In general, western medicines such as steroid ointments, nonsteroidal anti-inflammatory drugs, and antiviral and antifungal drugs are applied for stomatitis and oral mucositis according to the causes and symptoms. In contrast to western medicines which generally include a single component, the Kampo formulae contain multiple components and their effects are exerted through complex mechanisms of action. Use of the Kampo formulae may be an alternative treatment option for patients who failed to respond to conventional therapies. In addition, the concomitant use of Kampo formulae with western medicines may be useful. Kobayashi [42] reported effective cases in which the concomitant use of HST with steroid ointment was applied. In this review, we introduced the clinical applications and summarized the available evidence of the Kampo formulae for the treatment of stomatitis and oral mucositis. Despite the availability of clinical reports, the evidence (except for that related to treatment with HST) is limited. Future clinical and basic research studies are warranted to further investigate the effectiveness on the Kampo formulae against these conditions.