Perspectives on the Use of Ninjin'yoeito in Modern Medicine: A Review of Randomized Controlled Trials

Background Ninjin'yoeito (NYT), a traditional Japanese (Kampo) medicine that originates from China, has been used to treat qi and blood deficiency based on its original concept. Kampo medicine has been widely used to treat many conditions and disorders combined with western medicine or Kampo medicine alone in modern situation. Aims We reviewed randomized controlled trials (RCTs) of NYT and discussed various standpoints regarding its use in modern situation. Methods We searched PubMed, Cochrane Library, and Evidence Reports of Kampo Treatment (EKAT) for articles written in English, and Ichushi, J-Stage, and EKAT for those written in Japanese. Articles published before January 1, 2019, were retrieved using the keywords “ninjinyoeito” and “ninjin'yoeito,” and RCTs were selected from these extracted articles. Result Of 734 articles, 13 were RCTs, 46 were non-RCTs or studies of other designs, 15 were case reports, and 36 were experimental studies using NYT. NYT was evaluated for its use as a treatment for cancer and related conditions, refractory blood diseases and conditions, and otorhinolaryngologic symptom in 13 RCTs. Based on the use of Kampo medicine in modern situation called as Yasui's classification, 10 of 13 RCTs were categorized as “the side effects of Western medicinal treatment are mitigated when combined with Kampo treatment” and the remaining 3 were categorized as “treatment effect of Kampo medicine is increased in combination with standard Western medicinal treatment.” Conclusion. Several studies demonstrated the efficacy of NYT in refractory diseases and other conditions, and the accompanied side effects of treatment with western medicine.


Introduction
Ninjin'yoeito (NYT), a traditional Japanese (Kampo) medicine that originates from China, is used to treat qi and blood deficiency pattern based on its original concept. NYT is especially used to treat spleen and lung qi deficiency pattern, and heart and liver blood deficiency pattern. NYT contains 12 crude drugs: Japanese Pharmacopoeia Seventeenth Edition (JP) Rehmannia Root, JP Japanese Angelica declined constitution after recovery from diseases, fatigue and malaise, anorexia, perspiration during sleep, cold limbs, and anemia (Tsumura & Co., Japan, Kracie Pharmaceutical Ltd. Japan, and Ohsugi Pharmaceutical Co., Ltd Japan) [2], as well as for ill complexion, thin body, slight fever, chills, persistent cough, severe malaise, anorexia, mental disequilibrium, insomnia, night sweating, tendency to constipation, enhancement of physical strength after disease or childbirth, and delicate constitution (Kotaro Pharmaceutical Co., Ltd. Japan) [2]. Kampo medicine is widely used for the treatment of various conditions in modern medicine, and it has been applied to treat several conditions and disorders based on ancient concepts. Recently, NYT was applied to treat frailty in gastrointestinal, respiratory, and urinary functions in clinical settings. However, a review of its efficacy when used to treat several conditions or diseases has not been presented. us, in this study, we reviewed randomized controlled trials (RCTs) with NYT and discussed various standpoints regarding its use in modern medicine.

Literature Search.
Using the keywords, "ninjinyoeito" or "ninjin'yoeito," we conducted a database search of PubMed, Cochrane Library, and Evidence Reports of Kampo Treatment (EKAT) [3] for articles written in English, and Ichushi, J-Stage, and EKAT for those written in Japanese. e search was restricted to articles published before January 1, 2019. We also performed an additional "hand search" for recently published articles.

Selection Criteria.
RCTs based on NYT were selected from a pool of research articles published in English or Japanese.

Data Extraction.
Eligible articles were categorized by two independent researchers (STand RA) who extracted and tabulated specific information from the articles. RCTs were classified based on their study design, number of subjects, intervention, control, and results. RCTs were then categorized into one of the following four types given in "Yasui's classification," which depicts the recent prescription of Kampo medicine in Japan [4][5][6][7][8][9][10]: type 1, treatment is effective using Kampo medicine alone; type 2, the treatment effect is increased using Kampo medicine in combination with the standard western medicinal treatment; type 3, the side effects of western medicinal treatment are mitigated when combined with Kampo medicine; and type 4, situations where western medicine cannot be applied due to allergy, etc.

Results
e review process and number of eligible articles are shown in Figure 1. Of the 734 retrieved articles, there were 13 RCTs (Table 1), 46 clinical studies of non-RCTs or studies of other designs (17 articles on treatment for cancer and related conditions, 9 articles on blood diseases, 5 articles on otorhinolaryngology, 5 articles on collagen diseases, 5 articles on urogenital diseases, 5 articles in the other diseases), 15 case reports (7 articles on respiratory disorders, 3 articles on refractory blood diseases, 5 articles on the other diseases), and 36 experimental studies. (Table 1) 3.1.1. Cancer Treatment and Related Condition. In 2004, Oda et al. reported the efficacy of NYT for bone-marrow suppression when chemotherapy was given to patients with gynecologic cancer. During the third cycle of chemotherapy, the duration of neutrophil count under 1,000/μL was shorter in the NYT group than the control group, while total dose of granulocyte colony-stimulating factor (G-CSF) was significantly lower in the NYT group than the control group. Similarly, compared to the first cycle, the nadir hemoglobin level was significantly shorter in the second cycle in the NYT group, but not in the control group [11].

Randomized Controlled Trials (RCTs) of NYT
In 1995, Sugimachi reported the efficacy of NYT in reducing adverse effects and improving performance status (PS) in patients undergoing postoperative adjuvant chemotherapy (fluoropyrimidine anticancer drug) for gastric cancer. No significant difference was found between the groups regarding changes in body weight, PS, decline in white blood cell (WBC), red blood cell (RBC), and platelet (PLT) count, and subjective symptoms [12].
In 1995, Okawa et al. reported an improvement in subjective symptoms and leukopenia after NYT administration to patients undergoing radiotherapy for thoracoabdominal tumors. e proportion of patients with WBC count >3000/μL at the end of treatment (weeks 4-8) was higher in the NYT group than the control group. Improvement in subjective symptoms and laboratory test results was also observed more frequently in the NYT group than the control [13].
In 1994, Hasegawa et al. reported the clinical usefulness of Kampo medicine including NYT for side effects in gynecologic cancer chemotherapy. Treatment with Kampo medicine did not significantly affect the decline in WBC, RBC, and PLT counts but tended to promote their reversal. Kampo medicine also reduced nephrotoxicity (i.e., normalized blood urea nitrogen level and reduced creatinine   Evidence-Based Complementary and Alternative Medicine 9  fluctuation), but subjective gastrointestinal symptoms did not improve [14]. In 1994, Yamamoto et al. reported the effects of NYT on subjective and objective symptoms and bone-marrow function during chemotherapy or radiotherapy in patients with genital cancer. An additional treatment with NYT significantly improved myelosuppressive symptoms, but not the subjective and objective symptoms associated with anticancer drug administration. It also improved anorexia and fatigue/ malaise during radiotherapy. One patient had acute hepatitis with an unknown causal relationship with NYT [15].
In 1993, Ohara et al. reported the efficacy of Kampo medicine including NYT for cancer treatment with fluorouracil-related drugs. e subjective symptoms before and after treatment (nausea/vomiting, bowel movement abnormality, motivation, and fatigue/malaise) were significantly improved in the NYT group. Overall improvement was noted in 33.9% of patients in the NYTgroup and 14.3% of patients in the control group; a significant difference was found between the groups. Overall objective symptom improvement was noted in 39.3% of patients in the NYT group and 0.4% of patients in the control group; a significant difference was noted in the percentage of patients showing improvement between the two groups. e percentage of patients showing improvement in both subjective and objective symptoms was significantly greater in the NYT group than the control group but this was only for patients with gastric cancer. Side effects were present in 11.5% of patients. Efficacy, as determined by the attending doctor based on symptom improvement and side effects, was significantly greater than with conventional treatment [16].
In 1993, Mizuno et al. reported the efficacy of NYT for the relief of subjective symptoms and the improvement of activities related to daily living in patients after surgery for gynecologic cancer. Administering NYT could significantly reduce the subjective symptoms of physical strength, general fatigue, coldness in hand and foot, and night sweating compared to control. Only one case showed appetite loss and general fatigue, and these were categorized as side effects of treatment. e efficacy as determined by the attending doctor based on symptom improvement and side effects was significantly higher in the NYT group than the control [17].
Araki et al. reported the effect of NYT on immunostimulation and improved nutritional status in postoperative patients with colorectal cancer in 1992. At week 2 and month 3 after operation, % change in lymphocyte count was significantly greater in the NYT group than the control group. Changes in T-cell number were also significantly greater in the NYT group than the control group at 3 and 6 months after operation. Percent change in PHA-stimulated lymphocyte proliferation was significantly greater in the NYT group than the control group at 6 months after operation. For interleukin-2 receptor-positive cell ratio 6 months after operation, there was a significant reduction from the preoperative value in the NYT group [18].

Blood Diseases and Related Conditions.
In 1999, Aoe et al. evaluated the efficacy of juzentaihoto or NYT combined with an erythropoietin (EPO) preparation in preoperative autologous blood donation for patients with cancer. e increase in reticulocyte count from the time of donation to the time of operation was larger in the group administered with juzentaihoto and NYT and the EPO group than the iron group. In addition, the increase in hemoglobin level was greater in the EPO group than the iron group and significantly larger in the juzentaihoto and NYT group than the EPO group [19].
In 1997, the same authors (Aoe et al.) reported the combined effect of EPO and NYT on anemia after autologous blood donation. Compared to the iron treatment group, the EPO and NYT group had significantly increased RBC count, hemoglobin, and hematocrit at the time of preoperative blood collection; this was not observed in the iron + EPO group [20].
In 1995, Yanagihori et al. revealed the efficacy of NYT for iron deficiency anemia due to menorrhagia. Elevation in hemoglobin levels from predosing to postdosing was significantly higher in the NYTgroup than in the control group. Meanwhile, palpitation, shortness of breath, and symptoms for which NYT should be effective (anorexia, night sweats, and cold limbs) were improved to a similar degree in the NYT and control groups [21].
In 2005, Motoo et al. reported that NYT ameliorates ribavirin-induced anemia in chronic hepatitis C. Maximum decrease in hemoglobin levels in the NYT group was significantly smaller than that in the control group [22].

Symptoms Related to
Otorhinolaryngology. In 1994, Miyazaki et al. reported the efficacy of NYT when used to improve xerostomia induced by oxybutynin hydrochloride. After a 2-week treatment with oxybutynin hydrochloride, 80% of patients developed xerostomia. NYT administration could reduce the symptom of dry mouth in 75% of patients. In addition, a reduction (0%) was not observed in the control group (nonadministration). Gum test also showed improvement in saliva secretion in the NYT group [23].

Use of Yasui's Classification Method to Categorize RCTs.
Ten of the 13 RCTs were classified as Type 3, "the side effects of Western medicinal treatment are mitigated when combined with Kampo treatment" [11-18, 22, 23] and the remaining 3 were classified as Type 2, "the treatment effect of Kampo medicine is increased in combination with standard Western medicinal treatment" [19][20][21] (Figure 2).

Discussion
We reviewed RCTs where NYT was used to treat cancer and related conditions, refractory blood diseases and conditions, and otorhinolaryngologic symptom.
Yasui [4][5][6][7][8][9][10] reported his view regarding the use of Kampo medicine in modern medicine and suggested that the indications of Kampo medicine can be classified into 4 types: type 1, effective using Kampo medicine alone; type 2, effective combined with western medicine; type 3, mitigation for side effects of western medicine; and type 4, western Evidence-Based Complementary and Alternative Medicine medicine cannot be applied. In this study, we categorized the RCTs that we reviewed using Yasui's classification method (Figure 2). Ten of the 13 RCTs were classified as type 3 while the remaining 3 were classified as type 2; these correspond to side effects of treatment with western medicine and combination therapy using NYT and western medicine, respectively, and reflect the application of NYT in modern-day situations. In clinical trials, most studies were conducted using western medicine treatment, which prompted their classification into the type for combination therapy with western medicine and Kampo medicine. As a lack of effect using western medicine was observed in some cases, treatment with Kampo medicine can also be considered another possible application. Altogether, these reports suggest that treatment with NYT for pharyngeal vascular malformation [24], frailty [25], respiratory disorder [26], infectious disease [27], dysphagia [28], and sarcoidosis [29] may be feasible.
Many mechanisms of NYT have been reported in experimental studies, and the 12 components within NYT that contribute to these mechanisms have been summarized by Miyano et al [30]. ese researchers evaluated the following effects of the 12 components: anti-inflammatory, antitumor, antioxidative, antiosteoporotic, antineurodegenerative, and neuroprotective activities; regulation of Na + /Ca 2+ exchanger 3; inhibition of enzyme conversion from acyl ghrelin (active) to des-acyl ghrelin (inactive); maintenance of ghrelin levels as pachymic acid; elevation of adiponectin production; enhancement of skeletal muscle endurance; pain relief; and Ca 2+ channel inhibition. erefore, not only have these components been presented in the literature, but their effects (NYT formula) have also been elucidated. According to Makino et al. [31,32], NYT improves 1/ 2 balance, active oxygen scavenging action in inflammation, lupus nephritis, and anti-inflammation in mouse cytomegalovirus pneumonia; protects from candida infection; exhibits antitumor effects via natural killer activity, and enhances antitumor effect of anticancer drugs; suppresses lung metastasis of rectal cancer, enhances cancer vaccine through CD8 T cells; suppresses carcinogenesis; improves dementia via stimulating acetylcholine neuron; protects against mitochondrial dysfunction and intestinal mucosal failure which decline with age and necrosis of the skin flap; improves myelination hypoplasia by activating mitogen-activated protein kinase cascade, attenuates neuropathic pain (a side effect of anticancer drug treatment), recovers WBC, RBC, and PLT counts and olfactory disorder after anticancer treatment; mitigates transplant rejection; inhibits fibrosis and cirrhosis; and prevents hepatic disorder when sorafenib is administered. eir findings support the results of RCTs using NYT. Figure 3 conveys our understanding of the original concept, indication, RCT, mechanisms, and possible application of NYT in modern medicine. With regards to the original concept, NYT can be used to treat qi and blood deficiency pattern in the body, especially spleen and lung qi deficiency pattern and heart and liver blood deficiency pattern. ese deficiencies are accompanied by symptoms such as fatigue, malaise, and cognitive impairment which are related to vital energy, hormone, and neurotransmitters; appetite loss and digestive disorder which are related to vital energy, neurotransmitters, and the autonomic nervous system; and body weight loss, mis-swallowing, dyspnea, and urinary disfunction, all of which are related to muscle weakness, sarcopenia, and the autonomic nervous system. erefore, our review highlights the need to evaluate NYT for its side effects when used to treat cancer or xerostomia and refractory blood diseases. Based on the original concept, NYT can also be applied to a variety of other conditions and diseases such as frailty, dementia, or respiratory disorder.
Recently, NYT has been highlighted in the treatment of frailty and cognitive dysfunction in elderly patients.  [36]. ey found that NYT caused a significant decrease in the score for anorexia and a significant increase in food intake by week 4. Moreover, the total NPI score and NPI subcategory scores for apathy and eating disturbance significantly decreased by week 4. A significant decrease in total caregiver distress scores was also observed from week 8. MMSE was significantly increased at week 12 compared to that at baseline. ese reports suggest the possibility of NYT application for frailty and cognitive dysfunction in elderly patients.
With regards to side effects, some that are deemed adverse were reported in RCTs and a case report. Side effects of NYT were suspected in 3.6% of patients included in the RCTs. Symptoms exhibited by the patients include skin eruption, gastrointestinal disorder, fatigue, and liver dysfunction. A case report where skin eruption was diagnosed as a side effect of NYT treatment was reported by Ueda et al in 2001 [37]. A 73-year-old male complained of an itchy bullous eruption with erythema on the trunk, but he also had an erosion on the lower lip which appeared after he was given NYT. Patch testing to confirm these occurrences were NYT-triggered yielded a positive reaction and likewise, drug-induced lymphocyte stimulation test indicated a positive result. is suggests that physicians should pay keen attention to adverse effects when prescribing NYT.

Conclusions
By conducting RCTs, researchers could reveal the efficacy of NYT when used to treat refractory diseases and other conditions. With respect to modern medicine, many studies evaluated the additional effects that either occur by combining NYT and standard western medicinal treatment or handling the side effects of western medicinal treatment. In a future study, we aim to clarify the usefulness of NYT in modern medicine.    Figure 3: Overview of the original concept, indication, randomized control trials, mechanisms, and possible application of NYT in modern medicine.