Review of frequently used Kampo prescriptions: Part 4, Ninjin'yoeito

The source of ninjin'yoeito (NYT) is considered the ‘Formulary of Bureau of Taiping People's Welfare Pharmacy’, written around 1241–52 AD. NYT is used to treat patients with chronic fatigue, malaise with qi deficiency, and exhaustion of all five parenchymatous viscera with difficulty in recovering.


HISTORY OF NINJIN'YOEITO
Traditional Japanese herbal medicine, known as Kampo, is part of East Asian medicine based on traditional Chinese medicine (TCM).Although some prescriptions were first formulated in Japan, many Kampo formulae have been derived from the Chinese medical literature.
Kampo prescriptions containing ginseng root and Astragalus root are categorized as the ginseng and Astragalus root drug group, used to treat fatigue and malaise in physically and mentally exhausted patients with reduced gastrointestinal function [1].For example, hochuekkito, juzentaihoto, seishoekkito, kihito, hangebyakujutsutemmato, and seishinrenshiin are the major formulations of the ginseng and Astragalus root drug group [1].Ninjin'yoeito (NYT) can also be classified in the ginseng and Astragalus root drug group because NYT is formulated excluding Cnidium rhizome from juzentaihoto while adding Citrus unshiu peel, Polygala root, and Schisandra fruit.Distinguishing the prescriptions in the ginseng and astragalus root drug group is crucial in clinical medicine, as each Kampo prescription has been continually updated and improved in response to current demands since it was first formulated.Therefore, a comprehensive review of the origin and historical transition of NYT could help to distinguish it from other prescriptions in the Ginseng and Astragalus Root drug group, particularly from juzentaihoto.
NYT, defined initially in the Chinese medical literature, has been widely used in Japan for hundreds of years since the Edo period.As Kampo medicine has its own system of diagnosis and healing philosophy, rooted in the Japanese way of thinking, NYT has various instructions for its use, so-called kuketsu, transmitted in the classical Japanese literature over many decades.
We begin by tracing the origin of NYT in classical Chinese literature and then review its historical development from the Edo period to the present day; thus, exploring the application of NYT in treating diverse disease entities.We illustrate the evolving instructions for using NYT (kuketsu) through reexaminations of the classical instructions in light of clinical practice.

Origin and clinical indications of NYT in classical Chinese literature
The classical Chinese literature referring to NYT is summarized in Table 1.The origin of NYT goes back to the 'Formulary of Bureau of Taiping People's Welfare Pharmacy' [2], written around 1241-1252 AD.NYT consists of 12 herbs: ginseng root, angelica root, peony root, Rehmannia root, Atractylodes rhizome, Poria sclerotium, Cinnamon bark, Astragalus root, Citrus unshiu peel, Polygala root, Schisandra fruit, and Glycyrrhiza.The description of NYT found in the section of Treatment for Chronic Coldness (Supplement on Diabetes) in Volume 5 of the 'Formulary of Bureau of Taiping People's Welfare Pharmacy' is as follows: it is used to treat chronic fatigue and malaise, dullness of extremities, aching body pain, shallow breathing, shortness of breath on exertion, muscle strain in the lower abdominal region, back pain, susceptibility to palpitation, dry throat and lips, tasteless feeling, yin-yang deficiency, depression, tendency to lie down, weight loss over a prolonged period, qi deficiency, and exhaustion of all five parenchymatous viscera with difficulties in recovery.It is also employed for patients experiencing cough, diarrhea, wheezing, dyspnea, vomiting, and sputum caused by lung [ ™ 1] and large intestine [ ™ 1] deficiencies.
Notably, in 1174 AD, approximately 70 years before the first description of NYT, an herbal drug called 'yoeito', with similar instructions to NYT, was already mentioned in the section of Treatment for Frailty in Volume 13 of the 'Treatise on Three Categories of Pathogenic Factors and Prescriptions' [3].Yoeito also appears in Volume 10 of the same treatise, specifically in the section on treatments for jaundice.Yoeito is prescribed for weak and fatigued patients with jaundice experiencing leg weakness, palpitations, tastelessness, tinnitus, mild coldness, fever, dyspnea, and whitish turbid urine.
The description of yoeito can also be found in the 'Summary of Pattern/Syndrome Identifications and Treatments' [4].Bukuryohoshinto, a combination of jinsoin and shimotsuto, is recommended for treating fever associated with blood deficiency after blood loss and frailty.Subsequently, yoeito or juzentaihoto can be used to address blood deficiency.Juzentaihoto, yoeito, kenchuto, and others can be applied to treat fever and symptoms caused by exhaustion of the five parenchymatous viscera.
NYT and yoeito are mentioned in the 'Subtle Meaning of the Jade Swivel' [5].NYT is utilized for patients with chronic fatigue and malaise, experiencing dry mouth, loss of appetite, cough, diarrhea, susceptibility to palpitations, and fever with spontaneous sweating.Yoeito is listed in the section on treatments for jaundice, as quoted from the 'Treatise on Three Categories of Pathogenic Factors and Prescriptions'.
In the 'Essentials of Internal Medicine' [6], Xue Ji explains that NYT is effective for patients with spleen [ ™ 1] and lung [ ™ 1] deficiency, presenting symptoms such as fever with chills, weak and exhausted extremities, thin skin and muscles, shallow complexion with shortness of breath, and reduced appetite accompanied by diarrhea.He also mentions that this prescription can be applied effectively for various conditions caused by qi and blood deficiencies.
A similar description can be found in the 'Mirror of Ancient and Modern Medicine' [7].The section on tonifying qi, blood, yang, and yin states that NYT is used to NYT treats patients with chronic fatigue and malaise, dullness of extremities, aching body pain, shallow breathing, shortness of breath on exertion, muscle strain in the lower abdominal region, back pain, susceptibility to palpitation, dry throat and lips, tasteless feeling, yin-yang deficiency, sorrow and depressed feeling, tendency to lie down, losing weight between 100 days and several years, qi-deficiency, and exhaustion of all five parenchymatous viscera with difficulty in recovering.It is also used for patients with cough, diarrhea, wheezing, dyspnea, vomiting, and sputum caused by deficiencies of the lung and large intestine.treat patients with chronic fatigue and malaise, exhausted extremities, thin skin and muscles, shallow complexion with shortness of breath, and reduced appetite.
In 'Introduction to Medicine' [8], NYT and juzentaihoto are employed to treat coldness resulting from yinyang deficiencies.Chochuekkito and NYT can be used for patients with exhaustion and shortness of breath caused by scattered qi.NYT is also utilized for weak and exhausted patients with spontaneous sweating due to chronic illness, dryness of the five parenchymatous viscera, and excessive bleeding from skin eruptions.Therefore, NYT is expected to alleviate symptoms of anemia caused by excessive bleeding.Fever resulting from qi and blood deficiencies can be treated with either juzentaihoto or NYT, with the addition of Anemarrhena rhizome and Phellodendron bark to enrich yang and yin.Furthermore, NYT is administered to patients with severe blood deficiency experiencing 'tidal fever' with sweating, as cited under the practical indication of NYT in the section on Fever in the 'Restoration of Health from the Myriad Diseases' [9].
Additionally, Xue Kai explains in the 'Essentials of Infant Care' [10] that spontaneous sweating indicates yang deficiencies, while night sweating indicates yin deficiencies.He describes that NYT can treat spontaneous and night sweating caused by qi and blood deficiencies and can be used for insomniac patients with poor mental condition.
In the 'Investigations of Medical Prescriptions' [11], under the section on consumptive disease and chronic infectious disease, it is mentioned that NYT is effective for the decline of cognitive functions and pale complexion accompanied by loss of hair and eyebrows.These symptoms are observed in patients suffering from circulation disorders with blood loss associated with heart dysfunction.
NYT is classified as a formula for qi and blood supplementation, resembling juzentaihoto in its composition.The 'Golden Mirror of Medicine' [12] discusses the difference between NYT and juzentaihoto.Severe qi and blood deficiencies require qi supplementation throughout the body.NYT is used more frequently than juzentaihoto for patients with more severe qi and blood deficiencies because it contains Citrus unshiu peel for qi circulation while excluding Cnidium rhizome, which affects blood circulation.
NYT's applications extend to dermatological and menstrual conditions as well.'Patterns and Examples for External Medicine' [13], 'Essentials of External Medicine' [14], and 'Orthodox Manual of External Medicine' [15] discuss the use of NYT for skin ulcers.In the 'Compendium of Effective Prescriptions for Women' [16], NYT is classified within the prescriptions for menstrual disorders with blood deficiency of the spleen [ ™ 1]   meridian.Moreover, NYT is employed to treat patients with skin ulcers who experience limb weariness, emaciation, poor appetite, and other ailments, as described in the section on treatments for scrofula among women.Classical Chinese literature portrays NYT as a successful treatment for patients with severe qi and blood deficiencies, including fever, spontaneous and night sweating, insomnia, skin ulcers, menstrual disorders, anemia, and cognitive function decline.

Development in clinical application of NYT in Japan
Clinical references of NYT are more practical and concrete in the classical Japanese literature, which is summarized in Table 2.Many Chinese classical literatures have influenced NYT use in Kampo medicine since the Edo period.
Manase, in the 'Standards for a Multitude of Prescriptions' [17], noted that NYT is effective for patients experiencing qi deficiency after a serious illness and who exhibit symptoms such as absentmindedness, pale complexion, decline of cognitive functions, and a tendency to lie down.He also mentioned that this prescription can be widely applied to patients with symptoms caused by qi and blood deficiencies, modeled after the description by Xue Ji.
Nagasawa highlighted that the composition of NYT is based on juzentaihoto with the addition of Schisandra fruit and Polygala root in 'The Collection of Clinical Pearls on Medical Formulary' [18], referring to 'Investigations of Medical Prescriptions'.
Kitao [19] described that NYT and juzentaihoto were effective against slight fevers and had a similar sho, leading to a diagnosis based on Kampo principles.He also explained that NYT should be used to treat heart [ ™ 1] deficiencies, as it is effective for patients with hypofunction and slight fever who have symptoms of heart [ ™ 1] deficiency and phlegm stagnation.
Tsuda described the clinical application of NYT in the 'Notes on Experiences of Medical Treatments' [20].NYT should be used to treat patients with symptoms such as loss of hair, dull complexion, forgetfulness, appetite loss, insomnia with palpitations, dry skin, unhealthy nails, and muscle atrophy.Furthermore, he mentioned that NYT, juzentaihoto, and kihito were modeled after ogikenchuto.Among these prescriptions, NYT is applied to patients with fluid depletion, while juzentaihoto is useful for patients with coldness as well as qi and blood deficiencies, and kihito is effective for patients with blood deficiency of the heart [ ™ 1] and spleen [ ™ 1] .
The similar use between NYT and ogikenchuto is highlighted in the 'Oral Tradition of Gochikuro's Formulary' [21].NYT, referred to as yoeito in this text, is described as helpful in treating consumptive diseases without fever, such as ogikenchuto and shakanzoto.
Azai noted in the 'Oral Tradition about Collection of Ancient and Modern Prescriptions' [22] that NYT is applied to patients with spleen [ ™ 1] and lung [ ™ 1] deficiencies in the same way as juzentaihoto, kihito, hochuekkito, and hatimotsuto (shikunshito and shimotsuto) are applied.He also mentioned that patients with blood and qi deficiencies of the spleen [ ™ 1] and lung [ ™ 1] , who receive poor relief with juzentaihoto and kihito, could be treated with NYT on the basis of the efficacy of the Chinese herbs composing NYT.For example, Citrus unshiu peel improves qi stagnation in the chest, while Schisandra fruit controls the lung [ ™ 1] fluid.The combination of ginseng and Angelica roots activates lung function, and Polygala root maintains the balance of heart function.
In 'Traditional Key of Formulary of Futsugo Pharmacy' [23], Asada explained that NYT is used to treat patients with both qi and blood deficiencies and that it can be more effective than juzentaihoto in improving the spleen [ ™ 1] and lung [ ™ 1] function, focusing on the fact that NYT includes Polygala root, Citrus unshiu peel, and Schisandra fruit.He described that NYT can be used to treat patients with diarrhea, wheezing, and shortness of breath due to lung [ ™ 1] and colon deficiencies, as written in the 'Treatise on Three Categories of Pathogenic Factors and Prescriptions'.He also wrote in the 'Collected essays on excellent achievements by old physicians' [24] that shimotsuto, hachinto, juzentaihoto, and NYT enriched with Ophiopogon root and Jujube seed are helpful for patients with palpitations caused by blood deficiency.
Hanaoka and Homma recommended NYT as a treatment for anal fistula in 'Formulary of the Treatment of Sores' [25] and 'Secret Records about Treatment of Sores' [26], respectively.
NYT's application has expanded to include more diverse symptoms and diseases.Yakazu summarizes the practical application of NYT [27] as follows: 'Pulmonary tuberculosis with dry skin because of fluid depletion, slight fever without sweating, but not severely weak abdominal power.Chronic pleurisy or peritonitis with dry skin and stiff stool.Be careful with diarrhea.Involuntary ejaculation caused by fluid depletion, with the addition of Fossilized Bone to NYT.Weakness after childbirth.Cancer cachexia.Severe weakness after febrile illness, including loss of hair and forgetfulness'.

Interpretation of clinical use of NYT
NYT was initially concocted to treat patients with a weak constitution experiencing general fatigue or physical exhaustion after disease recovery.It is also prescribed for patients with sorrow and depression, as demonstrated in the 'Formulary of Bureau of Taiping People's Welfare Pharmacy'.Sorrow and depression are related to the lungs [ ™ 1] and spleen [ ™ 1] , respectively, in the five viscera theory.NYT is effective for many symptoms in the Chinese literature, including muscle strain in the lower abdominal region, back pain, shallow breathing, and shortness of breath with activity, which are related to kidney malfunction.Some of the clinical symptoms for which shokenchuto is indicated are similar to those of NYT as described in the Tonifying Kidney section in 'Essential Prescriptions Worth a Thousand Gold for Emergencies' [28], written around the 7th Century, as well as in the 'Handbook of Prescriptions for Emergencies' [29], written around the 4th Century.The description of shokenchuto was written before NYT was introduced.Hachimigan is also listed in the Tonifying Kidney section in the 'Essential Prescriptions Worth a Thousand Gold for Emergencies'.NYT and shokenchuto are compared in Figure 1.NYT is different from shokenchuto in that NYT is also used to treat patients with cough, diarrhea, wheezing, dyspnea, vomiting, and sputum caused by lung [ ™ 1] and large intestine [ ™ 1] deficiencies, as stated at the end of the paragraph.However, the Lung [ ™ 1] deficiency and excess section in 'Essential Prescriptions Worth a Thousand Gold for Emergencies', it is written that shokenchuto is also used to treat symptoms related to lung [ ™ 1] and large intestine [ ™ 1] deficiencies.Thus, the clinical symptoms and signs for which NYT is prescribed are similar to those of shokenchuto.
Tsuda mentioned that NYT, juzentaihoto, and kihito were modeled after ogikenchuto, which is based on shokenchuto with the addition of Astragalus root.Among these three prescriptions, as Azai insisted, NYT can treat more severe blood and qi deficiencies than juzentaihoto and kihito because NYT contains unshiu peel, Schisandra fruit, and Polygala root.

PHARMACEUTICAL INFORMATION OF NYT Composition, description, and dosage and administration
In Japan, the NYT formula consists of the following 12 crude drugs: JP Rehmannia root, JP Japanese angelica root, JP Atractylodes rhizome or JP Atractylodes lancea rhizome, JP Poria sclerotium, JP ginseng, JP cinnamon bark, JP Polygala root, JP peony root, JP Citrus unshiu peel, JP Astragalus root, JP Glycyrrhiza, and JP Schisandra fruit (JP: Japanese Pharmacopeia eighteenth edition, JP XVIII [30]).The extracts and decoctions of NYT are available in Japan.The extract formulations are classified into Kampo extract formulations for a medical prescription (ethical Kampo formulation), and over-the-counter (OTC) Kampo extract formulations for self-medication.The decoction includes the formulation by doctors' prescription and by pharmacists dispensing without doctors' prescription (in-pharmacy formulation).These forms of NYT were approved by the JP XVIII, the Guidebook of the Approval Standard for OTC Kampo Products (Revised Edition), and the Sixth Edition of the Guidelines for Pharmacy Preparation.
The original formulation of NYT is a decoction made by boiling a mixture of crude drugs in water at room temperature.Boiling the mixture under low heating in 500-600 mL of water reduces the volume to half.After removing the crude drug residue, the extraction fluid is divided into two or three doses to be taken daily before or between meals.
Currently, NYT extract formulations are mainly distributed in Japan.The quantity of crude drugs in each formulation is presented in Table 3.Only four pharmaceutical companies manufacture Kampo extract formulations for medical prescriptions of NYT.The usual dose for adult patients consists of two or three divided doses for oral administration before or between meals.The dosage forms are granules and fine granules.The OTC formulations of NYT usually contain fewer crude drugs than that for a medical prescription.

Constituents
The high-performance liquid chromatography profile of an NYT extract is depicted in Figure 2. The key characteristics of the crude drugs and their major compounds, along with their pharmacological activities, are outlined below.

JP Ginseng
Ginseng is the root of Panax ginseng C. A. Meyer (Panax schinseng Nees) (Araliaceae), from which rootlets have been removed, or the root has been quickly passed through hot water [30].
It contains at least 0.10% of ginsenoside Rg 1 and 0.20% of ginsenoside Rb 1 , calculated on the basis of dried material.Ginsenoside saponins are the main components of ginseng, and more than 80 saponins have been isolated from raw or processed ginseng [42].There have been numerous ginseng research studies.

Cinnamon bark
Cinnamon bark refers to the trunk bark of Cinnamomum cassia J. Presl (Lauraceae), or a portion of which the periderm has been removed [30].Cinnamon bark has multiple constituents, including essential oils, polyphenols, diterpenes, flavonoids, polysaccharides, and other compounds.The pharmacological range of cinnamon bark includes antiinflammatory, antibacterial, antioxidant, and antitumor properties; it also has therapeutic effects on glucose and lipid metabolism, mediates neuroprotection, and more [43].

CLINICAL RESULTS AND APPLICATIONS FROM CLINICAL TRIALS AND CASE REPORTS OF NYT
Nowadays, NYT is widely used to treat various conditions.NYT extract for medical use is covered by the National Health Insurance system of Japan for convalescence after recovery from diseases, fatigue and malaise, anorexia, perspiration during sleep, cold limbs, anemia, ill complexion, thin body, slight fever, chills, persistent cough, severe malaise, anorexia, mental disequilibrium, insomnia, night sweating, a tendency to constipation, enhancement of physical strength after disease or childbirth, and delicate constitution.Recently, the number of prescriptions of NYT has increased in Japan, especially for those aged over 80 years [58].
Using the keywords 'ninjinyoeito' or 'ninjin'yoeito', we conducted a database search of PubMed, Web of Science, and Traditional and Kampo Medicine for articles written in English.The search was restricted to articles published before 31 December 2022.We also performed an additional hand search for recently published articles.Clinical studies, including interventional and observational studies, as well as case reports based on NYT, were selected from a pool of research articles published in English.Table 4 presents the list of clinical studies and Table 5 presents the list of case reports of NYT according to the search strategy.Five randomized clinical trials (RCT) [59][60][61][62][63], four observational studies [64][65][66][67], and 12 case reports were searched [68][69][70][71][72][73][74][75][76][77][78][79][80].Herein, we summarize the findings of clinical studies on NYT.

Anemia
Kawakami et al. reported the RCT of the effect of NYT on postpartum anemia and the development of postpartum depression.By comparing the NYT (n = 532; 7.5 g/day of NYT for 4 weeks) and control groups (n = 534; oral iron preparation for 4 weeks), it was found that the Hb level increased significantly in both groups.Fatigue decreased significantly in the NYT group but did not change in the control group.The prevalence of postpartum depressive symptoms in the NYT group was also lower than that for the control group [59].
Yagi et al. reported the RCT of the effectiveness and safety of NYT in addition to iron supplementation for patients with anemia who were scheduled for gynecological surgery.By comparing the NYT (n = 19; 7.5 g/day of NYT with iron supplementation) and control groups (n = 21; 100 mg/day of iron supplementation), it was found that Hb significantly increased in both groups.The Cancer Fatigue Scale and Visual Analogue Scale for Anxiety scores decreased significantly only in the NYT group.Liver dysfunction was an adverse reaction observed in a patient of the NYT group [60].
Motoo et al. reported the RCT of the efficacy of NYT for ribavirin-induced anemia patients with chronic hepatitis C. By comparing the NYT (n = 10; 9 g/day of NYT for 24 weeks with Interferon-alpha 2b and ribavirin regimen) and control groups (n = 13; Interferon-alpha 2b and ribavirin regimen), it was found that anemia was significantly reduced in the NYT group compared with the control group.The maximal decrease of Hb in the NYT group was significantly smaller than that for the control group [61].

Cancer treatment support
Motoo et al. also reported the RCT of the prophylactic effect of NYT for oxaliplatin-induced cumulative peripheral neuropathy for patients with Stage 3 colorectal cancer.By comparing the NYT (n = 26; 9.0 g/day of NYT from day 1 of cycle 1 throughout each cycle) and control groups (n = 26; non-administration of NYT), it was found that the incidence of grade 2 or greater cumulative peripheral neuropathy at the 8th chemotherapy cycle was significantly lower in the NYT group than those of the control group.The relative dose intensity of oxaliplatin was significantly higher in the NYT group than that of the control group.Hypokalemia and leg edema were observed as adverse reactions in a patient of the NYT group [62].
Takayama et al. reported cases of anorexia during the treatment of malignant melanoma and esophageal cancer.In both cases, anorexia improved after the administration of NYT [63,64].Aomatsu  2020 [66] Ethical (Kracie Pharmaceutical Ltd., Tokyo, Japan)

Patient of pulmonary nontuberculous mycobacterial infection (1)
Weight gain and marked reduction in the lung cavity lesions were shown.

Patients with frailty (3)
In case 1, general fatigue was improved.In case 2, coldness, with general fatigue and dry cough, were improved.In case 3, coldness, with general fatigue and a tendency to catch colds, were improved.

[72]
N/A Patients with frailty in COPD (1) Body weight, muscle mass, frailty score, COPD score, and anxiety and depression score were improved.
the supportive role of NYT on postoperative weakness or during anticancer treatment in colon cancer [65,66].

Cognitive functions, anorexia, and apathy in dementia
Kudoh et al. reported the non-randomized, open-label prospective clinical trial that examined the effects of NYT on cognitive functions and mood status.Patients with mild-to-moderate Alzheimer's disease (AD) treated with donepezil who responded insufficiently were registered and assigned to the NYT group (n = 12; 5 mg/day donepezil and 7.5 g/day NYT) or control group (n = 11; 5 mg/day donepezil).Mini-Mental State Examination results showed no significant differences.Furthermore, significant improvements were observed in the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version and the Neuropsychiatric Inventory depression scores of patients who received the combined therapy of donepezil and NYT [74].Ohsawa et al. reported the open-label trial that determined whether NYT improves anorexia and apathy in patients with AD and their cognitive functions.Scores before and after admiration of NYT were compared (n = 20; 6-9 g/day of NYT for 12 weeks).After 4-week administration, significant improvements were observed in the scores for anorexia, apathy, and meal ingestion amount in the Neuropsychiatric Inventory.The Vitality Index and Mini-Mental State Examination scores were also significantly improved by the 12-week administration [75].
Matsui et al. reported three cases whose appetite loss, weight loss, and muscle mass were improved by NYT [76].

Fatigue/malaise and anorexia
Suzuki S et al. reported the open-label, noncomparative, post-marketing survey to investigate the post-marketing safety and efficacy of NYT in elderly patients.By comparing before and after admiration of NYT (n = 808), it was found that NYT significantly improved Visual Scale Scores related to fatigue/ malaise at weeks 8, 16, and 24 and those of anorexia at weeks 8 and 24, respectively.Mean body weight and body mass index also increased significantly [77].
Sato et al. reported four cases of apathy and fatigue in patients with autistic spectrum disorder whose fatigue and apathy were improved by NYT [78].

Lung diseases
Kushima et al. reported NYT improved loss of appetite and lassitude in patients of idiopathic pulmonary fibrosis [79].Nogami reported a case of refractory pulmonary Mycobacterium avium complex infection, despite administration of antituberculosis drugs for 2 years [80].After the administration of NYT, weight gain and marked reduction in the lung cavity lesions were shown.

Frailty
Frailty is a psychosomatic condition in which muscle volume decreases with aging, leading to a decline in physical function.It is classified into three types: physical frailty, psychological frailty, and social frailty.Among them, NYT is expected to be effective in physical frailty and psychological frailty.

Cancer treatment support
NYT is currently used in cancer treatment support.It is administered to prevent anticancer drug-or radiotherapy-related hematopoietic disorders or immune hypofunction.NYT has been shown to promote recovery from leukopenia induced by anticancer drugs, such as cyclophosphamide and 5-fluorouracil, primarily involving neutrophils.Furthermore, it restored the reduction in the pluripotent hemopoietic stem cell (CFU-S) count [111].Experiments using irradiated models revealed that NYT attenuated the reduction in the numbers of erythroid burst-forming units (BFU-E), platelets, and leukocytes [112,113].These findings indicate that NYT extensively promotes the differentiation of multi-system cells that differentiate from CFU-S, including erythrocytes and platelets (Figure 5).However, NYT also increased the CFU-S count in normal mice [114]; therefore, the hematopoiesis-promoting effects of NYT may be mediated by the production of hematopoietic cytokines, such as interleukin-1, interleukin-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF), by macrophages to favor a hematopoietic microenvironment [112,115].
NYT also enhances appetite, ameliorates fatigue, and systemic health conditions.NYT maintained the skeletal muscle mass by improving the dysfunction of amino acid metabolism in cancer cachexia [116].NYT increased food intake and body weight in mice with anorexia caused by cisplatin as anticancer drug [83].Orexin receptors may be involved in this mechanism [82] via ghrelin-responsive and unresponsive NPY pathways [81,82].
Furthermore, cancer treatment causes pain in many patients; however, NYT may be effective for neuropathic pain through the suppression of neuritelike outgrowth [117,118] and the normalization of painassociated factors [119].

Immunity
Previous studies indicated that NYT ameliorated the decrease of immune cells in immune-compromised models [111][112][113] as well as in thymic atrophy [85,120], suggesting the broad involvement of NYT in immune cell recovery.Furthermore, NYT may restore the excessive decrease of Type 1 T helper (Th1) and Type 2 T helper (Th2) cytokine production [121], which are useful for the treatment of diseases related to a Th1/Th2 imbalance in the immune system, such as infection [122] (Figure 5).In addition to infection control, NYT suppresses overactive immune responses through the regulation of cytokine levels, and is also effective for autoimmune diseases [109,120,[123][124][125].

ADVERSE REACTIONS AND POST-MARKETING SURVEILLANCE OF NYT
In Japan, all drugs causing adverse events, including suspected causal drugs and drugs for which a causal relationship cannot be ruled out, should be reported to the Pharmaceutical and Medical Devices Agency (PMDA) by pharmaceutical companies, attending physicians, and pharmacists identifying them.The Japanese Adverse Drug Event Report database by PMDA revealed 23 adverse reactions related to NYT reported from 2004 to 2022 [126].Of these, six cases were reported with NYT as the suspected causal drug, and the remainder were reported with concomitant medications as the causal drug.Four of the six cases were drug eruptions and pruritus.There was one case of drug-related hypersensitivity and one case of heart failure.
Suzuki et al. conducted an adverse drug reaction frequency study of Kracie NYT Extract Fine Granules for ethical use, a representative dosage form of NYT, with a maximum observation period of 24 weeks, to clarify the safety profile, particularly the frequency of adverse drug reactions [127].The safety analysis involved 808 patients (mean age 77.8 ± 7.35 years; 210 men, 598 women) and revealed 31 adverse reactions in 25 (3.09%) patients after the start of the drug administration.The most common adverse effects were gastrointestinal disorders (2.1%), followed by metabolic and nutritional disorders, including hypokalemia, general and systemic disorders, administration site conditions, and skin and subcutaneous puncture disorders (0.37%).As for hepatobiliary system disorders, cholecystitis was observed in one case, but drug-induced liver disorder or interstitial lung disease did not occur.
Arai et al. surveyed randomized controlled clinical trials of Kampo preparations from the Kampo Treatment Database to determine the number of patients treated with Kampo preparations and the number and type of adverse events [128].Adverse events were observed in 6 (2.03%) of 295 cases treated with NYT, including 4 cases of gastrointestinal disorders, 1 case of hepatic disorder, and 1 case of anaphylaxis.
Gastrointestinal disorders and drug eruptions are the most common adverse effects of NYT.As NYT contains Glycyrrhizae radix, pseudoaldosteronism can occur, although rarely.PMDA has reported a few cases of pseudoaldosteronism in combination with other herbal medicines containing Glycyrrhizae radix.Thus, care should be taken not to increase the dosage of Glycyrrhizae radix when multiple Kampo medicines are used together.
Gastrointestinal disorders caused by NYT are challenging to predict before administration, but often recover after discontinuation of the drug.Therefore, the drug should be discontinued promptly if any adverse events occur.In addition, drug eruptions are generally difficult to predict before administration.If a skin rash is observed after the administration, drug eruption should be suspected, and drug administration should be discontinued.
Although not a side effect, NYT contains Polygalae radix (Onji in Japanese) as a component herb.Polygalae radix is rich in 1,5-anhydroglucitol, which may be at high levels in the serum of people taking Polygalae radix [129].Caution should be exercised when using 1,5-anhydroglucitol to evaluate the pathophysiology of patients with diabetes.

SUMMARY
The source of NYT is considered to be the 'Formulary of Bureau of Taiping People's Welfare Pharmacy', written around 1241-52 AD.NYT is used to treat patients with chronic fatigue, malaise with qi deficiency, and exhaustion of all five parenchymatous viscera with difficulty in recovering.NYT formula consists of 12 types of crude drugs.NYT extract for medical use is covered by the National Health Insurance system of Japan for convalescence after recovery from diseases, fatigue and malaise, anorexia, perspiration during sleep, cold limbs, and anemia, among others.
Clinical studies have shown several clinical effects of NYT: treatment of anemia, cancer treatment support, efficacy for frailty, cognitive dysfunctions, apathy, fatigue/malaise, and anorexia.
Preclinical studies have found results that support clinical studies; activating ghrelin-neuropeptide Y pathwaymediated appetite-enhancing effects, inhibiting muscle volume loss through the Akt/mTOR pathway-mediated hyperphosphorylation of 4E-BP1 and FoxO1-mediated Atrogin-1, suppressing the hypothalamic-pituitary-adrenal axis by downregulating the sympathetic-adrenal-medullary axis and GABA neurons for improving sociability, promoting recovery from skeletal muscle atrophy with the activation of PGC-1α, hematopoiesis-promoting effects, and increasing the number of immune cells in immune-compromised models, among others.The incidence of adverse events of NYT is low, with the most significant adverse effects of NYT being gastrointestinal disorders.

CONCLUSION
The source of ninjin'yoeito (NYT) is considered to be the 'Formulary of Bureau of Taiping People's Welfare Pharmacy', written around 1241-52 AD.Recently, NYT has been widely used to treat several symptoms and conditions under the national health insurance system.Recent clinical studies showed efficacy for anemia, frailty, cognitive dysfunctions, anorexia, apathy, and fatigue/malaise, as well as for long-term cancer treatment support.The pharmacological mechanisms supporting its effects are also being reported.

T A B L E 1
Summary of Chinese classical literatures.AD Chinese classical literatures Instructions for application Treatise on Three Categories of Pathogenic Factors and Prescriptions <Yoeito> • Treatment for Frailty section • Treatment for Jaundice section 1241-52 Formulary of Bureau of Taiping People's Welfare Pharmacy <Ninjinyoeito (NYT)> • Treatment for Chronic Coldness section (Supplement on Diabetes):

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I G U R E 1 Description of the comparison between NYT and shokenchuto.

F I G U R E 2
High-performance liquid chromatography profile of a NYT extract produced by Tsumura & Co.(a) and Kracie Pharma, Ltd. (b).

Frailty
Hirai et al. reported the RCT of the efficacy of NYT in frailty or pre-frailty patients with chronic obstructive pulmonary disease (COPD).By comparing the NYT (n = 31; 7.5 g/day of NYT for 24 weeks) and control groups (n = 31; conventional treatment), significant changes in the Simplified Nutritional Appetite Questionnaire, COPD Assessment Test, Hospital Anxiety and Depression Scale-Anxiety, and Hospital Anxiety and Depression Scale-Depression scores were observed in the NYT group.Four patients had mild diarrhea as adverse reaction, probably associated with NYT[67].Sakisaka et al. reported the cohort study that examined the effects of NYT on frailty.By comparing the NYT (n = 64; 7.5 g/day of NYT) and control groups (n = 49; conventional treatment), it was found that NYT significantly improved hand grip strength.A significant change was also observed in the Muscle Quality Score between the groups[68].Sakisaka also reported three cases whose grip strength and muscle quality scores were improved by NYT[69].Kashima et al. reported that worsened SF-36 scores after discharge following acute illness improved in three cases by NYT[70].Morinaga et al. reported a case with hip fracture and sarcopenia whose appetite loss, nutritional status, body weight, and muscle mass improved by NYT[71].Kimura et al. reported three cases whose general fatigue was improved by NYT[72].Hirai et al. also reported a case whose body weight, muscle mass, frailty score, COPD score, and anxiety and depression score were improved by NYT[73].

F I G U R E 4
Effect of NYT on the frailty cycle.F I G U R E 5 Effect of NYT on immune cells.CLP, common lymphoid progenitor; CMP, common myeloid progenitor; BFU-E, burst forming unit-erythroid; GMP, granulocyte-monocyte progenitor; IFN-γ, interferon gamma; IL-4, interleukin-4; Th, T helper.
Section of Menstrual Disorder: blood deficiency of spleen meridian • Section of Treatment for Scrofula among Women ※The original version does not exist, and only the revised and annotated version written by XueJi who lived during 1488-1558 AD is available.Therefore, it is plausible that the description of NYT was added in the revised version.
<NYT>• Difference between NYT and juzentaihoto is discussed.Since NYT is used for patients with more severe qi and blood deficiency than juzentaihoto, NYT consists of Citrus unshiu peel for qi circulation, while excluding Cnidium rhizome as it has an effect on blood circulation.
T A B L E 2 Summary of Japanese classical literatures.NYT is based on juzentaihoto with addition of Schisandra fruit and Polygala root, referring to 'Investigations of Medical Prescriptions'.
Plant names and part of each ingredient.Note: The content of each ingredient is the amount contained in an adult daily dose of the extract formulation, listed by each pharmaceutical company.JP, The Japanese Pharmacopeia (Latest 18th edition).(1) Kotaro pharmaceutical Co., Ltd., Kracie Pharma, Ltd. and Ohsugi Pharmaceutical Co., Ltd., (2) Tsumura & Co.
T A B L E 3 a Either JP Atractylodes rhizome or JP Atractylodes lancea rhizome is used.REVIEW OF NINJIN'YOEITO Clinical studies in Ninjin'yoeio.
et al. reported T A B L E 4 Abbreviation: AD, Alzheimer's disease; COPD, chronic obstructive pulmonary disease; Hb, hemoglobin; NYT, ninjin'yoeito; RCT, randomized controlled trial.REVIEW OF NINJIN'YOEITO T A B L E 5 Case reports.
List of non-clinical trials on ninjin'yoeito.
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