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

Table 1

Overview of randomized control trials using NYT in this review.

Publication year	Author	Subjects	Intervention	Control	Outcome	Result	Adverse events
2005	Motoo et al.	Chronic hepatitis C patients treated with interferon alpha-2b and ribavirin (n = 23).	Interferon alpha-2b and ribavirin plus 9.0 g/day of Tsumura NYT (NYT group: n = 10).	Interferon alpha-2b and ribavirin (control group: n = 13).	Maximum decrease in RBC count (max∆RBC); maximum decrease in Hb level (max∆Hb); minimum Hb level (min Hb), WBC count, PLT count, T-helper 1 cell (Th1) count, T-helper 2 cell (Th2) count, Th1/Th2, and glutathione peroxidase level in peripheral blood.	Peripheral max∆Hb and min Hb were significantly improved in the NYT group ( and , respectively). No between-group differences were observed in max∆RBC, WBC count, PLT count, Th1 count, Th2 count, Th1/Th2, and glutathione peroxidase level. In addition, antiviral effects did not differ.	No adverse effect
2004	Oda et al.	Patients who underwent surgery for gynecologic cancer and received granulocyte colony-stimulating factor (G-CSF) for neutropenia during the first cycle of chemotherapy with cyclophosphamide, epirubicin, and cisplatin (total n = 8: ovarian cancer, 6; uterine cancer, 1; or fallopian tube cancer, 1).	Administration of 7.5 g/day of Kanebo NYT from 1 to 2 weeks prior to the start of the second cycle of chemotherapy (NYT group: n = 4).	Without NYT (control group: n = 4).	Nadir WBC and Neu count, the length of time for Neu count to fall below 1,000/μL, total dose of G-CSF, duration of Neu counts under 1,000/μL, and nadir Hb level and PLT count.	There was no significant difference between the groups in nadir WBC, Neu, and PLT counts or the length of time for the Neu count to fall below 1,000/μL. Duration of Neu count under 1,000/μL tended to be shorter in the NYT group than in control group during the second cycle, and became significantly shorter during the third cycle. Total dose of G-CSF tended to be lower in NYT group than in non-NYT group during the second cycle, and became significantly lower during the third cycle. Nadir Hb level during the second cycle, compared to that during the first cycle, was significantly shorter in NYT group, but not in the control group.	N/A
1999	Aoe et al.	Patients with gynecologic malignant tumors and preoperatively donated 800 mL or more of autologous blood. Intravenous administration of an iron preparation to patients with Hb level ≥14 g/dL. Randomization of patients with Hb < 14 g/dL to receive intravenous iron preparation + Kampo formulation + EPO or intravenous iron preparation + EPO. (total n = 90).	Intravenous administration of iron preparation (240 mg weekly) + intravenous drip infusion of 6000 units of EPO three times weekly + oral administration of 7.5 g/day of Tsumura Juzentaihoto or 7.5 g/day of NYT from the day of the first donation to the day before the operation (Kampo group: n = 36).	Intravenous administration of an iron preparation (240 mg weekly) from the day of the first donation to the day before the operation (iron group: n = 16); intravenous administration of an iron preparation (240 mg weekly) + intravenous drip infusion of 6000 units of EPO three times weekly, from the day of the first donation to the day before the operation (iron + Epo group: n = 38).	Hematological profile and serum biochemical profile measured before donation (before administration) and preoperatively (immediately after completion of administration).	The increase in reticulocyte count from the time of donation to the time of operation was larger in the Kampo group (n = 36) and EPO group than in the iron group (n = 15). The increase in Hb level was larger in the EPO group (1.73 ± 1.30 g/dL) than the iron group (0.92 ± 0.70 g/dL), and significantly () larger in the Kampo group (2.33 ± 1.11 g/dL) than the EPO group.	None
1997	Aoe et al.	Patients who donated 800 mL or more of blood for autologous transfusion. The control group (iron preparation only) consisted of patients who donated blood for autologous transfusion.	Iron preparation (intravenous administration of 80 mg three times a week) + Epogin (6000 units three times a week) + (9 g/day) of Tsumura NYT (NYT group: n = 26).	Iron preparation monotherapy (intravenous administration of 80 mg three times a week) (Iron group: n = 10); iron preparation (intravenous administration of 80 mg three times a week) + Epogin (6000 units three times a week) (iron + Epo froup: n = 37).	Hematological profile and serum biochemical profile measured before blood donation and before surgery.	Compared to iron group, but not iron + Epo group, NYT group had significantly increased RBC count, Hb, and hematocrit at the time of preoperative blood collection.	None
1995	Yanagihori et al.	Patients diagnosed with iron deficiency anemia (Hb, 9.0 mg/dL or less) due to menorrhagia and metrorrhagia associated with uterine myoma, uterine adenomyoma, endometrial polyp, etc. (n = 39).	5 g/day of Kanebo NYT + ferrous citrate 100 mg/day for 4 weeks (NYT group: n = 21).	Ferrous citrate 100 mg/day for 4 weeks (control group: n = 18)	Changes in hematological values, including serum iron and ferritin and subjective symptoms (general malaise, shortness of breath, and palpitation) from predose to postdose.	Elevation in Hb value from predoseto postdose was significantly higher in NYT group (). Palpitation and shortness of breath and symptoms for which NYT should be effective (anorexia, night sweats, and cold limbs) were similarly improved in both groups.	None
1995	Okawa et al.	Patients with thoracoabdominal tumors undergoing radiotherapy (lung cancer: 42, esophageal cancer: 19, breast cancer: 9, rectal cancer: 7, cervical cancer: 33, and other cancers: 16) (total n = 116).	7.5 g/day of Kanebo NYT during radiotherapy (NYT group: n = 63).	Radiotherapy only (control group: n = 63).	Subjective symptoms (anorexia, general malaise, diarrhea, coldness, nausea, and vomiting), hematological parameters, body weight, and blood pressure. Biochemical values. Primary physicians evaluated the response of patients based on the above measures on a 4-point scale (marked, moderate, mild, or none).	There were no between-group differences in mean WBC count at baseline and at weeks 1–4. The proportion of patients with WBC count >3000/μL at the end of treatment (weeks 4–8) was higher in NYT group (51/56) than in control group (42/60) (). Improvement in subjective symptoms (at least mild response) was observed more frequently in NYT group (44/56) than control group (6/60) (). Improvement in laboratory test results (at least mild response) was observed more frequently in NYT group (43/56) than in control group (23/60) ().	4 patients in NYT group respectively had drug eruption, abdominal discomfort, abdominal pain + diarrhea, and diarrhea.
1995	Sugimachi	Postoperative patients with stage I–IV gastric cancer undergoing gross curative resection (n = 46).	Fluoropyrimidine anticancer drug + 7.5 g/day of Kanebo NYT from 2 to 14 weeks postoperatively (NYT group: n = 27).	Fluoropyrimidine anticancer drug alone (control group: n = 19).	Hematological measures, body weight, PS, subjective symptoms (appetite, nausea/vomiting, and diarrhea) at 14 weeks after the start of administration.	Change in body weight, PS: no significant difference between the groups. Decrease in RBC count, platelet count: a smaller decrease in NYT group, although not significantly smaller. Decrease in WBC count: no significance between the group difference. Degree of improvement in subjective symptoms: no significance between the group difference.	None
1994	Miyazaki et al.	Patients who complained of dry mouth out of 20 patients who were diagnosed with psychogenic frequency or unstable bladder (chronic cystitis, neurogenic bladder) and received oxybutynin hydrochloride (6 mg/day) for 2 weeks (n = 16).	18.0 g/day of NYT under oxybutynin hydrochloride medication for 4 weeks (NYT group: n = 8).	Oxybutynin hydrochloride alone for 4 weeks (control group: n = 8).	Severity of dry mouth (on a 5-point scale), chewing gum test, frequency of urination evaluated by interview at baseline, 2 weeks, and 4 weeks.	After a 2-week treatment with oxybutynin hydrochloride, 16 of 20 patients (80%) developed xerostomia symptoms. NYT administration for 2 weeks could reduce the symptom of dry mouth in 75% patients, but 0% in control group. Gum test also showed improvement of saliva in NYT group.	N/A
1994	Yamamoto et al.	Patients undergoing cancer chemotherapy or radiotherapy (n = 40).	Chemotherapy + 7.5 g/day of Kanebo NYT (chemo with NYT: n = 11) Radiotherapy + 7.5 g/day of Kanebo NYT (rad with NYT: n = 10).	Chemotherapy + cepharanthine 2 tablets t.i.d. (chemo in control: n = 12). radiotherapy + cepharanthine 2 tablets t.i.d. (rad in control: n = 7).	Four performance status items evaluated on a 5-point scale, nausea/vomiting evaluated on a 4-point scale, hematology, and urinalysis.	NYT treatment significantly improved myelosuppressive symptoms but not subjective and objective symptoms associated with anticancer drug administration. It also improved anorexia and fatigue/malaise during radiotherapy.	One patient had acute hepatitis with unknown causal relationship with NYT.
1994	Hasegawa et al.	Patients with ovarian, uterine cervical, or uterine corpus cancer undergoing cyclophosphamide, adriamycin, and cisplatin therapy. (n = 32).	7.5 g/day of Kanebo NYT and 7.5 g/day of Kanebo Juzentaihoto for 5 weeks from 1 week before to 4 weeks after administration of anticancer drugs (n = 19).	No administration (n = 13)	Pretreatment and posttreatment myelosuppression and nephrotoxicity evaluated by hematology, and subjective symptoms (general malaise, anorexia, and vomiting) evaluated on a 4-point scale using a standard questionnaire.	Kampo medicine treatment did not significantly affect decreases in WBC, RBC, and PLT counts but tended to promote their reversal. Kampo medicine also reduced nephrotoxicity (i.e., normalized blood urea nitrogen (BUN) level and reduced creatinine fluctuation). Subjective gastrointestinal symptoms were not improved.	No adverse effect
1993	Mizuno et al.	Gynecologic cancer (uterine cervical, uterine corpus, ovarian, etc.); more than 1 month since the completion of the initial treatment or treatment for recurrence; at least one of the following subjective symptoms: anorexia, fatigue/malaise, decreased physical strength, cold limbs, night sweats, and lightheadedness.	7.5 g/day of Kanebo NYT for 12 weeks (NYT group: n = 46).	No NYT administration (control group: n = 44).	Improvement in subjective symptom scores was used to measure efficacy.	Subjective symptoms such as physical strength, general fatigue, coldness in hand and foot, and night sweating were significantly improved in the NYT group compared to the control group. The efficacy determined by the doctor according to symptom improvement and side effects was significantly higher in the NYT group than in the control group.	Only one case showed appetite loss and general fatigue which was categorized as a side effect.
1993	Ohara et al.	Patients with cancer including gastric cancer (n = 91), colorectal cancer (n = 63), breast cancer (n = 18), and other cancers (n = 6) receiving an anticancer drug (tegafur 400 mg/day or 600 mg/day) (total n = 178).	7.5 g/day of Kanebo Hochuekkito for 6 months (n = 57) or 7.5 g/day of Kanebo NYT for 6 months (NYT group: n = 56).	Tegafur alone for 6 months (control group: n = 49).	Subjective symptoms (appetite, nausea/vomiting, etc.), objective symptoms (performance status (PS), body weight, blood pressure, etc.), hematology (blood counts, carcinoembryonic antigen, and immunosuppressive acidic protein), and biochemistry at baseline and after 2, 4, and 6 months of treatment.	Subjective symptoms compared between predose and postdose, nausea/vomiting, bowel movement abnormality, motivation, and fatigue/malaise were significantly improved in NYT group. Overall, improvement was noted in 19/56 patients (33.9%) in NYT group, and 7/49 patients (14.3%) in control group, with significant differences in the percentage of patients showing improvement between the groups. Overall, objective symptom improvement was noted in 22/56 patients (39.3%) in NYT group and 10/49 patients (20.4%) in control group, with significant differences in the percentage of patients showing improvement between NYT group and control group. Hematology: there were no significant differences between the groups. Cancer type: only in patients with gastric cancer, the percentage showing improvement in both subjective and objective symptoms was significantly greater in the NYT group than control group.	Side effects were observed in 11.5%.
1992	Araki et al.	Postoperative patients with colorectal cancer on chemotherapy (n = 23).	9.0 g/day of Tsumura NYT from the start of postoperative oral feeding (NYT group: n = 12).	No treatment (control group: n = 11).	Peripheral blood cell count, percentage of T cells (%), phytohemagglutinin (PHA) lymphocyte transformation, lymphocyte surface markers (CD4, CD8, and CD25), NK cell activity (%), and interleukin-2 responsiveness, measured preoperatively, and at postoperative week 2 and months 3 and 6 as indices of immunological status. Patient prognosis (observation for 3 years and 6 months to 4 years and 4 months) in both arms. Prognostic nutritional index.	Percent change in lymphocyte count: greater in arm 1 than arm 2 at week 2 and month 3 after operation (). Change in the T cell number (in %): Greater in arm 2 than arm 1 () at week 2 after operation, but greater in arm 1 than arm 2 () at months 3 and 6 after operation. Percent change in PHA-stimulated lymphocyte proliferation: Greater in arm 1 than arm 2 at month 6 after operation (). Changes in NK cell activity (in %) and prognostic nutritional index: no significant difference between arms. Changes in the number of CD4-and CD8-positive cells (in %) and interleukin-2 responsiveness ratio: all tended to be greater in arm 1 than arm 2 at week 2 and month 3 after operation. Interleukin-2 receptor-positive cell ratio: Tended to be greater in arm 1 than arm 2 at week 2 and month 6 after operation. At month 6 after operation, there was a significant reduction from the preoperative value in arm 1 ().	N/A

WBC: white blood cell; Neu: neutrophil;RBC: red blood cell; PLT: platelet; PS: performance status; N/A: not assigned.