Evaluation of the Safety of Daily Consumption of Kaempferia parviflora Extract (KPFORCE): A Randomized Double-Blind Placebo-Controlled Trial

Abstract

This study's aim was to evaluate the safety of daily consumption of Kaempferia parviflora extract (KPE) using a randomized double-blind placebo-controlled study with 52 recruited healthy Japanese subjects. Each subject received five KPE tablets (containing 150 mg of KPFORCE^™/tablet) or placebo daily for 4 weeks. There were no adverse events related to KPE intake or any abnormalities compared with placebo group in anthropometric, cardiovascular, blood, and urine parameters during the course of the study. Thus, daily KPE ingestion was found to be safe in healthy Japanese men and women.

Introduction

Kaempferia parviflora (KP), a plant commonly known as Black Ginger or Krachai Dam, belongs to the family of Zingiberaceae. KP rhizome has been applied for health promotion and treatment of gastrointestinal disorders,¹ improvement of blood flow,^2,3 and treatment of inflammatory and allergic disorders.^4
–6

Several beneficial effects of KP extract (KPE) have been reported previously and include anti-inflammatory,^4

–7 spasmolytic,⁸ gastric ulcer–ameliorative,⁹ antioxidative,¹⁰ vasodilatory effects,^2,8,11 and it suppresses hypertrophy of adipocyte.^12,13 In a previous study, daily supplementation with KPE in obese mice suppressed body weight increase, accumulation of abdominal fat, and glucose intolerance.^14
–16 Human studies revealed an increase in energy expenditure and fat utilization after oral intake of KPE.^16
–18 Furthermore, dietary intake of KPE decreased visceral as well as subcutaneous fat in both overweight and preobese subjects.¹⁹

KPE in various forms has been consumed as a dietary supplement for >30 years and no adverse effects were reported, suggesting that KPE is safe for consumption. A previous murine study showed that daily intake of KPE (500 mg/kg body weight) did not lead to any toxic effects during a 6-month period.²⁰ Similarly, other studies failed to find any adverse changes in blood biochemical and cellular parameters, urinary parameters, and physical fitness, after a 12-week course of KPE ingestion.^19,21 Although available evidence suggests that consumption of KPE is safe, there are no human studies that evaluated the safety of high-dose KPE intake (750 mg per day). Therefore, in this study we evaluated the safety of daily intake of high-dose KPE in healthy subjects, using a randomized controlled trial.

Materials and Methods

Study design

According to study design, this was a randomized double-blind placebo-controlled trial. The research followed the principles outlined in the Declaration of Helsinki, as well as “Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects.” All related documents of this trial were approved by the Institutional Review Board of the Miyawaki Orthopedics Clinic (approval no.: 17063, approval date: November 27, 2017). All subjects provided signed informed consent in the trial. This clinical trial was registered under UMIN000030585 and run between December 2017 and February 2018 at Fukuhara Clinic.

Subjects

Subjects were recruited by New Drug Research Center, Inc., Japanese individuals of both genders aged between 20 and 65 years were included in the study.

The exclusion criteria were as follows: systolic blood pressure of >90 mm Hg; a history of or current severe heart failure, liver disease, or kidney damage; body mass index (BMI) of >30 kg/m²; metabolic syndrome that was defined as visceral fat area of ≥100 cm² and two or more of the following: elevated triglyceride levels and/or reduced high-density lipoprotein values, increased blood pressure, and high serum glucose²²; medical treatment or surgery within 1 month before the study; continuous intake of oral medications or foods that could affect the study outcome; either possible pregnancy, pregnancy, or lactation; alcohol consumption of at least 40 g alcohol per day or heavy smoking (21 cigarettes per day); collecting blood difficulty; donation of >200 mL of blood within 1 month before the trial; constipation >5 days; shift work; and allergy to the test foods.

Randomization

The subjects were randomly assigned to control and treatment groups using a permuted block randomization by Statcom Co., Ltd. (Japan). After stratification by age, gender, and BMI, participants were randomized to the KPE group and placebo group with the balanced allocation ratio (1:1). An allocation manager generated a sequence list of random numbers. Both the subjects and investigators were blinded to the outcomes of randomization process.

Interventions

The study food consisted of tablets (300 mg each) of either KPE (containing KPE 150 mg; KPFORCE^™, lot no. 81025100) or placebo. KPFORCE was developed by Maruzen Pharmaceuticals Co., Ltd. (Japan). KPFORCE was used in the KPE tablets contained standardized polymethoxyflavone (8–12%), a total of six compounds (5,7-dimethoxyflavone, 3,5,7-trimethoxyflavone, 5,7,4′-trimethoxyflavone, 3,5,7,4′-tetramethoxyflavone, 5,7,3′,4′-tetramethoxyflavone, and 3,5,7,3′,4′-pentamethoxyflavone) were confirmed by high-performance liquid chromatography.

The KPE tablets contained KPFORCE, maltitol syrup, microcrystalline cellulose, sugar fatty acid ester, silicon dioxide, and shellac. For the placebo, lactose and cornstarch were substituted for KPFORCE (Supplementary Table S1). KPE tablets and placebo tablets were indistinguishable in color, size, packaging, and flavor.

Study schedule

Each day subjects received five tablets of either KPE or placebo during 4 weeks. Apart from the initial measurements (at 0 weeks, 0W), the subjects visited the clinic for follow-up at 2 weeks' intervals (2W, 4W, and 6W). They were asked to restrict any intake after 9 P.M. on the day before measurement to water only. On the day of the measurement, the subjects were required not to smoke. Subjects were instructed not to change their lifestyle during the study period, compared with that before study initiation.

We assessed anthropometric parameters (body height, weight, BMI, and waist circumference), cardiovascular parameters (pulse rate and blood pressure), body temperature, blood biochemical and hematological parameters, urine biochemical parameters, and adverse events for all subjects.

Measurements

We measured the subjects' height and weight and calculated BMI at the initial examination. Systolic and diastolic blood pressure (SBP and DBP) as well as pulse rate were measured in sitting position after the subject rested for 5 min.

The following hematological blood parameters were analyzed: white and red blood cell counts, hematocrit, hemoglobin level, platelets count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. Biochemical blood parameters assessed encompassed total proteins and albumin levels, total bilirubin concentration, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, γ-glutamyl transpeptidase, creatine phosphokinase, glucose level, total cholesterol, as well as cholesterol fractions (high-density-lipoproteins and low-density lipoproteins), triglycerides, uric acid, blood urea nitrogen, creatinine, iron, sodium, potassium, calcium, magnesium, and chloride.

In the fasting urine samples, the following parameters were assessed semiquantitatively: urinary protein, glucose, ketone bodies, urobilinogen, bilirubin, as well as occult blood. All analyses of blood and urine samples were performed by SRL, Inc. (Japan).

Statistical analysis

Data in this study were expressed as mean values, with standard deviations (SDs) as measures of variability. Subjects' background data are reported based on Intention-To-Treat, whereas full analysis set data are reported for the safety evaluation.

Homoscedasticity between the KPE group and placebo group was assessed using an F-test. We applied the Student's t-test with homoscedasticity, while Aspin–Welch's t-test was chosen for comparison of data with unequal variances. To compare the semiquantitative urine parameters between the KPE and placebo group, we performed Wilcoxon's rank sum test. To compare the incidence of adverse events between the KPE and placebo group, Fisher's exact probability test was done. The statistical significance level was set at 0.05. All statistical calculations were performed using Microsoft Excel^® 2013 (Microsoft Corp., USA) and SAS^® 9.3 (SAS Institute, Inc., USA).

Results

Subjects and compliance

After randomization procedure, 52 subjects (17 men and 35 women) were allocated to KPE group (n = 26) and placebo group (n = 26). Two subjects declined to participate in the study at 0W. In the KPE group, one individual dropped out of the trial at 4W, and another subject dropped out at 6W due to personal reasons unrelated to the trial. We did not observe any significant difference in baseline characteristics between the KPE group and placebo group (Table 1). The mean rate of test food consumption was 98.7 ± 2.7% in the active KPE group and 99.4 ± 1.7% in the placebo, with no difference (P = .26).

Table 1.

Characteristics of Study Subjects

Variable	Placebo (n = 26)	KPE (n = 26)	P
Female:male	18:8	17:9
Age (years)	45.0 ± 10.7	45.2 ± 10.5	0.9482
Height (cm)	160.30 ± 8.11	161.75 ± 8.05	0.5206
Body weight (kg)	60.64 ± 8.01	61.76 ± 8.30	0.6230
BMI	23.60 ± 2.49	23.55 ± 2.23	0.9442
Temperature (°C)	36.48 ± 0.36	36.52 ± 0.27	0.6940
SBP (mm Hg)	116.5 ± 9.6	116.5 ± 9.2	0.9883
DBP (mm Hg)	70.4 ± 10.2	70.4 ± 7.8	1.0000
Pulse (beats/min)	66.8 ± 7.3	69.1 ± 8.1	0.2948

Values are presented as mean ± SD.

There were no significant differences between the groups.

BMI, body mass index; DBP, diastolic blood pressure; KPE, Kaempferia parviflora extract; SBP, systolic blood pressure; SD, standard deviation.

Adverse events

Five subjects in the KPE group reported adverse events, and these included influenza, cough, and strained back (Table 2). There was no significant difference in the incidence of adverse events between the two groups. No symptoms of allergic reactions were observed in any of the subjects during the study.

Table 2.

Incidence of Adverse Events

Variable	KPE (n = 25)	P
Influenza	2 (8.0)	0.490
Cough	2 (8.0)	0.490
Strained back	1 (4.0)	1.000

Data shown as n (%).

There were no significant differences between the groups.

Anthropometric parameters

Anthropometric data, temperature, SBP, DBP, and pulse of study subjects were similar in both groups (Table 3).

Table 3.

Changes in Physical Parameters

Parameter	Group	Intake period
		Weeks			Follow-up period
		0	2	4	6
Body weight (kg)	Placebo	61.05 ± 8.30	61.12 ± 8.10	61.17 ± 7.86	61.08 ± 8.04
Body weight (kg)	KPE	61.74 ± 8.60	61.78 ± 8.73	61.44 ± 8.64	61.43 ± 8.46
BMI (kg/m²)	Placebo	23.68 ± 2.66	23.70 ± 2.62	23.75 ± 2.65	23.71 ± 2.69
BMI (kg/m²)	KPE	23.53 ± 2.27	23.56 ± 2.41	23.38 ± 2.22	23.39 ± 2.22
Temperature (°C)	Placebo	36.46 ± 0.43	36.41 ± 0.45	36.45 ± 0.29	36.39 ± 0.47
Temperature (°C)	KPE	36.40 ± 0.36	36.42 ± 0.43	36.40 ± 0.38	36.35 ± 0.38
SBP (mm Hg)	Placebo	120.0 ± 11.9	117.3 ± 13.4	118.2 ± 15.3	121.0 ± 15.8
SBP (mm Hg)	KPE	121.6 ± 10.2	120.0 ± 12.6	118.5 ± 12.7	117.3 ± 9.1
DBP (mm Hg)	Placebo	70.8 ± 11.9	69.8 ± 12.0	70.9 ± 11.7	70.9 ± 12.4
DBP (mm Hg)	KPE	73.2 ± 8.5	73.6 ± 12.0	74.1 ± 8.2	71.2 ± 6.8
Pulse (beats/min)	Placebo	66.4 ± 7.0	67.4 ± 7.0	66.5 ± 8.3	66.4 ± 8.3
Pulse (beats/min)	KPE	70.1 ± 8.0	70.8 ± 9.2	71.4 ± 9.1	70.2 ± 6.0

Values are presented as mean ± SD.

There were no significant differences between the groups.

Blood hematology and biochemistry

Hematological and biochemical parameters of the study subjects are summarized in Tables 4 and 5, respectively. There were no intergroup differences in hematological parameters. Although the KPE group showed higher triglyceride levels at 0W and 2W compared with the placebo, such difference was lost at all other time points. Moreover, no significant intergroup differences were noted for other biochemical parameters. Neither group exhibited abnormal changes in hematological or biochemical parameters during the study.

Table 4.

Changes in Hematological Parameters

Parameter	Standard value	Group	Intake period
			Weeks			Follow-up period
			0	2	4	6
WBC (/μL)	M: 3900–9800	Placebo	5188 ± 1466	5420 ± 1588	5464 ± 1732	5460 ± 1165
WBC (/μL)	F: 3500–9100	KPE	5736 ± 1343	5672 ± 1627	5446 ± 1472	5552 ± 1186
RBC ( × 10⁴/μL)	M: 427–570	Placebo	475.2 ± 38.1	470.4 ± 34.6	466.0 ± 39.0	473.0 ± 33.0
RBC ( × 10⁴/μL)	F: 376–500	KPE	462.5 ± 35.5	459.5 ± 32.3	456.9 ± 35.2	458.6 ± 35.9
Hb (g/dL)	M: 13.5–17.6	Placebo	14.24 ± 1.07	14.06 ± 1.03	14.00 ± 1.24	14.14 ± 0.95
Hb (g/dL)	F: 11.3–15.2	KPE	14.05 ± 1.29	13.92 ± 1.17	13.88 ± 1.28	13.90 ± 1.35
Ht (%)	M: 39.8–51.8	Placebo	43.60 ± 2.93	43.18 ± 2.85	42.44 ± 3.31	43.63 ± 2.43
Ht (%)	F: 33.4–44.9	KPE	43.19 ± 3.40	42.95 ± 3.05	42.39 ± 3.40	43.03 ± 3.66
Plts ( × 10⁴/μL)	M: 13.1–36.2	Placebo	26.47 ± 5.67	26.00 ± 5.51	25.88 ± 5.07	25.97 ± 5.72
Plts ( × 10⁴/μL)	F: 13.0–36.9	KPE	26.36 ± 5.58	26.95 ± 5.59	25.92 ± 5.28	26.97 ± 6.70
MCV (fL)	M: 82.7–101.6	Placebo	91.91 ± 4.07	91.91 ± 4.00	91.20 ± 3.91	92.41 ± 4.23
MCV (fL)	F: 79.0–100.0	KPE	93.45 ± 3.89	93.55 ± 3.94	92.84 ± 3.95	93.89 ± 4.20
MCH (pg)	M: 28.0–34.6	Placebo	30.01 ± 1.37	29.92 ± 1.46	30.07 ± 1.46	29.93 ± 1.55
MCH (pg)	F: 26.3–34.3	KPE	30.38 ± 1.62	30.32 ± 1.71	30.38 ± 1.76	30.30 ± 1.73
MCHC (%)	M: 31.6–36.6	Placebo	32.65 ± 0.69	32.55 ± 0.60	32.97 ± 0.70	32.38 ± 0.61
MCHC (%)	F: 30.7–36.6	KPE	32.50 ± 0.82	32.39 ± 0.79	32.70 ± 0.99	32.27 ± 0.73

Values are presented as mean ± SD.

There were no significant differences between the groups.

The number for the placebo group was 25.

In the KPE group, the number of subjects at various time points was 25 (0 and 2 weeks), 24 (4 weeks), and 23 (6 weeks).

F, female; Hb, hemoglobin; Ht, hematocrit; M, male; MCH, mean corpuscular hemoglobin; MCHC, MCH concentration; MCV, mean corpuscular volume; Plts, platelets; RBC, red blood cell; WBC, white blood cell.

Table 5.

Changes in Biochemical Parameters

Parameter	Standard value	Group	Intake period
			Weeks			Follow-up period
			0	2	4	6
TP (g/dL)	6.7–8.3	Placebo	7.14 ± 0.41	7.09 ± 0.33	7.03 ± 0.29	7.12 ± 0.37
TP (g/dL)	6.7–8.3	KPE	7.04 ± 0.35	7.04 ± 0.31	7.03 ± 0.38	7.01 ± 0.40
Albumin (g/dL)	3.8–5.2	Placebo	4.45 ± 0.36	4.33 ± 0.32	4.27 ± 0.32	4.26 ± 0.28
Albumin (g/dL)	3.8–5.2	KPE	4.41 ± 0.35	4.24 ± 0.30	4.20 ± 0.33	4.17 ± 0.34
T-bil (mg/dL)	0.3–1.2	Placebo	0.72 ± 0.26	0.71 ± 0.29	0.66 ± 0.19	0.66 ± 0.20
T-bil (mg/dL)	0.3–1.2	KPE	0.61 ± 0.19	0.61 ± 0.19	0.53 ± 0.18	0.66 ± 0.23
AST (U/L)	10–40	Placebo	19.0 ± 3.7	19.8 ± 4.2	18.3 ± 2.9	18.9 ± 3.2
AST (U/L)	10–40	KPE	19.0 ± 4.4	19.5 ± 4.6	19.8 ± 5.1	19.3 ± 4.8
ALT (U/L)	5–40	Placebo	18.6 ± 7.4	17.7 ± 9.1	16.8 ± 5.2	17.6 ± 6.1
ALT (U/L)	5–40	KPE	17.5 ± 6.2	17.1 ± 6.4	16.8 ± 4.7	16.3 ± 5.4
γ-GTP (U/L)	M: <70	Placebo	18.9 ± 7.9	17.8 ± 7.2	16.7 ± 6.4	17.2 ± 7.1
γ-GTP (U/L)	F: <30	KPE	22.7 ± 15.2	22.6 ± 13.9	19.0 ± 10.2	17.6 ± 9.4
LDH (U/L)	115–245	Placebo	175.7 ± 23.1	181.4 ± 25.5	177.4 ± 22.8	182.8 ± 22.4
LDH (U/L)	115–245	KPE	175.0 ± 29.4	178.3 ± 29.9	182.0 ± 32.5	182.8 ± 27.1
ALP (U/L)	115–359	Placebo	184.6 ± 41.1	182.5 ± 47.2	179.4 ± 46.1	178.2 ± 39.5
ALP (U/L)	115–359	KPE	184.1 ± 46.0	184.7 ± 45.2	179.0 ± 43.5	182.0 ± 45.8
T-Cho (mg/dL)	150–219	Placebo	202.5 ± 24.0	201.0 ± 27.3	197.0 ± 23.4	197.4 ± 27.8
T-Cho (mg/dL)	150–219	KPE	198.9 ± 31.4	200.5 ± 28.9	197.5 ± 31.4	196.0 ± 29.9
HDL-Cho (mg/dL)	M: 40–86	Placebo	71.2 ± 13.6	69.9 ± 12.7	69.9 ± 13.6	70.9 ± 12.9
HDL-Cho (mg/dL)	F: 40–96	KPE	65.4 ± 13.9	65.4 ± 13.1	64.6 ± 14.4	64.9 ± 14.7
LDL-Cho (mg/dL)	70–139	Placebo	119.2 ± 23.5	118.0 ± 26.6	115.7 ± 24.9	116.2 ± 26.2
LDL-Cho (mg/dL)	70–139	KPE	119.2 ± 22.7	119.7 ± 22.5	117.5 ± 21.0	116.6 ± 20.7
Triglyceride (mg/dL)	50–149	Placebo	70.3 ± 24.3	71.4 ± 24.8	70.2 ± 26.5	66.3 ± 27.1
Triglyceride (mg/dL)	50–149	KPE	96.3 ± 50.0^a	98.2 ± 58.8^a	88.1 ± 41.1	85.9 ± 48.1
Glucose (mg/dL)	70–109	Placebo	86.4 ± 7.2	87.3 ± 6.8	89.4 ± 7.9	86.7 ± 7.0
Glucose (mg/dL)	70–109	KPE	88.4 ± 7.1	91.0 ± 7.3	89.6 ± 6.5	88.3 ± 7.7
CPK (U/L)	M: 62–287	Placebo	106.2 ± 40.5	145.7 ± 143.6	101.7 ± 38.8	112.6 ± 77.0
CPK (U/L)	F: 45–163	KPE	109.0 ± 56.6	101.9 ± 43.8	122.5 ± 86.4	122.6 ± 127.3
Uric acid (mg/dL)	M: 3.7–7.0	Placebo	4.61 ± 0.94	4.71 ± 1.11	4.58 ± 1.00	4.46 ± 0.95
Uric acid (mg/dL)	F: 2.5–7.0	KPE	4.42 ± 1.12	4.45 ± 1.08	4.40 ± 1.07	4.35 ± 0.90
BUN (mg/dL)	8.0–22.0	Placebo	13.32 ± 2.91	12.59 ± 2.46	12.29 ± 2.67	12.36 ± 2.94
BUN (mg/dL)	8.0–22.0	KPE	11.93 ± 2.97	11.98 ± 3.24	12.08 ± 2.84	11.73 ± 2.85
Creatinine (mg/dL)	M: 0.61–1.04	Placebo	0.684 ± 0.098	0.681 ± 0.083	0.670 ± 0.086	0.664 ± 0.085
Creatinine (mg/dL)	F: 0.47–0.79	KPE	0.656 ± 0.114	0.661 ± 0.118	0.655 ± 0.109	0.643 ± 0.113
Na (mEq/L)	136–147	Placebo	140.7 ± 1.5	140.2 ± 1.2	140.5 ± 1.5	140.2 ± 1.4
Na (mEq/L)	136–147	KPE	140.5 ± 1.8	139.9 ± 1.7	140.2 ± 1.5	139.9 ± 1.5
K (mEq/L)	3.6–5.0	Placebo	4.40 ± 0.30	4.44 ± 0.35	4.42 ± 0.27	4.30 ± 0.33
K (mEq/L)	3.6–5.0	KPE	4.32 ± 0.29	4.35 ± 0.30	4.29 ± 0.23	4.35 ± 0.37
Cl (mEq/L)	98–109	Placebo	106.8 ± 1.6	106.4 ± 1.3	106.3 ± 1.5	106.0 ± 1.6
Cl (mEq/L)	98–109	KPE	106.4 ± 1.5	106.2 ± 2.0	106.3 ± 2.0	105.7 ± 1.7
Ca (mg/L)	8.5–10.2	Placebo	8.82 ± 0.39	8.87 ± 0.35	8.79 ± 0.36	8.87 ± 0.31
Ca (mg/L)	8.5–10.2	KPE	8.84 ± 0.30	8.91 ± 0.27	8.81 ± 0.27	8.85 ± 0.29
Mg (mg/L)	1.8–2.6	Placebo	2.24 ± 0.16	2.24 ± 0.14	2.29 ± 0.15	2.21 ± 0.16
Mg (mg/L)	1.8–2.6	KPE	2.17 ± 0.12	2.20 ± 0.17	2.27 ± 0.17	2.21 ± 0.13
Fe (μg/L)	M: 54–200	Placebo	138.1 ± 44.0	129.4 ± 39.9	121.8 ± 34.9	126.2 ± 34.4
Fe (μg/L)	F: 48–154	KPE	126.1 ± 60.5	123.0 ± 43.5	120.2 ± 54.1	126.3 ± 46.2

Values are presented as mean ± SD.

The number for the placebo group was 25.

In the KPE group, the number of subjects at each time point was 25 (0 and 2 weeks), 24 (4 weeks), and 23 (6 weeks).

Significant difference between the groups (P < .05).

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Ca, calcium; Cho, cholesterol; Cl, chloride; F, female; Fe, iron; γ-GTP, γ-glutamyltranspeptidase; HDL, high-density lipoprotein; K, potassium; KPE, Kaempferia parviflora extract; LDH, lactate dehydrogenase; LDL, low-density lipoprotein; M, male; Mg, magnesium; Na, sodium; T-bil, total bilirubin; TP, total protein.

Urinalysis

There were no statistically significant differences in the evaluated parameters of urine between the KPE and placebo groups (Table 6).

Table 6.

Changes in Urinalysis Parameters

Parameter	Standard value	Group	Intake period												Follow-up period
			0 weeks				2 weeks				4 weeks				6 weeks
			−	±	+	2+	−	±	+	2+	−	±	+	2+	−	±	+	2+
Urine protein	(−)	Placebo	19	5	1		18	7	0		20	5	0		18	6	1
Urine protein	(−)	KPE	15	9	1		15	10	0		15	8	1		21	2	0
Urine glucose	(−)	Placebo	25	0	0		25	0	0		25	0	0		25	0	0
Urine glucose	(−)	KPE	25	0	0		25	0	0		24	0	0		23	0	0
Urobilinogen	(±)	Placebo	0	25	0		0	25	0		0	25	0		0	25	0
Urobilinogen	(±)	KPE	0	25	0		0	25	0		0	24	0		0	23	0
Bilirubin	(−)	Placebo	25	0	0		25	0	0		25	0	0		25	0	0
Bilirubin	(−)	KPE	25	0	0		25	0	0		24	0	0		23	0	0
Ketone bodies	(−)	Placebo	25	0	0	0	25	0	0	0	25	0	0	0	25	0	0	0
Ketone bodies	(−)	KPE	25	0	0	0	25	0	0	0	22	2	0	0	23	0	0	0
Occult blood	(−)	Placebo	20	0	3	2	20	0	4	1	21	0	2	2	19	0	4	2
Occult blood	(−)	KPE	18	0	3	4	21	0	3	1	18	0	3	3	20	0	3	0
Specific gravity	1.005–1.030	Placebo	1.0179 ± 0.0080				1.0164 ± 0.0066				1.0161 ± 0.0064				1.0185 ± 0.0086
Specific gravity		KPE	1.0185 ± 0.0055				1.0186 ± 0.0060				1.0185 ± 0.0067				1.0182 ± 0.0054
pH	5.0–7.5	Placebo	6.44 ± 0.89				6.52 ± 0.62				6.62 ± 0.85				6.50 ± 0.75
pH		KPE	6.76 ± 0.91				6.66 ± 0.81				6.48 ± 0.77				6.72 ± 0.78

Urine protein, glucose, urobilinogen, bilirubin, ketone bodies, and occult blood: values indicate the number of subjects. Status is indicated as follows: −, negative; ±, false-positive; +, positive (mild); 2+, positive (moderate).

Specific gravity and pH: values are presented as mean ± SD.

There were no significant differences between the groups.

The number for the placebo group was 25.

In the KPE group, the number of subjects at each time point was 25 (0 and 2 weeks), 24 (4 weeks), and 23 (6 weeks).

Discussion

KPE has been widely used for more than three decades in various forms, and the absence of reported adverse effects suggests that KPE is safe. Previous chronic toxicity studies in rats given an extract of KP at doses of 5, 50, and 500 mg/kg per day for 6 months found no clear pharmacotoxic signs or abnormalities associated with KPE.²⁰ Moreover, previous clinical studies of KPE consumption (180 mg per day during 12 weeks) failed to report any significant effects on blood biochemistry parameters.²¹

Our previous study revealed that daily consumption of 150 mg per day of KPFORCE decreases body fat and has no adverse effects on blood and urine parameters in overweight and preobese subjects.¹⁹ Although consumption of 150 mg per day of KPFORCE is considered safe, there are no reports describing assessments of the safety of consuming high doses of KPE. In this study, we investigated the safety of daily consumption of KPE at a fivefold higher level for 4 weeks in healthy Japanese subjects.

Previous studies involved consumption of lower doses of KPE, such as 150 mg per day for 12 weeks¹⁹ or 180 mg per day for 12 weeks,²¹ compared with the consumption of 750 mg per day for 4 weeks in this study. So far, neither of the previous studies showed an increased rate of adverse events in the KPE group compared with placebo. Although influenza, cough, and strained back were observed in the KPE group in this trial, these symptoms did not persist or occur on a daily basis and were thus not related to consumption of the test food. Moreover, no biochemical parameters except triglycerides differed significantly. A previous study reported decreased plasma triglyceride levels with daily KPE intake.¹⁹ We observed a decline in triglyceride levels in the active KPE group at 4 weeks, but the intergroup difference was not significant, perhaps because the subjects were healthy men and women, and the ingestion period was only 4 weeks.

We evaluated the effects of consuming KPE at five times the effective dose and found no KPE-associated side effects or adverse events in terms of anthropometric, hematological, biochemical, or urinalysis parameters. Compliance with KPE consumption was high (98.7 ± 2.7% in the active KPE group and 99.4 ± 1.7% in the placebo group).

In conclusion, this trial adds substantially to previous data indicating that KPE consumption is safe. Although our study involved a relatively short 4-week ingestion period, the results are important. Based on the absence of data indicating safety concerns in a healthy population that consumed KPE daily, longer-duration studies evaluating other populations should be conducted to further confirm the safety of KPE.

Footnotes

Acknowledgments

We are grateful to the volunteers who took part in this study. We also express our gratitude to Ms. Nozomi Takeda for close monitoring of the study and Mr. Fujio Matsuo for generating randomization codes and creating the allocation list. We are also thankful to all the study staff for their contributions.

Author Disclosure Statement

S.Y., R.A., Y.M., and H.K. are employees of Maruzen Pharmaceuticals Co. Ltd. (the study sponsor). I.F. was the principal investigator. H.S., Y.E., and S.T. are employees of New Drug Research Center, Inc., a contract research organization. All authors declare that they have no other conflicting interest associated with this study.

Funding Information

This research did not receive any specific grant.

Supplementary Material

Supplementary Table S1

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