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J Acupunct Res > Volume 32(4); 2015 > Article
Lee, Ha, Kim, Kim, Lee, Lee, Chung, and Kim: Multiple-dose Intramuscular Toxicity Study of Shinbaro Pharmacopuncture in Sprague-Dawley Rats over a 4-week period※
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Abstract

Objectives:

To evaluate the safety of multiple-dose intramuscular Shinbaro Pharmacopuncture in male and female Sprague-Dawley(SD) rats over a period of 4 weeks(12 sessions)

Methods:

In order to test the safety of multiple-dose intramuscular Shinbaro Pharmacopuncture we used 40 healthy male and female 6-week old SD rats(male weight 171.79~196.37 g, female weight 127.93~146.43 g). Shinbaro Pharmacopuncture was administered intramuscularly to male and female SD rats at doses of 4.6 (low dose group, n=10), 9.2 (moderate dose group, n=10), and 18.5mg/kg(high dose group, n=10), respectively. General symptoms, body weight changes, blood tests, biochemical testing, necropsy, organ weight and histopathogical findings were examined over a 4-week period.

Results:

  1. No mortalities or adverse effects were caused by the investigational substance were observed during the study period.

  2. There was no significant difference in body weight caused by the the investigational substance across all groups.

  3. No significant between-group difference was found to be caused by the investigational substance in blood tests and biochemical testing.

  4. No abnormalities were detected by a necropsy examination with the unaided eye at the macro level after treatment with the investigational substance.

  5. Difference in organ weight between groups caused by the investigational substance was not found.

  6. All groups did not exhibit pathological findings caused by the investigational substance in histopathogical examination.

Conclusions:

According to these results, Shinbaro Pharmacopuncture has no systemic or organ toxicity with multiple-dose intramuscular administrations in male and female SD rats over a 4-week period (12 sessions). These results imply that no adverse effects are observed at a level (NOAEL) of Shinbaro Pharmacopuncture of 18.5 mg/kg.

Fig. 1
Body weight changes of male and female SD rat with shinbaro pharmacopuncture for four weeks
*: Significant difference between control and 18.5 mg/kg group value by Dunnett’s T test, p<0.0
acup-32-4-77f1.gif
Table 1
Group composition for assessment of four weeks repeated-dose toxic test in SD rats
Group Sex Animal No.1 Dose (mg/kg/day)
G12 Male G1-1~G1-10 0
Female G1-51~G1-60
G2 Male G2-16~G2-25 4.6
Female G2-66~G2-75
G3 Male G3-26~G3-35 9.2
Female G3-76~G3-85
G4 Male G4-36~G4-45 18.5
Female G4-86~G4-95

1 No: Numbers

2 G1: Control group(0 mg/kg), G2~G4: Experimental group (4.6, 9.2, 18.5 mg/kg)

Table 2
Hematological values of male and female SD rat with shinbaro pharmacopuncture for four weeks
sex: Male
Hematological G124(n = 10) G2 (n = 10) G3 (n = 10) G4 (n = 10)
0 mg/kg 4.6 mg/kg 9.2 mg/kg 18.5 mg/kg
wbc1(K/μL) 8.99±2.42 11.04±2.82 10.16±2.72 9.24±3.26
NE2(K/μL) 0.89±0.24 1.37±0.47* 1.38±0.40* 1.09±0.23
ly3(K/μL) 7.68±2.15 9.27±2.42 8.41 ±2.35 7.84±2.95
mo4(K/μL) 0.18±0.05 0.22±0.08 0.18±0.08 0.16±0.08
eo5(K/μL) 0.05±0.01 0.05±0.02 0.05±0.02 0.05±0.03
BA6(K/μL) 0.00±0.00 0.01 ±0.00 0.01 ±0.01 0.01±0.01
LUC7(K/μL) 0.19±0.15 0.12±0.06 0.13±0.10 0.10±0.07
NEP8(%) 10.25±2.42 12.35±2.75 13.77±2.51* 12.36±2.28
LYP9(%) 85.14±2.94 84.04±2.78 82.49±2.91 84.32±2.41
MOP10(%) 1.95±0.37 1.92±0.48 1.84±0.71 1.68±0.44
EOP11(%) 0.63±0.21 0.49±0.31 0.53±0.23 0.51±0.23
BAP12(%) 0.05±0.05 0.08±0.04 0.07±0.08 0.11±0.12
LUP13(%) 1.97±1.23 1.12±0.70 1.26±1.22 0.99±0.41
rbc14(M/μL) 7.90±0.20 8.18±0.32 8.12±0.36 7.94±0.24
Hb15(g/dL) 17.22±0.47 17.86±0.67 17.58±0.78 17.35±0.62
HCT16(%) 47.30±1.49 48.55±2.02 48.17±1.57 47.72±1.48
MCV17(fL) 59.90±1.64 59.43±2.12 59.37±1.93 60.13±1.65
MCH18(pg) 21.80±0.55 21.82±0.60 21.69±0.85 21.88±0.66
MCHC19(g/dL) 36.38±0.46 36.76±0.74 36.51±0.67 36.35±0.97
RDW20(%) 11.39±0.30 11.13±0.30 11.37±0.36 11.17±0.40
PLT21(K/μL) 1077.90±89.33 1154.80±129.89 1115.10±218.20 1117.50±92.20
MPV22(fL) 6.76±0.36 6.48±0.24 6.91±0.39 6.69±0.54
Reti23(%) 2.61±0.48 2.46±0.37 2.47±0.48 2.65±0.23
sex: Female
Hematological G124(n = 10) G2 (n = 10) G3 (n = 10) G4 (n = 10)
0 mg/kg 4.6 mg/kg 9.2 mg/kg 18.5 mg/kg
wbc1(K/μL) 7.02±0.88 7.72±1.43 6.41 ±1.06 7.11±2.40
ne2(K/μL) 0.76±0.31 1.59±2.36 0.69±0.21 0.51 ±0.21
ly3(K/μL) 5.91±0.68 5.66±1.88 5.48±0.94 6.35±2.36
mo4(K/μL) 0.15±0.05 0.27±0.36 0.12±0.03 0.11±0.03
eo5(K/μL) 0.07±0.04 0.05±0.03 0.05±0.01 0.05±0.02
BA6(K/μL) 0.01±0.01 0.01±0.01 0.01±0.00 0.01±0.00
LUc7(K/μL) 0.12±0.13 0.14±0.14 0.08±0.03 0.09±0.06
NEP8(%) 10.70±3.80 18.09±20.42 10.74±2.51 8.05±4.43
LYP9(%) 84.46±4.90 75.96±22.76 85.40±2.54 88.31±4.83
MOP10(%) 2.17±0.50 3.01±3.12 1.85±0.44 1.67±0.44
EOP11(%) 0.99±0.56 0.71±0.36 0.76±0.24 0.72±0.26
BAP12(%) 0.09±0.07 0.12±0.09 0.10±0.04 0.09±0.05
LUP13(%) 1.59±1.35 2.09±2.29 1.15±0.36 1.15±0.48
rbc14(M/μL) 7.84±0.34 7.76±0.36 7.81±0.39 7.83±0.37
Hb15(g/dL) 17.26±0.80 16.63±0.79 16.88±0.83 16.93±0.94
HCT16(%) 45.44±2.43 44.56±2.23 45.68±2.41 45.30±2.89
MCV17(fL) 57.92±1.10 57.48±2.01 58.52±1.70 57.86±1.56
MCH18(pg) 22.00±0.38 21.45±0.70 21.64±0.36 21.65±0.53
MCHC19(g/dL) 38.02±0.84 37.34±0.45* 37.00±0.72* 37.40±0.57
RDW20(%) 10.62±0.98 10.51±0.38 10.43±0.28 10.33±0.24
PLT21(K/μL) 1240.30±147.30 1209.30±129.69 1165.00±169.52 1193.50±88.04
MPV22(fL) 6.63±0.29 6.69±0.42 6.76±0.28 6.66±0.25
Reti23(%) 2.50±1.16 2.28±0.45 2.22±0.35 2.11±0.45

1 White blood cell

2 Neutrophils

3 Lymphocyte

4 Monocyte

5 Eosinophil

6 Basophil

7 Large unstained cell

8 Percent of neutrophils

9 Percent of lymphocyte

10 Percent of monocyte

11 Percent of eosinophil

12 Percent of basophil

13 Percent of large unstained cel

14 Red blood cell

15 Hemoglobin

16 Hematocrit

17 Mean corpuscular volume

18 Mean corpuscular hemoglobin

19 Mean corpuscular hemoglobin concentration

20 Red cell distribution width

21 Platelet

22 Mean platelet volume

23 Reticulocyte

24 G1: Control group(0 mg/kg), G2~G4: Experimental group(4.6, 9.2, 18.5 mg/kg),

* Significant difference compared with control value by Dunnett’s T test, p<0.05

1 White blood cell

2 Neutrophils

3 Lymphocyte

4 Monocyte

5 Eosinophil

6 Basophil

7 Large unstained cell

8 Percent of neutrophils

9 Percent of lymphocyte

10 Percent of monocyte

11 Percent of eosinophil

12 Percent of basophil

13 Percent of large unstained cel

14 Red blood cell

15 Hemoglobin

16 Hematocrit

17 Mean corpuscular volume

18 Mean corpuscular hemoglobin

19 Mean corpuscular hemoglobin concentration

20 Red cell distribution width

21 Platelet

22 Mean, platelet volume

23 Reticulocyte

24 G1: Control group(0 mg/kg), G2~G4: Experimental group(4.6, 9.2, 18.5 mg/kg), Group(n) / Dose(mg / kg)

* Significant difference compared with control value by Dunnett’s T test, p<0 05

Table 3
Serum biochemical values of male and female SD rat with shinbaro pharmacopuncture for four weeks
sex: Male
Serum G123(n = 10) G2 (n = 10) G3 (n = 10) G4 (n = 10)
0 mg/kg 4.6 mg/kg 9.2 mg/kg 18.5 mg/kg
AST1 (IU/L) 133.20±29.70 130.10±35.62 121.60±28.92 121.00±32.86
ALT2 (IU/L) 31.10±4.01 37.70±7.39 34.60±6.90 34.20±6.14
ALP3 (IU/L) 707.80±57.14 785.10±137.19 681.50±83.95 719.70±174.69
GGT4 (IU/L) 0.90±0.30 0.80±0.40 0.90±0.30 1.00±0.00
LDH5 (IU/L) 1288.80±709.57 1061.70±915.57 847.20±770.71 921.40±766.96
BUN6 (mg/dL) 17.69±2.34 19.09±2.06 17.94±1.33 17.50±2.34
CRE7 (mg/dL) 0.52±0.05 0.55±0.05 0.55±0.05 0.51±0.02
GLU8 (mg/dL) 213.80±22.10 218.40±27.10 203.60±25.80 206.30±41.68
CHO9 (mg/dL) 68.40±12.00 80.90±10.25 72.00±11.94 73.50±11.67
TP10 (g/dL) 6.68±0.27 6.88±0.26 6.79±0.31 6.77±0.21
CPK11 (U/L) 843.30±404.87 726.90±519.65 584.60±392.44 648.80±447.59
ALB12 (g/dL) 2.75±0.11 2.81±0.13 2.78±0.14 2.76±0.10
T-BIL13 (mg/dL) 0.04±0.02 0.03±0.02 0.03±0.20 0.04±0.02
A/G ratio14 0.70±0.04 0.69±0.04 0.69±0.03 0.69±0.03
TG15 (mg/dL) 50.20±22.17 51.30±25.41 62.90±16.92 64.00±26.59
UA6 (mg/dL) 2.63±0.61 3.24±0.74 3.06±0.59 2.88±0.49
Ca17 (mg/dL) 13.13±0.61 13.18±0.41 13.05±0.47 13.35±0.67
IP18 (mg/dL) 12.54±0.97 12.72±0.75 12.65±0.99 12.87±0.75
Cl19 (mmol/L) 105.70±1.42 106.10±1.14 106.20±1.33 106.00±1.41
Mg20 (mg/dL) 3.10±0.26 3.36±0.34 3.20±0.32 3.21±0.28
Na21 (mmol/L) 144.80±1.17 144.90±1.45 145.40±0.92 146.10±1.64
K22 (mmol/L) 5.41 ±0.62 5.72±0.28 6.06±0.91 5.88±0.67
sex: Female
Serum G123(n = 10) G2 (n = 10) G3 (n = 10) G4 (n = 10)
0 mg/kg 4.6 mg/kg 9.2 mg/kg 18.5 mg/kg
AST1 (IU/L) 163.40±57.47 129.60±36.10 116.70±18.32 139.70±31.07
ALT2 (IU/L) 37.10±13.20 34.80±5.74 30.10±4.66 34.80±7.53
ALP3 (IU/L) 427.60±103.61 408.70±116.02 460.80±86.69 438.10±85.90
GGT4 (IU/L) 0.30±0.46 0.30±0.46 0.50±0.50 0.60±0.49
LDH5 (IU/L) 1316.50±704.54 1164.40±941.13 835.20±518.99 1346.80±716.47
BUN6 (mg/dL) 20.55±2.39 20.00±3.35 21.51 4.38 19.49±1.75
CRE7 (mg/dL) 0.59±0.06 0.56±0.05 0.61±0.07 0.57±0.05
GLU8 (mg/dL) 165.40±40.76 167.10±26.18 160.90±28.77 170.30±31.23
CHO9 (mg/dL) 85.10±13.58 96.40±9.33 99.00±23.32 102.00±17.98
TP10 (g/dL) 7.35±0.37 7.11 ±0.41 7.18±0.51 7.17±0.38
CPK11 (U/L) 807.50±321.17 682.90±472.68 488.60±217.21 731.90±297.78
ALB12 (g/dL) 3.17±0.24 3.09±0.23 3.12±0.27 3.16±0.21
T-BIL13 (mg/dL) 0.06±0.04 0.06±0.03 0.05±0.02 0.05±0.02
A/G ratio14 0.76±0.10 0.77±0.05 0.77±0.05 0.79±0.06
TG15 (mg/dL) 26.80±11.14 29.00±6.32 33.40±14.57 26.10±11.16
UA6 (mg/dL) 2.67±0.52 2.55±0.47 2.64±0.45 2.96±0.62
Ca17 (mg/dL) 13.10±1.06 13.67±2.23 13.71±1.62 12.90±0.52
IP18 (mg/dL) 11.46±1.27 12.09±0.70 12.09±0.87 11.59±0.83
Cl19 (mmol/L) 106.20±1.99 105.30±1.55 106.20±1.83 106.90±4.18
Mg20 (mg/dL) 3.37±0.17 3.38±0.21 3.46±0.39 3.40±0.47
Na21 (mmol/L) 143.50±1.69 141.70±1.55 143.40±1.91 144.30±5.50
K22 (mmol/L) 5.30±1.00 5.90±1.04 5.35±0.86 5.63±0.91

1 Aspartate aminotransferase

2 Alanine aminotransferase

3 alkaline phosphatase

4 Gamma(γ)-glutamyl transferase

5 Lactate dehydrogenase

6 Blood urea nitrogen

7 Creatinine

8 Glucose

9 Total cholesterol

10 Total protein

11 Creatine phosphokinase

12 Albumin

13 Total bilirubin

14 Albumin/Globulin ratio

15 Triglyceride

16 Uric acid

17 Calcium

18 Inorganic phosphorus

19 Chloride

20 Magnesium

21 Sodium

22 Potassium

23 G1: Control group(0 mg/kg), G2~G4: Experimental group(4.6, 9.2, 18.5 mg/kg), Group(n) / Dose(mg / kg)

* : Significant difference compared with control value by Dunnett’s T test, p<0.05

1 Aspartate aminotransferase

2 Alanine aminotransferase

3 alkaline phosphatase

4 Gamma(γ)-glutamyl transferase

5 Lactate dehydrogenase

6 Blood urea nitrogen

7 Creatinine

8 Glucose

9 Total cholesterol

10 Total protein

11 Creatine phosphokinase

12 Albumin

13 Total bilirubin

14 Albumin/Globulin ratio

15 Triglyceride

16 Uric acid

17 Calcium

18 Inorganic phosphorus

19 Chloride

20 Magnesium

21 Sodium

22 Potassium

23 G1: Control group(0 mg/kg), G2~G4: Experimental group(4.6, 9.2 18.5 mg/kg), Group (n) / Dose(mg / kg)

* : Significant difference compared with control value by Dunnett’s T test, p<0.05

Table 4
Gross findings of male and female SD rat with shinbaro pharmacopuncture for four weeks
Sex Organ Sign Group (mg/kg)
G11 (n = 10, 0) G2 (n = 10, 4.6) G3 (n = 10, 9.2) G4 (n = 10, 18.5)
Male All organs Normal 10 / 10 10 / 10 10 / 10 10 / 10
Female All organs Normal 10 / 10 10 / 10 10 / 10 10 / 10

* Number of animals with the sign / Number of animals examined

1 G1: Control group(0 mg/kg), G2~G4: Experimental group(4.6, 9.2, 18.5 mg/kg)

Table 5
Organ weights of male and female SD rat with shinbaro pharmacopuncture for four weeks
sex: Male (g)
Organ G11 (n = 10) G2 (n = 10) G3 (n = 10) G4 (n = 10)
0 mg/kg 4.6 mg/kg 9.2 mg/kg 18.5 mg/kg
Body weigh 362.46±30.55 349.16±32.27 347.94±33.89 356.71±37.30
Testis(Lt.) 1.61±0.08 1.69±0.15 1.64±0.13 1.71±0.11
Testis(Rt.) 1.64±0.09 1.68±0.13 1.64±0.12 1.69±0.12
Prostate 0.58±0.12 0.62±0.13 0.62±0.10 0.66±0.10
Spleen 0.77±0.09 0.76±0.06 0.69±0.07 0.75±0.12
Liver 10.53±1.05 10.15±1.15 10.42±1.35 10.75±1.54
Adrenal gland(Lt.) 0.03±0.00 0.14±.34 0.03±0.00 0.03±0.00
Adrenal gland(Rt.) 0.03±0.01 0.03±0.01 0.03±0.00 0.03±0.00
Kidney(Lt.) 1.26±0.12 1.19±0.39 1.28±0.10 1.33±0.12
Kidney(Rt.) 1.30±0.11 1.31±0.09 1.33±0.11 1.36±0.12
Heart 1.33±0.11 1.23±0.10 1.28±0.14 1.34±0.14
Lung 1.47±0.14 1.52±0.14 1.45±0.19 1.53±0.20
Brain 2.02±0.09 2.06±0.10 203±0.08 204±0.06
Pituitary 0.01±0.00 0.01±0.00 0.01±0.00 0.01±0.00
Thymus 0.51±0.15 0.49±0.14 0.48±0.09 0.46±0.10
sex: Female (g)
Organ G11 (n = 10) G2 (n = 10) G3 (n = 10) G4 (n = 10)
0 mg/kg 4.6 mg/kg 9.2 mg/kg 18.5 mg/kg
Body weigh 226.01 ±11.21 219.97±8.85 223.46±9.87 220.46±12.84
Testis(Lt.) 0.05±0.01 0.05±0.01 0.05±0.01 0.05±0.00
Testis(Rt.) 0.05±0.01 0.05±0.01 0.05±0.00 0.05±0.00
Prostate 0.38±0.07 0.53±0.24 0.49±0.10 0.51±0.15
Spleen 0.53±0.10 0.53±0.11 0.52±0.09 0.51±0.08
Liver 6.82±0.44 6.86±0.37 6.97±0.57 6.83±0.75
Adrenal gland(Lt.) 0.03±0.00 0.03±0.00 0.03±0.00 0.04±0.00
Adrenal gland(Rt.) 0.03±0.00 0.03±0.00 0.03±0.01 0.04±0.00
Kidney(Lt.) 0.78±0.09 0.79±0.06 0.83±0.07 0.83±0.09
Kidney(Rt.) 0.80±0.07 0.83±0.08 0.86±0.09 0.85±0.08
Heart 0.83±0.08 0.88±0.06 0.88±0.10 0.85±0.07
Lung 1.18±0.11 1.19±0.13 1.24±0.08 1.27±0.22
Brain 1.85±0.06 1.88±0.07 1.91±0.11 1.88±0.06
Pituitary 0.01±0.00 0.01 ±0.00 0.01±0.00 0.01±0.00
Thymus 0.45±0.06 0.45±0.06 0.46±0.06 0.42±0.07

1 G1: Control group(0 mg/kg), G2~G4: Experimental group(4.6, 9.2, 18.5 mg/kg)

* Significant difference compared with control value by Dunnett’s T test, p<0.05, Group(n) / Dose(mg/kg)

Table 6
Histopathological findings of male and female SD rat with shinbaro pharmacopuncture for four weeks
Organ / findings (Number of animals) Male Female
G11 (n=10, 0 mg/kg) G4 (n=10, 18.5mg/kg) G1 (n=10, 0mg/kg) G4 (n=10, 18.5mg/kg)
Liver –Bile duct hyperplasia ±2 (n=1) NR3 NR NR
–Cell infiltration, mononuclear, perivascular ± (n=1) NR NR NR
–Cell infiltration, mononuclear, multifocal ± (n=2) NR NR NR
–Cell infiltration, mononuclear, focal ± (n=1) ± (n=4) ± (n=3) ± (n=3)
–Necrosis, focal NR NR ± (n=2) NR
Thyroid –Ultimobranchial cyst ± (n=1) ± (n=1) NR NR
–Ectopic thymus ± (n=1) NR ± (n=1) NR
Lung –Osseous metaplasia ± (n=1) NR NR NR
–Accumulation, alveolarmacrophage, focal NR ± (n=1) NR NR
Heart –Edema, perivascular NR ± (n=1) NR NR
–Cellinfiltration, mononuclear, focal ± (n=2) NR NR NR
Kidney –Basophilic tubule, with inflammatory cell infiltration, focal, cortex NR ± (n=1) NR NR
–Cyst, with inflammatory cell infiltration, cortex NR NR NR ± (n=1)
Pituitary –Cyst, parsdistalis NR ± (n=1) NR NR
There were no remarkable changes in the other organ.

1 G1: Control group(0 mg/kg), G2~G4: Experimental group (4.6, 9.2, 18.5 mg/kg), 2. Grade: minimal(±), mild(+), 3. NR: No remarkable lesions

V.
V.

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