A Comparative Study about Cerebrovascular Reactivity from a Single Medication and Continuous Medication on Healthy Subjects

(1)

서 론

1107 ¹⁾ .

牛黃淸心元

황재웅, 김창현, 민인규, 김영지, 임정태, 나병조, 박성욱, 박정미, 고창남, 배형섭, 정우상, 문상관, 조기호, 김영석

경희대학교 한의과대학 심계내과학교실

Original Article

A Comparative Study about Cerebrovascular Reactivity from a Single Medication and Continuous Medication on Healthy Subjects

Jae-Woong Hwang, Chang-Hyun Kim, In-Kyu Min, Young-Ji Kim, Jung-Tae Leem, Byong-Jo Na, Sung-Wook Park, Jung-Mi Park, Chang-Nam Ko, Hyung-Sup Bae,

Woo-Sang Jung, Sang-Kwan Moon, Ki-Ho Cho, Young-Suk Kim Department of Cardiovascular and Neurologic Diseases(StrokeCenter)

College of Oriental Medicine, Kyung-Hee University

Objectives: Uwhangchungsim-won (UC) has been used in various medical fields such as stroke, hypertension, atherosclerosis, autonomic imbalance and mental instability, etc. The aim of this study was to evaluate the effect of UC on cerebral hemodynamics and estimate the appropriate dose of UC.

Methods: We studied changes of hyperventilation-induced cerebrovascular reactivity and mean blood flow velocity of middle cerebral arteries (MCA) using transcranial Doppler. We observed the changes of mean blood pressure, pulse rate and expiratory CO2 using S/5 Compact Anesthesia Monitor from 10 healthy young volunteers who were administered UC twice a day in the 1st section and then once a day in the 2nd section.

Results: Mean blood pressure tended to decrease at 1 hour and pulse rate tended to decrease at 2 hours after second administration. After 2 hours, mean blood pressure rose to state before administration, but pulse rate maintained from 2 hours to 4 hours. The changes were not statistically significant.

Cerebral blood flow velocity in middle cerebral artery was not statistically significant after second administration.

Cerebrovascular reactivity increased from 2 hours to 4 hours after second administration.

Conclusions: This study provides that administration of UC twice a day is more effective on hyperventilation-induced cerebrovascular reactivity than administration of UC once a day.

Key Words : Uwhangchungsim-won, transcranial Doppler (TCD), cerebral blood flow velocity, cerebrovascular reactivity

접수：2008년 8월 25일 수정：2008년 12월 23일 채택：2008년 12월 29일

교신저자：황재웅(Jae-Woong Hwang)

서울특별시 동대문구 회기동 1번지 경희의료원 한방병원 2내과학교실

Tel：+82-2-958-9129, Fax：+82-2-958-9132, E-mail：[email protected]

(2)

, , , ,

, , ,

2-6) .

Transcranial Doppler(TCD) Doppler effect

,

TCD ^7-13) .

TCD

Pulsatility index(PI) Breath holding index (BHI)

7) . TCD

,

120 , 180

8) .

,

18) . TCD

8) 1

.

. ,

.

1 2 , 2

, 24

.

1 2 , ,

, 1 1

.

연구방법

1. 연구대상

20 10

, 25.5±1.3 .

10 , ,

.

2. 시험약재

(HH075)

, 1 pill (full dose)

Table 1 .

3. 연구 디자인

cross-over study .

4 1 1

10 1

, , ,

.

1 1

3 1 2

10 , 2 2

, , ,

(Fig. 1).

2 ,

13) 8)

Raw

Data 1 1

.

4. 평가내용

(3)

1) (Cerebrovascular Reactivity = CO 2 Reactivity)

2) (Mean blood flow velocity, Vm) 3)

4)

5) (PETCO 2 )

5. 평가 방법

1)

.

constituent herbs weight (mg/pill)

山藥 rhizome of Dioscorea japonica 315.0

甘草 (炙) rhizome of Glycyrrhiza uralensis Fisch(broiled) 225.0

人蔘 root of Panax ginseng C.A. MEY. 112.5

蒲黃(炒) pollen of Typha orientalis(parched) 112.5

神曲 (炒) Massa Medicata Fermentata(parched) 112.5

大豆黃券(炒) seed of Glycine max(parched) 79.0

肉桂 stem bark of Cinnamomum cassia PRESL. 79.0

阿膠珠 Equus asinus L. 79.0

白芍藥 root of Paeonia lactiflora 67.5

麥門冬 tuber of Liriope platyphylla 67.5

黃芩 root of Scutellaria baicalensis 67.5

當歸 root of Angelica gigas Nakai 67.5

防風 root of Ledebouriella divaricata 67.5

白朮 rhizome of Atractylodes macrocephala 67.5

柴胡 root of Bupleurum falcatum L. 56.5

桔梗 root of Platycodon grandiflorum(Jacq.) A. DC. 56.5

杏仁 seed of Prunus armeniaca var ansu 56.5

白茯 fungus of Poria cocos 56.5

川芎 rhizome of Cnidium officinale 56.5

牛黃 gallstone of Bos taurus domesticus GMELIN. 45.0

羚羊角 horn of Saiga tatarica 45.0

龍腦 Borneolum 45.0

麝香 musk deer gland of Moschus moschiferus 37.5

白 rhizome of Ampelopsis japonica 30.0

柏子仁 seed of Biota orientalis 30.0

酸棗仁 seed of Ziziyphus spinosa 30.0

石菖蒲 rhizome of Acorus gramineus 30.0

乾薑(炒) dried rhizome of Zingiberis officinale Rosc.(parched) 30.0

大棗 fruit of Zizyphus jujuba Mill. 1200.0

蜂蜜 saccharine substances obtained from honeycomb of Apis mellifera 1000.0

金箔 Gold q.s.

Total amount 3750mg

Table 1.

(4)

5 .

TCD Multi-Dop X4 system(DWL , Germany) , mode 1 channel 1 depth monitoring 2MHz probe

. (depth)

50-65mm , sample gain

,

.

bilateral probe holder(LAM-Rack, DWL ,

Germany) probe

monitoring ,

, .

CO 2 reactivity .

5 , 1

30

Fig. 2.

TW - ce a d ay

UC 1st Administration

UC 2nd Administration

TCD moniter

UC Administration

O n ce a d ay

TCD moniter

9:30 (base)

10:00 1hr 14:00 1hr 2hrs 3hrs 4hrs 9:30

(2

^nd

base) 10:00

TCD moniter

9:30 (base)

10:00 9:30

(2

^nd

base) 10:00

Fig. 1.

(5)

.

Cardiocap S/5(Datex-Ohmeda

, Finland) .

TCD

monitoring 2 4

. Oxymetry

. CO 2 (PETCO 2 ) Nasal prong

monitoring . 3

S/5 Collector PC

, (Fig. 2)

1 2

base , 10

, 14

1 , 2 , 3 , 4

base 6

. 1 1 base

10 ,

base 2

. 20

,

. 2)

off-line analysis .

probe

TCD monitoring ,

3 .

CO 2 Reactivity 3

interval

(V rest ) 1

30 (V hypocapnia ), PETCO 2

26) . CO 2 Reactivity %/

min . ( PETCO 2 : the change in PETCO 2 from baseline to maximal hyperventilation)

CO 2 Reactivity=100 [(V rest V hypocapnia )/V rest ] / PETCO 2

CO 2

PaCO 2 40mmHg

(Corrected blood velocity at 40mmHg of CO 2 tension;

CV40) ²⁷⁾

.(b : CO 2 reactivity, V1 : velocity at P 1 CO 2 )

CV40 cm/sec .

CV40=V 1 e b(PCO2 40mmHg P1CO2)

4 .

, P ETCO2 S/5 Collector snapshot

. 3)

.

1 2 2

2 1 ¹³⁾

8) .

1 1 2

base 24

1 2

.

6. 통계분석

SPSS(Statistical Program for Social Science) 12.0 for Windows .

Repeated Measures of ANOVA

(6)

, 24 Mann-

Whitney U Test ( ,

, , ) p-value

0.05 .

연구결과

1. 1 일 2 회 복용군의 시간에 따른 변화

1)

1 2 2

1 . (Within-subject effect) .(p<0.001)

1 (Table 2, Fig. 3).

2)

1 2 2

,

Before

administration

After administration

p-value

1hr 2hrs 3hrs 4hrs

BP (mmHg)

Bid 86.9±5.8 81.4±5.7 86.9±5.7 87.2±5.1 89.8±5.5 <0.001^＊

Control^♣ 85.8±6.5 85.9±6.0 85.7±7.5 86.9±7.7 88.1±6.0 0.888^†

Qd^¶ 78.6±7.3 80.2±5.4 81.5±5.2 83.0±4.3 0.064^‡

♣

Control Group from Jung

¹³

's raw data

¶

Once administration group from Kim

⁸

's raw data Values are Means±SD

UC : Uwhangchungsimwon BP : mean blood pressure

Bid : Twice administration per a day(administration at 10:00 a.m., 2:00 p.m.)

＊

: Within-subject effect at Bid during 4hours

†

: Between-subject effect(Bid and Control) during 4hours

‡

: Between-subject effect(Bid and Qd) during 3hours

Table 2.

B P ( % )

15.0 Base 1hr 2hrs 3hrs 4hrs

10.0

5.0

0.0 Bid Control

^♣

Qd

^¶

-5.0

Fig. 3.

(7)

.

(Table 3, Fig. 4).

3)

1 2 3

. 4

.

(Table 4, Fig. 5).

4)

2 1

2 4 ,

(Within-subject effects)

(p=0.019). 4

(Interaction, p=0.014), 3 1

(p=0.002).

Before administration

p-value

1hr 2hrs 3hrs 4hrs

PR (bpm)

Bid 76.4±12.4 72.4±12.5 73.0±10.4 71.9±11.3 72.9±9.0 0.174^＊

Control^♣ 71.0±8.7 66.7±9.6 64.4±9.4 64.1±9.7 66.8±10.3 0.147^†

Qd^¶ 66.8±8.1 62.3±6.3 61.9±8.1 62.1±6.3 0.063^‡

♣

Control Group from Jung

¹³

's raw data

¶

Once administration group from Kim

⁸

's raw data Values are Means±SD

UC : Uwhangchungsimwon

Bid : Twice administration per a day(administration at 10:00 a.m., 2:00 p.m.)

＊

: Within-subject effect at Bid during 4hours

†

: Between-subject effect(Bid and Control) during 4hours

‡

: Between-subject effect(Bid and Qd) during 3hours

Table 3.

Bid Control

^♣

Qd

^¶

P R ( % )

5.0

0.0 -5.0

-10.0

-15.0

Base 1hr 2hrs 3hrs 4hrs

Fig. 4.

(8)

3 1 , 2 ,

(Between- subject effects, p=0.001)

(Table 5, Fig. 6).

2. 1 일 2 회 복용군과 1 회 복용군 24 시간 후 비교 1)

1 1 2 24

(Table 6).

2)

1 1 2

24 (Table 7).

3)

1 1 2 24

(Table 8).

4)

1 1 2 24

Before administration

p-value

1hr 2hrs 3hrs 4hrs

CV40 (cm/sec)

Bid 52.5±10.7 50.1±8.9 52.1±9.5 54.7±9.8 53.9±9.8 0.059^＊

Control^♣ 51.7±8.5 50.4±6.8 50.3±8.3 50.8±6.5 51.8±7.3 0.679^†

Qd^¶ 52.2±6.4 52.2±7.1 52.8±8.1 52.8±5.3 0.982^‡

♣

Control Group from Jung

¹³

's raw data

¶

Once administration group from Kim

⁸

's raw data UC : Uwhangchungsimwon

Bid : Twice administration per a day(administration at 10:00 a.m., 2:00 p.m.) Values are Means±SD

＊

: Within-subject effect at Bid during 4hours

†

: Between-subject effect(Bid and Control) during 4hours

‡

: Between-subject effect(Bid and Qd) during 3hours

Table 4.

C V 40 ( % )

15.0

10.0

5.0

0.0 -5.0

Base 1hr 2hrs 3hrs 4hrs

Bid Control

^♣

Qd

^¶

Fig. 5.

(9)

(Table 9).

고 찰

, ,

,

5) , ,

2) .

,

14) ,

15) .

norepinephrine ,

3) ,

6) .

Before

administration

p-value

1hr 2hrs 3hrs 4hrs

CO2

Reactivity (%/min)

Bid 2.12±0.38 2.08±0.45 2.35±0.52 2.44±0.71 2.42±0.42 0.019^＊

Control^♣ 2.67±0.37 2.44±0.30 2.43±0.32 2.48±0.31 2.57±0.37 0.014^†

Qd^¶ 2.99±0.31 3.26±1.04 3.09±0.34 3.00±.045 0.002^‡

♣

Control Group from Jung

¹³

's raw data

¶

Once administration group from Kim

⁸

's raw data Values are Means±SD

UC : Uwhangchungsimwon

Bid : Twice administration per a day(administration at 10:00 a.m., 2:00 p.m.)

＊

: Within-subject effect at Bid during 4hours

†

: Interaction effects(Bid and Control) during 4hours

‡

: Between-subject effect(Bid and Qd) during 3hours

Table 5.

C O 2 R ea ct iv ity ( % )

15.0 10.0

5.0 0.0 -5.0

-10.0

Base 1hr 2hrs 3hrs 4hrs

Bid Control

^♣

Qd

^¶

Fig. 6.

(10)

Pulsatility index(PI) Breath holding index (BHI)

7) , TCD 120 ,

180 ⁸⁾ .

1 . 1 2

,

, TCD

.

1st day 2nd day p-value

BP (mmHg)

Bid 86.9±5.8 85.7±4.6

0.659

Qd 84.6±6.8 85.6±3.9

Values are Means±SD

1st day is base line before administration 2nd day is after 24 hours from base BP : Blood Pressure

Bid : Twice administration per a day(administration at 10:00 a.m., 2:00 p.m.) Qd : Once administration per a day(administration at 10:00 a.m.)

Table 6.

CV40 Bid 52.5±10.7 56.8±12.1

0.691

Qd 55.0±10.9 54.0±8.1

Values are Means±SD

1st day is base line before administration 2nd day is after 24 hours from base

CV40 : Corrected blood flow velocity at PETCO

2

=40mmHg

Bid : Twice administration per a day(administration at 10:00 a.m., 2:00 p.m.) Qd : Once administration per a day(administration at 10:00 a.m.)

Table 8.

PR (bpm)

Bid 76.4±12.4 70.2±8.9

0.340

Qd 71.9±13.8 67.6±9.0

Values are Means±SD

1st day is base line before administration 2nd day is after 24 hours from base PR : Pulse Rate

Bid : Twice administration per a day(administration at 10:00 a.m., 2:00 p.m.) Qd : Once administration per a day(administration at 10:00 a.m.)

Table 7.

CO2

Reactivity (%/min)

Bid 2.12±0.38 2.24±0.55

0.895

Qd 2.31±0.59 2.17±0.38

Values are Means±SD

1st day is base line before administration 2nd day is after 24 hours from base

Bid : Twice administration per a day(administration at 10:00 a.m., 2:00 p.m.)

Qd : Once administration per a day(administration at 10:00 a.m.)

Table 9.

(11)

2 1

. 1

.

1 .

60 , 40

8)

,

.

. TCD (transcranial Doppler) , TCD

,

, ¹⁷⁾ .

monitoring

(minute-to-minute readings) .

CO 2

. TCD

CO 2

CO 2 (40mmHg)

(CV40) .

1 .

, 1

.

8) 40

.

8) CO 2

, CO 2

(CV40) .

. TCD

parameter ,

(cerebrovascular reactivity)

20) . (cerebrovascular reactivity)

autoregulatory reserve

,

CO 2 , O 2 21) .

.

SPECT, PET, TCD

22) .

Czernicki Dotarizine

Flunarizine

23,24)

, Eicke

CO 2 acetazolamide

(12)

25) ,

7) .

CO 2 Reactivity TCD

13)

. CO 2 Reactivity

BHI(Breathing

Hold Index) , BHI

CO 2 Reactivity CO 2

, CO 2

.

CO 2 CO 2

.

,

1 ,

2 3

4 Base

. 1 ,

.

8) 40 120

, 1

2 ,

.

1 1 2

24 , , ,

.

1 2

,

( 10 ), ( 2 )

.

1 1

1 2

, ,

.

결 론

1 2

, , ,

TCD ,

.

1. 1 2

2 1

,

. 2.

.

3. 1 2

.

4. 2 4

,

. .

5. 1 2

.

1 2 1 1

.

참고문헌

1. . . . .

(13)

1975;3.

2. Hong ND, Kim NJ, Kim KS. Studies on the Efficacy of Combined Preparation of Crude Drugs( ) Effect of Woohwangchungsimwon on the Cardiovascular System. Natural Product Sciences. 1987;18(4):241-48.

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1998.

4. . .

. . 1976.

5. Sang Gyung Nam. Experimental Studies on The Effect of Woohwangchungsimwon and Sohaphy- angwon. The Journal of Kyung Hee University Medical Center. 1990;6(2):220-37.

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9. Seong-Uk Park, Sang-Kwan Moon, Chang-Nam Ko, Ki-Ho Cho, Young-Suk Kim, Hyung-Sup Bae, Kyung-Sup Lee. The Clinical Study of The Effect of Electrical Stimulation at Sugu-Sung- jang Point(GV26-CV24) on Blood Pressure,

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15. Cho TS, Lee SM, Kim ND, Huh IH, Ann HS,

Kwon KI, Park SK, Shim SH, Shin DH, Park

DK. Pharmacological Actions of New Wonbang

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Woohwangchungsimwon Liquid on Cardiovas- cular System. Journal of Applied Pharmacology.

1999;7:320-32.

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Effect of nitroglycerin on cerebral circulation measured by transcranial doppler and SPECT.

Stroke. 1989;20:1733-36.

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. . 2004;14-5.

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19. Hee-Joon Hae. Various Clinical Applications of TCD. Korean Journal of Stroke. 2001;3(1):21-30.

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815-824.

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:237-244.

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A Comparative Study about Cerebrovascular Reactivity from a Single Medication and Continuous Medication on Healthy Subjects

서 론

1107 1) .

Original Article

A Comparative Study about Cerebrovascular Reactivity from a Single Medication and Continuous Medication on Healthy Subjects

, , , ,

, , ,

2-6) .

Transcranial Doppler(TCD) Doppler effect

,

TCD 7-13) .

TCD

Pulsatility index(PI) Breath holding index (BHI)

7) . TCD

,

120 , 180

8) .

,

18) . TCD

8) 1

.

. ,

.

1 2 , 2

, 24

.

1

2 , ,

, 1 1

.

연구방법

1. 연구대상

20 10

, 25.5±1.3 .

10 , ,

.

2. 시험약재

(HH075)

, 1 pill (full dose)

Table 1 .

3. 연구 디자인

cross-over study .

4 1 1

10 1

, , ,

.

1 1

3 1 2

10 , 2 2

, , ,

(Fig. 1).

2

,

13) 8)

Raw

Data 1 1

.

4. 평가내용

1) (Cerebrovascular Reactivity = CO 2 Reactivity)

2) (Mean blood flow velocity, Vm) 3)

4)

5) (PETCO 2 )

5. 평가 방법

1)

.

5 .

TCD Multi-Dop X4 system(DWL , Germany) , mode 1 channel 1 depth monitoring 2MHz probe

. (depth)

50-65mm , sample gain

,

.

bilateral probe holder(LAM-Rack, DWL ,

Germany) probe

monitoring ,

, .

CO 2 reactivity .

5 , 1

30

TW - ce a d ay

UC 1st Administration

1107 ¹⁾ .

TCD ^7-13) .

CV40) ²⁷⁾

1 ¹³⁾